Limiting Overdistention or Collapse When Mechanically Ventilating Injured Lungs: A Randomized Study in a Porcine Model.

Rationale: It is unknown whether preventing overdistention or collapse is more important when titrating positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS). Objectives: To compare PEEP targeting minimal overdistention or minimal collapse or using a compromise between collapse and overdistention in a randomized trial and to assess the impact on respiratory mechanics, gas exchange, inflammation, and hemodynamics. Methods: In a porcine model of ARDS, lung collapse and overdistention were estimated using electrical impedance tomography during a decremental PEEP titration. Pigs were randomized to three groups and ventilated for 12 hours: PEEP set at ⩽3% of overdistention (low overdistention), ⩽3% of collapse (low collapse), and the crossing point of collapse and overdistention. Measurements and Main Results: Thirty-six pigs (12 per group) were included. Median (interquartile range) values of PEEP were 7 (6-8), 11 (10-11), and 15 (12-16) cm H2O in the three groups (P < 0.001). With low overdistension, 6 (50%) pigs died, whereas survival was 100% in both other groups. Cause of death was hemodynamic in nature, with high transpulmonary vascular gradient and high epinephrine requirements. Compared with the other groups, pigs surviving with low overdistension had worse respiratory mechanics and gas exchange during the entire protocol. Minimal differences existed between crossing-point and low-collapse animals in physiological parameters, but postmortem alveolar density was more homogeneous in the crossing-point group. Inflammatory markers were not significantly different. Conclusions: PEEP to minimize overdistention resulted in high mortality in an animal model of ARDS. Minimizing collapse or choosing a compromise between collapse and overdistention may result in less lung injury, with potential benefits of the compromise approach.

Impact of Reverse Triggering Dyssynchrony during Lung-Protective Ventilation on Diaphragm Function: An Experimental Model.

Rationale: Reverse triggering dyssynchrony (RT) is a patient-ventilator interaction where a respiratory muscle contraction is triggered by a passive mechanical insufflation. Its impact on diaphragm structure and function is unknown. Objectives: To establish an animal model of RT with lung injury receiving lung-protective ventilation and to assess its impact on the structure and function of the diaphragm. Methods: Lung injury was induced by surfactant depletion and high-stress ventilation in 32 ventilated pigs. Animals were allocated to receive passive mechanical ventilation (Vt: 10 ml/kg; respiratory rate [RR]: 30-35 breaths/min; n = 8) or a more lung-protective strategy (Vt: 6-8 ml/kg; n = 24) with adjustments in RR to facilitate the occurrence of RT for 3 hours. Diaphragm function (transdiaphragmatic pressure [Pdi] during phrenic nerve stimulation [force/frequency curve]) and structure (biopsies) were assessed. The impact of RT on diaphragm function was analyzed according to the breathing effort assessed by the pressure-time product. Measurements and Main Results: Compared with passive ventilation, the protective ventilation group with RT received significantly lower Vt (7 vs. 10 ml/kg) and higher RR (45 vs. 31 breaths/min). An entrainment pattern of 1:1 was the most frequently occurring in 83% of the animals. Breathing effort induced by RT was highly variable across animals. RT with the lowest tercile of breathing effort was associated with 23% higher twitch Pdi compared with passive ventilation, whereas RT with high breathing effort was associated with a 10% lower twitch Pdi and a higher proportion of abnormal muscle fibers. Conclusions: In a reproducible animal model of RT with variable levels of breathing effort and entrainment patterns, RT with high effort is associated with impaired diaphragm function, whereas RT with low effort is associated with preserved diaphragm force.

Prone Position Minimizes the Exacerbation of Effort-dependent Lung Injury: Exploring the Mechanism in Pigs and Evaluating Injury in Rabbits.

