Edward N. Pattishall

Aerosolized Surfactant in Adults with Sepsis-Induced Acute Respiratory Distress Syndrome

BACKGROUND Patients with acute respiratory distress syndrome (ARDS) have a deficiency of surfactant. Surfactant replacement improves physiologic function in such patients, and preliminary data suggest that it may improve survival. METHODS We conducted a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 725 patients with sepsis-induced ARDS. Patients were stratified according to the risk of death at base line (indicated by their score on the Acute Physiological and Chronic Health Evaluation [APACHE III] index) and randomly assigned to receive either continuously administered synthetic surfactant (13.5 mg of dipalmitoylphosphatidylcholine per milliliter, 364 patients) or placebo (o.45 percent saline; 361 patients) in aerosolized form for up to five days. RESULTS The demographic and physiologic characteristics of the two treatment groups were similar at base line. The mean (+/- SD) age was 50 +/- 17 years in the surfactant group and 53 +/- 18 years in the placebo group, and the mean APACHE III scores at randomization were 70.4 +/- 25 and 70.5 +/- 25, respectively. Hemodynamic measures, measures of oxygenation, duration of mechanical ventilation, and length of stay in intensive care unit did not differ significantly in the two groups. Survival at 30 days was 60 percent for both groups. Survival was similar in the groups when analyzed according to APACHE III score, cause of death, time of onset and severity of ARDS, presence or absence of documented sepsis, underlying disease, whether or not there was a do-not-resuscitate order, and medical center. Increased secretions were significantly more frequent in the surfactant group; the rates of other complications were similar in the two groups. CONCLUSIONS The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival, length of stay in the intensive care unit, duration of mechanical ventilation, or physiologic function.

The Relation of Pneumothorax and Other Air Leaks to Mortality in the Acute Respiratory Distress Syndrome

BACKGROUND In patients with the acute respiratory distress syndrome, pneumothorax and other air leaks - any extrusion of air outside the tracheobronchial tree - have been attributed to high ventilatory pressures or volumes and linked to increased mortality. METHODS We analyzed data from a prospective trial of aerosolized synthetic surfactant in 725 patients with the acute respiratory distress syndrome induced by sepsis. We compared the ventilatory pressures and volumes in the patients without any air leaks (the highest values during the five-day study) with the pressures and volumes in those with pneumothorax or with any air leaks (the highest values during the 16- and 24-hour periods before the complication developed). RESULTS Fifty patients (6.9 percent) had pneumothorax and 77 (10.6 percent) had pneumothorax or other air leaks. There were no significant differences between patients with air leaks and those without air leaks in any pressure or volume examined. Overall mortality at 30 days was 40.0 percent (95 percent confidence interval, 36.4 to 43.6); among the patients with pneumothorax, it was 46.0 percent (95 percent confidence interval, 32.2 to 59.8), and among those without pneumothorax, it was 39.3 percent (95 percent confidence interval, 35.6 to 43.0; P=0.35). The mortality rate was 45.5 percent (95 percent confidence interval, 34.4 to 56.6) in the group with any air leaks and 39.0 percent (95 percent confidence interval, 35.3 to 42.8) in the group without air leaks (P=0.28). CONCLUSIONS In patients with sepsis-induced acute respiratory distress syndrome who were receiving mechanical ventilation with conventional pressures and volumes, there were no significant correlations between high ventilatory pressures or volumes and the development of pneumothorax or other air leaks. Pneumothorax or other air leaks were not associated with a significantly increased mortality rate.

Development and evaluation of a common data model enabling active drug safety surveillance using disparate healthcare databases

OBJECTIVE Active drug safety surveillance may be enhanced by analysis of multiple observational healthcare databases, including administrative claims and electronic health records. The objective of this study was to develop and evaluate a common data model (CDM) enabling rapid, comparable, systematic analyses across disparate observational data sources to identify and evaluate the effects of medicines. DESIGN The CDM uses a person-centric design, with attributes for demographics, drug exposures, and condition occurrence. Drug eras, constructed to represent periods of persistent drug use, are derived from available elements from pharmacy dispensings, prescriptions written, and other medication history. Condition eras aggregate diagnoses that occur within a single episode of care. Drugs and conditions from source data are mapped to biomedical ontologies to standardize terminologies and enable analyses of higher-order effects. MEASUREMENTS The CDM was applied to two source types: an administrative claims and an electronic medical record database. Descriptive statistics were used to evaluate transformation rules. Two case studies demonstrate the ability of the CDM to enable standard analyses across disparate sources: analyses of persons exposed to rofecoxib and persons with an acute myocardial infarction. RESULTS Over 43 million persons, with nearly 1 billion drug exposures and 3.7 billion condition occurrences from both databases were successfully transformed into the CDM. An analysis routine applied to transformed data from each database produced consistent, comparable results. CONCLUSION A CDM can normalize the structure and content of disparate observational data, enabling standardized analyses that are meaningfully comparable when assessing the effects of medicines.

