Carolyn H. Welsh

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.

Excess Body Weight Is Not Independently Associated with Outcome in Mechanically Ventilated Patients with Acute Lung Injury

Context Although obesity poses many health risks, clinicians have been uncertain whether excess body weight adversely affects the outcomes of severe illnesses such as acute lung injury requiring mechanical ventilation. Contribution Among patients in a trial of mechanical ventilation strategies, obese patients and lean patients had similar mortality and ventilation outcomes. Implications Physicians should not assume that intubated obese patients fare worse than those who are of normal weight. Whether excess body weight puts patients at risk for poor outcomes in other types of critical illness is a subject for future study. The Editors Sixty-four percent of U.S. adults are overweight or obese, and this trend is accelerating (1, 2). Despite the well-described chronic health consequences of excess weight (3), we know little about the effect of obesity on outcomes from acute illnesses, particularly those requiring admission to the intensive care unit. Obese patients have a greater prevalence of comorbid conditions that may affect outcome (3), and they experience physiologic changes (4, 5) that may impair their ability to compensate for the stresses of critical illness. Because of these findings, conventional wisdom holds that obesity increases mortality and morbidity for patients in the intensive care unit. However, an independent effect of obesity on outcome from critical illness has never been conclusively demonstrated. If, in fact, obese persons are at risk, investigators should determine the mechanism of this increased risk and target interventions to this group. Acute lung injury is an inflammatory pulmonary condition associated with a variety of initiating insults. Acute lung injury is a frequent cause of respiratory failure requiring mechanical ventilation and a common indication for admission to the intensive care unit. The reported mortality rate is 40% to 60% (6). We performed a secondary analysis of a randomized trial of ventilator management in patients with acute lung injury (7) to better describe the influence of excess body weight on the outcome of critical illness. In that trial, patients randomly assigned to low tidal volume had better outcomes than patients assigned to high tidal volume. The experimental protocols for this trial required measurement of height to determine assigned tidal volume. This measurement also allowed calculation of body mass index (BMI) for each patient, a variable not often recorded for critically ill patients. Some argue that larger tidal volumes are beneficial for obese patients requiring mechanical ventilation (8). This raises concern that patients with different BMIs may require different ventilator strategies. By evaluating the interaction between the assigned ventilator protocol and BMI, we were able to determine whether the beneficial effect of lower tidal volume extends to obese patients with acute lung injury. Methods Setting and Sample We examined data on patients who participated in the National Heart, Lung, and Blood Institutes multicenter, randomized trials of the Acute Respiratory Distress Syndrome Network (7, 9, 10). Of the 902 patients in these studies, the first 861 participated in a randomized trial of mechanical ventilation that compared lower tidal volume with higher tidal volume (6 mL/kg of predicted body weight vs. 12 mL/kg, respectively). In a factorial design, 2 other trials evaluated ketoconazole versus placebo (234 patients) or lisofylline versus placebo (194 patients). After the ventilator trial ended because it showed a significant benefit associated with lower tidal volumes, an additional 41 patients received lisofylline or placebo plus the lower tidal volume strategy. Neither lisofylline (9) nor ketoconazole (10) affected outcomes of acute lung injury. Details of these studies and inclusion and exclusion criteria are described elsewhere (7, 9, 10). In brief, patients were eligible if they required mechanical ventilation and met diagnostic criteria for acute lung injury. Patients with a weight-to-height ratio (kilograms divided by centimeters) of 1.0 or greater were excluded. Analysis was done on an intention-to-treat basis. Measures of Excess Body Weight We used BMI as a measure of the degree of excess body weight. We calculated BMI from data in enrollment documents by dividing the patients body weight in kilograms by the square of his or her height in meters. Ventilator and Weaning Protocols The protocol for mechanical ventilator management is described elsewhere (7). The major difference between the two study groups was the selected tidal volume. Investigators calculated predicted body weight from the patients height and sex and used this predicted weight to determine the initial tidal volume for each patient. In the group assigned to higher tidal volumes, the initial tidal volume was 12 mL/kg of predicted body weight. In the group treated with lower tidal