Faculty Bibliography

PURPOSE/OBJECTIVE:Breath stacking dyssynchrony generates higher tidal volumes than intended, potentially increasing lung injury risk in acute respiratory distress syndrome (ARDS). Lack of validated criteria to quantify breath stacking dyssynchrony contributes to its under-recognition. This study evaluates performance of novel, objective criteria for quantifying breath stacking dyssynchrony (BREATHE criteria) compared to existing definitions and tests if neuromuscular blockade eliminates high-volume breath stacking dyssynchrony in ARDS. METHODS:Airway flow and pressure were recorded continuously for up to 72 h in 33 patients with ARDS receiving volume-preset assist-control ventilation. The flow-time waveform was integrated to calculate tidal volume breath-by-breath. The BREATHE criteria considered five domains in evaluating for breath stacking dyssynchrony: ventilator cycling, interval expiratory volume, cumulative inspiratory volume, expiratory time, and inspiratory time. RESULTS:The observed tidal volume of BREATHE stacked breaths was 11.3 (9.7-13.3) mL/kg predicted body weight, significantly higher than the preset volume [6.3 (6.0-6.8) mL/kg; p < 0.001]. BREATHE identified more high-volume breaths (≥2 mL/kg above intended volume) than the other existing objective criteria for breath stacking [27 (7-59) vs 19 (5-46) breaths/h; p < 0.001]. Agreement between BREATHE and visual waveform inspection was high (raw agreement 96.4-98.1 %; phi 0.80-0.92). Breath stacking dyssynchrony was near-completely eliminated during neuromuscular blockade [0 (0-1) breaths/h; p < 0.001]. CONCLUSIONS:The BREATHE criteria provide an objective definition of breath stacking dyssynchrony emphasizing occult exposure to high tidal volumes. BREATHE identified high-volume breaths missed by other methods for quantifying this dyssynchrony. Neuromuscular blockade prevented breath stacking dyssynchrony, assuring provision of the intended lung-protective strategy.

Prevention of ventilator-induced lung injury (VILI) can attenuate multiorgan failure and improve survival in at-risk patients. Clinically significant VILI occurs from volutrauma, barotrauma, atelectrauma, biotrauma, and shear strain. Differences in regional mechanics are important in VILI pathogenesis. Several interventions are available to protect against VILI. However, most patients at risk of lung injury do not develop VILI. VILI occurs most readily in patients with concomitant physiologic insults. VILI prevention strategies must balance risk of lung injury with untoward side effects from the preventive effort, and may be most effective when targeted to subsets of patients at increased risk.

OBJECTIVES/OBJECTIVE:Pulmonary dead-space fraction is one of few lung-specific independent predictors of mortality from acute respiratory distress syndrome. However, it is not measured routinely in clinical trials and thus altogether ignored in secondary analyses that shape future research directions and clinical practice. This study sought to validate an estimate of dead-space fraction for use in secondary analyses of clinical trials. DESIGN/METHODS:Analysis of patient-level data pooled from acute respiratory distress syndrome clinical trials. Four approaches to estimate dead-space fraction were evaluated: three required estimating metabolic rate; one estimated dead-space fraction directly. SETTING/METHODS:U.S. academic teaching hospitals. PATIENTS/METHODS:Data from 210 patients across three clinical trials were used to compare performance of estimating equations with measured dead-space fraction. A second cohort of 3,135 patients from six clinical trials without measured dead-space fraction was used to confirm whether estimates independently predicted mortality. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Dead-space fraction estimated using the unadjusted Harris-Benedict equation for energy expenditure was unbiased (mean ± SD Harris-Benedict, 0.59 ± 0.13; measured, 0.60 ± 0.12). This estimate predicted measured dead-space fraction to within ±0.10 in 70% of patients and ±0.20 in 95% of patients. Measured dead-space fraction independently predicted mortality (odds ratio, 1.36 per 0.05 increase in dead-space fraction; 95% CI, 1.10-1.68; p < 0.01). The Harris-Benedict estimate closely approximated this association with mortality in the same cohort (odds ratio, 1.55; 95% CI, 1.21-1.98; p < 0.01) and remained independently predictive of death in the larger Acute Respiratory Distress Syndrome Network cohort. Other estimates predicted measured dead-space fraction or its association with mortality less well. CONCLUSIONS:Dead-space fraction should be measured in future acute respiratory distress syndrome clinical trials to facilitate incorporation into secondary analyses. For analyses where dead-space fraction was not measured, the Harris-Benedict estimate can be used to estimate dead-space fraction and adjust for its association with mortality.

