Intravenous immunoglobulins in association with antibiotics: a therapeutic trial in septic intensive care unit patients. Immunoglobulin therapy in patients with endotoxemia and postoperative sepsis--a prospective randomized study. [Intravenous immunoglobulin in the treatment of neonatal septicemia]. 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. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. 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. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis: another point of view. Observations using antiendotoxin antibody (E5) as adjuvant therapy in humans with suspected, serious, gram-negative sepsis. Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery. 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. The effects of IgM-enriched immunoglobulin preparations in patients with severe sepsis [ISRCTN28863830]. [Immunoglobulin therapy of postoperative sepsis]. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group. [Effect of adjuvant immunoglobulin therapy on infections in patients in an surgical intensive care unit. Results of a randomized controlled study]. Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Treatment of septic thrombocytopenia with immune globulin. Pepsin-treated human gamma globulin in bacterial infections. A randomized study in patients with septicaemia and pneumonia. Anti-lipopolysaccharide immunotherapy in management of septic shock of obstetric and gynaecological origin. 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. 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. Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial.
The therapeutic use of iv immunoglobulins of the G class in association with antibiotics in patients with severe sepsis is reported. As compared to the randomized control group of patients treated with antibiotics alone, patient survival was only slightly improved (from 25% to 42%; NS); however, the defervescence time was significantly shorter (10 vs. 16 days), and a greater percentage of microbiologically positive cultures became negative (40% vs. 8%; p less than .01). The percentage of days on antibiotic treatment during ICU hospitalization was consequently reduced (38% vs. 95%; p less than .01). The therapeutic use of iv immunoglobulin G is discussed in terms of antibody substitution and modulation of the immune system. nan Thirty-seven neonates with confirmed septicemia through hemoculture were studied. Of them, 18 were treated with antibiotic and the other 19 were given 500 mg/kg of intravenous immunoglobin with a pH of 4.25 (IGIV). The greater part of the neonates in this study were full-term or near full-term. There were no differences in age, gestational age and weight, nor in mortality, the bacterias found and the clinical manifestations which were seen in both groups. Yet, the hospitalary stay was shorter for those in the group treated with IGIV (13.9 +/- 5.7 days) than in the trial group (24.4 +/- 10.3 days); as well as some clinical manifestations like diarrhea and splenomegalia (P < 0.05). The serum of the neonates from the IGIV group showed a greater capacity of opsonization and inhibition of bacterial growth than those in the trial group (P < 0.001), coinciding with an increase of 300 mg/dL in the serum levels of IgG of the group treated with IGIV from the 3rd day of the study and the C4 and B-Properdine factor serum levels from the 7th day of the study, while in the trial group, there were no changes in these factors (P < 0.001). Even though no differences were seen in the mortality rate due to septicemia, the results suggest a much shorter evolution of the illness in patients treated with IGIV. In addition, the serum of those patients treated with IGIV showed in in vitro studies, a better bacteriostatic activity and a better capacity to opsonize the bacterias isolated in the hemocultures.(ABSTRACT TRUNCATED AT 250 WORDS) 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. The efficacy and safety of high-dose intravenous polyspecific immunoglobulin G (IVIG) as adjunctive therapy in streptococcal toxic shock syndrome (STSS) were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The trial was prematurely terminated because of slow patient recruitment, and results were obtained from 21 enrolled patients (10 IVIG recipients and 11 placebo recipients). The primary end point was mortality at 28 days, and a 3.6-fold higher mortality rate was found in the placebo group. A significant decrease in the sepsis-related organ failure assessment score at days 2 (P=.02) and 3 (P=.04) was noted in the IVIG group. Furthermore, a significant increase in plasma neutralizing activity against superantigens expressed by autologous isolates was noted in the IVIG group after treatment (P=.03). Although statistical significance was not reached in the primary end point, the trial provides further support for IVIG as an efficacious adjunctive therapy in STSS. Meningococcal septic shock has a rapid onset and characteristic skin hemorrhages that allow bedside diagnosis. Initial plasma endotoxin levels are high and correlate closely with clinical outcome. In a double-blind, randomized, placebo-controlled trial (planned, n = 270; actual, n = 269), we compared the effectiveness of HA-1A (6 mg/kg of body weight iv; maximum, 100 mg), a human monoclonal antibody to endotoxin, and placebo in reducing the 28-day all-cause mortality rate among children with a presumptive clinical diagnosis of meningococcal septic shock. Treatment groups were well balanced for baseline characteristics and prespecified prognostic variables. In this trial no significant benefit of HA-1A could be demonstrated. The 28-day mortality rates in the intention-to-treat analysis were as follows: placebo, 28%; HA-1A, 18%; reduction in mortality, 33% (P = .11, per Fisher's exact test, two-tailed; odds ratio = 0.59; 95% confidence interval for the difference, 0.31-1.05). All patients tolerated HA-1A well, and no antibodies to HA-1A were detected. To evaluate the effectiveness of a polyclonal immunoglobulin (Ig) preparation containing IgG, IgM, and IgA as an adjunctive therapy for septic shock.
