Intensive insulin therapy and pentastarch resuscitation in severe sepsis. Early dexamethasone treatment for septic shock patients: a prospective randomized clinical trial. Filgrastim in patients with pneumonia and severe sepsis or septic shock. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Selective bowel decontamination for the prevention of infection in acute myelogenous leukemia: a prospective randomized trial. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. 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 prospective comparison of gentamicin and metronidazole and moxalactam in the prevention of septic complications associated with elective operations of the colon and rectum.
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 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. Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation.
                Multicenter, double-blind, randomized, placebo-controlled study.
                ICU, multicenter.
                Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n = 12) and placebo (n = 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively.
                Filgrastim (300 microg) or placebo was administered IV daily for up to 5 days. Measurements and results: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality. Cytokine and endotoxin levels were highly variable in both groups. By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died. There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients.
                Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock. Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted. 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. A randomized prospective double-blind trial was performed to compare the safety and efficacy of human activated protein C (APC) and unfractionated heparin for the treatment of disseminated intravascular coagulation (DIC). One hundred thirty-two patients with DIC were enrolled in this study: 63 patients received APC (12.5 U [2.5 microg]/kg body wt per hour) and 69 patients received heparin (8 U/kg body wt per hour) by intravenous infusion for 6 days. Forty-nine APC-treated patients and 55 heparin-treated patients were evaluated for efficacy, and 52 APC-treated patients and 55 heparin-treated patients were evaluated for safety. The 2 groups were similar with respect to sex, age, body weight, underlying diseases, and coagulation/fibrinolysis parameters before treatment. Aggravation of bleeding was seen after treatment in 8 patients receiving heparin, but in none of the patients receiving APC. The number of patients who showed alleviation of bleeding was significantly higher in the APC group than the heparin group (P = .009). The effects on DIC-related organ dysfunction were not significantly different between the 2 groups. Fibrinogen-fibrin degradation products, D-dimer, thrombin-antithrombin complex (TAT), and plasmin-plasmin inhibitor complex (PIC) were all significantly decreased by treatment in both groups. Fibrinogen, protein C, and antithrombin were significantly increased in the APC group, whereas only protein C was significantly increased in the heparin group. Platelet count in the nonleukemic group was significantly increased in those patients receiving APC but not increased in those patients receiving heparin. Improvement of coagulation/fibrinolysis was assessed by scoring 4 parameters (soluble fibrin monomers, D-dimer, TAT, and PIC), and the results indicated that the APC group showed significantly greater improvement than the heparin group (P = .046). There was, however, no significant difference in the rate of complete recovery from DIC between the 2 groups. The rate of death from any cause within 28 days after treatment was 20.4% in the APC group, significantly lower than the 40% death rate observed in the heparin group (P < .05). There were no severe adverse events in either group. These results suggest that APC in a relatively small dosage can improve DIC more efficiently than can heparin, without increasing bleeding, and may be a better alternative. Infection is still a frequent cause of morbidity and mortality in acute myelogenous leukemia (AML) patients receiving chemotherapy. Recently the main cause of infection has changed from gram-negative to gram-positive bacteria and the resistance to antibiotics has increased. This study aimed to access the effectiveness of antimicrobial prophylaxis (AP) with orally absorbable antibiotics.
                Ninety-five AML patients receiving chemotherapy at Catholic Hemopoietic Stem Cell Transplantation Center from March 1999 to July 1999 were randomly divided into the AP group (250 mg ciprofloxacin twice a day, 150 mg roxithromycin twice a day, 50 mg fluconazole once a day) and the control group for a prospective analysis.
                The incidence of fever was 82.6% in the AP group and 91.6% in the control group (p = 0.15). Though classification and sites of infections showed no difference between the two groups, the catheter associated infection occurred more frequently in the AP group in significance. The time interval between initiation of chemotherapy and onset of fever, white blood cell (WBC) count at the onset of fever, duration of leukopenia (WBC < 1,000/mm3), duration of systemic antibiotic therapy, mortality due to infection and hospitalization period from the data starting chemotherapy showed no differences between the two groups. Infections due to gram negative bacteria decreased to 33.3% in the AP group (vs. 92% in the control group), but infections due to gram positive bacteria increased to 66.7% (vs. 8% in the control group). Gram negative bacteria showed 100% resistance to ciprofloxacin in the AP group and gram-positive bacteria showed 90-100% resistance to erythromycin, regardless of the presence of AP.
                The AP could not reduce the occurrence of infection or infection associated death in AML patients receiving chemotherapy. On considering increased gram-positive infection and resistance to fluoroquinolone and macrolide, routine prescription of AP should be reconsidered. Further studies that assess the effectiveness of AP in other malignancies, aplastic anemia and bone marrow transplantation are required. 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. 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. 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.
This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.