No major trial evaluating prone positioning for acute respiratory distress syndrome (ARDS) has incorporated a high-positive end-expiratory pressure (high-PEEP) strategy despite complementary physiological rationales. We evaluated generalizability of three recent proning trials to patients receiving a high-PEEP strategy. All trials employed a relatively low-PEEP strategy. After protocol ventilator settings were initiated and the patient was positioned per treatment assignment, post-intervention PEEP was not more than 5 cm H2O in 16.7 % and not more than 10 cm H2O in 66.0 % of patients. Post-intervention PEEP would have been nearly twice the set PEEP had a high-PEEP strategy been employed. Use of either proning or high-PEEP likely improves survival in moderate-severe ARDS; the role for both concomitantly remains unknown.

PURPOSE/OBJECTIVE:Prone positioning for ARDS has been performed for decades without definitive evidence of clinical benefit. A recent multicenter trial demonstrated for the first time significantly reduced mortality with prone positioning. This meta-analysis was performed to integrate these findings with existing literature and test whether differences in tidal volume explain conflicting results among randomized trials. METHODS:Studies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review. Included were randomized trials evaluating the effect on mortality of prone versus supine positioning during conventional ventilation for ARDS. The primary outcome was risk ratio of death at 60 days meta-analyzed using random effects models. Analysis stratified by high (>8 ml/kg predicted body weight) or low (≤ 8 ml/kg PBW) mean baseline tidal volume was planned a priori. RESULTS:Seven trials were identified including 2,119 patients, of whom 1,088 received prone positioning. Overall, prone positioning was not significantly associated with the risk ratio of death (RR 0.83; 95% CI 0.68-1.02; p = 0.073; I (2) = 64%). When stratified by high or low tidal volume, prone positioning was associated with a significant decrease in RR of death only among studies with low baseline tidal volume (RR 0.66; 95% CI 0.50-0.86; p = 0.002; I (2) = 25%). Stratification by tidal volume explained over half the between-study heterogeneity observed in the unstratified analysis. CONCLUSIONS:Prone positioning is associated with significantly reduced mortality from ARDS in the low tidal volume era. Substantial heterogeneity across studies can be explained by differences in tidal volume.

Advances in critical care practice have led to a substantial decline in the incidence of ARDS over the past several years. Low tidal volume ventilation, timely resuscitation and antimicrobial administration, restrictive transfusion practices, and primary prevention of aspiration and nosocomial pneumonia have likely contributed to this reduction. Despite decades of research, there is no proven pharmacologic treatment of ARDS, and mortality from ARDS remains high. Consequently, recent initiatives have broadened the scope of lung injury research to include targeted prevention of ARDS. Prediction scores have been developed to identify patients at risk for ARDS, and clinical trials testing aspirin and inhaled budesonide/formoterol for ARDS prevention are ongoing. Future trials aimed at preventing ARDS face several key challenges. ARDS has not been validated as an end point for pivotal clinical trials, and caution is needed when testing toxic therapies that may prevent ARDS yet potentially increase mortality.

OBJECTIVE:Obstructive sleep apnea (OSA) is associated with increased risk of adverse cardiovascular events. Because cardiopulmonary exercise testing (CPET) aids in prognostic assessment of heart disease, there is rising interest in its utility for cardiovascular risk stratification of patients with OSA. However, the relationship between OSA and exercise capacity is unclear. This study was conducted to test the hypothesis that OSA is associated with impaired exercise capacity. METHODS:Fifteen subjects with moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥15 events/h) and 19 controls with mild or no OSA (AHI <15 events/h) were enrolled. Subjects underwent standard polysomnography to determine AHI and exclude other sleep disorders. Resting metabolic rate was measured via indirect calorimetry, followed by maximum, symptom-limited CPET. Subjects completed a sleep diary and physical activity questionnaire characterizing behaviors in the week prior to testing. RESULTS:Percent predicted peak oxygen uptake (V˙O2) was significantly lower in OSA subjects than controls (70.1%±17.5% vs 83.8%±13.9%; p = 0.02). Each 1-unit increase in log-transformed AHI was associated with a decrease in percent predicted peak V˙O2 of 3.20 (95% CI 0.53-5.88; p = 0.02). After adjusting for baseline differences, this association remained significant (p < 0.01). AHI alone explained 16.1% of the variability observed in percent predicted peak V˙O2 (p = 0.02). CONCLUSIONS:OSA is associated with impaired exercise capacity. Further study is needed to evaluate the utility of CPET for prognostic assessment of patients with OSA.