David Zaccardelli

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.

An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock

ObjectiveTo assess the effects of the nitric oxide synthase inhibitor, 546C88, in patients with septic shock and to evaluate the range of dose rates that sustain mean arterial pressure (MAP) of >or=to70 mmHg.DesignMulticenter, open-label, uncontrolled, dose range finding study.SettingTen intensive c

Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension.

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, chemical instability and a short half-life have caused limitations in its use. The chemically stable prostacyclin analogue treprostinil has a longer half-life, and improves hemodynamics and signs/symptoms of PAH. This study investigated the feasibility of transitioning patients with PAH from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in a 12 week prospective open label study. Patients were switched from intravenous epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of the medication reservoir from epoprostenol to treprostinil. The dose of treprostinil was adjusted throughout the study to achieve a 2-fold increase of treprostinil compared with the baseline epoprostenol dose. Rapid transition to treprostinil was achieved without serious adverse events and, baseline clinical status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28 ± 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 ± 30 ng/kg/min. All patients reported less prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. Selected patients with PAH can be safely transitioned from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol.

Dose Proportionality of Treprostinil Sodium Administered by Continuous Subcutaneous and Intravenous Infusion

This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open–label, multiple–cohort, steady‐state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty‐nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083–1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809–1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.

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.

Pharmacokinetics of the nitric oxide synthase inhibitor L‐NG‐methylarginine hydrochloride in patients with septic shock

To characterize the pharmacokinetics of L‐N G‐methylarginine in patients with septic shock.

Stability and antimicrobial effectiveness of treprostinil sodium in Sterile Diluent for Flolan.

Introduction:  Long‐term intravenous infusion of epoprostenol and treprostinil for treatment of pulmonary arterial hypertension (PAH) via a central venous catheter is associated with the risk of bloodstream infection (BSI). While several potential explanations exist for possible differences in BSI incidence among intravenous prostanoids, one hypothesis suggests that the alkaline pH of epoprostenol in Sterile Diluent for Flolan (SDF) has greater antimicrobial activity compared with the neutral pH of other common diluents such as sterile saline or water, which have been used for treprostinil.

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 dense, high-volume, artificial surfactant aerosol on a heated exhalation filter system

ObjectiveTo evaluate a supplemental heated filter system during mechanical ventilation with continuous nebulization of an artificial surfactant by a new, high-volume nebulizer. Design and MethodsA new nebulizer system, containing artificial surfactant, provided half of a 20-L minute ventilation and the remainder of this minute ventilation was provided by a commonly used mechanical ventilator. Ventilation sources were joined in the inspiratory limb of the breathing circuit, which was connected to a test lung system. A supplemental filter system was placed upstream of the ventilators heated filter in the expiratory limb of the circuit. Circuit pressures at the inlet of the supplemental filter (P1), between the filters (P2), and after the ventilator expiratory filter (P3) were monitored and recorded. Nebulizer canisters containing artificial surfactant were replaced every 4 hrs. The performance of four supplemental filters in continuous use was examined. Another four filters were each used over 4 hrs, steam autoclaved, and reused. SettingsThe ventilator was set at a rate of 20 breaths/min, with a tidal volume of 0.5 L, a flow rate of 40 L/min, and positive end-expiratory pressure of 10 cm H2O. The nebulizer provided an equal volume and flow rate so that the delivered tidal volume was 1.0 L with a flow rate of 80 L/min. ResultsVentilator failure and/or excessive airway pressure caused by increased filter resistance occurred at a mean of 7.3 ± 1.3 (SD) hrs of continuous ventilation. Mean P1-peak increased from 67.5 ± 8.2 to 94.0 ± 10.7 cm H2O (p < .001) and P1-baseline increased from 9.3 ± 1.0 to 53.5 ± 17.1 cm H2O (p = .014). Filters that were autoclaved after 4 hrs of ventilation and reused lasted a total of 7.0 ± 1.3 hrs. Mean P1-peak increased from 68.9 ± 4.9 to 84.8 ± 19.1 cm H2O and P1-baseline increased from 9.5 ± 1.7 to 30.8 ± 14.2 cm H2O (p < .05). ConclusionsThe supplemental filter system was able to protect the ventilatory exhalation sensors for approximately 7 hrs at a minute ventilation of 20 L/min. Steam sterilization did not extend the supplemental filter life. (Crit Care Med 1993; 21:125–130)