Gary T. Kinasewitz

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.

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.

Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis

Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).

Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis.

Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy.

The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.

ObjectiveIn the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-center trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. DesignBlinded, critical, integrated review of data. SettingParticipating sites. PatientsThe 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. InterventionsWe performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main ResultsThe optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69–0.99 vs. 0.806, 95% confidence interval 0.69–0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57–0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. ConclusionsThe survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC.

ObjectiveWork toward a better definition of disseminated intravascular coagulation (DIC) by characterizing the difference between compensated and uncompensated responses of the hemostatic system to inflammatory stress in baboons and human subjects using global coagulation and molecular marker assays of hemostatic, inflammatory, and endothelial perturbation. DesignWe conducted prospective evaluation of the response of baboons to increasing concentrations of intravenous Escherichia coli, human subjects to intravenous endotoxin, and baboons to intraperitoneal E. coli. SettingAnimal laboratory and medical intensive care facilities, University of Oklahoma Medical School laboratories. SubjectsCynocephalus baboons; normal healthy male human subjects (age, 24–37 yrs). Measurements and Main ResultsGlobal coagulation assays, white blood cell counts, and molecular marker assays (ELISA) of components of the inflammatory and hemostatic systems, neutrophil release products, and endothelial injury. A fall in both fibrinogen concentration and platelet counts indicated a decompensated hemostatic response to inflammatory stress (ie, overt DIC). These responses were observed 2–6 hrs after intravenous infusion of 109 and 1010 colony-forming units (CFU)/g of E. coli and after implantation of 1011 CFU/g of E. coli into the peritoneal cavity. However, 6 hrs after E. coli challenge, these tests were much less reliable as markers of overt DIC because the fibrinogen underwent an acute phase response and the platelet count fell and remained depressed for 48 hrs in the face of a coagulopathic response that was already beginning to resolve, as reflected by a rising fibrinogen concentration. This lack of reliability was particularly evident in the E. coli peritonitis studies, in which one third of the animals recovered, one third remained sick for up to 14 days, and one third died.In contrast, fibrin degradation products and the molecular markers thrombin/antithrombin, soluble fibrin monomer, protein C, and activated protein C/inhibitor complexes responded consistently in a dose-dependent manner regardless of the length of time after challenge. These variables exhibited this dose response to 106 and 108 CFU/g of E. coli in absence of a fall in fibrinogen concentration. This was defined as a compensated hemostatic response to inflammatory stress (ie, non-overt DIC). The values of these variables correlated closely with rising concentrations of markers of neutrophil activation (elastase/∝ 1 antitrypsin) and endothelial injury (soluble thrombomodulin). This was particularly evident in the human response to endotoxin, in which there was abundant evidence of hemostatic marker response in absence of a fall in platelet or fibrinogen concentration, both immediately after endotoxin infusion (first stage, 0–8 hrs after endotoxin) and later (second stage, 12–48 hrs after endotoxin). ConclusionGlobal coagulation tests are most useful in detecting overt consumptive coagulopathy (overt DIC) near the time of challenge or injury (1 to 6 hrs). Molecular markers can detect and grade the degree of hemostatic stress of a non-overt consumptive coagulopathy (nonovert DIC). These markers correlate with degree of endothelial cell injury and reveal a reperfusion injury stage (second stage) in the human endotoxin model of compensated hemostatic stress after all clinical symptoms have subsided and the subjects have returned to work.

Value of routine daily chest x-rays in the medical intensive care unit.

To ascertain the value of the daily routine chest x-ray in the medical ICU, we determined prospectively the number of unsuspected abnormalities observed on 507 consecutive chest films and the consequent management changes in 94 ICU patients. Primary diagnoses were classified as pulmonary, hemodynamically unstable cardiac, uncomplicated cardiac, or miscellaneous. Admission films and those taken after procedures or a change in clinical status were excluded. Ventilator status and the tubes and catheters visible on the films were also noted. After clinical evaluation, management plans were made by ICU physicians and then the chest x-ray was examined and unsuspected abnormalities and resulting management changes were noted. Of the 507 chest films, 76 (15%) revealed an unsuspected abnormality, 71 (93%) of which led to a management change. There were significantly (p < .02) more unsuspected abnormalities and management changes, in the pulmonary and unstable cardiac patients, independent of ventilator status. Patients with two or more catheters and/or tubes visible on the chest film also had significantly more management changes (51/312 vs. 11/150, p < .05). We conclude that while routine chest films affect the management of pulmonary and unstable cardiac patients in the ICU, routine films rarely influence management of uncomplicated cardiac patients and those without heart or lung disease, and are not warranted in this group.

A Multicenter, Open-Label, Randomized Comparison of Levofloxacin and Azithromycin Plus Ceftriaxone in Hospitalized Adults with Moderate to Severe Community-Acquired Pneumonia

BACKGROUND Changing etiologic patterns and the growing problem of antimicrobial resistance, particularly an increase in macrolide-resistant pneumococcal bacteremia, are causing physicians to adopt new approaches to the treatment of community-acquired pneumonia (CAP). OBJECTIVE The relative efficacy and tolerability of levofloxacin monotherapy and azithromycin and ceftriaxone combination therapy were assessed in hospitalized adults with moderate to severe CAP. METHODS This Phase IV, multicenter, open-label, randomized trial compared 2 treatment regimens: (1) levofloxacin 500 mg PO or IV q24h, and (2) azithromycin 500 mg IV q24h for > or = 2 days plus ceftriaxone 1 g IV q24h for 2 days, followed by an optional transition to azithromycin 500 mg PO q24h at the investigators discretion. The total duration of therapy was to be a minimum of 10 days in both treatment groups. Ceftriaxone was included in the initial azithromycin regimen to ensure coverage against pneumococcal bacteremia. RESULTS Of 236 patients in the intent-to-treat population, completion or withdrawal information was available for 110 patients in the levofloxacin group and 114 in the azithromycin group. Baseline demographic and disease characteristics were comparable between groups. At the end of treatment, the clinical success rate (cured + improved) in clinically evaluable patients was 94.1% in the levofloxacin group and 92.3% in the azithromycin group. The respective posttherapy microbiologic eradication rates were 89.5% and 92.3%. Levofloxacin was as well tolerated as azithromycin, with an incidence of drug-related adverse events (AEs) for all body systems of 5.3% and 9.3%, respectively. None of the drug-related AEs were considered serious [corrected]. CONCLUSIONS In this study in hospitalized patients with moderate to severe CAP, levofloxacin monotherapy was at least as effective as a combination regimen of azithromycin and ceftriaxone in providing coverage against the current causative pathogens in CAP. In addition, levofloxacin was as well tolerated as the combination of azithromycin and ceftriaxone.

Troponin-I as a prognosticator of mortality in severe sepsis patients ☆ ☆☆ ★

PURPOSE The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients. METHODS Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [>or=0.06 ng/mL], n = 451). RESULTS Cardiac troponin-I-positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65). CONCLUSION This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.

Iloprost Improves Gas Exchange and Exercise Tolerance in Patients with Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

Background: Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained. Objectives: To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH. Methods: Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 µg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (VE/VO2) and carbon dioxide (VE/VCO2) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose. Results: Mean differences in VE/VCO2 and VE/VO2 were –13.3 (95% CI –36.5 to –2.7; p = 0.002) and –15.0 (95% CI –36.7 to –0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was –3.7 mm Hg (95% CI –6.1 to –1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen. Conclusions: Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance.