• ARDS
• airway pressure release ventilation
• electrical impedance tomography
• low tidal volume ventilation
• ventilation/perfusion matching

• Humans
• Male
• Female
• Respiratory Distress Syndrome/therapy
• Respiratory Distress Syndrome/physiopathology
• Tidal Volume/physiology
• Middle Aged
• Continuous Positive Airway Pressure/methods
• Aged
• Respiration, Artificial/methods
• Electric Impedance
• Tomography/methods

• Mathematical model
• Over-distension
• Porcine lavage model
• Respiratory system impedance
• Ventilator-induced lung injury

• Animals
• Swine
• Oscillometry/methods
• Exhalation/physiology
• Pulmonary Atelectasis/prevention & control
• Pulmonary Atelectasis/physiopathology
• Pulmonary Atelectasis/etiology
• Respiratory Distress Syndrome/physiopathology
• Respiratory Distress Syndrome/therapy
• Respiratory Mechanics/physiology
• Continuous Positive Airway Pressure/methods
• Respiration, Artificial/methods
• Respiration, Artificial/adverse effects
• Disease Models, Animal

• R01 HL142702 NHLBI NIH HHS
• HL142702 NHLBI NIH HHS
• W81XWH-20-1-0696 U.S. Department of Defense
• National Heart, Lung, and Blood Institute

• Acute respiratory syndrome distress
• Airway pressure release ventilation
• Low tidal volume
• Mechanical ventilation
• Randomized controlled trial

• Humans
• China
• Continuous Positive Airway Pressure/methods
• Intensive Care Units
• Multicenter Studies as Topic
• Prospective Studies
• Randomized Controlled Trials as Topic
• Respiration, Artificial/methods
• Respiratory Distress Syndrome/therapy
• Respiratory Distress Syndrome/physiopathology
• Tidal Volume

• Humans
• Continuous Positive Airway Pressure/methods
• Lung
• Respiratory Distress Syndrome
• Respiration, Artificial/adverse effects
• Respiration
• Ventilator-Induced Lung Injury/prevention & control

• APRV
• ARDS
• Mechanical ventilation
• Nursing
• Saudi Arabia

• APRV
• ARDS
• ARMA
• Acute respiratory distress syndrome
• Alveolar opening and collapse time constants
• Driving pressure
• Dynamic alveolar mechanics
• Open lung approach
• Regional alveolar instability
• Stress-multipliers
• TCAV
• Tidal volume
• VILI
• Ventilator-induced lung injury
• Viscoelastic

• Humans
• Respiration, Artificial/methods
• Lung/pathology
• Pulmonary Alveoli/pathology
• Respiratory Distress Syndrome/diagnosis
• Respiratory Distress Syndrome/therapy
• Respiratory Distress Syndrome/pathology
• Continuous Positive Airway Pressure/methods
• Tidal Volume
• Ventilator-Induced Lung Injury/prevention & control
• Ventilator-Induced Lung Injury/pathology

• K08 HL168205 NHLBI NIH HHS
• R01 HL142702 NHLBI NIH HHS
• R01HL142702 NHLBI NIH HHS
• National Heart, Lung, and Blood Institute
• U.S. Department of Defense

• APRV
• ARDS
• OLA
• SLA
• TCAV
• VILI
• acute respiratory distress syndrome
• airway pressure release ventilation
• open lung approach
• protective mechanical ventilation
• stabilize lung approach
• time-controlled adaptive ventilation
• ventilator-induced lung injury

• R01 HL142702 NHLBI NIH HHS

• Acute respiratory distress syndrome
• Airway pressure release ventilation
• Electrical impedance tomography
• Heterogeneity
• Ventilation/perfusion matching
• Ventilator-induced lung injury

• EVLP
• Marginal lung allografts
• Ventilation strategy

• acute respiratory distress syndrome (ARDS)
• heterogeneous lung injury
• overdistention
• recruitment/derecruitment
• ventilator-induced lung injury (VILI)

• Animals
• Acute Lung Injury/etiology
• Lung
• Respiration, Artificial/adverse effects
• Respiratory Distress Syndrome/therapy
• Swine
• Tidal Volume
• Ventilator-Induced Lung Injury/etiology

• R01 HL136706 NHLBI NIH HHS
• R01 HL142702 NHLBI NIH HHS

• Congressionally Directed Medical Research Programs
• National Heart, Lung, and Blood Institute

A hallmark of ARDS is progressive shrinking of the ‘baby lung,’ now referred to as the ventilator-induced lung injury (VILI) ‘vortex.’ Reducing the risk of the VILI vortex is the goal of current ventilation strategies; unfortunately, this goal has not been achieved nor has mortality been reduced. However, the temporal aspects of a mechanical breath have not been considered. A brief expiration prevents alveolar collapse, and an extended inspiration can recruit the atelectatic lung over hours. Time-controlled adaptive ventilation (TCAV) is a novel ventilator approach to achieve these goals, since it considers many of the temporal aspects of dynamic lung mechanics.

• Acute respiratory distress syndrome (ARDS)
• Protective mechanical ventilation
• Ventilator-induced lung injury (VILI)

• APRV
• TCAV
• airway pressure release ventilation (APRV)
• myth
• time controlled adaptive ventilation

• Acute respiratory distress syndrome
• Airway pressure release ventilation
• Organ protection
• Outcome
• Ventilator-induced lung injury

Pediatric acute respiratory distress syndrome (PARDS) remains a significant cause of morbidity and mortality, with mortality rates as high as 50% in children with severe PARDS. Despite this, pediatric lung injury and mechanical ventilation has been poorly studied, with the majority of investigations being observational or retrospective and with only a few randomized controlled trials to guide intensivists. The most recent and universally accepted guidelines for pediatric lung injury are based on consensus opinion rather than objective data. Therefore, most neonatal and pediatric mechanical ventilation practices have been arbitrarily adapted from adult protocols, neglecting the differences in lung pathophysiology, response to injury, and co-morbidities among the three groups. Low tidal volume ventilation has been generally accepted for pediatric patients, even in the absence of supporting evidence. No target tidal volume range has consistently been associated with outcomes, and compliance with delivering specific tidal volume ranges has been poor. Similarly, optimal PEEP has not been well-studied, with a general acceptance of higher levels of F_iO₂ and less aggressive PEEP titration as compared with adults. Other modes of ventilation including airway pressure release ventilation and high frequency ventilation have not been studied in a systematic fashion and there is too little evidence to recommend supporting or refraining from their use. There have been no consistent outcomes among studies in determining optimal modes or methods of setting them. In this review, the studies performed to date on mechanical ventilation strategies in neonatal and pediatric populations will be analyzed. There may not be a single optimal mechanical ventilation approach, where the best method may simply be one that allows for a personalized approach with settings adapted to the individual patient and disease pathophysiology. The challenges and barriers to conducting well-powered and robust multi-institutional studies will also be addressed, as well as reconsidering outcome measures and study design.

• National Heart, Lung, and Blood Institute

• alveolar heterogeneity
• emphysema
• hyperinflation
• right ventricle function
• time-controlled adjusted ventilation

• ARDS
• P-SILI
• SARS-CoV-2
• alveolar pressure
• computational model
• edema

• R01 HL136141 NHLBI NIH HHS

• High-frequency ventilation
• airway-pressure release ventilation
• mechanical ventilation
• neurally adjusted ventilatory assist (NAVA)
• pediatric

• acute respiratory distress syndrome
• computational model
• lung elastance
• mechanical ventilation
• recruitment and derecruitment
• ventilator-induced lung injury
• volutrauma

• R01 HL142702 NHLBI NIH HHS

• acute respiratory distress syndrome
• biofluid mechanics
• fluid–structure interactions
• high-performance computing
• multi-scale modeling
• surfactant

