Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Reverse Trigger Phenotypes in Acute Respiratory Distress Syndrome.

Rationale: Reverse triggering is an underexplored form of dyssynchrony with important clinical implications in patients with acute respiratory distress syndrome.Objectives: This retrospective study identified reverse trigger phenotypes and characterized their impacts on Vt and transpulmonary pressure.Methods: Fifty-five patients with acute respiratory distress syndrome on pressure-regulated ventilator modes were included. Four phenotypes of reverse triggering with and without breath stacking and their impact on lung inflation and deflation were investigated.Measurements and Main Results: Inflation volumes, respiratory muscle pressure generation, and transpulmonary pressures were determined and phenotypes differentiated using Campbell diagrams of respiratory activity. Reverse triggering was detected in 25 patients, 15 with associated breath stacking, and 13 with stable reverse triggering consistent with respiratory entrainment. Phenotypes were associated with variable levels of inspiratory effort (mean 4-10 cm H2O per phenotype). Early reverse triggering with early expiratory relaxation increased Vts (88 [64-113] ml) and inspiratory transpulmonary pressures (3 [2-3] cm H2O) compared with passive breaths. Early reverse triggering with delayed expiratory relaxation increased Vts (128 [86-170] ml) and increased inspiratory and mean-expiratory transpulmonary pressure (7 [5-9] cm H2O and 5 [4-6] cm H2O). Mid-cycle reverse triggering (initiation during inflation and maximal effort during deflation) increased Vt (51 [38-64] ml), increased inspiratory and mean-expiratory transpulmonary pressure (3 [2-4] cm H2O and 3 [2-3] cm H2O), and caused incomplete exhalation. Late reverse triggering (occurring exclusively during exhalation) increased mean expiratory transpulmonary pressure (2 [1-2] cm H2O) and caused incomplete exhalation. Breath stacking resulted in large delivered volumes (176 [155-197] ml).Conclusions: Reverse triggering causes variable physiological effects, depending on the phenotype. Differentiation of phenotype effects may be important to understand the clinical impacts of these events.

Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS). Objective: To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS. Design, Setting, and Participants: Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018. Interventions: Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes. Main Outcomes and Measures: The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy. Results: Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2. Conclusions and Relevance: Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS. Trial Registration: ClinicalTrials.gov Identifier NCT01681225.

Revisiting atelectasis in lung units with low ventilation/perfusion ratios.

Patients on high inspired O2 concentrations are at risk of atelectasis, a problem that has been quantitatively assessed using analysis of ratio of ventilation to perfusion (V̇a/Q̇) equations. This approach ignores the potential of the elastic properties of the lung to support gas exchange through "apneic" oxygenation in units with no tidal ventilation, and is based on an error in the conservation of mass equations. To fill this gap, we correct the error and compare the pressure drops associated with apneic gas exchange with the pressure differences that can be supported by lung recoil. We analyze a worst case scenario: a small test unit in the Weibel model A tree structure with zero tidal ventilation, 100% inspired O2, the rest of the lung being normally ventilated tidally. We first computed the gas flux to the (unventilated) test unit and estimated the associated pressure drops. We then computed the difference in local gas pressure relative to the surrounding lung that would cause the unit to collapse. We compared these two, and finally computed the degree of airway narrowing that would effect change from the stable (apneic gas exchange) regime to the unstable regime leading to collapse. We find that except under extreme conditions of loss of airway caliber exceeding roughly 90%, lung recoil is sufficient to maintain oxygenation through convective transport alone. We further argue that the fundamental V̇a/Q̇ equations are invalid in these circumstances, and that the issue of atelectasis in low V̇a/Q̇ will require modifications to account for this additional mode of gas exchange. NEW & NOTEWORTHY Breathing high concentrations of oxygen increases the likelihood of atelectasis because of oxygen absorption, which is thought to be inevitable in regions with relatively low ventilation/perfusion ratios. However, airspaces of the lung resist collapse because of the forces of interdependence, and can, with low or even zero active tidal ventilation, draw in an inspiratory flow of oxygen sufficient to replace the oxygen consumed, thus preventing collapse of airspaces served by all but the most narrowed airways.

Should we titrate peep based on end-expiratory transpulmonary pressure?-yes.

