Sepsis

Intensive Care Med, 1996 Oct, 22 Suppl 4, S474 - 81
Monocyte deactivation--rationale for a new therapeutic strategy in sepsis; Volk HD et al.; Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli . The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock . TNF-alpha, acting synergistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in several experimental models . Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years . Unfortunately, these trials have failed to demonstrate a therapeutic benefit . One reason for this may be the lack of exact immunologic analyses during the course of septic disease . Recently, we demonstrated that there is a biphasic immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammatory one . The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called "immunoparalysis" . While anti-inflammatory therapy (e.g . anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during "immunoparalysis".

Acta Paediatr, 1996 Oct, 85(10), 1244 - 6
Markers of oxidative stress before and after exchange transfusion for neonatal sepsis; Kokk T et al.; Oxidative status before and after ET was assessed in eight septic newborns who received exchange transfusion (ET) . Short-term elevations of conjugated dienes (CDs) and thiobarbituric acid reactive substances (TBARSs) (p < 0.05) and increased serum antioxidant capacity (AOC) (p = 0.06) were noted . Chromatographic migration of the red blood cells (CM RBCs), a measure of RBC deformability, also improved after ET . ET for neonatal sepsis does not cause significant oxidative stress; rather, it may help to restore the antioxidant depots and improve RBC deformability and microcirculation.

Am J Respir Crit Care Med, 1996 Oct, 154(4 Pt 1), 931 - 7
Microcirculatory changes in rat skeletal muscle in sepsis; Piper RD et al.; The aim of this study was to confirm that microvascular perfusion was abnormal during the early phases of normotensive sepsis and to determine whether these changes were due to the development of tissue edema . Skeletal muscle red blood cell (RBC) flow was studied in rats made septic by cecal ligation and perforation (CLP) . After anesthesia with halothane, arterial and venous cannulae were inserted and, in the treatment group, a CLP performed . At 6, 24, and 48 h after entry into the study, the incidence of microcirculatory absence of flow in the extensor digitorum longus muscle (EDL) was examined with intravital microscopy . The number of capillaries containing RBCs were counted over a 60-s interval, and the flow status of each capillary was recorded . A significant increase in the number of stopped-flow capillaries was observed in the CLP group (p < 0.01) as compared with time-matched controls . In both groups the number of capillaries with stopped flow was greater than in naive animals . The severity of absence of flow was negatively correlated with the systemic hemoglobin concentration . These changes were not associated with an increase in tissue wet/dry weight ratio or albumin flux . This study shows that sepsis was associated with increased RBC flow heterogeneity . These changes, which occur within 24 h of the septic insult, are a persistent feature of the evolving septic process in the absence of tissue edema . These observations support the view that extrinsic compression of the microcirculation by tissue edema is not the primary cause of alterations in microcirculatory flow in sepsis.

Crit Care Med, 1996 Oct, 24(10), 1670 - 7
Histamine release in sepsis: a prospective, controlled, clinical study; Neugebauer E et al.; OBJECTIVE: To determine if histamine release occurs in clinical sepsis . DESIGN: Prospective, controlled, clinical study . SETTING: Interdisciplinary intensive care unit and trauma ward . PATIENTS: Sepsis was confirmed in 20 patients (test group) by the criteria of the Veterans Administration Systemic Sepsis Cooperative Study Group (1987) and was verified by positive blood culture . In addition, patients were scored by the Elebute and Stoner Sepsis Score (1983), as modified by Dionigi et al (1985) . A concomitant control group consisted of 20 postoperative patients with non-life-threatening trauma to the extremities and without signs of local or systemic infection . INTERVENTIONS: Observational study . Blood samples were collected for determination of plasma histamine concentrations in both groups at the time of study entry and on five succeeding days . MEASUREMENTS AND MAIN RESULTS: The patients were well matched, and the groups were not significantly different for all criteria known to influence histamine release . Comparison of the median values of each group on days 1 through 5 demonstrated significantly higher plasma histamine values in the test group on days 1 through 4, but these values were no longer significantly higher on day 5 . While none of the nonseptic control patients achieved a plasma histamine concentration of > 1 ng/mL (the concentration of which was considered to be the pathologic cutoff point representing histamine release), these values (i.e., > 1 ng/ mL) were found in nine of 20 test group patients . In the test group, nonsurvivors (n = 9) had significantly higher plasma histamine concentrations than survivors (n = 11) throughout the whole study and eight of nine nonsurvivors showed a plasma histamine concentration of > 1 ng/mL . Correlation of plasma histamine concentrations on day 1 to sepsis severity (initial Sepsis Score) showed that all but one patient with a combined low Sepsis Score (< 20 points) and histamine concentration of < 1 ng/mL survived, while all patients with a Sepsis Score of > 20 points and histamine release (plasma histamine concentration of > 1 ng/mL) died . CONCLUSION: Increased histamine concentrations were shown to be causally associated (contributory determinant) with sepsis.

Crit Care Med, 1996 Oct, 24(10), 1649 - 53
Xanthine oxidase activity and free radical generation in patients with sepsis syndrome; Galley HF et al.; OBJECTIVE: To determine xanthine oxidase activity, free radical concentrations, and lipid peroxidation in patients with sepsis syndrome compared with noninfected critically ill patients . DESIGN: A prospective observational study . SETTING: A nine-bed intensive care unit in a university teaching hospital trust . PATIENTS: Fourteen consecutive patients who met the established criteria for sepsis syndrome with multiple organ dysfunction syndrome, and ten noninfected critically ill patients were studied . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Xanthine oxidase activity was increased in septic patients compared with both healthy volunteers (p < .01) and noninfected patients (p < .05), and was highest in the six patients who survived (p < .05) . Lipid peroxides were increased in both septic patients (p < .001) and nonseptic controls (p < .001) . Xanthine oxidase activity did not relate to the Acute Physiology and Chronic Health Evaluation (APACHE) II score or to the presence of organ dysfunction . The mean ascorbyl radical concentration (arbitrary units) determined by electron paramagnetic resonance following spin trapping was increased in patients compared with healthy subjects (p < .05) . CONCLUSIONS: Patients with sepsis have xanthine oxidase activation, high free-radical concentrations, and evidence of free radical damage . The finding that xanthine oxidase activity was lower in those patients who died, coupled with increased lactate concentrations implies more severe ischemia with incomplete reperfusion resulting in less xanthine oxidase "wash out" into the circulation . Increased ascorbyl radical concentrations may be due to an increased radical generation and oxidant scavenging, but appears to be unrelated to xanthine oxidase activity within the circulation.

Am J Surg, 1996 Oct, 172(4), 341 - 4
Endotoxin inhibitor prevents sepsis-induced alterations in intestinal ion transport; Whang EE et al.; BACKGROUND: The intestine is a target of septic insult . The aims of this study were to characterize sepsis-induced alterations in intestinal ion transport and to determine the role endotoxin plays in mediating these changes . METHODS: Rats underwent cecal manipulation alone (control), cecal ligation and puncture (CLP), or CLP plus intraperitoneal injection of 0.2 mg of a recently synthesized endotoxin inhibitor . At 24 hours, distal ileum was harvested, and transport parameters were determined . RESULTS: Cecal ligation and puncture produced a significant increase in short-circuit current (Isc) that was attributable to the induction of chloride secretion . There were no alterations in transepithelial resistance or fluxes of mannitol and sodium . The sepsis-induced increase in Isc was prevented by administration of the endotoxin inhibitor . CONCLUSIONS: In this model of sepsis, the primary alteration in ileal ion transport is an induction of electrogenic chloride secretion . Endotoxin inhibition may represent a strategy for prophylaxis against the intestinal effects of sepsis.

J Trauma, 1996 Oct, 41(4), 653 - 62
Elevated selectin levels after severe trauma: a marker for sepsis and organ failure and a potential target for immunomodulatory therapy; Simons RK et al.; Severe injury is frequently complicated by sepsis and organ failure . Activated neutrophils adherent to inflamed endothelia have been implicated in the pathogenesis of these complications . Identification of high-risk patients to target immunomodulatory therapy, however, remains an elusive goal . We postulated that (1) patients at risk for sepsis and organ failure could be identified by measuring shed selectin adhesions molecules as a marker of endothelial activation after injury and reperfusion, and (2) these elevated selectin levels would correlate with injury severity, shock, major complications, and mortality . METHODS: Blood samples were drawn from 50 patients with multiple trauma every 2 hours after admission for the first 24 hours, and every 6 hours for the subsequent 24 hours, and assayed for levels of shed E- and P-selectin . Patients were then stratified according to Injury Severity Score (ISS), presence or absence of shock, presence or absence of organ failure and/or infectious complications, and finally, death versus survival . RESULTS: Trauma patients who had ISS < 30, who did not develop shock, sepsis, or organ dysfunction, had minimal increase in circulating E- and P-selectin over admission levels . In patients who subsequently developed infectious complications, organ dysfunction, or both, or subsequently went on to die, elevated levels of E-selectin levels were evident by 36 hours, and in some cases, earlier . Differences between nonsurvivors and survivors was statistically significant . There was also a trend toward increased levels of P-selectin in the same group of patients, although these differences were not significant . There was no differentiation in either of the two selections when patients were stratified according to ISS or presence of shock . CONCLUSION: A subset of major trauma patients manifest increased levels of circulating E-selectin adhesion molecules after resuscitation . These patients seem to be at increased risk of death and possibly at risk for infections complications and organ failure . Selectin blockade is a potential new immunomodulatory strategy in this subgroup of patients.

J Trauma, 1996 Oct, 41(4), 581 - 98
"Sepsis/SIRS," physiologic classification, severity stratification, relation to cytokine elaboration and outcome prediction in posttrauma critical illness; Rixen D et al.; OBJECTIVE: To develop a quantitative severity stratification within the framework of a Physiologic State Classification (PSSC) system that can be applied to critically ill post-trauma patients with "sepsis/SIRS" and to relate PSSC to the nature of the plasma cytokine response . MATERIALS AND METHODS: At each study time period, a patient was classified into one of seven physiologic States previously derived from clustering 17 cardiopulmonary and metabolic variables from 338 critically ill patients: R = reference, A = normal stress response, B = metabolic insufficiency, C1 (early) and C2 (late) = respiratory insufficiency, D = cardiogenic insufficiency, H = nonshock hypovolemia . MAIN RESULTS: The PSSC used State data from a developmental set of 159 trauma patients in a logistic model (L2PDEATH) to provide a quantitative index of severity . This severity index was tested on 80 new trauma patients (mean injury Severity Score (ISS) = 27.6, 64% survivors) . Using PSSC State distributions for evaluation of enzyme-linked immunosorbent assay (ELISA) measured cytokines interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF) showed the multicytokine score to be greatest in those C2- and B-State regions associated with a higher severity as measured by L2PDEATH . Compared with ARDEATH of the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system, L2PDEATH provided a better indicator of severity of sepsis/systemic inflammatory response syndrome (SIRS) for posttrauma patients . CONCLUSIONS: PSSC allows classification of the physiologic and cytokine mediator response to trauma and permits stratification of severity in posttrauma critical illness.

Surg Clin North Am, 1996 Oct, 76(5), 1111 - 22
Surgical management and treatment of sepsis associated with gastrointestinal fistulas; Rolandelli R et al.; The development of sepsis associated with a GI fistula can be a catastrophic complication of any surgical procedure in the vicinity of the abdominal cavity . The predominant sites of infection directly associated with GI fistulas are in the surgical wound and within the abdominal cavity . Some patients present with florid signs of sepsis, whereas others may have minimal signs of infection . CT scanning is the main diagnostic method for intra-abdominal collections . Often, it also provides a means of treatment by percutaneous placement of catheters . Patients who develop extensive cellulitis or necrotizing fasciitis, intra-abdominal collections incompletely drained by percutaneously placed catheters, multiple intra-abdominal collections not amenable to percutaneous drainage, dissociation of the ends of an anastomosis with flow of enteric contents into the peritoneal cavity, large intra-abdominal hematoma, or a septic course without identifiable source should be taken to the operating room on an urgent basis . The operative approach varies with the particular situation and extends from incision and drainage of the wound, extraperitoneal drainage of an abscess, and formal exploratory laparotomies, to the placement of tube enterostomies for decompression and drainage . The overall mortality of fistulas has decreased owing to better fluid and electrolyte replacement and the proper use of parenteral nutrition . However, patients continue to die from fistulas, and the cause of death is nearly always infection . The burden is on the surgeon to expeditiously diagnose and treat sepsis associated with GI fistulas.

Cas Lek Cesk, 1996 Sep 18, 135(18), 580 - 3
{Sepsis . I . {Definition of the concept and comments on pathophysiology}; Makovicky P et al.; During the past five years a marked development occurred as regards knowledge on sepsis and its complications . A new term was introduced-SIRS (systemic inflammatory response syndrome) . Two substantial changes pertain to the following facts . First the clinical picture of sepsis need not be due only to infection, and the patient is not an innocent victim of infection, but the organ damage is the results of the patient's active fight with the inducing cause . The authors review recent views regarding the pathophysiology of sepsis.

Nutr Hosp, 1996 Sep-Oct, 11(5), 274 - 8
{Decrease of the incidence of sepsis syndrome after early enteral nutrition of patients with severe burns}; Pereira JL et al.; The objective of this study was to evaluate the effect of early enteral nutrition on the incidence of the septic syndrome as well as its tolerance, in patients with severe burns . We retrospectively studied 64 patients older than 15 years of age, with a greater than 20% burned body surface area . They were divided into 2 groups as a function of the time elapsed between the beginning of Enteral Nutrition and the time of the burning: 23 patients were given Enteral Nutrition within 24 hours after the burn, and in 41 patients the enteral nutrition was started later than 24 hours after sustaining the thermal injury . Both groups were similar with respect to age, sex, percentage of 2nd and 3rd degree burns, incidence of inhalation, and deaths . All patients received the Enteral Nutrition through a nasogastric tube, with administration of a polymeric, hyperprotein and hypocaloric formula through a continuous infusion pump . In our study we saw a reduction of the incidence of the septic syndrome in the patients who received early enteral Nutrition (26%; 6 patients of a total of 23), with respect to those who did non receive early Enteral Nutrition (54%; 22 patients of a total of 41), with a statistical significance of p > 0.05 . There were no differences between both groups with respect to the digestive tolerance to Enteral Nutrition . From our study we can deduce that early Enteral Nutrition reduces the incidence of septic complications, without this increasing the digestive intolerance to the same.

Br J Surg, 1996 Sep, 83(9), 1186 - 96
Sepsis and fat metabolism; Samra JS et al.; Sepsis is a common surgical problem which can induce profound changes in the plasma concentrations of cytokines and hormones, leading to a catabolic state . Hypertriglyceridaemia and increased fat oxidation are the main features of altered fat metabolism encountered in this state . The endogenous catabolism of sepsis can be reduced by administering exogenous lipid emulsions as a source of metabolic fuel, although the changes in lipid metabolism associated with sepsis may affect the handling of these exogenous lipids . An exciting area for future research is an examination of the ability of lipid emulsions to reduce the morbidity and mortality associated with sepsis by altering immune responses, in addition to limiting catabolism.

Intensive Care Med, 1996 Sep, 22(9), 867 - 71
The clinical use of 99m-Tc-labeled WBC scintigraphy in critically ill surgical and trauma patients with occult sepsis; Minoja G et al.; OBJECTIVE: To evaluate the clinical use of radionuclide-labeled white blood cell scintigraphy in the detection of focal sepsis . DESIGN: Prospective clinical study . SETTING: A medical/surgical 12-bed intensive care unit (ICU) in a university hospital . PATIENTS: 26 trauma and surgical patients affected by sepsis of unknown origin were studied . MEASUREMENTS AND RESULTS: After the usual diagnostic approach, patients were submitted to a total body scan by using the patient's leukocytes labeled with technetium-99m (99m-Tc) HMPAO; three scintigraphy were performed within 20 h of tracer injection; the result of scan was completed with all clinical and instrumental data, including ultrasound (US) arnd computed tomography (CT), and the diagnostic efficacy was demonstrated for each patient on discharge from the ICU . The scan was able to detect 20 sites of infection; it was possible to rule out 11 suspected sites; only in two cases was the result considered to be false positive or false negative; in two cases the result was considered to be uncertain . These results show the high sensitivity (95%), specificity (91%) and accuracy (94%) of the method . CONCLUSIONS: In ICU patients with sepsis, nuclear medicine can provide additional data, as the injection of radionuclide-labeled white blood cells (WBCs) allows the imaging of sites of infection . Analysis of our results suggests that scintigraphy with 99m-Tc-labeled WBCs can be considered a useful tool in the detection of the source of infection.

JPEN J Parenter Enteral Nutr, 1996 Sep-Oct, 20(5), 363 - 70
Sequential changes in insulin-like growth factor 1, plasma proteins, and total body protein in severe sepsis and multiple injury; Clark MA et al.; BACKGROUND: Our group wanted to test the hypothesis that plasma levels of insulin-like growth factor 1 (IGF-1), transferrin, and prealbumin are useful markers of nutritional progress in severe sepsis and multiple injury . METHODS: Measurements of IGF-1 and plasma proteins were made in critically ill patients as soon as they were hemodynamically stable and 5, 10, 15, and 21 days later . The magnitude and direction of the measured changes were compared with the magnitude and direction of the change in total body protein in the same time period . RESULTS: Fourteen patients with severe sepsis and 10 multiply injured patients were studied . As a group they had an increased metabolic expenditure that peaked at 153% of normal and lost approximately 12.0% of total body protein . An early fall in IGF-1 and plasma proteins accompanied a marked acute phase response, and recovery occurred while hypermetabolism and net proteolysis continued . No correlation existed between changes in IGF-1 or plasma proteins and the change in total body protein . CONCLUSIONS: Plasma levels of IGF-1, transferrin, and prealbumin are not useful for following changes in protein stores early in the course of critical illness.

JPEN J Parenter Enteral Nutr, 1996 Sep-Oct, 20(5), 332 - 7
Assessment of involuntary muscle function in patients after critical injury or severe sepsis; Finn PJ et al.; BACKGROUND: Study of involuntary skeletal muscle function (MFA) has been well accepted in the area of nutrition assessment and potentially offers a means for following progress of the critically ill patient . We report on the application of this technique to intensive care patients . METHODS: MFA was performed by study of the contraction/relaxation characteristics of the adductor pollicis muscle of the thumb after ulnar nerve stimulation . Serial measurements were made in 16 critically injured patients and 28 patients with severe sepsis and were compared with those obtained from 26 control subjects . Extent of loss of total body protein (TBP) was quantified with in vivo neutron activation . RESULTS: Significant difficulties exist in applying this technique to intensive care patients . In the critically injured, only five acceptable traces could be obtained from a possible 58 measurements . For patients with severe sepsis it was possible to obtain an acceptable trace on 12 of 56 occasions . Neuromuscular blockade and lack of patient cooperation were significant impediments to MFA study . Although frequently perceived as unpleasant by these patients, there was no long-term morbidity associated with MFA . No significant differences were seen in maximal relaxation rate at 30 Hz (MMR30) or force frequency ratios (F10/50 and F30/ 50) between trauma patients and controls . In the sepsis patient group, a significantly higher F10/50 was measured (52% +/- 3% severe sepsis vs 40% +/- 1% control subjects, p < .01) . Six patients had MFA measured approximately 21 days after the illness, by which stage they had lost 11% of their initial TBP . Compared with control subjects, no significant differences were observed in MRR30 or F30/50, whereas a higher value for F10/50 was measured (48% +/- 1% critical illness vs 40% +/- 1% control subjects, p < .01) . CONCLUSIONS: The MFA technique is difficult to apply to intensive care patients . No significant disturbance to MFA is seen after critical injury . Severe sepsis results in an elevation of F10/ 50 only . When able to be obtained, MFA results do not reflect the extent of proteolysis but are indicative of the state of cellular energetics.

Ann Clin Lab Sci, 1996 Sep-Oct, 26(5), 426 - 32
Prognostic potential of cytokines, nitrates, and APACHE II score in sepsis; Bencosme A et al.; The prognostic potentials of physiological ({Acute Physiologic and Chronic Health Evaluation} APACHE II score) and biochemical (Interleukin 6 {IL-6}, Interleukin 6 soluble receptor {IL-6sR}, and Interleukin 2 receptor {IL-2R}, nitrates) measures were evaluated in sepsis . The APACHE II scores were calculated, and concentrations of the biochemical markers were measured, based upon information and samples obtained from 68 septic patients at time of diagnosis . Outcome (survival/non-survival) was determined at the end of the hospital stay associated with the septic episode . Statistically significant differences between survivors (S) and non-survivors (non-S) were found for APACHE II (p < 0.0001), IL-6 (p < 0.005), IL-6sR (p < 0.05), IL-2R (p < 0.02) . No significant differences were found for nitrates . None of the markers could serve individually as an effective prognostic indicator . However, those markers demonstrating a significant difference between survivors and non-survivors may be able to contribute to a multi-parameter prognostic model.

J Perinat Neonatal Nurs, 1996 Sep, 10(2), 56 - 71
Percutaneous central venous catheters in neonates: a descriptive analysis and evaluation of predictors for sepsis; Trotter CW; The article describes the experience with percutaneous central venous catheters in 565 neonates with birth weights of 400 to 6810 g . The catheter-related sepsis incidence was 19.1%, or 13.5 infections per 1000 catheter days . By discriminant function analysis, 86% of all neonates studied were correctly classified into the confirmed sepsis and no sepsis groups on the basis of six predictor variables . The model did not accurately predict the neonates who would develop confirmed sepsis . The weight at catheter insertion and length of time for which the catheter was in place were identified as variables that contributed significantly to differentiation between sepsis and no sepsis groups.

Am J Physiol, 1996 Sep, 271(3 Pt 1), L409 - 18
Reduced in vivo plasma fibronectin content of lung matrix during postoperative sepsis; Rebres RA et al.; Sepsis after surgery, trauma, or burn contributes to altered lung endothelial permeability and respiratory failure . Fibronectin (Fn), an opsonic and adhesive glycoprotein, exists in both a soluble form in plasma and an insoluble form in the extracellular matrix (ECM) . Recent studies {E . M . Wheatley, P . J . McKeown-Longo, P . A . Vincent, and T . M . Saba, Am . J . Physiol . 265 (Lung Cell . Mol . Physiol . 9): L148-L157, 1993} suggest that the ECM content of Fn may influence lung vascular permeability . We evaluated the incorporation of plasma-derived Fn (pFn) into the ECM of the lung during postoperative sepsis . Postoperative nonseptic and postoperative septic rats were compared, using a model of laparotomy followed by cecal ligation and puncture . To label the pFn pool, rats received intravenously 3 micrograms of purified rat 125I-labeled Fn/100 g body weight 6 h after surgery (laparotomy) . 125I-Fn in the deoxycholate detergent-insoluble fraction of tissues was used to quantify matrix-incorporated Fn at 4 h after infusion with 125I-Fn . Septic rats exhibited a peripheral leukopenia as well as reduction in plasma volume, Fn halflife, and total pFn pool . Incorporation of pFn in the liver and spleen of postsurgical septic rats was not different (P > 0.05) from sham-operated (postsurgical nonseptic) rats, but incorporation was significantly decreased (P < 0.05) in vivo in the lung . However, under controlled in vitro conditions, lung tissue harvested from septic or sham-operated rats demonstrated a similar tissue incorporation of soluble 125I-pFn as well as similar rates of retention/turnover of ECM 125I-Fn, based on pulse-chase experiments . These data suggest that the in vivo inflammatory environment in the lung during postoperative sepsis, which cannot be reproduced in vitro, may alter the Fn content of the ECM of the lung . Such reduced levels of pFn in the lung ECM may be a factor influencing lung vascular integrity during postoperative sepsis.

Am J Physiol, 1996 Sep, 271(3 Pt 1), E513 - 20
Regulation of peptide-chain initiation in muscle during sepsis by interleukin-1 receptor antagonist; Vary TC et al.; The mechanism by which interleukin-1 (IL-1) regulates protein synthesis in skeletal muscle during hypermetabolic sepsis in rats was investigated . Treatment of septic rats with a specific interleukin-1 receptor antagonist (IL-1ra) prevented the sepsis-induced inhibition of protein synthesis and translational efficiency in gastrocnemius . Analysis of ribosomal subunits revealed that the increase in free 40S and 60S ribosomal subunits observed in septic rats was prevented by infusion of IL-1ra, indicating peptide-chain initiation was maintained at control values . The failure of sepsis to inhibit peptide-chain initiation after infusion of IL-1ra correlated with a maintenance of the epsilon-subunit of eukaryotic initiation factor (eIF) 2B (eIF-2B epsilon) protein at control values . The alterations in the eIF-2B epsilon protein content in gastrocnemius of septic rats treated with or without IL-1ra were associated with corresponding changes in the abundance of eIF 2B epsilon mRNA . The results provide evidence that infusion of IL-1ra attenuates the sepsis-induced inhibition of protein synthesis by preventing the inhibition of peptide-chain initiation and downregulation of eIF-2B expression during sepsis.

Crit Care Med, 1996 Sep, 24(9), 1537 - 42
Dantrolene, an inhibitor of intracellular calcium release, fails to increase survival in a rat model of intra-abdominal sepsis; Cameron EM et al.; OBJECTIVE: Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis . We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release . DESIGN: A prospective, randomized controlled trial . SETTING: An experimental animal laboratory in a university hospital . SUBJECTS: Two hundred fourteen male Sprague-Dawley rats . INTERVENTIONS: Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment . A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations . Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin . MEASUREMENTS AND MAIN RESULTS: Over the 7-day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis . Mean whole blood lactate for each group peaked at 6 hrs after induction of infection . There were no significant differences in lactate concentration among the groups at any of the time points examined . Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha . In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha . CONCLUSIONS: We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats . The importance of excessive intracellular calcium release in sepsis remains to be elucidated.

Crit Care Med, 1996 Sep, 24(9), 1455 - 9
Circulating erythropoietin and interleukin-6 concentrations increase in critically ill children with sepsis and septic shock; Krafte-Jacobs B et al.; OBJECTIVES: To investigate a possible relationship between plasma erythropoietin and interleukin-6 (IL-6) in critically ill children with sepsis or septic shock . To examine the modulatory effects of plasma from these patients on erythropoietin production in vitro, employing a cell culture system that uses the erythropoietin-producing Hep 3B cell line . DESIGN: A prospective, controlled clinical and laboratory study . SETTING: A pediatric intensive care unit and research laboratory facility at a children's hospital . PATIENTS: Children admitted to the pediatric intensive care unit with the diagnosis of sepsis or septic shock (n = 16), and control patients without infection or anemia (n = 16) were admitted to the study . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained from 16 children with sepsis or septic shock, and 16 age-matched controls . Plasma erythropoletin and IL-6 concentrations were measured using an enzyme-linked immunoassay . Plasma erythropoietin concentrations were significantly higher in children with sepsis or septic shock (120 +/- 26 mlU/mL) than in controls (10 +/- 2 mlU/mL) (p < .001) . Plasma IL-6 concentrations were greater in children diagnosed with sepsis or septic shock (12,405 +/- 6662 pg/mL) than in control patients (7 +/- 1 pg/mL) (p < .001), and higher in septic shock patients (27,469 +/- 13,647 pg/mL) than sepsis patients (688 +/- 258 pg/mL) (p = .03) . Hep 3B cells were incubated under hypoxic conditions in media containing plasma from control patients, or patients diagnosed with sepsis or septic shock . Media concentrations of erythropoietin were measured using an enzymelinked immunoassay . Hep 3B cells incubated with plasma from patients diagnosed with sepsis or septic shock produced more erythropoietin (216 +/- 23 mlU/mL) than Hep 3B cells incubated under the same conditions in media containing plasma from control patients (152 +/- 11 mlU/mL) (p = .04) . Hypoxic Hep 3B cell erythropoietin production in media incubated with plasma from patients diagnosed with sepsis or septic shock correlated significantly (although weakly) with plasma IL-6 values from these same patients (p = .03, r2 = .28) . CONCLUSIONS: Plasma erythropoietin and IL-6 values are increased in critically ill children with sepsis or septic shock in comparison with controls . The data indicate that one or more plasma factors are responsible for stimulation of hypoxia-induced erythropoietin production in the Hep 3B cell line and suggest a possible role for IL-6 in the regulation of erythropoletin production in critically ill children with sepsis or septic shock.

Crit Care Med, 1996 Sep, 24(9), 1448 - 54
Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis; Miller EJ et al.; OBJECTIVE: To test the hypothesis that significantly higher concentrations of interleukin-8 (IL-8) are found in the pulmonary edema fluid and plasma of patients with a septic vs . a nonseptic etiology of acute respiratory distress syndrome (ARDS) . DESIGN: Prospective measurement of IL-8 concentrations in previously collected edema fluid and plasma . SETTING: Adult intensive care units at a university medical center . PATIENTS: There were 27 patients with ARDS (16 patients with a septic etiology and nine patients with a nonseptic etiology) plus eight control patients with hydrostatic pulmonary edema . MEASUREMENTS AND MAIN RESULTS: IL-8 was present in the pulmonary edema fluid of all patients with ARDS, but the median IL-8 concentration was higher in the edema fluid of patients with ARDS associated with sepsis (84.2 ng/mL, n = 16) compared with the ARDS patients without sepsis (14.8 ng/mL, n = 11) (p < .05) . In patients with cardiogenic edema, IL-8 concentration (5.0 ng/mL,n = 8, p < .05) was significantly lower than those values in patients with ARDS . Median plasma concentration of IL-8 was increased in septic individuals (1.3 ng/mL), but these concentrations were not significantly higher than in patients with a nonseptic etiology of ARDS (0.35 ng/mL) (p = .14) or those patients with cardiac failure (0.21 ng/mL) . CONCLUSIONS: The high concentrations of IL-8 in pulmonary edema fluid, coupled with the relatively low concentrations of IL-8 in the plasma, suggest that the lung was the primary source of IL-8 in the patients with ARDS . The markedly increased concentrations of IL-8 in the pulmonary edema fluid of patients with ARDS from sepsis suggests that this group of patients may be particularly suitable for potential trials directed at inhibiting the activity of this important chemokine.

Crit Care Med, 1996 Sep, 24(9), 1431 - 40
INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis . International Sepsis Trial Study Group; Cohen J et al.; OBJECTIVE: To determine the safety and efficacy of BAY x 1351, a murine monoclonal antibody to recombinant human tumor necrosis factor (TNF)-alpha, in patients with sepsis . DESIGN: An international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups . SETTING: Forty acute clinical care facilities in 14 countries . PATIENTS: Of the 564 patients enrolled in the study, 553 patients received study drug or placebo . INTERVENTIONS: Patients received 15 mg/kg or 3 mg/kg of BAY x 1351, or placebo, as a single intravenous infusion . MEASUREMENTS AND MAIN RESULTS: The patients were well matched for severity of illness and for risk factors known to influence the outcome of sepsis . There was no difference in 28-day mortality rates between groups (placebo group 66 {39.5%} of 167;3 mg/kg group 57 {31.5%} of 181; 15 mg/kg group 87 {42.4%} of 205) . Approximately 9 months after this study had begun, an interim safety examination of NORASEPT, a North American Sepsis Trial using the same monoclonal antibody, indicated that there was no benefit to patients in the nonshock group and further enrollment of these nonshock septic patients into INTERSEPT was stopped . The analysis therefore focused on the 420 patients in shock . The primary efficacy variable was the 28-day, all-cause mortality rate: placebo group 57 (42.9%) of 133; 3-mg/kg group 51 (36.7%) of 139; and 15-mg/kg group 66 (44.6%) of 148 (not significant) . Two secondary efficacy variables were identified prospectively: shock reversal and frequency of organ failures . Life-table analysis showed that in patients who survived 28 days, there was a more rapid reversal of shock in both treatment groups compared with placebo (15-mg/kg group vs . placebo group log-rank statistic p = .007, 3-mg/kg group vs . placebo group p = .01) . Similarly, in patients surviving 28 days, there was a significant delay in the time to the onset of first organ failure (log rank 15 mg/kg vs . placebo p = .03, 3 mg/kg vs . placebo p = .07), and more patients in the placebo group developed at least one organ failure: 15-mg/kg group 33 (40.2%) of 82; 3-mg/kg group 39 (44.3%) of 88; and placebo group 45 (59.2%) of 76 (15 mg/kg vs . placebo p = .03, 3 mg/kg vs . placebo p = .06) . No significant adverse events were associated with the monoclonal antibody treatment . CONCLUSIONS: INTERSEPT provides additional clinical data implicating TNF-alpha as an integral mediator of septic shock . The study suggested a possible role for anti-TNF antibody as adjunctive therapy, but this possibility requires confirmation by another clinical trial.

Am J Gastroenterol, 1996 Sep, 91(9), 1697 - 710
Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome; Pastores SM et al.; The incidence of multiple organ failure syndrome (MOFS) has increased dramatically in most intensive care units (ICU) in the United States and is now the leading cause of death after sepsis, trauma, and burns (1) . Despite advances in resuscitation, availability of potent antibiotics, and modern techniques of organ support (2), the survival of critically ill patients with MOFS has not significantly improved since the syndrome was first described over 2 decades ago (3) . In the ICU, the monitoring and management of critically ill patients with MOFS has relied, in large part, on readily available measurements of global hemodynamics and oxygen transport . Given the increased understanding of the special role of splanchnic hypoperfusion in the pathophysiology of sepsis and MOFS (4-5), investigators have focused more recently on regional blood flow and oxygen metabolism in these patients (6) . In this article, we first present a clinical overview of sepsis and MOFS . Current concepts of the pathogenesis and pathophysiology of MOFS are discussed, with particular emphasis on the roles of splanchnic ischemia and gut barrier failure in the development of both sepsis and the maintenance of the systemic inflammatory response that leads to MOFS . Alterations in both global and regional oxygen transport in septic shock are described to emphasize the limitations of global monitoring in the assessment of splanchnic tissue oxygenation . The role of gastric tonometry in the monitoring of splanchnic oxygenation and its utility in critically ill patients is then analyzed . In addition, the effects and clinical implications of commonly used vasoactive agents on intestinal oxygenation are discussed . Finally, novel therapeutic strategies based on the "gut-origin hypothesis" of MOFS are reviewed.

Arch Surg, 1996 Sep, 131(9), 986 - 9
No difference in catheter sepsis between standard and antiseptic central venous catheters . A prospective randomized trial; Pemberton LB et al.; OBJECTIVE: To determine the efficacy of antiseptic compared with standard triple lumen central venous catheters (CVCs) in reducing the incidence of catheter sepsis and catheter site infection in patients with CVCs for total parenteral nutrition . DESIGN: A prospective, randomized, controlled trial . SETTING: Truman Medical Center, the public teaching hospital for University of Missouri, Kansas City, School of Medicine . PATIENTS: Seventy-two inpatients on the Metabolic Support Service received a CVC for the infusion of total parenteral nutrition . Diagnoses included pancreatic disease, cancer, bowel obstruction, and intestinal surgery, among others . Patients who had a higher risk for contamination during insertion, such as those with a catheter placed through an introducer, inserted in the emergency department, or changed over a guidewire were excluded from the study . INTERVENTION: The control group received a standard CVC without antiseptics . The treatment group received a CVC with a coating of silver sulfadiazine and chlorhexidine gluconate . Each CVC was inspected for infection or malfunction by the Metabolic Support Service 5 times per week . A transparent occlusive dressing was changed every 7 days or more often if there were signs of infection or nonocclusion . When the CVC was removed, the catheter tip, the blood, and the insertion site were cultured . MAIN OUTCOME MEASURES: Although 88 catheters were inserted, only 72 catheters were evaluable . There were 40 patients in the standard group and 32 in the antiseptic group . There were no statistically significant differences between the 2 groups for diagnosis, sex, age, length of stay, days with a CVC, or catheter location . The catheter sepsis rate in the standard group was 8% and in the antiseptic group it was 6% . There were no statistically significant differences between the 2 groups in frequency of site infections or catheter sepsis . CONCLUSIONS: In this study, there were no statistically significant differences in the incidence of catheter-related sepsis or catheter site infections between the standard and antiseptic groups . Future prospective, randomized controlled trials with a larger number of antiseptic catheters are encouraged to confirm or refute these results.

Rev Med Chil, 1996 Aug, 124(8), 938 - 46
{Acute kidney failure in patients with and without sepsis: prognosis and clinical course}; Vega J et al.; The purpose of this prospective study was to determine whether the course and prognosis of acute renal failure (ARF) in patients with and without sepsis are different . Two hundred fifty-two (8%) of 3086 consecutive patients admitted to a medical-surgical intensive care unit (ICU) developed ARE . One hundred forty-nine (59%) were septic and 103 (41%) were non-septic . No differences were found between groups regarding the incidence of oliguria, hyperkalemia, hypercatabolism, gastrointestinal bleeding, duration of oligria and renal deficit, severity of axotemia, dialysis requirements and duration of stay in the hospital . There were statistically significant differences between septic and non septic patients with respect of hyponatremia (67.8 vs 54.4%, p < 0.04), respiratory failure (68 vs 54%, p < 0.04), and thrombocytopenia (64 vs 48%, p < 0.02) . Mortality in septic patients was higher than in non-septics (56 vs 42.7%, p < 0.009) . Factors associated with increased mortality in ARF septic patients were respiratory failure, metabolic acidosis and oliguria while in the non-septics they were hepatic dysfunction, hyperkalemia, respiratory failure and infection acquired during the course of renal failure . We conclude that ARF developing in septic patients has a higher mortality than that of non-septic patients, whereas the incidence of hypercatabolism and oliguria was not different between both groups.

J Appl Physiol, 1996 Aug, 81(2), 976 - 84
Circulatory sequelae of administering CPAP in hyperdynamic sepsis are time dependent; Fox GA et al.; Evidence questions the circulation's ability to acutely compensate for abrupt changes in O2 delivery (Qo2) . Because both sepsis and continuous positive airway pressure (CPAP) may alter the metabolic regulation of tissue oxygenation, we designed an experiment to determine the interaction, if any, between sepsis and time on circulatory homeostasis after the application of CPAP . Twenty-four sheep were randomized to cecal ligation and perforation (CLP) or sham procedure (Sham) and then rerandomized to receive either CPAP (10 mmHg) or no CPAP (No CPAP; CLP/CPAP, n = 8; CLP/No CPAP, n = 8; Sham/CPAP, n = 4; Sham/No CPAP, n = 4) . Forty-eight hours later, CLP animals demonstrated an elevated cardiac index (+63%), systemic Qo2 (+49%), and systemic O2 uptake (+28%) . Organ blood flow, measured with radiolabeled microspheres, was augmented to the heart and depressed in organs comprising the splanchnic circulation . Compared with the CLP/No CPAP group and both Sham groups, myocardial Qo2 in the CLP/ CPAP group was significantly elevated when measured both 2 and 8 h after CPAP . These changes were unrelated to differences in mean heart work between the study groups . Simultaneously, QO2 to all of the small gut, large gut, pancreas, and kidney in the CLP/CPAP group was elevated during the 2-h study yet reverted to levels not different from baseline by the 8-h study . These data demonstrate 1) a unique sepsis x time interaction with the use of 10 mmHg of CPAP, particularly in the "nonvital" circulations, and 2) CPAP effects on the septic coronary circulation, which were unexplained by changes in external determinants of myocardial O2 need.

J Arthroplasty, 1996 Aug, 11(5), 543 - 7
Aspiration as a guide to sepsis in revision total hip arthroplasty; Fehring TK et al.; One hundred sixty-five patients underwent 171 preoperative aspiration arthrograms to evaluate a painful total hip arthroplasty . Intraoperative cultures and histologic specimens were obtained in all cases . Of the 166 aspirations where fluid was obtained, there were 140 true negative, 5 true positive, 18 false positive, and 3 false negative cultures . Sensitivity of hip aspiration to identify periprosthetic sepsis correctly was 50%; specificity was 88% . Hip aspiration with a 50% sensitivity rate lacks the ability to consistently predict those patients with occult periprosthetic sepsis . The routine use of aspiration in evaluation of a painful total hip is probably not indicated . Selective use in patients with a history of wound healing problems, radiographic changes, and elevated laboratory values should be considered.

Anaesth Intensive Care, 1996 Aug, 24(4), 430 - 4
The influence of surgery on cytokines in patients with intra-abdominal sepsis; Hammond JM et al.; The cytokine cascade which is triggered by severe sepsis may contribute to progressive organ dysfunction and death from sepsis . This cascade may be accentuated by surgery for sepsis and pre-treatment with cytokine blockers could possibly ameliorate the response . This prospective controlled study determined the effect of surgery in 11 haemodynamically stable patients undergoing laparotomy for intra-abdominal sepsis . Serum levels of endotoxin, IL-1, IL-6, IL-8 and TNF-alpha were determined; blood cultures, features of systemic inflammatory response, and organ dysfunction were monitored over the peri-operative period . There was considerable variation in the serum cytokine levels . The preoperative IL-6 levels were significantly elevated in the septic patients and a threefold increase in IL-6 levels occurred in both groups postoperatively . An increase in TNF-alpha did not achieve significance because of high levels in control patients with cancer . Cytokine release which occurs during abdominal surgery is increased in patients with intra-abdominal sepsis.

Pediatr Emerg Care, 1996 Aug, 12(4), 317 - 24
Sepsis, septic shock, acute abdomen? The ability of cardiac disease to mimic other medical illness; Mahle WT et al.; Transport medicine offers the challenge of patient diagnosis based only on the relayed history an the impressions of referring medical personnel . A thorough pretransport review of the patient's history, physical examination, radiographs, laboratory values, and other supporting information can help avoid surprises upon arrival at the patient's bedside and lead to an appropriate diagnosis and management plan . One must approach the transported child with an open mind, however, to avoid misdiagnosis and inadequate or inappropriate intervention and management . One of the advantages of pediatric specialty transport services is the ability to critically assess a referred patient and offer diagnostic and therapeutic guidance in addition to transportation to the receiving center . These above two examples illustrate difficult cases where the diagnostic skills of the transport medical personnel enabled the patients to receive appropriate acute interventional and specific disease-related therapy.