volumes, the initial tidal volume was 6 mL/kg. Investigators performed a daily weaning screen on every patient in an attempt to standardize the process of liberation from mechanical ventilation. Outcome Measures The primary outcome measure was survival to 28 days after study enrollment. Secondary dependent variables included achievement of unassisted ventilation by day 28, survival to discharge to home or to 180 days (the duration of follow-up in the primary studies), and the number of ventilator-free days. Unassisted ventilation was defined as liberation from mechanical ventilation for 48 or more consecutive hours. The number of ventilator-free days is the number of days of unassisted ventilation from day 1 to day 28. Statistical Analysis We performed unadjusted analyses by comparing values for patients across the 3 BMI categories (normal vs. overweight vs. obese) for outcome variables of interest and for other predictors. Unadjusted associations between other predictors and the outcomes were also explored. We used a 2-sided Fisher exact test for dichotomous variables; a 2-sided likelihood ratio chi-square test for nondichotomous categorical variables; and a KruskalWallis test, analysis of variance, or Wilcoxon rank-sum test for continuous variables, as appropriate. We constructed correlation matrices to guide regression estimation. We used logistic regression for the dichotomous outcome variables and linear regression for the continuous outcome variables. To estimate the base regressions, we selected variables for inclusion on the basis of several considerations, including significant differences in unadjusted analyses and clinical relevance. Among variables with a correlation greater than 0.50, only 1 was considered for inclusion to minimize multicollinearity. Variables that were thought to be strongly clinically relevant to the outcome and those found to have a statistically significant unadjusted effect (P < 0.05) were ultimately included in the base model. Variables in addition to those in Table 1 that were evaluated for inclusion were study site, ethnicity, diagnosis of diabetes, peak glucose level within 24 hours of enrollment, nonpulmonary organ failures, use of vasopressors, fluid balance in the 24 hours before study entry, and pneumonia as primary cause of lung injury. Unless otherwise stated, variables reflected the patients clinical state at the time of study enrollment. Table 1. Characteristics of the Sample After estimation of the base regressions, we forced the indicators of excess body weight into the model and determined their predictive values. We performed analyses in several different ways. We used the National Heart, Lung, and Blood Institute divisions of BMI to categorize patients as normal weight (BMI of 18.5 to 24.9 kg/m2), overweight (BMI of 25.0 to 29.9 kg/m2), or obese (BMI 30 kg/m2). To test any effect across BMI category, we used a categorical variable with 2 degrees of freedom in the regression. Because of concern that we would not be able to detect an effect that was nonincremental, we compared the overweight BMI group with the normal BMI group and the obese BMI group with the normal BMI group. To examine whether the efficacy of lower tidal volume ventilation varied by degree of excess body weight, we estimated the interaction effects between BMI group and assignment to the higher tidal volume protocol. Because the interaction effects between BMI category and treatment assignment were not significant (as tested by using a likelihood ratio test with 2 degrees of freedom), a main effects model was fit. This likelihood-ratio test was also used to test the significance of the 3-category BMI variable. To examine the patients with extreme excess body weight, patients were divided into 4 BMI categories (normal, overweight, obese [BMI of 30 to 39.9 kg/m2], and severely obese [BMI 40 kg/m2]). This categorical variable with 3 degrees of freedom was also tested in the regression. In addition to these analyses, we also used BMI as a continuous variable. Because critically ill patients often receive fluid resuscitation or diuresis, we recalculated BMI as adjusted for the net fluid balance for each patient over the 24 hours before study entry (fluid-adjusted BMI). Negative fluid balances were added to the patients body weight and positive fluid balances were subtracted from his or her weight to calculate BMI. We substituted the median fluid balance for the patients study site if the individual fluid balance was unavailable (51 records). We used a MantelHaenszel chi-square test for the ordinally categorical variables and a Wilcoxon rank-sum test for continuous variables. Pearson chi-square test produced results similar (P > 0.2) to those of the MantelHaenszel test. We used SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina), for all analyses. A P value less than 0.05 was considered statistically significant. Protection of Human Subjects The institutional review boards of each participating center approved the primary studies. Patients or their sur

Use of morning report to enhance adverse event detection.

