Purpose

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.

Objective

Global lung stress varies considerably with low tidal volume ventilation for acute respiratory distress syndrome. High stress despite low tidal volumes may worsen lung injury and increase risk of death. No widely available parameter exists to assess global lung stress. We aimed to determine whether the volume delivered during a recruitment maneuver (V(RM)) is inversely associated with lung stress and mortality in acute respiratory distress syndrome.

Design

Substudy of an acute respiratory distress syndrome clinical trial on esophageal pressure-guided positive end-expiratory pressure titration.

Setting

U.S. academic medical center.

Patients

Forty-two patients with acute respiratory distress syndrome in whom airflow, airway pressure, and esophageal pressure were recorded during the recruitment maneuver.

Interventions

A single recruitment maneuver was performed before initiating protocol-directed ventilator management. Recruitment maneuvers consisted of a 30-second breath hold at 40 cm H2O airway pressure under heavy sedation or paralysis. V(RM) was calculated by integrating the flow-time waveform during the maneuver. End-inspiratory stress was defined as the transpulmonary (airway minus esophageal) pressure during end-inspiratory pause of a tidal breath and tidal stress as the transpulmonary pressure difference between end-inspiratory and end-expiratory pauses.

Measurements and main results

V(RM) ranged between 7.4 and 34.7 mL/kg predicted body weight. Lower V(RM) predicted high end-inspiratory and tidal lung stress (end-inspiratory: β = -0.449; 95% CI, -0.664 to -0.234; p < 0.001; tidal: β = -0.267; 95% CI, -0.423 to -0.111; p = 0.001). After adjusting for PaO2/FIO2 and either driving pressure, tidal volume, or plateau pressure and positive end-expiratory pressure, V(RM) remained independently associated with both end-inspiratory and tidal stress. In unadjusted analysis, low V(RM) predicted increased risk of death (odds ratio, 0.85; 95% CI, 0.72-1.00; p = 0.026). V(RM) remained significantly associated with mortality after adjusting for study arm (odds ratio, 0.84; 95% CI, 0.71-1.00; p = 0.022).

Conclusions

Low V(RM) independently predicts high lung stress and may predict risk of death in patients with acute respiratory distress syndrome.

Study objectives

Both anatomical and nonanatomical traits are important in obstructive sleep apnea (OSA) pathogenesis. We have previously described a model combining these traits, but have not determined its diagnostic accuracy to predict OSA. A valid model, and knowledge of the published effect sizes of trait manipulation, would also allow us to predict the number of patients with OSA who might be effectively treated without using positive airway pressure (PAP).

Design, participants and intervention

Fifty-seven subjects with and without OSA underwent standard clinical and research sleep studies to measure OSA severity and the physiological traits important for OSA pathogenesis, respectively. The traits were incorporated into a physiological model to predict OSA. The model validity was determined by comparing the model prediction of OSA to the clinical diagnosis of OSA. The effect of various trait manipulations was then simulated to predict the proportion of patients treated by each intervention.

Measurements and results

The model had good sensitivity (80%) and specificity (100%) for predicting OSA. A single intervention on one trait would be predicted to treat OSA in approximately one quarter of all patients. Combination therapy with two interventions was predicted to treat OSA in ∼50% of patients.

Conclusions

An integrative model of physiological traits can be used to predict population-wide and individual responses to non-PAP therapy. Many patients with OSA would be expected to be treated based on known trait manipulations, making a strong case for the importance of non-anatomical traits in OSA pathogenesis and the effectiveness of non-PAP therapies.

Purpose

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.

Rationale

Body habitus is a major determinant of obstructive sleep apnea (OSA). However, many individuals do not have OSA despite being overweight/obese (body mass index > 25 kg/m(2)) for reasons that are not fully elucidated.

Objectives

To determine the key physiologic traits (upper-airway anatomy/collapsibility, upper-airway muscle responsiveness, chemoreflex control of ventilation, arousability from sleep) responsible for the absence of OSA in overweight/obese individuals.

Methods

We compared key physiologic traits in 18 overweight/obese subjects without apnea (apnea-hypopnea index < 15 events per hour) with 25 overweight/obese matched patients with OSA (apnea-hypopnea index ≥ 15 events per hour) and 11 normal-weight nonapneic control subjects. Traits were measured by repeatedly lowering continuous positive airway pressure to subtherapeutic levels for 3 minutes during non-REM sleep.

Measurements and main results

Overweight/obese subjects without apnea exhibited a less collapsible airway than overweight/obese patients with apnea (critical closing pressure: -3.7 ± 1.9 vs. 0.6 ± 1.2 cm H2O; P = 0.003; mean ± 95% confidence interval), but a more collapsible airway relative to normal-weight control subjects (-8.8 ± 3.1 cm H2O; P < 0.001). Notably, overweight/obese subjects without apnea exhibited a threefold greater upper-airway muscle responsiveness than both overweight/obese patients with apnea (Δgenioglossus EMG/Δepiglottic pressure: -0.49 [-0.22 to -0.79] vs. -0.15 [-0.09 to -0.22] %max/cm H2O; P = 0.008; mean [95% confidence interval]) and normal-weight control subjects (-0.16 [-0.04 to -0.30] %max/cm H2O; P = 0.02). Loop gain was elevated (more negative) in both overweight/obese groups and normal-weight control subjects (P = 0.02). Model-based analysis demonstrated that overweight/obese individuals without apnea rely on both more favorable anatomy and collapsibility and enhanced upper-airway dilator muscle responses to avoid OSA.

Conclusions

Overweight/obese individuals without apnea have a moderately compromised upper-airway structure that is mitigated by highly responsive upper-airway dilator muscles to avoid OSA. Elucidating the mechanisms underlying enhanced muscle responses in this population may provide clues for novel OSA interventions.

The upper airway is often modeled as a Starling resistor, which predicts that flow is independent of inspiratory effort during flow limitation. However, while some obstructive sleep apnea (OSA) patients exhibit flat, Starling resistor-like flow limitation, others demonstrate considerable negative effort dependence (NED), defined as the percent reduction in flow from peak to mid-inspiration. We hypothesized that the variability in NED could be due to differences in phasic pharyngeal muscle activation between individuals. Therefore, we induced topical pharyngeal anesthesia to reduce phasic pharyngeal muscle activation to see if it increased NED. Twelve subjects aged 50±10 years with a BMI of 35±6 kg/m(2) and severe OSA (apnea-hypopnea index=52±28 events/h) were studied. NED and phasic genioglossus muscle activity (EMG(GG)) of flow limited breaths were determined before and after pharyngeal anesthesia with lidocaine. Pharyngeal anesthesia led to a 33% reduction in EMG(GG) activity (p<0.001), but NED worsened only by 3.6±5.8% (p=0.056). In conclusion, phasic EMG(GG) had little effect on NED. This finding suggests that individual differences in phasic EMG(GG) activation do not likely explain the variability in NED found among OSA patients.