Shock, 1996 Aug, 6(2), 150 - 4
Steroid hormone alterations following induction of chronic intraperitoneal sepsis in male rats; Sharma AC et al.; The influence of sepsis on male reproductive function in chronic animal models has not been extensively investigated . On the basis of earlier clinical studies, it was hypothesized that chronic intraperitoneal (i.p.) sepsis in rats would modulate the circulating levels of steroid reproductive hormones . Male Sprague-Dawley rats (300-375 g) were randomized to septic and nonseptic groups . Sepsis was induced with cecal slurry (200 mg/kg/5 mL 5% dextrose in water (D5W); i.p.) in septic rats, while nonseptic rats received only sterile D5W . The rats (n = 8-12) were catheterized to measure systemic hemodynamics and to collect blood at 0, 12, 24, and 48 h after induction of sepsis/sham sepsis . A separate group of normal rats was included to serve as an unoperated control group . The plasma concentration of corticosterone, progesterone, and testosterone in serum was determined using radioimmunoassay . The heart rate was significantly increased at t = 12, 24, and 48 h following induction of sepsis . However, septic rats did not display any significant alterations in the mean arterial pressure and pulse pressure . Basal circulating concentrations of serum corticosterone, progesterone, and testosterone were 356 +/- 124 ng/mL, 2.37 +/- 1.03 ng/mL, and 1.88 +/- .29 ng/mL, respectively, in the unoperated rats . At t = 0 h there was a significant increase in the levels of corticosterone in septic rats and in the levels of progesterone in both septic and nonseptic rats . The elevations in the concentrations of corticosterone and progesterone returned to basal values after 24 and 48 h . The septic animals had significantly decreased levels of testosterone at t = 24 and 48 h as compared with basal values and nonseptic groups . Our model of sepsis produced a time-dependent decrease in levels of testosterone, an end product of male steroidogenesis . This, along with unchanged levels of corticosterone and progesterone at 24 and 48 h following sepsis, indicates that separate mechanisms for steroidogenesis regulating synthesis of these steroid hormones (progesterone and testosterone) occur with sepsis . It is concluded that in our chronic septic rat model, induction of i.p . sepsis produced dysfunction in steroidogenesis, which selectively affected the synthesis of testosterone.

Shock, 1996 Aug, 6(2), 142 - 9
Evaluation of enzyme-linked immunosorbent assays for quantitation of eicosanoid mediators of sepsis syndrome; Quinn JV et al.; Thromboxane, prostacyclin, and the leukotrienes are eicosanoids that have been implicated as mediators of the host inflammatory response to infection and injury . Commercial enzyme-linked immunosorbent assays (ELISA) are being increasingly utilized to quantitate plasma eicosanoid concentrations in both clinical and experimental systemic inflammatory conditions . The objectives of this study were to 1) critically examine the performance characteristics of commercial ELISA kits for thromboxane B2, 6 keto-prostaglandin F1 alpha, leukotriene B4, and leukotrienes C4, D4, and E4; 2) apply the four ELISA kits in obtaining actual eicosanoid plasma values under both baseline and septic conditions; and 3) recommend quality control measures for general use . Although averages of multiple standard curves from individual assays were variable, there was a strong linear regression relationship between the backfit dose and nominal dose for each level of standard . Precision profiles constructed for each assay type defined a working range where the intra-assay coefficient of variation is less than 10% . Backfit doses deviated most from nominal doses at both extremes of the standard curves and this variation is reflected in the higher percentage errors in these regions . Recovery of each eicosanoid analyte was 96-103% . Calculated sensitivities were somewhat higher than the manufacturer's specifications . When applied to actual measurements in human and porcine plasma, the assays yielded values that fell within the working ranges of the standard curves with the exception of leukotriene B4 . Thus, the ELISAs examined were reproducible, precise, and accurate within a specific working range for each assay type . However, internal controls were lacking in the commercial kits examined, which made assessment of intra- and inter-assay variation difficult.

Shock, 1996 Aug, 6(2), 89 - 94
Sepsis-induced alterations in pyruvate dehydrogenase complex activity in rat skeletal muscle: effects on plasma lactate; Vary TC; The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating) . In skeletal muscle, a decreased proportion of PDH complex in the active, nonphosphorylated form (PDHa) limits glucose oxidation and promotes the conversion of pyruvate to lactate . Increased lactate formation with the accompanying hyperlactatemia is a frequent metabolic complication of sepsis . The time course for inactivation of the PDH complex in skeletal muscle during sepsis was contrasted with changes in PDHa during sterile inflammation 3,7, or 14 days following the implantation of the foreign body nidus . Total PDH complex activity was not altered in any of the conditions examined . Sepsis, but not sterile inflammation, caused a reduction in the muscle PDHa measured 3 or 7 days following induction of sepsis . The inhibition of the muscle PDHa during sepsis was associated with a sustained hyperlactatemia . PDH kinase activity measured in extracts of mitochondria was enhanced twofold during this period . Fourteen days after induction of sepsis, there were no differences in the PDHa or plasma lactate concentrations in septic rats compared with either control or sterile inflammation . Furthermore, the PDH kinase activity was decreased to values observed in control values . The results are consistent with the hypothesis that a reduced PDHa in skeletal muscle during sepsis is responsible, in part, for the hyperlactatemia characteristic of septic hypermetabolism . Furthermore, the results provide evidence that the decrease in PDHa results from a stable stimulation of PDH kinase activity.

Clin Infect Dis, 1996 Aug, 23(2), 335 - 6
Capnocytophaga canimorsus sepsis complicated by myocardial infarction in two patients with normal coronary arteries; Ehrbar HU et al.; We describe two patients who had acute myocardial infarctions during episodes of Capnocytophaga canimorsus sepsis . C . canimorsus is associated with severe infection in patients who are immunocompromised; one of these patients had undergone splenectomy for Hodgkin's disease 11 years earlier, and the other consumed significant amounts of alcohol regularly . Both patients owned dogs that had licked them or produced minor skin wounds shortly before they became ill . Coronary angiographic findings were normal for both patients . The association of acute myocardial infarction and sepsis with a specific pathogen is unique . This finding suggests that endothelial damage and coronary thrombosis due to C . canimorsus sepsis is a possible mechanism of acute myocardial necrosis.

AACN Clin Issues, 1996 Aug, 7(3), 339 - 50; quiz 459-60
The immune system: relation to sepsis and multiple organ failure; Kellum JA et al.; The immune system plays a dual role in the pathogenesis of sepsis and organ failure, intended for host defense but also possessing significant cytodestructive capacity . As the understanding of the epidemiology and pathophysiology of these disorders improves, so too does the appreciation for the complexity of this system . No longer is the immune response viewed as simply cellular or humoral but rather as a network of cells, chemical mediators, and molecular elements . The interactions between these various components serve to regulate and coordinate the inflammatory response . When this fine balance is lost, the inflammatory response becomes pathologic and self-destructive . Organ injury ensues, and with this injury, further escalation of the inflammatory response occurs; becoming a self-perpetuating process . Conventional therapy is limited to supportive care and has been ineffective in improving mortality . To date, efforts to modulate the inflammatory response by inhibition of specific components have been unsuccessful . In the future, better patient selection, combination therapy (perhaps using strategies of early augmentation followed by inhibition), and alternative techniques such as blood purification may prove to be more effective.

Surgery, 1996 Aug, 120(2), 389 - 93; discussion 393-4
Sepsis increases endocytosis of endotoxin into hepatocytes; Ghermay AP et al.; BACKGROUND: Chylomicrons bind endotoxins and accelerate their clearance from plasma to the liver . This results in reduced mortality from septic shock in a rodent model . We hypothesized that the clearance of the LPS-chylomicron (LPS-CM) complex by hepatocytes is due to receptor-mediated endocytosis and that sepsis up-regulates this process . METHODS: Three groups of Sprague-Dawley rats; (1) control; (2) pretreated with 10 micrograms/kg LPS 24 hours before treatment; and (3) pretreated with 17-alpha-ethinyl estradiol (EE, 5 mg/kg subcutaneously for 3 days), were infused with labeled I125-LPS alone or with I125-LPS bound to chylomicron . Livers were removed 2.5, 15, and 30 minutes after LPS injection, and hepatic endosomes were isolated from the liver homogenates by serial ultracentrifugation in sucrose gradients . RESULTS: The injection of I125-LPS-CM complexes resulted in higher levels of endosomal I125-LPS in all groups, as compared with I125-LPS alone . In addition, the endosomal uptake of I125-LPS was markedly increased by both LPS and EE pretreatments . CONCLUSIONS: These data strongly suggest a primary role for receptor-mediated endocytosis in the increased clearance of LPS when bound to chylomicron . In addition, exposure to LPS appears to increase the accumulation of LPS in endosomes by a mechanism similar to that of EE, which is known to up-regulate receptor-mediated lipoprotein uptake . This endogenous pathway for the catabolism of endotoxins may provide a teleological explanation for the hypertriglyceridemia observed during sepsis.

Surgery, 1996 Aug, 120(2), 367 - 73
Pentoxifylline maintains vascular endothelial cell function during hyperdynamic and hypodynamic sepsis; Wang P et al.; BACKGROUND: Although pentoxifylline produces various beneficial effects after endotoxemia or sepsis occurs, it is not known whether this agent attenuates the depressed endothelial cell function during sepsis . Therefore the aim of this study was to determine whether pentoxifylline maintains vascular endothelial cell function (i.e., improves the release of endothelium-derived nitric oxide) during hyperdynamic and hypodynamic stages of polymicrobial sepsis . METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP), after which 3 ml/100 gm body wt normal saline solution was injected subcutaneously in these and rats in a sham-operated group . At 1 hour after the onset of sepsis, pentoxifylline (50 mg/kg body wt) or an equal volume of normal saline solution was infused intravenously during a 30 minute period . At 10 and 20 hours after CLP was performed (10-hour CLP, hyperdynamic sepsis; 20-hour CLP, hypodynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers . Norepinephrine (2 x 10(-7) mol/L) was used to achieve near maximal tension . Dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were carried out . The changes in percentage relaxation in the aortic rings by these agonists were then determined . RESULTS: Endothelium-dependent (acetylcholine-induced) vascular relaxation decreased significantly at 10 and 20 hours after CLP . Administration of pentoxifylline, however, maintained acetylcholine-induced vascular relaxation at both time points . In contrast, no significant reduction in nitroglycerine-induced vascular relaxation was seen in rats with sepsis irrespective of pentoxifylline treatment . CONCLUSIONS: Because pentoxifylline prevented endothelial cell dysfunction at 10 and 20 hours after CLP occurred, this agent appears to be a useful agent for maintaining vascular endothelial function during the hyperdynamic and hypodynamic stages of polymicrobial sepsis.

Am Surg, 1996 Aug, 62(8), 641 - 6
Failure of antiseptic bonding to prevent central venous catheter-related infection and sepsis; Ciresi DL et al.; Infection associated with the use of triple lumen catheters in hospitals is a frequent and serious complication . The prevailing hypothesis for the origin of catheter-related infection (CRI) is bacterial colonization and subsequent infection of the skin insertion site and catheter interface . The recently released ARROWgard catheter contains a bonded synergistic combination of silver sulfadiazine and chlorhexidine, which is thought to render the catheter resistant to bacterial colonization and subsequent sepsis . The purpose of this study is to compare the incidence of CRI and catheter-related sepsis (CRS) between a standard triple lumen catheter and ARROWgard antiseptic coated catheter in patients receiving total parenteral nutrition (TPN) . A randomized, prospective clinical trial was conducted at a community referral center from January 1993 through April 1994 . One-hundred-ninety-one patients with need for TPN were randomized to receive either the ARROWgard or a standard triple lumen catheter placed under a strict sterile protocol . CRI was defined as >/= 15 colony forming units by semiquantitative culture technique of the catheter tip or intracutaneous segment . CRS was defined as growth of the same organism on the catheter and at least one peripheral blood culture . All catheters were cultured . Ninety-two patients received the ARROWgard catheter, and 99 patients received the standard catheter . There were no differences between the average age, sex, length of hospital stay, days on TPN, number of catheters/patient, indications for TPN, primary diagnoses, or duration of the central line between the two groups . The overall rate of CRI was 11.5 per cent, and CRS was 8.4 per cent in this study . The rate of CRI for the ARROWgard was 10.9 per cent, compared with 12.9 per cent for the standard catheter (P = NS) . The rate of CRS for the ARROWgard was 8.7 per cent, compared with 8.1 per cent for the standard catheter (P = NS) . The coating of central venous catheters with silver sulfadiazine and chlorhexidine does not reduce the rate CRI or CRS when compared with standard central venous catheters in patients receiving TPN.

Crit Care Med, 1996 Aug, 24(8), 1408 - 16
Sepsis and the systemic inflammatory response syndrome: neuromuscular manifestations; Bolton CF; OBJECTIVE: To describe the various conditions of peripheral nerve, neuromuscular junction, and muscle associated with the systemic inflammatory response syndrome (SIRS) . DATA SOURCES: Publications in the scientific literature and personal observations during the last 15 yrs . DATA EXTRACTION: Computer search of the literature and review of patient records relating to polyneuropathy, neuromuscular transmission defects, and myopathies associated with sepsis, the septic syndrome, and SIRS . SYNTHESIS: SIRS is a new concept in which infection and trauma induce a systemic inflammatory response affecting the microcirculation to organs throughout the body . The nervous system is commonly affected in the forms of septic encephalopathy and critical illness polyneuropathy . Neuromuscular blocking agents and corticosteroids may have additional toxic effects on the neuromuscular system that are manifest as transient neuromuscular blockade, an axonal motor neuropathy, or a thick filament myopathy . Clinical examination in the critical care unit is often unreliable and electrophysiologic studies, at times accompanied by magnetic resonance imaging of the spinal cord, measurement of the circulating creatine phosphokinase concentration, and muscle biopsy, are often necessary to establish the diagnosis . Variants of critical illness polyneuropathy may occur outside the critical care unit . The precise mechanism of these neuromuscular conditions is not known, and further basic research is needed . CONCLUSIONS: A variety of neuromuscular conditions complicates SIRS . The identification of these conditions is important in patient management and in rendering a prognosis.

Blood, 1996 Aug 1, 88(3), 881 - 6
Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients; Mesters RM et al.; Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III . We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia . This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock . Sixty-two patients with febrile infectious events were accrued to the study . Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria . At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001) . The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation . These differences were sustained throughout the septic episode (P < .0001) . FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively . In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001) . Thus, septic shock in neutropenic patients is associated with increased thrombin generation . Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.

J Surg Res, 1996 Jul 15, 64(1), 63 - 7
Identification of Altered Gene Expression in Skeletal Muscle during Sepsis Using Differential Display
Tiao GM, Hudson K, Lieberman MA, Fischer JE, Hasselgren PO.
Different aspects of muscle metabolism are altered during sepsis and there is evidence that some of these changes may be regulated at the gene level . Differential display is a recently described technique to identify genes whose expression has changed during a biological process . This technique utilizes reverse transcriptase-polymerase chain reaction (RT-PCR) to compare mRNA signals in tissues during two different conditions . We used differential display to test the hypothesis that gene expression is altered in skeletal muscle during sepsis . Sepsis was induced in rats by cecal ligation and puncture (CLP) . Control rats were sham-operated . Sixteen hours after CLP or sham operation, extensor digitorum longus muscles were harvested and RNA was extracted . Following differential display, 30 fragments (F1-F30) were identified that appeared to be uniquely expressed in muscles from sham-operated or septic rats . These fragments were reamplified by PCR and used as probes in Northern blot analysis . Messenger RNA levels corresponding to 2 of the 30 fragments (F5 and F24) were confirmed to be increased by Northern blot analysis in septic muscle . Following cloning and sequencing, F5 was found to display significant homology to the gene sequence of the guanine nucleotide releasing protein MSS4 . The sequence of F24 did not match any reported gene sequence and may therefore represent a previously unidentified gene . The results support the hypothesis that gene expression is altered in skeletal muscle during sepsis.

J Surg Res, 1996 Jul 15, 64(1), 95 - 101
Dosage and timing of anti-TNF-alpha antibody treatment determine its effect of resistance to sepsis after injury; O'Riordain MG et al.; Antibody against tumor necrosis factor-alpha (TNF-alpha) has improved survival in certain models of sepsis, but it remains unproven in clinical studies . In most of the successful animal studies, efficacy has been shown in previously healthy animals subjected to a septic challenge . Patients at risk for sepsis, however, may be ill for some time before the sepsis supervenes . This situation has been described as a "two-hit" model of critical illness . We have developed an animal burn-sepsis model which conforms to this "two-hit" concept . We have quantified macrophage TNF-alpha production at different times after the burn (first "hit") and determined the effect of neutralizing antibody against TNF-alpha during this period on survival after subsequent sepsis (second "hit") . The objective of this study was to determine the role of TNF-alpha and the effect of neutralizing antibody against TNF-alpha in a burn-sepsis model . Animals were subjected to a full thickness burn or sham burn . In vitro TNF-alpha production from cultured lipopolysaccharide-stimulated splenic adherent cells was determined at various time points thereafter by enzyme-linked immunosorbent assay . Separate animals were treated with neutralizing antibody against TNF-alpha at different time points after the thermal injury, and survival was determined after septic challenge (cecal ligation and puncture) on Day 10 after the burn . TNF-alpha production from adherent splenocytes was not elevated in the early days after thermal injury, but was significantly enhanced from Day 6 onward compared with sham-burned animals . Nine percent of the burned mice survived septic challenge compared with 69% of the sham-burned control mice (P < 0.001) . Therapy with anti-TNF antibody at 1 x 10(4) neutralizing units (n.u.) kg-1 markedly improved outcome if given when TNF-alpha production was elevated at Day 7 after the burn (survival, 36%; P = 0.01) but did not improve survival when administered at Days 0 or 4 or at the time of the septic challenge (Day 10) . High doses of antibody (3.2 x 10(5) n.u.kg-1) were not beneficial and may have been detrimental . These results show that neutralizing antibody against TNF-alpha may reduce the susceptibility to infection seen after thermal injury, but the timing of administration of the antibody and the dose of antibody used are critical to the outcome . This should be considered when neutralizing antibody against TNF is used in the clinical setting.

J Surg Res, 1996 Jul 15, 64(1), 63 - 7
Identification of altered gene expression in skeletal muscle during sepsis using differential display; Tiao GM et al.; Different aspects of muscle metabolism are altered during sepsis and there is evidence that some of these changes may be regulated at the gene level . Differential display is a recently described technique to identify genes whose expression has changed during a biological process . This technique utilizes reverse transcriptase-polymerase chain reaction (RT-PCR) to compare mRNA signals in tissues during two different conditions . We used differential display to test the hypothesis that gene expression is altered in skeletal muscle during sepsis . Sepsis was induced in rats by cecal ligation and puncture (CLP) . Control rats were sham-operated . Sixteen hours after CLP or sham operation, extensor digitorum longus muscles were harvested and RNA was extracted . Following differential display, 30 fragments (F1-F30) were identified that appeared to be uniquely expressed in muscles from sham-operated or septic rats . These fragments were reamplified by PCR and used as probes in Northern blot analysis . Messenger RNA levels corresponding to 2 of the 30 fragments (F5 and F24) were confirmed to be increased by Northern blot analysis in septic muscle . Following cloning and sequencing, F5 was found to display significant homology to the gene sequence of the guanine nucleotide releasing protein MSS4 . The sequence of F24 did not match any reported gene sequence and may therefore represent a previously unidentified gene . The results support the hypothesis that gene expression is altered in skeletal muscle during sepsis.

Patol Fiziol Eksp Ter, 1996 Jul-Sep, (3), 13 - 8
{Ultrastructural characteristics in neutrophilic leukocytes in patients with sepsis}; Galankin VN et al.; Electron microscopic studies of neutrophilic leukocytes from patients with sepsis have revealed that substantial counts of these cells are prone to degradation just in the blood, the organelles of the degraded cells many of which may be identified are present in the blood plasma . The degradation of neutrophilic leukocytes in systemic circulation may be one of the morphological signs of sepsis.

J Wound Care, 1996 Jul, 5(7), 325 - 8
Care of the open wound in abdominal sepsis; Westrate JT; A recent development in the treatment of patients with intra-abdominal sepsis is to leave the abdomen open after the first laparotomy, thus presenting nurses with the problem of adequate wound care . Over the past 10 years, nurses in the surgical intensive care unit at University Hospital Rotterdam have developed an improved wound-dressing routine, consisting of the application of a large surgical film dressing over the entire abdominal wound . Two suction catheters are positioned under the film, and these are connected to a low-vacuum suction system (1-2kPa) to allow wound drainage . The effectiveness of this method was evaluated in 12 patients . The overall results showed that patients needed a change of dressing once every six days and the majority of problems related to the traditional method of wound care were overcome.

Infection, 1996 Jul-Aug, 24(4), 314 - 8
Tumor necrosis factor alpha (TNF-alpha) and sepsis: evidence for a role in host defense; Rigato O et al.; Serum levels of TNF-alpha were evaluated in 29 patients with sepsis, using TNF-alpha sensitive L929 cells (sensitivity = 15 pg/ml) . Blood samples were collected serially at the first 24-36 h of symptoms . Seventeen patients had severe underlying disease and 12 patients had mild or no underlying disease . Shock was present in 25 patients . Overall mortality was 62.1% . TNF-alpha was detected in nine patients (range: 57.7-3,169 pg/ml) . There was a tendency to detect TNF-alpha in patients with mild or no underlying disease (p = 0.07) . Detection of TNF-alpha was associated with survival (p = 0.0003) even when adjusted for severity of underlying disease (p = 0.005), shock (p = 0.0005), coagulation abnormality (p = 0.002) and immunosuppressive therapy (p = 0.005), using a bivariate analysis . In this investigation, detection of circulating TNF-alpha was predictive of good outcome in septic patients, suggesting a role for this cytokine in host-defense against this kind of infection.

Intensive Care Med, 1996 Jul, 22(7), 631 - 6
Hemostatic abnormalities and the severity of illness in patients at the onset of clinically defined sepsis . Possible indication of the degree of endothelial cell activation?
Leithauser B, Matthias FR, Nicolai U, Voss R.
OBJECTIVE: To find out whether changes within the hemostatic system are related to the severity of illness and organ failure in patients at the onset of clinically defined sepsis and to find some indications for the contribution of endothelial cell activation or perturbation to the patient's status . The following measurements were undertaken: Acute Physiology and Chronic Health Evaluation (APACHE) II score, multiple organ failure (MOF) score, plasma levels of thrombin-antithrombin III complexes (TAT), antithrombin III (AT III), protein C antigen, factor XII, and plasminogen activator inhibitor type 1 antigen (PAI-1), neopterin, and interleukin 6 (IL-6) . DESIGN: A prospective case series study . SETTING: Intensive care unit (ICU) of the Department of Internal Medicine, Justus Liebig University, Giessen, Germany . PATIENTS: 28 consecutive patients (11 females, 17 males; mean age 58 years) with clinically defined sepsis . Eleven patients were admitted from the surgical ICU (9 after elective surgery, 2 after trauma surgery) . The operations were done 1-26 days (mean 14 days) prior to the onset of sepsis . MAIN RESULTS: At the onset of sepsis we found elevated plasma levels of TAT, PAI-1, neopterin, and IL-6, and lowered plasma levels of AT III, factor XII, and protein Cantigen . Neopterin, PAI-1, IL-6, and factor XII showed a statistically significant correlation with the APACHE II score . The MOF score is significantly correlated with IL-6 and neopterin . The extent of hemostatic abnormalities was related to increasing levels of IL-6 . CONCLUSIONS: Clinical evidence of a septic process is most likely to be preceded by activation of the hemostatic system, the vascular endothelium, and the monocyte/macrophage system . IL-6 may have a regulatory function for hemostasis in inflammation . Laboratory monitoring could be helpful in deciding whether to start early intensive therapy in patients at risk for sepsis.

J Obstet Gynecol Neonatal Nurs, 1996 Jul-Aug, 25(6), 500 - 6
Sepsis outcomes in infants and children with central venous catheters: percutaneous versus surgical insertion; Chathas MK et al.; OBJECTIVE: To review the literature on central venous catheters (CVCs) in infants and children . DATA SOURCES: Published surgical, medical, nursing, and nutritional studies from 1968 to the present . STUDY SELECTION: More than 250 studies were reviewed; selection criteria for the 64 studies chosen included age, percutaneous CVC (PCVC) or surgical CVC (SCVC) use, and defined rate of sepsis . DATA EXTRACTION: Included study purpose, sample size and age, indications for total parenteral nutrition, insertion method and sites, number of CVCs, and sepsis outcomes . DATA SYNTHESIS: Yielded weighted mean sepsis rates that were 3.5 times higher for SCVC use in neonatal and/or pediatric populations; subanalyses of homogeneous groups of studies yielded rates that were 2.5 to 3.8 times higher . CONCLUSIONS: Percutaneous CVC insertion should be given primary consideration for neonatal and pediatric intensive-care patients.

Shock, 1996 Jul, 6(1), 46 - 51
A novel nonanticoagulant heparin prevents vascular endothelial cell dysfunction during hyperdynamic sepsis; Morrison AM et al.; Although a novel nonanticoagulant heparin (i.e., GM1892) produces various beneficial effects after hemorrhage and resuscitation, it remains unknown whether this agent has any salutary effects on the depressed vascular endothelial cell function during sepsis . To determine this, rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 1 h after CLP, GM1892 (7 or 14 mg/kg body wt), conventional heparin (7 or 14 mg/kg), or an equal volume of saline was administered intravenously . At 5 h after CLP (i.e., hyperdynamic sepsis), the thoracic aortae were isolated and placed in organ chambers . Dose-response relaxation curves were determined for acetylcholine (ACh; 10(-8) to 10(-5) M), which stimulates endothelial nitric oxide production, and for nitroglycerine (10(-9) to 10(-6) M), which directly provides nitric oxide in vivo . ACh-induced relaxation was depressed at 5 h after CLP while there was no significant alteration in nitroglycerine-induced relaxation . Treatment with 14 mg/kg GM1892 or 14 mg/kg heparin (but not with 7 mg/kg GM1892 or 7 mg/kg heparin), however, prevented the decrease of ACh-induced relaxation . Thus, GM1892 (which does not possess any significant anticoagulant properties) at the higher dosage appears to be useful for maintaining vascular endothelial cell function during hyperdynamic sepsis.

Shock, 1996 Jul, 6(1), 13 - 8
Sepsis inhibits synthesis of myofibrillar and sarcoplasmic proteins: modulation by interleukin-1 receptor antagonist; Vary TC et al.; The breakdown of myofibrillar and sarcoplasmic (nonmyofibrillar) proteins are regulated independently in sepsis, however, the factors regulating their synthesis are unknown . In this study, we assessed the effects of sepsis and interleukin-1 receptor antagonist on sarcoplasmic and myofibrillar protein synthesis in gastrocnemius . The rate of sarcoplasmic protein synthesis was 3.5 times that of myofibrillar proteins in control and septic rats . The synthesis of both sarcoplasmic and myofibrillar proteins was diminished proportionately during sepsis (p < .05) . Infusion of interleukin-1 receptor antagonist (2 mg.kg.-1.h.-1) prevented the sepsis-induced inhibition of total, sarcoplasmic, and myofibrillar protein synthesis . Changes in the abundance of messenger RNA could not account for the inhibition of protein synthesis observed in sepsis . Furthermore, in vitro translation of messenger RNA isolated from control and septic muscle revealed no major differences . These results suggest the following: 1) the inhibition of total mixed proteins during sepsis is a consequence of reduced synthesis of both myofibrillar and sarcoplasmic proteins; 2) IL-1ra maintains control values of protein synthesis by sparing the reduction in synthesis of both myofibrillar and sarcoplasmic proteins during sepsis; and 3) the abundance of messenger RNA is not a rate-limiting determinant of protein synthesis in muscle from septic rats . An alteration in the translational efficiency of existing mRNA appears to be the major mechanism responsible for the inhibition of protein synthesis during sepsis.

Pediatr Infect Dis J, 1996 Jul, 15(7), 579 - 83
Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis; Slusher T et al.; OBJECTIVE: To determine the effect of moderate dose dexamethasone administered before antibiotics on the outcome of African children with sepsis . METHODS: The design was a randomized, double blinded, placebo-controlled trial of dexamethasone (0.2 mg/kg) vs . placebo given intravenously before antibiotic therapy . Patients were recruited from the patient populations at two missionary hospitals . Primary outcome variables were determined before analysis of data . RESULTS: Seventy-two children with sepsis were enrolled in the study . Treatment with dexamethasone was not associated with improved outcome for any of six outcome variables: survival to discharge (83%, dexamethasone group; 89%, placebo group); hemodynamic stability at 48 h (33%, dexamethasone group; 49%, placebo group); median length of hospital stay (11 days, dexamethasone group; 11 days, placebo group); normal at discharge (90%, dexamethasone group; 75%, placebo group); normal at follow-up (90%, dexamethasone group; 72%, placebo group); and afebrile at 48 to 72 h (61%, dexamethasone group; 44%, placebo group) . CONCLUSIONS: These data indicate that a moderate dose of dexamethasone given before antibiotic therapy did not improve outcome in the pediatric patients with sepsis whom we studied.

J Cardiovasc Pharmacol, 1996 Jul, 28(1), 30 - 5
Cyclooxygenase inhibition and vascular reactivity in a rat model of hyperdynamic sepsis; Fox GA et al.; We postulated that the attenuated pulmonary and systemic vascular contractility observed in sepsis was secondary to the release of vasodilator prostaglandins . We used the cyclooxygenase inhibitor meclofenamate to inhibit prostaglandin synthesis in an unanesthetized, chronically instrumented model of hyperdynamic sepsis . Sixteen male Sprague-Dawley rats (300-350 g) were randomized to either sepsis induced by cecal ligation and perforation (CLP, n = 8) or a sham procedure (Sham, n = 8) . Vascular reactivity was assessed by measuring the hypoxic (FiO2 = 0.08) pulmonary pressor response (HPV), and the systemic pressor response to an intravenous infusion of phenylephrine (1.5-7.5 micrograms/kg/min) before and after the administration of meclofenamate (5 mg/kg intravenously, i.v.) . Twenty-four hours postoperatively, CLP animals had significantly increased cardiac output (CO) as compared with Sham animals (204 +/- 12 vs . 148 +/- 5 ml/min, p < 0.05), slightly decreased mean arterial pressure (MAP) (109 +/- 4 vs . 118 +/- 3 mm Hg, p < 0.05), and decreased total systemic vascular resistance (TSVR) (0.546 +/- 0.046 vs . 0.805 +/- 0.030 mm Hg.min.ml-1, p < 0.05) . Mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance (TPVR) were similar in both groups (p > 0.05) . In response to hypoxia, the change in MPAP (delta MPAP) was 3.6 +/- 1.0 and 6.9 +/- 0.8 (mm Hg) in CLP and Sham animals, respectively (p < 0.05) . Similarly, the change in TPVR (delta TPVR) during hypoxia was 0.012 +/- 0.006 and 0.038 +/- 0.009 mm Hg.min.ml-1 in CLP and Sham (p < 0.05) . The pulmonary and systemic blood pressure (BP) response to phenylephrine was also attenuated in CLP as compared with Sham animals . After treatment with meclofenamate, differences were no longer apparent in the HPV response between CLP and Sham animals, due to a slight increase in the HPV response of CLP animals and a slight decrease in the HPV response in Sham animals . The attenuated pressor response to phenylephrine was not changed in either the pulmonary or the systemic circulation after the administration of meclofenamate . These data suggest that vasodilator prostaglandins may contribute to the attenuated pulmonary pressor response in sepsis . However, the mechanism of the attenuated HPV may be different than the attenuated response to exogenous catecholamines since meclofenamate had no effect on either the pulmonary or systemic response to a phenylephrine infusion in septic animals.

Am J Physiol, 1996 Jul, 271(1 Pt 1), G137 - 46
Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis; Moseley RH et al.; Intrahepatic cholestasis in the setting of extrahepatic bacterial infection has been attributed to the effects of endotoxin and cytokines such as tumor necrosis factor-alpha (TNF-alpha) on bile acid transport . To define the mechanism of sepsis-associated cholestasis, taurocholate transport was examined in basolateral (bLPM) and canalicular (cLPM) rat liver plasma membrane vesicles derived from control and endotoxin {lipopolysaccharide (LPS)}-treated animals and in plasma membrane vesicles prepared after TNF-alpha treatment . Na(+)-dependent {3H}taurocholate uptake and both membrane-potential-dependent and ATP-dependent {3H}taurocholate transport were reduced in bLPM and cLPM vesicles, respectively, after LPS treatment . In membrane vesicles from TNF-alpha-treated animals, Na(+)-dependent {3H}taurocholate uptake was also reduced . Northern blot hybridization, using cDNA probes for the putative sinusoidal bile acid transporter (Ntcp) and canalicular ecto-adenosinetriphosphatase, demonstrated decreased mRNA levels after LPS and TNF-alpha treatment . Immunoblot analysis of membrane extracts from LPS-treated animals revealed decreased levels of these putative bile acid transporters . Impaired bile acid transport at the sinusoidal and canalicular membrane domains by these and other mediators of the inflammatory response may account for sepsis-associated cholestasis.

QJM, 1996 Jul, 89(7), 515 - 22
The systemic inflammatory response syndrome as a predictor of bacteraemia and outcome from sepsis; Jones GR et al.; Criteria defining the systemic inflammatory response syndrome (SIRS) were used to assess prospectively 270 clinical episodes in which blood cultures were taken from patients in general medicine . SIRS, severe sepsis and septic shock occurred in 149 (55%), 13 (5%) and 9 (3%) episodes, respectively . However, evidence of organ hypoperfusion indicating severe sepsis was recorded as sought in only 26% of episodes of SIRS . Crude mortality at 28 days increased sequentially as more SIRS criteria were met, rising from 12% in non-SIRS blood culture episodes, to 36% when all four criteria were met . Mortality from severe sepsis and septic shock was 38% and 56%, respectively . In 61/64 (95%) episodes of clinically important bacteraemia, patients fulfilled SIRS criteria when the blood culture was taken . However, the positive predictive value of SIRS for predicting bacteraemia was only 7% . Patients who did not fulfil SIRS criteria when blood cultures were taken were at low risk of bacteraemia and comprised 45% (121/270) of the study population . Three patients in this low-risk group had bacteraemia . Mortality in bacteraemic patients with severe sepsis or septic shock who were initially treated with ineffective antibiotics for up to 48 h was 80%, compared to 42% in those always treated appropriately.

Br J Anaesth, 1996 Jul, 77(1), 110 - 7
Sepsis and cytokines: current status; Blackwell TS et al.; Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection . This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation . Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of sepsis . In addition to pro-inflammatory cytokines, soluble cytokine receptors, cytokine receptor antagonists and counter-inflammatory cytokines are also produced in large quantities in patients with sepsis; however, the specific role of these molecules in sepsis remains undefined . A complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical presentation and course of sepsis . Intervening in this sequence of events to modify the host inflammatory responses may prove to be a beneficial treatment strategy for sepsis, but currently tested anticytokine therapies have been largely unsuccessful.

Am J Respir Crit Care Med, 1996 Jul, 154(1), 57 - 62
Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis; Walmrath D et al.; The present study was performed on 10 patients with severe adult respiratory distress syndrome (ARDS), all suffering from sepsis (mean lung injury score {LIS} (1): 3.25 +/- 0.1; duration of mechanical ventilation upon study entry: 3.1 +/- 0.6 d) . Ex vivo analysis of the alveolar surfactant system, obtained by bronchoalveolar lavage (BAL), showed severe impairment of surfactant function . Three hundred milligrams of natural surfactant/kg body weight (Alveofact) was delivered bronchoscopically in separate doses to each segment of both lungs . This caused an immediate increase in PaO2/FlO2 from 85 +/- 7 mm Hg to 200 +/- 20 mm Hg (p < 0.001), mainly due to a decrease in shunt flow (42 +/- 4 to 20 +/- 2% {p < 0.001}) . Reanalysis of the alveolar surfactant showed that its function was significantly improved . In five patients the increase in arterial oxygenation was partially lost within the next few hours, and a second dose of 200 mg/kg surfactant was applied 18 to 24 h later, again increasing PaO2/FlO2 values . Eight patients survived the subsequent 14-d observation period with progressive improvement of gas exchange, and five patients were definitely weaned from the respirator . All fatalities were due to non-respiratory causes . We conclude that the bronchoscopic application of a high dose of surfactant aimed at overcoming inhibitory factors in the alveolar space of these patients, may offer a feasible and safe approach to improving gas exchange in severe ARDS.

Ann Surg, 1996 Jul, 224(1), 97 - 102
Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability; Gore DC et al.; OBJECTIVE . The purpose of this study was to quantitate the derangements in intermediary carbohydrate metabolism and oxygen use in severely septic patients in comparison with healthy volunteers . SUMMARY BACKGROUND DATA . It commonly has been assumed that the development of lactic acidosis during sepsis results from a deficit in tissue oxygen availability . Dichloroacetate (DCA), which is known to increase pyruvate oxidation but only when tissue oxygen is available, provides a means to assess the role of hypoxia in lactate production . METHODS . Stable isotope tracer methodology and indirect calorimetry was used to determine the rates of intermediary carbohydrate metabolism and oxygen use in five severely septic patients with lactic acidosis and six healthy volunteers before and after administration of DCA . RESULTS . Oxygen consumption and the rates of glucose and pyruvate production and oxidation were substantially greater (p < 0.05) in the septic patient compared with healthy volunteers . Administration of DCA resulted in a further increase in oxygen consumption and the percentage of glucose and pyruvate directed toward oxidation . Dichloroacetate also decreased glucose and pyruvate production, with a corresponding decrease in plasma lactate concentration . CONCLUSIONS . These findings clearly indicate that the accumulation of lactate during sepsis is not the result of limitations in tissue oxygenation, but is a sequelae to the markedly increased rate of pyruvate production . Furthermore, the substantially higher rate of pyruvate oxidation in the septic patients refutes the notion of a sepsis-induced impairment in pyruvate dehydrogenase activity.

Crit Care Med, 1996 Jul, 24(7), 1179 - 83
Plasma antioxidant potential in severe sepsis: a comparison of survivors and nonsurvivors; Cowley HC et al.; OBJECTIVE: To determine the plasma antioxidant potential of patients in the intensive care unit (ICU) with severe sepsis and secondary organ dysfunction and relate these findings to outcome . DESIGN: A prospective, cohort study . SETTING: A nine-bed ICU in a university teaching hospital . PATIENTS: Fifteen consecutive patients, who were within 16 hrs of development of severe sepsis and secondary organ dysfunction . INTERVENTIONS: Plasma samples were obtained within 16 hrs of the onset of secondary organ dysfunction and subsequently on days 2, 3, 4, 6, 8, 10, and 15 until patients either left the ICU or died . Plasma antioxidant potential was determined by an ultraviolet spectrophotometric technique . MEASUREMENTS AND MAIN RESULTS: The mean initial plasma antioxidant potential was lower than our range for healthy volunteers (p < .05) . Survivors had an initial plasma antioxidant potential that was greater than nonsurvivors (p < .01), and serial subset analysis demonstrated that survivors, despite having a low initial plasma antioxidant potential rapidly attained normal or supranormal values . While plasma antioxidant potential also increased in nonsurvivors over time, values in this subset never reached the normal range and remained below values in survivors at all time points studied (p < .05) . CONCLUSIONS: Plasma antioxidant potential is initially decreased in patients with sepsis who develop organ dysfunction, and it increases over time . While we have no clear evidence to prove that this reduction has a causal relationship, failure to achieve a normal plasma antioxidant potential is strongly associated with an unfavorable outcome.

Crit Care Med, 1996 Jul, 24(7), 1137 - 43
Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure; Doughty LA et al.; OBJECTIVE: To examine the relationship of circulating proinflammatory and anti-inflammatory cytokine concentrations to nitric oxide and organ failure in pediatric sepsis . DESIGN: Prospective study . SETTING: Pediatric intensive care unit (ICU), children's Hospital of Pittsburgh, University of Pittsburgh . PATIENTS: Nineteen patients with a diagnosis of sepsis admitted to the pediatric ICU . Twelve uninfected critically iII patients served as controls . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Plasma interleukin (IL)-10, IL-6, and nitrite/nitrate concentrations were measured and compared with an index of organ failure daily for 3 days after presentation with the sepsis syndrome . Children with increased plasma IL-6 concentrations (n = 6) had increased plasma nitrite/nitrate concentrations (p < 0.01 on each day), increased organ failure scores (p < .05 on days 1 and 3), and the highest plasma IL-10 concentrations (p < .05 on days 1 and 3, p = .054 on day 2) when compared with children with sepsis and undetectable IL-6 concentrations . Children with sepsis and detectable IL-6 concentrations, and children with undetectable IL-6 concentrations, both had increased nitrite/nitrate concentrations (p < .005 on days 1 through 3) and increased IL-10 concentrations (p < .05 on days 1 and 2) compared with controls . Children with increased IL-6 concentrations had higher organ failure on each day (p < .01), and children with undetectable IL-6 concentrations had higher organ failure on days 1 and 2 only (p < .005) when compared with controls . Organ failure improved over time in the children with undetectable IL-6 concentrations (p < .005) . CONCLUSIONS: Increased plasma nitrite/nitrates and increased organ failure scores occurred in the children with sepsis who had an exaggerated proinflammatory state, despite a pronounced anti-inflammatory response . When the anti-inflammatory response predominated and the proinflammatory state was dampened, organ failure status improved.