Clinical diagnostic criteria of the adult respiratory distress syndrome in the intensive care unit

OBJECTIVES To determine the use of commonly used diagnostic criteria for adult/acute respiratory distress syndrome (ARDS), evaluate physiologic variables of most value in diagnosing ARDS, and assess the frequency of newly diagnosed ARDS. DESIGN Self-administered questionnaire by mail. SETTING Hospital intensive care units (ICUs). SUBJECTS Intensive care physicians (n = 923) in the United States listed as ICU directors in the Society of Critical Care Medicine Membership Directory. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 448 (48.5%) physicians responded, with 301 questionnaires completed. Bilateral infiltrates on chest radiograph, the PaO2/FIO2 ratio, and pulmonary artery occlusion pressure were the most commonly used diagnostic criteria. However, the actual values used to diagnose ARDS were highly variable. The most important clinical physiologic variable used in determining the respiratory status of the ARDS patient was the PaO2/FIO2 ratio, followed by shunt fraction, alveolar-arterial oxygen tension gradient, FIO2, PaO2, respiratory system compliance, and minute ventilation. Respondents indicated that 9% of ICU beds at their institutions were occupied by a patient diagnosed with ARDS within the previous 7 days and 18.6% of all mechanically ventilated patients had ARDS by their own criteria. Based on the total number of ICU beds, the predicted incidence of ARDS would be approximately 275,000 patients per year in the United States. CONCLUSION A wide range of diagnostic criteria are utilized by clinicians in the diagnosis of ARDS.

Effects of Aerosolized Synthetic Surfactant, Atovaquone, and the Combination of These on Murine Pneumocystis carinii Pneumonia

An immunosuppressed rat model was used to determine the pharmacokinetics of aerosolized atovaquone (administered with and without a synthetic surfactant) and to evaluate the efficacy of inhaled atovaquone in the prevention and treatment of Pneumocystis carinii pneumonia (PCP). After a single dose by aerosol, mean peak concentrations of atovaquone averaged 52 microg/mL in plasma and 31 microg/g in lungs of rats infected with P. carinii. When atovaquone was combined with surfactant, mean peak concentrations of 94 microg/mL in plasma and 51 microg/g in lung were achieved. Aerosolized synthetic surfactant alone significantly increased survival of rats with PCP and, when combined with atovaquone, increased plasma and lung concentrations of the drug and eradication of the organism.

Semi-automated risk estimation using large databases: quinolones and clostridium difficile associated diarrhea†

The availability of large databases with person time information and appropriate statistical methods allow for relatively rapid pharmacovigilance analyses. A semi‐automated method was used to investigate the effect of fluoroquinolones on the incidence of C. difficile associated diarrhea (CDAD).

Surfactant Replacement for Ventilator-Associated Pneumonia: A Preliminary Report

Background: Surfactant abnormalities have been described in bacterial pneumonia. Objective: To determine the safety and effect of exogenous surfactant replacement in patients with ventilator-associated pneumonia (VAP). Methods: Patients with VAP were randomized in a double-blind study to receive either an artificial surfactant (Exosurf) consisting mostly of disaturated phospholipids (DSPL) or saline via a continuous nebulizer system for 5 days. Patients underwent bronchoscopy and bronchoalveolar lavage (BAL) prior to and after 4 days of therapy. Results: Twenty-two patients were randomized, with 8 receiving Exosurf. There was no detected difference in outcome between the saline- and Exosurf-treated patients in terms of days on ventilator, 30-day or hospital mortality. At the follow-up lavage, the patients treated with Exosurf had a significant rise in the level of DSPL (p < 0.05), while the saline group did not, suggesting delivery of drug. Also at the follow-up lavage, the percentage of neutrophils in the BAL fell in the Exosurf patients (p < 0.01), but not in the saline group. Conclusion: Exogenous surfactant replacement given to patients with VAP increased the amount of DSPL retrieved by BAL. This treatment was associated with a fall in the neutrophil response to pneumonia.

Effects of Aerosolized Surfactant in Patients with Stable Chronic Bronchitis: A Prospective Randomized Controlled Trial

CONTEXT Chronic bronchitis, estimated to affect more than 13 million adults in the United States, is characterized in part by retention of airway secretions, but no approved or effective therapy for airway mucus retention in patients with chronic bronchitis has been established. Surfactant reduces sputum adhesiveness, which contributes to difficulty in clearing secretions, but surfactant has not been tested in patients with chronic bronchitis. OBJECTIVE To examine the effects of exogenous surfactant on sputum clearance and pulmonary function in patients with stable chronic bronchitis. DESIGN A prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled comparison of the effects of 2 weeks of treatment with 3 doses of aerosolized surfactant (palmitoylphosphadidylcholine [DPPC]) or saline (placebo). SETTING Four US teaching hospitals. PARTICIPANTS A total of 87 adult patients with the diagnosis of stable chronic bronchitis. MAIN OUTCOME MEASURES Pulmonary function, respiratory symptoms, and sputum properties before treatment (day 0), after 2 weeks of treatment (day 14), and 7 days after stopping treatment (day 21). RESULTS A total of 66 patients were randomized to surfactant treatment and 21 to saline treatment. Patient demographic characteristics between groups were similar at baseline. In patients who received a DPPC dose of 607.5 mg/d for 2 weeks, prebronchodilator forced expiratory volume in 1 second (FEV1) increased from 1.22 L (SEM, 0.08 L) at day 0 to 1.33 L (SEM, 0.09 L) at day 21 (P=.05), an improvement of 11.4%; postbronchodilator FEV1 improved 10.4% by days 14 and 21 (P=.02); and the ratio of residual volume to total lung capacity, a measure of thoracic gas trapping, decreased 6.2% by day 21 (P=.009). In the surfactant groups, there was a dose-dependent increase in the ability of sputum to be transported by cilia in vitro. CONCLUSION Aerosolized surfactant improved pulmonary function and resulted in a dose-related improvement in sputum transport by cilia in patients with stable chronic bronchitis.