Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Single or combination therapy of staphylococcal endocarditis in intravenous drug abusers. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. Antithrombin III and local serum application: adjuvant therapy in peritonitis. Randomized trial of beta-lactam regimens in febrile neutropenic cancer patients. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. [Immunoglobulin therapy of postoperative sepsis]. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Fluconazole improves survival in septic shock: a randomized double-blind prospective study. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. Early antibiotic treatment in acute necrotising pancreatitis. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Treatment of septicaemia in immunocompromised patients with ceftazidime or with tobramycin and cefuroxime, with special reference to renal effects. Prevention of indwelling central venous catheter sepsis. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. [The study of hypertonic saline and hydroxyethyl starch treating severe sepsis]. [Antibiotic prophylaxis using cefuroxime in bile duct endoscopy]. 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. Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients. Pentoxifylline reduces plasma tumour necrosis factor-alpha concentration in premature infants with sepsis. A randomized controlled trial of granulocyte colony-stimulating factor for the treatment of severe sepsis due to melioidosis in Thailand. Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. A prospective randomized trial of ceftazidime versus netilmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. Oral gentamicin therapy in the prevention of neonatal necrotizing enterocolitis. A controlled double-blind trial. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. Does the type of volume therapy influence endothelial-related coagulation in the critically ill? A prospective comparison of gentamicin and metronidazole and moxalactam in the prevention of septic complications associated with elective operations of the colon and rectum. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. [Comparison of Tarivid and Biseptol in the prevention of bacterial infections in patients with acute leukemia]. The influence of N-acetyl-L-cystein infusion on cytokine levels and gastric intramucosal pH during severe sepsis. Treatment of neonatal sepsis with intravenous immune globulin. Two randomized controlled trials of ceftazidime alone versus ceftazidime in combination with trimethoprim-sulfamethoxazole for the treatment of severe melioidosis. A randomised controlled trial of glutamine-enriched neonatal parenteral nutrition in Malaysia. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study. Influence of different volume therapy regimens on regulators of the circulation in the critically ill. A randomized, controlled trial of prophylactic granulocyte-macrophage colony-stimulating factor in human newborns less than 32 weeks gestation. Monotherapy with a broad-spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial. The Severe Generalized Peritonitis Study Group. Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. Early dexamethasone treatment for septic shock patients: a prospective randomized clinical trial. Piperacillin penetration into tissue of critically ill patients with sepsis--bolus versus continuous administration?
We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. Study design: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization.
                No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy.
                We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement. The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids.
                In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points.
                The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate.
                The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)
                2008 Massachusetts Medical Society HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia.
                To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol.
                Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected.
                HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known.
                We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis.
                Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation.
                Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population. Staphylococcus aureus is the commonest cause of acute endocarditis in intravenous drug abusers. In-vitro and in-vivo animal studies have found increased killing of organisms with the combination of a beta-lactam antibiotic and an aminoglycoside. These findings have created a controversy about the use of such combination therapy. We randomly treated 25 episodes of S. aureus endocarditis in intravenous drug abusers with either single or combination antibiotic regimens. Mean days to defervescence were similar in both groups: 6.3 d (SEM, 1.49 d) for the single drug group and 6.6 d (SEM, 1.02 d) for the group treated in combination with an aminoglycoside. There were no bacteriologic failures or relapses in either group. No patients needed valvular surgery, and the mortality rate was zero. Thus, it appears that single drug therapy with an appropriate beta-lactam antibiotic is adequate and appropriate in intravenous drug abusers with S. aureus endocarditis. To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis.
                Double-blind, randomized, placebo-controlled trial.
                Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals.
                Hospitalized adults with signs of gram-negative infection and a systemic septic response.
                Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later.
                Mortality over the 30-day study period, resolution of organ failures, and safety.
                Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified.
                Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated. To evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis.
                A multicenter, randomized, double-blind, placebo-controlled trial.
                Fifty-three hospitals across the United States, including university medical centers, Veterans Affairs Medical Centers, and community hospitals.
                847 patients were randomized into this study. Enrolled patients met criteria for three conditions: a) known or suspected Gram-negative infection; b) clinical evidence of sepsis; and c) signs of end-organ dysfunction. Patients with refractory shock were excluded from the study.
                Two doses of E5 (2 mg/kg/day by intravenous infusion 24 hrs apart), or placebo that was identical in appearance were administered. In addition, all patients received standard supportive therapy and broad-spectrum antibiotics.
                The primary end point was mortality over 30 days. Secondary outcome measures included the resolution and prevention of organ failure in the same two populations. Additionally, the safety of E5 was evaluated. There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo (n = 530; p = .21). In addition, E5 did not improve survival for patients with Gram-negative sepsis and organ failure (n = 139; p = .3). However, a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5, compared with those patients who received placebo (n = 139; 48% E5 vs. 25% placebo; p = .005). This result extended to all patients who entered the study with one or more major organ failures, regardless of the etiology of the infection (n = 225; 41% E5 vs. 27% placebo; p = .024). E5 also provided protection against the development of some organ failures, but significant prevention was only observed for adult respiratory distress syndrome (p = .007) and central nervous system dysfunction (p = .050). Hypersensitivity reactions attributable to E5 occurred in 2.6% of patients. An asymptomatic antibody response occurred in 44% of the E5-treated patients and in 12% of the patients who received placebo.
                In this study, E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure. However, E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis. This benefit extended to those patients with suspected Gram-negative etiology. This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results. In addition, E5 resulted in the prevention of adult respiratory distress syndrome and central nervous system organ failure. However, more studies are needed to determine if this result can be extended to organ failure in general. E5 is safe as a treatment for patients with Gram-negative sepsis. Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival.
                We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days.
                The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups.
                The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function. To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis.
                Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial.
                Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden.
                42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo.
                Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo.
                All patients were evaluated for safety and for 30-day all-cause mortality.
                The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis. To evaluate the efficacy and safety of anti-tumor necrosis factor alpha monoclonal antibody (TNF-alpha MAb) in the treatment of patients with sepsis syndrome.
                Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.
                A total of 31 hospitals in the United States and Canada.
                There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug.
                Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-alpha MAb, 7.5 mg/kg of TNF-alpha MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period.
                Twenty-eight-day all-cause mortality.
                The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-alpha MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-alpha MAb. In septic patients with shock (n = 478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-alpha MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-alpha MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P = .01; 7.5 mg/kg: 48.7% reduction vs placebo, P = .004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-alpha MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P = .20 for 7.5 mg/kg and P = .15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-alpha MAb were reported. Serum sickness-like reactions were seen in 2.5% of patients receiving TNF-alpha MAb.
                There was no decrease in mortality between placebo and TNF-alpha MAb in all infused patients. In septic shock patients who received TNF-alpha MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-alpha MAb, the difference in mortality among shock patients treated with placebo or TNF-alpha MAb was not significant. Patients with diffuse peritonitis show an overall mortality of about 20%, probably caused by the breakdown of local defence mechanisms combined with a systemic outspread of bacteria and toxins, which often results in sepsis syndrome.
                In a prospective, randomized, controlled study 50 patients with diffuse secondary peritonitis were included. Patients in the therapy group were treated with an adjuvant medication consisting of a continuous intravenous infusion of antithrombin III and two intraperitoneal instillations of fresh frozen human donor serum. The aim of the study was the reduction of mortality and incidence of multiple organ failure.
                Mean antithrombin III plasma levels in the therapy group were raised above 140% for 4 days and were significantly higher than in the control group. With the intraperitoneal application of fresh frozen serum and antithrombin III opsonic capacity as well as thrombin, inhibitory activity in the exudate could be significantly elevated over 2 days. The 90-day-mortality rate was 6/26 (23%) in the control group and 6/24 (25%) in the therapy group. Although no improvement of mortality was achieved, a slight but not significant reduction of the severity of the multiple organ failure was seen.