Pol Tyg Lek, 1996 Jun, 51(23-26), 314 - 7
{Sepsis--generalized infection . The treatment of adults based on personal observations}; Olejnik Z et al.; Basing on the own experience, the authors discuss causative treatment of sepsis, mainly of unknown etiology . Emphasis is on the depression of immunological system in the acute phase of the disease . Therefore, a combined treatment with 2, often 3 or even 4 bacterial antibiotics is recommended, together with passive immunotherapy, and in certain cases surgical removal of the infection foci.

Thromb Haemost, 1996 Jun, 75(6), 902 - 7
Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis; Mesters RM et al.; Variables of the fibrinolytic system were prospectively studied in patients with haematologic malignancies in chemotherapy-induced leukocytopenia at onset and during the course of septicemia to evaluate their prognostic value . This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective testing of fibrinolytic variables prior to and during evolving sepsis or septic shock . 62 patients with febrile infectious events were accrued to the study . Of these, 13 patients progressed to severe sepsis and an additional 13 patients to septic shock as defined according to standard diagnostic criteria . At onset of fever, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen levels increased from normal baseline levels and were significantly higher in the group of patients who developed septic shock compared to those with severe sepsis (medians: 10.6 versus 1.3 U/ml, p = 0.0001; 50.0 versus 5.0 ng/ml, p = 0.0002) . The increase in PAI activity and antigen in septic shock was accompanied by an increase in tissue-type plasminogen activator antigen and total fibrin(ogen) degradation products and a decrease in alpha(2)-antiplasmin activity (p < 0.006) . In contrast, in the group of patients that developed severe sepsis the variables of the fibrinolytic system remained unchanged at onset of fever . These differences between septic shock and severe sepsis were sustained throughout the septic episode for all variables (p < 0.0001) . PAI activity of > 5 U/ml at onset of fever predicted a lethal outcome with a sensitivity of 92% and a specificity of 100% . Thus, septic shock in leukocytopenia is associated with significant activation of the fibrinolytic system presumably as a response of the vascular endothelium to inflammatory injury . Furthermore, PAI activity measurements are sensitive markers of an unfavourable prognosis.

Eur J Surg, 1996 Jun, 162(6), 499 - 504
Platelet activating factor antagonism improves cardiovascular function in non-hypotensive sepsis in pigs; Abu-Zidan FM et al.; OBJECTIVE: To study the effects of platelet activating factor (PAF) antagonism on cardiovascular function in Escherichia coli endotoxaemia in non-hypotensive anaesthetised pigs . DESIGN: Experimental study . SETTING: Trauma research unit, Sweden . MATERIAL: 24 Domestic juvenile pigs . INTERVENTIONS: 18 Pigs received a continuous infusion of E coli endotoxin in a dose of 36 micrograms/kg/hour for 5 hours . They were allocated to two groups of 9 each . The first group (BB-882 group) received a continuous infusion of BB-882 (a novel potent PAF antagonist) 33 mg/kg/hour 30 minutes before the endotoxin while the second group (placebo group) received vehicle alone . Another 6 pigs (control group) received only BB-882 . MAJOR OUTCOME MEASURES: Blood temperature, rigors, heart rate, intravascular pressure, cardiac and stroke volume indices and systemic vascular resistance . RESULTS: Animals in the BB-882 group had significantly fewer rigors (p < 0.001) and episodes of tachycardia (p < 0.001) than the placebo group . BB-882 significantly reduced the endotoxin-induced systemic hypertension (p < 0.001) and the rise in systemic vascular resistance (p < 0.001) . BB-882 group had significantly higher central venous pressure (p < 0.05), pulmonary capillary wedge pressure (p < 0.001), cardiac index (p < 0.02), and stroke volume index (p < 0.001) . CONCLUSIONS: Pretreatment with a potent PAF receptor antagonist improved the cardiovascular function during non-hypotensive E coli endotoxaemia in pigs.

J Hosp Infect, 1996 Jun, 33(2), 93 - 108
Prevention of sepsis in total joint arthroplasty; An YH et al.; Because of the adoption of effective prophylactic measures such as improved operating room techniques and systemic antibiotics, the prosthetic infection rate for artificial joint procedures has been reduced to 1-2% . However, because of the devastating results and large number of prosthetic procedures, prosthetic infection remains a major challenge . Common pathogens and mechanisms of infection, methods of preventing bacterial adherence to biomaterial surfaces, and clinical preventive strategies for prosthetic infections are discussed.

Clin Chest Med, 1996 Jun, 17(2), 307 - 17
Immunotherapy for sepsis; Ralston DR et al.; In recent years, an improved understanding of the pathogenesis of sepsis, along with an explosion in the biotechnology industry, has led to the development of a variety of agents with potential to interdict the pathogenesis of sepsis at many points . This article reviews the rationale, efficacy and shortcomings of these immunotherapeutic agents as they relate to the management of human septic shock.

Clin Chest Med, 1996 Jun, 17(2), 289 - 305
Pharmacotherapy of sepsis; Weikert LF et al.; During the past few years, many promising new agents for the treatment of sepsis have been studied to varying degrees in vitro as well as in vivo in animals and humans . Although there is a relative plethora of animal data, full-scale clinical trials of size sufficient to yield clear answers are rare . Many of the agents appear to hold promise based on preliminary data in animals or from small human studies, and some are undergoing multicenter clinical investigation . At present, however, none of the agents discussed clearly has shown survival benefit when administered to patients with sepsis . Certainly, none can be recommended as standard therapy, and others such as glucocorticoids should be avoided . Nevertheless, the pharmacotherapy of sepsis remains an area of intense research, and ongoing clinical trials as well as continuing basic research into the pathophysiologic mechanisms of sepsis yet may yield a well-studied drug that offers survival benefit to patients with sepsis.

Clin Chest Med, 1996 Jun, 17(2), 279 - 87
Hemodynamic support during sepsis; Ognibene FP; Hemodynamic support during sepsis should focus on aggressive resuscitation coupled with vasopressors aimed at restoration of blood pressure and end-organ perfusion and preservation . The choice of vasopressors should be based on the degree and persistence of peripheral vasodilatation as well as the degree of cardiac stimulation required . Norepinephrine can and should be used when dopamine fails to improve blood pressure and perfusion after adequate volume resuscitation . Dopamine's role of renovascular preservation remains controversial . Therapeutic strategies aimed at supranormal improvements in cardiac index or oxygen delivery have no documented effect in septic patients and should not be part of their therapy.

Clin Chest Med, 1996 Jun, 17(2), 263 - 78
Oxygen delivery and consumption during sepsis; Chittock DR et al.; This article discusses the oxygen consumption (VO2) and delivery (DO2) relationship as it pertains to animal models of sepsis and human sepsis syndrome and septic shock . Pathologic dependence of VO2 on DO2 is not present in resuscitated patients who have sepsis syndrome and septic shock . Defects in oxygen extraction and use at the individual organ level with maldistribution of blood flow probably do occur in sepsis; however, there is no clinical evidence that augmenting DO2 to supernormal levels decreases organ dysfunction or mortality in sepsis . We need improved techniques to assess tissue hypoxia at the organ level, and we need to test therapies directed at correcting the maldistribution of blood flow and O2 use defects of sepsis.

Clin Chest Med, 1996 Jun, 17(2), 249 - 61
Metabolic consequences of sepsis . Correlation with altered intracellular calcium homeostasis; Crouser ED et al.; The availability of adequate substrate for energy homeostasis is a minimal requirement for vital organ function that normally is provided through dietary intake . When dietary sources of nutrients are inadequate, the body relies on alternate sources of energy provided by gluconeogenesis, lipolysis, and ketogenesis . Sepsis is associated with disruption of virtually all these provisional sources of energy substrate (see Fig . 4) . In addition, sepsis impairs the function of the glycolytic pathway, the integrity of which is necessary for glucose to be used effectively for energy production . These abnormalities, coupled with disruption of the intracellular energy-producing machinery (e.g., glycolytic and gluconeogenic enzymes, mitochondria) eventually lead to a reduction in intracellular ATP . Furthermore, a reduction in intracellular ATP can undermine virtually all the energy-consuming functions of the cell, including energy substrate formation (e.g., failed gluconeogenesis), antioxidant production, and calcium homeostasis . High levels of intracellular calcium, in turn, are known to activate many potentially destructive enzymatic pathways (e.g., proteases, phospholipases, endonucleases) that further diminish cell function and may result in cell death . In this context, iCa2+ accumulation may play an important role in the progression from early sepsis to MODS, the most common cause of mortality in the ICU.

Clin Chest Med, 1996 Jun, 17(2), 213 - 35
Current concepts of sepsis and acute lung injury; Sessler CN et al.; Acute respiratory distress syndrome continues to be a vexing clinical problem with no specific therapy . Epidemiologic and basic sciences have advanced our understanding of the clinical syndrome and have brought us to the brink of effective intervention strategies . This article carefully examines the current state of knowledge, with reference to acute lung injury and current efforts, to arrive at effective pharmacologic approaches.

Clin Chest Med, 1996 Jun, 17(2), 199 - 212
Early detection and markers of sepsis; Parsons PE et al.; In vitro and animal models of sepsis have provided a template for studies of the pathogenesis of sepsis in patients at risk for and with the syndrome . Numerous potential markers have been identified in these models and then looked for in patients . No single marker or combination of markers convincingly identifies sepsis, predicts the development of sepsis, predicts the development of complications of sepsis, or predicts mortality . As discussed, the clinical studies have been complicated by many confounding variables, including the lack of adherence to rigorous definitions, differences in assay methods, differences in timing of the studies, and differences in outcome variables analyzed . In spite of the limitations, the studies have been critical in helping determine the pathogenesis of sepsis in humans . As new mediators and modulators of inflammation are identified, it will be important to study their role as markers, individually and in combination, in human disease.

Clin Chest Med, 1996 Jun, 17(2), 175 - 81
The sepsis syndrome . Definition and general approach to management; Bone RC; Sepsis is the systemic response to severe infection in critically ill patients . Sepsis, sepsis syndrome, and septic shock represent the increasingly severe stages of the same disease . Severe sepsis and septic shock occur in persons with preexisting illness or trauma . If sepsis is not diagnosed and treated early, it can become self-perpetuating, and elderly persons, in particular, are at a greater risk of death from sepsis.

J Crit Care, 1996 Jun, 11(2), 77 - 94
Applications of molecular biology and biotechnology: antibody therapy of sepsis; Wheeler AP et al.; The use of antibody therapy for the treatment of infections and inflammatory disease is well established . Unfortunately, clinical studies of antiendotoxin and anti-TNF monoclonal antibodies have failed to show clear physiological or survival benefit . Little information is available regarding the effect of antibodies to cytokines other than TNF in human sepsis . Limited pre-clinical data indicate that IL-6 antibodies may abrogate the effects of endotoxin infusion, but no human studies have been performed . Although both monoclonal and polyclonal antibodies have the potential to protect septic humans, at this time it is the polyclonal antibodies that have shown the greatest promise . Each type of antibody possesses specific advantages and limitations, the ultimate effectiveness of which will need to be proven in large randomized clinical trials.

Br J Surg, 1996 Jun, 83(6), 778 - 80
Severe complications of perianal sepsis in patients with human immunodeficiency virus; Consten EC et al.; Fifty human immunodeficiency virus (HIV)-infected patients with perianal sepsis were studied . Seven (14 per cent) had serious septic complications, four patients with severe necrotizing gangrene, and three with abscesses in the mediastinum, liver and brain respectively . CD4+ lymphocyte counts were significantly lower in patients with severe septic complications as compared with those with uncomplicated perianal sepsis (P < 0.05) . In patients with HIV presenting with rare (metastatic) abscesses, perianal sepsis must always be kept in mind as a possible focus . Although HIV-infected patients have a limited life expectancy perianal fistulas and abscesses should be aggressively treated, because of the high risk of severe complications.

Occup Med (Lond), 1996 Jun, 46(3), 231 - 2
Post-splenectomy sepsis--the role of occupational health; Brew I et al.; Persons who have had their spleens removed (asplenics) have a high risk of infection . The risks from infection are life-long and the illness can be a quick, overwhelming, septicaemia, that can lead to death within 48 hours, without appropriate treatment . Many persons who have had elective splenectomy, especially before 1977, may not have had prophylactic vaccinations, antibiotics or advice . This paper describes the risks of serious infection, the prophylaxis available and the role of the occupational health department in protecting asplenic employees.

Crit Care Med, 1996 Jun, 24(6), 1025 - 33
Surfactant replacement in the treatment of sepsis-induced adult respiratory distress syndrome in pigs; Nieman GF et al.; OBJECTIVE: To evaluate the efficacy of treating sepsis-induced adult respiratory distress syndrome (ARDS) by instillation of exogenous surfactant in a porcine endotoxin model . DESIGN: Prospective trial . SETTING: Laboratory at a university medical center . SUBJECTS: Fifteen hybrid pigs, weighing 15 to 20 kg . INTERVENTIONS: Pigs were anesthetized and surgically prepared for hemodynamic and lung function measurements . Animals were randomized into three groups: a control group (group I; n=4) that received sham Escherichia coli lipopolysaccharide (endotoxin); an endotoxin group (group II; n=6) that received endotoxin (25 micrograms/kg); and an endotoxin + surfactant (Infasurf, ONY, Amherst, NY) instillation group (group III; n=5) that received endotoxin (25 micrograms/kg) followed by surfactant (100 mg/kg) instillation; all groups were studied for 6 hrs after the start of endotoxin injection . At necropsy, lung water and surfactant function (Wilhelmy balance) were measured and the right middle lung lobe was fixed for histologic analysis . Surfactant function was expressed as the surface tension at the minimum trough area . MEASUREMENTS AND MAIN RESULTS: Surfactant treatment (group III) significantly (p<.05) decreased venous admixture (group III = 41.5 +/- 9.1%; group II = 61.6 +/- 4.7%), PaCO2 (group III = 46.6 +/- 1.3 torr {6.2 +/- 0.2 kPa}; group II = 54.4 +/- 2.6 torr {7.25 +/- 0.34 kPa}, and surface tension minimum (group III = 8.8 +/- 1.8 dyne/cm; group II = 20.0 +/- dyne/cm), as compared with endotoxin without treatment (group II) 6 hrs after endotoxin infusion . However, surfactant instillation did not significantly improve PaO2 (group III = 62.8 +/- 6.8 torr {8.4 +/- 0.9 kPa2}; group II = 50.3 +/- 3.7 torr {6.7 +/- 0.49 kPa}) or reduce the amount of pulmonary edema (group III = 7.1 +/- 0.39 ratio; group II = 6.8 +/- 0.24 ratio) seen 6 hrs following endotoxin injection . Histologic analysis showed that endotoxin caused edema accumulation around airways and pulmonary vessels, and a large increase in the number of marginated leukocytes with or without surfactant treatment . Surfactant treatment significantly increased the total number of leukocytes in the pulmonary parenchyma . CONCLUSIONS: We conclude that endotoxin caused lung injury typical of ARDS as demonstrated by pulmonary edema, an increase in PaCO2, and a decrease in PaO2, a decrease in static lung compliance and inhibition of surfactant function . Exogenous surfactant treatment effected only moderate improvements in lung function (i.e., reduced venous admixture and restored surfactant function) in this sepsis-induced ARDS model.

Br J Anaesth, 1996 Jun, 76(6), 790 - 4
Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies; Matta BF et al.; We have studied cerebral autoregulation and vasoreactivity to carbon dioxide in 10 patients with the sepsis syndrome receiving intensive therapy . All patients were sedated with infusions of midazolam and fentanyl, and their lungs were ventilated mechanically with oxygen-air to maintain normoxia and normocapnia . Inotropic support and antibiotics were administered as necessary . During a period of constant level of sedation and stable haemodynamics, cerebral autoregulation was tested by increasing mean arterial pressure (MAP) by 23 (SD 2) mm Hg from baseline with an infusion of phenylephrine and simultaneously recording middle cerebral artery blood flow velocity (vmca) using transcranial Doppler ultrasonography . Carbon dioxide reactivity was tested by varying PaCO2 between 3.0 and 7.0 kPa and simultaneously recording vmca . There was no significant change in vmca (57 (22) and 59 (23) cm s-1) during the increase in MAP (75 (11) to 98 (10) mm Hg) . The mean index of autoregulation (IOR) was 0.92 (SEM 0.03), which was not significantly different from 1, indicating near perfect autoregulation . Although absolute carbon dioxide reactivity was lower than reported previously in awake subjects, relative carbon dioxide reactivity was within normal limits for all patients (11.6 (SEM 0.8) cm s-1 and 20.3 (3) % kPa-1, respectively) . We conclude that cerebral carbon dioxide reactivity and pressure autoregulation remained intact in patients with the sepsis syndrome, providing indirect evidence that at least in the early stages of the syndrome, the widespread sepsis-induced vasoparalysis does not involve the cerebral vasculature.

Infect Immun, 1996 Jun, 64(6), 2201 - 5
Passive transfer of poly-(1-6)-beta-glucotriosyl-(1-3)-beta-glucopyranose glucan protection against lethal infection in an animal model of intra-abdominal sepsis; Cisneros RL et al.; Previous studies have established the efficacy of soluble polymers of poly-(1-6)-beta-glucotriosyl-(1-3)-beta-glucopyranose (PGG) glucan, a biological-response modifier, in protecting against mortality associated with experimentally induced peritonitis in a rat model . PGG glucan-treated animals showed increases in total leukocyte counts and enhanced bacterial clearance from blood . To further explore the mechanisms) by which this agent confers protection, studies were performed to examine whether protection could be transferred from PGG glucan-treated animals to naive recipients via spleen cells (SC), SC lysates, or serum . Passive-transfer experiments indicated that the responsible factor(s) was transferable by whole SC and SC lysates, as well as by peripheral leukocytes or serum from animals treated with PGG glucan . The transferable factor(s) was resistant to pronase and trypsin digestion, was heat stable at 56 or 80 degrees C, and was not removed by NH4SO4 precipitation . The protective effect of PGG glucan was abrogated by treatment with indomethacin, a potent inhibitor of prostaglandin synthesis . Administration of a purified prostaglandin extract from the sera of PGG glucan-treated animals protected against mortality in the peritonitis model . Furthermore, treatment of rats with exogenous synthetic prostaglandin E2 also conferred protection against mortality . These results suggest that the protective effect exhibited by PGG glucan in the rat peritonitis model is mediated, at least in part, by prostaglandins.

J Immunol, 1996 Jun 1, 156(11), 4401 - 7
Release of leukemia inhibitory factor in primate sepsis . Analysis of the role of TNF-alpha; Jansen PM et al.; Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis . We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli . In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E . coli challenge was administered (n=4) . LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively . TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml) . Circulating LIF correlated with plasma levels of IL-6, both after E . coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001) . Moreover, the E . coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity . These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.

South Med J, 1996 Jun, 89(6), 612 - 4
Agranulocytosis and near fatal sepsis due to 'Mexican aspirin' (dipyrone); Dorr VJ et al.; The use of "unconventional" or alternative medicine has been reported in up to one third of American households, yet only 28% report the use of such agents to their physician . We present here a case of near fatal sepsis and agranulocytosis . The agranulocytosis is attributed to the use of dipyrone (Dolo-Tiaminol), which the patient obtained in Mexico as a stronger form of generic "aspirin." The pyrazolone class of analgesics, of which dipyrone is a derivative, was introduced in the late 19th century and had a meteoric rise in use until an associated rise in fatal agranulocytosis was discovered . These agents were banned by the Food and Drug Administration (FDA) in 1977 . Dipyrone is thought to induce agranulocytosis by inducing an antibody response . With the widespread use of alternative treatments, it is important for physicians to inquire as to the use of unprescribed drugs . Several resources are available to aid with the identification of foreign drugs.

Med Pediatr Oncol, 1996 Jun, 26(6), 405 - 8
Prevention of indwelling central venous catheter sepsis; Daghistani D et al.; In an attempt to decrease the incidence of central venous catheter sepsis in children with cancer, we conducted a study to evaluate the benefit of adding broad-spectrum antibiotics to the catheter "flush solution." In a prospective, placebo-controlled, double-blinded, randomized trial, 69 children with different types of malignancies were studied . The central venous catheters in these children were flushed with either the standard solution (normal saline + 100 U/ml of heparin) or the study solution (25 microgram/ml of both amikacin and vancomycin added to the standard solution) . At the conclusion of the study, 64 children with a total of 67 indwelling central venous lines were assessable . The total catheter days on study were 20,700 days, with a median of 323 catheter days per patient . We documented 10 events of catheter-related infections (0.49 events/1,000 catheter days at risk) . Five of these events were catheter-related sepsis (0.24 sepses/1,000 catheter days): two were fungal and three were bacterial . Due to the low incidence of catheter-related sepsis in this study, no statement regarding the prophylactic use of antibiotics could be made . The extremely low rate of catheter-related sepsis reported herein may be retrospectively attributed to continuous staff education regarding aseptic techniques in handling these catheters . Staff education is essential, and probably the most effective factor in preventing catheter-related sepsis.

N Engl J Med, 1996 May 30, 334(22), 1417 - 21
Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome . Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group; Anzueto A et al.; BACKGROUND . Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant . Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival . METHODS . We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS . Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation {APACHE III} index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days . RESULTS . The demographic and physiologic characteristics of the two treatment groups were similar at base line . The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively . Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups . Survival at 30 days was 60 percent for both groups . Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center . Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups . CONCLUSIONS . The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.

Blood, 1996 May 15, 87(10), 4261 - 75
Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators; Ayala A et al.; Apoptosis (Ao), is a process by which cells undergo a form of nonnecrotic cellular suicide . Although for most cells this is a constitutive process, it can be induced in immature and differentiating immune cell populations by stress mediators associated with inflammation . This inducible form of A(o) is referred to as programmed cell death . However, it is not clear whether hematopoietic cell populations such as the thymus and bone marrow are induced to undergo A(o) during polymicrobial sepsis . To assess this, thymocytes, bone marrow cells, or splenocytes (as a source of comparative nonhematopoietic cells) were harvested from C3H/HeN mice at 1, 4, or 24 hours after cecal ligation and puncture (CLP; to induce polymicrobial sepsis) or sham-CLP (Sham) . The results showed that mixed bone marrow cells ex vivo, although not to the same extent as thymus, showed a marked increase in the percentage of cells in A(o), increased endonuclease activity, and a significant decrease in cell yield at 24 hours but not at 4 hours after CLP . Similar changes were not evident in splenocytes . Phenotypic, as well as morphologic assessment, indicated that most of the increase in apoptotic cells in the thymus was associated with the immature T cells (CD4+CD8+) and CD8-CD4- cells . In contrast, the increase in bone marrow cell A(o) was associated with only the B220+ cells, with no significant contribution from myeloid cells . Treatment of CLP mice in vivo with either RU-38486 or PEG-(rsTNF-R1)2 was unable to reverse the increased A(o) in the bone marrow of these animals . Taken together, these findings indicate that A(o) as a process induced by polymicrobial sepsis is not limited to the thymus, but can also be detected in the bone marrow . However, unlike thymic A(o), bone marrow is not affected directly/indirectly by glucocorticoids or tumor necrosis factor released during sepsis.

Shock, 1996 May, 5(5), 333 - 40
Sepsis increases putrescine concentration and protein synthesis in mucosa of small intestine in rats; Noguchi Y et al.; Recent studies suggest that sepsis stimulates mucosal polyamine and protein synthesis . It is not known in which cell type polyamine biosynthesis is increased during sepsis and if polyamines regulate mucosal protein synthesis . We examined the effect of sepsis in rats on polyamine biosynthesis in isolated jejunal enterocytes and measured mucosal protein synthesis following inhibition of ornithine decarboxylase (ODC) activity with difluoromethylornithine . ODC and S-adenosylmethionine decarboxylase (SAMDC) activities and putrescine concentrations were increased in isolated jejunal enterocytes 16 h after induction of sepsis by cecal ligation and puncture . Enterocyte spermidine and spermine levels were not influenced by sepsis . Mucosal ODC and SAMDC activities and polyamine levels were increased following treatment of rats with interleukin-1 but not tumor necrosis factor . Treatment of rats with difluoromethylornithine prevented the sepsis-induced increase in mucosal ODC activity, putrescine concentration, and protein synthesis rate . The results suggest that sepsis increases ODC and SAMDC activities and putrescine concentrations in enterocytes of the small intestine . This metabolic response to sepsis may be regulated by interleukin-1 although other mechanisms may also be involved . Increased mucosal protein synthesis during sepsis may at least in part be regulated by increased putrescine levels.

Am J Physiol, 1996 May, 270(5 Pt 2), R927 - 38
Mechanism of hepatocellular dysfunction during hyperdynamic sepsis; Wang P et al.; Because of its central role in metabolism and host defense mechanisms, the liver is thought to be a major organ responsible for the initiation of multiple organ failure during sepsis . It is, therefore, important to discuss whether hepatocellular dysfunction occurs during early sepsis and, if so, whether this occurs prior to hepatocellular damage as evidenced by elevation in serum enzyme levels . Because indocyanine green clearance has been demonstrated to be an early and extremely sensitive measure of active hepatocyte transport function, a technique for repeated measurement of hepatocellular function by in vivo indocyanine green clearance was developed in small animals, such as the rat . Studies have indicated that hepatocellular function is markedly depressed during early stages of polymicrobial sepsis despite the increased cardiac output and hepatic blood flow and decreased peripheral vascular resistance . The depression in hepatocellular function in early, hyperdynamic stages of sepsis does not appear to be due to any reduction in hepatic profusion but is associated with elevated levels of circulating proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6 . Furthermore, administration of recombinant murine TNF-alpha at a dose that does not reduce cardiac output and hepatic perfusion produces hepatocellular dysfunction and increases plasma levels of IL-6 . Thus upregulation of TNF and/or IL-6 may be responsible for producing hepatocellular dysfunction during early, hyperdynamic stages of sepsis.

Hepatogastroenterology, 1996 May-Jun, 43(9), 515 - 8
Masking of the symptoms of esophageal and bowel perforation by combination treatment of sepsis with polyvalent immunoglobulins and low-dose hydrocortisone; Bohrer H et al.; Sepsis is usually treated with surgical drainage, antibiotics, oxygenation optimization and volume resuscitation . Recent monoclonal and polyclonal anti-bodies have been used to treat sepsis by neutralizing the endotoxins and cytokines found in septic patients . This method does not significantly reduce mortality except in certain sub-populations of the treatment groups . We introduced a combination approach for sepsis treatment . This adjuvant therapy consists of polyclonal human immunoglobins together with infusion of low-dose hydrocortisone . This paper reports the results of this treatment in two different cases.

JPEN J Parenter Enteral Nutr, 1996 May-Jun, 20(3), 215 - 8
Rapid diagnosis of catheter-related sepsis using the acridine orange leukocyte cytospin test and an endoluminal brush; Tighe MJ et al.; BACKGROUND: In neonates, the acridine orange leukocyte cytospin (AOLC) test has been found to be a highly sensitive test for the detection of infected i.v . catheters in situ, which provides a result in less than 1 hour . Preliminary data suggested that the AOLC test was of limited value in adults . We report here a modification of the test for adult patients with indwelling central venous catheters . METHODS: A prospective study was performed on two groups of 50 adult patients with suspected sepsis and a central venous catheter . The AOLC test was carried out after the clinical decision to remove the catheter had been made . In group 1 patients, a blood sample was withdrawn from the catheter for the AOLC test . In the patients in group 2, an endoluminal brush was used to "sweep" the catheter before the collection of the blood sample . Results of the AOLC test were compared with culture of the removed catheter tip . RESULTS: From the catheters in group 1 (no brush), 17 catheter tips were found to be infected, but the AOLC was positive in only two patients (12%) . In group 2 (brush), 18 tips were infected, and the AOLC test was positive in 15 patients (83%) . The use of the endoluminal brush significantly improved the yield of the AOLC test (p < .01) to levels reported in neonates . The AOLC test produced no false positives in either group CONCLUSION: When used independently, the AOLC test was not sensitive enough to detect catheter-related sepsis . However, in combination with an endoluminal brush, the AOLC test was much more sensitive and has the potential to provide a simple, rapid, and accurate diagnostic test for catheter-related sepsis, which does not require removal of the catheter.

New Horiz, 1996 May, 4(2), 168 - 78
Hypoxic alterations in cellular signal transduction in shock and sepsis; West MA et al.; Many different cellular processes are altered by microenvironmental changes in the oxygen level, particularly hypoxia . In most cases, these hypoxic effects are mediated via alterations in cellular signal transduction pathways . Low oxygen states are generally viewed as deleterious; however, recent studies show that alterations in oxygen levels are physiologically important, influencing cells in a variety of ways . Low oxygen levels can stimulate cellular processes, such as the production of tumor necrosis factor, interleukin (IL)-1, IL-8, and nuclear factor kappa B . Kupffer cell-mediated alterations in cocultured hepatocyte function are altered by pre-exposure to hypoxic culture conditions, whereas superoxide production, intracellular pH, and adenosine triphosphate levels are decreased by hypoxia . Hypoxia followed by reoxygenation stimulates tyrosine kinase enzymes and increases intracellular calcium in a variety of cells . This review highlights recent findings concerning the manner and mechanisms by which low oxygen levels influence cell functions and cellular signaling systems . Detailed information is still lacking about the location and mechanism of most hypoxic-mediated alterations in cell signaling pathways . However, information about how factors altered by trauma and sepsis, such as Po2, acidosis, and endotoxin, effect cellular signaling pathways is rapidly emerging . Understanding the mechanism by which oxygen availability alters cell function will be important to the development of optimal therapies for post-traumatic shock and organ dysfunction.

Eur J Pediatr, 1996 May, 155(5), 404 - 9
Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis; Lauterbach R et al.; Increased plasma tumour necrosis factor alpha (TNF) concentration correlates with mortality in sepsis . We suggested that pentoxifylline (PTXF), which is known to inhibit TNF production, may improve survival and attenuate clinical symptoms of sepsis in neonates . Plasma TNF levels were evaluated in 29 newborn infants with sepsis . Patients were randomly assigned into two groups, receiving PTXF in a dose of 5 mg/kg per hour for 6 h or placebo (saline), on 3 successive days . Both groups were subjected to the same conventional therapy . TNF was evaluated before and after PTXF or placebo administration on the 1st and 3rd days of therapy . There was a statistically significant decrease in plasma TNF level in the PTXF group when the values before the first and after the last PTXF infusion were compared {mean: 671.5 pg/ml; SD: 438; med: 729.6 vs mean: 41.0 pg/ml; SD: 64.1; med: 11.5; P < 0.000004} . In the placebo group, decrease was not significant {mean: 633.0 pg/ml SD: 488.6; med: 618.9 vs 246.9 pg/ml; SD: 243.9; med: 191.0} . A significantly higher plasma TNF level, evaluated after the last PTXF infusion, was found in the placebo group {246.9 pg/ml vs 41.0 pg/ml; P < 0.001} . Only one of four infants with signs of shock in the placebo group survived, whereas all of five newborns with symptoms of shock in the PTXF group survived {P < 0.04} . An increased incidence of metabolic acidosis {P < 0.05}, necrotizing enterocolitis {P < 0.04} and renal insufficiency {P < 0.05} was observed in infants in the placebo group . CONCLUSION: PTXF inhibits production of TNF and may have therapeutic value in the treatment of premature infants with sepsis complicated by shock.

Crit Care Med, 1996 May, 24(5), 850 - 4
Effect of sepsis and 3,5,3'-triiodothyronine replacement on myocardial integrity during oxidant challenge; Davidson SB et al.; OBJECTIVE: To determine whether sepsis, with or without thyroid hormonal augmentation, induces myocardial tolerance to an oxidant challenge . DESIGN: A prospective, randomized, controlled animal trial . SETTING: University research laboratory . SUBJECTS: Twenty male Sprague-Dawley rats . INTERVENTIONS: After anesthesia, animals underwent cecal ligation and puncture, with or without 3,5,3'-triiodothyronine replacement (3 ng/hr), or sham surgery . Twenty-four hours later, the heart was rapidly excised for retrograde Langendorff perfusion . Oxyradical challenge consisted of the addition of 200 microM of hydrogen peroxide to the perfusate for 60 mins . MEASUREMENTS AND MAIN RESULTS: Myocardial contractility and relaxation were continuously recorded . Perfusate glutathione and lactate dehydrogenase concentrations were determined enzymatically at 30-min intervals for 90 mins . Oxyradical perfusion alone significantly increased glutathione efflux and decreased myocardial contractility when compared with control animals . Prior cecal ligation and puncture decreased oxidant-mediated glutathione efflux and maintained myocardial contractility . 3,5,3'-triiodothyronine supplementation appeared to increase late cardiac contractility and cellular integrity during oxidant challenge . However, this increase was not statistically significant . CONCLUSIONS: Antecedent septic challenge appears to induce tolerance to further myocardial oxyradical exposure and improves myocardial functional and biochemical integrity . Thyroid hormonal supplementation may provide a modest additional benefit in septic animals.

Crit Care Med, 1996 May, 24(5), 820 - 6
Granulocyte colony-stimulating factor improves survival rate and reduces concentrations of bacteria, endotoxin, tumor necrosis factor, and endothelin-1 in fulminant intra-abdominal sepsis in rats; Lundblad R et al.; OBJECTIVE: To study the therapeutic effect of granulocyte colony-stimulating factor (G-CSF) on the mortality rate and host defense pattern in fulminant intra-abdominal sepsis . DESIGN: Prospective, randomized, controlled trial . SETTING: Research laboratory in a university hospital . SUBJECTS: Adult male Wistar rats . INTERVENTIONS: Fulminant polymicrobial intra-abdominal sepsis was induced by a 4-mm cecal perforation . Survival experiments were performed with two different doses of G-CSF (20 and 100 microg/kg/24 hrs), and therapy was started 7 days or 1 day before, or 4 hrs after sepsis induction (n = 24) . To examine alterations in host response pattern, G-CSF (20 microg/kg/24 hrs) was given at sepsis induction, and rats were killed 4, 8, 12 and 24 hrs later (n = 8-16 per time period) . Histologic examination of lung, liver, spleen, and kidney was performed, and blood concentrations of bacteria, endotoxin, tumor necrosis factor (TNF), endothelin-1, packed cell volume, and lactate were determined . MEASUREMENTS AND MAIN RESULTS: G-CSF (20 microg/kg/24 hrs), given 4 hrs after sepsis induction, reduced the mortality rate from 96% to 42% . Increasing the dose (100 micrograms/kg/24 hrs), or giving G-CSF as prophylaxis (starting 7 days or 1 day before sepsis), gave no further protection . G-CSF attenuated the sepsis-induced enhancement of circulating bacteria, endotoxin, TNF, and endothelin-1, resulting in improved fluid balance and reduced lactate concentration . No histopathologic alterations were observed after G-CSF treatment . CONCLUSIONS: G-CSF improves host defense and survival rate in experimentally induced fulminant intra-abdominal sepsis . Clearance of bacteria and endotoxin is improved, concentrations of TNF and endothelin-1 are suppressed, and microvascular flow is improved . G-CSF does not induce neutrophil-mediated tissue damage.

Crit Care Med, 1996 May, 24(5), 765 - 70
High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan; Zwaveling JH et al.; OBJECTIVES: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreatment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma . To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity . SETTING: A 12-bed surgical intensive care unit (ICU) in a university referral hospital . DESIGN: Prospective, descriptive study . PATIENTS: Consecutive patients (n=25) treated with hyperthermic isolated limb perfusion . INTERVENTIONS: Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha . Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter . MEASUREMENTS AND MAIN RESULTS: All patients developed features of sepsis syndrome and required intensive care treatment . Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25) . Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs . Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days . Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p < .01), cardiac index (p < .02), Lung Injury Score (p < .02), prothrombin time (p < .02), and activated partial thromboplastin time (p < .05) . CONCLUSIONS: Hyperthermic isolated limb perfusion with recombinant TNF-alpha leads to high systemic concentrations of TNF-alpha, probably due to leakage of recombinant TNF-alpha from the perfusion circuit, mainly through collateral blood flow . A sepsis-like syndrome is seen in all patients . Despite high concentrations of systemic TNF-alpha, this sepsis syndrome is short-lived and recovery is rapid and complete in most patients.

World J Surg, 1996 May, 20(4), 487 - 92
Animal models as the basis of pharmacologic intervention in trauma and sepsis patients; Redl H et al.; With limited resources and the current concerns about using animals for research purposes, the needs must be clear when setting up trauma and sepsis experiments for pharmacologic interventions . Such interventions are performed typically for four reasons: (1) to study the pathophysiologic role of certain mediators (which can be influenced by pharmacologic agents); (2) to study the therapeutic efficacy of treatment strategies; (3) to study the overall safety of new drugs under trauma/sepsis conditions, which are adjunct studies to standard toxicology; (4) to test new diagnostic procedures in a defined trauma or sepsis setting . Intervention in the inflammatory response may be performed at several levels: (1) at the primary induction site (e.g., by antilipopolysaccharide or by preventing complement activation); (2) at the intermediate mediator level (e.g., by antitumor necrosis factor); (3) at the final mediator level (e.g . , by block of polymorphonuclear neutrophil elastase, and (4) at the target (e.g., by membrane stabilization or enhanced antioxidant defense).

World J Surg, 1996 May, 20(4), 460 - 4
Metabolism of sepsis and multiple organ failure; Michie HR; "Septic autocannabalism" been coined to describe the metabolic response that follows severe sepsis in humans . The normal protein- and energy-conserving mechanisms evoked during simple starvation are not observed following the onset of sepsis . The metabolic response to sepsis entails rapid breakdown of the body's reserves of protein, carbohydrate, and fat . Hyperglycemia with insulin resistance, profound negative nitrogen balance, and diversion of protein from skeletal muscle to splanchnic tissues are prominent features . These responses are believed to be mediated in large part by inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6 . Secondary induction of catecholamines, cortisol, and glucagon by cytokines is likely to be another important effector mechanism . Infection and inflammation elicit a complex network of interwoven responses, and no single mediator alone accounts for the responses observed . Sepsis also commonly involves alterations in cardiovascular function with altered flow to key metabolic sites, hypoxia, damage to the gut's mucosal barrier, secondary organ failure, and alterations in capillary permeability . These structural and functional alterations also strongly influence the metabolic profile during infection . If these catabolic responses persist for more than a few days, severe malnutrition results and is likely to be an important risk factor for mortality in these patients . The altered metabolic milieu during sepsis prevents effective use of exogeneously delivered glucose and protein; at best, administration of these agents ameliorates but does not prevent the persistence of catabolism . Delivery of agents that antagonize cytokines and other moieties such as glutamine and growth hormone may, in the future, help to restore nitrogen balance during sepsis.

World J Surg, 1996 May, 20(4), 386 - 91
Sepsis, SIRS, and MODS: what's in a name?
Nathens AB, Marshall JC.
Progress in the care of the critically ill patient with life-threatening infection has been hampered by inconsistent, often confusing terminology . The clinical syndrome of sepsis-familiar to all yet definable by none-describes a highly heterogeneous group of disorders with different causes and differing prognoses . The imminent availability of mediator-directed therapy has created a sense of urgency to develop better methods for delineating discrete clinical syndromes and to modulate the host response, which may bring both benefit and harm, depending on the clinical circumstances . The term systemic inflammatory response syndrome (SIRS) was introduced several years ago to describe the familiar clinical syndrome of sepsis, independent of its cause . SIRS can result from trauma, pancreatitis, drug reactions, autoimmune disease, and a host of other disorders; when it arises in response to infection, sepsis is said to be present . SIRS describes a dynamic process that has adaptive survival value for the host . The maladaptive consequence of this process in the critically ill patient is the development of progressive but potentially reversible remote organ dysfunction-the multiple organ dysfunction syndrome . The development of cogent conceptual frameworks for classification of the septic response in critically ill patients is more than a question of linguistic pedantry . Optimal therapy presupposes identification of an homogeneous patient population with a characteristic disease process and a predictable response to an intervention . Although progress has been made in identifying such groups of critically ill patients, the disappointing results of clinical trials of agents that so clearly demonstrate efficacy in animal models indicates that considerable work remains.

Am J Respir Crit Care Med, 1996 May, 153(5), 1577 - 84
Sepsis depresses the metabolic oxygen reserve of the coronary circulation in mature sheep; Bloos FM et al.; This study was undertaken to describe the metabolic O2 reserve of the coronary circulation in an awake sheep model of hyperdynamic sepsis . Forty-eight hours after sheep were randomized to either a SHAM group (n = 8) or a cecal ligation and perforation (CLP) group (n = 8), we measured hemodynamics, organ blood flows, and systemic and myocardial O2 metabolism variables at baseline and through four stages of progressive hypoxia . A significant elevation in arterial lactate levels occurred at a higher O2 delivery in the CLP group (527 +/- 55 ml/min/m2) than in the SHAM group (357 +/- 29 ml/min/m2, p < 0.05) . The heart's metabolic O2 reserve (difference in circulatory determinants of O2 availability between baseline and where O2 uptake could not be sustained) was exhausted at an O2 content of 56.9 +/- 4.2 ml O2/L in SHAM sheep and 79.6 +/- 7.2 ml O2/L (p < 0.05) in CLP sheep . An increase in coronary blood flow was three times greater in SHAM than in CLP animals . Myocardial O2 extraction increased in hypoxia in SHAM sheep (0.78 +/- 0.03 to 0.88 +/- 0.02, p < 0.05), but not in CLP sheep (0.79 +/- 0.02 to 0.80 +/- 0.04) . We conclude that the metabolic O2 reserve of the coronary circulation is depressed in this model of hyperdynamic sepsis as the ability to increase both coronary blood flows and myocardial O2 extraction was significantly limited.