BACKGROUND: Vigorous spontaneous effort can potentially worsen lung injury. This study hypothesized that the prone position would diminish a maldistribution of lung stress and inflation after diaphragmatic contraction and reduce spontaneous effort, resulting in less lung injury. METHODS: A severe acute respiratory distress syndrome model was established by depleting surfactant and injurious mechanical ventilation in 6 male pigs ("mechanism" protocol) and 12 male rabbits ("lung injury" protocol). In the mechanism protocol, regional inspiratory negative pleural pressure swing (intrabronchial balloon manometry) and the corresponding lung inflation (electrical impedance tomography) were measured with a combination of position (supine or prone) and positive end-expiratory pressure (high or low) matching the intensity of spontaneous effort. In the lung injury protocol, the intensities of spontaneous effort (esophageal manometry) and regional lung injury were compared in the supine position versus prone position. RESULTS: The mechanism protocol (pigs) found that in the prone position, there was no ventral-to-dorsal gradient in negative pleural pressure swing after diaphragmatic contraction, irrespective of the positive end-expiratory pressure level (-10.3 ± 3.3 cm H2O vs. -11.7 ± 2.4 cm H2O at low positive end-expiratory pressure, P = 0.115; -10.4 ± 3.4 cm H2O vs. -10.8 ± 2.3 cm H2O at high positive end-expiratory pressure, P = 0.715), achieving homogeneous inflation. In the supine position, however, spontaneous effort during low positive end-expiratory pressure had the largest ventral-to-dorsal gradient in negative pleural pressure swing (-9.8 ± 2.9 cm H2O vs. -18.1 ± 4.0 cm H2O, P < 0.001), causing dorsal overdistension. Higher positive end-expiratory pressure in the supine position reduced a ventral-to-dorsal gradient in negative pleural pressure swing, but it remained (-9.9 ± 2.8 cm H2O vs. -13.3 ± 2.3 cm H2O, P < 0.001). The lung injury protocol (rabbits) found that in the prone position, spontaneous effort was milder and lung injury was less without regional difference (lung myeloperoxidase activity in ventral vs. dorsal lung, 74.0 ± 30.9 µm · min-1 · mg-1 protein vs. 61.0 ± 23.0 µm · min-1 · mg-1 protein, P = 0.951). In the supine position, stronger spontaneous effort increased dorsal lung injury (lung myeloperoxidase activity in ventral vs. dorsal lung, 67.5 ± 38.1 µm · min-1 · mg-1 protein vs. 167.7 ± 65.5 µm · min-1 · mg-1 protein, P = 0.003). CONCLUSIONS: Prone position, independent of positive end-expiratory pressure levels, diminishes a maldistribution of lung stress and inflation imposed by spontaneous effort and mitigates spontaneous effort, resulting in less effort-dependent lung injury.

Repeated endo-tracheal tube disconnection generates pulmonary edema in a model of volume overload: an experimental study.

BACKGROUND: An abrupt lung deflation in rodents results in lung injury through vascular mechanisms. Ventilator disconnections during endo-tracheal suctioning in humans often cause cardio-respiratory instability. Whether repeated disconnections or lung deflations cause lung injury or oedema is not known and was tested here in a porcine large animal model. METHODS: Yorkshire pigs (~ 12 weeks) were studied in three series. First, we compared PEEP abruptly deflated from 26 cmH2O or from PEEP 5 cmH2O to zero. Second, pigs were randomly crossed over to receive rapid versus gradual PEEP removal from 20 cmH2O. Third, pigs with relative volume overload, were ventilated with PEEP 15 cmH2O and randomized to repeated ETT disconnections (15 s every 15 min) or no disconnection for 3 h. Hemodynamics, pulmonary variables were monitored, and lung histology and bronchoalveolar lavage studied. RESULTS: As compared to PEEP 5 cmH2O, abrupt deflation from PEEP 26 cmH2O increased PVR, lowered oxygenation, and increased lung wet-to-dry ratio. From PEEP 20 cmH2O, gradual versus abrupt deflation mitigated the changes in oxygenation and vascular resistance. From PEEP 15, repeated disconnections in presence of fluid loading led to reduced compliance, lower oxygenation, higher pulmonary artery pressure, higher lung wet-to-dry ratio, higher lung injury score and increased oedema on morphometry, compared to no disconnects. CONCLUSION: Single abrupt deflation from high PEEP, and repeated short deflations from moderate PEEP cause pulmonary oedema, impaired oxygenation, and increased PVR, in this large animal model, thus replicating our previous finding from rodents. Rapid deflation may thus be a clinically relevant cause of impaired lung function, which may be attenuated by gradual pressure release.