                The chosen therapeutic approach was feasible and showed no side-effects. Yet, neither mortality nor multiple organ failure were significantly improved by the applied short-term adjuvant therapy. Thus, for future trials in severely-ill patients a longer treatment period and/or combinations of antithrombin III with other anti-inflammatory agents should be considered. A three-arm prospective randomized trial was designed to compare the efficacies of piperacillin plus vancomycin, ceftazidime plus vancomycin, or all three drugs as initial therapy for fever in neutropenic cancer patients. The objectives were to determine whether a broad-spectrum penicillin was as effective as a broad-spectrum cephalosporin and whether two beta-lactam antibiotics were more effective than one. Four hundred and seventy of the 519 febrile episodes entered in the study could be evaluated for response. Ceftazidime plus vancomycin was significantly more effective than piperacillin plus vancomycin, considering all febrile episodes (79 percent versus 61 percent, p = 0.001), documented infections (79 percent versus 57 percent, p = 0.004), gram-negative infections (88 percent versus 47 percent, p = 0.001), and bacteremias (81 percent versus 51 percent, p = 0.01). The addition of piperacillin to ceftazidime (piperacillin plus ceftazidime and vancomycin versus ceftazidime plus vancomycin) did not improve the response rate and was associated with a significantly higher incidence of skin rash. Vancomycin plus ceftazidime provides adequate antibiotic coverage for initial treatment of fever in neutropenic patients. This combination was equally effective, less expensive, and less toxic than the double beta-lactam combination used in this study. To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis.
                Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis.
                Ninety-one academic medical center intensive care units in North America and Europe.
                Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo.
                Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo.
                The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study.
                A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial. 35 patients with septic postoperative complications entered a prospectively randomized study. The clinical state of these patients was daily determined using the sepsis score described by Elebute and Stoner. Endotoxin and antithrombin III were measured in the plasma using the limulus-amoebocyte-lysat test for endotoxin determination. The septic patients were treated with an immunoglobulin preparation (Pentaglobin) administered by the intravenous route. This preparation is enriched in IgM and IgA. Due to the immunoglobulin therapy the endotoxin titres decreased; simultaneously a reduction of mortality and shortening of time of hospitalization and of mechanical ventilation were observed. To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome (ARDS).
                A prospective, double-blind, placebo-controlled, randomized, parallel, multicenter pilot clinical trial.
                A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome.
                Patients were randomized into four treatment groups in a 2:1:2:1 ratio, as follows: 12 hours of surfactant per day, 12 hours of 0.6% saline per day, 24 hours of surfactant per day, and 24 hours of 0.6% saline per day. Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration.
                Ventilatory data, arterial blood gases, and hemodynamic parameters were measured at baseline, every 4 or 8 hours during the 5 days of treatment, 24 hours after treatment, and 30 days after treatment, at which time mortality was also assessed. Safety was evaluated throughout the 30 days of the study.
                Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system. Although there were no differences in any physiological parameters between the treatment groups, there was a dose-dependent trend in reduction of mortality from 47% in the combined placebo group to 41% and 35% in the groups treated with 12 hours and 24 hours of surfactant per day, respectively.
                Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days; however, at the doses given, it did not result in significant improvements in patients with sepsis-induced ARDS. ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study.
                120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.
                ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline.
                The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only. Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation (DIC). Numerous uncontrolled clinical studies have reported that antithrombin III (ATIII) substitution might prevent DIC and death in septic shock.
                We conducted a randomized double-blind placebo-controlled trial in patients with a documented septic shock and DIC. The patients received either a placebo or ATIII (90 to 120 IU/kg in loading dose, then 90 to 120 IU/kg/d during 4 days). Administration of fresh frozen plasma, platelets, and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time, platelet count, and fibrinogen levels.
                Thirty-five patients entered the study (18 placebo, 17 ATIII). Both groups were well balanced for all demographic, hemodynamic, and biologic data. Three patients were excluded before the treatment allocation code was broken. In the ATIII group, ATIII levels were rapidly corrected and remained over normal levels until day 10; sequential protein C and protein S levels were not modified. The duration of DIC was significantly reduced: in the ATIII group, 64 percent of patients were cured of DIC at day 2, and 71 percent were cured at the end of treatment vs in the placebo group, 11 percent (p < 0.01) and 33 percent (p < 0.05), respectively. In the 32 included patients, the mortality in ICU was reduced by 44 percent in the ATIII group (p = 0.22, NS). Care loads and transfusion requirements were not different. No side effect was observed.
                Mortality was reduced by 44 percent in this trial, but the difference did not reach the statistical significance. Circulating protein C and protein S levels were not modified by ATIII supplementation. High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock. The trend toward improved survival suggests further randomized studies. To demonstrate whether fluconazole reduces multiple organ failure and mortality in early septic shock (<24 hrs).
                A prospective randomized double-blind study.
                A medical and surgical adult intensive care unit in a tertiary referral center.
                Values were obtained from 71 general adult intensive care unit patients.
                During a 2.5-yr period, December 1998-June 2001, 71 patients with septic shock attributed to either nosocomial pneumonia (n = 37) or intra-abdominal sepsis (n = 34) were admitted to our intensive care unit and met the criteria of early septic shock and were entered into this study. All patients were randomized by our clinical pharmacist to receive daily either 200 mg of fluconazole in isotonic saline (fluconazole group = 32) or isotonic saline alone (placebo group = 39) intravenously during the course of their septic shock.
                All patients were closely monitored with pulmonary artery catheters and parameters to calculate daily organ dysfunction and Acute Physiology and Chronic Health Evaluation II scores. There was a highly significant increase in 30-day survival in the fluconazole-treated patients compared with the placebo patients (78% vs. 46%). However, fluconazole was found to be more effective in patients with septic shock attributed to intra-abdominal sepsis than to nosocomial pneumonia. Increased survival in the intra-abdominal sepsis clinical category was mirrored by a significantly lower number of organ failures in the treated group compared with the placebo group whereas the number of organ failures in the fluconazole group attributed to nosocomial pneumonia were not significantly increased compared with the control group. The septic shock state was considered in all cases to be attributed to bacterial and not to disseminated yeast infection with the exception of one patient in the control group who was admitted with candidemia. The mechanisms by which fluconazole exerts its protective effect against septic shock in patients is far from clear. However, fluconazole has been shown to enhance bactericidal activity of neutrophils and also to inhibit transmigration and adhesion of neutrophils in capillaries of distant organs.
                The development of organ failure and mortality in septic shock was significantly reduced by fluconazole given intravenously. The mechanism of action of fluconazole in reducing multiple organ dysfunction in this group of patients may be attributed to the ability of fluconazole to increase recruitment, improve bactericidal activity of neutrophils, and to contain microorganisms locally. Intravenous immunoglobulin as an adjunctive treatment in sepsis was regarded as promising by a Cochrane meta-analysis of smaller trials. In this phase III multicenter trial, we assessed whether intravenous immunoglobulin G (ivIgG) reduced 28-day mortality and improved morbidity in patients with score-defined severe sepsis.
                Randomized, double-blind, placebo-controlled, multicenter trial.
                Twenty-three medical and surgical intensive care units in university centers and large teaching hospitals.
                Patients (n = 653) with score-defined sepsis (sepsis score 12-27) and score-defined sepsis-induced severity of disease (Acute Physiology and Chronic Health Evaluation II score 20-35).
                Patients were assigned to receive either placebo or ivIgG (day 0, 0.6 g/kg body weight; day 1, 0.3 g/kg body weight).