Clin Exp Immunol, 1996 May, 104 Suppl 1, 83 - 90
Supplemental immune globulins in sepsis: a critical appraisal; Werdan K et al.; For 'the total population of patients with sepsis, sepsis syndrome or SIRS', the question of whether intravenous immune globulin (IVIG) reduces mortality is neither proved nor disproved . For the sepsis subgroups 'postoperative sepsis with a sepsis score more than 19' and 'endotoxaemic, early septic shock', a significant reduction in mortality by IVIG has been documented in a single, placebo-controlled, small trial of each subgroup; subsequent studies are needed for confirmation . The incidence of some severe infections in defined 'patients at risk' and 'operations at risk' is lowered by IVIG prophylaxis . Postoperative APACHE II-score identification of high-risk cardiac surgery patients prone to sepsis and severe SIRS may represent one approach to optimize individual, early therapy . Applying this concept to immune globulin treatment in a pilot study, the administration of IgG-IVIG and IgGMA-IVIG yielded similar results.

J Trauma, 1996 May, 40(5), 694 - 700; discussion 701-1
Inhibition of the biologic activity of tumor necrosis factor maintains vascular endothelial cell function during hyperdynamic sepsis; Wang P et al.; BACKGROUND AND OBJECTIVE: Although vascular endothelial cell function (i.e., the release of endothelium-derived nitric oxide) decreases and plasma tumor necrosis factor (TNF) increases during sepsis, it is not known whether the elevated TNF is responsible for the depression of endothelial cell function under such conditions . The aim of this study, therefore, was to determine if inhibition of TNF biologic activity by polyethylene glycol dimerized conjugate of the recombinant human form of the p55 soluble TNF receptor (PEG-(rsTNF-R1)2) maintains endothelial function during sepsis . DESIGN, MATERIALS AND METHODS: Rats were subjected to sepsis by cecal ligation and puncture (CLP) . Immediately before the onset of sepsis, 600 microgram/rat PEG-(rsTNF-R1)2 or an equal volume of saline was infused intravenously . At 10 hours after CLP (i.e., hyperdynamic sepsis), the thoracic aorta was isolated, cut into rings, and placed in organ chambers . Dose responses for an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerine (NTG), were determined . Endothelial cell structure was examined by transmission electron microscopy . RESULTS: Endothelium-dependent vascular relaxation was depressed at 10 hours after the onset of sepsis . Administration of PEG-(rsTNF-R1)2 before CLP, however, maintained ACh-induced relaxation . In contrast, no significant difference in NTG-induced relaxation was seen, irrespective of administration of PEG-(rsTNF-R1)2 Furthermore, the deterioration in endothelial structure during sepsis was prevented by PEG-(rsTNF-R1)2 pretreatment . CONCLUSION: Since administration of PEG-(rsTNF-R1)2 maintains vascular endothelial cell structure and function, it can be concluded that TNF plays a pivotal role in producing endothelial dysfunction during sepsis . Thus, pharmacologic agents that inhibit TNF biologic activity and/or its production may be useful for protecting endothelial cells during sepsis.

Blood, 1996 Apr 15, 87(8), 3282 - 8
Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome; Pruitt JH et al.; Plasma interleukin-1 (IL-1) activity is modulated in part through the simultaneous appearance of several inhibitors of IL-1 action, including interleukin-1 receptor antagonist (IL-1ra) and the soluble IL-1 type II receptor (IL-1RII) . However, little is known concerning the plasma appearance of these inhibitors in patients following operative trauma or those with sepsis syndrome . In the present report, plasma IL-1beta, IL-1ra, and soluble IL-1RI and IL-1RII concentrations were evaluated in 118 patients with sepsis syndrome or after elective operative trauma . Plasma concentrations of IL-1ra increased significantly following elective operative repair of thoraco-abdominal and abdominal aortic aneurysms, and after bowel resection for inflammatory bowel disease, but did not increase after laparoscopic cholecystectomy . Plasma IL-1ra levels were also elevated in patients with sepsis syndrome . In contrast, soluble IL-1RII levels were only increased in patients after operative repair of thoraco-abdominal aortic aneurysms and in sepsis syndrome, whereas concentrations were unaffected by the other more modest surgical procedures . Plasma IL-1RI concentrations decreased in all postoperative patients in the first 24 hours after surgery . We conclude that both plasma IL-1ra and soluble IL-1RII concentrations often increase in sepsis and following some operative trauma . Less severe operative trauma increases the plasma concentration of only IL-1ra, whereas both IL-1ra and soluble IL-1RII are increased in patients with sepsis syndrome or following thoraco-abdominal aneurysm repair.

Am J Physiol, 1996 Apr, 270(4 Pt 1), E621 - 6
Prevention of skeletal muscle catabolism in sepsis does not impair visceral protein metabolism; Cooney RN et al.; We investigated whether the preservation of gastrocnemius proteins by interleukin-1 receptor antagonist (IL-1ra) during sepsis altered protein metabolism in visceral tissues . Sepsis was induced by creation of an abdominal abscess followed by infusion of saline of IL-1ra . Five days later, the tissue protein content and rate of protein synthesis were measured . IL-1ra did not significantly alter hepatic protein metabolism in septic or control animals . In kidney, the protein content and rate of protein synthesis were both decreased by sepsis and significantly ameliorated by the infusion of IL-1ra . Sepsis decreased the rate of protein synthesis in the small intestine . IL-1ra increased intestinal protein synthesis in both control and septic animals; however, the effects were localized to the seromuscular layer . The preservation of muscle protein by IL-1ra in sepsis did not adversely affect protein synthesis in any of the visceral tissues examined . IL-1 appears to mediate the sepsis-induced changes in protein synthesis in kidney and small intestine but not in liver or spleen . Protein synthesis in each visceral organ responds differently to the septic insult and modulation of IL-1 bioactivity.

Eur J Pediatr, 1996 Apr, 155(4), 315 - 22
Risk factors for nosocomial sepsis in newborn intensive and intermediate care units; Moro ML et al.; A multicentre prospective study was performed to estimate the incidence of hospital infections and to identify the most relevant risk factors for sepsis in a large and unselected population of high-risk newborns . The study involved 49 neonatal intensive care units and 17 neonatal intermediate care units in Italy . Newborns were followed up from admittance to the units until discharge . Data on demographics and clinical characteristics, exposure to the principal invasive procedures, and onset of infectious complications were prospectively collected . Only infections developing after 48 h from admittance to the unit were recorded . A multiple logistic regression was performed to identify which factors were independently associated with sepsis . Among the 8263 newborns included in the analysis, the incidence of infected newborns was 14.4 per 100 newborns and 0.9/100 days of stay . The incidence of infections was 19.1/100 newborns and 1.2/100 days of stay . Sepsis represented 15.4% of all infections (incidence 2.9/100 newborns and 0.2/100 days of stay) . The following factors were independently associated with sepsis: umbilical catheterization, both through the vein and the artery for more than 5 days; mechanical ventilation for more than 5 days; necrotizing enterocolitis; birth weight equal to or less than 2500 g; nasogastric tube; total parenteral nutrition; and transfer from other hospitals . Umbilical catheters accounted for the highest proportion of sepsis (62%), followed by arterial catheters (31%), nasopharyngeal cannulae (26%), tracheal cannulae (20%), and nasal cannulae (20%) . The population attributable risk for the other procedures was less than 10% . Conclusion: This study demonstrates that in a large and unselected newborn population, several host factors and invasive procedures are independently associated with an increased risk of sepsis . After adjustment for clinical severity, intravascular catheterization and assisted ventilation were found to be responsible for a considerable proportion of observed sepsis . They should therefore be considered as priorities for interventions, aimed both at reducing unnecessary use and promoting more strict compliance with aseptic practices.

Neonatal Netw, 1996 Apr, 15(3), 15 - 28
Percutaneous central venous catheter-related sepsis in the neonate: an analysis of the literature from 1990 to 1994; Trotter CW; Percutaneous central venous catheters (PCVCs) have been used in neonates since the 1970s . During the 1980s, they were introduced in many NICUs . Most studies published to date employ a descriptive methodology . There are very few randomized clinical trials with PCVCs in neonates, and no integrated literature reviews have been published to date . Furthermore, infection in neonates with PCVCs has become a major concern . This integrated literature review was conducted to delineate the scope of the problem of sepsis in neonates with central venous catheters and to identify current research directed at methods to reduce catheter-related sepsis (CRS) in high-risk neonates . Twenty-five references were found and analyzed for this review . The definitions used to identify CRS in neonates varied greatly among studies . The method of calculating the CRS rate varied as well . The CRS rates ranged from 0 to 29 percent or from 0 to 15.3 infections per 1,000 catheter days . Strategies employed to reduce CRS rates are presented along with recommendations for future research.

Anaesthesist, 1996 Apr, 45(4), 312 - 22
{The physiopathology of sepsis . Current concepts}; Bauer M; Clinical manifestations of sepsis, such as systemic inflammatory response and multiple organ dysfunction syndrome, are considered to be the results of a decompensated host defense response . If tissue injury is sufficiently severe to overwhelm local defense mechanisms, systemic activation of these essentially protective mechanisms may lead to autodestructive "host defense failure disease." This is not always caused by invading bacteria; sterile inflammation such as results from multiple trauma or pancreatitis can initiate a similar response . Evidence suggests that the activation of the macrophage/monocyte system that underlies the systemic inflammatory response may reflect one facet of a more generalized dysregulation of intercellular communication, as well as a dysfunction of such subcellular processes as signal transduction or stress gene expression . Alterations in signal transduction or stress gene expression can affect the host defense response to subsequent stressful events in either a negative or a positive sense . In particular, the sequential induction of acute phase and heat shock response may initiate programmed cell death, reflecting a potential molecular mechanism for the development of multiple organ dysfunction syndrome . The development of anti-inflammatory treatment strategies seems to be hampered by the discrepancy between locally protective and systemically detrimental properties of the host defense response.

Br J Surg, 1996 Apr, 83(4), 535 - 9
Laparotomy for abdominal sepsis in the critically ill; Anderson ID et al.; Among 125 patients admitted to an intensive care unit (ICU) with severe abdominal sepsis over a 3-year period, further laparotomy was required in 60 (48 per cent) . The median age of these 60 patients was 67 (range 22-88) years and their admission APACHE (Acute Physiology and Chronic Health Evaluation) II score was 24 (range 7-40); 25 patients (42 per cent) survived to leave the ICU but only 19 (32 per cent) survived to leave hospital . These patients underwent 95 (median 1; range 1-6) operations after admission to the ICU and survival fell with increasing number of operations in the ICU (P = 0.01) . A total of 81 operations (85 per cent) were therapeutic in that pus was drained or dead tissue removed, and 41 operations (43 per cent) resulted in improvement in the patient's condition within 48 h of surgery . Only nine per cent of patients not improved by their first operation in the ICU survived (P < 0.0001) . The source of sepsis was eradicated from the abdomen in 37 patients (62 per cent); this was a prerequisite for survival but was achieved less frequently with increasing number of operations (P < 0.002) . When operations were delayed until the diagnosis was clear, the need for subsequent procedures was significantly increased (P < 0.05) . Multiple operations for patients with abdominal sepsis in the ICU were associated with diminishing returns and alternative surgical strategies merit active consideration.

J Clin Endocrinol Metab, 1996 Apr, 81(4), 1449 - 53
Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis; Hirata Y et al.; Human adrenomedullin (hAM), a potent vasodilatory peptide originally identified in pheochromocytoma, has been shown to be present in various human tissues and circulate in human plasma . We measured plasma concentrations of immunoreactive hAM in patients with sepsis who had been admitted to intensive care unit (ICU) . Plasma hAM concentrations in 12 septic patients upon entering the ICU were extremely elevated (107 +/- 139 fmol/ml: mean +/- SD) compared to those of 16 age-matched normal subjects (7.9 +/- 3 fmol/mL) . Among 10 patients with normal renal function, plasma hAM levels either decreased or increased during the hospital course; the former group survived and the latter group succumbed . Two patients with acute renal failure had markedly elevated plasma hAM levels during the early course, which declined rapidly during the recovery course . High performance liquid chromatography of plasma extracts from one patient with acute renal failure revealed a single major component of immunoreactive hAM coeluting with authentic hAM (1-52) during acute and recovery phase . Plasma hAM concentration showed positive correlations with heart rate, right atrial pressure, and serum creatinine concentration, but not with other hemodynamic variables . These data suggest that a marked increase in circulating hAM in sepsis may be caused by its decreased clearance and/or its enhanced synthesis by multiple organ dysfunction, and that increased endogenous hAM may be involved in the mechanism of cardiovascular abnormalities associated with sepsis.

Chest, 1996 Apr, 109(4), 1033 - 7
Epidemiology of sepsis and multiple organ dysfunction syndrome in children; Proulx F et al.; STUDY OBJECTIVES: To determine the cumulated incidence and the density of incidence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) in critically ill children; to distinguish patients with primary from those with secondary MODS . DESIGN: Prospective cohort study . SETTING: Pediatric ICU of a university hospital . PATIENTS: One thousand fifty-eight consecutive hospital admissions . INTERVENTIONS: None . MEASUREMENTS AND RESULTS: SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died . The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9 +/- 3.6 (no SIRS), 7.0 +/- 7.0 (SIRS), 9.5 +/- 8.3 (sepsis), 8.8 +/- 7.8 (severe sepsis), 21.8 +/- 15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis . The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups) . Among, patients with MODS, the difference in mortality between groups did not reach significance (p=0.057) . Children with secondary MODS had a longer duration of organ dysfunction (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 {2.7 to 15.9}, p<0.0001) than patients with primary MODS . CONCLUSIONS: SIRS and sepsis occur frequently in critically ill children . The presence of SIRS, sepsis, or septic shock is associated with a distinct risk of mortality among critically ill children admitted to the pediatric ICU; more data are needed concerning children with MODS . Secondary MODS is much less common than primary MODS, but it is associated with an increased morbidity and mortality; we speculate that distinct pathophysiologic mechanisms are involved in these two conditions.

Arch Surg, 1996 Apr, 131(4), 434 - 7
Monocyte tumor necrosis factor receptor levels as a predictor of risk in human sepsis; Calvano SE et al.; OBJECTIVE: To assess peripheral blood monocyte tumor necrosis factor receptor (TNFR) levels and plasma soluble tumor necrosis factor receptor (sTNFR) concentrations in critically ill patients with sepsis syndrome . DESIGN: Prospective, descriptive cohort study with no interventions . SETTING: Surgical intensive care unit of a tertiary-care hospital associated with a university medical school . PATIENTS: Twenty-one patients with a documented source of infection who met currently accepted criteria for sepsis syndrome/septic shock . MAIN OUTCOME MEASURES: Plasma sTNFR p55 and p75 values were quantified by enzyme-linked immunosorbent assay, and monocyte TNFR levels were assessed by fluorescence flow cytometry after the monocytes were stained with biotinylated human recombinant TNF-alpha and streptavidin-phycoerythrin . RESULTS: Compared with healthy controls, plasma sTNFR p55 and p75 values were significantly higher (P <.01) in both surviving and nonsurviving patients with sepsis; in nonsurviving patients with sepsis, however, only sTNFR p55 values were significantly (P < .05) higher than in surviving patients with sepsis . By contrast, monocytes from the nonsurviving patients with sepsis manifested a significant (P < .01) and sustained (up to 4 days) decrease in cell surface TNFR values compared with either the normal controls or the surviving patients with sepsis . CONCLUSIONS: Assessment of monocyte surface TNFR values may provide a rapid prognostic indicator for patients with sepsis who are at increased risk of death.

J Trauma, 1996 Apr, 40(4), 613 - 6; discussion 616-7
Interleukin-10 is associated with the development of sepsis in trauma patients; Sherry RM et al.; Interleukin-10 (IL-10) is a potent regulator of proinflammatory cytokines, including tumor necrosis factor-alpha, IL-1, IL-6, and interferon-gamma . We retrospectively evaluated 66 severely injured patients for detectable plasma IL-10 . the presence or absence of IL-10 was correlated with clinical parameters . Forty of 66 patients had detectable levels of IL-10 . Plasma IL-10 was associated with admission hypotension (p < 0.01) and the development of sepsis (p < 0.05) . There was no difference between IL-10-positive and -negative patients with respect to age, mechanism or severity of injury, blood transfusion, operative interventions, or the subsequent development of ARDS, hepatic dysfunction, or renal insufficiency . We conclude that IL-10 can be detected in the plasma of some severely injured patients and that it is associated with the development of sepsis . Further investigation of the immunoregulatory effects of IL-10 after trauma is indicated.

J Trauma, 1996 Apr, 40(4), 568 - 73; discussion 573-4
Is sepsis-induced apoptosis associated with macrophage dysfunction?
Ayala A, Urbanich MA, Herdon CD, Chaudry IH.
Apoptosis (A O) is a pathological process by which cells undergo a form of inducible nonnecrotic cellular suicide . In vitro studies suggest that changes in the rate of macrophage (Mo) A O may be associated with elevated proinflammatory cytokine secretory capacity, such as interleukin-1 beta (IL-1 beta) (via IL-1 converting enzyme activation) . Furthermore, it has been reported that Mo are activated during early (0-4 hours) experimental septic insult to act as sources of proinflammatory cytokines, such as IL-1 . However, with the progression of sepsis, these same cells become refractory to further stimulation (appearing dysfunctional) . Nonetheless, it remains unknown if this acquired immunosuppression (dysfunction) is associated with an acceleration in macrophage A O . To determine this, male C3H/HeN mice were subjected to sepsis (cecal ligation and puncture, CLP) or sham-CLP and 4 or 24 hours thereafter Mo were isolated from the peritoneum (PMo) and liver (KMo) . Macrophage monolayers were lysed either after stimulation with lipopolysaccharide (LPS) (10 microgram/mL, 24 hours) in vitro or immediately (ex vivo) before LPS stimulation and the cytoplasmic cell fraction was retained . The extent of A O was determined using a cell-death enzyme-linked immunosorbent assay, which detects the presence of cytoplasmic oligonucleosomes and changes in the propidium iodide staining intensity . The results indicate that, early after CLP (4 hours) only PMo stimulated with LPS in vitro showed evidence of increasing A O . At 24 hours (late) after the onset of sepsis, the ex vivo extent of A O in PMo was increased but it was decreased in KMo . However, the addition of LPS in vitro results in a marked increase in both septic PMo and KMo A O . This latter result suggests that the inability of Mo to release cytokines in response to stiumulants, such as LPS during late sesis (24 hours), may be because of induciton of accelerated A O in these Mo populations.

Crit Care Med, 1996 Apr, 24(4), 596 - 600
Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor-p55 concentrations; Pilz G et al.; OBJECTIVE: To investigate the prognostic value of increased serum concentrations of soluble tumor necrosis factor (TNF) receptors in patients at high risk for sepsis . DESIGN: Prospective study . SETTING: Cardiac surgical intensive care unit in a University Hospital . PATIENTS: Those 27 of 870 consecutive postcardiac surgical patients who met a previously validated high-risk criterion for imminent sepsis (Acute Physiology and Chronic Health Evaluation II {APACHE II} score of > or = 24 on the first postoperative day {day 1}) . In this population, systemic inflammatory response syndrome was present in 96% of the patients and the in-hospital mortality rate was 30% . In addition, ten postcardiac surgical patients with an uncomplicated course (mortality rate 0%) were studied for comparison . INTERVENTIONS: Blood sampling for measurements of serum concentrations of TNF and soluble TNF receptors 55 kilodalton (TNF receptor-p55) and 75 kilodalton (TNF receptor-p75) on days 1, 2, 3, and 5 . MEASUREMENTS AND MAIN RESULTS: Compared with the ten patients with an uncomplicated course (group A), the high-risk patients had significantly higher baseline (day 1) serum concentrations of soluble TNF receptor-p55 (9.2 vs . 4.2 ng/mL) and soluble TNF receptor-p75 (9.2 vs . 5.5 ng/mL) . These high-risk patients could be further differentiated into two subgroups: one (B) with a prompt decrease in APACHE II score and a good prognosis (mortality rate 0%) and another (C) with a persisting high risk of sepsis and mortality rate (40%, p < .05) . Although baseline APACHE II score was similar in both high-risk subgroups, soluble TNF receptor-p55 concentrations were significantly higher in subgroup C compared with subgroup B already at baseline (10.7 vs . 4.7 ng/mL) . The receiver operating characteristic curve for subgroup classification by soluble TNF receptor-p55 was in a discriminating position with an area (0.773 +/- 0.096), confirming soluble TNF receptor-p55 as a predictor of mortality . TNF and soluble TNF receptor-p75 concentrations were less predictive at baseline . CONCLUSIONS: This study suggest that increased soluble TNF receptor-p55 concentrations in the serum of postcardiac surgical patients allow earlier prognostication of subsequent hospital course than APACHE II scores alone . This study further suggests that the combination of physiologic scores and cytokine receptor measurements could improve the predictive power of early postoperative risk stratification.

J Clin Invest, 1996 Apr 1, 97(7), 1610 - 7
Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways; Voisin L et al.; We studied the alterations in skeletal muscle protein breakdown in long lasting sepsis using a rat model that reproduces a sustained and reversible catabolic state, as observed in humans . Rats were injected intravenously with live Escherichia coli; control rats were pair-fed to the intake of infected rats . Rats were studied in an acute septic phase (day 2 postinfection), in a chronic septic phase (day 6), and in a late septic phase (day 10) . The importance of the lysosomal, Ca2+ -dependent, and ubiquitin-proteasome proteolytic processes was investigated using proteolytic inhibitors in incubated epitrochlearis muscles and by measuring mRNA levels for critical components of these pathways . Protein breakdown was elevated during the acute and chronic septic phases (when significant muscle wasting occurred) and returned to control values in the late septic phase (when wasting was stopped) . A nonlysosomal and Ca2+ -independent process accounted for the enhanced proteolysis, and only mRNA levels for ubiquitin and subunits of the 20 S proteasome, the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates, paralleled the increased and decreased rates of proteolysis throughout . However, increased mRNA levels for the 14-kD ubiquitin conjugating enzyme E2, involved in substrate ubiquitylation, and for cathepsin B and m-calpain were observed in chronic sepsis . These data clearly support a major role for the ubiquitin-proteasome dependent proteolytic process during sepsis but also suggest that the activation of lysosomal and Ca2+ -dependent proteolysis may be important in the chronic phase.

Clin Perform Qual Health Care, 1996 Apr-Jun, 4(2), 96 - 103
Predicting survival of patients with sepsis by use of regression and neural network models; Flanagan JR et al.; OBJECTIVES: (1) To predict at the time of diagnosis of sepsis the subsequent occurrence of multiple organ failure and patient death; and (2) to compare the prediction accuracies of standard multiple logistic regression (MLR) and neural network (NN) models . METHODS: The data were collected during a 5-year period for all patients (n=173) who met prospectively determined criteria for sepsis and had positive blood culture results while admitted in the surgical intensive care unit at the University Hospital of Geneva, Switzerland . These data formed the basis for a retrospective cohort study described elsewhere . The MLR model was adapted from existing data . An NN model of the feed-forward, back-propagation type was constructed for predicting the outcome of sepsis with bloodstream infection . Both models were constructed from randomly chosen subsets of patients and subsequently were evaluated on the remaining (independent) patients . RESULTS: Survival after sepsis was predicted with an accuracy of 80% by the NN model, which used only information collected at the time of the diagnosis of sepsis . The development of multiple organ failure after the diagnosis of sepsis was predicted accurately (81.5%) with either the MLR or the NN model . Both the MLR and the NN methods depended on the interpretation of a likelihood quantity, requiring the choice of a threshold to make a survival prediction . The accuracy of the MLR models was very sensitive to the threshold value . The accuracy of the NN models was not sensitive to the choice of threshold, because they generated likelihood predictions that were distributed far from the middle range where the threshold was placed . CONCLUSION: Compared with MLR models, the NN models were slightly more accurate and much less sensitive to the arbitrary threshold parameter.

Eur J Clin Invest, 1996 Mar, 26(3), 224 - 30
Elevated serum neopterin level: its relation to endotoxaemia and sepsis in patients with major burns; Yao YM et al.; The present study was conducted to determine the relationship between levels of neopterin and endotoxin in the circulation, and whether the neopterin level was related to the development of severe sepsis after extensive burns . This prospective study included 35 patients with burn size greater than 30% (30-98%), and 22 healthy volunteers who served as a comparison group . Neopterin levels increased in most patients on day 3 post-burn, but they were not significantly correlated with the extent of the burn surface (P > 0 center dot 05) . A high serum neopterin level was found in patients with sepsis (n = 15), and a marked elevation persisted throughout the observation period . The difference between septic and non-septic patients (n = 20) became significant on 14 and 28 days post-burn . Although the presence of early endotoxaemia did not influence the alterations in serum neopterin, patients with endotoxaemia had much higher neopterin values than those who showed no endotoxaemia from the second week onward (P < 0 center dot 05-0 center dot 01) . In addition, circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxaemia on day 14 (r = 0 center dot 368, P < 0 center dot 05) and day 21 (r = 0 center dot 439, P < 0 center dot 01) after major burns . These results suggest that thermal injury can lead to an elevation of serum neopterin independent of the burn surface area . The initial increase in the neopterin level may be a part of the acute-phase response to tissue injury itself, whereas the endotoxin release in the circulation may be responsible for the continuous induction of neopterin during the late stage . In addition, the presence of a constant high neopterin level is associated with a critical event in the development of severe burn sepsis.

J Crit Care, 1996 Mar, 11(1), 2 - 8
Pulmonary lactate release in patients with sepsis and the adult respiratory distress syndrome; Brown SD et al.; PURPOSE: Elevated arterial lactate concentrations in patients with sepsis have been interpreted as evidence of peripheral, nonpulmonary tissue hypoxia . These patients often develop pulmonary failure manifested by the acute respiratory distress syndrome (ARDS) . As the result of tissue hypoxia or inflammation, the lungs of patients with sepsis and ARDS may become a source of lactate release into the circulation . MATERIALS AND METHODS: Pulmonary lactate release was measured in 19 patients with sepsis, arterial lactate > or = 2.2 mm, and gastric mucosal pH > 7.30 . A normal gastric mucosal pH served as a marker of adequate splanchnic oxygenation . Pulmonary lactate release was computed as the product of the cardiac index and the difference in plasma L-lactate concentration in simultaneously obtained arterial and mixed venous blood samples . Lung injury was graded with the Lung Injury Score using radiographic and physiologic data . RESULTS: The lungs of patients with minimal or no lung injury (lung injury score <1) produced significantly less lactate than those with moderate or severe lung injury (lung injury score > or = 1) (P < .005) . The Lung Injury Score correlated with pulmonary lactate release (r2 = .73; P < .0001) . This relationship resulted primarily from increases in mixed venous-arterial lactate differences (r2 = .59) . The Lung Injury Score correlated weakly with the cardiac index (r2 = .32) . Arterial lactate concentration did not correlate with pulmonary lactate release, systemic oxygen transport, or systemic oxygen consumption . CONCLUSIONS: The lungs of patients with sepsis and ARDS may produce lactate . Pulmonary lactate release correlates with the severity of lung injury . The contribution of pulmonary lactate release should be considered when interpreting arterial lactate concentration as an index of systemic hypoxia.

Cytokine, 1996 Mar, 8(3), 260 - 5
Filgrastim (RHG-CSF) related modulation of the inflammatory response in patients at risk of sepsis or with sepsis; Weiss M et al.; Over a period of 14 days a longitudinal analysis was performed on the effects of filgrastim (recombinant human granulocyte colony stimulating factor, rhG-CSF) administered to 20 postoperative/posttraumatic patients at risk of or with sepsis . The following parameters were determined: leukocyte counts, serum cytokine levels and the surface expression of functional antigens and adhesion molecules . Filgrastim (1 mu g/kg.day) was infused continuously on the first 3 days and tapered to 0.5 mu g/kg.day on the following 4 days or until discharge from the surgical intensive care unit . During infusion of filgrastim, G-CSF levels increased in 16 out of the 20 patients within 48 h . In these 16 patients, leukocyte counts increased in 15 out of 16 patients . Expression of CD64 was upregulated within 24 h . The expression of CD32 was upregulated in 8 out of 9 patients with an initial expression < 55% . LAM-1 expression was downregulated in all patients revealing an initial expression of LAM-1 > 40% . Soluble ICAM increased in 9 out of 11 patients . IL-8 decreased in all 6 patients presenting initial values of IL-8 > 90 pg/ml . IL-1RA increased in 10 patients . Filgrastim had no effect on the expression of CD14, CD16 and CD34 and on the levels of TNF-alpha and sTNF-R type I (p55) . In conclusion, infusion of filgrastim in postoperative/post traumatic patients at risk of and with sepsis resulted in improved generation and function of neutrophils and appeared to counterregulate hyperactivation of proinflammatory processes.

Res Commun Mol Pathol Pharmacol, 1996 Mar, 91(3), 329 - 38
Changes in adhesion molecule levels in sepsis; Nakae H et al.; We measured the levels of soluble intercellular adhesion molecule-1 (sICAM-1), CD11a, CD11b, CD18, endotoxin, and various inflammatory cytokines to clarify the relationship between adhesive molecules and cytokines in sepsis . We studied 21 patients with sepsis (sepsis group) and 13 patients with trauma not complicated by infection (trauma group) . The mean sICAM-1 level was significantly higher in the sepsis group than in the trauma group . No significant difference was observed in the CD11a, CD11b, and CD18 levels between the two groups . The sICAM-1 levels significantly correlated with the levels of endotoxin, tumor necrosis factor alpha (TNF-alpha), and IL-8, but CD11a, CD11b, and CD18 levels did not correlate with endotoxin or cytokine levels . These findings suggest that ICAM-1 production is induced by endotoxins and cytokines produced in excess by inflammatory reactions and that endotoxins and cytokines are involved in qualitative, but not quantitative changes in LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18).

Minerva Anestesiol, 1996 Mar, 62(3), 89 - 92
{Respiratory failure caused by myopathy in severe sepsis}; Veschi G et al.; OBJECTIVE: To describe a generalized myopathic disorder occurred in the convalescence phase of illness of a critically ill patient . SETTING: Neurological Intensive Care Unit . PATIENT: A 43-year-old man with acute leukoencephalopathy and severe sepsis complicated by sustained and prolonged cardiovascular, respiratory and renal failure . After 15 days of complete respiratory autonomy, the patient presented an acute ventilatory failure associated with generalized muscle weakness . Neither a relapse of sepsis nor neurological worsening were detected . MEASUREMENTS AND RESULTS: Electromyogram resulted in normal conduction velocity in both motor and sensitive nervous fibers . Muscular biopsy showed marked fiber size variability with several hypotrophic fibers type II fiber grouping, several areas of degeneration-necrosis with macrophage invasion, dishomogeneous oxidative enzymatic activity, no increase in glycogen or lipid content . CONCLUSIONS: These results excluded critical illness polyneuropathy and all the other known myopathies . Prolonged period of sepsis with multiple organ failure can result in a direct generalized myopathy . This possibility should be kept in mind while treating long term critically ill survivors.

Infection, 1996 Mar-Apr, 24(2), 162 - 3
Sepsis syndrome induced by tuberculous perforation of the esophagus; Schroder J et al.; Perforation of the esophagus induced by tuberculosis with no evidence of HIV infection is an extremely unusual presentation of the disease . We report on a 41-year-old man presenting with an esophageal perforation who developed a sepsis syndrome characterized by multiple organ dysfunction . The perforation was covered endoscopically with a tube, the patient recovered from cardiovascular, renal and pulmonary dysfunction under intensive care treatment, including antimycobacterial therapy . In response to endoscopic and medical treatment the size of the lesion decreased and disappeared 56 days after diagnosis . The patient could be discharged 2 months after admission and remained asymptomatic after a 12 month follow-up examination.

Infection, 1996 Mar-Apr, 24(2), 103 - 8
Secretory non-pancreatic phopholipase A2 in severe sepsis: relation to endotoxin, cytokines and thromboxane B2; Guidet B et al.; Circulatory secretory non-pancreatic phospholipase A2 (snp-PLA2) was measured prospectively at the onset (day 0) of severe sepsis in 52 patients as well as on day 1 and 2 in 25 patients, in order to answer two questions: 1) does the snp-PLA2 plasma concentration differ according to the type and severity of infection? 2) what is the relation between snp-PLA2 and other mediators involved in severe sepsis, such as endotoxin, cytokines (TNF alpha, IL-1 beta, IL-6) and thromboxane B2 (the stable metabolite of thromboxane A2)? On day 0, the snp-PLA2 circulatory level was 78 +/- 17 nmol/min/ml in patients with severe sepsis as compared to 3.5 +/- 2 nmol/min/ml in 40 healthy volunteers . There was no statistical difference according to the outcome, the presence of shock, or the type of infection on day 0 . However, snp-PLA2 remained elevated or even increased in patients who ultimately died, while it decreased in survivors (p = 0.01 by ANOVA) . The cytokine profiles during the 2-day follow-up were similar to that of snp-PLA2, but the differences were not statistically significant between survivors and non-survivors . No correlation was found between snp-PLA2 and other mediators for either initial or peak values.

Intensive Care Med, 1996 Mar, 22(3), 226 - 9
Elevated serum bleomycin-detectable iron concentrations in patients with sepsis syndrome; Galley HF et al.; OBJECTIVE: To determine serum bleomycin-detectable inverted question markfree' iron in patients with septic shock and to relate these findings to both outcome and a marker of free radical damage . DESIGN: A prospective observational study . SETTING: A nine-bed intensive care unit in a university teaching hospital . PATIENTS: Sixteen consecutive patients with septic shock, defined as: (1) Clinical evidence of acute infection; (2) hypo- or hyperthermia ( < 35.6 degrees or > 38.3 degrees C); (3) tachypnoea ( > 20 breaths/min or ventilated); (4) tachycardia ( > 90 beats min); (5) shock (systolic pressure < 90mmHg) or on inotropes . Fourteen patients also had secondary organ dysfunction . MEASUREMENTS AND RESULTS: Bleomycin-detectable iron concentrations were elevated in all patients (37.2 +/- 11.0 mumols/l vs 5.1 +/- 3.3 mumols/l in healthy subjects, P < 0.0001), but there was no difference between patients who died and those who survived (39.2 +/- 9.3 and 36.2 +/- 12.3 mumols/l, respectively) . Thiobarbituric acid reactive substances (an index of lipid peroxidation) were higher in those who died (3.33 +/- 2.29 mumols/l) than in the surviving patients (0.99 +/- 0.14 mumols/l, P < 0.01) or healthy subjects (0.92 +/- 0.39 mumols/l, P < 0.01) . Free iron did not correlate with thiobarbituric acid-reactive substances . However, a significant correlation was found between lipid peroxidation and clinical severity (APACHE II) score (r = 0.54, P < 0.05) . CONCLUSIONS: The present study provides evidence of lipid peroxidation in patients who die with septic shock . The data suggest that iron-catalysed hydroxyl radical generation does not form an important contribution to this lipid peroxidation in patients with sepsis.

Intensive Care Med, 1996 Mar, 22(3), 213 - 9
Renal effects of low-dose dopamine in patients with sepsis syndrome or septic shock treated with catecholamines; Lherm T et al.; OBJECTIVE: To evaluate the renal effects of low-dose dopamine in patients with sepsis syndrome or septic shock treated with catecholamines . DESIGN: Prospective, clinical study using sequential periods . SETTING: A 12-bed surgical intensive care unit in a university hospital . PATIENTS: 14 patients with sepsis syndrome and 15 patients with septic shock treated with exogenous catecholamines were studied . They had no diuretic treatment . INTERVENTION: Two periods of 2 h each with and without 2 micrograms.kg-1.min-1 of dopamine infusion . Hemodynamic and renal data were obtained at the end of each period . Measurements were repeated after 48 h of dopamine infusion in patients with sepsis syndrome . All data were evaluated by the Wilcoxon rank test . MEASUREMENTS AND RESULTS: In patients with sepsis syndrome, diuresis and creatinine clearance increased significantly by 100% and 60%, respectively, during low-dose dopamine infusion without any change in systemic hemodynamics . The renal response to dopamine decreased significantly after 48 h of dopamine infusion (P < 0.01) . In patients with septic shock treated with catecholamines, no variation of either systemic hemodynamics or renal function was noted during low-dose dopamine infusion . CONCLUSION: The renal effects of low-dose dopamine in patients with sepsis syndrome decrease with time . No renal effect of low-dose dopamine was observed in patients with septic shock treated with catecholamines . These findings suggest a desensitization of renal dopaminergic receptors.

Shock, 1996 Mar, 5(3), 229 - 32
Amrinone prevents the inhibition of muscle pyruvate dehydrogenase complex activity during sepsis; Vary TC; A decreased proportion of active pyruvate dehydrogenase complex (PDH) in skeletal muscle has been implicated as an important factor in elevating plasma lactate concentrations in hypermetabolic sepsis . The mediators of the septic process responsible for the inhibition of PDH complex in muscle are unknown . To assess the role of tumor necrosis factor in mediating the effects of sepsis, the effect of daily injections of amrinone (5 mg/kg/day), which inhibits the release of tumor necrosis factor during sepsis, on the proportion of PDH in the active form (PDHa) was investigated in a model of chronic hypermetabolic sepsis . In skeletal muscle from untreated septic rats, PDHa was decreased 50% . Treatment of septic rats with amrinone for 5 days prevented the sepsis-induced decrease in PDHa . Sepsis caused a 2.5-fold elevation in plasma lactate concentrations . The maintenance of the PDH complex activity at control values following injection of amrinone in septic rats was associated with reduced lactate concentrations in plasma . Thus, amrinone prevented the sepsis-induced abnormalities in skeletal muscle PDH activity and plasma lactate concentrations.

Shock, 1996 Mar, 5(3), 223 - 8
Alterations in coagulation and fibrinolysis during sepsis; Kidokoro A et al.; Circulating levels of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) in 49 septic patients (23 patients with organ dysfunction (OD), 26 without OD) and 11 postgastrectomy patients were measured to determine the significance of the coagulation-fibrinolytic systems in the development of OD . Tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and thrombomodulin were also measured . The mean level of TAT on the day when OD occurred was significantly higher compared with the maximum level of TAT in septic patients without OD (P < .01) or postoperative patients (P < .01) . There was no difference in PIC levels between the three groups . The TAT/PIC ratio was significantly higher in septic patients with OD compared with the other groups (P < .001) . Septic patients with OD showed higher levels of PAI-1 (P < .001) but not of t-PA . Thrombomodulin levels were significantly higher in the septic patients with OD compared with the others (P < .001) . We conclude that suppression of the fibrinolytic system contributes to the imbalance between coagulation and fibrinolysis, and that this hypercoagulable millieu on the endothelial surface leads to the onset of OD.

Crit Care Nurs Clin North Am, 1996 Mar, 8(1), 1 - 6
Sepsis in the elderly; Stanley M; Sepsis in the elderly occurs frequently and carries a high rate of mortality . With increasing numbers of elderly patients being cared for in critical care units, the critical care nurse must have a thorough understanding of the unique aspects of this patient population . Nurses must be prepared to deliver expert nursing care that is knowledge-based and incorporates current research findings . Unit protocols that encompass the preventive measures needed by these special patients will assist in reducing the incidence of sepsis . When sepsis occurs, careful trending of data will signal the need for timely and precise interventions that may result in a good outcome for the elderly patient with sepsis.

Br J Surg, 1996 Mar, 83(3), 396 - 400
Correlation between Acute Physiology and Chronic Health Evaluation (APACHE) III score and immunological parameters in critically ill patients with sepsis; Rogy MA et al.; A relationship between physiological parameters of severe sepsis and immunological function has not been established . In ten severely ill patients with sepsis physiological risk was assessed by the Acute Physiology and Chronic Health Evaluation (APACHE) III score, while one component of immunological function was evaluated using peripheral blood mononuclear cell (PBMC) cytokine production after stimulation with lipopolysaccharide (LPS) in vitro . Five of the ten patients died . Mean (s.e.m.) APACHE III scores at admission were not significantly different between survivors and non-survivors (82(13) versus 95(13)) but after 72 h they were lower in survivors (51(13) versus 111(15), P < 0.05) . Downregulation of cytokine production by PBMC on LPS stimulation was a transient event in survivors . Survivors had a three-fold increase in tumour necrosis factor alpha bioactivity within 72 h, but there was no increase in non-survivors . A similar pattern was demonstrated for interleukin (IL) 1 beta (P < 0.05 between survivors and non-survivors) and IL-6 (P = 0.06) immunoactivity . Physiological as well as immunological parameters in critically ill patients with sepsis independently predicted hospital survival (r2 = 0.2) . These data demonstrate a relationship between the pattern of cytokine production in vitro and survival.

Am J Physiol, 1996 Mar, 270(3 Pt 1), E430 - 7
IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis; Lang CH et al.; The purpose of the present investigation was to determine whether endogenously produced interleukin (IL)-1 mediates the changes in insulin-like growth factor (IGF) I and IGF binding proteins (IGFBP) induced by chronic abdominal sepsis in rats and to correlate the changes in the IGF system with the alternations in protein synthesis . A constant infusion of IL-1 receptor antagonist (IL-1ra) was begun after the induction of sepsis and was continued for 5 days . Sepsis decreased IGF-I levels in the blood, liver, and gastrocnemius muscle, increased the content in the kidney, and did not alter IGF-I levels in heart, jejunum, and spleen . IL-1ra attenuated the sepsis-induced decrease in plasma IGF-I and completely prevented the changes in IGF-I observed in liver, kidney, and the gastrocnemius . IGFBP-1 was increased in the blood, liver, and muscle of septic rats . IL-1ra prevented this increase in IGFBP-1 in blood and liver but not in muscle . The rate of in vivo protein synthesis was decreased in the gastrocnemius and kidney and unaltered in the heart, liver, jejunum, and spleen . A strong linear correlation existed between levels of IGF-I and the rate of protein synthesis determined simultaneously in the gastrocnemius . These results provide evidence for the role of IL-1 as an endogenous mediator of the sepsis-induced changes in IGF-I and IGFBP-1 and suggest that the accompanying changes in muscle protein synthesis are partially mediated via changes in IGF-I.