                Prospective, randomized clinical trial.
                A clinical immunology ward at the center for internal medicine in a university hospital.
                Fifty-five patients with septic shock were randomly allocated to two groups according to criteria of septic shock.
                One group of patients (n = 27) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacterial endotoxin) during the first 3 days after inclusion in the study. The other randomized group (n = 28) did not receive any immunoglobulin preparation.
                During the period of less than or equal to 6 wks after the beginning of clinically apparent septic shock, death related to the septic process occurred in one (4%) of 27 patients who received immunoglobulin. By comparison, nine (32%) of 28 control group patients died during this period (p less than .01). Within the first 48 hrs after onset of the clinically apparent septic process, significantly increased activity of circulating endotoxin and simultaneously decreased specific IgG serum titers to lipid A were detected in the group of nonsurvivors.
                Administration of a polyclonal immunoglobulin preparation in the early phase of septic shock was associated with significantly improved survival. 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. nan To evaluate the safety and efficacy of E5 (Xomen-E5), a murine monoclonal immunoglobulin M antibody, in reducing mortality in patients with serious Gram-negative infections. Phase II, single-site study.
                Randomized, double-blind, placebo-controlled study.
                Surgical, neurosurgical and medical ICUs, comprising approximately 30 beds in a multidisciplinary university hospital.
                Patients with clinical evidence of serious infection admitted to the ICU for monitoring of vital signs and for intensive care nursing. Of the 39 patients enrolled in the study, 23 had documented Gram-negative infection.
                Patients suspected of having life-threatening Gram-negative infections received one of two doses of E5 or placebo. Safety and efficacy were assessed by survival on days 3, 7, and 21, appearance of adverse reactions, development of antimurine antibodies, and effects on BP, urine output, WBC count, and temperature.
                Mortality rate from Gram-negative infection 3 days after the last drug (or placebo) infusion was two (22%) of nine deaths in the placebo group compared with 0 of nine for E5 2.5 mg/kg and 0 of five for E5 7.5 mg/kg. At 21 days after therapy, three patients treated with E5 had died. Only one of these three deaths resulted from infection. Eight of 15 E5 patients tested had immunoglobulin G antimurine antibodies by 3 wks after therapy began, but all were asymptomatic.
                E5 was well tolerated and may have the potential to reduce early morbidity and the mortality rate in seriously ill patients with Gram-negative infections. Results from larger phase III studies are needed to confirm these findings. 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. 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. 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. 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 further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome.
                Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial.
                A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo.
                Twenty-eight-day all-cause mortality.
                There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002).
                There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater. To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome.
                Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra.
                Twelve academic medical center intensive care units in the United States.
                Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo.
                Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality.
                A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated.
                This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings. To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.
                Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.
                One hundred fifty-seven intensive care units in the United States and Canada.
                Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.
                Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.
                In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.
                Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels. 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. The value of IgM-enriched immunoglobulin therapy in 44 preterm infants with neonatal sepsis was evaluated in a prospective randomized study. All infants received antibiotic therapy and fresh plasma and/or whole blood transfusions. Twenty randomly-chosen infants were allocated to receive 5 ml/kg/d of IgM-enriched immunoglobulin intravenously for three days. Although the mortality rate in preterm infants whose gestational ages were 31-34 weeks in the immunotherapy group was slightly lower than in the control group, the general mortality rate from sepsis in the control group (9/24) and in the immunotherapy group (6/20) showed no statistically significant difference (37.5% vs 30.0%, p < 0.05). To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group.
                Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571).
                Seven academic intensive care units in Europe.
                Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care.
                Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg.
                The humanized anti-TNF-alpha antibody was well tolerated. The overall all-cause 28-day mortality rate was 62%. Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days. This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately with the dose. The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels. While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group.