                The prospectively defined primary end point was death from any cause after 28 days. Prospectively defined secondary end points were 7-day all-cause mortality, short-term change in morbidity, and pulmonary function at day 4. Six hundred fifty-three patients from 23 active centers formed the intention-to-treat group, 624 patients the per-protocol group (placebo group, n = 303; ivIgG group, n = 321). The 28-day mortality rate was 37.3% in the placebo group and 39.3% in the ivIgG group and thus not significantly different (p = .6695). Seven-day mortality was not reduced, and 4-day pulmonary function was not improved. Drug-related adverse events were rare in both groups. Exploratory findings revealed a 3-day shortening of mechanical ventilation in the surviving patients and no effect of ivIgG on plasma levels of interleukin-6 and tumor necrosis factor receptors I and II.
                In patients with score-defined severe sepsis, ivIgG with a total dose of 0.9 g/kg body weight does not reduce mortality. In this prospective, randomized controlled study, we aimed to evaluate the effect of IgM-enriched immunoglobulin treatment on progression of organ failure and septic shock in patients with severe sepsis.
                Forty-two patients with severe sepsis were enrolled in the study. Patients in the study group (n = 21) received an intravenous immunoglobulin preparation (Pentaglobin in addition to standard therapy. Pentaglobin therapy was commenced on the day of diagnosis of severe sepsis: 5 ml/kg per day Pentaglobin (38 g/l IgG, 6 g/l IgM, and 6 g/l IgA) was infused over 6 hours and repeated for 3 consecutive days. Patients in the control group (n = 18) received standard sepsis therapy, but no immunoglobulin administration. Blood samples for procalcitonin (PCT) measurements were taken daily for 8 days. Severity of critical illness and development of organ failure were assessed by obtaining daily acute physiological and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores.
                Procalcitonin levels showed a statistically significant decrease in the Pentaglobin group (P < 0.001); however, an improvement in SOFA scores could not be demonstrated. Procalcitonin levels and SOFA scores did not change significantly in the control group. Septic shock incidence (38% versus 57%) and 28-day mortality rate (23.8% versus 33.3%) were found to be similar between the Pentaglobin and control groups. The evaluation of serial APACHE II scores did not demonstrate a difference between Pentaglobin and control groups either.
                Present data could not demonstrate any beneficial effects of polyclonal immunoglobulin preparation Pentaglobin on organ morbidity, septic shock incidence and mortality rate in patients with severe sepsis. Despite improvements in surgical treatment and intensive care, mortality from severe acute pancreatitis remains high. We have carried out a randomised study of 60 consecutive patients with alcohol-induced necrotising pancreatitis to find out whether early antibiotic treatment can improve outcome. 30 patients were assigned cefuroxime (4.5 g/day intravenously) from admission. In the second group, no antibiotic treatment was given until clinical or microbiologically verified infection or after a secondary rise in C-reactive protein. The inclusion criteria were C-reactive protein concentration above 120 mg/L within 48 h of admission and low enhancement (< 30 Hounsfield units) on contrast-enhanced computed tomography. There were more infectious complications in the non-antibiotic than in the antibiotic group (mean per patient 1.8 vs 1.0, p = 0.01). The most common cause of sepsis was Staphylococcus epidermidis; positive cultures were obtained from pancreatic necrosis or the central venous line in 14 of 18 patients with suspected but blood-culture-negative sepsis. Mortality was higher in the non-antibiotic group (seven vs one in the antibiotic group; p = 0.03). Four of the eight patients who died had cultures from pancreatic necrosis positive for Staph epidermidis. We conclude that cefuroxime given early in necrotising pancreatitis is beneficial and may reduce mortality, probably by decreasing the frequency of sepsis. Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients.
                To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.
                Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.
                A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).
                All-cause mortality 28 days after initiation of study medication.
                Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).
                High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin. Fifty-two immunocompromised patients with suspected septicaemia were randomized on 61 occasions to treatment with ceftazidime or with tobramycin and cefuroxime. Most (90%) of the patients had haematological malignancies and were neutropenic (granulocytes less than 1 X 10(9)/1 in 40 of the 61 episodes). Blood cultures were positive in 22 (39%) febrile episodes and in four other instances positive cultures were obtained from other sources. Clinical cure or improvement was noted in 10 of 12 culture verified infections in the tobramycin and cefuroxime group and 11 of 14 episodes in the ceftazidime-group. The effect on the kidney of the two antibiotic regimens was studied by following the serum levels of creatinine, urea and beta 2-microglobulin and the urinary excretion of alanine aminopeptidase, N-acetyl-beta-D-glucosaminidase (beta-NAG) and beta 2-microglobulin. No clinically important renal side effects were observed. However, an increase in the urinary excretion of AAP was seen in both groups with significantly greater elevation in the tobramycin and cefuroxime group. Urinary beta-NAG increased only in the tobramycin and cefuroxime group. In an attempt to decrease the incidence of central venous catheter sepsis in children with cancer, we conducted a study to evaluate the benefit of adding broad-spectrum antibiotics to the catheter "flush solution." In a prospective, placebo-controlled, double-blinded, randomized trial, 69 children with different types of malignancies were studied. The central venous catheters in these children were flushed with either the standard solution (normal saline + 100 U/ml of heparin) or the study solution (25 microgram/ml of both amikacin and vancomycin added to the standard solution). At the conclusion of the study, 64 children with a total of 67 indwelling central venous lines were assessable. The total catheter days on study were 20,700 days, with a median of 323 catheter days per patient. We documented 10 events of catheter-related infections (0.49 events/1,000 catheter days at risk). Five of these events were catheter-related sepsis (0.24 sepses/1,000 catheter days): two were fungal and three were bacterial. Due to the low incidence of catheter-related sepsis in this study, no statement regarding the prophylactic use of antibiotics could be made. The extremely low rate of catheter-related sepsis reported herein may be retrospectively attributed to continuous staff education regarding aseptic techniques in handling these catheters. Staff education is essential, and probably the most effective factor in preventing catheter-related sepsis. Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
                In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
                Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
                Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.). To evaluate the effect of 7.5% hypertonic saline (HS) and 6% hydroxyethyl starch (HES) 130/0.4 on early fluid resuscitation for severe sepsis.
                Prospective randomized control trial was carried out in intensive care unit (ICU) of the Affiliated Hospital of Jianghan University. One hundred and thirty five patients with severe sepsis were randomly divided into three groups, each group consisted of 45 patients. Patients in HS+HES group received lactated Ringer solution following 4 ml/kg of 7.5% HS and 6% HES 130/0.4 500 ml, those in HES group received lactated Ringer solution following 6% HES 130/0.4 500 ml, and those in the lactated Ringer group (RL group) received lactated Ringer solution only.Mean arterial pressure (MAP), oxygenation index (PaO₂/FiO₂),arterial lactate (Lac),lactate clearance rate, acute physiology and chronic health evaluation II(APACHEII) score,fluid infusion volume, urine output as well as incidence of multiple organ dysfunction syndrome (MODS), and mortality were compared among three groups at 6 hours and 24 hours after ICU admission.