Crit Care Med, 1996 Mar, 24(3), 525 - 37
Is it time to reposition vasopressors and inotropes in sepsis?
Rudis MI, Basha MA, Zarowitz BJ.
OBJECTIVES: To review the literature on the current use of vasopressors and inotropes in patients with sepsis and sepsis syndrome with respect to the choice of agent, therapeutic end points, and safe and effective doses to be used . To examine the available evidence that supports or refutes goal-directed therapy toward supranormal oxygen transport in optimizing the outcome of critically ill sepsis syndrome patients . DATA SOURCES: All pertinent English and French articles dealing with hemodynamic support with selected vasopressors and inotropic agents in human sepsis and sepsis syndrome retrieved from a computerized MEDLINE search from 1985 to 1994 . STUDY SELECTION: Clinical studies with norepinephrine, epinephrine, phenylephrine, dopamine, and dobutamine in sepsis syndrome were considered if goal-directed therapy with oxygen transport variables was utilized . Emphasis was placed on prospective, randomized, controlled comparative trials . However, open-label, observational, and comparative studies, or case series, were also evaluated when limited data were available . DATA EXTRACTION: From the selected studies, information was obtained regarding patient population, dosing regimen, type of therapeutic goals or end points (hemodynamic, or normal vs . supranormal oxygen transport variables) and outcome data (e.g., achievement of goals, resolution of the episode, mortality rate, and development of end-organ dysfunction) . DATA SYNTHESIS: When used in larger than usual doses, epinephrine, norepinephrine, and phenylephrine uniformly increased hemodynamic values . Epinephrine may increase oxygen transport values more reliably than norepinephrine . Dobutamine doses in the range of 2.5 to 6 microgram/kg/min increase oxygen transport variables and hemodynamics to predetermined goals in only 30% to 70% of patients . Larger infusion rates offer no further benefits . CONCLUSIONS: Insufficient evidence exists to support goal-directed therapy with vasopressors and inotropes in the treatment of sepsis syndrome . No definitive recommendations can be made about the superiority of a vasopressor or inotropic agent due to the lack of data . However, it may be that evaluation of vasopressors earlier in sepsis syndrome will yield more promising results . Large, comparative, controlled trials assessing mortality rate and development of multiple organ system dysfunction are needed.

Crit Care Med, 1996 Mar, 24(3), 381 - 4
A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis; Stuber F et al.; OBJECTIVES: To determine the allele frequency and genotype distribution of a bi-allelic tumor necrosis factor (TNF) gene polymorphism and plasma TNF-alpha concentrations in postoperative intensive care unit (ICU) patients suffering from severe sepsis . DESIGN: Prospective, consecutive entry study of patients with severe sepsis in a postoperative ICU . SETTING: University hospital . PATIENTS: Forty patients with diagnosis of severe sepsis, admitted to the ICU between June 1993 and December 1994 . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: A 782 basepairs fragment of genomic DNA, including the polymorphic site of the restriction enzyme Ncol within the TNF locus, was amplified by means of polymerase chain reaction . The genotype of each patient was determined after Ncol digestion of the amplified product and subsequent agarose gel electrophoresis . Reading the size of the resulting DNA bands from the agarose gel demonstrated the genotype, as defined by the two alleles TNFB1 and TNFB2 . Serial blood samples were drawn every sixth hour during the first 48 hrs and every 12th hour thereafter, for < or = 96 hrs after diagnosis . TNF-alpha plasma concentrations were detected by an enzyme-linked immunosorbent assay . Assessment of organ dysfunction was performed by calculating a Multiple Organ Failure score . The overall allele frequency (TNFB1 0.35; TNFB2 0.65) and genotype distribution (TNFB1 homozygotes 10%; TNFB1/TNFB2 heterozygotes 48%; TNFB2 homozygotes 42%) in 40 patients with severe sepsis were comparable with those values found in normal individuals . Development of multiple organ failure occurred in 33 (82.5%) of 40 patients, whereas 23 (57.5%) of 40 patients did not survive . In contrast to the overall allele frequency, nonsurvivors showed a significantly higher prevalence of the allele TNFB2(p < .005) . Patients homozygous for the allele TNFB2 demonstrated a higher mortality rate than heterozygous (TNFB1/TNFB2) patients (p = .0022) . In addition, patients with TNFB2 homozygotes displayed higher circulating TNF-alpha concentrations as well as higher Multiple Organ Failure scores compared with heterozygous (TNFB1/TNFB2) patients . CONCLUSIONS: The bi-allelic Ncol polymorphism within the TNF locus is a genomic marker for patients with increased TNF-alpha response and poor prognosis in severe sepsis . The amount of TNF released in situations of severe infection and sepsis appears to be influenced genetically . TNFB2 homozygous individuals displaying increased circulating TNF plasma concentrations combined with high mortality rate may be included in future studies testing anti-TNF strategies in severe sepsis.

South Med J, 1996 Mar, 89(3), 354 - 5
Acute retroviral disease masquerading as bacterial sepsis: the "bands" play on; Flemmer M et al.; We describe a case of acute human immunodeficiency virus infection that initially appeared to be bacterial sepsis . A marked increase in band forms was seen in the peripheral blood of our patient, with no increase in atypical lymphocytes . Having reviewed the most recent literature, we find this to be common, particularly in the first few days of acute retroviral illness . We suggest that the absence of atypical lymphocytes in the peripheral blood can be misleading in some cases and may militate against the primary diagnosis of acute retroviral disease.

J Surg Res, 1996 Feb 15, 61(1), 190 - 6
Decreased capillary density in vivo in bowel mucosa of rats with normotensive sepsis; Farquhar I et al.; Translocation of bacteria and endotoxin leading to sepsis occurs in animals subjected to burns or intestinal ischemia . This may be mediated in part by bowel mucosal microcirculatory dysfunction . However, the direct effect of sepsis on the mucosal microcirculation is unknown . The objective of this study was to develop a technique for intravital microscopy of the mucosa of the small bowel in an animal model of normotensive sepsis . We tested the hypothesis that normotensive sepsis induced by cecal ligation and perforation leads to a decrease in perfused capillaries in the small bowel mucosa at 24 hr . Twelve male Sprague-Dawley rats were hemodynamically monitored and randomly assigned to cecal ligation and perforation (CLP) or control laparotomy (sham) . Twenty-four hours after initial surgery each animal was reanesthetized and the mucosal surface of the distal small bowel prepared for intravital microscopy . Laser doppler measurements of bowel wall blood flow were made immediately and repeated after a 30-min stabilization period . Intravital microscopy of the mucosal microcirculation of six villi per animal was performed and the images recorded on videotape (2 min/villus) . The areas surrounded by perfused capillaries (intercapillary area) were then measured using video analysis software . Laser doppler flowmetry revealed a decrease in bowel wall blood flow during the stabilization period in the shams that did not occur in the CLP rats . The intercapillary areas were significantly greater in the CLP rats compared to sham rats (1329 +/- 316 microns2 vs 979 +/- 217 microns2, P = 0.044) . The intercapillary areas were also more highly variable in the CLP group (median coefficient of variation 102 vs 83% in the sham group, P = 0.025) . Intravital microscopy may be used to examine microcirculatory function of the small bowel mucosa . Sepsis induced by CLP leads to a decrease in the number of perfused capillaries in the small bowel mucosa.

J Appl Physiol, 1996 Feb, 80(2), 656 - 64
Hyperdynamic sepsis depresses circulatory compensation to normovolemic anemia in conscious rats; Morisaki H et al.; This study was designed to determine whether sepsis modifies the ability to preserve vital organ O2 delivery (QO2) across a clinically relevant range of hematocrits . Ninety rats were randomly allocated to cecal ligation and perforation (CLP) or a sham (Sham) procedure . With the use of rat plasma, rat whole blood, or packed rat red blood cells, respectively, randomization into three different hematocrit subgroups followed: low (21-28%), middle (33-40%), and high (45-52%) . Organ blood flow values (Q) were measured by the radioactive microsphere technique, and organ QO2 values were calculated . Twenty-four hours after laparotomy, the hematocrit grouping had not modified the interorgan distribution of Q or QO2 in either the CLP or Sham rats . To characterize overall metabolic O2 reserve, rats were then exposed to hypoxia (inspired O2 fraction, 0.08) for 20 min . Whereas cardiac output increased significantly during hypoxia in all experimental groups, myocardial QO2 failed to increase in the low hematocrit Sham subgroup and fell significantly in both the middle- and low-hematocrit CLP subgroups . There was also a lesser redistribution of QO2 away from the small intestine in the low-hematocrit compared with the high-hematocrit CLP subgroup . We conclude that myocardial QO2 is more effectively maintained in septic hypoxic rats if the hematocrit is maintained at levels >45%.

Anasthesiol Intensivmed Notfallmed Schmerzther, 1996 Feb, 31(1), 9 - 14
{History and definition of sepsis--do we need new terminology?}; Kreymann G et al.; The history of sepsis demonstrates that despite current knowledge about its pathogenesis the definition of sepsis is more contested than ever . However, a definite terminology is necessary to define the entrance criteria for future clinical studies concerning patients with sepsis or septic shock . For this purpose, in 1991 a consensus conference was held in the US, but its recommendations have not found unequivocal acceptance . These recommendations and their historical background are presented and their consequences discussed.

Intensive Care Med, 1996 Feb, 22(2), 122 - 8
Circulating adhesion molecules in the critically ill: a comparison between trauma and sepsis patients; Boldt J et al.; OBJECTIVE: The time course of circulating adhesion molecules was monitored in traumatized and sepsis patients . DESIGN: Prospective, descriptive . SETTING: A surgical intensive care unit of a university hospital . PATIENTS: A total of 30 consecutive critically ill patients suffering either from trauma (n = 15) or postoperative sepsis (n = 15) . INTERVENTIONS: All patients were on continuous analgo-sedation and mechanical ventilation . MEASUREMENTS AND RESULTS: From arterial blood samples, plasma levels of soluble adhesion molecules {endothelial leukocyte adhesion molecules (sELAM-1), intercellular adhesion molecule-1 (sICAM-1)}, and vascular cell adhesion molecule-1 (sVCAM-1) were measured on the day of admission (trauma patients) or on the day of diagnosis of sepsis (= baseline values), and during the following 5 days . In the trauma group, sELAM-1 (57.9 +/- 11.0 ng/ml) and sVCAM-1 (698 +/- 93 ng/ml) were within normal ranges at baseline, whereas they were markedly elevated in the sepsis group (sELAM-1: 340 +/- 95 ng/ml; sVCAM-1; 1,042 +/- 449 ng/ml) . In the sepsis patients, sELAM-1 significantly decreased and sVCAM-1 increased, but remained almost unchanged in the trauma patients . Non-survivors showed markedly elevated plasma levels of sELAM-1 and sVCAM-1 . sICAM-1 was elevated in both groups at baseline and was higher in the sepsis group (1,266 +/- 261 ng/ml) than in the trauma group . In the septic patients, sICAM-1 increased further (2,022 +/- 609 ng/ml) and remained unchanged in the trauma group . All non-survivors showed sICAM-1 plasma levels of > 800 ng/ml . CONCLUSIONS: Endothelial damage may result in multiple-organ dysfunction syndrome . Adhesion molecules are considered to be a cornerstone in this process . Trauma patients showed lower plasma levels of circulating adhesion molecules than did sepsis patients indicating more pronounced (inflammatory related) endothelial activation or damage in sepsis . Therapeutic modulation of circulating adhesion molecules may be of benefit to the patients outcome and therefore warrants further study.

Shock, 1996 Feb, 5(2), 141 - 8
The effects of diaspirin cross-linked hemoglobin in sepsis; Mourelatos MG et al.; We tested the hypothesis that diaspirin cross-linked hemoglobin (DCLHb; Baxter Healthcare Corp.) would improve blood pressure, organ perfusion, and mortality during sepsis . Rats were catheterized to assess general hemodynamics (protocol 1) or regional blood flow (protocol 2) . Sepsis was induced by intraperitoneal introduction of a cecal slurry (100 mg/kg) . In protocol 1, rats received either 100 or 250 mg/kg DCLHb, or albumin at 1, 2, or 4 h after sepsis induction . Hemodynamics were recorded at these times and daily for 72 h . DCLHb increased blood pressure, prevented 72 h leukocytosis, and reduced mortality, but the timing of DCLHb administration was crucial . In protocol 2 only moribund septic animals received 100 mg/kg DCLHb or iso-oncotic albumin i.v . Hemodynamics and regional organ blood flows were measured at baseline, immediately before and after treatment, and at 24 h . DCLHb immediately increased blood pressure with no changes in cardiac output, heart rate, or regional perfusion . DCLHb increased regional perfusion to vital areas at 24 h (compared to albumin group) . Distribution of cardiac output in albumin-treated rats was significantly skewed toward skeletal muscle at a time when cardiac output was significantly lower as compared with DCLHb treated animals . In conclusion, DCLHb safely elicited a pressor response, and improved regional perfusion to selected tissues . However, DCLHb benefits were best obtained when given within a specific time frame.

Shock, 1996 Feb, 5(2), 130 - 4
Hypertonic saline in stabilized hyperdynamic sepsis; Hannemann L et al.; Hypertonic saline with or without colloidal solution has been successfully used for treating hemorrhagic shock in animal experiments and clinical studies . Due to its various effects at systemic, organ, and microcirculatory levels, the substance appears to be a promising candidate for improving tissue oxygenation in sepsis . We therefore investigated the hypothesis that infusion of hypertonic saline would further improve O2 delivery, O2 extraction, and O2 uptake in hyperdynamic septic shock patients already stabilized by adequate volume and catecholamine infusion . Twenty-one patients received 2-4 mL/kg body weight of hypertonic saline in hydroxyethyl starch within 15 min . This hypertonic saline infusion caused a rapid significant increase in O2 delivery by 14% but only a marginal increase in O2 consumption (7% by cardiovascular Fick {p < .05}, 4% by respiratory gases {n.s.}) . Hypertonic saline increased the already elevated cardiac output by 24% . The pulmonary capillary wedge pressure increased from 14 +/- 3 to 23 +/ 3 mmHg and pulmonary shunt fraction increased 15%, but arterial PO2 did not fall . Except for the increase in pulmonary capillary wedge pressure, none of the cardiovascular changes lasted longer than 60 min . Plasma sodium levels increased from 138 +/- 25 to 163 +/- 38 mmol/L and normalized within 24 h . In these hyperdynamic septic patients, hypertonic saline infusion produced a transient increase in circulation, but no evidence of a substantial increase in O2 consumption . Either there was no significant O2 debt due to the already elevated O2 delivery levels at baseline (700 mL/min/m2) or the global O2 measurements we used were not able to detect discrete regional hypoxia.

Shock, 1996 Feb, 5(2), 122 - 9
Role of nitric oxide in sepsis-induced hyporeactivity in isolated rat lungs; Li S et al.; The aim of the present study was to test the hypothesis that pulmonary microvascular reactivity is depressed in sepsis and that inducible nitric oxide synthase (iNOS) contributes to the vascular hyporeactivity . Rats were made septic by cecal ligation and puncture . After 16 h, pulmonary vascular reactivity was evaluated by measurement of perfusion pressures while the vasculature was challenged with angiotensin II and KCl . The results showed that vascular reactivity was significantly depressed in lungs from septic rats in comparison to sham-operated controls . Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) restored the depressed vasoreactivity while the nitric oxide (NO) synthase substrate L-arginine (1 mM) reversed the contraction-restoring effect of L-NAME . NO production in lungs from septic rats increased about 4-fold in comparison to sham-operated controls . iNOS protein was expressed in lung tissues, mainly the resistance vessels, from septic rats but not from sham-operated controls . Reverse transcription and polymerase chain reaction also showed a strong induction of iNOS mRNA in lung tissues from septic rats . These results suggest that increased iNOS expression and NO production may contribute to depressed pulmonary vascular reactivity in sepsis.

Nephrol Dial Transplant, 1996 Feb, 11(2), 293 - 9
Prognostic factors in acute renal failure due to sepsis . Results of a prospective multicentre study . The French Study Group on Acute Renal Failure; Neveu H et al.; BACKGROUND . Sepsis is a major cause of acute renal failure in hospital patients, but its incidence and the associated prognostic factors have rarely been assessed prospectively by multivariate analysis . METHODS . We conducted a prospective 6-month study in 20 multidisciplinary intensive care units to assess the prognosis of patients hospitalized with acute renal failure due to sepsis . Sepsis syndrome and septic shock were defined according to the criteria of the Society of Critical Care Medicine Consensus Conference . Severity scoring indexes (SAPS, APACHE II, and organ system failure (OSF)) were measured on ICU admission and on inclusion . The end-point was hospital mortality . RESULTS . Acute renal failure had a septic origin in 157 patients (Group 1), comprising 68 with septic shock and 89 with sepsis syndrome, and did not result from infection in 188 patients (Group 2) . Patients with septic acute renal failure were older (mean age: 62.2 versus 57.9 years, P<0.02) and had on inclusion a higher SAPS (19.3 versus 16.1, P<0.001), APACHE II (29.6 versus 24.3, P<0.001), and OSF (2.07 versus 1.52, P<0.001) than patients with non-septic acute renal failure . They had a higher need for mechanical ventilation (69.1% versus 47.3%, P<0.001), and acute renal failure was more often delayed during the ICU stay than was present on admission (47.7% versus 32.4% respectively, P<0.005) . Hospital mortality was higher in patients with septic acute renal failure (74.5%) than in those whose renal failure did not result from sepsis (45.2%, P<0.001) . Mortality was influenced by the presence of a septic shock (79.4%) or of a sepsis syndrome on inclusion (70.8%) . Using a stepwise logistic regression model, sepsis was an independent predictor of hospital mortality (OR, 2.51; 95% CI, 1.44-4.39) as well as a delayed occurrence of acute renal failure, oliguria, an altered previous health status hospitalization prior to ICU, need for mechanical ventilation, age and severity scoring indexes on inclusion . In total patients, mortality was higher in dialyzed than in non-dialyzed patients (P<0.001), and in those treated by continuous compared to intermittent techniques (P<0.01) . Patients dialyzed with biocompatible membranes had a lower mortality than those treated with cellulose membranes (P<0.005) . CONCLUSIONS . Patients with acute renal failure due to sepsis have a worse prognosis than those with non-septic acute renal failure . Sepsis and the above-defined predictive factors are to be considered in studies on prognosis of ARF patients . Our results suggest that the use of biocompatible membranes may reduce significantly mortality in these patients.

New Horiz, 1996 Feb, 4(1), 58 - 71
Calcium: a regulator of the inflammatory response in endotoxemia and sepsis; Hotchkiss RS et al.; Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia . There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis . Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure . In this article, we focus on a) new insights into calcium's regulation of the inflammatory cascade, b) the controversy concerning whether free cytosolic calcium concentration ({Ca2+}i) is increased in the disorder, and c) the potential therapeutic uses of calcium antagonists . An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis . Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis . Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented.

Br J Surg, 1996 Feb, 83(2), 196 - 202
Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis; Koea JB et al.; The clinical and metabolic effects of 7 days of recombinant human growth hormone (rhGH) and total parenteral nutrition (TPN) in surgical patients with sepsis were determined in a randomized controlled trial . In patients with a mean(s.e.m.) pretreatment rate of net protein catabolism (NPC) of 1.5 g per kg per day or less rhGH treatment decreased NPC from 0.93(0.14) to -0.20(0.24) g per kg per day (n = 5; P < 0.0005) and rendered these patients anabolic . TPN alone decreased NPC from 1.12(0.11) to 0.61(0.11) g per kg per day (n = 5; P < 0.001) . In patients with an initial NPC of more than 1.5 g per kg per day rhGH treatment decreased NPC from 2.72(0.12) to 1.08(0.24) g per kg per day (n = 5; P < 0.001) while TPN alone decreased it from 2.41(0.32) to 1.28(0.28) g per kg per day (n = 5; P < 0.005) . Use of rhGH was not associated with any adverse effects or improvement in clinical course but did decrease the mean systolic and diastolic pressures during the study period . Thus rhGH is a useful anabolic agent and may have a role in the haemodynamic management of the catabolic patient with sepsis.

Nephrol Dial Transplant, 1996 Feb, 11(2), 293 - 9
Prognostic factors in acute renal failure due to sepsis . Results of a prospective multicentre study
Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P.
Background . Sepsis is a major cause of acute renal failure in hospital patients, but its incidence and the associated prognostic factors have rarely been assessed prospectively by multivariate analysis . Methods . We conducted a prospective 6-month study in 20 multidisciplinary intensive care units to assess the prognosis of patients hospitalized with acute renal failure due to sepsis . Sepsis syndrome and septic shock were defined according to the criteria of the Society of Critical Care Medicine Consensus Conference . Severity scoring indexes (SAPS, APACHE II, and organ system failure (OSF)) were measured on ICU admission and on inclusion . The end-point was hospital mortality . Results . Acute renal failure had a septic origin in 157 patients (Group 1), comprising 68 with septic shock and 89 with sepsis syndrome, and did not result from infection in 188 patients (Group 2) . Patients with septic acute renal failure were older (mean age: 62.2 versus 57.9 years, P Conclusions . Patients with acute renal failure due to sepsis have a worse prognosis than those with non-septic acute renal failure . Sepsis and the above-defined predictive factors are to be considered in studies on prognosis of ARF patients . Our results suggest that the use of biocompatible membranes may reduce significantly mortality in these patients . Keywords: acute renal failure; hospital mortality; prognosis; scoring systems; sepsis

Scott Med J, 1996 Feb, 41(1), 17 - 9
Overwhelming pneumoccoccal sepsis in two patients splenectomised more than ten years previously; Hassan IS et al.; Asplenic individuals are known to be at a higher risk of developing serious and occasionally fatal sepsis . Prophylactic measures are generally recommended for the first few years post-splenectomy . We report two cases of severe Pneumococcal Sepsis occurring more than 10 years post-splenectomy leading to prolonged hospitalisation and long term morbidity and suggest that Prophylactic Penicillin should be taken life-long.

J Clin Invest, 1996 Jan 15, 97(2), 339 - 48
Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids; Tiao G et al.; Recent studies suggest that sepsis-induced increase in muscle proteolysis mainly reflects energy-ubiquitin-dependent protein breakdown . We tested the hypothesis that glucocorticoids activate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis . Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h later . The glucocorticoid receptor antagonist RU 38486 or vehicle was administered to groups of septic and sham-operated rats . In other experiments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats . Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively . Energy-dependent proteolysis was determined in incubated muscles depleted of energy with 2-deoxyglucose and 2,4-dinitrophenol . Levels of muscle ubiquitin mRNA and free and conjugated ubiquitin were determined by Northern and Western blot, respectively . RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates and blunted the increase in ubiquitin mRNA levels and free ubiquitin . Some, but not all, sepsis-induced changes in ubiquitin protein conjugates were inhibited by RU 38486 . Injection of dexamethasone in normal rats increased energy-dependent proteolysis and ubiquitin mRNA levels . The results suggest that glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.

Biol Neonate, 1996, 70(4), 206 - 12
Immunologic parameters in cord blood indicating early-onset sepsis; Lehrnbecher T et al.; Different immunologic parameters were measured in cord blood to test their usefulness in the early diagnosis of early onset sepsis . Cord blood levels of circulating intercellular adhesion molecule-1 (cICAM-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) were significantly elevated in septic compared to nonseptic neonates . No significant difference between either population was seen for cord blood C3a and elastase-alpha 1-proteinase inhibitor complex (E alpha 1 PI) . Measured concentrations of cICAM-1, IL-6 and IL-8 in fetal and maternal blood did not correlate, indicating that the neonate's response to sepsis is clearly different from the mother . Our data suggest that cord blood measurements of cICAM-1, IL-6 and IL-8 might be useful in identifying neonates with early-onset sepsis.

Free Radic Biol Med, 1996, 20(1), 139 - 43
Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading; Galley HF et al.; Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage . Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions . We measured baseline total vitamin C and bleomycin-detectable "free" iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects . Vitamin C concentrations were decreased in patients compared to healthy subjects (p < 0.0001), and "free" iron was increased (p < 0.002) . Preinfusion ascorbyl radical concentrations were not different in patients and controls . Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls . In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging . This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised "free" iron levels.

Res Exp Med (Berl), 1996, 196(4), 247 - 50
Effects of naloxone on beta-endorphin and cortisol release in sepsis; Okur H et al.; We investigated the effects of the opiate antagonist naloxone on the release of beta-endorphin and cortisol in rats subjected to sepsis . Sepsis was induced in weanling male Wistar albino rats (3-4 weeks old, 75-90 g) by cecal ligation and double perforation (CLP) . Forty animals were randomly allocated to four groups . Group 1 was given naloxone hydrochloride 0.5 mg/kg subcutaneously after CLP and this treatment was repeated at 2-h intervals until the rats were killed . Group 2 rats underwent a sham operation . Group 3 (control group) rats had CLP . Group 4 consisted of nonoperated animals used to establish normal reference values . Eighteen hours after CLP or sham operation, the rats were killed by cervical dislocation and a blood sample was drawn via cardiac puncture to determine the beta-endorphin and cortisol levels . The beta-endorphin levels were significantly higher in the control group than in the sham-operated, naloxone-treated (NT), and nonoperated rats (P < 0.05) . However, there were no significant differences in plasma beta-endorphin levels between sham-operated, NT and nonoperated rats (P > 0.05) . Plasma cortisol levels were significantly higher in the control group compared with the other three groups and this difference was more significant in sham-operated and nonoperated rats (P < 0.01) . However, no difference existed between sham-operated, NT, and nonoperated rats (P > 0.05) . This study demonstrates that the endogenous opioid system may play a role in the activation of the pituitary-adrenal axis following sepsis, and shows that the increase in beta-endorphin and cortisol could be blocked by naloxone.

Intensive Care Med, 1996 Jan, 22(1), 52 - 6
Endothelin production in sepsis and the adult respiratory distress syndrome; Sanai L et al.; OBJECTIVE: Septic shock is characterised by a decrease in systemic vascular resistance . Nevertheless, regional increases in vascular resistance can occur which may predispose to organ dysfunction, including the adult respiratory distress syndrome (ARDS) . Because endothelial damage is a major feature of acute lung injury, we examined whether the potent endothelial vasoconstrictor peptide endothelin-1 plays a pathophysiological role in sepsis or ARDS . DESIGN: Plasma endothelin was measured in mixed venous, pulmonary capillary and arterial blood, and the relationship with outcome measures was determined . SETTING: The intensive care unit of a university teaching hospital . PATIENTS AND PARTICIPANTS: A consecutive series of well-characterised patients with sepsis syndrome, both with (n = 11) and without (n = 15) ARDS, and ventilated controls without sepsis or ARDS (n = 7) . MEASUREMENTS AND RESULTS: Plasma endothelin was significantly elevated in patients with sepsis alone and in patients with sepsis and ARDS . Plasma endothelin did not differ among mixed venous, pulmonary capillary and systemic arterial blood . On multiple regression analysis, plasma endothelin correlated positively with organ failure score and with oxygen consumption, and negatively with the PaO2 : FiO2 ratio . There was no correlation with plasma creatinine, suggesting that decreased renal clearance did not account for the high plasma endothelin concentrations . CONCLUSIONS: Although the lung does not appear to be the major site of endothelin production in critically ill patients with sepsis, increased endothelin production may contribute to regional increases in vascular {correction of vacular} resistance, hyperfusion, and the development of organ failure, including ARDS, in patients with sepsis.

Shock, 1996, 6 Suppl 1, S27 - 38
Immune dysfunction in murine polymicrobial sepsis: mediators, macrophages, lymphocytes and apoptosis; Ayala A et al.; Despite recent advances in antibiotic therapy, aggressive operative intervention and intravenous hyperalimentation, sepsis, and multiple organ failure are still reported to contribute to significant morbidity and mortality in the surgical intensive care unit . In light of this, it is essential to determine the mechanism underlying the pathophysiology of sepsis so that better therapeutic interventions can be designed . Experimental studies indicate that murine polymicrobial sepsis induces a marked suppression in both lymphocytic and macrophage function associated with decreased cellular adenosine triphosphate levels and increased Ca2+ . However, such changes are not detectable until approximately 12 h after the onset of sepsis . Alternatively, early (0-4 h) in sepsis, macrophages from the liver and peritoneum exhibit augmented innate secretion of proinflammatory cytokines, tumor necrosis factor, interleukin (IL)-6, and IL-1, associated with the systemic release of these agents . Sustained release of immunosuppressive agents transforming growth factor-beta, IL-4, IL-10, and PGE2, as well as glucocorticoids, are also observed during sepsis . In this regard, many investigators, including us, have suggested that an agent(s) released as a part of this systemic inflammatory response to sepsis may be responsible for the protracted suppression of immune cell function . Studies examining the effects of these mediators in vitro on various immune cells have shown that many of these agents also have the capacity to induce a process referred to as programmed cell death (PCD) or apoptosis (Ao) . We have presented evidence of marked changes in the rate of Ao in immune cells after the onset of sepsis . These data suggest the possibility that mediators released in response to septic insult contribute to the observed changes in immune cell function through the induction of Ao . Inasmuch, understanding the contribution of PCD to the pathophysiology of sepsis, should provide a better basis from which to develop more effective therapy for the septic patient.

Shock, 1996 Jan, 5(1), 28 - 33
Effect of immunoglobulin G on the hepatic microvascular inflammatory response during sepsis; McCuskey RS et al.; The effects of intravenous immunoglobulin G (ivIG) on the hepatic microvascular inflammatory response to sepsis were studied in rats by in vivo microscopy . High doses of ivIG (300 mg/kg bw) (Sandoglobulin or rat IgG) significantly improved the 48 h survival of septic rats from 25-66% when ivIG was given before or immediately after cecal ligation and puncture . Circulating endotoxin also was significantly reduced . Eight hours after inducing sepsis, the average number of leukocytes adhering to the sinusoidal endothelium increased 15-fold and the average decrease in the number of perfused sinusoids was 22% . IvIG administration minimized these responses . In both septic and nonseptic animals, ivIG also reduced the phagocytic activity of Kupffer cells . The results suggest that high doses of ivIG not only reduce lethality but also limit hepatic microcirculatory dysfunction during sepsis by minimizing leukocyte-endothelial interactions that may be a result of reducing circulating endotoxin and modifying Kupffer cell function.

Shock, 1996 Jan, 5(1), 22 - 7
IGF-I stimulates muscle glucose uptake during sepsis; Lang CH; The purpose of the present study was to determine whether insulin-like growth factor (IGF)-I would increase whole body and muscle glucose uptake in septic rats that are known to be insulin resistant . Animals were infused with either saline, low-dose IGF-I, high-dose IGF-I, or a maximally stimulating dose of insulin for 2 h, and the glucose metabolic response was assessed using a euglycemic clamp in combination with {3-3H}glucose . Under basal conditions, sepsis increased the rates of whole body glucose uptake, glycolysis, and hepatic glucose production . Under euglycemic hyperinsulinemic conditions, septic rats demonstrated a marked insulin resistance as evidenced by the impaired rate of insulin-stimulated glucose uptake and muscle glycogen synthesis . In contrast, the infusion of either dose of IGF-I increased total glucose uptake, glycolysis, and glycogen synthesis in both control and septic rats to the same extent . Furthermore, there was no difference in the IGF-I stimulation of glucose uptake (as determined by {14C}-2-deoxyglucose) in the gastrocnemius, soleus, and heart between control and septic rats . These results indicate that the glucose metabolic response to IGF-I is intact in insulin-resistant septic rats.

Am J Physiol, 1996 Jan, 270(1 Pt 1), E43 - 50
Altered expression of eukaryotic initiation factor 2B in skeletal muscle during sepsis; Voisin L et al.; Sepsis causes an inhibition of protein synthesis in skeletal muscles composed of fast-twitch fibers, in part, as a result of a decreased activity of the eukaryotic initiation factor 2B (eIF-2B) . In the present study, we investigated the expression of two subunits of eIF-2B, i.e., the beta- and epsilon-subunits during sepsis . The expression of both beta- and epsilon-subunits of eIF-2B in gastrocnemius was decreased approximately 50% from control values during the first 5 days after induction of sepsis . The decreased expression of eIF-2B epsilon during sepsis correlated with similar reductions in eIF-2B epsilon mRNA . Restoration of protein synthesis (10 days postsurgery) was associated with a return of eIF-2B epsilon expression to values observed in control rats . Expression of eIF-2B epsilon was not altered in heart during sepsis or in gastrocnemius from nonseptic abscess animals . Amrinone, which ameliorated the inhibition of protein synthesis during sepsis, also prevented the fall in eIF-2B epsilon protein after 5 days of infection . The data provide evidence that expression of eIF-2B epsilon is markedly influenced in gastrocnemius during the course of the septic episode and support the concept that this change is a mechanism responsible for the inhibition of protein synthesis observed under this condition.

Am J Physiol, 1996 Jan, 270(1 Pt 2), R254 - 63
Initial externalization followed by internalization of beta-adrenergic receptors in rat heart during sepsis; Tang C et al.; Changes in the distribution of beta-adrenergic receptors in two subcellular fractions, the sarcolemma and the light vesicle, of rat heart during sepsis were studied, using {3H}dihydroalprenolol ({3H}DHA) binding and photoaffinity labeling with {125I}iodocyanopindolol ({125I}ICYP) . Sepsis was induced by cecal ligation and puncture (CLP) . Septic rat hearts exhibit an initial hypercardiodynamic (9 h after CLP; early sepsis) and a subsequent hypocardiodynamic (18 h after CLP; late sepsis) state . {3H}DHA-binding studies show that, during early sepsis, the maximum binding capacity (Bmax) was increased by 35% in sarcolemma but was decreased by 25% in light vesicles, whereas during late sepsis, the Bmax was decreased by 39% in sarcolemma but was increased by 30% in light vesicles . Photoaffinity labeling studies show that the incorporation of {125I}ICYP into 64,000-Da peptide during early sepsis was increased by 32% in sarcolemma but was decreased by 27% in light vesicles, whereas during late sepsis, the incorporation was decreased by 30% in sarcolemma but was increased by 35% in light vesicles . These data indicate that beta-adrenergic receptors in the rat heart were externalized from light vesicles to sarcolemma during the hyperdynamic phase but were internalized from surface membranes to intracellular sites during the hypodynamic phase of sepsis . Because beta-adrenergic receptors mediate adrenergic control of cardiac muscle contraction, a biphasic intracellular redistribution of beta-adrenergic receptors in the heart may contribute to the development of the initial hypercardiodynamic and subsequent hypocardiodynamic states during sepsis.

Stomatologiia (Mosk), 1996, 75(2), 37 - 9
{The clinico-laboratory characteristics and diagnosis of acute stomatogenic sepsis}; El'kova NL et al.; Thirty-four patients with acute stomatogenic sepsis developing in grave ulcerative necrotic stomatitis (including that in Stevens-Johnson's and Lyell's syndromes) were examined . Homeostasis parameters were shifted in these patients . To facilitate timely diagnosis of acute stomatogenic sepsis, the authors offer a differential diagnostic table . Patients with grave forms of stomatitis are recommended to be referred for examination and treatment to specialized dentistry hospitals in order to early diagnose the disease and prevent the development of acute sepsis.

Surg Today, 1996, 26(4), 225 - 9
Chronological changes in the complement system in sepsis; Nakae H et al.; The time courses of serum complement levels and the severity of sepsis were compared in two groups of septic patients, one in which the patients survived (surviving group) and one in which they did not (nonsurviving group) . The components of the complement system, namely, C3a, C4a, C5a, CH50, C3, C4, and C5, were measured at several points in time after the diagnosis of sepsis had been established . A 2-antibody radioimmunoassay was used to measure C3a, C4a, and C5a; the latex agglutination test was used to measure C3 and C4; nephelometry was used to measure C5; and Meyer's 50% hemolysis method was used to measure CH50 . Following the diagnosis of sepsis, the levels of CH50, C3, and C4 were significantly lower in the nonsurviving than the surviving group, while the levels of C3a and C4a were significantly higher in the nonsurviving than the surviving group . The C5a levels were significantly higher in the nonsurviving than the surviving group, although no significant intergroup differences were subsequently noted . These results suggest that the serum levels of C3a, C4a, C5a, CH50, C3, and C4 could serve as indices of the severity of sepsis . Thus, monitoring the complement system may be useful for predicting the outcome of patients with sepsis.

Ginekol Pol, 1996 Jan, 67(1), 12 - 6
{Intensive therapy of puerperal disorders with a life-threatening state caused by sepsis}; Skorupa A et al.; The paper reviews intensive, complex therapeutical procedure introduced in 19 critically ill puerperal women due to severe sepsis . In 6 cases only the generative organ was the primary source of infection . It is underlined that sepsis can predispose to various complications and multiorgan failure.

J Surg Res, 1996 Jan, 60(1), 270 - 7
Clinically accessible cell signaling: second messengers in sepsis and trauma; Rehring TF et al.; Inflammatory mediators of trauma and sepsis transduce cellular events through cell surface receptors initiating intricate membrane and cytosolic reaction cascades that funnel through surprisingly few checkpoints in order to provoke a cellular response . As critical care surgeons, we can explore these cell signalling systems . The purpose of this article is to delineate the six known second messenger pathways relevant to surgical sepsis and trauma . Our comprehension of these signaling systems may offer us an opportunity to blunt post-traumatic cellular injury and promote a constructive response.

J Surg Res, 1996 Jan, 60(1), 101 - 6
The effect of surgical treatment following peritoneal sepsis on hepatic gene expression; Barke RA et al.; Peritoneal sepsis results in downregulation of the gene that codes for the hepatic mitochondrial enzyme carnitine palmitoyltransferase (CPT) . The inhibition of hepatic CPT transcription by sepsis is thought to be mediated, in part, by increased expression of the leucine-zipper DNA transcription factor c-fos . In a cecal ligation and puncture (CLP) model, we examined the temporal effect of surgical treatment (cecal excision) on sepsis-induced inhibition of CPT gene expression . We investigated the hypothesis that Fos protein level will inversely correlate with the regulation of CPT gene expression . Specifically, we studied hepatic Fos nucleoprotein accumulation and CPT gene expression as measured by total mitochondrial CPT activity, CPT protein, and CPT mRNA . We investigated the following groups: (i) CLP followed by cecal excision 6, 12, or 24 hr following initial insult, (ii) concurrent CLP control group, and (iii) concurrent sham CLP reference group . When measured 48 hr following initial surgical insult, we conclude that: (i) in the absence of surgical treatment, peritoneal contamination results in a decrease in hepatic CPT gene expression and an increase in Fos nucleoprotein accumulation; (ii) surgical treatment at 6 or 12 hr following initial insult prevents the downregulation in hepatic CPT gene expression and does not result in Fos nucleoprotein accumulation; and (iii) surgical treatment at 24 hr following insult did not prevent the downregulation of hepatic CPT gene expression and results in an increase in hepatic Fos nucleoprotein accumulation . These data are consistent with the hypothesis that sepsis-induced regulation of hepatic c-fos gene expression, in part, is responsible for the downregulation of CPT gene expression.

Crit Care Med, 1996 Jan, 24(1), 46 - 56
Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis . The rhIL-1ra Phase III Sepsis Syndrome Study Group; Knaus WA et al.; OBJECTIVES: To investigate a novel anticytokine therapy in patients with sepsis syndrome, and the relationship between a patient's baseline mortality risk and survival benefit . DESIGN: Data from a recent phase III, double-blind, placebo-controlled, multicenter clinical trial with patients randomized to three treatment arms: an intravenous loading dose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/hr, or 2.0 mg/kg/hr), or placebo for 72 hrs . SETTING: Sixty-three investigative centers in eight countries . PATIENTS: The study population consisted of 893 patients: 302 placebo patients; 298 patients treated with 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/hr of rhIL-1ra . MEASUREMENTS AND MAIN RESULTS: An independent, sepsis-specific, log-normal regression model that predicts the risk of mortality over 28 days was applied to all patients enrolled into the rhIL-1ra sepsis study . The ability of the Predicted Risk of Mortality model to predict 28-day mortality in the placebo patients was determined and the relationship between mortality risk and efficacy of rhIL-1ra was investigated . The trial data were also analyzed using two other risk-assessment models for comparison with Predicted Risk of Mortality . A significant increase in survival time was demonstrated for all patients treated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log-normal), but patients with a Predicted Risk of Mortality of < 24% derived little benefit . Retrospective examination of time-to-death data demonstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with > or = 24% Predicted Risk of Mortality (n = 580, p < .005 Predicted Risk of Mortality log-normal) . This same effect was not present in patients with a Predicted Risk of Mortality of < 24% on entry into the study . The Predicted Risk of Mortality model predicted a 28-day mortality rate of 35% for placebo patients compared with 34% observed and accurately stratified patients along the full range of risks . There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categorical subgroups, such as shock and organ system dysfunction . Two alternate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a statistically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality log-normal) for all patients treated . CONCLUSIONS: Using an appropriate analytic model, a statistically significant increase in survival time from rhIL-1ra was measured . A direct relationship was found between a patient's Predicted Risk of Mortality at study entry to efficacy of rhIL-1ra . Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeutic approaches to sepsis and for monitoring outcomes at the bedside.