                The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis. A randomized controlled clinical trial was conducted on the effects of immunoglobulin in therapy for infections in 104 intensive care patients. At the first sign of infection, one group of 50 patients received an i.v. preparation of immunoglobulin (4 X 100 ml) combined with antibiotics. The other 54 control patients received antibiotics alone. The most common infections in these patients were pneumonia, septicemia, peritonitis and wound sepsis. Infections were significantly seldom the cause of death, especially in patients with high-risk surgery who had been treated with immunoglobulin (p less than or equal to 0.05). Likewise ventilation time in the high-risk surgery group averaged only 5.5 days for those receiving immunoglobulin as opposed to 12.7 days in controls (p less than or equal to 0.01). Whereas the control group, in particular patients with pneumonia, remained in intensive care an average of 21.5 days, those receiving immunoglobulin stayed only 14.8 days (p less than or equal to 0.01). In general, patients treated with immunoglobulin recovered more rapidly from infections than did controls (p less than or equal to 0.01). To determine whether therapy with intravenous immunoglobulin G (IVIG) would decrease mortality in neonatal sepsis.
                Three tertiary care neonatal intensive care units in the city of Bangalore.
                All neonates admitted to the Neonatal Intensive Care Units with the clinical diagnosis of sepsis and having at least C-reactive protein and one other rapid diagnostic criteria positive were enrolled. Neonates with a birth weight of less than 1000 g and those with any major congenital malformation were excluded. The neonates were randomized to receive 1 g/kg of IVIG on three consecutive days or an equivalent amount of placebo. The rest of the treatment including antibiotics and supportive care was as per the treating physician's decision. The main outcome variable was survival.
                The trial was carried out over a period of 8 months and recruited 58 neonates. Seven neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one baby who received only one dose of IVIG was excluded from the analysis. Twenty-five neonates were enrolled into the IVIG arm and 25 in the placebo arm. The neonates in the therapy and placebo groups were comparable in terms of birth weight (2144+/-675 g vs. 2072+/-682 g), gestation (37.0+/-3.56 vs. 35.8+/-3.52 weeks), sex distribution, duration of stay, and number requiring ventilation. The placebo group had a significantly higher number of babies with positive blood culture. Seven babies in each group died (p>0.05). There was no significant benefit in using IVIG (OR 1.0; 95% CI 0.25-4.07) (p = 0.74).
                In the sample studied therapy with IVIG did not reduce mortality in neonatal sepsis Despite the development of newer generation of antibiotics, mortality from neonatal sepsis remains high. In a prospective, randomized study, we investigated the use of IgM-enriched immunoglobulin therapy in neonatal sepsis. Two groups of 30 infants each (matched for gestational age, sex, weight, and other variables) were randomly allocated to receive either antibiotics alone (control group) or antibiotics plus 5 mL/kg/d for four days of IgM-enriched immunoglobulin intravenously (immunotherapy group). Mortality from sepsis in the control group was 20% (6/30), while in the immunotherapy group it was 3.3% (1/30). We conclude that IgM-enriched immunoglobulin therapy in conjunction with antibiotic therapy significantly reduces mortality from neonatal sepsis. To investigate the safety, biological effects, and efficacy of the anti-tumor necrosis factor (TNF) antibody fragment, MAK 195F, in a phase II trial in patient with severe sepsis.
                Prospective, randomized, open label, placebo-controlled, dose-ranging, multicenter, multinational clinical trial.
                Sixteen academic medical centers' intensive care units in six European countries.
                One hundred twenty-two patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy.
                Patients received one of three different doses of the anti-TNF antibody (0.1 mg/kg, 0.3 mg/kg, or 1.0 mg/kg) or placebo; the antibody or placebo was given in nine doses at 8-hr intervals over 3 days.
                There were no significant differences in mortality rates among the groups receiving various doses of the anti-TNF antibody or placebo, but patients with baseline serum interleukin (IL)-6 concentrations of > 1000 pg/mL appeared to benefit from MAK 195F in a dose-dependent fashion. Increased circulating IL-6 concentrations, but not TNF concentrations, were found to be important prognostic indicators for mortality for the patients in the placebo and the two lower dosage groups but not in the high dosage group (1 mg/kg). IL-6 concentrations decreased during the first 24 hrs of treatment in all three anti-TNF groups but not in the placebo group. MAK 195F was well tolerated by all patients. Human antimurine antibodies developed in 40% of the patients receiving the antibody.