                At 6 hours after ICU admission,MAP[mm Hg (1 mm Hg=0.133 kPa): 68.7 ± 3.0], PaO₂/FiO₂(mm Hg: 262.2 ± 17.4), lactate clearance rate [(21 ± 4)%] in HS+HES group were significantly higher than those in HES group [MAP: 63.8 ± 3.5,PaO(2)/FiO(2): 252.0 ± 21.2, lactate clearance rate: (11 ± 2)%] and RL group [MAP: 62.6 ± 3.6, PaO₂/FiO₂:248.4 ± 17.0,lactate clearance rate: (9 ± 1)%, all P <0.01]. Arterial Lac in HS+HES group (mmol/L: 3.5 ± 0.7) was significantly lower than that in HES group (4.1 ± 0.7) and RL group (4.0 ± 0.7, both P <0.01). There was no significant difference in APACHE II score between HS+HES group (13.2 ± 1.9) and HES group (14.0 ± 1.6), and the APACHEII score in HS+HES group was significantly lower than that in RL group (15.2 ± 1.7, P <0.01). At 24 hours after ICU admission, PaO₂/FiO₂ (mm Hg: 303.3 ± 17.3) was significantly higher in HS+HES group than that in HES group (282.9 ± 21.1) and RL group (268.9 ± 15.2, both P <0.01). There was no significant difference in MAP, arterial Lac, lactate clearance rate and APACHEII score among three groups. At 6 hours and 24 hours after ICU admission, fluid infusion volume in HS+HES group (ml, 6 hours: 1 877.8 ± 215.2, 24 hours: 5 475.6 ± 208.8) was markedly less than that in HES group (6 hours: 2 505.6 ± 276.2, 24 hours: 6 383.3 ± 287.4) and RL group (6 hours: 3 496.7 ± 325.5,24 hours: 7 439.6 ± 229.6), yet urine output in HS+HES group (ml, 6 hours: 294.2 ± 36.9, 24 hours : 2 793.8 ± 37.1) was significantly higher than that in HES group (6 hours: 248.9 ± 25.3, 24 hours : 2 248.9 ± 25.3) and RL group (6 hours: 178.9 ± 14.8, 24 hours: 2 000.4 ± 147.0, all P <0.01). The incidence of MODS in HS+HES group (6.7%) was statistically lower than that in RL group (28.9%, P <0.05), while no obvious difference was found between HS+HES group and HES group (17.8%, P >0.05). There was no significant difference in mortality among three groups (HS+HES group: 2.2%, HES group: 4.4%, RL group: 8.9%, all P >0.05).
                7.5%HS and 6%HES 130/0.4 could improve the effect of early fluid resuscitation on severe sepsis, and it could lower the incidence of MODS. To assess prospectively the effectiveness of a single prophylactic dose of cefuroxim before therapeutic endoscopy, in view of the general practice not to give antibiotics routinely.
                In a prospective study endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography with drainage (PTCD) together with simultaneous stone extraction, dilatation or stent implantation were performed in 99 patients (51 men, 48 women; mean age 60.6 +/- 19.2 years). Group A (n = 49) received 1500 mg cefuroxim i.e. 30 min before the procedure, while none was given to group A patients (n = 50). Several blood cultures were taken up to 60 min after the endoscopy. The number of septicaemias (bacteraemia with fever, rigor, circulatory reactions, leukocytosis or leukopenia) were noted. Bile cultures were obtained in 56 patients with indwelling biliary drainage.
                Incidence of bacteraemia was 6.1% (3 of 49) in group A, 16% (8 of 50) in group B, but this difference is not statistically significant. The septicaemia rate was 6.1% in group A and 10% in group B (not significant). There were eleven positive blood cultures with 12 different microorganisms, Escherichia coli in four (A: n = 3). In vitro cefuroxim sensitivity was 53.3%. 25 different bacterial species were isolated from 73.2% of bile cultures, of which 53.4% were sensitive to cefuroxim and 8.2% moderately so.
                Although the obtained differences between the two groups were not statistically different, the reduction in bacteraemia/septicaemia rate may be of clinical use. Further studies are needed with higher dosages or antibiotic combinations to improve these results. 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.
                An international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups.
                Forty acute clinical care facilities in 14 countries.
                Of the 564 patients enrolled in the study, 553 patients received study drug or placebo.
                Patients received 15 mg/kg or 3 mg/kg of BAY x 1351, or placebo, as a single intravenous infusion.
                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.
                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. Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broad-spectrum and highly bactericidal antibiotics, the need of combining beta-lactams with aminoglycosides for the treatment of severe infections should be reassessed. A prospective randomized controlled study was performed to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. A total of 313 patients were enrolled, and 280 were assessable. The antibiotic treatment was successful in 113 of 142 patients (80%) given the monotherapy and in 119 of 138 patients (86%) given the combination (P = 0.19). The failure rates for the most important type of infection, i.e., pneumonia, were similar in the two groups, as well as the number of superinfections. While creatinine increase was associated with factors not related to antibiotic therapy for all eight patients of the monotherapy group, no factor other than the antibiotics could be found for 6 of the 14 cases of nephrotoxicity observed in the combination group (P = 0.014). Finally, the emergence of Pseudomonas aeruginosa resistant to imipenem occurred in 8 monotherapy patients and in 13 combination therapy patients. In conclusion, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmicin for the treatment of severe infection. The addition of netilmicin increased nephrotoxicity, and it did not prevent the emergence of P. aeruginosa resistant to imipenem. Increased plasma tumour necrosis factor alpha (TNF) concentration correlates with mortality in sepsis. We suggested that pentoxifylline (PTXF), which is known to inhibit TNF production, may improve survival and attenuate clinical symptoms of sepsis in neonates. Plasma TNF levels were evaluated in 29 newborn infants with sepsis. Patients were randomly assigned into two groups, receiving PTXF in a dose of 5 mg/kg per hour for 6 h or placebo (saline), on 3 successive days. Both groups were subjected to the same conventional therapy. TNF was evaluated before and after PTXF or placebo administration on the 1st and 3rd days of therapy. There was a statistically significant decrease in plasma TNF level in the PTXF group when the values before the first and after the last PTXF infusion were compared [mean: 671.5 pg/ml; SD: 438; med: 729.6 vs mean: 41.0 pg/ml; SD: 64.1; med: 11.5; P < 0.000004]. In the placebo group, decrease was not significant [mean: 633.0 pg/ml SD: 488.6; med: 618.9 vs 246.9 pg/ml; SD: 243.9; med: 191.0]. A significantly higher plasma TNF level, evaluated after the last PTXF infusion, was found in the placebo group [246.9 pg/ml vs 41.0 pg/ml; P < 0.001]. Only one of four infants with signs of shock in the placebo group survived, whereas all of five newborns with symptoms of shock in the PTXF group survived [P < 0.04]. An increased incidence of metabolic acidosis [P < 0.05], necrotizing enterocolitis [P < 0.04] and renal insufficiency [P < 0.05] was observed in infants in the placebo group.
                PTXF inhibits production of TNF and may have therapeutic value in the treatment of premature infants with sepsis complicated by shock. Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis.
                In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 mu g per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand.
                Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61-1.06; P=.2), including among patients with confirmed melioidosis (83% vs. 96%; P=.3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31-1.00; P=.05).
                Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may "buy time" for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis. Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high-dose supplementation of sodium-selenite would improve the outcome of patients with severe sepsis and septic shock.
                Prospective randomized, placebo-controlled, multiple-center trial.
                Eleven intensive care units in Germany.
                Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70.
                Patients received 1000 microg of sodium-selenite as a 30-min bolus injection, followed by 14 daily continuous infusions of 1000 microg intravenously, or placebo.
                The primary end point was 28-day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum glutathione-peroxidase-3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention-to-treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium-treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39-1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28-day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32-1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score > or =102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase-3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high-dose sodium-selenite treatment.