Crit Care Med, 1996 Jan, 24(1), 131 - 6
Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide; Hinder F et al.; OBJECTIVE: To test whether renal excretory function decreases after nitric oxide synthase inhibition during experimental hyperdynamic sepsis . DESIGN: Prospective, randomized, controlled animal trial . SETTING: Research laboratory at a large university medical center . SUBJECTS: Chronically instrumented Merino breed ewes (n = 18) . INTERVENTIONS: Continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) for the experimental period of 32 hrs . One group received a bolus of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (25 mg/kg), after 24 hrs, and the remaining sheep were given the carrier, sodium chloride 0.9% . MEASUREMENTS AND MAIN RESULTS: The sheep developed a hyperdynamic cardiovascular response characterized by a decrease in systemic vascular resistance index (p < .05), and an increased cardiac index (p < .05) by 24 hrs . The sheep retained fluid, with creatinine clearance decreasing in the presence of chronically increased atrial natriuretic peptide . After the administration of N omega-nitro-L-arginine methyl ester, systemic vascular resistance index and cardiac index returned to baseline values, fluid balance normalized, and glomerular filtration rate increased (p < .05), while the control animals continued to retain fluid and their creatinine clearance continued to decrease . The concentrations of atrial natriuretic peptide did not differ significantly between groups after N omega-nitro-L-arginine methyl ester administration . CONCLUSIONS: In this ovine model of experimental hyperdynamic sepsis, renal excretory function decreases in the presence of chronically increased concentrations of atrial natriuretic peptide . Administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, reverses the vasodilatory state, thereby improving fluid balance and glomerular filtration.

Am J Surg, 1996 Jan, 171(1), 102 - 7; discussion 107-8
Intra-abdominal sepsis impairs colonic reparative collagen synthesis; Ahrendt GM et al.; BACKGROUND: Intra-abdominal infection is generally considered a contraindication to primary colon anastomosis . In order to elucidate the mechanisms by which sepsis affects colonic healing, we studied anastomotic new collagen and protein synthesis and collagen gene expression in a relevant animal model . METHODS: Forty male Sprague-Dawley rats (240 to 260 g) underwent sham laparotomy (SHAM, n = 18) or cecal ligation and single puncture (CLP, n = 22) . After 24 hours, animals underwent single-layer left colon anastomosis . Animals were sacrificed either 1 or 4 days postanastomosis . Anastomotic segments of colon were excised, minced, and incubated with 4.5 muCi 3H-proline . After 3 hours, tissue 3H-proline incorporation was quantitated as an index of total new protein synthesis . The protein fraction was then digested with purified collagenase enzyme to determine 3H-proline incorporation into collagenase-digestible protein, an index of new collagen synthesis . Total RNA was extracted from anastomotic tissue samples and subjected to Northern blot analysis for type I and type III collagen genes . RESULTS: Intra-abdominal sepsis resulted in markedly less new collagen synthesis 1 day postanastomosis (9,163 +/- 1,234 versus 3,744 +/- 444 disintegrates per minute 3H-proline/mg of protein, P < 0.0001) and 4 days postanastomosis (8,462 +/- 956 versus 5,708 +/- 802 dpm/mg of protein P < 0.05) . Noncollagenous protein synthesis was also impaired in anastomotic tissue from CLP rats on postanastomosis day 1 (37,497 +/- 3,740 versus 18,593 +/- 2,695 dpm/mg of of protein, P < 0.001) and postanastomosis day 4 (28,238 +/- 834 versus 17,784 +/- 1,415 dpm/mg of of protein, P < 0.0001) . The expression of type I and type III collagen was altered relative to the normal temporal sequence observed in SHAM animals . CONCLUSION: Intra-abdominal infection impairs colonic reparative collagen and protein synthesis . In addition, regulation of type I and type III collagen genes is altered by intra-abdominal sepsis, and the alteration likely contributes to impaired new collagen synthesis and decreased colonic mechanical strength.

J Pediatr, 1996 Jan, 128(1), 135 - 7
A two-year follow-up of neonates with presumed sepsis treated with recombinant human granulocyte colony-stimulating factor during the first week of life; Rosenthal J et al.; We have previously reported that recombinant human granulocyte colony-stimulating factor was well tolerated and resulted in sustained neutrophilia and improvement of neutrophil functions in newborn infants with presumed sepsis . We now report a 2-year follow-up on 21 of the initial cohort of 28 patients . Treatment with recombinant human granulocyte colony-stimulating factor in neonates with presumed sepsis was not associated with any long-term adverse hematologic, immunologic, or developmental effects.

Arch Surg, 1996 Jan, 131(1), 57 - 62
Effects of hyperoxia on bacterial translocation and mortality during gut-derived sepsis; Gennari R et al.; BACKGROUND: While hyperoxia is commonly used for treating carbon monoxide poisoning, chronic nonhealing ulcers, acute traumatic and chronically ischemic wounds, and refractory osteomyelitis, its efficacy is unproven in numerous clinical situations, including treatment during severe sepsis . OBJECTIVE: To test the effects of hyperoxia on bacterial translocation and mortality during gut-derived sepsis in a clinically relevant model of infection . METHODS: Balb/c mice were gavaged with 10(9) Escherichia coli and subjected to a 20% burn injury . Then, the animals were randomized to receive hyperoxia for different periods of time . Survival and the extent of translocation were determined, as well as intestinal histologic features . RESULTS: Hyperoxia treatment preserved gut morphology and improved gut barrier function, decreasing the amount of bacterial translocation . Short-term (4- or 8-hour) hyperoxia (100% oxygen) treatment improved survival only on day 1 after injury but did not affect the final outcome . Short-term (8-hour) hyperoxia (100% oxygen) plus 5-day 40% oxygen environment significantly improved long-term survival . CONCLUSION: Tissue pO2 may be an important regulator of gut barrier function . Hyperoxia treatment appears to play a major role in preserving gut barrier function.

Metabolism, 1996 Jan, 45(1), 28 - 33
Influence of sepsis and endotoxemia on polyamine metabolism in mucosa of small intestine in rats; Noguchi Y et al.; We examined the influence of sepsis and endotoxemia in rats on the biosynthesis of polyamines in small-intestinal mucosa . Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham-operated . In other experiments, rats were treated with two subcutaneous injections of endotoxin (1 mg/kg) or corresponding injections of sterile saline . Ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activities and concentrations of putrescine, spermidine, and spermine were measured in jejunal mucosa at intervals during 16 hours . Sepsis stimulated ODC and SAMDC activities and increased putrescine and spermidine concentrations in jejunal mucosa . Injection of endotoxin resulted in metabolic changes similar to those observed following CLP . The results suggest that sepsis and endotoxemia stimulate polyamine biosynthesis in mucosa of small intestine . The role of polyamines in the regulation of cell proliferation and metabolic changes in the intestinal mucosa during sepsis remains to be determined.

Am J Respir Crit Care Med, 1996 Jan, 153(1), 191 - 5
Skeletal muscle microvascular blood flow and oxygen transport in patients with severe sepsis; Neviere R et al.; To compare skeletal muscle microvascular blood flow at rest and during reactive hyperemia in septic patients, a prospective, controlled trial was conducted on 16 patients with severe sepsis and a control group of 10 patients free of infection in the intensive care unit of a university hospital . Systemic hemodynamics, whole-body oxygen transport, and skeletal muscle microvascular blood flow at rest and during reactive hyperemia were measured . Reactive hyperemia was produced by arrest of leg blood flow with a pneumatic cuff; on completion of the 3 min ischemic phase the occluding cuff was rapidly deflated to 0 . Hemodynamic and oxygen-derived variables were determined invasively . Skeletal muscle microvascular blood flow data were obtained using a laser Doppler flowmetry technique and values expressed in millivolts . Whole-body oxygen delivery in septic patients was increased compared with control subjects . Resting skeletal muscle blood flow was decreased in septic patients compared with control subjects (233 +/- 52 versus 394 +/- 93 mV; p < 0.05) . Peak flow during reactive hyperemia was also decreased in septic patients compared with control subjects (380 +/- 13 versus 2,033 +/- 853 mV; p < 0.05) . Cyclic variation in blood flow (vasomotion) was observed in control subjects but not in septic patients . Skeletal muscle microvascular perfusion is altered in patients with severe sepsis despite normal or elevated whole-body oxygen delivery . These microvascular abnormalities may further compromise tissue nutrient flow and may contribute to the development of organ failure in septic patients.

Radiol Clin North Am, 1996 Jan, 34(1), 177 - 90
Evaluation of the abdomen in sepsis of unknown origin; McDowell RK et al.; The radiologic evaluation of sepsis of unknown origin has changed dramatically since the introduction of cross-sectional imaging . Interventional procedures such as abscess drainage, cholecystostomy, biliary drainage, nephrostomy, and fluid aspiration have reduced the morbidity and mortality associated with occult sources of sepsis . This article examines some of the common etiologies and treatments of sepsis in the hospitalized patient.

Biochem Biophys Res Commun, 1995 Dec 26, 217(3), 839 - 44
Ubiquitin gene expression in skeletal muscle is increased during sepsis: involvement of TNF-alpha but not IL-1; Garcia-Martinez C et al.; Septic rats showed an enhanced expression in skeletal muscle of both 1.2 (500%) and 2.4 (530%) kb mRNAs for the peptide ubiquitin, which reflects the activity of the ATP-ubiquitin-dependent proteolytic system . An acute intravenous administration of 100 micrograms/kg body weight of human recombinant tumour necrosis factor-alpha (TNF) also resulted in an important increase in the levels of ubiquitin mRNAs in rat skeletal muscle, while administration of a similar amount of human recombinant interleukin-1-beta did not . The results presented here, together with previous observations demonstrating that TNF increases the conjugation of proteins with ubiquitin in rat skeletal muscle (1), suggest that the ubiquitin system for non-lysosomal protein degradation could have a very important role in the mechanism triggered by TNF which is responsible for enhanced muscle proteolysis in sepsis and other pathological states.

Prehospital Disaster Med, 1996 Jan-Mar, 11(1), 27 - 36
Early predictors of sepsis in the motor-vehicle crash trauma victim; Previdi JK et al.; INTRODUCTION: Sepsis is a major cause of late morbidity and mortality in the victim of trauma . Currently, there is no method that is clinically practical and accurate for predicting the occurrence of sepsis in trauma victims . METHODS: Data were collected on 3,759 motor-vehicle crash victims from 16 hospitals during a 4 1/2 year period . Retrospective analysis was done to examine the relationship of patient and injury factors known within the first 24 hours of admission on the development of sepsis . RESULTS: Sepsis developed in 154 patients (4.1%) who had a mortality rate of 17.5% . Significant early predictors of sepsis included: 1) certain pre-existing conditions; 2) blood transfusion required; 3) seven or more injuries; 4) Glasgow Coma Scale score <10 and hypotension {corrected}; 5) major blood vessel injury; 6) head trauma; 7) internal injury of the chest or abdomen; 8) spinal-cord injury; and 9) certain fracture types . CONCLUSIONS: These predictors might help target high-risk patients and, thus, promote earlier and more effective treatment for those patients.

J Appl Physiol, 1995 Dec, 79(6), 1878 - 82
Oxygen tension in the bladder epithelium rises in both high and low cardiac output endotoxemic sepsis; Rosser DM et al.; The effect of endotoxin on tissue oxygen tension measured at the bladder epithelium was assessed in spontaneously breathing Sprague-Dawley rats anesthetized with halothane . Hyperdynamic (high cardiac output, group A, n = 6) and hypodynamic (low cardiac output, group B, n = 6) circulatory responses were achieved by intravenous administration of Escherichia coli lipopolysaccharide, 10 mg/kg over 30 min or 20 mg/kg over 1 min, respectively . Comparison was made against sham-operated control rats (group C, n = 6) . Aortic and renal blood flows increased in group A and fell in group B (P < 0.001) . However, in both groups, bladder epithelial oxygen tension rose significantly compared with control (P < 0.01), despite an increasing metabolic acidosis . This is in contradistinction to previous studies of nonseptic insults where bladder epithelial oxygen tension fell in line with an increasing arterial base deficit . If a raised tissue oxygen tension could be demonstrated in other organ beds, this would suggest that decreased utilization of oxygen rather than reduced tissue oxygen availability is responsible for the apparent anaerobic respiration seen in sepsis.

Res Commun Mol Pathol Pharmacol, 1995 Dec, 90(3), 413 - 21
Plasma levels of type II phospholipase A2 and cytokines in patients with sepsis; Endo S et al.; Plasma levels of type II phospholipase A2 (type II PLA2), cytokines and endotoxin were determined in patients with sepsis to investigate their interrelations and their role in the patient's prognosis . Type II PLA2 was measured by radioimmunoassay, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and IL-8 were each measured by enzyme-linked immunosorbent assay (ELISA) . Endotoxin was determined by a method based on an endotoxin-specific synthetic substrate . Plasma levels of type II PLA2 were significantly higher in the patients who died of sepsis than in those who survived the illness . There was a significant correlation between type II PLA2 and TNF-alpha and IL-6 . Type II PLA2, TNF-alpha, IL-6, and IL-8 may be useful as indices of disease severity . The results suggest that TNF-alpha and IL-6 stimulate the production of type II PLA2 in the plasma of patients with sepsis.

Ann Trop Paediatr, 1995 Dec, 15(4), 307 - 11
Role of body surface cultures in prediction of sepsis in a neonatal intensive care unit; Puri J et al.; An analysis of surface cultures of 35 preterm infants of less than 33 weeks gestational age hospitalized in a neonatal intensive care unit was made . The babies had received neither antiseptic nor antibiotic therapy prior to collection of specimens . Surface cultures were collected on the 4th or 5th day of life from 16 skin or mucosal sites . At the onset of a febrile episode within 14 days of collection of surface swabs, a blood culture was done on 31 infants (four did not develop fever) and the results were compared with the surface cultures . Sepsis was diagnosed by positive blood culture in twenty neonates (57.1%) . With this frequency of sepsis, the optimum sensitivity, specificity and positive predictive values of surface cultures were 60%, 27% and 60%, respectively . These values did not improve substantially for any anatomic site cultured or for any pathogen recovered . We conclude that surface cultures are of limited value in predicting the aetiology of sepsis in neonates.

Shock, 1995 Dec, 4(6), 425 - 32
Protective effects of hydroxyethyl starch-deferoxamine in early sepsis; Moch D et al.; The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats . Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure . Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes . In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point . At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05) . Glutathione and myoloperoxidase levels were less affected . Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO . Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator . Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals . In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis . Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.

Shock, 1995 Dec, 4(6), 403 - 10
Sepsis stimulates polyamine biosynthesis in the liver and increases tissue levels of ornithine decarboxylase mRNA; Tiao G et al.; The influence of sepsis on polyamine metabolism in the liver was studied in rats . Sepsis was induced by cecal ligation and puncture; control rats were sham-operated . Sepsis resulted in increased concentrations in liver tissue of putrescine and spermidine and stimulated activity of the enzymes ornithine decarboxylase (ODC) and s-adenosylmethionine decarboxylase . A similar metabolic response was seen following the subcutaneous injection of 1 mg/kg of endotoxin or following the e intraperitoneal injection of 100 micrograms/kg of human recombinant tumor necrosis factor (TNF)-alpha or interleukin-1 alpha (IL-1 alpha) . ODC mRNA levels determined by Northern blots were increased in liver tissue of septic rats, suggesting that the increase in ODC activity may be regulated at the transcriptional level although increased stability of the messenger could give rise to similar results . Treatment of rats with either TNF antiserum, recombinant IL-1 receptor antagonist, or the glucocorticoid receptor antagonist RU 38486, did not prevent the sepsis-induced increase in hepatic ODC activity . The data suggest that sepsis stimulates the biosynthesis of polyamines in liver tissue and that this response to sepsis may not primarily be mediated by TNF, IL-1, or glucocorticoids . The biological role of increased liver polyamines during sepsis, in particular their relationship with the synthesis of acute phase proteins, remains to be determined.

Anaesthesist, 1995 Dec, 44 Suppl 3, S573 - 9
{Analgesia and sedation on patients with sepsis syndrome}; Adams HA; AIMS AND PATHOPHYSIOLOGY . Intensive care patients are exposed to a number of noxious stimuli . They require individual analgesia and sedation to reduce and moderate the stress response to endogenous and exogenous stressors . In patients with SIRS (systemic inflammatory response syndrome), pathophysiological conditions with multiple organ dysfunction or failure demand special efforts and a specific regimen of analgosedation . The main goals are the absence of cardiocirculatory depression or, if at all possible, cardiocirculatory stabilization, absence of negative pulmonary, renal, hepatic and immunological side effects, preservation of a moderate stress response, and vertical and horizontal control appropriate to the clinical situation . CHARACTERIZATION OF ANALGETICS AND SEDATIVES . Amongst the analgesic drugs, opioids and morphine have moderate cardiocirculatory side effects, but reduce the intestinal motility . Due to intrinsic sympathomimetic activity, ketamine has stabilizing cardiocirculatory effects, reduces the exogenous catecholamine requirement and has no negative gastrointestinal side effects . Amongst the sedative drugs, midazolam has only moderate cardiocirculatory side effects . Propofol has cardiovascular depressant properties, but horizontal control of propofol sedation is excellent . CONCLUSION . The pharmacological profile of analgesic and sedative components suggests, that the combination of ketamine and midazolam can be recommended for analgosedation of patients with SIRS . This is supported by several clinical investigations . In specific situations, that require excellent vertical control, the combination of ketamine and propofol should be preferred.

Br J Plast Surg, 1995 Dec, 48(8), 546 - 50
Free flaps in the management of intrathoracic sepsis; Perkins DJ et al.; Experience with 5 free flaps, 1 TRAM and 4 latissimus dorsi flaps, transferred intrathoracically for the management of chronic sepsis is described . Healing and elimination of sepsis was achieved in all cases despite the infection being resistant to all previous more traditional forms of treatment including thoracoplasty . The results were achieved with minimal morbidity and argue for the early consideration of free flaps in the management of chronic intrathoracic sepsis in appropriate circumstances . A review of the limited available literature concerning this topic is presented.

J Surg Res, 1995 Dec, 59(6), 783 - 6
Mixed-function oxidase activity in sepsis; Godellas CV et al.; Hepatic dysfunction is a major contributor to death in multiple organ system failure . To evaluate whether this dysfunction increases with the length of sepsis, we studied the effect of fulminant CLP peritonitis with hyperoxia on mixed-function oxidase-MFO (cytochrome P450 content and activity) and lipid peroxidation in rat livers . Livers were harvested at 18, 21, 24, and 27 hr, homogenized, and microsomal fractions prepared . Cytochrome P450 concentration was determined by assay and P450 activity was determined by the metabolism of ethoxyresorufin and ethoxycoumarin . Lipid peroxidation was estimated by measuring malondialdehyde content . Septic rats showed decreases in P450 levels and activity, which worsened with duration of sepsis . These decreases were partially lessened by hyperoxia . Although there was a trend toward increased lipid peroxidation, this effect was not statistically significant . This study suggests that while MFO content and activity decrease with sepsis, these decreases do not appear to be related to the production of oxygen-derived free radicals . Furthermore, hyperoxia actually appears to have a protective role in this instance.

J Surg Res, 1995 Dec, 59(6), 658 - 65
A new model of intraabdominal abscess: usefulness for hydrosaline metabolism studies in parenteral nutrition associated with sepsis; Guirao X et al.; The present study was set up to develop a new model of intraabdominal abscess (IAA) useful for hydrosaline metabolism studies based on the ligation of the appendix (AL) and wrapping of the appendix tip with omentum . Two experiments were designed: (1) to characterize the model and (2) to investigate extracellular volume (ECV) changes during parenteral nutrition (PN) . Four groups of rabbits were studied at 3 (3DA) and 7 days (7DA) after AL or sham operation . PN was given for 6 days to two groups of septic rabbits: high volume HV) and low volume (LV) groups received 100 and 70 ml/kg.day of water with 7 and 0 meq/day of ClNa, respectively . Serum albumin (SA), ECV, and weight, water and sodium balances were determined . In 3DA, weight loss, reduced spontaneous intake, negative water balance, and reduction in SA were noted . Low SA, higher weight loss, and reduced intake were still observed in 7DA . SA correlated with ECV (r2 = 0.61, P = 0.003) in 7DA . Positive nitrogen balance was achieved during PN . The HV group had higher water and sodium balances than LV . In the HV group only, SA negatively correlated with sodium balance and with ECV at the end of PN (r2 = 0.87, P = 0.0007 and r2 = 0.9, P = 0.0001) . The impact on hydrosaline metabolism of IAA in this model resembles that of moderate sepsis in humans . SA decrease appears to have two major components: escape around the inflammatory area and dilution . ECV expansion after PN is influenced by the initial SA concentration.

Crit Care Med, 1995 Dec, 23(12), 1997 - 2007
Goal-directed therapy with dopexamine, dobutamine, and volume expansion: effects of systemic oxygen transport on hepatic ultrastructure in porcine sepsis; Tighe D et al.; OBJECTIVES: Can the hepatic structural deterioration that occurs during peritonitis be attenuated by increasing cardiac output and oxygen consumption (VO2)? Do the agents used to achieve these increases have any characteristic affects on these hepatic structural changes? DESIGN: Randomized, prospective, observational animal study . SETTING: Research laboratory of a university medical school . SUBJECTS: Twenty-five Middle White adolescent pigs, weighing 25 to 30 kg, divided into five groups . INTERVENTIONS: A thermodilution flotation catheter was advanced into the pulmonary artery . Additional catheters were inserted into the jugular, portal, and hepatic veins, and into the femoral artery . Ultrasound flow probes were placed around the portal vein and the hepatic artery . A metabolic cart was attached to the ventilator . Baseline measurements were made and cardiac output was increased by > 25% by administering either dobutamine (10 micrograms/min), dopexamine (10 micrograms/kg/min), or colloid . A control group had its cardiac output maintained at its baseline value . Peritonitis was induced in the four groups by contamination with cecal content and maintained for 6 hrs . Hepatic tissue was then removed for ultrastructural analysis and the animals were killed . MEASUREMENTS AND MAIN RESULTS: Before infection, cardiac output, VO2, and hepatic blood flow were increased in the three treatment groups . In the dobutamine and dopexamine groups, oxygen delivery increased, but decreased in the volume group . Mean arterial pressure increased in the dobutamine and dopexamine groups, but in the volume group, mean arterial pressure was maintained . Six hours after infection, cardiac output and VO2 had further increased in the dobutamine and volume groups, but both variables had decreased in the dopexamine group . After infection in the control group, cardiac output had decreased, although oxygen delivery and VO2 increased . There were no significant differences between hepatic hemodynamic or oxygen transport variables in any of the groups during the infection period . Hepatic ultrastructure was well maintained in the dopexamine group, while considerable deterioration was seen in the volume and control groups . In the dobutamine group, hepatic deterioration was greater than in the other three groups . CONCLUSIONS: Increasing cardiac output and VO2 before and during infection was only protective when dopexamine was administered . Dobutamine infusion was associated with greater hepatic deterioration than that effect seen in either the control or volume groups.

Crit Care Med, 1995 Dec, 23(12), 1945 - 53
Anti-interleukin-6 antibody treatment improves survival during gut-derived sepsis in a time-dependent manner by enhancing host defense; Gennari R et al.; OBJECTIVE: To determine the in vivo neutralizing activities of anti-interleukin-6 (IL-6) antibody on survival rate and host defense in a clinically relevant model of infection . DESIGN: Prospective, randomized, experimental animal study . SETTING: University and Shriners Burns Institute research laboratories . SUBJECTS: Two hundred seventy-six adult, female Balb/c mice . INTERVENTIONS: Balb/c mice were treated with 10 micrograms of antimurine IL-6 antibody, nonspecific murine immunoglobulin G (IgG), or placebo at 2, 4, or 8 hrs after they underwent bacterial challenge by gavage of 10(10) Escherichia coli and thermal injury . The survival rate was determined . The number of viable translocated bacteria, the total amount of translocation, and the percentage of bacteria that survived were also studied in different tissues . MEASUREMENTS AND MAIN RESULTS: Survival rate after burn and gavage was significantly improved in animals treated with antimurine IL-6 antibody at 2 and 4 hrs but not at 8 hrs after injury compared with control animals treated with nonspecific IgG or saline . The IL-6 serum concentration was significantly lower after burn and gavage in the animals treated 2 and 4 hrs after injury compared with nontreated animals . Better killing of translocated bacteria was observed in the tissues of animals treated with antimurine IL-6 antibody 2 hrs after injury . CONCLUSIONS: Treatment with antimurine IL-6 antibody at 2 and 4 hrs after injury, but not at 8 hrs after injury, positively affects outcome during gut-derived sepsis . Moreover, the beneficial effect of treatment after 2 hrs was related to an enhanced clearance of translocated bacteria.

Res Commun Mol Pathol Pharmacol, 1995 Nov, 90(2), 277 - 88
Blood levels of endothelin-1 and thrombomodulin in patients with disseminated intravascular coagulation and sepsis; Endo S et al.; We evaluated the roles of plasma endothelin-1 and plasma thrombomodulin in the development of disseminated intravascular coagulation (DIC) in patients with sepsis . Plasma endothelin-1 was measured by radioimmunoassay (RIA) . Plasma thrombomodulin and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay (ELISA), and serum protein C (protein C) was measured by the synthetic substrate method . Endotoxin was measured by the Endospecy test, a synthetic substrate method . A new perchloric acid method was used for the pretreatment of plasma . Blood levels of endothelin-1 and thrombomodulin were significantly higher in patients with DIC than in those without DIC (p < 0.0001) . Endothelin-1 and thrombomodulin levels were positively correlated (r = 0.8645, p = 0.0001), as were endothelin-1 and TNF-alpha levels (r = 0.5441, p = 0.0002) . Thrombomodulin and protein C levels were negatively correlated (r = -0.5627, p = 0.0001) . Endotoxin was elevated above the normal level 14.3% (6/42) for these patients . TNF-alpha is involved in the production of endothelin-1 and thrombomodulin, which play a role in the pathogenesis of DIC and whose blood levels reflect its severity.

Sao Paulo Med J, 1995 Nov-Dec, 113(6), 1053 - 60
Hypertonic volume therapy: feasibility in the prevention and treatment of multiple organ failure and sepsis; Monteiro Pacheco A Jr et al.; Small-volume resuscitation by means of bolus infusion of hypertonic saline solutions was first applied for the primary treatment of severe hemorrhagic and traumatic shock and promptly restored central hemodynamics and regional organ blood flow . Mechanisms of action are diverse--i . maintenance of high cardiac output (direct myocardial stimulation; increase in intravascular volume); ii . maintenance of peripheral arterial vasodilation (effect of hyperosmolality; plasma volume effect) and iii . reduction of tissue edema (shifting of tissue water along the osmotic gradient) . These mechanisms promote the restoration of the severely impaired microcirculation frequently seen also in sepsis . Hypertonic volume therapy has been the object of several experimental studies of acute hyperdynamic endotoxemia, however, a greater number of clinical studies have to be developed for the better understanding of the positive, and perhaps hazardous, effects of small-volume resuscitation in sepsis and multiple organ failure . The aim of this paper is to review the concepts involving such solutions, and their potential use in treatment of profound hypovolemia and microcirculatory deterioration associated with sepsis and endotoxic shock.

Mycoses, 1995 Nov-Dec, 38(11-12), 467 - 71
Peracute disseminated fatal Aspergillus fumigatus sepsis as a complication of corticoid-treated systemic lupus erythematosus; Nenoff P et al.; Immunocompromised and granulocytopenic patients and those receiving long-term or high-dose corticoid treatment are predisposed to disseminating Aspergillus infections . However, Aspergillus infection has been described only rarely in patients with autoimmune diseases . We report on a woman suffering from systemic lupus erythematosus treated by antibiotics and high-dose corticosteroids, a primary risk factor, who developed a peracute disseminated fatal Aspergillus fumigatus infection involving the central nervous system . The present case is compared with 10 previous reports of invasive aspergillosis in systemic lupus erythematosus found by a literature search.

Anesteziol Reanimatol, 1995 Nov-Dec, (6), 9 - 11
{Assessment of the severity of patient status in sepsis and septic shock}; Rudnov VA et al.; A score for quantitative evaluation of the severity of clinical status has been created for a more objective assessment of the clinical status of patients with sepsis and septic shock . The system includes five sections: physiological parameters, level of respiratory support, age, localization of the focus, concomitant diseases . The final score represents a sum of scores for the above sections . ROC analysis demonstrated a higher prognostic value of the proposed score in comparison with the APACHE-II for patients with grave sepsis.

Intensive Care Med, 1995 Nov, 21 Suppl 2, S264 - 8
Coagulation inhibitor substitution during sepsis; Fourrier F et al.; This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis . Activation of the contact system induces activation of the classical complement pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis . Physiologic inhibition depends on the C1-inhibitor (C1-Inh.) . Septic patients exhibit a relative deficiency of biologically active C1-Inh . Substitution with concentrations of C1-Inh has been safely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septic shock . The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIC . Endothelial and monocyte generation of tissue factor (TF) is activated by bacterial products and endotoxin . Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPI) . The potential for TFPI substitution to inhibit the activation of the coagulation cascade in sepsis requires further study . Thrombin generation is inhibited by antithrombin III (AT III) and the protein C-protein S system . During sepsis, AT III is consumed and degraded by elastase . Animal studies have shown that DIC and death were prevented by high doses of AT III concentrates . Although a significant reduction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of AT III substitution in human sepsis is still debated . None of the studies was able to document a statistically significant reduction in mortality . Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa . The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory protein . During sepsis, protein C activity is significantly reduced, either by acute consumption or by thrombomodulin down-regulation, and increased levels of plasma C4bBP inhibit protein S . Infusion of activated protein C and protein S substitution both protect animals from the lethal effects of bacteria . Combining these different coagulation inhibitors should be carefully studied before its use in septic patients is recommended.

Intensive Care Med, 1995 Nov, 21 Suppl 2, S258 - 63
Time course of cytokine levels in sepsis; Thijs LG et al.; In severe sepsis, a network of proinflammatory cytokines (TNF, IL-1 beta, IL-6, IL-8) is activated and blood levels of these cytokines are elevated, albeit inconsistently and with large individual variations . In addition, elevated blood levels of anti-inflammatory cytokines (IL-10), as well as of soluble cytokine receptors (sTNF-RI and II, IL-1ra), have been found . They seem to have a regulatory function in the host response . Levels of TNF and IL-6 are usually highest at the time of admission, whereas the time course of IL-1 beta levels (when detectable) can vary considerably . Limited data on IL-8 levels suggest that they may remain elevated for longer periods . Elevated levels of sTNFR and IL-1ra may also persist for a prolonged period of time . The pathogenetic significance of these observations is still unclear, but persistingly high levels of proinflammatory cytokines may be associated with organ failure and mortality.

Intensive Care Med, 1995 Nov, 21 Suppl 2, S244 - 9
The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis and septic shock; Salvo I et al.; This prospective, multicenter, epidemiological study was carried out in 99 Italian ICUs, distributed throughout the country, from April 1993 to March 1994 . In the study, we applied the new ACCP/SCCM classification system for sepsis (SIRS, sepsis, severe sepsis and septic shock) and determined the prevalence, incidence, evolution and outcome of these categories in critically ill patients . The preliminary analysis of 1101 patients showed that on admission SIRS accounted for about half of the diagnoses (52%) with sepsis, severe sepsis and septic shock accounting for 4.5%, 2.1% and 3% of patients, respectively . Patients with severe sepsis or septic shock more frequently had high SAPS scores than patients without sepsis . Mortality rates were similar in patients with SIRS (26.5%) and without SIRS or infection (24%), but rose to 36% in patients with sepsis, to 52% in those with severe sepsis and to 81.8% in those with septic shock . Sepsis, severe sepsis and septic shock were more common in patients with medical diagnoses, and neither severe sepsis nor septic shock was observed in trauma patients . With respect to evolution, the incidence of septic shock was progressively higher in patients admitted with more severe "sepsis-related" diagnoses, while only a trivial difference in rates of incidence was observed between SIRS patients and those admitted without SIRS or any septic disorder (nil) . The breakdown of the various ACCP/SCCM "sepsis-related" diagnoses at any time during the study was: SIRS in 58% of the population, sepsis in 16.3%, severe sepsis in 5.5% and septic shock in 6.1% . It seems reasonable to expect from the final evaluation of our study answers to the questions raised by the ACCP/SCCM Consensus Conference about the correlations between "sepsis-related" diagnosis, severity score, organ dysfunction score and outcome.

Shock, 1995 Nov, 4(5), 356 - 60
Increased plasma glucose clearance in sepsis is due to increased exchange between plasma and interstitial fluid; Chinkes D et al.; It has long been unclear why plasma glucose clearance is increased during sepsis, an insulin-resistant state . To address this issue, we studied sheep given a constant infusion of endotoxin for at least 24 h (n = 5) . We gave a bolus of 6,6 d2 glucose and determined the fractional exchange of glucose between plasma and interstitial fluid using compartmental modeling techniques . We found that exchange of glucose between plasma and interstitial fluid was significantly increased in sepsis, but the fractional clearance of glucose from interstitial fluid was not significantly altered . Thus the observed increased plasma glucose clearance was solely due to alterations in glucose exchange between plasma and interstitial fluid and was unrelated to glucose transport into cells.

Shock, 1995 Nov, 4(5), 318 - 23
Interleukin-1 mediates increased plasma levels of eicosanoids and cytokines in patients with sepsis syndrome; Slotman GJ et al.; The purpose of this was to study evaluate the effects of interleukin-1 (IL-1) inhibition by human recombinant IL-1 receptor antagonist (IL-1ra) on plasma prostaglandin, leukotriene, and cytokine levels in sepsis syndrome . As part of a multisite, prospective, randomized, double-blind, placebo-controlled clinical trial, 19 septic patients received IL-1ra in a 100 mg bolus followed by 2.0 mg/kg/h i.v . for 72 h (n = 10) or placebo (n = 9) . Plasma thromboxane B2 (TXB2), prostaglandin 6-keto-F1 alpha (PGI), leukotriene B4 (LTB4), leukotrienes C4D4E4 (LTC4D4E4), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF) were measured by ELISA before study drug infusion (baseline) and at 24, 48, 72, and 96 h after the beginning of the study drug infusion . Differences between placebo and IL-1-ra for plasma LTB4 and TNF were not significant . Plasma TXB2, PGI, LTC4D4E4, and IL-6, expressed as % baseline, were significantly lower in patients receiving IL-1ra than in the placebo group (p < .05), while plasma IL-1 was increased significantly . IL-1 may be a necessary mediator of increased circulating PGI, TXB2, LTC4D4E4, and IL-6 levels in patients with sepsis syndrome . Plasma IL-1 is increased with infusion of IL-1ra . The clinical significance of IL-1 in modifying circulating eicosanoid and cytokine concentrations in clinical sepsis is not clear from the data.

J Pediatr Surg, 1995 Nov, 30(11), 1600 - 2
Acute renal failure caused by fungal bezoar: a late complication of Candida sepsis associated with central catheterization; Yoo SY et al.; The authors report a case of acute renal failure caused by fungal bezoar in the renal pelvis . The patient was successfully treated with bilateral percutaneous nephrostomy drainage . He had been admitted because of necrotizing enterocolitis, at the age of 26 days . Eventually, his bowel was reduced to 40 cm of small intestine, including 5 cm of terminal ileum . Candida sepsis developed during central total parenteral nutrition, at the age of 76 days . Five weeks after the diagnosis of systemic candidiasis, sudden anuria developed, and ultrasonography showed echogenic material in both renal pelvises . Bilateral percutaneous nephrostomy catheters were placed in the renal pelvises, and local irrigation with amphotericin B was performed for 3 weeks . The renal function of the baby was completely recovered, without systemic antifungal treatment.

Eur J Clin Invest, 1995 Nov, 25(11), 843 - 51
Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure; Gawaz M et al.; This study focuses on the role of platelet membrane glycoproteins and platelet-leucocyte adhesion in patients with sepsis and multiple organ failure (MOF) . Specifically, the study raises the following issues: (1) the influence of sepsis and MOF on platelet activation as assessed by surface expression of platelet membrane glycoproteins GPIIb-IIIa and thrombospondin; and (2) the effect of sepsis and MOF on platelet adhesion to circulating leucocytes . In addition, platelet activation and platelet-leucocyte adhesion are evaluated according to clinical outcome . Forty-five patients with suspected sepsis or MOF were evaluated by intensive care scoring systems (APACHE II and Elebute) to assess severity of disease . Flow cytometric techniques were used to examine platelet membrane expression of various adhesion molecules on circulating platelets and the appearance of platelet specific antigen (CD41) on leucocytes as an index of platelet-leucocyte adhesion . The results were compared with severity of disease and according to outcome in patients . Twenty-eight patients of the total study population were septic and 17 were non-septic . Twenty-two of the 28 septic patients suffered from severe MOF (APACHE II > or = 20) whereas in six septic patients MOF was absent . Eleven of the non-septic group suffered from moderate MOF whereas in six, severe MOF was present . In septic patients fibrinogen receptor activity on platelets was significantly above normal values (P < 0.001) . When MOF was present, thrombospondin surface expression on circulating platelets also increased significantly (P < 0.05) . Concomitantly, platelet-leucocyte adhesion was increased in sepsis (P < 0.05) and decreased in patients with MOF (P < 0.05) . Significant lower levels of circulating platelet-leucocyte aggregates occurred in non-survivors (P < 0.05) . We conclude that sepsis is associated with increased surface expression of platelet adhesion molecules and an increased occurrence of circulating platelet-leucocyte aggregates . The decrease in circulating platelet-leucocyte peripheral sequestration . An increased platelet-leucocyte adhesion and sequestration might account for development of MOF in the course of sepsis.

Pediatr Radiol, 1995 Nov, 25 Suppl 1, S212 - 7
Sinusitis and intracranial sepsis: the CT imaging and clinical presentation; Saxton VJ et al.; The CT imaging and clinical presentation in 14 children with coexistent intracranial sepsis and sinusitis were reviewed . A routine CT head scan (10-mm thick semi-axial slices through the cranium done before and after intravenous contrast medium administration) was found to be an inadequate initial investigation as the intracranial collection was missed in four patients and the abnormal sinuses not shown in six . In half the children the diagnosis of sinusitis was unsuspected at the time of admission . The dominant clinical features were fever, intense headache and facial swelling in early adolescent males . In this clinical setting we recommend: (1) the routine scan is extended through the frontal and ethmoidal sinuses and photographed at a window level and width showing both bone detail and air/soft tissue interfaces; (2) direct coronal projections are performed through the anterior cranial fossa if no collection is seen on the routine study; (3) an early repeat scan within 48 h if the initial study shows no intracranial pathology but the fronto-ethmoidal sinuses are abnormal and there is a high clinical suspicion of intracranial sepsis; and (4) in the presence of intracranial sepsis the vault is viewed at bone window settings to exclude cranial osteomyelitis.

New Horiz, 1995 Nov, 3(4), 732 - 7
Continuous hemofiltration as blood purification in sepsis; Bellomo R; Continuous hemofiltration was first described as a new form of renal replacement for critically ill patients in the late 1970s . Since then, it has undergone remarkable technical and conceptual modifications and has become a widely used form of dialytic therapy in the ICU . More recent insights into the pathogenesis of sepsis and the role of soluble molecules in the mediation of organ injury during septic shock have led to a resurgence of the concept of blood purification during life-threatening infection . Recent studies have confirmed that cytokine extraction occurs in vivo in humans during continuous hemofiltration and that other smaller, potentially noxious molecules such as platelet-activating factor, complement factors C5a and C3a, and thromboxane are also removed from the circulation of septic patients or animals . Experimental studies have shown that continuous hemofiltration has beneficial hemodynamic effects in septic animals and that such effects may correlate with the intensity of ultrafiltration . Cardiac function also appears to improve and myocardial depressant factors are removed from the circulation . Continuous hemofiltration offers some promise as an adjunctive form of treatment in severe sepsis.

New Horiz, 1995 Nov, 3(4), 608 - 14
Sepsis or ischemia in experimental acute renal failure: what have we learned?
Johnson JP, Rokaw MD.
Acute renal failure (ARF) has been studied in experimental settings for many years and has led to many insights into the cell biology of renal injury . The development of more clinically relevant models of renal injury combining endotoxemia, hypoperfusion, and nephrotoxins has led to a new appreciation of the role of the immune system in the pathogenesis of ARF . Endotoxin produces profound declines in renal blood flow even when systemic pressures are preserved, and this effect appears to be mediated by systemically and locally generated vasoactive factors including cytokines, platelet-activating factor, endothelin, and adenosine . Activated neutrophils (PMN) contribute to injury through the generation of cytokines, production of oxidants, or interactions with renal endothelium . Specific inhibition of immune activation at various steps has been shown to ameliorate the course of experimental endotoxic and ischemic ARF . Inhibition of PMN adhesion to endothelial cells by monoclonal antibodies to binding proteins, and blockade of thromboxane or interleukin action with specific inhibitors have all been shown to improve renal outcome in experimental ARF . These studies demonstrate that immunologically activated mediators are important in the pathogenesis of ARF in sepsis . Strategies to reduce the levels or to block the binding of specific cytokines may hold promise for the treatment of ARF in the critically ill.

Kidney Int, 1995 Nov, 48(5), 1563 - 70
Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances; Hoffmann JN et al.; Continuous hemofiltration is widely used for renal replacement therapy in patients with acute renal failure . It has been suggested that hemofiltration may also eliminate toxic mediators thought to be important in the pathophysiology of sepsis . The present study examined whether hemofiltration can activate or eliminate inflammatory mediators in patients with sepsis, and whether ultrafiltrate can alter specific functions of peripheral blood mononuclear leukocytes (PBMC) in vitro . Veno-venous hemofiltration was performed in 16 patients and in 5 healthy volunteers . Pre-filter (afferent), post-filter (efferent) and ultrafiltrate concentrations of cytokines (IL-1 beta, IL-6, IL-8, TNF alpha) and of complement components (C3, C3adesArg, C5adesArg, terminal complement complex) were measured after the beginning of hemofiltration (t0), and 60 minutes later (t60) . PBMC, and monocyte and lymphocyte subfractions were incubated with ultrafiltrate, and cytokines were determined in the supernatants . Hemofiltration did not induce significant mediator activation . There was no evidence for significant cytokine elimination . However, pre-filter C3adesArg concentration showed a significant decline during hemofiltration (patients: t0 = 676.9 +/- 99.7 ng/ml, t60 = 545.4 +/- 83.2, P < 0.001; volunteers: t0 = 54.8 +/- 13.3 ng/ml, t60 = 33.9 +/- 10.7, P < 0.001) . Ultrafiltrate from septic patients significantly stimulated PBMC and monocyte TNF alpha release, but suppressed lymphocyte IL-2 and IL-6 production . Ultrafiltrate from volunteers was without effect . Hemofiltration effectively eliminates certain mediators such as C3adesArg . Ultrafiltrate contains compounds with significant immunomodulatory qualities . Therefore, hemofiltration may represent a new modality for removal of immunomodulatory mediators.