• R01 HL142702 NHLBI NIH HHS

• K23 HL130641 NHLBI NIH HHS
• R01 HL144599 NHLBI NIH HHS
• R21 AI137669 NIAID NIH HHS
• T32 HL007749 NHLBI NIH HHS

• alveolar heterogeneity
• alveolar stability
• in vivo microscopy
• lung injury
• micromechanics

Acute respiratory distress syndrome (ARDS) causes a heterogeneous lung injury and remains a serious medical problem, with one of the only treatments being supportive care in the form of mechanical ventilation. It is very difficult, however, to mechanically ventilate the heterogeneously damaged lung without causing secondary ventilator-induced lung injury (VILI). The acutely injured lung becomes time and pressure dependent, meaning that it takes more time and pressure to open the lung, and it recollapses more quickly and at higher pressure. Current protective ventilation strategies, ARDSnet low tidal volume (LVt) and the open lung approach (OLA), have been unsuccessful at further reducing ARDS mortality. We postulate that this is because the LVt strategy is constrained to ventilating a lung with a heterogeneous mix of normal and focalized injured tissue, and the OLA, although designed to fully open and stabilize the lung, is often unsuccessful at doing so. In this review we analyzed the pathophysiology of ARDS that renders the lung susceptible to VILI. We also analyzed the alterations in alveolar and alveolar duct mechanics that occur in the acutely injured lung and discussed how these alterations are a key mechanism driving VILI. Our analysis suggests that the time component of each mechanical breath, at both inspiration and expiration, is critical to normalize alveolar mechanics and protect the lung from VILI. Animal studies and a meta-analysis have suggested that the time-controlled adaptive ventilation (TCAV) method, using the airway pressure release ventilation mode, eliminates the constraints of ventilating a lung with heterogeneous injury, since it is highly effective at opening and stabilizing the time- and pressure-dependent lung. In animal studies it has been shown that by “casting open” the acutely injured lung with TCAV we can (1) reestablish normal expiratory lung volume as assessed by direct observation of subpleural alveoli; (2) return normal parenchymal microanatomical structural support, known as alveolar interdependence and parenchymal tethering, as assessed by morphometric analysis of lung histology; (3) facilitate regeneration of normal surfactant function measured as increases in surfactant proteins A and B; and (4) significantly increase lung compliance, which reduces the pathologic impact of driving pressure and mechanical power at any given tidal volume.

• APRV
• ARDS
• VILI (ventilator induced lung injury)
• alveolar mechanics
• mechanical ventilalion

Mortality in acute respiratory distress syndrome (ARDS) remains unacceptably high at approximately 39%. One of the only treatments is supportive: mechanical ventilation. However, improperly set mechanical ventilation can further increase the risk of death in patients with ARDS. Recent studies suggest that ventilation-induced lung injury (VILI) is caused by exaggerated regional lung strain, particularly in areas of alveolar instability subject to tidal recruitment/derecruitment and stress-multiplication. Thus, it is reasonable to expect that if a ventilation strategy can maintain stable lung inflation and homogeneity, regional dynamic strain would be reduced and VILI attenuated. A time-controlled adaptive ventilation (TCAV) method was developed to minimize dynamic alveolar strain by adjusting the delivered breath according to the mechanical characteristics of the lung. The goal of this review is to describe how the TCAV method impacts pathophysiology and protects lungs with, or at high risk of, acute lung injury. We present work from our group and others that identifies novel mechanisms of VILI in the alveolar microenvironment and demonstrates that the TCAV method can reduce VILI in translational animal ARDS models and mortality in surgical/trauma patients. Our TCAV method utilizes the airway pressure release ventilation (APRV) mode and is based on opening and collapsing time constants, which reflect the viscoelastic properties of the terminal airspaces. Time-controlled adaptive ventilation uses inspiratory and expiratory time to (1) gradually “nudge” alveoli and alveolar ducts open with an extended inspiratory duration and (2) prevent alveolar collapse using a brief (sub-second) expiratory duration that does not allow time for alveolar collapse. The new paradigm in TCAV is configuring each breath guided by the previous one, which achieves real-time titration of ventilator settings and minimizes instability induced tissue damage. This novel methodology changes the current approach to mechanical ventilation, from arbitrary to personalized and adaptive. The outcome of this approach is an open and stable lung with reduced regional strain and greater lung protection.