OBJECTIVE: To determine whether or not prompting of medical residents at morning report enhances reporting of adverse events in hospitalized patients.DESIGN: Prospective trial comparing 3-month blocks of intensive prompting, modest prompting, and no prompting on adverse event reporting by housestaff at morning report.SETTING: Inpatient internal medicine service at a university-affiliated, Veterans Affairs Medical Center teaching hospital.INTERVENTIONS: Intensive prompting (daily), modest prompting (once or twice weekly), and no prompting of medical residents to report hospital-associated adverse events.MEASUREMENTS AND MAIN RESULTS: The number, type, and severity of hospital-acquired adverse events occurring on an internal medicine service were determined during the various periods of intervention on a per houseofficer basis. Residents were reminded to record events once or twice weekly, daily, or not at all. These data were compared with those identified by usual hospital surveillance. The addition of housestaff reporting to usual hospital surveillance increased the numbers of adverse events reported. There was little overlap in episodes reported by the two strategies. Increasing the level of prompting increased the number of reports per houseofficer. Housestaff prompting increased reporting at all levels of adverse event severity from mild to serious and detected a wide variety of types of adverse events, especially adverse drug reactions and procedure complications.CONCLUSIONS: Our study demonstrates that physician self-reporting of adverse events adds to the usual hospital surveillance adverse event reporting, and finds that such reporting can be easily accomplished within the context of a daily teaching activity. The information provided about adverse events by housestaff at morning report is additive to that obtained by usual surveillance methods. The use of such a strategy provides information in a timely fashion.

Risk factors for upper gastrointestinal bleeding in intensive care unit patients: role of helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group

OBJECTIVE To determine the role of preexisting Helicobacter pylori infection in the development of acute upper gastrointestinal (GI) hemorrhage in intensive care unit (ICU) patients in relation to other potential predisposing risk factors. DESIGN Prospective, multicenter, cohort study. SETTING Medical and surgical ICUs in six tertiary care Department of Veterans Affairs Medical Centers. PATIENTS Eight-hundred seventy-four patients without previous GI bleeding or peptic ulcer disease who were enrolled in a multicenter, randomized, controlled trial of prophylactic intravenous immunoglobulin to prevent ICU-associated infections. INTERVENTIONS This substudy of the larger intravenous immunoglobulin study only involved data analysis and had no intervention. All patients were enrolled in the larger study where they received intravenous immunoglobulin or placebo as intervention. MEASUREMENTS AND MAIN RESULTS Patients were prospectively evaluated for the development of acute upper GI hemorrhage while in an ICU. Anti-H. pylori immunoglobulin G and immnoglobulin A concentrations were determined by enzyme immunoassay on preintervention serum samples. Seventy-six (9%) patients had over upper GI bleeding and a mortality rate of 49%, as compared with a 15% mortality rate in patients who did not bleed (p < .001). By logistic regression analysis, the following factors were associated with an increased risk of bleeding: acute hepatic failure, prolonged duration of nasogastric tube placement, alcoholism, and an increased serum concentration of anti-H. pylori immunoglobulin A. CONCLUSIONS Increased anti-H. pylori immunoglobulin A concentrations, prolonged nasogastric intubation, alcoholism, and acute hepatic failure were found to be independently correlated with the development of acute GI bleeding in an ICU setting. These observations should be prospectively confirmed in an independent population before being used for treatment guidelines.

Evaluation of patient-perceived health status using the Medical Outcomes Survey Short-Form 36 in an intensive care unit population