Positive End-Expiratory Pressure, Pleural Pressure, and Regional Compliance during Pronation: An Experimental Study.

Rationale: The physiological basis of lung protection and the impact of positive end-expiratory pressure (PEEP) during pronation in acute respiratory distress syndrome are not fully elucidated. Objectives: To compare pleural pressure (Ppl) gradient, ventilation distribution, and regional compliance between dependent and nondependent lungs, and investigate the effect of PEEP during supination and pronation. Methods: We used a two-hit model of lung injury (saline lavage and high-volume ventilation) in 14 mechanically ventilated pigs and studied supine and prone positions. Global and regional lung mechanics including Ppl and distribution of ventilation (electrical impedance tomography) were analyzed across PEEP steps from 20 to 3 cm H2O. Two pigs underwent computed tomography scans: tidal recruitment and hyperinflation were calculated. Measurements and Main Results: Pronation improved oxygenation, increased Ppl, thus decreasing transpulmonary pressure for any PEEP, and reduced the dorsal-ventral pleural pressure gradient at PEEP < 10 cm H2O. The distribution of ventilation was homogenized between dependent and nondependent while prone and was less dependent on the PEEP level than while supine. The highest regional compliance was achieved at different PEEP levels in dependent and nondependent regions in supine position (15 and 8 cm H2O), but for similar values in prone position (13 and 12 cm H2O). Tidal recruitment was more evenly distributed (dependent and nondependent), hyperinflation lower, and lungs cephalocaudally longer in the prone position. Conclusions: In this lung injury model, pronation reduces the vertical pleural pressure gradient and homogenizes regional ventilation and compliance between the dependent and nondependent regions. Homogenization is much less dependent on the PEEP level in prone than in supine positon.

Role of Positive End-Expiratory Pressure and Regional Transpulmonary Pressure in Asymmetrical Lung Injury.

Rationale: Asymmetrical lung injury is a frequent clinical presentation. Regional distribution of Vt and positive end-expiratory pressure (PEEP) could result in hyperinflation of the less-injured lung. The validity of esophageal pressure (Pes) is unknown.Objectives: To compare, in asymmetrical lung injury, Pes with directly measured pleural pressures (Ppl) of both sides and investigate how PEEP impacts ventilation distribution and the regional driving transpulmonary pressure (inspiratory - expiratory).Methods: Fourteen mechanically ventilated pigs with lung injury were studied. One lung was blocked while the contralateral one underwent surfactant lavage and injurious ventilation. Airway pressure and Pes were measured, as was Ppl in the dorsal and ventral pleural space adjacent to each lung. Distribution of ventilation was assessed by electrical impedance tomography. PEEP was studied through decremental steps.Measurements and Results: Ventral and dorsal Ppl were similar between the injured and the noninjured lung across all PEEP levels. Dorsal Ppl and Pes were similar. The driving transpulmonary pressure was similar in the two lungs. Vt distribution between lungs was different at zero end-expiratory pressure (≈70% of Vt going in noninjured lung) owing to different respiratory system compliance (8.3 ml/cm H2O noninjured lung vs. 3.7 ml/cm H2O injured lung). PEEP at 10 cm H2O with transpulmonary pressure around zero homogenized Vt distribution opening the lungs. PEEP ≥16 cm H2O equalized distribution of Vt but with overdistension for both lungs.Conclusions: Despite asymmetrical lung injury, Ppl between injured and noninjured lungs is equalized and esophageal pressure is a reliable estimate of dorsal Ppl. Driving transpulmonary pressure is similar for both lungs. Vt distribution results from regional respiratory system compliance. Moderate PEEP homogenizes Vt distribution between lungs without generating hyperinflation.