Ventilator management of patients with acute respiratory distress syndrome (ARDS) has been characterized by implementation of basic physiology principles by minimizing harmful distending pressures and preventing lung derecruitment. Such strategies have led to significant improvements in outcomes. Positive end expiratory pressure (PEEP) is an important part of a lung protective strategy but there is no standardized method to set PEEP level. With widely varying types of lung injury, body habitus and pulmonary mechanics, the use of esophageal manometry has become important for personalization and optimization of mechanical ventilation in patients with ARDS. Esophageal manometry estimates pleural pressures, and can be used to differentiate the chest wall and lung (transpulmonary) contributions to the total respiratory system mechanics. Elevated pleural pressures may result in negative transpulmonary pressures at end expiration, leading to lung collapse. Measuring the esophageal pressures and adjusting PEEP to make transpulmonary pressures positive can decrease atelectasis, derecruitment of lung, and cyclical opening and closing of airways and alveoli, thus optimizing lung mechanics and oxygenation. Although there is some spatial and positional artifact, esophageal pressures in numerous animal and human studies in healthy, obese and critically ill patients appear to be a good estimate for the "effective" pleural pressure. Multiple studies have illustrated the benefit of using esophageal pressures to titrate PEEP in patients with obesity and with ARDS. Esophageal pressure monitoring provides a window into the unique physiology of a patient and helps improve clinical decision making at the bedside.

Pressure-decay testing of pleural air leaks in intact murine lungs: evidence for peripheral airway regulation.

The critical care management of pleural air leaks can be challenging in all patients, but particularly in patients on mechanical ventilation. To investigate the effect of central airway pressure and pleural pressure on pulmonary air leaks, we studied orotracheally intubated mice with pleural injuries. We used clinically relevant variables - namely, airway pressure and pleural pressure - to investigate flow through peripheral air leaks. The model studied the pleural injuries using a pressure-decay maneuver. The pressure-decay maneuver involved a 3 sec ramp to 30 cmH2 0 followed by a 3 sec breath hold. After pleural injury, the pressure-decay maneuver demonstrated a distinctive airway pressure time history. Peak inflation was followed by a rapid decrease to a lower plateau phase. The decay phase of the inflation maneuver was influenced by the injury area. The rate of pressure decline with multiple injuries (28 ± 8 cmH2 0/sec) was significantly greater than a single injury (12 ± 3 cmH2 O/sec) (P < 0.05). In contrast, the plateau phase pressure was independent of injury surface area, but dependent upon transpulmonary pressure. The mean plateau transpulmonary pressure was 18 ± 0.7 cm H2 O. Finally, analysis of the inflation ramp demonstrated that nearly all volume loss occurred at the end of inflation (P < 0.001). We conclude that the air flow through peripheral lung injuries was greatest at increased lung volumes and limited by peripheral airway closure. In addition to suggesting an intrinsic mechanism for limiting flow through peripheral air leaks, these findings suggest the utility of positive end-expiratory pressure and negative pleural pressure to maintain lung volumes in patients with pleural injuries.

Effects of Prone Positioning on Transpulmonary Pressures and End-expiratory Volumes in Patients without Lung Disease.

BACKGROUND: The effects of prone positioning on esophageal pressures have not been investigated in mechanically ventilated patients. Our objective was to characterize effects of prone positioning on esophageal pressures, transpulmonary pressure, and lung volume, thereby assessing the potential utility of esophageal pressure measurements in setting positive end-expiratory pressure (PEEP) in prone patients. METHODS: We studied 16 patients undergoing spine surgery during general anesthesia and neuromuscular blockade. We measured airway pressure, esophageal pressures, airflow, and volume, and calculated the expiratory reserve volume and the elastances of the lung and chest wall in supine and prone positions. RESULTS: Esophageal pressures at end expiration with 0 cm H2O PEEP decreased from supine to prone by 5.64 cm H2O (95% CI, 3.37 to 7.90; P < 0.0001). Expiratory reserve volume measured at relaxation volume increased from supine to prone by 0.15 l (interquartile range, 0.25, 0.10; P = 0.003). Chest wall elastance increased from supine to prone by 7.32 (95% CI, 4.77 to 9.87) cm H2O/l at PEEP 0 (P < 0.0001) and 6.66 cm H2O/l (95% CI, 3.91 to 9.41) at PEEP 7 (P = 0.0002). Median driving pressure, the change in airway pressure from end expiration to end-inspiratory plateau, increased in the prone position at PEEP 0 (3.70 cm H2O; 95% CI, 1.74 to 5.66; P = 0.001) and PEEP 7 (3.90 cm H2O; 95% CI, 2.72 to 5.09; P < 0.0001). CONCLUSIONS: End-expiratory esophageal pressure decreases, and end-expiratory transpulmonary pressure and expiratory reserve volume increase, when patients are moved from supine to prone position. Mean respiratory system driving pressure increases in the prone position due to increased chest wall elastance. The increase in end-expiratory transpulmonary pressure and expiratory reserve volume may be one mechanism for the observed clinical benefit with prone positioning.

Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea.

