Physiological predictors of survival during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome.

INTRODUCTION: Data that provide clinical criteria for the identification of patients likely to respond to high-frequency oscillatory ventilation (HFOV) are scarce. Our aim was to describe physiological predictors of survival during HFOV in adults with severe acute respiratory distress syndrome (ARDS) admitted to a respiratory failure center in the United Kingdom. METHODS: Electronic records of 102 adults treated with HFOV were reviewed retrospectively. We used logistic regression and receiving-operator characteristics curve to test associations with oxygenation and mortality. RESULTS: Patients had severe ARDS with a mean (SD) Murray's score of 2.98 (0.7). Partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) ratio and oxygenation index improved only in survivors. The earliest time point at which the two groups differed was at three hours after commencing HFOV. An improvement of >38% in PaO2/FiO2 occurring at any time within the first 72 hours, was the best predictor of survival at 30 days (area under the curve (AUC) of 0.83, sensitivity 93%, specificity 78% and a positive likelihood ratio (LR) of 4.3). These patients also had a 3.5 fold greater reduction in partial pressure of carbon dioxide in arterial blood (PaCO2). Multivariate analysis showed that HFOV was more effective in younger patients, when instituted early, and in patients with milder respiratory acidosis. CONCLUSIONS: HFOV is effective in improving oxygenation in adults with ARDS, particularly when instituted early. Changes in PaO2/FiO2 during the first three hours of HFOV can identify those patients more likely to survive.

Adverse events and clinical outcome associated with drotrecogin alfa-activated: a single-center experience of 498 patients over 8 years.

PURPOSE: Licensed in 2002 for severe sepsis, drotrecogin alfa-activated (DAA) remains a much debated therapy particularly with respect to outcomes and a potentially increased risk of serious bleeding events (SBEs). Recent publications have suggested a significantly increased incidence of SBEs and death in those with baseline bleeding risks (BBRs). Our center is one of the highest prescribers of DAA worldwide; we describe our experience of SBEs and other clinical outcomes. METHODS: Prospectively collected data using a clinical guideline audit tool and database to track outcome and adverse events of DAA-treated severe sepsis patients were analyzed. RESULTS: Four hundred ninety-eight patients received DAA over an 8-year period. Hospital, critical care, and 28-day mortalities were 46.2%, 39.6%, and 35.1%, respectively. Contraindications were identified for 40 (8.0%) patients, of whom 24 (4.8%) had BBRs. Hospital mortality was 47.5% (19/40) for patients with any contraindication and 45.8% (11/24) for those with a BBR. Seventy-six (15.3%) bleeding events were reported; 22 (4.4%) were considered serious. Hospital mortality was 60.5% for patients with any bleeding event and 77.3% for those with SBEs. CONCLUSIONS: This large single-center case series demonstrates that DAA has an incidence of SBEs similar to initial clinical trials. As expected, SBEs were associated with a poor outcome.

Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).

OBJECTIVE: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DESIGN: Multicentered, randomized, placebo-controlled, safety and efficacy study. SETTING: Forty-eight intensive care units in Europe, North America, and Australia. PATIENTS: A total of 312 patients with septic shock diagnosed within 24 hr before randomization. INTERVENTIONS: Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). MEASUREMENTS AND MAIN RESULTS: Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. CONCLUSIONS: In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.

OBJECTIVE: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was survival at day 28. DESIGN: Multiple-center, randomized, two-stage, double-blind, placebo-controlled, safety and efficacy study. SETTING: A total of 124 intensive care units in Europe, North America, South America, South Africa, and Australasia. PATIENTS: A total of 797 patients with septic shock diagnosed for <24 hrs. INTERVENTIONS: Patients with septic shock were allocated to receive 546C88 or placebo (5% dextrose) for up to 7 days (stage 1) or 14 days (stage 2) in addition to conventional therapy. Study drug was initiated at 0.05 mL.kg(-1).hr(-1) (2.5 mg.kg(-1).hr(-1) 546C88) and titrated up to a maximum rate of 0.4 mL.kg(-1).hr(-1) to maintain mean arterial pressure between 70 and 90 mm Hg while attempting to withdraw concurrent vasopressors. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variables, organ function data, microbiological data, concomitant therapy, and adverse event data were recorded at baseline, throughout treatment, and at follow-up. The primary end point was day-28 survival. The trial was stopped early after review by the independent data safety monitoring board. Day-28 mortality was 59% (259/439) in the 546C88 group and 49% (174/358) in the placebo group (p <.001). The overall incidence of adverse events was similar in both groups, although a higher proportion of the events was considered possibly attributable to study drug in the 546C88 group. Most of the events accounting for the disparity between the groups were associated with the cardiovascular system (e.g., decreased cardiac output, pulmonary hypertension, systemic arterial hypertension, heart failure). The causes of death in the study were consistent with those expected in patients with septic shock, although there was a higher proportion of cardiovascular deaths and a lower incidence of deaths caused by multiple organ failure in the 546C88 group. CONCLUSIONS: In this study, the nonselective nitric oxide synthase inhibitor 546C88 increased mortality in patients with septic shock.