Abrupt Deflation after Sustained Inflation Causes Lung Injury.

RATIONALE: Ventilator management in acute respiratory distress syndrome usually focuses on setting parameters, but events occurring at ventilator disconnection are not well understood. OBJECTIVES: To determine if abrupt deflation after sustained inflation causes lung injury. METHODS: Male Sprague-Dawley rats were ventilated (low Vt, 6 ml/kg) and randomized to control (n = 6; positive end-expiratory pressure [PEEP], 3 cm H2O; 100 min) or intervention (n = 6; PEEP, 3-11 cm H2O over 70 min; abrupt deflation to zero PEEP; ventilation for 30 min). Lung function and injury was assessed, scanning electron microscopy performed, and microvascular leak timed by Evans blue dye (n = 4/group at 0, 2, 5, 10, and 20 min after deflation). Hemodynamic assessment included systemic arterial pressure (n = 6), echocardiography (n = 4), and right (n = 6) and left ventricular pressures (n = 6). MEASUREMENTS AND MAIN RESULTS: Abrupt deflation after sustained inflation (vs. control) caused acute lung dysfunction (compliance 0.48 ± 1.0 vs. 0.82 ± 0.2 m/cm H2O, oxygen saturation as measured by pulse oximetry 67 ± 23.5 vs. 91 ± 4.4%; P < 0.05) and injury (wet/dry ratio 6.1 ± 0.6 vs. 4.6 ± 0.4; P < 0.01). Vascular leak was absent before deflation and maximal 5-10 minutes thereafter; injury was predominantly endothelial. At deflation, left ventricular preload, systemic blood pressure, and left ventricular end-diastolic pressure increased precipitously in proportion to the degree of injury. Injury caused later right ventricular failure. Sodium nitroprusside prevented the increase in systemic blood pressure and left ventricular end-diastolic pressure associated with deflation, and prevented injury. Injury did not occur with gradual deflation. CONCLUSIONS: Abrupt deflation after sustained inflation can cause acute lung injury. It seems to be mediated by acute left ventricular decompensation (caused by increased left ventricular preload and afterload) that elevates pulmonary microvascular pressure; this directly injures the endothelium and causes edema, which is potentiated by the surge in pulmonary perfusion.

Adverse Heart-Lung Interactions in Ventilator-induced Lung Injury.

RATIONALE: In the original 1974 in vivo study of ventilator-induced lung injury, Webb and Tierney reported that high Vt with zero positive end-expiratory pressure caused overwhelming lung injury, subsequently shown by others to be due to lung shear stress. OBJECTIVES: To reproduce the lung injury and edema examined in the Webb and Tierney study and to investigate the underlying mechanism thereof. METHODS: Sprague-Dawley rats weighing approximately 400 g received mechanical ventilation for 60 minutes according to the protocol of Webb and Tierney (airway pressures of 14/0, 30/0, 45/10, 45/0 cm H2O). Additional series of experiments (20 min in duration to ensure all animals survived) were studied to assess permeability (n = 4 per group), echocardiography (n = 4 per group), and right and left ventricular pressure (n = 5 and n = 4 per group, respectively). MEASUREMENTS AND MAIN RESULTS: The original Webb and Tierney results were replicated in terms of lung/body weight ratio (45/0 > 45/10 ≈ 30/0 ≈ 14/0; P < 0.05) and histology. In 45/0, pulmonary edema was overt and rapid, with survival less than 30 minutes. In 45/0 (but not 45/10), there was an increase in microvascular permeability, cyclical abolition of preload, and progressive dilation of the right ventricle. Although left ventricular end-diastolic pressure decreased in 45/10, it increased in 45/0. CONCLUSIONS: In a classic model of ventilator-induced lung injury, high peak pressure (and zero positive end-expiratory pressure) causes respiratory swings (obliteration during inspiration) in right ventricular filling and pulmonary perfusion, ultimately resulting in right ventricular failure and dilation. Pulmonary edema was due to increased permeability, which was augmented by a modest (approximately 40%) increase in hydrostatic pressure. The lung injury and acute cor pulmonale is likely due to pulmonary microvascular injury, the mechanism of which is uncertain, but which may be due to cyclic interruption and exaggeration of pulmonary blood flow.