OBJECTIVE Baseline patient functional status as assessed by providers is correlated with mortality after intensive care unit (ICU) admission. We wanted to see if patient self-perception of health status before admission to an ICU correlated with functional outcome. DESIGN Prospective survey on a convenience sample. SETTING Single urban university-affiliated Veterans Affairs Medial Center. PATIENTS One hundred ninety-nine patients in surgical and medical/coronary ICUs. INTERVENTIONS None. MEASUREMENTS Patient-assessed baseline health status was monitored with the Medical Outcome Survey Short-Form 36 (SF-36), consisting of 36 questions that evaluate eight health status concepts. In addition, baseline functional status (Zubrod scale) was determined and severity of illness (Acute Physiology and Chronic Health Evaluation [APACHE] II) data were collected. Zubrod functional status, which includes mortality, was determined 6 wks and 6 months after ICU admission, and correlation coefficients were calculated. MAIN RESULTS We found it feasible to collect SF-36 health status data on a 9% sample in this setting. Less than 1% of responses were completed by proxy. The SF-36 data were internally consistent, and several of its scales including general health perception and physical functioning correlated with patient Zubrod functional status (r2 = .08, p < .001; r2 = .14, p < .001) at 6 wks as did vitality (r2 = .04, p < .01), social function (r2 = .03, p < .05), and physical role function (r2 = .02, p = .053), although to a lesser extent. Similar correlations were also found with 6-month functional status. CONCLUSIONS We conclude that use of the SF-36 is time efficient in an ICU setting and correlates with 6-wk and 6-month functional outcome. It correlates as well with functional outcome as either the baseline Zubrod functional status or the APACHE II severity of illness measurement. The five-question general health evaluation portion correlated almost as well with outcome as the more extensive 36-item questionnaire. Use of the SF-36 may define patient populations for comparison across hospitals. It may also target individuals with needs for additional posthospitalization care, including rehabilitation services or nursing home placement.

Long-term functional outcome after intensive care

OBJECTIVE: Although age‐related mortality after intensive care unit (ICU) admission has been studied, functional recovery for different age groups following ICU admission is not well characterized. We hypothesized that compared with younger age groups, fewer patients older than age 65 admitted to an ICU would regain their full prehospitalization functional ability and that their recovery would be slower than that of younger patients.

Activated Protein C Resistance Assay Detects Thrombotic Risk Factors Other Than Factor V Leiden

Activated protein C (APC) resistance is a common risk factor for venous thromboembolism (VTE) attributed to various mechanisms, including factor V Leiden (FVL) polymorphism. FVL is considered responsible for up to 95% of APC resistance; however, other factor V polymorphisms and elevated factor VIII levels also have been implicated. We assessed whether additional mechanisms contribute to APC resistance in a blinded case-control study of 65 subjects by measuring APC resistance using 3 methods: 2 activated partial thromboplastin time-based methods with and without dilution in factor V-deficient plasma and 1 Russell viper venom-based assay (RVV). Without factor V-deficient plasma, 24 subjects were APC resistant; with factor V-deficient plasma, the assay identified fewer APC-resistant subjects, as did RVV. All assays detected the 7 heterozygous FVL subjects. Thirteen subjects had factor VIII levels above 150% (1.50). After excluding subjects with FVL or elevated factor VIII levels, 4 subjects still had APC resistance. VTE risk trended higher for subjects with APC resistance in the absence of FVL. Measurement of APC resistance without dilution in factor V-deficient plasma is needed to assess for potentially important thrombotic risk factors other than FVL.

Prostaglandin E1, fails to reduce endotoxin-induced pulmonary vascular protein leak in the dog☆

Prostaglandin E1 (PGE1) treatment may improve survival in human adult respiratory distress syndrome, but whether it decreases lung injury, improves pulmonary hemodynamics, or alters post-injury lung repair is unclear. We evaluated the effects of PGE1 pretreatment (30 ng/kg/min continuous infusion) on endotoxin-induced lung injury, measured as increases in extravascular protein leak, in the anesthetized dog. Hemodynamic effects of treatment were slight and unsustained. Measurements with a double isotope tracer technique indicated that endotoxin produced a large increase in the protein leak index compared with control (40 − 5 × 10−4 v 16 − 2 × 10−4 cm−1). This increase was unaffected by PGE1 treatment (37 − 6 × 10−4 cm−1) and PGE1 itself had no effect on protein leak (18 ± 10−4 cm−1). Similarly, the increase in gravimetric extravascular lung water (measured as wet to dry weight ratio) with endotoxin was not attenuated by PGE1 (control, 3.9 ± 0.2 g wet/g dry bloodless lung; endotoxin, 4.3 ± 0.5; PGE1 plus endotoxin, 4.8 ± 0.5; PGE1 alone, 3.8 ± 0.2). We conclude that PGE1 does not ameliorate lung injury induced by endotoxin in the dog.