                The adjuvant treatment of patients with high-dose sodium-selenite reduces mortality rate in patients with severe sepsis or septic shock. Aminoglycosides are frequently used to treat sepsis in patients with liver disease. However, it has been suggested that cirrhotic patients are particularly sensitive to aminoglycoside-induced renal dysfunction. We investigated the efficacy and incidence of renal impairment with netilmicin plus mezlocillin compared with ceftazidime in 128 cirrhotic patients who required empirical treatment for sepsis. Renal impairment developed in 8 of 63 (13%) patients receiving netilmicin compared with 2 of 65 (3%) patients receiving ceftazidime (P < .05); it occurred despite regular monitoring of trough netilmicin levels. Renal impairment was present at the time of death in 1 of 13 (8%) patients treated with ceftazidime compared with 5 of 9 (56%) of the netilmicin patients (P < .05). Mortality rates were similar in the two groups (ceftazidime 20%, aminoglycoside 14%; P = NS). Renal dysfunction is significantly more frequent in cirrhotic patients treated with netilmicin but with careful attention to dosage and fluid management the clinical effect is likely to be relatively modest. To determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis.
                This study was multicenter, double-blind, and randomized.
                Intensive care units PATIENTS Adult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction.
                Standard antibiotic therapy with or without filgrastim (300 microg/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 x 10(9) cells/L.
                The primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 x 10(9) cells/L from a baseline of 12.3 x 10(9) cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups.
                The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection. Knowledge and understanding of gram-negative sepsis have grown over the past 20 years, but the ability to treat severe sepsis successfully has not.
                To assess the efficacy and safety of E5 in the treatment of patients with severe gram-negative sepsis.
                A multicenter, double-blind, randomized, placebo-controlled trial conducted at 136 US medical centers from April 1993 to April 1997, designed with 90% power to detect a 25% relative risk reduction, incorporating 2 planned interim analyses.
                Intensive care units at university medical centers, Veterans Affairs medical centers, and community hospitals.
                Adults aged 18 years or older, with signs and symptoms consistent with severe sepsis and documented or probable gram-negative infection.
                Patients were assigned to receive 2 doses of either E5, a murine monoclonal antibody directed against endotoxin (n = 550; 2 mg/kg per day by intravenous infusion 24 hours apart) or placebo (n = 552).
                The primary end point was mortality at day 14; secondary end points were mortality at day 28, adverse event rates, and 14-day and 28-day mortality in the subgroup without shock at presentation.
                The trial was stopped after the second interim analysis. A total of 1090 patients received study medication and 915 had gram-negative infection confirmed by culture. There were no statistically significant differences in mortality between the E5 and placebo groups at either day 14 (29.7% vs 31.1%; P = .67) or day 28 (38.5% vs 40.3%; P = .56). Patients presenting without shock had a slightly lower mortality when treated with E5 but the difference was not significant (28.9% vs 33.0% for the E5 and placebo groups, respectively, at day 28; P = .32). There was a similar profile of adverse event rates between E5 and placebo.
                Despite adequate sample size and high enrollment of patients with confirmed gram-negative sepsis, E5 did not improve short-term survival. Current study rationale and designs should be carefully reviewed before further large-scale studies of patients with sepsis are conducted. The value of prophylactic oral gentamicin sulfate therapy in the prevention of necrotizing enterocolitis (NEC) was evaluated in a group of 42 high-risk neonates over a four-month period in a randomized, double-blind controlled trial. Twenty babies in the treatment group received 2.5 mg/kg of gentamicin sulfate every six hours for one week after birth, and 22 babies received dextrose-and-water placebo in an equivalently small volume. None of the 20 gentamicin-treated babies developed NEC. Four of the control babies did. Two of these babies died, and their diagnosis was pathologically confirmed. This difference in the incidence of NEC between the treatment and control group was significant at the .05 level. These results support the prophylactic use of orally given gentamicin for selected babies at high risk for NEC, particularly those born prematurely and those who have a history of perinatal asphyxia or umbilical artery catheterization or both. Continued surveillance for changes in antimicrobial sensitivity patterns is recommended. The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial. Our study was designed as a prospective, randomized, double-blind, placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock. Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia (rectal temperature greater than 38.3 degrees C [101 degrees F] or less than 35.6 degrees C [96 degrees F]), tachypnea (greater than 20 breaths per minute), tachycardia (greater than 90 beats per minute), and the presence of one of the following indications of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels, or oliguria. Three hundred eighty-two patients were enrolled. Treatment--either methylprednisolone sodium succinate (30 mg per kilogram of body weight) or placebo--was given in four infusions, starting within two hours of diagnosis. No significant differences were found in the prevention of shock, the reversal of shock, or overall mortality. In the subgroup of patients with elevated serum creatinine levels (greater than 2 mg per deciliter) at enrollment, mortality at 14 days was significantly increased among those receiving methylprednisolone (46 of 78 [59 percent] vs. 17 of 58 [29 percent] among those receiving placebo; P less than 0.01). Among patients treated with methylprednisolone, significantly more deaths were related to secondary infection. We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock. The endothelium plays an important role in the regulation of haemostasis by producing substances such as thrombomodulin (TM). The influence of long-term volume replacement with different types of fluid on the TM-protein C-protein S system was investigated in a prospective, randomized study. Thirty trauma patients and 30 patients suffering from sepsis after major surgery received either 10% low-molecular weight (LMW) hydroxyethylstarch solution (HES-trauma, n = 15; HES-sepsis, n = 15) or 20% human albumin (HA-trauma, n = 15; HA-sepsis, n = 15) for 5 days to maintain central venous pressure (CVP) between 12 and 16 mm Hg. Plasma concentrations of TM, protein C, (free) protein S and thrombin-antithrombin (TAT) were measured in arterial blood samples obtained on the day of admission to the intensive care unit or on the day of diagnosis of sepsis and over the next 5 days. There were no differences between HA- and HES-treated trauma patients. Protein C and protein S also did not differ between HA- and HES-treatments. At baseline, TM plasma concentrations were increased to > 40 micrograms litre-1 in both sepsis groups only. In the HA-sepsis group, TM increased significantly (from 48.1 (SD 13.9) to 68.4 (13.0) micrograms litre-1), whereas it remained almost unchanged in the HES-sepsis group. In HES-sepsis patients, protein C (from 51.0 (10.1) to 71.9 (8.9)%) and protein S (from 19.0 (6.0) to 40.8 (11.4)%) increased significantly during the study, whereas both remained reduced in HA-patients. TAT (indicating intravascular coagulation) did not differ between the two fluid groups. We conclude that in trauma patients, the type of volume therapy had no influence on the TM-protein C-protein S system. In sepsis patients, volume therapy with HES was beneficial, whereas infusion of HA had no substantial positive effect on endothelial-associated coagulation. Bacteriologic evidence suggests that Latamoxef (moxalactam) is effective against colonic bacteria which cause infection during colonic and rectal operations. In a prospective comparative study, 86 patients undergoing colorectal operations were randomized to receive intravenously 24 hour antibiotic cover with either gentamicin and metronidazole or moxalactam. Six patients (13 per cent) in the gentamicin and metronidazole group and five (12 per cent) in the moxalactam group had wound sepsis develop. Perineal wound sepsis (31 per cent) was significantly more common than abdominal wound sepsis (7 per cent). No complications were noted from the use of moxalactam. No clinical evidence of abnormal bleeding was seen and the results of studies on coagulation and platelet function postoperatively were normal. The results suggest that moxalactam provides effective, safe prophylaxis comparable with established antibiotic combinations in patients undergoing