Role of cardiopulmonary interactions in development of ventilator-induced lung injury-Experimental evidence and clinical Implications.

Ventilator-induced lung injury (VILI) impacts outcomes in ARDS and optimization of ventilatory strategies improves survival. Decades of research has identified various mechanisms of VILI, largely focusing on airspace forces of plateau pressure, tidal volume and driving pressure. Experimental evidence indicates the role of adverse cardiopulmonary interaction during mechanical ventilation, contributing to VILI genesis mostly by modulating pulmonary vascular dynamics. Under passive mechanical ventilation, high transpulmonary pressure increases afterload on right heart while high pleural pressure reduces the RV preload. Together, they can result in swings of pulmonary vascular flow and pressure. Altered vascular flow and pressure result in increased vascular shearing and wall tension, in turn causing direct microvascular injury accompanied with permeability to water, proteins and cells. Moreover, abrupt decreases in airway pressure, may result in sudden overperfusion of the lung and result in similar microvascular injury, especially when the endothelium is stretched or primed at high positive end-expiratory pressure. Microvascular injury is universal in VILI models and presumed in the diagnosis of ARDS; preventing such microvascular injury can reduce VILI and impact outcomes in ARDS. Consequently, developing cardiovascular targets to reduce macro and microvascular stressors in the pulmonary circulation can potentially reduce VILI. This paper reviews the role of cardiopulmonary interaction in VILI genesis.

Mechanical Ventilation in ARDS With an Automatic Resuscitator.

BACKGROUND: The Oxylator is an automatic resuscitator, powered only by an oxygen cylinder with no electricity required, that could be used in acute respiratory failure in situations in which standard mechanical ventilation is not available or feasible. We aimed to assess the feasibility and safety of mechanical ventilation by using this automatic resuscitator in an animal model of ARDS. METHODS: A randomized experimental study in a porcine ARDS model with 12 pigs randomized to the Oxylator group or the control group (6 per group) and ventilated for 4 h. In the Oxylator group, peak pressure was set at 20 cm H2O and PEEP was set at the lowest observed breathing frequency during a decremental PEEP titration. The control pigs were ventilated with a conventional ventilator by using protective settings and PEEP at the crossing point of collapse and overdistention, as indicated by electrical impedance tomography. Our end points were feasibility and safety as well as respiratory mechanics, gas exchange, and hemodynamics. RESULTS: After lung injury, the mean ± SD respiratory system compliance and PaO2 /FIO2 were 13 ± 2 mL/cm H2O and 61 ± 17 mm Hg, respectively. The mean ± SD total PEEP was 10 ± 2 cm H2O and 13 ± 2 cm H2O in the control and Oxylator groups, respectively (P = .046). The mean plateau pressure was kept to < 30 cm H2O in both groups. In the Oxylator group, the tidal volume was transiently > 8 mL/kg but was 6 ± 0.4 mL/kg at 4 h, whereas the breathing frequency increased from 38 ± 4 to 48 ± 3 breaths/min (P < .001). There was no difference in driving pressure, compliance, PaO2 /FIO2 , and pulmonary shunt between the groups. The mean ± SD PaCO2 was higher in the Oxylator group after 4 h, 74 ± 9 mm Hg versus 58 ± 6 mm Hg (P < .001). There were no differences in hemodynamics between the groups, including blood pressure and cardiac output. CONCLUSIONS: Short-term mechanical ventilation by using an automatic resuscitator and a fixed pressure setting in an ARDS animal model was feasible and safe.

