Howard Levy

Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.

ObjectiveTo assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). DesignUnivariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. SettingA total of 164 medical centers in 11 countries. PatientsA total of 1,690 patients with severe sepsis. Measurements and Main ResultsWe report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a ≥20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. ConclusionsThe administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.

Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.

Objective:To investigate community-acquired pneumonia (CAP) as a cause of severe sepsis in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial and to evaluate the effect of drotrecogin alfa (activated) (DrotAA) in this subgroup. Design:Retrospective analysis of the severe CAP subgroup in the PROWESS trial. Setting:Tertiary care institutions in 11 countries. Interventions:DrotAA (n = 850), 24 &mgr;g·kg−1·hr−1 for 96 hrs, or placebo (n = 840). Participants:The 1,690 patients with severe sepsis enrolled in the PROWESS trial. Measurements and Main Results:Patients were classified as having CAP if lung was the primary site of infection and if they were enrolled directly from home (private residence) with ≤4 days in the hospital before receipt of study drug in the PROWESS trial. Survival at 28 days, hospital discharge, and 90 days was compared in DrotAA and placebo groups in the CAP subgroup of PROWESS and CAP subgroups based on disease severity. Of the 1,690 PROWESS patients, 35.6% (DrotAA, n = 324; placebo, n = 278) were classified as severe CAP. Of these severe CAP patients, 26.1% had Streptococcus pneumoniae infections. Within CAP, 79.1% were enrolled by the end of the second calendar day in the hospital, and approximately 90% of CAP patients were at high risk of death according to the Pneumonia Severity Index category. Based on their dependence on vasopressors, 59% of CAP patients were judged at high risk of death. Biomarkers of coagulation and inflammation were markedly abnormal in severe CAP patients. In severe CAP patients treated with DrotAA, a relative risk reduction in mortality of 28% was observed at 28 days, with a relative risk reduction in mortality of 14% observed at 90 days from the start of study drug infusion. The survival benefit was most pronounced in severe CAP patients with S. pneumoniae and in severe CAP patients at high risk of death as indicated by Acute Physiology and Chronic Health Evaluation II score of ≥25, Pneumonia Severity Index score of ≥4, or CURB-65 (confusion, urea, respiratory rate, blood pressure, age) score of ≥3. Conclusions:CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo.

Cardiopulmonary manifestations of hantavirus pulmonary syndrome.

OBJECTIVE To describe the clinical characteristics of a group of patients infected with the newly recognized hantavirus in the Southwestern United States. DESIGN Case series. SETTING Tertiary referral center. PATIENTS All patients with confirmed hantavirus infection admitted to the University of New Mexico Hospital between May 1, 1993 and January 1, 1994. INTERVENTIONS Records of patients with hantavirus infection were reviewed to collect all pertinent clinical data. MEASUREMENTS AND MAIN RESULTS Pulmonary disease in these patients was characterized by hypoxemia covering a wide range of severity. The cause of hypoxemia was an increased permeability (noncardiac) pulmonary edema which could be differentiated from hydrostatic (cardiac) pulmonary edema by its association with low pulmonary artery occlusion pressures and increased protein content of edema fluid. Hemodynamic measurements in severe cases showed a shock state characterized by a low cardiac index (range 1.6 to 3.0 L/min/min2), a low stroke volume index (range 10.5 to 29 mL/m2), and high systemic vascular resistance index (range 1,653 to 2,997 dyne.sec/cm5.m2). Progression to death was associated with worsening cardiac dysfunction unresponsive to treatment and causing oxygen debt and lactic acidosis. CONCLUSIONS The two major life-threatening pathophysiologic changes in Hantavirus Pulmonary Syndrome are increased permeability pulmonary edema, and an atypical form of septic shock caused by myocardial depression and hypovolemia.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

Objectives:To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. Design:Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. Setting:Two hundred and thirty-three ICUs in 17 countries. Patients:All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. Interventions:Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. Measurements and Main Results:A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran–Mantel–Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. Conclusions:ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Systemic Host Responses in Severe Sepsis Analyzed by Causative Microorganism and Treatment Effects of Drotrecogin Alfa (Activated)

Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.

Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill

ObjectiveTo determine whether adding erythromycin to a gastric feeding regimen could render it as effective in meeting nutritional needs as transpyloric feeding. DesignRandomized, controlled study. SettingUniversity hospital medical, surgical, and neurologic care intensive care units. PatientsCritically ill patients, requiring a projected 96 hrs of enteral feeding, who had no specific indication for tube location (gastric or transpyloric). Eighty patients were randomized. InterventionsPatients were randomized to gastric feeding with erythromycin (200 mg iv) given every 8 hrs or feeding through a transpylorically placed feeding tube. Goal rate and feeding advancement were determined by protocol. Measurements and Main Results During the 96-hr period, the gastric group received 74% of their goal calories and the transpyloric group received 67%. The only day on which gastric feedings were superior was the first study day, where the gastric group attained 55% of their goal, compared with 44% in the transpyloric group. This 1-day difference was the result of an initial failure of tube placement in some subjects. Exclusion of these patients did not change overall results. Nutritional indexes, length of stay in the intensive care unit, ventilator dependence, and survival were not different between the two groups. ConclusionsGastric feeding with erythromycin as a prokinetic is equivalent to transpyloric feeding in meeting the nutritional goals of the critically ill.

Community-acquired pneumonia of diverse aetiology: prognostic features in patients admitted to an intensive care unit and a “severity of illness” score

In a retrospective study of 73 patients with community-acquired lobar pneumonia of diverse aetiology admitted to an intensive care unit, an attempt was made to identify those factors among the demographic and clinical features and results of initial laboratory investigations that were predictive of the ultimate outcome. A lower mean white cell count (p=0.03), platelet count (p=0.02), total serum protein (p=0.005) and albumin (p=0.02) and a higher mean serum creatinine (p=0.03) and phosphate level (p=0.02) appeared to be predictive of a poor prognosis. The most significant variable predictive of mortality, was the presence of bacteraemia (p=0.0005). Severity of illness scoring systems by omitting microbiological data appear to underestimate predicted patient mortality. The mortality rate of critically ill patients with community-acquired lobar pneumonia remains high, despite advances in antimicrobial chemotherapy and intensive care unit facilities, particularly in the presence of certain negative prognostic factors of which the presence of bacteraemia is the most important.

Successful treatment of adults with severe Hantavirus pulmonary syndrome with extracorporeal membrane oxygenation.

OBJECTIVE To describe our experience with the use of extracorporeal membrane oxygenation (ECMO) as a rescue therapy in adult patients with severe cardiopulmonary failure from Hantavirus pulmonary syndrome. DESIGN Case series. SETTING Tertiary referral center. PATIENTS Patients with confirmed Hantavirus infection, who developed severe cardiopulmonary failure in which conventional therapy was assessed as being unsuccessful. INTERVENTIONS Records of previous patients treated for Hantavirus pulmonary syndrome were reviewed and findings consistent with 100% mortality were found. MEASUREMENTS AND MAIN RESULTS Findings associated with a 100% mortality rate were a) cardiac index of <2.5 L/min/m2; b) serum lactate concentration of >4.0 mmol/L (normal range 0.0 to 2.2); c) pulseless electrical activity or ventricular fibrillation or ventricular tachycardia; and d) refractory shock despite fluid resuscitation, and vasoactive medications. From 1994 to 1996, seven patients were admitted with confirmed Hantavirus pulmonary syndrome and severe cardiopulmonary failure. Three of the seven patients had at least two of the four criteria for a 100% mortality rate listed above, and appeared to be failing optimal conventional therapy. These three patients received support with venoarterial ECMO. The first patient was placed on ECMO during cardiac arrest and died. The next two patients who received ECMO for Hantavirus pulmonary syndrome survived after relatively short, uncomplicated ECMO runs, and were discharged without complications. CONCLUSIONS ECMO successfully provided cardiopulmonary support in two patients with severe Hantavirus pulmonary syndrome who survived with a good outcome. Our experience suggests that ECMO is a beneficial therapy for patients critically ill with Hantavirus pulmonary syndrome.

Confirming the reliability of the sedation-agitation scale administered by ICU nurses without experience in its use.

Study Objectives. To determine the validity and reliability of the Sedation‐Agitation scale (SAS) when administered by intensive care unit (ICU) nurses with no experience in its use.

Acute respiratory failure in active tuberculosis.

We describe 15 patients whose acute respiratory failure associated with pulmonary tuberculosis necessitated their ICU admission during a 42-month period. There was a 1.5% incidence of respiratory failure in hospitalized tuberculosis patients. Eleven of the 15 patients required ventilatory assistance for a mean 17.3 days. Five patients died in ICU (early mortality = 33%), and two others died within 3 months of discharge (total mortality = 47%). We began specific anti-tuberculous chemotherapy in these patients within 3 ± 4 (SD) days after hospital admission. Pulmonary histology was available in five cases. Despite the clinical and radio-logic features compatible with the adult respiratory distress syndrome in these patients, histology showed confluent tuberculous bronchopneumonia with no evidence of the syndrome.