                There was no increase in survival from sepsis for the patients receiving anti-TNF treatment in the overall study population. Retrospective stratification of patients by IL-6 concentrations suggests beneficial effects of the drug for patients with baseline circulating IL-6 concentrations of > 1000 pg/mL. This hypothesis requires validation in a larger, blinded, prospective study. Newborn infants may have IgG deficiencies that increase their susceptibility to bacterial infection. To determine whether intravenous immune globulin (IVIG) therapy improves survival rates in early-onset sepsis, we prospectively entered 753 neonates (birth weight 500 to 2000 gm, gestation less than or equal to 34 weeks, age less than or equal to 12 hours) into a multicenter, double-blind, controlled trial. Blood culture specimens were obtained and infants randomly assigned to receive 10 ml (per kilogram) intravenously of a selected IVIG (500 mg/kg) or albumin (5 mg/kg) preparation. Maternal and neonatal risk factors were not different between groups. Thirty-one babies (4.2%) had early-onset sepsis; the causative organisms were group B streptococcus (12 babies), Escherichia coli (6), and others (13). Of these 31 neonates, 7 (23%) died. Total serum IgG was higher for 7 days after IVIG therapy than after albumin treatment (p less than 0.05). During these 7 days, 5 (30%) of 17 albumin-treated and none of 14 IVIG-treated patients died (p less than 0.05). The survival rate at 56 days of age, however, was not significantly improved. Group B streptococcus type-specific IgG antibody was significantly increased after IVIG treatment and appeared to be related to the amount of IVIG specific antibody. Infusion-related adverse reactions were less frequent in patients receiving IVIG therapy (0.5%) than in those receiving albumin. The IVIG therapy in neonates with early-onset sepsis, while reducing the early mortality rate, did not significantly affect the overall survival rate. Further studies are necessary to confirm these findings and to determine more effective therapeutic regimens. Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.
                In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.
                382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, p=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, p<0.001; day 28, p=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.
                We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival. Thrombocytopenia frequently complicates systemic infection and results from multiple possible mechanisms. We and others have demonstrated that platelet-associated IgG (PAIgG) levels are elevated in the majority of patients with septic thrombocytopenia. Corticosteroids may be undesirable as a treatment for thrombocytopenia for patients with severe infection because of their potential for suppressing the immune response. We hypothesized that septic thrombocytopenia is, in most cases, an immune disorder analogous to idiopathic thrombocytopenic purpura (ITP) which might respond to intravenous gamma-globulin as a treatment for increasing the platelet count in this disorder. Intravenous immune globulin (IVIG), 400 mg/kg daily for 3 days, was administered in a randomized double-blind placebo-controlled trial. Twenty-nine patients who developed thrombocytopenia during a documented, septic episode were studied. Patients with disseminated intravascular coagulation (DIC), hypersplenism, or drugs known to cause thrombocytopenia were excluded. Elevated PAIgG levels were documented in 52% of evaluable patients. Mean platelet counts in the IVIG group rose from 43K at study entry to 178K (411% rise) by Day 9. In the placebo group platelets rose from 51K to 125K (261% rise; P = 0.02). Seventy-seven percent of the IVIG group had a minimum peak rise of 35K, vs 56% of the placebo group. Three patients in the placebo group had a serious bleeding episode, vs one in the IVIG group. The use of IVIG to treat septic thrombocytopenia not associated with DIC leads to a more rapid, more sustained, and greater increase in platelet count than placebo. Its use is recommended in the septic patient who is bleeding or is likely to need invasive or surgical procedures. 59 patients with suspected or verified septicaemia and 87 patients with suspected or verified bacterial pneumonia were treated with either antibiotics alone or antibiotics combined with a pepsin-treated human gamma globulin (Gamma-Venin). The gamma globulin was given intravenously in repeated doses of 0.15 g/kg body weight. Extensive clinical and laboratory investigations were performed repeatedly in a strictly standardized fashion. Neither the septicaemia group nor the pneumonia group presented significant differences between treated patients and controls for any of the clinical and laboratory variables studied. Hospital stay, duration of fever and symptoms were also unaffected by the gamma globulin treatment. Subdivision of the material according to aetiology provided no additional information. In 9 patients adverse reactions were seen, e.g., shock in 2 individuals. Freeze-dried human plasma rich in anti-lipopolysaccharide (anti-LPS) immunoglobulin G was used to treat septic shock (systolic pressure less than or equal to 80 mm Hg, central venous pressure greater than or equal to 6 cm H2O) in obstetric and gynaecological patients. Mortality in conventionally treated patients was 9/19 (47.4%) compared with 1/14 (7.1%) in anti-LPS-treated patients. Anti-LPS caused the mean arterial pressure to rise from 45.1 +/- 7.36 mm Hg to 69.1 +/- 9.07 mm Hg within 75 min of administration. The mean hospital stay of survivors was 28.1 days for controls and 14.2 days for the anti-LPS-treated patients. The development of complications of septic shock was much reduced in the treated group. Anti-LPS thus appears significantly to reduce mortality and morbidity in septicaemia. 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. 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. To evaluate in Gram-negative sepsis patients the human monoclonal immunoglobulin M antibody (MAB-T88) directed at the enterobacterial common antigen which is a specific surface antigen closely linked to lipopolysaccharide and shared by all members of the Enterobacteriaceae family of Gram-negative bacteria.