colorectal operations. Activation of thrombin and of the coagulation system plays an important role in the pathophysiology of sepsis-associated organ dysfunction. Antithrombin III (AT III) is a natural inhibitor of thrombin, a central procoagulatory factor with pleiotropic activities. Experimental supplementation of AT III improved coagulation parameters and ameliorated organ dysfunction. To determine whether long-term AT III supplementation has beneficial effects on organ function, we conducted a randomized, prospective study in surgical patients with severe sepsis. The study evaluated the long-term effect of AT III supplementation (duration of treatment: 14 days). After randomization (AT III vs. control group), AT III was infused continuously over 14 days to obtain plasma AT III activities > 120%. Forty consecutive patients were recruited (20 AT III/20 control group). Eleven patients had a rapid fatal course and did not met the criterion of a 14 day treatment period. From these 11 patients, 8 patients (5 AT III/3 control group) died within 72 h due to septic shock. The remaining 14 AT III patients and 15 controls survived 14 days and showed no differences in baseline parameters of organ function. AT III caused a disappearance of disseminated intravascular coagulation (DIC) in all patients with DIC, whereas in control patients, the frequency of DIC remained constant (p < .05). In AT III patients a progressive increase in oxygenation index (PaO2/FiO2 ratio) and a continuous decrease in pulmonary hypertension index (mean pulmonary artery pressure/mean arterial pressure (PAP/MAP) ratio) indicated an improvement of lung function (p < .05 vs. control). AT III prevented the continuous rise in total serum bilirubin concentration observed in control patients and diminished the frequency of artificial renal support therapy (p < .05). Long-term supplementation with AT III may improve lung function and prevent the development of septic liver and kidney failure in patients with severe sepsis. The objective of this study was to assess the impact on outcome of adjuvant therapy (high-dose of immunoglobulin [Ig] M-enriched intravenous Ig, IVIG) in intensive care unit (ICU) patients who underwent surgery by abdominal sepsis. This was a prospective, randomized, double-blind, controlled study set in the medical/surgical ICUs of seven teaching hospitals. Patients with severe sepsis and septic shock of intra-abdominal origin admitted to the ICU within 24 h after the onset of symptoms were included in the study. Polyvalent IgM-enriched Ig (Pentaglobin; IVIG group) at a dosage of 7 mL/kg/day for 5 days or an equal amount of 5% human albumin (control group) was randomized. Fifty-six patients were enrolled. The overall mortality rate was 37.5.%. Twenty patients had shock and 36 had severe sepsis (the mortality rate was 55.0% and 25.0%, respectively). In the intent-to-treat analysis, the mortality rate was reduced from 48.1% in patients treated with antibiotic (ATB) plus albumin to 27.5% (P = 0.06) for patients with ATB plus IVIG. The organ failure score (1.0 +/- 0.6 vs. 1.2 +/- 0.9), organ dysfunction score (1.7 +/- 1.1 vs. 1.8 +/- 1.0), and reoperation rate (17.2% vs. 29.6%) were not different between IVIG and control groups, respectively. Eight patients (14.3%) received inappropriate ATB initial therapy (IAT), and seven died (87.5%). IAT was the only variable independently associated with death (odds ratio, 19.4) in a logistic regression model. We conclude that IVIG administration, when used in combination with adequate antibiotics, improved the survival of surgical ICU patients with intra-abdominal sepsis. The initial choice of antibiotic has a dramatic impact on outcome. To determine whether adjunctive therapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could reverse sepsis-associated neonatal neutropenia and improve neonatal survival and to assess its safety compared with conventional therapy in a control group.
                This prospective, randomized, controlled trial was performed in 60 infants with neutropenia and clinical signs of sepsis. A subcutaneous injection of rhGM-CSF (5 microgram/kg/day) was administered to 30 of the patients for 7 consecutive days. Hematologic parameters (absolute neutrophil, eosinophil, monocyte, lymphocyte counts, and platelet number) and outcome were compared with 30 conventionally treated (control) patients.
                Twenty-five patients from the GM-CSF-treated group and 24 from the conventionally treated group had early-onset sepsis (</=3 days' postnatal age), and the other 11 patients had late-onset sepsis (>3 days' postnatal age). There was no difference between groups in terms of birth weight; gestational age; gender; maturity; maternal age; and incidence of prolonged rupture of membranes, maternal hypertension, or severity of sepsis. All neonates tolerated GM-CSF well with no adverse reactions. The absolute neutrophil count on day 7 was significantly increased in the GM-CSF-treated group compared with the conventionally treated group: 8088 +/- 2822/mm(3) versus 2757 +/- 823/mm(3). The mean platelet count was significantly higher on days 14 in the GM-CSF-treated group compared with conventionally treated group: 266 867 +/- 55 102/mm(3) versus 229 200 +/- 52 317/mm(3). Hematologic parameters were otherwise similar between groups before treatment and on day 28. Twenty-seven neonates in the rh-GMCSF group and 21 in the control group survived to hospital discharge. The mortality rate in the rhGM-CSF group (10%) was significantly lower than in the conventionally treated group (30%).
                Treatment with rhGM-CSF is associated with an increase in absolute neutrophil, eosinophil, monocyte, lymphocyte, and platelet counts and decreased mortality in critically ill septic neutropenic neonates. These results suggest that rhGM-CSF may be effective in the treatment of neonatal sepsis with neutropenia, and further randomized trials are needed to confirm its beneficial effects. In 42 patients with induction treatment of acute myeloblastic and lymphoblastic leukaemia the authors compared efficacy of selective decontamination of the gastrointestinal tract in prevention of infections during neutropenia less than 0.5.10(9)/l in two comparable groups. Twenty-two patients were treated with Ofloxacin (Tarivid, Hoechst Co.), 20 patients with Trimetroprim-Sulfamethoxazol (Biseptol, Polfa Co.). Both groups had concurrently also Ketoconazol in prevention of mycotic infection. The investigation revealed that Tarivid is a suitable alternative drug for selective decontamination, because it delays the onset of acquired infection, as compared with Biseptol, it reduced more efficiently the frequency of Gram-negative colonization and life-threatening Gram-negative sepsis, caused by resistent strains; its tolerance is significantly better. There was no significant difference in the occurrence of febrile days, febrile episodes, the duration of antibiotic treatment, the number of sepsis in two groups. The effect of Tarivid and Biseptol on the Gram-positive microbial flora is inadequate. Subclavian catheter increases in particularly the risk of Gram-positive sepsis in both groups. The purpose of the present study was to evaluate the effects of continuously infused N-acetyl-L-cystein (NAC) on serum cytokine levels and gastric intramucosal pH in humans suffering from severe sepsis.
                Fifty-three patients were included in the study. In the NAC group (n = 27), after an initial intravenous bolus of NAC (150 mg/kg over 5 min), a continuous intravenous infusion of 12.5 mg/kg per hour was given for 6 hours. Patients in the control group (n = 26) were administered dextrose (5% solution) at the same dosage. We recorded the following: haemodynamic parameters, nasopharyngeal temperature, arterial blood gas changes, plasma cytokine levels, biochemical parameters, intramucosal pH, length of stay in the intensive care unit, duration of of mechanical ventilation and mortality. All measurements were taken at baseline (15 min before the start of the study) and were repeated immediately after the bolus infusion, and at 24 and 48 hours after initiation of the continuous NAC infusion.
                No differences were found between groups in levels of the major cytokines, duration of ventilation and intensive care unit stay, gastric intramucosal pH and arterial oxygen tension/inspired fractional oxygen ratio (P > 0.05).
                We found that NAC infusion at the doses given did not affect cytokine levels, outcomes, or gastric intramucosal pH in patients with severe sepsis. Because of the limited number of patients included in the study and the short period of observation, our findings need confirmation in larger clinical trials of NAC infused in a dose-titrated manner. However, our results do not support the use of NAC in patients with severe sepsis. Neonatal sepsis is a major cause of death and complications despite antibiotic treatment. Effective adjunctive treatments are needed. Newborn infants are relatively deficient in endogenous immunoglobulin. Meta-analyses of trials of intravenous immune globulin for suspected or proven neonatal sepsis suggest a reduced rate of death from any cause, but the trials have been small and have varied in quality.
                At 113 hospitals in nine countries, we enrolled 3493 infants receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either polyvalent IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart. The primary outcome was death or major disability at the age of 2 years.
                There was no significant between-group difference in the rates of the primary outcome, which occurred in 686 of 1759 infants (39.0%) who received intravenous immune globulin and in 677 of 1734 infants (39.0%) who received placebo (relative risk, 1.00; 95% confidence interval, 0.92 to 1.08). Similarly, there were no significant differences in the rates of secondary outcomes, including the incidence of subsequent sepsis episodes. In follow-up of 2-year-old infants, there were no significant differences in the rates of major or nonmajor disability or of adverse events.
                Therapy with intravenous immune globulin had no effect on the outcomes of suspected or proven neonatal sepsis. Two antibiotic regimens are used commonly in Thailand for the initial treatment of severe melioidosis: ceftazidime in combination with trimethoprim-sulfamethoxazole (TMP-SMX) and ceftazidime monotherapy. It is not known whether TMP-SMX provides an additional benefit.
                Two prospective, randomized trials that compared these regimens for patients presenting with acute severe melioidosis were started independently at tertiary care hospitals in Ubon Ratchathani and Khon Kaen (in northeastern Thailand), and the results were analyzed together as a prospective, individual-patient data meta-analysis. The primary end point was in-hospital mortality rate.
                The in-hospital mortality rate among all enrolled patients (n=449) was not significantly different between those randomized to ceftazidime alone (25.1%; 56 of 223 subjects) and those randomized to ceftazidime with TMP-SMX (26.6%; 60 of 226 subjects; odds ratio [OR], 1.08; 95% confidence interval [CI], 0.7-1.7; stratified P=.73). Of the 241 patients with culture-confirmed melioidosis, 51 (21.2%) died. Of these 241 patients, 31 (12.9%) died > or =48 h after the time of study entry. Among patients with melioidosis, there was no difference in death rate between the 2 treatment groups for either all deaths (OR, 0.88; 95% CI, 0.48-1.6; stratified P=.70) or for deaths that occurred > or =48 h after hospital admission (OR, 0.88; 95% CI, 0.41-1.9; stratified P=.73). Conditional logistic regression analysis revealed that bacteremia, respiratory failure, and renal failure were independently associated with death and treatment failure. Drug regimens were not associated with death or treatment failure in this model.
                We conclude that the addition of TMP-SMX to ceftazidime therapy during initial treatment of severe melioidosis does not reduce the acute mortality rate. The addition of glutamine to parenteral nutrition (PN) in neonates has not shown significant benefits as compared to adults thus far. This study aimed to determine the potential benefits of the addition of glutamine to neonatal PN in a tertiary hospital in a middle-income country.
                This was a double-blinded randomised controlled trial. Babies who were admitted to the neonatal intensive care unit (NICU) and who required PN were eligible for inclusion in the study. The subjects were randomised to receive either glutamine-added PN (intervention) or standard PN (control). The most important outcomes included time to full enteral nutrition, incidence of sepsis and necrotising enterocolitis (NEC), clinical or culture-proven sepsis.
                Out of 270 subjects, 132 were randomised to the intervention group and 138, to the control group. Baseline data were comparable in both groups. The median time taken to reach full enteral nutrition was similar for both intervention and control groups (six days in each group, p-value is 0.52). The incidences of NEC, clinical sepsis and culture-proven sepsis did not differ significantly in the intervention and control groups (5.8 vs. 7.1 percent, p-value is 0.68; 15.7 percent vs. 10.2 percent, p-value is 0.21 and 16.5 percent vs. 15.7 percent, p-value is 0.38, respectively). Other outcomes such as duration of ventilation, duration of NICU stay and a subgroup analysis for preterm and term babies also showed no statistically significant differences.
                Addition of glutamine to neonatal PN was not shown to improve outcome. In septic shock, decreased splanchnic blood flow is reported, despite adequate systemic hemodynamics. Aacetylcysteine (NAC) was found to increase hepatosplanchnic blood flow in experimental settings. In septic shock patients, NAC improved the clearance of indocyanine green and the relationship of systemic oxygen consumption to oxygen demand. We investigated the influence of NAC on liver blood flow, hepatosplanchnic oxygen transport-related variables, and liver function during early septic shock.
                Prospective, randomized, double-blind study.
                Septic shock patients admitted to an interdisciplinary surgical intensive care unit.
                We examined 60 septic shock patients within 24 hrs after onset of sepsis. They were conventionally resuscitated with volume and inotropes and were in stable condition. A gastric tonometer was inserted into the stomach and a catheter into the hepatic vein. Microsomal liver function was assessed by using the plasma appearance of monoethylglycinexylidide (MEGX).
                Subjects randomly received either a bolus of 150 mg/kg iv NAC over 15 mins and a subsequent continuous infusion of 12.5 mg/kg/hr NAC over 90 mins (n = 30) or placebo (n = 30).
                Measurements were performed before (baseline) and 60 mins after beginning the infusion (infusion). After NAC, a significant increase in absolute liver blood flow index (2.7 vs. 3.3 L/min/m2; p = .01) and cardiac index (5.0 vs. 5.7 L/min/m2; p = .02) was observed. Fractional liver blood flow index (cardiac index-related liver blood flow index) did not change. The difference between arterial and gastric mucosal carbon dioxide tension decreased (p = .05) and MEGX increased (p = .04). Liver blood flow index and MEGX correlated significantly (r(s) = .57; p < or = .01).
                After NAC treatment, hepatosplanchnic flow and function improved and may, therefore, suggest enhanced nutritive blood flow. The increase of liver blood flow index was not caused by redistribution to the hepatosplanchnic area, but by an increase of cardiac index. Because of its correlation with liver blood flow index, MEGX may be helpful in identifying patients who benefit from NAC treatment in early septic shock. Various vasoactive substances are involved in the regulation of the macro- and microcirculation. We have investigated if these regulators change during long-term volume therapy with human albumin (HA) or hydroxyethylstarch solution (HES) in trauma and sepsis patients. To maintain pulmonary capillary wedge pressure (PCWP) at 10-15 mm Hg, either 20% HA (HA-trauma, n = 14; HA-sepsis, n = 14) or 10% low-molecular weight HES solution (HES-trauma, n = 14; HES-sepsis, n = 14) were infused for 5 days, otherwise patient management did not differ between the two groups (trauma/sepsis). Mean arterial pressure (MAP), heart rate (HR), PCWP and cardiac index (CI) were monitored in all patients. Liver function was assessed using the monoethylglycinexylidide (MEGX) test, and gastric intramucosal pH (pHi) was monitored by tonometry to assess splanchnic perfusion. Plasma concentrations of vasopressin, endothelin-1, adrenaline, noradrenaline, atrial natriuretic peptide and 6-keto-prostaglandin F1 alpha were measured from arterial blood samples. All measurements were carried out on the day of admission to the intensive care unit (trauma patients) or on diagnosis of sepsis, and daily over the next 5 days at 12:00. MAP, HR and PCWP did not differ between the corresponding subgroups (trauma/sepsis). Cl increased significantly more in the HES than in the HA groups. pHi and MEGX plasma concentrations did not differ in the trauma patients throughout the study. Both were lower than normal in the sepsis groups and increased more markedly in the HES than in the albumin-treated patients (P < 0.05). In the trauma patients, concentrations of all vasoactive regulators were very similar in both groups. In both sepsis groups, vasopressors (vasopressin, endothelin-1, noradrenaline and adrenaline) were significantly increased above normal at baseline and decreased more markedly in HES than in HA patients. Concentrations of atrial natriuretic peptide increased only in the HA patients (from 159 (SD 31) to 215 (38) pg ml-1 on day 2). Plasma concentrations of 6-keto-prostaglandin F1 alpha decreased significantly only in the HES sepsis patients (from 112 (25) to 47 (15) pg ml-1). Preterm neonates undergoing intensive care have high morbidity from sepsis. These infants also frequently develop neutropenia, and when this is associated with sepsis, mortality is high. This study investigates the potential for granulocyte-macrophage colony-stimulating factor (GM-CSF) to effect a clinically relevant increase in neutrophil number when used prophylactically in high-risk preterm neonates, and assesses its safety in this population.