Study Objectives: Precision medicine for obstructive sleep apnea (OSA) requires noninvasive estimates of each patient's pathophysiological "traits." Here, we provide the first automated technique to quantify the respiratory arousal threshold-defined as the level of ventilatory drive triggering arousal from sleep-using diagnostic polysomnographic signals in patients with OSA. Methods: Ventilatory drive preceding clinically scored arousals was estimated from polysomnographic studies by fitting a respiratory control model (Terrill et al.) to the pattern of ventilation during spontaneous respiratory events. Conceptually, the magnitude of the airflow signal immediately after arousal onset reveals information on the underlying ventilatory drive that triggered the arousal. Polysomnographic arousal threshold measures were compared with gold standard values taken from esophageal pressure and intraoesophageal diaphragm electromyography recorded simultaneously (N = 29). Comparisons were also made to arousal threshold measures using continuous positive airway pressure (CPAP) dial-downs (N = 28). The validity of using (linearized) nasal pressure rather than pneumotachograph ventilation was also assessed (N = 11). Results: Polysomnographic arousal threshold values were correlated with those measured using esophageal pressure and diaphragm EMG (R = 0.79, p < .0001; R = 0.73, p = .0001), as well as CPAP manipulation (R = 0.73, p < .0001). Arousal threshold estimates were similar using nasal pressure and pneumotachograph ventilation (R = 0.96, p < .0001). Conclusions: The arousal threshold in patients with OSA can be estimated using polysomnographic signals and may enable more personalized therapeutic interventions for patients with a low arousal threshold.

Stable Breathing in Patients With Obstructive Sleep Apnea Is Associated With Increased Effort but Not Lowered Metabolic Rate.

Study objectives: In principle, if metabolic rate were to fall during sleep in a patient with obstructive sleep apnea (OSA), ventilatory requirements could be met without increased respiratory effort thereby favoring stable breathing. Indeed, most patients achieve periods of stable flow-limited breathing without respiratory events for periods during the night for reasons that are unclear. Thus, we tested the hypothesis that in patients with OSA, periods of stable breathing occur when metabolic rate (VO2) declines. Methods: Twelve OSA patients (apnea-hypopnea index >15 events/h) completed overnight polysomnography including measurements of VO2 (using ventilation and intranasal PO2) and respiratory effort (esophageal pressure). Results: Contrary to our hypothesis, VO2 did not differ between stable and unstable breathing periods in non-REM stage 2 (208 ± 20 vs. 213 ± 18 mL/min), despite elevated respiratory effort during stable breathing (26 ± 2 versus 23 ± 2 cmH2O, p = .03). However, VO2 was lowered during deeper sleep (244 to 179 mL/min from non-REM stages 1 to 3, p = .04) in conjunction with more stable breathing. Further analysis revealed that airflow obstruction curtailed metabolism in both stable and unstable periods, since CPAP increased VO2 by 14% in both cases (p = .02, .03, respectively). Patients whose VO2 fell most during sleep avoided an increase in PCO2 and respiratory effort. Conclusions: OSA patients typically convert from unstable to stable breathing without lowering metabolic rate. During sleep, OSA patients labor with increased respiratory effort but fail to satisfy metabolic demand even in the absence of overt respiratory events.

Airflow Shape Is Associated With the Pharyngeal Structure Causing OSA.

BACKGROUND: OSA results from the collapse of different pharyngeal structures (soft palate, tongue, lateral walls, and epiglottis). The structure involved in collapse has been shown to impact non-CPAP OSA treatment. Different inspiratory airflow shapes are also observed among patients with OSA. We hypothesized that inspiratory flow shape reflects the underlying pharyngeal structure involved in airway collapse. METHODS: Subjects with OSA were studied with a pediatric endoscope and simultaneous nasal flow and pharyngeal pressure recordings during natural sleep. The mechanism causing collapse was classified as tongue-related, isolated palatal, lateral walls, or epiglottis. Flow shape was classified according to the degree of negative effort dependence (NED), defined as the percent reduction in inspiratory flow from peak to plateau. RESULTS: Thirty-one subjects with OSA (mean apnea-hypopnea index score ± SD, 54 ± 27 events/h) who were 50 ± 9 years of age were studied. NED was associated with the structure causing collapse (P < .001). Tongue-related obstruction (n = 13) was associated with a small amount of NED (median, 19; interquartile range [IQR], 14%-25%). Moderate NED was found among subjects with isolated palatal collapse (median, 45; IQR, 39%-52%; n = 8) and lateral wall collapse (median, 50; IQR, 44%-64%; n = 8). The epiglottis was associated with severe NED (median, 89; IQR, 78%-91%) and abrupt discontinuities in inspiratory flow (n = 9). CONCLUSIONS: Inspiratory flow shape is influenced by the pharyngeal structure causing collapse. Flow shape analysis may be used as a noninvasive tool to help determine the pharyngeal structure causing collapse.