Understanding clinical and biological heterogeneity to advance precision medicine in paediatric acute respiratory distress syndrome.

Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous clinical syndrome that is associated with high rates of mortality and long-term morbidity. Factors that distinguish PARDS from adult acute respiratory distress syndrome (ARDS) include changes in developmental stage and lung maturation with age, precipitating factors, and comorbidities. No specific treatment is available for PARDS and management is largely supportive, but methods to identify patients who would benefit from specific ventilation strategies or ancillary treatments, such as prone positioning, are needed. Understanding of the clinical and biological heterogeneity of PARDS, and of differences in clinical features and clinical course, pathobiology, response to treatment, and outcomes between PARDS and adult ARDS, will be key to the development of novel preventive and therapeutic strategies and a precision medicine approach to care. Studies in which clinical, biomarker, and transcriptomic data, as well as informatics, are used to unpack the biological and phenotypic heterogeneity of PARDS, and implementation of methods to better identify patients with PARDS, including methods to rapidly identify subphenotypes and endotypes at the point of care, will drive progress on the path to precision medicine.

A Gas-Powered, Patient-Responsive Automatic Resuscitator for Use in Acute Respiratory Failure: A Bench and Experimental Study.

BACKGROUND: During the COVID-19 pandemic, a need for innovative, inexpensive, and simple ventilator devices for mass use has emerged. The Oxylator (CPR Medical Devices, Markham, Ontario, Canada) is an FDA-approved, fist-size, portable ventilation device developed for out-of-hospital emergency ventilation. It has not been tested in conditions of severe lung injury or with added PEEP. We aimed to assess the performance and reliability of the device in simulated and experimental conditions of severe lung injury, and to derive monitoring methods to allow the delivery of safe, individualized ventilation during situations of surge. METHODS: We bench-tested the functioning of the device with an added PEEP valve extensively, mimicking adult patients with various respiratory mechanics during controlled ventilation, spontaneous breathing, and prolonged unstable conditions where mechanics or breathing effort was changed at every breath. The device was further tested on a porcine model (4 animals) after inducing lung injury, and these results were compared with conventional ventilation modes. RESULTS: The device was stable and predictable, delivering a constant flow (30 L/min) and cycling automatically at the inspiratory pressure set (minimum of 20 cm H2O) above auto-PEEP. Changes in respiratory mechanics manifested as changes in respiratory timing, allowing prediction of tidal volumes from breathing frequency. Simulating lung injury resulted in relatively low tidal volumes (330 mL with compliance of 20 mL/cm H2O). In the porcine model, arterial oxygenation, CO2, and pH were comparable to conventional modes of ventilation. CONCLUSIONS: The Oxylator is a simple device that delivered stable ventilation with tidal volumes within a clinically acceptable range in bench and porcine lung models with low compliance. External monitoring of respiratory timing is advisable, allowing tidal volume estimation and recognition of changes in respiratory mechanics. The device can be an efficient, low-cost, and practical rescue solution for providing short-term ventilatory support as a temporary bridge, but it requires a caregiver at the bedside.

Ventilator-Induced Lung Injury: Classic and Novel Concepts.

Ventilator-induced lung injury (VILI) is a central confounder to improving outcomes from use of positive-pressure ventilation in critical illness. Therefore, with increasing use of positive-pressure ventilation, awareness to prevent VILI has grown. Because VILI cannot be diagnosed at the bedside, its prevention can only be attained by identifying the clinical mechanisms of harm, such as high tidal volume, high plateau pressure, and so forth, which, in turn, are derived from decades of laboratory work. The practice of positive-pressure ventilation has undergone a significant change; most important in the past decade is the preference to use noninvasive ventilation. Although noninvasive ventilation prevents the complications of intubation, it has potential to cause harm, especially in patients with de novo respiratory failure. This review covers some of the classic and emerging concepts of VILI genesis and their role during noninvasive ventilation. Combined modulation of these mechanisms could have a potential to impact outcomes.