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