Barbara Finkel

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Underuse of lung protective ventilation: analysis of potential factors to explain physician behavior.

Objective:To determine the frequency of use of low-tidal-volume ventilation in appropriate patients with acute lung injury (ALI) and the factors associated with the choice of tidal volume. Design:Prospective observational cohort study of patients identified with ALI or acute respiratory distress syndrome from September 2000 to November 2002. Setting:Medical and surgical intensive care unit (ICU) at an academic tertiary-care hospital. Measurements and Main Results:Measurements included the proportion for whom the ventilation tidal volume (TV) was ≤7.5 mL/kg predicted body weight (PBW) on days 2, 4, and 7 of ALI and the proportion for whom the ventilation TV was ≤6.5 and ≤8.5 mL/kg/PBW (sensitivity analysis). Demographic and clinical characteristics of patients undergoing ventilation with low and high TV were compared. Of 88 total patients studied, 39% had ventilation with TV ≤7.5 mL/kg/PBW on day 2 of ALI, 49% on day 4, and 56% on day 7. In contrast, 49% of patients had ventilation with TV >8.5 mL/kg/PBW on day 2 of ALI, 30% on day 4, and 24% on day 7. The use of low TV was significantly associated with clinical parameters indicative of worse disease severity, including low values for Pao2 (p = .01), Pao2/Fio2 (p = .08), and static compliance of the respiratory system (p = .006). Conclusions:Ventilation with a low TV was used in a minority of patients with ALI, despite results published in 1998 and 2000 supporting this approach. This may be related to clinicians’ underrecognition of less severe cases of ALI, their reserving of low-TV ventilation for more severe cases, or both.

The impact of development of acute lung injury on hospital mortality in critically ill trauma patients

Objective:The additional impact of development of acute lung injury on mortality in severely-injured trauma patients beyond baseline severity of illness has been questioned. We assessed the contribution of acute lung injury to in-hospital mortality in critically ill trauma patients. Design:Prospective cohort study. The contribution of acute lung injury to in-hospital mortality was evaluated in two ways. First, multivariable logistic regression models were used to test the independent association of acute lung injury with in-hospital mortality while adjusting for baseline confounding variables. Second, causal pathway models were used to estimate the amount of the overall association of baseline severity of illness with in-hospital mortality that is attributable to the interval development of acute lung injury. Setting:Academic level 1 trauma center. Patients:Two hundred eighty-three critically ill trauma patients without isolated head injury and with an Injury Severity Score ≥16 were evaluated for development of acute lung injury in the first 5 days after trauma. Measurements and Main Results:Of the 283 patients, 38 (13.4%) died. The unadjusted mortality rate was nearly three-fold greater in the acute lung injury group (23.9% vs. 8.4%; odds ratio = 3.36; 95% confidence interval 1.67-6.77; p = 0.001). Acute lung injury remained an independent risk factor for death after adjustment for age, baseline Acute Physiologic and Chronic Health Evaluation III score, Injury Severity Score, and blunt mechanism of injury (odds ratio = 2.87; 95% confidence interval 1.29-6.37; p = 0.010). Forty percent of the total association of the baseline Acute Physiologic and Chronic Health Evaluation III score with mortality occurred via an indirect association through acute lung injury, and the remaining 60% via a direct effect. Conclusions:Development of acute lung injury in critically ill trauma patients without isolated head injury contributes independently to in-hospital mortality beyond baseline severity of illness measures. In addition, a significant portion of the association between baseline illness severity and risk of death in these patients might be explained by the interval development of acute lung injury.

Performance of an automated electronic acute lung injury screening system in intensive care unit patients.

Objective:Lung protective ventilation reduces mortality in patients with acute lung injury, but underrecognition of acute lung injury has limited its use. We recently validated an automated electronic acute lung injury surveillance system in patients with major trauma in a single intensive care unit. In this study, we assessed the systems performance as a prospective acute lung injury screening tool in a diverse population of intensive care unit patients. Design:Patients were screened prospectively for acute lung injury over 21 wks by the automated system and by an experienced research coordinator who manually screened subjects for enrollment in Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSNet) trials. Performance of the automated system was assessed by comparing its results with the manual screening process. Discordant results were adjudicated blindly by two physician reviewers. In addition, a sensitivity analysis using a range of assumptions was conducted to better estimate the systems performance. Setting:The Hospital of the University of Pennsylvania, an academic medical center and ARDSNet center (1994–2006). Patients:Intubated patients in medical and surgical intensive care units. Interventions:None. Measurements and Main Results:Of 1270 patients screened, 84 were identified with acute lung injury (incidence of 6.6%). The automated screening system had a sensitivity of 97.6% (95% confidence interval, 96.8–98.4%) and a specificity of 97.6% (95% confidence interval, 96.8–98.4%). The manual screening algorithm had a sensitivity of 57.1% (95% confidence interval, 54.5–59.8%) and a specificity of 99.7% (95% confidence interval, 99.4–100%). Sensitivity analysis demonstrated a range for sensitivity of 75.0–97.6% of the automated system under varying assumptions. Under all assumptions, the automated system demonstrated higher sensitivity than and comparable specificity to the manual screening method. Conclusions:An automated electronic system identified patients with acute lung injury with high sensitivity and specificity in diverse intensive care units of a large academic medical center. Further studies are needed to evaluate the effect of automated prompts that such a system can initiate on the use of lung protective ventilation in patients with acute lung injury.

An Alternative Method of Acute Lung Injury Classification for Use in Observational Studies

BACKGROUND In observational studies using acute lung injury (ALI) as an outcome, a spectrum of lung injury and difficult-to-interpret chest radiographs (CXRs) may hamper efforts to uncover risk factor associations. We assessed the impact of excluding patients with difficult-to-classify or equivocal ALI diagnosis on clinical and genetic risk factor associations for ALI after trauma. METHODS This study was of a prospective cohort of 280 critically ill trauma patients. The primary outcome was the development of ALI. Patients were classified into one of three groups: (1) definite ALI (patients who fulfilled the American-European Consensus Conference [AECC] criteria for ALI), (2)equivocal ALI (patients who had difficult-to-interpret CXRs), and (3) definite non-ALI. We compared clinical and genetic ALI risk factor associations between two classification schemes: AECC classification (definite ALI vs rest) and alternative classification (definite ALI vs definite non-ALI, excluding equivocal ALI). RESULTS Ninety-three (35%) patients were classified as definite ALI, 67 (25%) as equivocal, and 104 (39%) as definite non-ALI. Estimates of clinical and genetic ALI risk factor associations were farther from the null using the alternative classification. In a multivariable risk factor model, the C statistic of the alternative classification was significantly higher than that derived from the AECC classification (0.82 vs 0.74; P < .01). CONCLUSIONS The ability to detect ALI risk factors may be improved by excluding patients with equivocal or difficult-to-classify ALI. Such analyses may provide improved ability to detect clinical and genetic risk factor associations in future epidemiologic studies of ALI.