                Prospective, randomized, double-blinded, placebo-controlled, multicenter trial.
                Thirty-three academic medical centers in the United States.
                Patients were entered with a clinical diagnosis of sepsis, the presence of either shock or multiple organ dysfunction, and presumptive evidence for Gram-negative infection.
                Patients received a single intravenous infusion, over 30 mins, of either 300 mg of MAB-T88 formulated in albumin, or placebo (albumin).
                The primary analysis group was prospectively identified as those patients with documented evidence of an infection with bacteria of the family Enterobacteriaceae at any site. The primary end point was survival within the first 28 days. A total of 826 patients were enrolled with 55% (n = 455) in the primary analysis group. There were no significant differences between the intervention and control primary analysis group study groups for sites of infection, severity of illness, underlying medical conditions, adequacy of antibiotic or surgical treatment, or other baseline variables except for a higher frequency of chronic renal failure in the MAB-T88 group (4.4% vs. 1.3%, p=.051). The average Acute Physiology and Chronic Health Evaluation II scores were 26.8 +/- 8.6 (mean +/- sd) in the MAB-T88-treated group and 26.5 +/- 8.3 in the placebo-treated group (p =.72). There was no significant difference between MAB-T88- and placebo-treated groups during the first 28-day all-cause mortality in the primary analysis group (34.2% vs. 30.8%, p=.44) or in all 826 patients enrolled (37.0% vs. 34.0%, p=.36). On subset analysis, the use of MAB-T88 was not associated with significant mortality trends. More adverse events were seen with the use of MAB-T88 in the bacteremic enterobacterial common antigen group (p <.05).
                Use of the human monoclonal antibody, MAB-T88, did not improve the mortality in patients with presumed Gram-negative sepsis or in those patients with proven enterobacterial common antigen infections. No subset trends were identified that would support further investigation of this agent in sepsis. 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. 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. To evaluate the effect of intravenous IgMA-enriched immunoglobulin (ivIGMA) therapy on mortality in neutropenic patients with hematologic malignancies and sepsis syndrome or septic shock.
                Multiple-center, prospective randomized, controlled study.
                Six university hospitals in Germany.
                Patients were 211 neutropenic patients with sepsis syndrome or septic shock after chemotherapy for severe hematologic disorders between 1992 and 1999.
                Patients received 1300 mL of ivIGMA (7.8 g IgM, 7.8 g IgA, and 49.4 g IgG) infused intravenously within a period of 72 hrs or human albumin according to the same schedule as ivIGMA.
                All-cause mortality at 28 days, sepsis-related mortality at 28 days, all-cause mortality at 60 days, mortality from septic shock, and mortality from microbiologically proven Gram-negative sepsis and septic shock were recorded. Immunoglobulin had no benefit over human albumin. The 28-day mortality rate was 26.2% and 28.2% in the ivIGMA and control patients, respectively (difference, 2.0% [95% confidence interval, -10.2 to 14.2 percentage points]). Likewise, the 60-day mortality rate did not differ between both arms (29.6% vs. 34.7% in the ivIGMA and control patients, respectively). Mortality rates in patients with sepsis syndrome (17.1% vs. 16.7%) and septic shock (51.9% vs. 54.8%) were also found to be similar between both groups.
                Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.
Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates, no reduction in mortality was seen with polyclonal IVIG. Most of the trials were small and the totality of the evidence is insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.