Br J Surg, 1995 Nov, 82(11), 1460 - 7
Manipulation of local and systemic host defence in the prevention of perioperative sepsis; Windsor AC et al.; This review addresses some of the immunological issues surrounding the complex problem of perioperative sepsis . It identifies an immunological paradox between the relative immunosuppression of the immediate postoperative period and the relative immune activation of established sepsis, in addition to discussing current knowledge of the mechanisms surrounding these phenomena . Much remains unknown about perioperative immunoregulation; there are a number of potential mechanisms, however, whereby local and systemic immune defences can be modified or enhanced . Provided patients at risk can be identified, such manipulations may find application in preventing infection and sepsis after surgery.

Rev Esp Enferm Dig, 1995 Nov, 87(11), 817 - 20
{Intestinal obstruction and sepsis caused by Torulopsis glabrata}; Antequera Perez A et al.; A 27-year-old woman previously diagnosed of aplastic anemia secondary to treatment with gold salts for rheumatoid arthritis, presented with an episode of intestinal occlusion with acute renal failure . A CT scan revealed dilated intestinal loops, thickening of the ileum wall without cecal involvement, and multiple punctuate lesions (micro-abcesses) of liver, spleen and kidneys . At laparotomy, one meter of proximal jejunum was resected . The cultures of jejunal biopsy specimens yielded Torulopsis glabrata . The patient underwent multiorgan failure and died on the 8th postoperative day.

Pancreas, 1995 Nov, 11(4), 365 - 73
The influence of abdominal sepsis on acute pancreatitis in rats: a study on mortality, permeability, arterial pressure, and intestinal blood flow; Andersson R et al.; Bacterial infection increases mortality and morbidity in acute pancreatitis . The aim of the present study was to analyze possible mechanisms by which bacterial infectious complications may worsen the course of the disease . Systemic arterial pressure, mucosal microcirculation, and intestinal, peritoneal, and pulmonary permeability of 125I-labeled human serum albumin were measured 3, 6, 12, 24, 48, and 72 h after sham operation, induction of pancreatitis (AP), abdominal sepsis (AS), or AP+AS . The mortality rate at 48 and 72 h was 33% in AS and 58 and 75%, respectively, in AP+AS, whereas there were no deaths in the AP or sham-operated groups . The systemic arterial pressure and intestinal blood flow decreased early in all study groups, with the lowest values for AP+AS . Bacterial infection aggravated the increase in intestinal, peritoneal, and pulmonary permeability to labeled albumin in pancreatitis . This was true for both intestinal endothelial permeability (blood to tissue) and mucosal barrier permeability (blood to lumen) . The findings demonstrate the occurrence of circulatory failure and changes of the capillary barrier in multiple organs in acute pancreatitis . Moreover, the changes were aggravated by an intraabdominal septic challenge . The observations imply that bacterial infection may play a role in the development of multiple organ failure in acute pancreatitis, tentatively by aggravating alterations in tissue barrier function.

J Formos Med Assoc, 1995 Nov, 94(11), 655 - 9
Density of muscarinic receptors in rat myocardium during early sepsis; Hwang TL et al.; The muscarinic receptor changes in two subcellular fractions of rat myocardium during sepsis, the sarcolemma (SL) and light vesicles (LV), were studied . {3H}-quinuclidinyl benzilate ({3H}-QNB) was used as a radioligand . Sepsis was induced by cecal ligation and puncture (CLP) . The septic rats had higher pulse rates and slightly higher blood glucose levels than control rats . The marker enzyme assays revealed that the SL fraction was enriched with 5'-nucleotidase and the Na(+)-K(+)-ATPase activity increased over 20-fold, while the LV fraction showed very little enrichment when compared with the homogenate . {3H}-QNB binding studies showed that Bmax increased by 58.8% in SL with no changes in LV during early sepsis (9 h post-CLP), but there was no significant change in the Kd value . These data indicate that muscarinic cholinergic receptors in rat heart SL increase during early sepsis . Since the muscarinic cholinergic receptors mediate parasympathetic modulation of myocardial contractility, changes in the number of muscarinic receptors in the cardiac SL may have a pathophysiologic significance in the development of hemodynamic changes during sepsis.

J Am Coll Surg, 1995 Nov, 181(5), 431 - 6
Failure of intestinal amino acid absorptive mechanisms in sepsis; Gardiner KR et al.; BACKGROUND: Sepsis has been shown to impair the barrier function and metabolism of the intestine . This study was done to investigate the effect of sepsis on intestinal absorption of proline, leucine, glutamic acid, and aminoisobutyric acid . STUDY DESIGN: Rats (six per group) were studied 24 hours after cecal ligation and puncture (CLP) or six hours after intraperitoneal injection of lipopolysaccharide (LPS) . Controls underwent sham laparotomy or saline solution injection . Four 7-cm everted proximal jejunal sacs were prepared from each rat and filled with 800 microL Krebs' bicarbonate buffer containing 100 mumol/L of amino acid . Paired sacs (septic and control) were incubated at 37 degrees C in flasks containing the same solution trace labeled with 3H containing the same solution trace labeled with 3H amino acid . Sac contents were aspirated 60 minutes later and amino acid uptake was determined by scintillation counting . RESULTS: Twenty-four hours after CLP and six hours after LPS administration there was significant impairment in the intestinal absorption of all amino acids studied . Absorption of glutamic acid was the least affected, followed by leucine, aminoisobutyric acid, and proline . CONCLUSIONS: Sepsis impairs the intestinal absorption of amino acids . The magnitude of this defect in absorption differed with the amino acid studied, suggesting that not all transport systems were affected equally . This differential response of transport systems to sepsis appears to be the inverse of what is observed after a period of starvation.

Am J Physiol, 1995 Nov, 269(5 Pt 2), R988 - 94
Endothelium-dependent relaxation is depressed at the macro- and microcirculatory levels during sepsis; Wang P et al.; The objective of this study was to determine whether endothelium-derived nitric oxide (NO) production is reduced at the macrocirculatory and microcirculatory levels during sepsis . To examine this, rats were subjected to sepsis by cecal ligation and puncture (CLP) . At 5 h after CLP (i.e., midpoint of hyperdynamic sepsis) or sham operation, the aorta and superior mesenteric artery were isolated . Responses to an endothelium-dependent vasodilator, acetylcholine (ACh), and an endothelium-independent vasodilator, nitroglycerin (NTG), were determined . In additional studies, the small intestine was isolated 5 or 20 h (hypodynamic sepsis) after CLP . Responses to ACh and NTG were determined in the isolated intestine . The results indicate that endothelium-dependent relaxation in both the aorta and superior mesenteric artery was depressed at 5 h after CLP . In contrast, there was no significant difference in the relaxation induced by NTG . Moreover, ACh-induced vascular relaxation in the isolated small intestine decreased at 5 and 20 h post-CLP without any significant alterations in NTG-induced relaxation . Since studies have shown that ACh-induced relaxation in the aorta is reduced at 20 h after CLP, it could be concluded that endothelium-derived NO release is depressed during hyperdynamic and hypodynamic stages of sepsis, not only in large arteries, but also at the microcirculatory level.

Am J Physiol, 1995 Nov, 269(5 Pt 1), E977 - 81
Insulin-like growth factor I accelerates protein synthesis in skeletal muscle during sepsis; Jurasinski CV et al.; Sepsis causes an inhibition of protein synthesis in gastrocnemius that is resistant to the anabolic effects of insulin . The purpose of the present studies was to investigate the effect of recombinant human insulin-like growth factor I (IGF-I) on protein synthesis during a 30-min perfusion of the isolated rat hindlimb from septic rats . Inclusion of IGF-I (1 or 10 nM) in the perfusate stimulated protein synthesis in gastrocnemius of septic rats 2.5-fold and restored rates of protein synthesis to those observed in control rats . The stimulation of protein synthesis did not result from an increase in the RNA content but was correlated with a 2.5-fold increase in the translational efficiency . The enhanced translational efficiency was accompanied by a 33 and 55% decrease in the abundance of free 40S and 60S ribosomal subunits, respectively, indicating that IGF-I accelerated peptide-chain initiation relative to elongation/termination . These studies provide evidence that IGF-I can accelerate protein synthesis in gastrocnemius during chronic sepsis by reversing the sepsis-induced inhibition of peptide-chain initiation.

Arch Surg, 1995 Nov, 130(11), 1209 - 15; discussion 1215-6
The possible role of a central nervous system dopaminergic mechanism in hepatic c-fos protein expression following peritoneal sepsis; Roy S et al.; OBJECTIVE: To investigate the hypothesis that a central dopaminergic mechanism may regulate hepatic c-fos and c-jun gene expression following peritoneal sepsis . METHODS: First, dopamine or vehicle was instilled into a stereotaxically placed intracerebral-ventricular (ICV) cannula with or without D1 (SCH 23390) or D2 (haloperidol) antagonist pretreatment in a rat model, and the effect on hepatic c-fos or c-jun protein expression was investigated . Second, we investigated the effect of haloperidol and vehicle treatment following cecal ligation and puncture (CLP)-induced sepsis with respect to hepatic c-fos protein expression, c-jun protein expression, and survival . RESULTS: Intracerebral-ventricular dopamine treatment increased hepatic c-fos immunoreactive protein but had no effect on hepatic c-jun immunoreactive protein expression . Pretreatment with SCH 23390 inhibited ICV dopamine treatment-induced hepatic c-fos immunoreactive protein expression . Haloperidol pretreatment synergized with ICV dopamine treatment to overexpress hepatic c-fos protein . Haloperidol treatment significantly increased CLP-induced hepatic c-fos and c-jun protein expression and improved survival following CLP . CONCLUSIONS: Hepatic c-fos protein expression may be regulated, in part, by a central nervous system-mediated dopaminergic D1 receptor mechanism . Treatment with the D2 receptor antagonist, haloperidol, increases sepsis-induced hepatic c-fos and c-jun protein expression and improves survival following peritoneal contamination.

Arch Surg, 1995 Nov, 130(11), 1178 - 84; discussion 1184-5
Does endotoxin play a major role in inducing the depression of macrophage function during polymicrobial sepsis?
Ayala A, Deol ZK, Lehman DL, Herdon CD, Chaudry IH.
BACKGROUND: Endotoxin (ETX) is thought to be the primary inducer of proinflammatory mediator release associated with bacterial sepsis . Furthermore, a number of studies indicate that preexposure of animals to high doses of ETX produces macrophages (M luminal diameters) that are refractory to ex vivo stimulation with ETX . However, it is unknown if levels of ETX comparable to those typically encountered in sepsis induce a similar refractory state in M luminal diameters . DESIGN: To assess this, peritoneal M luminal diameters (PM luminal diameters) were harvested from C3H/HeN mice (ETX sensitive) at 1 hour (early) or 24 hours (late) following cecal ligation and puncture (CLP) to induce polymicrobial sepsis, sham CLP, or laparotomy followed by peritoneal implantation of a minipump delivering either saline or ETX (0.025 microgram/g of body weight, every 24 hours) . Peritoneal M luminal diameter cultures were incubated with ETX, either 0 or 10 micrograms/mL, for 24 hours, and their ability to release interleukin-1, interleukin-6, and tumor necrosis factor was assessed by bioassay . RESULTS: Chronic low-dose ETX with 0 microgram of ETX media added produced early (at 1 hour) in vivo activation of PM luminal diameter interleukin-1 release, which was comparable to that seen in mice subjected to CLP . However, unlike PM luminal diameter taken from CLP mice, PM luminal diameters from mice implanted with the ETX minipump at 1 or 24 hours showed no marked decline in their ability to respond to ETX (10 micrograms) . Comparable changes were seen for interleukin-6 and tumor necrosis factor release . CONCLUSIONS: Bacterial component(s) other than ETX per se induces the sustained dysfunction in PM luminal diameter capacity to produce proinflammatory cytokines during sepsis and/or peritonitis . Thus, agents directed against ETX alone may not be adequate in the treatment of polymicrobial sepsis.

Arch Surg, 1995 Nov, 130(11), 1171 - 6; discussion 1176-7
Except for alanine, muscle protein catabolism is not influenced by alterations in glucose metabolism during sepsis; Gore DC et al.; OBJECTIVE: To assess any relationship between hyperglycemia and muscle protein catabolism associated with critical illness . DESIGN: Cohort analytic study . SETTING: Clinical research center and intensive care unit of a university hospital . PARTICIPANTS: Six healthy volunteers and five patients with severe sepsis . INTERVENTIONS: Study subjects were given infusions of 6,6,d2 glucose and 15N lysine for 6 hours . After infusion of the stable isotopes for 2 hours (basal period), dichloroacetate, which accelerates pyruvate oxidation, was given (dichloroacetate period) . Leg blood flow was measured by indocyanine green dye dilution, and femoral artery and vein substrate concentrations were quantitated . MAIN OUTCOME MEASURES: The metabolic rates of glucose production, oxidation, and clearance; the whole-body protein breakdown rate; and the net efflux of amino acids from the leg were determined . RESULTS: In comparison with the healthy volunteers, septic patients had significant elevations in glucose production, oxidation, and clearance, accelerated protein catabolism, and greater net peripheral efflux of amino acids . Dichloroacetate significantly decreased glucose production and increased the percentage of glucose directed toward oxidation in both healthy volunteers and septic patients . However, this dichloroacetate-induced perturbation of glucose utilization had no significant effect on whole-body protein breakdown or the efflux of specific amino acids from the leg except for alanine, whose net efflux doubled (P < or = .05) . CONCLUSIONS: The findings of this study demonstrate a universal acceleration in the metabolic rates of both intermediary glucose metabolism and protein/amino acid catabolism during sepsis . Except for alanine, however, there appears to be no coupling between these two physiologic responses to sepsis.

Clin Infect Dis, 1995 Oct, 21(4), 1032 - 4
Stenotrophomonas maltophilia: an unusual cause of biliary sepsis; Papadakis KA et al.; We report three cases of cholangitis caused by Stenotrophomonas maltophilia and review two other cases reported in the literature . All five episodes occurred in patients with hepatobiliary malignancy complicated by biliary tract obstruction . All five episodes occurred in patients with hepatobiliary malignancy complicated by biliary tract obstruction . All patients had undergone biliary tract instrumentation . Before infection developed, four of the five patients had received therapy with antibiotics that do not have in vitro activity against this organism . Four patients responded to appropriate antibiotic therapy and biliary tract decompression, whereas the fifth patient, who had persistent biliary obstruction, did not respond to appropriate antibiotic therapy.

Shock, 1995 Oct, 4(4), 269 - 73
Sustained elevation in circulating catecholamine levels during polymicrobial sepsis; Hahn PY et al.; Although studies have indicated that the levels of catecholamines increase during sepsis, it remains unknown whether the elevated levels of epinephrine, norepinephrine, and dopamine observed in early sepsis are sustained during late, hypodynamic stages of sepsis . In this study, rats were subjected to sepsis by cecal ligation and puncture (CLP, i.e., polymicrobial sepsis) . Immediately after CLP or sham operation, animals received 3 mL/100 g body weight normal saline subcutaneously . At .5, 2, 10 (i.e., early sepsis), or 20 h (late sepsis) after CLP, blood samples were drawn and the plasma was separated . Plasma levels of epinephrine, norepinephrine, and dopamine were determined using a {3H}-radioenzymatic assay . The results indicate that plasma levels of epinephrine, norepinephrine, and dopamine increased significantly as early as .5 h after CLP . The increase in catecholamine levels persisted throughout the study periods . Thus, circulating levels of catecholamines were elevated in both early and late stages of polymicrobial sepsis . These results suggest that the increased catecholamine levels at .5-10 h after CLP may contribute to the hypermetabolic conditions that occur during early, hyperdynamic sepsis . However, there is a lack of an association between the elevated plasma catecholamine levels and hypometabolic/hypodynamic state in late sepsis.

Shock, 1995 Oct, 4(4), 257 - 61
Changes in inositol 1,4,5-triphosphate binding in microsomal fractions from the rat liver during sepsis; Hwang TL et al.; Inositol 1,4,5-triphosphate has been proposed as a second messenger for calcium mobilization . The addition of inositol 1,4,5-triphosphate at a low concentration has been shown to cause calcium release from intracellular microsomal stores in rat hepatocytes . The effects of sepsis on the inositol 1,4,5-triphosphate binding from microsomal fractions of rat liver were investigated . Sepsis was induced by cecal ligation and puncture (CLP) . Control rats were sham operated . Three microsomal fractions (rough, intermediate, and smooth I) were isolated from the rat liver . The study of inositol 1,4,5-triphosphate receptor binding was performed with tritium-labeled inositol 1,4,5-triphosphate . Our results showed that the Bmax of inositol 1,4,5-triphosphate binding in early septic, late septic, and control groups was 14.9 +/- .9 fmol/mg, 9.8 +/- 1.0 fmol/mg, and 17.2 +/- 1.3 fmol/mg, respectively . The binding activity was unaffected during early sepsis but was significantly depressed by 40-50% (p < .05, vs . control) during late sepsis (18 h after CLP) in all three subfractions of endoplasmic reticulum . Because the inositol 1,4,5-triphosphate binding plays an important role in the regulation of intra-cellular calcium homeostasis in hepatocytes, an impairment of the calcium release due to depressed inositol 1,4,5-triphosphate binding in the endoplasmic reticulum may have a pathophysiological significance in contributing to altered hepatic metabolism during septic shock.

J Obstet Gynecol Neonatal Nurs, 1995 Oct, 24(8), 725 - 33
Pathogenesis of sepsis with central venous catheter use: alternate locus-related versus central venous catheter-related sepsis; Chathas MK et al.; OBJECTIVE: To review literature identifying a central venous catheter (CVC) as either a primary or a secondary source of sepsis . DATA SOURCES: Studies of CVC use in adults, children, and infants from 1968 to 1994 . STUDY SELECTION: Selection of 10 studies was based on documented distinction between CVC-related and alternate infectious locus-related sepsis . DATA EXTRACTION: Abstracted from each study were either total sepsis or colonization rates, as well as the percentages of infection related to the CVC and to alternate infectious loci . DATA SYNTHESIS: Percentages of alternate-locus-related sepsis can be two to four times greater than percentages of CVC-related sepsis . CONCLUSIONS: The potential exists for the development of alternate-locus-related sepsis in patients with CVCs . Surveillance measures should reflect this potential.

Biochem J, 1995 Oct 1, 311 ( Pt 1), 203 - 8
Reduced expression of kan-1 (encoding putative bile acid-CoA-amino acid N-acyltransferase) mRNA in livers of rats after partial hepatectomy and during sepsis; Furutani M et al.; We isolated a cDNA clone, kan-1, from a rat liver cDNA library using a reverse transcriptase PCR cloning method . The kan-1 cDNA encoded a polypeptide of 420 amino acids, and was 70 and 69% identical in nucleotide and amino acid sequences respectively with human liver bile acid-CoA-amino acid N-acyltransferase (BAT) . Thus Kan-1 is probably a rat homologue of human BAT (rBAT) . Kan-1/rBAT mRNA was mainly expressed in the livers of adult rats and rats immediately after, but not before, birth . It was expressed in the hepatocytes, the sinusoidal endothelial cells and the Kupffer cells of the liver . An anti-Kan-1/rBAT polyclonal antibody detected a protein of molecular mass 46 kDa in the liver . After partial hepatectomy, the levels of Kan-1/rBAT mRNA decreased at 6 and 12 h in the regenerating liver . In a sepsis model, hepatic expression of Kan-1/rBAT mRNA decreased at 6 and 12 h after caecal ligation and puncture . The kinetics of Kan-1/rBAT mRNA expression suggests that it may play a role in acute-phase reactions.

Arch Surg, 1995 Oct, 130(10), 1115 - 22
Growth hormone and insulinlike growth factor I enhance host defense in a murine sepsis model; Inoue T et al.; OBJECTIVE: To investigate the effects of exogenous growth hormone (GH) and insulinlike growth factor I (IGF-I) on host defense and survival in a murine model of Escherichia coli sepsis . DESIGN: Prospective randomized experimental trials . SETTING: Laboratory . MATERIALS: Nine-week-old female BALB/c mice . INTERVENTIONS: Mice were injected subcutaneously with 4.8 or 0.48 mg/kg of body weight per day of GH, 24 or 2.4 mg/kg of body weight per day of IGF-I or, as a control, normal saline solution, for 6 days . Mice were then challenged intraperitoneally with 1 x 10(8) colony-forming units per body of E coli . MAIN OUTCOME MEASURES: Fifty mice were observed for survival . In the next experiments, samples from the high-dose GH, high-dose IGF-I, and saline control groups were harvested before or at 4 or 6 hours after challenge . Numbers of peritoneal exudative cells and tissue-viable bacterial counts were determined . Peritoneal exudative cells were cultured with lipopolysaccharide (10 micrograms/mL) for 24 hours . Levels of tumor necrosis factor, interleukin-1, and interleukin-6 in the peritoneal lavage fluid, plasma and supernatants of peritoneal exudative cell culture were measured . RESULTS: Both high and low doses of GH and high-dose IGF-I significantly prolonged survival . Growth hormone and IGF-I significantly increased peritoneal exudative cell numbers and reduced viable bacterial counts in the peritoneal lavage fluid and the liver . These hormones significantly suppressed excessive systemic cytokine production, while enhancing in vitro cytokine production and preserving local cytokine responses . CONCLUSION: The immunomodulation produced by administration of GH or IGF-I leads to improved host defense in this murine model of E coli sepsis.

J Surg Res, 1995 Oct, 59(4), 460 - 7
Regulation of the transcription factor C/EBP alpha following peritoneal sepsis; Chapin RB et al.; The transcription factors C/EBP alpha and C/EBP beta belong to the leucine-zipper C/EBP (CCAAT/enhancer binding protein) family of DNA-binding proteins . C/EBP alpha and C/EBP beta are expressed in the liver and are implicated in the control of transcriptional events following following sepsis . It is hypothesized that inhibition of C/EBP alpha gene expression following sepsis may lead to some of the phenotypic features we recognize as sepsis syndrome such as decreased visceral protein (albumin) synthesis . In this study we demonstrate that C/EBP alpha mRNA accumulation is transiently inhibited 12 hr following peritoneal insult, consistent with previous data . However, we demonstrate that (1) there is increased binding of hepatic nuclear protein to the C/EBP alpha DNA response element 48 hr following insult, (2) a marked increase in C/EBP alpha protein is observed 48 hr following CLP insult compared with no increase in hepatic C/EBP alpha protein at 12 hr postinsult, (3) the increase in hepatic C/EBP alpha protein at 48 hr following cecal ligation and puncture is not associated with an increase in C/EBP alpha mRNA accumulation, (4) the increase in hepatic C/EBP alpha protein is associated with an increase in C/EBP beta protein, and (5) hepatic albumin mRNA accumulation is decreased at 12 and 48 hr following insult and does not correlate with the C/EBP alpha protein synthesis . We conclude that the possible role of the transcription factor C/EBP alpha with respect to decreased albumin gene expression following sepsis must be reevaluated.

J Surg Res, 1995 Oct, 59(4), 446 - 9
The beneficial effects of immunostimulation in posttraumatic sepsis; Austin OM et al.; Granulocyte macrophage-colony stimulating factor (GM-CSF) is a myelopoietic cytokine that may enhance immune mechanisms directed against bacterial infection . Injury is associated with an increased incidence of such infection . This study assessed the potential immunostimulatory role of GM-CSF in the injured host predisposed to infection . Six- to eight-week old female CD-1 mice underwent trauma and were then randomized to received either GM-CSF or saline vehicle control intraperitoneally for 5 days . They then received a septic challenge in the form of a cecal ligation and puncture . Following this, assessment was made of survival and bacterial growth indices in blood cultures, and peritoneal cells were harvested for assessment of peritoneal immune function . Intraperitoneal GM-CSF administration daily for 5 days following injury was associated with significantly greater survival following cecal ligation and puncture compared to controls (40 vs 5%, P < 0.05) . There was a significant increase in peritoneal cell yields in the GM-CSF group compared to the control group (11 +/- 1 x 10(6) vs 8 +/- 1 x 10(6) P < 0.05) . PMA-stimulated macrophages released significantly higher amounts of both superoxide anion (1.4 +/- 0.1 vs 0.93 +/- 0.1, P < 0.05) and tumor necrosis factor (5.2 +/- 0.6 vs 2.6 +/- 0.7, P < 0.03) and significantly less nitric oxide compared to the control group (175 +/- 8 vs 267 +/- 24, P < 0.003) . Finally, bacterial growth indices were significantly reduced following GM-CSF administration (194 +/- 6 vs 218 +/- 4, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

J Trauma, 1995 Oct, 39(4), 635 - 40
Increased levels of circulating interleukin-8 in patients with large burns: relation to burn size and sepsis; Vindenes H et al.; Large burns are followed by significant trauma-induced immunomodulation, and activated neutrophils can be demonstrated in the circulation of burn patients shortly after injury . Interleukin-8 (IL-8) is a recently described molecule with neutrophil activating properties and in the present study we have measured the concentration of this cytokine in plasma from 27 patients with large burns during hospitalization using an enzyme linked immunosorbent assay (ELISA) . The mean patient plasma concentration of IL-8 at admission was about 60 times higher than that of healthy controls . Furthermore, patients with total body surface area burn of more than 40% had significantly higher IL-8 concentrations in plasma than patients with smaller burns . For patients without serious infectious complications, the IL-8 concentration fell gradually after injury, whereas in patients with complicating sepsis a second peak of IL-8 was demonstrated . Thus, the increased IL-8 concentrations seem to be related to burn size and to have a role in the pathophysiology of sepsis in patients with large burns . The large amounts of circulating IL-8 following thermal injury may contribute to the strong and sustained activation of neutrophils reported earlier in patients with large burns.

Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi, 1995 Sep-Oct, 36(5), 328 - 30
Hypothermia and sepsis: the major causes of mortality in gastroschisis; Tsai MC et al.; From 1984 to 1993, 25 neonates with gastroschisis were treated at Chianghua Christian Hospital (CCH) . Twenty-one patients were outborn, and only four were inborn babies . Eighteen patients were treated by primary fascial closure of the abdominal wall defect and seven, by the silastic sac technique . One patient required creation of intestinal stomas for ileal atresia; Two patients received further operation because of pus formation and intestinal obstruction . Four patients (16%) had associated anomalies, including one ileal atresia, two malrotations and one deformity of the hand . Seven (28%) patients were small for their gestational age . Eight patients died (32%); 17 survived (68%) . Nine patients (36%) were hypothermic upon arrival at the hospital, with body temperatures of 32.5 degrees C to 35.8 degrees C . Among those, three died of intractable metabolic disorders related to hypothermia and two who were hypothermal and acidotic, developed sepsis and expired . Six patients (24%) developed sepsis and only one survived . Metabolic acidosis related to hypothermia and sepsis were the major causes of death in this study (P values of 0.024 and 0.01 respectively) . It is no doubt that an experienced pediatrician is essential for immediate neonatal care to prevent unnecessary insults.

Chin Med Sci J, 1995 Sep, 10(3), 174 - 7
Changes of nitric oxide and protective effects of nitric oxide inhibitors in newborn rats with sepsis; Shi Y et al.; In a newborn rat model of sepsis, the changes of nitric oxide and the protective effects of methylene blue or/and dexamethason were investigated . The results revealed that plasma nitric oxide levels were elevated at 6 h and peaked at 12 h after bacterial challenge . The treatment with methylene or/and dexamethasone was found to blunt hypoglycemia and hyperlacticemia, to reduce the occurrence rate of loss of response to pain, and to prolong the survival time . Moreover, therapy by dexamethasone was shown to decrease the 24 h mortality . The results suggested that nitric oxide play an important role during the course of fatal P . aeruginosa sepsis, but it is clear that the clinical value of nitric oxide and its inhibitors need to be further studied.

Heart Lung, 1995 Sep-Oct, 24(5), 380 - 92; quiz 392-3
Treatment of sepsis and septic shock: a review; Wiessner WH et al.; Septic shock is one of the leading causes of death in intensive care units, and its incidence is increasing . Mortality rates as high as 95% are reported, with rates of 60% or more even when diagnosed and treated promptly . This review examines the definition of septic shock, its pathogenesis, and supportive therapy, with particular attention to intervention during the septic shock cascade.

Clin Nephrol, 1995 Sep, 44(3), 185 - 92
Role of calcium channel blockers in diabetic renal transplant patients: preliminary observations on protection from sepsis; Weinrauch LA et al.; BACKGROUND: Diabetic recipients of kidney transplants have an excessively high risk of allograft loss, infectious complications with sepsis, cardiovascular events and early death . This study was designed in order to determine whether post-transplantation medical management influenced long-term results . METHODS: Seventy consecutive diabetic recipients of cadaveric renal allografts were followed from the time of transplant . Treatment regimens were based on the clinical judgement of transplant nephrologists and surgeons, not by the study team . Patients were followed for 2 to 9 years (mean follow-up of 50.85 months, one lost to follow-up) . Groups were classified by HLA match, type of immunosuppression, prior cardiovascular history, type of antihypertensives (36 on calcium channel blockers, 32 on beta blockers, 8 ACE inhibitors) . Events were defined as myocardial infarction, CVA, graft loss with return to dialysis, life-threatening sepsis, or death . RESULTS: Twenty allografts failed during the study, 24 patients died . Potentially cardioprotective drugs did not impact significantly on cardiac death, MI or CVA . Survivals were better when calcium channel blockers were used (mean 71.7 vs 38.6 months, p < 0.05; 4-year survival 84 vs 58%) . When both beta and calcium channel blockers were used (n = 20), patients mean survival was 72.5 months vs 36.8 months for 21 patients who were not treated with blockers (p < 0.005) . There was a lower incidence of graft loss when beta blockers and calcium channel blockers were used: at mean patient survival of 36.8 months, the no-blockers group had a mean graft survival of 19.3 months vs 72.5 months for blocker-treated patients (p < 0.002) . Reinstitution of dialysis occurred less often with calcium channel blockers (17 vs 42%) or beta blockers (19 vs 38%) used either individually or together (5 vs 42%), all p < 0.05 . Calcium channel blocker treated patients had 1/9 the number of septic deaths, fewer patients had multiple septic episodes, all p < 0.02 . CONCLUSION: Allograft success and patient survivals may be improved and sepsis related events diminished when diabetic renal allograft recipients are treated with calcium channel blocking agents, plus or minus beta blockers . Considerable savings can be accomplished and graft results with these drugs can approach non-diabetic and live-related transplant results.

Burns, 1995 Sep, 21(6), 427 - 31
Expression of the adhesion molecule CD11b and polymerization of actin by polymorphonuclear granulocytes of patients endangered by sepsis; Brom J et al.; The integrin CD11b is an important adhesion molecule mediating the transendothelial migration of circulating polymorphonuclear granulocytes into an inflammatory region . The expression of CD11b is closely related to the ability to polymerize actin, a major component of the cytoskeleton within the phagocyte . In this study we compared the CD11b expression as well as the polymerization of actin of isolated neutrophils from patients endangered by sepsis with cells from healthy donors . The patient population was subdivided into a group of patients with severe thermal injuries and a group of patients who were admitted to an intensive care unit on suspicion of sepsis . The following results were obtained: (1) cells from burn patients, but not from non-burn patients, showed a reduced basal expression of CD11b during the first week after the burn trauma; (2) stimulation with the chemotactic peptide formyl-Met-Leu-Phe (FMLP) led to a strong overexpression of CD11b on the cells from the burn patients, this effect was not observed using cells of the second subgroup; (3) the content of polymerized actin was reduced within resting and stimulated cells from burn patients during the first 2 weeks postinjury, non-burn patient cells showed an enhanced F-actin content within the first week; (4) the ability of burn and non-burn patient cells to polymerize actin after stimulation with FMLP was slightly impaired during the first week post injury/admission . The results demonstrate that cells from patients endangered by sepsis show dysfunctions on the level of adhesion molecule expression and the strongly related actin polymerization.(ABSTRACT TRUNCATED AT 250 WORDS)

Clin Diagn Lab Immunol, 1995 Sep, 2(5), 549 - 53
Pattern of cytokines and pharmacomodulation in sepsis induced by cecal ligation and puncture compared with that induced by endotoxin; Villa P et al.; The production of tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 and their pharmacomodulation were evaluated in a model of polymicrobial sepsis induced in mice by cecal ligation and puncture (CLP) and were compared with the effects of endotoxin (lipopolysaccharide {LPS}) treatment . LPS levels rose as early as 1 h after CLP and increased further after 2 and 21 h . TNF-alpha was detectable in serum, spleen, liver, and lungs during the first 4 h, with a peak 2 h after CLP . IL-1 beta was measurable in serum after 24 h, and levels increased significantly in spleen and liver 4 and 8 h after CLP . IL-6 levels increased significantly in serum throughout the first 16 h after CLP . These cytokines were detectable after LPS injection, with kinetics similar to those after CLP but at a significantly higher level . To cast more light on the differences between these two animal models of septic shock, we studied the effects of different reference drugs . Pretreatment with dexamethasone (DEX); ibuprofen (IBU), an inhibitor of cyclooxygenase; and NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, significantly reduced survival, while chlorpromazine (CPZ) and TNF did not affect it . Only the antibiotics and pentoxifylline significantly increased survival in mice with CLP . However, CPZ and DEX protected the mice from LPS mortality . On inhibiting TNF-alpha with DEX, CPZ, or pentoxifylline, survival was reduced, unchanged, and increased, respectively, and on increasing TNF-alpha with IBU and TNF, survival was decreased or unchanged, respectively, suggesting that the modulation of this cytokine does not play a significant role in sepsis induced by CLP, unlike treatment with LPS . The negative effects of IBU and N(G)-nitro-L-arginine suggest a protective role by prostaglandins and nitric oxide in sepsis induced by CLP.

Crit Care Med, 1995 Sep, 23(9), 1512 - 8
Failure of prophylactic and therapeutic use of a murine anti-tumor necrosis factor monoclonal antibody in Escherichia coli sepsis in the rabbit; Stack AM et al.; OBJECTIVE: To determine the efficacy of a murine anti-tumor necrosis factor (TNF) monoclonal antibody in the treatment of Escherichia coli peritonitis and sepsis in the rabbit . DESIGN: Prospective, paired, randomized, blinded, controlled animal trial . SETTING: Animal research laboratory . SUBJECTS: Male New Zealand white rabbits . INTERVENTIONS: Anesthetized rabbits were cannulated with indwelling femoral arterial and venous catheters . Peritonitis and sepsis were induced by intraperitoneal challenge using live E . coli O18ac bacteria . All animals were treated with gentamicin and ceftriaxone 1 hr after challenge . One group (prophylaxis experiment) consisting of ten rabbit pairs (the prophylaxis group), was treated with either murine anti-TNF monoclonal antibody or an equivalent volume of 5% albumin 3 hrs before E . coli challenge . A second group (therapeutic experiment) of 17 rabbit pairs, the treatment group, was also treated with murine anti-TNF monoclonal antibody or albumin control 1 hr after E . coli challenge . MEASUREMENTS AND MAIN RESULTS: All animals were bacteremic 1 hr after challenge . Physiologic measures of sepsis (heart rate, mean arterial pressure, serum bicarbonate, and arterial pH) did not differ between control, prophylaxis, and treatment groups . Peak serum TNF concentration was significantly (p < .01) lower in animals receiving anti-TNF monoclonal antibody, in both the prophylaxis and treatment groups, than in control animals . The survival rate was not improved significantly in either the prophylaxis or treatment group . CONCLUSIONS: Prophylactic and therapeutic use of anti-TNF monoclonal antibody in a rabbit model of E . coli peritonitis and sepsis significantly lowers TNF concentrations but does not ameliorate the physiologic effects of sepsis and does not significantly improve survival.

Crit Care Med, 1995 Sep, 23(9), 1461 - 9
CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock . CPD571 Sepsis Study Group; Dhainaut JF et al.; OBJECTIVES: To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group . DESIGN: Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571) . SETTING: Seven academic intensive care units in Europe . PATIENTS: Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care . INTERVENTIONS: Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg . MEASUREMENTS AND MAIN RESULTS: The humanized anti-TNF-alpha antibody was well tolerated . The overall all-cause 28-day mortality rate was 62% . Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days . This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline . The peak CDP571 concentrations and area under the curve increased proportionately with the dose . The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody . An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels . While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group . CONCLUSIONS: The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock . Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis.

Am J Physiol, 1995 Sep, 269(3 Pt 2), R584 - 91
Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene; Deutschman CS et al.; Sepsis is associated with alterations in hepatic gluconeogenesis . We have previously demonstrated that this change is associated with reduced expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene, despite an endogenous hormonal milieu that should favor increased expression of the gene . To further elucidate the mechanisms involved, we induced sepsis in fasted Sprague-Dawley rats via cecal ligation and single puncture, with sham-operated animals serving as controls, and we performed two sets of experiments . First, liver tissue was obtained from septic and sham-operated animals at 2, 6, 16, and 24 h after the induction of sepsis . Northern blot hybridization analysis revealed a progressive, sepsis-induced decrease in expression of PEPCK and an increase in the expression of beta-fibrinogen, an acute-phase reactant . In the second set of experiments, we tested whether this reduced expression resulted from an attenuated response to 1) glucagon and 2) 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) . Twenty-four hours after the induction of sepsis, the liver was isolated and perfused with either Krebs buffer with substrate only (unstimulated controls), Krebs buffer + substrate + 10(-8) M glucagon, or Krebs buffer + substrate + 10(-5) M 8-BrcAMP . In sham-operated animals, perfusion with glucagon increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone did not change mRNA levels and decreased activity . Glucagon perfusion of septic livers did not change either PEPCK mRNA levels or activity . Perfusion of sham-operated animals with 8-BrcAMP increased PEPCK mRNA levels and activity, whereas perfusion with buffer alone resulted in a decrease in mRNA levels and activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolism, 1995 Sep, 44(9), 1130 - 8
Modulation of skeletal muscle protein synthesis by amino acids and insulin during sepsis; Jurasinski C et al.; Effects of different concentrations of insulin and amino acids on protein synthesis in skeletal muscle of young, fed septic rats were determined in the perfused rat hindlimb . Rates of protein synthesis in gastrocnemius were measured by incorporation of {3H}-phenylalanine into protein . Perfusion of hindlimb muscles from young, fed control rats with medium containing either insulin and a complete mixture of amino acids at plasma concentration (1x) or a mixture of amino acids at 10-fold (10x) plasma concentration resulted in an approximately twofold stimulation of the rate of protein synthesis . The effect of amino acids on protein synthesis was partly accounted for by elevated concentrations of branched-chain amino acids ({BCAA} leucine, isoleucine, and valine) . In young, fed septic rats, the rate of protein synthesis in muscle perfused with buffer containing the normal concentration of amino acids was reduced 40% as compared with control levels (P < .05) . In contrast to controls, addition of insulin (1,000 microU/mL) did not augment protein synthesis in muscle from young, fed septic rats perfused with the complete mixture of amino acids . Addition of insulin 10,000 microU/mL stimulated protein synthesis approximately 80% in gastrocnemius of septic rats (P < .05) . However, the rate of protein synthesis remained less than that observed in young, fed control rats at similar insulin concentrations . Perfusion with medium containing 10x plasma amino acids stimulated protein synthesis approximately fourfold in young, fed septic rats as compared with control animals . In contrast to controls, BCAA at 10x plasma concentration did not augment protein synthesis in young, fed septic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

W V Med J . 1995 Sep-Oct;91(6):273.
The effect of granulocyte colony stimulating factor in patients with leukopenia due to sepsis; Bittner EW et al.; The use of granulocyte stimulating factor (G-CSF) (Neupogen, Amgen Inc., Thousand Oaks, Calif.) has become acceptable for treating both primary and acquired leukopenia . Leukopenia associated with infection is an ominous sign of overwhelming sepsis . In this article, we present two cases of infection that were related to leukopenia which were successfully treated with G-CSF.

J Child Neurol, 1995 Sep, 10(5), 346 - 52
Neuromuscular complications of sepsis in children; Sheth RD et al.; Sepsis occurs frequently in the pediatric intensive care unit and is a significant cause of morbidity and mortality . Multiple organ systems are adversely affected by sepsis . Approximately 70% of adult patients with sepsis have peripheral nervous system dysfunction on electrophysiologic studies, of whom 30% are symptomatic . Neuromuscular dysfunction in children with sepsis is increasingly reported; however, the incidence remains undefined . Flaccid quadriplegia with the inability to wean from ventilatory support despite full cardiopulmonary recovery is the typical presentation . However, lesser degrees of weakness may be demonstrated with careful evaluation . Electrophysiologic studies often demonstrate the presence of axonal polyneuropathies, abnormalities of neuromuscular transmission, or acute myopathies . Identifiable neuromuscular syndromes in children with sepsis include critical illness polyneuropathy, pure motor polyneuropathy, thick-filament myopathy, and necrotizing myopathy . The common underlying pathogenic process in these syndromes appears to be sepsis, which may be accentuated by the administration of steroids or neuromuscular blocking agents . Recovery in strength usually occurs over a period of weeks to months.