                In an open, randomized, controlled study, 75 neonates (25 small for gestational age) <32 weeks gestation were randomized to receive GM-CSF (10 microg/kg/d) by subcutaneous injection for 5 days from <72 hours after birth, or to a control group. The primary outcome measure was the neutrophil count during 14 days from study entry. The infants were monitored for potential toxicity. Clinical outcomes, sepsis, and mortality, were recorded, but this initial study was not designed to address clinical benefit.
                Prophylactic GM-CSF therapy completely abolished neutropenia in treated infants, when both well and septic, throughout the period of study. Neutropenia (</=1.7 x 10(9)/L) developed in 16 of 39 control infants. Five control infants experienced an acute decrease in neutrophil count coincident with the onset of sepsis. There was no evidence of hematologic, respiratory, or gastrointestinal toxicity in treated infants. Treated infants had a trend to fewer symptomatic, blood culture positive septic episodes than controls during 2 weeks from study entry (11/36 vs 18/39).
                Five-day prophylactic GM-CSF completely abolishes postnatal neutropenia and sepsis-induced neutropenia in preterm neonates at high risk of sepsis, and so removes an important risk factor for sepsis and sepsis-related mortality.GM-CSF, preterm neonates, neutropenia, sepsis. In a randomized trial conducted in 35 centers, we compared the clinical efficacy and safety of piperacillin plus tazobactam (TAZ) alone (monotherapy [MT]) versus those of TAZ combined with amikacin (AMK) (combined therapy [CT]) for the treatment of severe generalized peritonitis (SGP). Primary analysis consisted of blind assessment by an independent committee of the failure rate 30 days after the end of treatment in the modified intent-to-treat (ITT) analysis (mITT) population. Of the 241 patients with suspected SGP randomized into the study, 227 were eligible for ITT analysis, including 204 (99 in the MT group and 105 in the CT group) with confirmed SGP (mITT population). A total of 159 patients were eligible for per-protocol (PP) analysis. The clinical failure rates were equivalent in the mITT and PP populations (MT versus CT): 56 versus 52%, (odds ratio [OR] 0.87, 90% confidence interval [CI] = 0. 6 to 1.27) for mITT and 49 versus 49% (OR = 1.03, 90% CI = 0.67 to 1. 59) for PP analysis. Mortality rates (ITT population, 19%; PP population, 21%) and overall adverse event rates (ITT population, 55%; PP population, 54%) were also similar. Six patients (three in MT group and three in the CT group) developed acute renal failure. In conclusion, the addition of AMK to TAZ does not seem to be necessary for the treatment of SGP, even after adjustment for the simplified acute physiology score (SAPS II) and type of SGP. Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta-lactam antibiotics for serious Gram-negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis.
                Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg-1 8 hourly by bolus injection or 4 mg kg-1 h-1 by constant infusion following a 12 mg kg-1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters.
                Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l-1, giving a target concentration CT, of 8 mg l-1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.468 (0.241-0.573) l kg-1, 0.058 (0.005-0.159) l kg-1 h-1 and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0. 71; P < 0.001) and there was no evidence of significant nonrenal clearance.
                Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance = k * creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg-1 (1. 9-4.6) and infusion rate I = 0.46 mg kg h-1 (0.04-1.3) (which equals 14.8 mg kg-1 day-1). A nomogram for adjustment in renal failure is given. Sepsis and septic shock are very common conditions among critically ill patients that lead to multiple organ dysfunction syndrome (MODS) and death. Our purpose was to investigate the efficacy of early administration of dexamethasone for patients with septic shock, with the aim of halting the progression towards MODS and death.
                Prospective, randomized, double-blind, single-center study, developed in a surgical intensive care unit at Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo.
                The study involved 29 patients with septic shock. All eligible patients were prospectively randomized to receive either a dose of 0.2 mg/kg of dexamethasone (group D) or placebo (group P), given three times at intervals of 36 hours. The patients were monitored over a seven-day period by means of the sequential organ failure assessment score.
                Patients treated with dexamethasone did not require vasopressor therapy for as much time over the seven-day period as did the placebo group (p = 0.043). Seven-day mortality was 67% in group P (10 out of 15) and 21% in group D (3 out of 14) (relative risk = 0.31, 95% confidence interval 0.11 to 0.88). Dexamethasone enhanced the effects of vasopressor drugs.
                Early treatment with dexamethasone reduced the seven-day mortality among septic shock patients and showed a trend towards reduction of 28-day mortality. To describe a pharmacokinetic model of piperacillin concentrations in plasma and subcutaneous tissue when administered by bolus dosing and continuous infusion in critically ill patients with sepsis on days 1 and 2 of antibiotic therapy and to compare results against previous results for piperacillin from a cohort of patients with septic shock.
                Prospective randomized controlled trial.
                Eighteen-bed intensive care unit at 918-bed tertiary referral hospital.
                Thirteen critically ill adult patients with known or suspected sepsis in whom the treating physician deemed piperacillin-tazobactam appropriate therapy were conveniently sampled.
                Patients were randomized to receive different daily doses of piperacillin-tazobactam by bolus dosing or continuous infusion (continuous infusion--six patients; bolus dosing--seven patients). Serial plasma and tissue concentrations were determined on days 1 and 2 of treatment. Tissue concentrations of piperacillin were determined using a subcutaneously inserted microdialysis catheter. Separate pharmacokinetic models were developed for both bolus and continuous dosing.
                This is the first known article to report concurrent plasma and subcutaneous tissue concentrations of a beta-lactam antibiotic administered by bolus and continuous dosing in critically ill patients with sepsis. With a 25% lower piperacillin dose administered to the continuous infusion group, the infusion group had statistically significantly higher median plasma concentrations than the bolus group on day 2 (16.6 vs. 4.9 mg/L; p = 0.007). There was a trend to higher median plasma concentrations on day 1 in the bolus dosing group (8.9 vs. 4.9 mg/L; p = 0.078). Median tissue concentrations were not statistically different on day 1 (infusion group 2.4 mg/L vs. bolus group 2.2 mg/L; p = 0.48) and day 2 (infusion group 5.2 mg/L vs. bolus group 0.8 mg/L; p = 0.45). A two-compartment pharmacokinetic model was found to describe the data best. Tissue pharmacodynamic targets were achieved more successfully with infusion dosing.
                Patients with sepsis do not seem to have the same level of impairment of tissue distribution as described for patients with septic shock. A 25% lower dose of piperacillin administered by continuous infusion seems to maintain higher trough concentrations compared with standard bolus dosing. It is likely that the clinical advantages of continuous infusion are most likely to be evident when treating pathogens with high minimum inhibitory concentration, although without therapeutic drug monitoring and subsequent dose adjustment, infusions may never achieve target concentrations of organisms with very high minimum inhibitory concentrations in a small number of patients.
The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.