J Crit Care, 1995 Sep, 10(3), 122 - 35
Oxidative metabolism in sepsis and sepsis syndrome; Taylor DE et al.; The high mortality associated with sepsis syndrome and multiple organ dysfunction syndrome has persisted despite extraordinary research efforts in the laboratory and the intensive care unit . These syndromes produce systemic tissue damage that is likely to result from widespread inflammation and subsequent endothelial injury . This article reviews the oxidative metabolic effects and responses to sepsis syndrome at several levels: the oxygen transport system, the cell, and the mitochondrion . Specifically, aerobic metabolism of carbon substrates and oxygen is altered in sepsis . As a result of systemic inflammation and nonmetabolic oxygen use, oxidative stress may occur both outside and inside the cell . The consequences of these oxidative processes during sepsis may be ongoing cell damage mediated by reactive oxygen and nitrogen oxide species that culminates in multisystem organ failure.

J Am Board Fam Pract, 1995 Sep-Oct, 8(5), 384 - 91
Lemierre syndrome: postanginal sepsis; Leugers CM et al.; BACKGROUND: Lemierre syndrome, or postanginal sepsis, was first described in the early part of this century and is characterized by pharyngitis, followed by high fever and rigors, cervical adenopathy, thrombophlebitis of the internal jugular vein, distant abscess formation, and icterus, associated with isolation of Fusobacterium necrophorum from blood . METHODS: This report describes a case of postanginal sepsis and reviews the medical literature on postanginal sepsis obtained through the MEDLINE data base using Fusobacterium as the key search word . RESULTS: The features of Lemierre syndrome have changed little since the original description, through the prognosis has improved dramatically since the development of antibiotics . Appropriate management includes prompt administration of an antibiotic with good anaerobic coverage, drainage of persistent abscesses, and continued antibiotic therapy until radiographic resolution of abscess is achieved . CONCLUSIONS: Although Lemierre syndrome is a relatively uncommon disease, the primary care physician needs to be aware of the clinical features and management to treat appropriately.

Intensive Care Med, 1995 Aug, 21(8), 669 - 74
Dynamics of skin blood flow in human sepsis; Young JD et al.; OBJECTIVE: The study was undertaken to determine if sepsis alters the pattern of vasomotion and reactive hyperaemia in the skin . DESIGN: This was a prospective, observational study . SETTING: The study was performed in the medical and surgical intensive care units of a tertiary referral hospital . PATIENTS AND PARTICIPANTS: 11 patients with sepsis (using Bone's criteria {1}), were compared with 19 patients recovering from coronary artery bypass grafting who were used as non-septic controls . Nineteen normal volunteers were also studied . MEASUREMENTS AND RESULTS: Skin blood flow was measured on the forearm using laser Doppler flowmetry at rest and after 2 min arterial occlusion with a tourniquet . The resting blood signal was analyzed by calculating the mean skin blood flow, the power of the skin blood flow signal (variance) and the power spectrum . The rate of recovery after arterial occlusion was determined by calculating the peak increase in skin blood flow and the time constant of the decay of skin hyperaemia back to baseline flow . Patients with sepsis had a mean skin blood flow of 6.24 (3.48) ml min-1 per 100 g tissue compared with 4.35 (1.41) ml min-1 per 100 g tissue for the patients after coronary artery bypass grafting (p < 0.05) . The septic patients also showed a marked increase in the fraction of total power in the 0.1-0.15 Hz frequency band (0.19 (0.17) versus 0.068 (0.033), p < 0.05), a decreased peak hyperaemic response (40 (23)% increase in flow above baseline after cuff release versus 147 (19)%) and a prolonged time constant for recovery from hyperaemia (22.8 (12.7) versus 11.7 (8.5) seconds, p < 0.05) . These results imply an increased local rather than central control of skin blood flow . CONCLUSION: The laser Doppler flowmeter allows local rather than global haemodynamics to be studied . Abnormalities of skin blood flow control are found in sepsis, and this technique may prove useful to monitor the effects of treatment, especially if the use of laser Doppler flowmetry can be extended to other organs at risk of damage during sepsis such as gastro-intestinal mucosa.

J Trauma, 1995 Aug, 39(2), 381 - 5
Hemostatic competency and elastase-alpha 1-proteinase inhibitor levels in surgery, trauma, and sepsis; Viljoen M et al.; Previous studies investigated the effects of neutrophil elastase on isolated factors in the hemostatic process . Some of these reported effects are, however, procoagulative and others anticoagulative . The aim of this study was to ascertain the effect of elastase on the in vivo hemostatic competency . The effect of elastase activity on the hemostatic competency was determined in a group of 50 surgical intensive care unit patients and 23 control subjects . Surgical intensive care unit patients were subgrouped into a surgery, a trauma, and a sepsis-multiple organ failure group . Elastase activity was assessed by elastase-alpha 1-proteinase inhibitor levels and hemostatic competency by thromboelastography . Thromboelastography results showed a relatively normal coagulative ability in the surgery group, a varying degree of thromboelastographic hypocoagulability in the trauma group, and pronounced thromboelastographic instability in the sepsis-multiple organ failure group . Increases in elastase-alpha 1-proteinase inhibitor levels up to 200 micrograms/L were accompanied by a compromised coagulative ability as seen in a prolongation of both the first and second phases of the clotting time, as well as a decrease in the maximal clot elasticity.

Clin Exp Immunol, 1995 Aug, 101(2), 328 - 33
Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis; Haque KN et al.; In a prospective double-blind study, standard intravenous immunoglobulin (IVIG) was compared with an IgM-enriched IVIG in the treatment of neonatal sepsis . The two treatment groups were also compared with matched controls . One hundred and thirty babies (65 in each group) ranging from 0 to 24 days old, 480 to 4200 g in weight and born between 24 and 42 weeks of gestation who had, or were suspected of having, sepsis were given either standard IVIG or IgM-enriched IVIG (250 mg/kg per day) for 4 days in addition to supportive and antibiotic therapy . A further 65 babies who received similar supportive, antibiotic and fluids but not IVIG were used as matched controls . Mortality from infection in 'culture proven sepsis' was 3/44 (6.8%) in the IgM-enriched IVIG group, 6/42 (14.2%) in the standard IVIG group, and 11/43 (25.5%) in the control group (P = 0.017, IgM versus control, P = 0.19 standard IVIG versus control) . There was no statistical difference in the outcome between the two immunoglobulin therapy groups (P = 0.25) . The study indicates that IVIG improves outcome in neonatal sepsis when used as an adjunct to supportive and antibiotic therapy, but larger studies are required to confirm this.

Surgery, 1995 Aug, 118(2), 336 - 42
Sepsis and endotoxemia stimulate intestinal interleukin-6 production; Meyer TA et al.; BACKGROUND . Endotoxemia stimulates tumor necrosis factor (TNF) and interleukin-1 (IL-1) production in mucosa of the small intestine, but the effect on IL-6 production is not known . Intestinal IL-6 may be especially important, considering its role in the acute phase response . We tested the influence of endotoxemia and sepsis in mice on intestinal IL-6 and IL-6 messenger RNA (mRNA) levels . METHODS . Mice were injected with lipopolysaccharide (LPS 10 mg/kg) or saline solution . In some experiments animals were pretreated with indomethacin (5 mg/kg) or N-nitro-L-arginine (NNA, 100 mg/kg) before LPS injection . In other experiments, sepsis was induced by cecal ligation and puncture (CLP); controls were sham operated . Serum and jejunal mucosa were harvested at intervals during 16 hours, and IL-6 levels were determined by enzyme-linked immunosorbent assay . IL-6 mRNA was detected by polymerase chain reaction . RESULTS . Endotoxemia and sepsis increased serum and mucosal IL-6 and IL-6 mRNA, with maximum levels noted at 1 and 4 hours after LPS and at 8 hours after CLP . Pretreatment of endotoxemic mice with indomethacin or NNA blunted the increase in mucosal IL-6 . CONCLUSIONS . Results suggest that sepsis and endotoxemia stimulate IL-6 production in small intestinal mucosa and that this response may be transcriptionally regulated . The effect of endotoxemia may be partly mediated by prostaglandins and nitric oxide . The results also suggest that the intestinal mucosa may be a participant in the cytokine response, rather than just a passive bystander.

J Surg Res, 1995 Aug, 59(2), 287 - 91
Metabolic function of the isolated perfused rat liver in chronic sepsis; Dahn MS et al.; Significant alterations of liver function have been identified in experimental sepsis including changes in protein and glucose production . The specific changes which are evident in vivo appear to depend upon the specific experimental model and probably represent the relative contribution of hepatocellular function and extrahepatic influences as well as the time course of the septic process . Relatively few studies have focused on function of the whole organ . In an effort to study intrinsic hepatic function during chronic sepsis, control and septic animals (intraabdominal abscess) were studied using the isolated perfused liver model . Basal hepatic oxygen utilization was mildly elevated compared to that in control livers and the oxygen consumption response to a metabolic load was found to be essentially identical to that in control and septic livers . Glucose and albumin production were not substantially different in these two groups . These findings suggest that alterations in liver function following the induction of sepsis may result from extra hepatic factors, since intrinsic liver function appears to be normal.

Crit Care Med, 1995 Aug, 23(8), 1430 - 9
Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature; Cronin L et al.; OBJECTIVE: To determine the effect of corticosteroid therapy on morbidity and mortality in patients with sepsis . DATA SOURCES: We searched for published and unpublished research using MEDLINE, EMBASE, and the Science Citation Index, manual searching of Index Medicus, citation review of relevant primary and review articles, personal files, and contact with primary investigators . STUDY SELECTION: From a pool of 124 potentially relevant articles, duplicate independent review identified nine relevant, randomized, controlled trials of corticosteroid therapy in sepsis and septic shock among critically ill adults . DATA EXTRACTION: In duplicate, independently, we abstracted key data on population, intervention, outcome, and methodologic quality of the randomized controlled trials . DATA SYNTHESIS: Corticosteroids appear to increase mortality in patients with overwhelming infection (relative risk 1.13, 95% confidence interval 0.99 to 1.29), and have no beneficial effect in the subgroup of patients with septic shock (relative risk 1.07, 95% confidence interval 0.91 to 1.26) . Studies with the highest methodologic quality scores also suggest a trend toward increased mortality overall (relative risk 1.10, 95% confidence interval 0.94 to 1.29) . A similar trend was observed for patients with septic shock (relative risk 1.12, 95% confidence interval 0.95 to 1.32) . No difference in secondary infection rates was demonstrated in corticosteroid-treated patients with sepsis or septic shock . However, there was a trend toward increased mortality from secondary infections in patients receiving corticosteroids (relative risk 1.70, 95% confidence interval 0.70 to 4.12) . The occurrence rate of gastrointestinal bleeding was increased slightly in the treatment group (relative risk 1.17, 95% confidence interval 0.79 to 1.73) . CONCLUSIONS: Current evidence provides no support for the use of corticosteroids in patients with sepsis or septic shock, and suggests that their use may be harmful . These trials underscore the need for future methodologically rigorous trials evaluating new immune-modulating therapies in well-defined critically ill patients with overwhelming infection.

Crit Care Med, 1995 Aug, 23(8), 1382 - 90
Effect of volume support, antibiotic therapy, and monoclonal antiendotoxin antibodies on mortality rate and blood concentrations of endothelin and other mediators in fulminant intra-abdominal sepsis in rats; Lundblad R et al.; OBJECTIVE: To study the therapeutic effects of volume support, antibiotics, and a monoclonal antiendotoxin antibody on the mortality rate and blood concentrations of endothelin and other mediators in fulminant intra-abdominal sepsis in rats . DESIGN: Prospective, randomized, controlled trial . SETTING: Research laboratory in a university hospital . SUBJECTS: Adult male Wistar rats . INTERVENTIONS: Fulminant polymicrobial intra-abdominal sepsis was induced by a 4-mm cecal perforation . Treatment was performed with saline volume support, the antibiotic imipenem/cilastatin, and the monoclonal antiendotoxin antibody E5, both as monotherapy and as a combined regimen . Mortality rates were recorded and concentrations of bacteria, endotoxin, tumor necrosis factor (TNF), big endothelin, and endothelin-1 (21 amino acids) in blood were determined . MEASUREMENTS AND MAIN RESULTS: Substantial increases in circulating big endothelin and endothelin-1 concentrations were observed during sepsis . The combination of volume support with antibiotics reduced the mortality rate, but neither as monotherapy nor as a combined regimen did this intervention modify plasma endothelin-1 concentrations . This finding suggests that hypovolemia and bacteria per se are not important stimuli for endothelin synthesis and a high plasma level of endothelin-1 does not necessarily predict poor outcome in sepsis . The inactive big endothelin is enzymatically cleaved, leaving the biologically active 21-residue endothelin-1 . Intervention with E5 substantially reduced the mortality rate and concentrations of endotoxin, TNF, and plasma endothelin-1, while big endothelin and total endothelin immunoreactivity did not decrease . This finding indicates a suppressed conversion of big endothelin to endothelin-1 after E5 treatment . Because E5 has no direct effect on endothelin metabolism, E5 probably reduces the synthesis of endothelin-1 by suppressing the endothelin-activators endotoxin and TNF . A triple combination of volume support, imipenem/cilastatin, and E5 was the only regimen that reduced all of the end points: mortality rate, hemoconcentration, bacteria, endotoxin, TNF, and endothelin-1 . CONCLUSIONS: The concentration of plasma endothelin was increased during fulminant intra-abdominal sepsis in rats . Combining volume support with antibiotic therapy reduced the mortality rate, but did not modify concentrations of plasma endothelin-1 . The monoclonal antiendotoxin antibody E5 reduced the mortality rate and concentrations of endotoxin, TNF, and endothelin-1, but not big endothelin . This finding indicates that E5 therapy inhibits the conversion of big endothelin to 21-residue endothelin-1.

J Infect Dis, 1995 Aug, 172(2), 577 - 80
Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis; van der Poll T et al.; Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis . In baboons, IL-1 alpha induced increased levels of sTNFR types I and II . Infusion of Escherichia coli into baboons also led to higher sTNFR levels . Treatment with IL-1 receptor antagonist (ra) attenuated the rise in sTNFR-I, which was positively correlated with a partial preservation of renal function by IL-1ra . In patients with sepsis, treatment with IL-1ra also was associated with lower levels of sTNFR-1 but did not influence plasma creatinine levels . IL-1ra did not affect sTNFR-II in baboons or humans . These data suggest that IL-1 produced during sepsis is involved in increases in sTNFR-I . Such increases during rapidly fatal septic shock may in part be explained by an effect on the renal clearance of sTNFR-I.

Clin Endocrinol (Oxf), 1995 Aug, 43(2), 197 - 203
Temperature-induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leucocyte in patients with sepsis or septic shock; Molijn GJ et al.; OBJECTIVE: Activation of the hypothalamic-pituitary-adrenal axis is of vital importance during critical illness . We have studied the adaptive mechanisms which occur at the level of the glucocorticoid receptor in glucocorticoid target tissues in patients with sepsis or septic shock . DESIGN: The effects of hypercortisolaemia, hyperthermia and cellular composition on number of glucocorticoid receptors per cell and their affinity were evaluated, both in vitro and in vivo, in peripheral blood mononuclear leucocytes of control subjects and in patients with sepsis or septic shock . SUBJECTS: Fifteen patients (age 25-79) with sepsis or septic shock who were admitted to an intensive care unit were studied . The control group consisted of 24 healthy laboratory employees . MEASUREMENTS: The binding capacity and affinity of the glucocorticoid receptors were measured and compared to clinical data and the plasma cortisol concentrations . RESULTS: Hypercortisolaemia, in vitro, resulted in a decreased affinity and a decreased binding capacity of the glucocorticoid receptor . In vitro, hyperthermia as well as variations in the cellular composition did not influence the glucocorticoid receptor . In vivo, there was no change in the number of receptors per cell in patients with sepsis or septic shock as compared to healthy controls . However, a decreased affinity of the glucocorticoid receptor was observed . There was a weak but significant negative correlation between body temperature and the number of glucocorticoid receptors in the patient group . There was no relation between circulating cortisol concentrations and glucocorticoid receptor affinity and number . CONCLUSIONS: There is no obvious regulation of the number of glucocorticoid receptors by plasma cortisol concentrations in vivo . The decreased affinity of the glucocorticoid receptor together with the negative correlation between hyperthermia and the number of glucocorticoid receptors in patients with sepsis or septic shock suggest that hypothalamic-pituitary-adrenal axis activation during critical illness is accompanied by peripheral adaptation in glucocorticoid receptor number and affinity.

Sheng Li Xue Bao, 1995 Aug, 47(4), 357 - 65
{Alteration of phospholamban phosphatase activity associated with cardiac sarcoplasmic reticulum during sepsis in rats}; Yang Q et al.; In the present study, rat cardiac sarcoplasmic reticulum (SR) phospholamban (PLB) phosphatase was partially purified by chromatography on DEAE-Sephacel . This PLB phosphatase was indentical to phosphatase-1 . It was shown on electrophoresis of SDS-PAGE autoradiography that the PLB phosphatase in rats during early sepsis (ES) depressed dephosphorylation of substrates (32P-phosphorylase a and 32P-SR) . However, dephosphorylation of the substrates by the partially purified phosphatase during late sepsis (LS) was same as that in control rats . The partially purified PLB phosphatase activity in ES rats was significantly decreased, but showed no change in LS rats . The results above were confirmed by a studing of the substrate concentration (enzyme concentration, time)--enzyme reaction velocity curve in showing that both affinity and maximum initial velocity (Vmax) of the phosphatase in the ES rats were decreased, but had no change in those in the LS rats.

Lipids, 1995 Aug, 30(8), 707 - 12
Enteral feeding a structured lipid emulsion containing fish oil prevents the fatty liver of sepsis; Lanza-Jacoby S et al.; Fish oils (FO) have been shown to reduce plasma triglycerides (TG) . In this study we evaluated whether enteral feeding with a structured lipid emulsion (SLE) containing FO and medium-chain triglycerides (MCT) would prevent the hypertriglyceridemia and fatty infiltration of the liver that develops during sepsis . For five days, male Lewis rats (275-300 g) were fed intragastrically a nutritionally complete diet containing a SLE or a similar diet with a soybean oil emulsion (SOE) in place of the SLE . On the fifth day, sepsis was induced by intravenously injecting 8 x 10(7) live Escherichia coli colonies/100 g b.w.; 24 h later the control SLE, septic SLE, control SOE, and septic SOE rats were sacrificed . Diet, but not treatment, had a significant effect on serum TG and free fatty acids (FFA) . Feeding the SLE reduced the plasma FFA of the control and septic rats by more than 50% in comparison to both control and septic rats fed the SOE . Soleus muscle activity of lipoprotein lipase from the septic SLE rats was 44% higher than the control SLE rats . Soleus muscle from the septic SLE rats also had a twofold greater activity of lipoprotein lipase than the septic SOE rats . TG did not accumulate in the livers of the septic rats fed SLE when compared to the control SLE rats and the rats fed the SOE . Livers from the septic rats fed the SLE had a third of the TG that were present in the livers from the septic rats fed the SOE.(ABSTRACT TRUNCATED AT 250 WORDS)

JAMA, 1995 Jul 12, 274(2), 172 - 7
Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome . The Sepsis Intervention Group; Goldie AS et al.; OBJECTIVE--To assess the value of measuring circulating concentrations of mediators (endotoxin, tumor necrosis factor-alpha {TNF-alpha}, interleukin-1 beta {IL-1 beta}, and interleukin-6{IL-6}) and their endogenous antagonists (antiendotoxin core antibody {EndoCAb}, interleukin-1 receptor antagonist {IL-1ra}, and soluble TNF receptors {sTNF-R}) in predicting mortality and organ failure in sepsis syndrome . DESIGN--Cohort study with a follow-up period of 30 days . SETTING--Intensive therapy units of five tertiary referral centers in Scotland . SUBJECTS--A total of 146 intensive therapy unit patients with sepsis syndrome underwent repeated sampling during a 10-day period following admission to an intensive therapy unit . MAIN OUTCOME MEASURES--Circulating concentrations of mediators and antagonists were compared in survivors and nonsurvivors . RESULTS--Median Acute Physiology and Chronic Health Evaluation II score was 23 (range, 8 to 40) . Mortality at 30 days was 49% . On entry to the study, circulating endotoxin was detected in 66% of patients, TNF-alpha in 14%, and IL-1 beta in 29% . Levels did not predict mortality or organ failure . Patients with IL-6 concentrations in excess of 3000 pg/mL had an increased mortality rate (64% vs 40%, P = .02) . The incidence of IgG EndoCAb depletion on entry to the study was 26% in nonsurvivors and 10% in survivors (P = .02) . Initial concentrations of both type I and type II sTNF-R were significantly higher in nonsurvivors (P < .01) . Initial circulating IL-1ra concentrations were not of value in predicting mortality . Cytokine antagonists were present in concentrations 30- to 100,000-fold greater than their corresponding cytokine . CONCLUSION--The observed high circulating levels of the cytokine antagonists IL-1ra and sTNF-R and the relatively small proportion of patients developing EndoCAb depletion may contribute to the limitations of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines.

Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi, 1995 Jul, 11(4), 266 - 9
{Oxygen transport pattern in burned patient with sepsis under inotropic support}; Wu Z et al.; Hemodynamic and oxygen-kinetic data of 16 burn patients with sepsis were analysed to explore relationship between oxygen transport pattern and clinical outcome after dopamine and dobutamine therapy . Two patterns of oxygen transport were shown in the 16 patients . Of them, ten (62.5%) had optimal DO2 and VO2 values (model I), and six (37.5%) had lower DO2 and VO2 values than the optimal (model II) . All of 6 patients with model II developed lactic acidosis, septic shock and MOF and died . Two of 10 patients in model I developed MOF, only one died . The results indicate that, in burn patient with sepsis, the decreased response of DO2 and VO2 to inotropic therapy suggests failure of tissue perfusion, oxygen extraction and utilization, and may possibly predict the outcome.

Leuk Lymphoma, 1995 Jul, 18(3-4), 329 - 34
G-CSF stimulated donor granulocyte collections for neutropenic sepsis; Grigg A et al.; Granulocyte transfusions may be beneficial in neutropenic patients with progressive infections despite appropriate antibiotics . In order to evaluate both the feasibility of granulocyte collection in normal donors receiving granulocyte colony-stimulating factor (G-CSF) and the efficacy of infusing these cells into neutropenic patients with progressive sepsis, four donors received between 5-10 micrograms/kg G-CSF per day and underwent leucapheresis within a day of the first dose . Different red cell sedimenting agents and interface settings were evaluated to determine the optimal method of granulocyte collection . The number of granulocytes collected, the peripheral blood granulocyte level in the recipient at various time points after infusion, and the clinical response were evaluated . Results showed that G-CSF and the leucaphereses caused mild to moderate fatigue in two donors and profound fatigue and a brief episode of hypoxia in one donor . Efficient granulocyte collections were only obtained using dextran 40 or dextran 70 as the sedimenting agent and a deep interface setting which extended sampling into the upper red cell layer . Infusion of granulocytes obtained with this technique resulted in a sustained increase in circulating granulocyte numbers in three recipients, one of whom gained significant clinical benefit . In conclusion, granulocyte transfusions from donors given G-CSF are feasible and may be clinically beneficial, particularly if given early in the course of infection in neutropenic patients.

JPEN J Parenter Enteral Nutr, 1995 Jul-Aug, 19(4), 279 - 85
Is muscle protein turnover regulated by intracellular glutamine during sepsis?
Fang CH, James JH, Fischer JE, Hasselgren PO.
BACKGROUND: Low muscle glutamine levels during sepsis are associated with reduced protein synthesis and elevated protein breakdown, in particular myofibrillar protein breakdown . It is not known if this is a causal or coincidental relationship . We tested the hypothesis that muscle protein turnover rates are directly regulated by glutamine . METHODS: Paired extensor digitorum longus muscles from nonseptic (sham-operated) and septic rats (16 hours after cecal ligation and puncture) were incubated in the absence or presence of 15 mmol glutamine/L . The effect of glutamine was tested in unsupplemented medium or in medium containing 1 mU/mL of insulin or a mixture of amino acids at normal plasma concentrations . Protein synthesis was measured as incorporation of 14C-phenylalanine into protein; total and myofibrillar protein breakdown was determined by measuring tyrosine and 3-methylhistidine, respectively . RESULTS: Muscles accumulated intracellular glutamine well above normal concentrations in the presence of 15 mmol glutamine/L . In spite of this, protein synthesis was not affected by glutamine, neither when muscles were incubated in unsupplemented medium nor in medium containing insulin or amino acid mixture . Total protein breakdown was not influenced by glutamine when muscles were incubated in unsupplemented medium or with insulin but was reduced by glutamine in the presence of an amino acid mixture . Myofibrillar protein breakdown was unaffected by glutamine in unsupplemented medium and in medium containing insulin but was increased by glutamine in the presence of amino acid mixture . CONCLUSION: Reduced muscle protein synthesis and increased myofibrillar protein breakdown during sepsis are probably not caused by the low intracellular glutamine levels noticed in this condition.

Br J Surg, 1995 Jul, 82(7), 870 - 6
New concepts in the pathophysiology of oxygen metabolism during sepsis; Vlessis AA et al.; Sepsis is an intriguing pathological condition associated with many complex metabolic and physiological alterations . In this review a novel hypothesis in the pathophysiology of oxygen metabolism during sepsis is explored . It is proposed that the hypermetabolic response to sepsis results from enhanced reactive oxygen generation by phagocytes . Reactive oxygen detoxification by host enzyme systems subsequently leads to alterations in oxidative metabolism . The similarities between the metabolic consequences of reactive oxygen metabolism and the metabolic changes observed during sepsis are outlined . A unified concept is presented to help explain the pathophysiological changes in oxygen metabolism during sepsis.

Br J Haematol, 1995 Jul, 90(3), 541 - 7
Influence of white blood cells on the fibrinolytic response to sepsis: studies of septic patients with or without severe leucopenia; Haj MA et al.; In septic patients capable of normal white cell responses, high plasma levels of PAI-I, t-PA antigen and t-PA-PAI-I complex were observed . The ratios of t-PA and PAI-I were such that free PA activity was almost never observed . In patients severely leucopenic prior to becoming septic the changes were significantly less marked, so presence of leucocytes enhances the fibrinolytic inhibition occurring in sepsis . The non-leucopenic septic group showed greater evidence of thrombin generation in that FPA levels were higher but fibrinogen levels were only slightly less and antithrombin levels not different from those in the leucopenic group . A greater tendency to fibrin deposition and the striking fibrinolytic inhibition noted in patients with normal white cell responses may contribute to the development of some of the complications of sepsis in which fibrin deposition participates and may explain their relative rarity in leucopenic patients . When shock supervened, levels of PAI-I were high in both leucopenic and non-leucopenic groups, indicating that a source of PAI-I outwith the leucocytes themselves contributes to the phenomena observed.

J Trauma, 1995 Jul, 39(1), 53 - 7; discussion 57-8
Triiodothyronine (T3) supplementation maintains surfactant biochemical integrity during sepsis; Dulchavsky SA et al.; Surfactant functional effectiveness is dependent on phospholipid compositional integrity: sepsis decreases this through an undefined mechanism . Sepsis-induced hypothyroidism is commensurate and may be related . This study examines the effect of triiodothyronine (T3) supplementation on surfactant function, metabolism, and composition during sepsis . Male Sprague-Dawley rats (n = 75) underwent sham laparotomy or cecal ligation and puncture (CLP) with or without T3 supplementation (CLP/T3; 3 ng/hr) . Twenty-four hours later, surfactant was obtained by lavage . Total phospholipids were determined by chromatography . Choline phosphate cytidyltransferase (CT) activity was determined by the formation of cytidine diphosphate (CDP)-choline . In vivo lung compliance was determined by lung inflation; surfactant hysteresis plots were determined on a pulsating bubble surfactometer . Lung compliance and surfactant hysteresis plots were significantly affected by sepsis; T3 modulated this (dynamic compliance: sham = 0.66 +/- 0.02, CLP = 0.47 +/- 0.06, CLP/T3 = 0.56 +/- 0.02 mm Hg/mL; p < 0.05) . Sepsis produced a decrease in phosphatidylglycerol, and phosphatidic acid, with an increase in lesser surface active lipids phosphatidylserine and phosphatidylinositol . Hormonal replacement prevented these alterations . Lung CT activity was increased by sepsis independent of T3 treatment . Thyroid hormone may have an active role in lung functional preservation during sepsis caused by maintenance of surfactant biophysical and compositional homeostasis.

J Trauma, 1995 Jul, 39(1), 104 - 10; discussion 110-1
Polymicrobial sepsis following trauma inhibits interleukin-10 secretion and lymphocyte proliferation; Napolitano LM et al.; Immune competence declines following major injury, and predisposes the trauma patient to infection . Interleukin-10 (IL-10), although an immunosuppressive cytokine, is also important in the initiation of immune responses . This study investigated alterations in IL-10 and immune function associated with polymicrobial sepsis following trauma using murine femur fracture (FFx) and cecal ligation/puncture (CLP) models . Mice were randomized to Normal, FFx, Alcohol and FFx (EtOH + FFx), CLP, FFx + CLP, and EtOH + FFx + CLP . Polymicrobial sepsis was induced by performing CLP 4 days after FFx, and animals were killed 14 days later; immune function was assessed by in vitro splenocyte cultures . Lymphocyte proliferative responses were significantly suppressed in FFx and CLP animals . Splenocyte IL-10 production was significantly reduced in FFx and CLP animals, with concurrent increases in nitrite and tumor necrosis factor release . This study documents that trauma induces alterations in the inflammatory cytokine cascade that affect the immune response to subsequent septic challenges.

Arch Surg, 1995 Jul, 130(7), 739 - 48
Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis; Boermeester MA et al.; OBJECTIVE: To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection . STUDY DESIGN: All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome . POPULATION: Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour infusion of recombinant human interleukin-1 receptor antagonist (1.0 {n = 9} or 2.0 {n = 8} mg/kg per hour) or placebo (n = 9) . OUTCOME MEASURE: Responses up to 72 hours after initiation of treatment . RESULTS: Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P < .05) . Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-alpha 2-antiplasmin complexes, were also significantly reduced (P < .05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist . Neutrophil elastase-alpha 1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours . CONCLUSIONS: The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome . Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.

Anesthesiology, 1995 Jul, 83(1), 178 - 90
Effect of continuous arteriovenous hemofiltration combined with systemic vasopressor therapy on depressed left ventricular contractility and tissue oxygen delivery in canine Escherichia coli sepsis; Mink SN et al.; BACKGROUND: In a previous study, we showed that continuous arteriovenous hemofiltration (CAVH) reversed the depression in left ventricular (LV) contractility in canine Escherichia coli sepsis by the removal of a circulating substance the molecular weight of which is less than 30,000 . Despite the normalization of LV contractility, however, we were unable to demonstrate an improvement in systemic arterial blood pressure (BP), presumably because the mechanisms underlying the depression in LV contractility and the decrease in BP are different in sepsis . In the current study, we examined the effect of combined treatment with CAVH and the alpha-adrenergic agonist phenylephrine on LV mechanics and tissue oxygen delivery in our canine E . coli model . METHODS: Measurements were obtained at baseline (condition B), after 4 h of sepsis (condition S), and after 2 h of CAVH and phenylephrine (condition P) (total of 6 h of sepsis) . During P, phenylephrine was infused to restore BP to that found at baseline . The slope of the end-systolic pressure-dimension relation was used as the index of LV contractility; LV anterior-posterior dimensions were measured by sonomicrometry . RESULTS: During combined CAVH and phenylephrine treatment, the decrease in the slope of the end-systolic pressure-dimension relation otherwise observed at S was reversed . The slope (mean +/- SD) was 57.5 +/- 32 mmHg/mm at B versus 22.2 +/- 8 mmHg/mm at S (P < 0.05, B vs . S) versus 62 +/- 37 mmHg at P (P < 0.05 S vs . P) (analysis of variance) . Mean BP was restored to that found at B (123 +/- 19 mmHg versus 82 +/- 14 mmHg (P < 0.05 B vs . S) versus 116 +/- 27 mmHg (P < 0.05 S vs . P) . Combination treatment with CAVH and phenylephrine also improved stroke volume (39.3 +/- 13.5 versus 32 +/- 8 versus 44 +/- 12 ml) and tissue oxygen delivery during P compared with results obtained when phenylephrine was given alone . CONCLUSIONS: Our study offers a rationale for the combined use of phenylephrine and CAVH in the reversal of cardiac depression and hypotension in sepsis.

Surgery, 1995 Jul, 118(1), 54 - 62
Total energy expenditure during total parenteral nutrition: ambulatory patients at home versus patients with sepsis in surgical intensive care; Koea JB et al.; BACKGROUND . To avoid the complications associated with overfeeding or underfeeding, the energy requirements of patients receiving total parenteral nutrition (TPN) must be accurately prescribed . However, until recently it has not been possible to directly measure the rates of total energy expenditure (TEE) in surgical patients receiving TPN . METHODS . Values for total body water and TEE in four patients with sepsis (mean Acute Physiology and Chronic Health Evaluation {APACHE} score, 10) receiving TPN in surgical intensive care unit and in four patients with chronic intestinal failure receiving long-term TPN at home (HPN) have been determined by using the doubly labeled water technique . The values for TEE have been compared with those of resting energy expenditure obtained with indirect calorimetry (REE CAL) and calculated by using the Harris-Benedict equation (REE HB) . RESULTS . In both the patients with sepsis and the patients receiving HPN the proportion of body weight made up of water was normal for patient age and gender . In patients with sepsis the REE HB significantly (p < 0.05) underestimated the REE CAL (15.39 +/- 3.80 kcal/kg/day-1 versus 31.3 +/- 1.23 kcal/kg/day-1) and was significantly less than the TEE derived by using doubly labeled water (44.62 +/- 1.09 kcal/kg/day-1; p < 0.001) . In the ambulatory patients receiving HPN no difference was noted between the REE HB and the REE CAL (18.02 +/- 0.41 kcal/kg/day-1 versus 21.37 +/- 0.94 kcal/kg/day-1) . The average TEE for these patients was 30.25 +/- 3.42 kcal/kg/day-1, and this was significantly greater (p < 0.006) than both REE CAL and REE HB . CONCLUSIONS . This investigation has shown that in patients with sepsis TEE constitutes 1.4 times the REE CAL or approximately 40 kcal/kg/day, whereas in HPN patients TEE can be estimated by supplying 1.4 times the REE or approximately 30 kcal/kg/day-1.

Crit Care Med, 1995 Jul, 23(7), 1227 - 32
Reduced intestinal absorption of arginine during sepsis; Gardiner KR et al.; OBJECTIVE: To investigate the effect of sepsis on the intestinal absorption of arginine . DESIGN: Controlled, nonintervention study . SETTING: Surgical research laboratories of Sinai Hospital of Baltimore . SUBJECTS: Male Sprague-Dawley rats . INTERVENTIONS: Experimental sepsis induced by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide . MEASUREMENTS AND MAIN RESULTS: Sepsis assessed by peritoneal and blood cultures . Intestinal absorption estimated by measuring the transfer of 3H-arginine by everted jejunal sacs prepared from septic and control animals (n = 6 per group) at multiple time points after the induction of sepsis (6, 12, 24, 48, and 72 hrs after cecal ligation and puncture; 6 and 12 hrs after intraperitoneal injection of lipopolysaccharide) . Induction of peritonitis in the rat by cecal ligation and puncture significantly reduced the in vitro uptake of arginine by everted jejunal sacs at 12, 24, and 48 hrs after laparotomy . Arginine transfer by everted jejunal sacs was also significantly reduced in rats as early as 6 hrs after intraperitoneal injection of endotoxin (endotoxin 273 +/- 14; saline 377 +/- 14 nmol/sac/hr) . Data are expressed as mean +/- SEM . Recovery from sepsis was associated with normalization of arginine transfer by intestinal sacs . CONCLUSIONS: Experimental sepsis, induced by either cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide, resulted in impaired intestinal amino acid uptake . Impaired intestinal arginine absorption may explain the lack of benefit of enteral, compared with parenteral, arginine therapy on survival from a septic insult.

Crit Care Med, 1995 Jul, 23(7), 1184 - 93
Combined measurements of blood lactate concentrations and gastric intramucosal pH in patients with severe sepsis; Friedman G et al.; OBJECTIVE: To compare the prognostic value of blood lactate concentrations, gastric intramucosal pH, and their combination in patients with severe sepsis . DESIGN: Prospective, noninterventional study . SETTING: Medical/surgical intensive care unit of a university hospital . PATIENTS: The study included 35 consecutive patients (44 to 82 yrs) with severe sepsis as defined by fever or hypothermia (rectal temperature > 38.3 degrees or < 35.5 degrees C), tachycardia (heart rate > 100 beats/min), tachypnea (respiratory rate > 20 breaths/min) or mechanical ventilation, abnormal white blood cell count (> 10 or < 6 x 10(3) cells/mm3), hypotension (systolic arterial pressure < 90 mm Hg), and evidence of organ dysfunction (oliguria or deterioration of mental status) . INTERVENTIONS: Arterial lactate concentration and intramucosal pH were measured at the time of study entry, and at 4 and 24 hrs later . Hemodynamic data and oxygen-derived variables were determined at the time of study entry and 24 hrs later . Arterial blood and balloon saline gases were also determined to obtain the pH gap (arterial pH-intramucosal pH) and the PCO2 gap (intramural PCO2-PaCO2) . MEASUREMENTS AND MAIN RESULTS: Of the 35 patients, 19 survived the intensive care unit stay . At the time of study admission, 23 (66%) patients had an increased lactate concentration (> 2 mEq/L) and 26 (74%) had a low intramucosal pH (< 7.32) . Initially, there were no significant differences in blood lactate concentrations between nonsurvivors and survivors (3.2 +/- 1.5 vs . 2.8 +/- 2.3 mEq/L) . Lactate concentrations remained high in nonsurvivors and progressively decreased in survivors (4 hrs: 3.3 +/- 1.1 mEq/L in nonsurvivors vs . 2.2 +/- 0.9 mEq/L in survivors {p < .01}; 24 hrs: 3.5 +/- 2.0 mEq/L in nonsurvivors vs . 1.9 +/- 1.1 mEq/L in survivors {p < .05}) . Intramucosal pH was lower in the nonsurvivors than in the survivors initially (7.19 +/- 0.15 in nonsurvivors vs . 7.30 +/- 0.14 in survivors {p < .05}), at 4 hrs (7.18 +/- 0.17 in nonsurvivors vs . 7.29 +/- 0.13 in survivors {p = .06}), and at 24 hrs (7.19 +/- 0.31 in nonsurvivors vs . 7.30 +/- 0.17 in survivors {p < .05}) . Of the 23 patients with initially high lactate concentrations, 12 (60%) of the 20 patients with low intramucosal pH died, as compared with one (33%) of the three patients with normal intramucosal pH (p = .052) . Of the 14 patients with persistently high lactate concentrations at 24 hrs, all nine (100%) patients with low intramucosal pH, but only two (40%) of five patients with normal intramucosal pH died (p < .001) . No significant relationship was found between lactate or intramucosal pH and oxygen-derived variables . Intramucosal pH correlated better with gastric intramural PCO2 (r2 = .58) than with arterial bicarbonate or base deficit/excess . Intramural PCO2 was a more specific predictor of mortality than intramucosal pH . When compared with patients with normal lactate concentrations, those patients with high lactate concentrations had a higher pH gap (0.22 +/- 0.22 vs . 0.07 +/- 0.13 {p < .01}) and PCO2 gap {21.0 +/- 33.9 vs . 1.8 +/- 9.8 torr {2.79 +/- 4.5 vs . 0.24 +/- 1.34 kPa}; p < .01) . CONCLUSIONS: Both lactate concentrations and intramucosal pH represent reliable prognostic indicators in severe sepsis, and their combination improves the prognostic assessment in these patients . Both variables are better prognostic indicators than oxygen-derived variables . Intramural PCO2 appears to be a more specific variable than intramucosal pH, which partially reflects systemic metabolic acidosis . Combined determinations of blood lactate concentrations and intramucosal pH or intramural PCO2 may help to predict outcome from severe sepsis.

Shock, 1995 Jul, 4(1), 11 - 20
Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids, lipid metabolism, and survival in sepsis; Larsson-Backstrom C et al.; The effects of dietary treatment for 3 weeks with soybean oil, linseed- and safflower oil (high alpha-linolenic acid, ALA), or borage oil (high gamma-linolenic acid, GLA) on the liver fatty acid profile and lipid metabolism in fed rats, in normal fasted rats, and septic fasted rats, and on survival from sepsis, were studied . The results were the following: 1) Dietary ALA increased incorporation of alpha-linolenic (18:3w3), eicosapentaenoic (20:5w3), and docosapentaenoic (22:5w3) acids in neutral lipids and phospholipids, and docosahexaenoic (22:6w3), dihomo-gamma-linolenic (20:3w6), arachidonic (20:4w6), stearic (18:0), oleic (18:1w9), and linoleic (18:2w6) acids in phospholipids in the livers of fed, fasted, and septic fasted rats . Dietary GLA increased all w6 fatty acids except 18:2w6, and reduced all w3 fatty acids in neutral lipids and phospholipids . 2) Dietary ALA increased liver phospholipid content in fasted as well as in septic fasted rats and was more potent than GLA in lowering serum cholesterol and liver neutral lipids . 3) Dietary ALA counteracted sepsis-related changes in liver weight, platelet count, body temperature, prekallikrein, serum glucose, beta-hydroxybutyrate, and free fatty acids . 4) Dietary GLA reduced survival from sepsis . The results suggest a role for w3 fatty acids to balance w6 fatty acids in the septic state.

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