• Acute lung injury
• acute respiratory distress syndrome
• airway pressure release ventilation

Supplemental Digital Content is available in the text.

Low tidal volume (= tidal volume ≤ 6 mL/kg, predicted body weight) ventilation using volume control benefits patients with acute respiratory distress syndrome. Airway pressure release ventilation is an alternative to low tidal volume-volume control ventilation, but the release breaths generated are variable and can exceed tidal volume breaths of low tidal volume-volume control. We evaluate the application of a low tidal volume-compatible airway pressure release ventilation protocol that manages release volumes on both clinical and feasibility endpoints.

We designed a prospective randomized trial in patients with acute hypoxemic respiratory failure. We randomized patients to low tidal volume-volume control, low tidal volume-airway pressure release ventilation, and traditional airway pressure release ventilation with a planned enrollment of 246 patients. The study was stopped early because of low enrollment and inability to consistently achieve tidal volumes less than 6.5 mL/kg in the low tidal volume-airway pressure release ventilation arm. Although the primary clinical study endpoint was Pao₂/Fio₂ on study day 3, we highlight the feasibility outcomes related to tidal volumes in both arms.

Four Intermountain Healthcare tertiary ICUs.

Adult ICU patients with hypoxemic respiratory failure anticipated to require prolonged mechanical ventilation.

Low tidal volume-volume control, airway pressure release ventilation, and low tidal volume-airway pressure release ventilation.

We observed wide variability and higher tidal (release for airway pressure release ventilation) volumes in both airway pressure release ventilation (8.6 mL/kg; 95% CI, 7.8–9.6) and low tidal volume-airway pressure release ventilation (8.0; 95% CI, 7.3–8.9) than volume control (6.8; 95% CI, 6.2–7.5; p = 0.005) with no difference between airway pressure release ventilation and low tidal volume-airway pressure release ventilation (p = 0.58). Recognizing the limitations of small sample size, we observed no difference in 52 patients in day 3 Pao₂/ Fio₂ (p = 0.92). We also observed no significant difference between arms in sedation, vasoactive medications, or occurrence of pneumothorax.

Airway pressure release ventilation resulted in release volumes often exceeding 12 mL/kg despite a protocol designed to target low tidal volume ventilation. Current airway pressure release ventilation protocols are unable to achieve consistent and reproducible delivery of low tidal volume ventilation goals. A large-scale efficacy trial of low tidal volume-airway pressure release ventilation is not feasible at this time in the absence of an explicit, generalizable, and reproducible low tidal volume-airway pressure release ventilation protocol.

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in intensive care units. Distal airway mucus clearance has been shown to reduce VAP incidence. Studies suggest that mucus clearance is enhanced when the rate of expiratory flow is greater than inspiratory flow. The time-controlled adaptive ventilation (TCAV) protocol using the airway pressure release ventilation (APRV) mode has a significantly increased expiratory relative to inspiratory flow rate, as compared with the Acute Respiratory Distress Syndrome Network (ARDSnet) protocol using the conventional ventilation mode of volume assist control (VAC). We hypothesized the TCAV protocol would be superior to the ARDSnet protocol at clearing mucus by a mechanism of net flow in the expiratory direction.

Preserved pig lungs fitted with an endotracheal tube (ETT) were used as a model to study the effect of multiple combinations of peak inspiratory (I_PF) and peak expiratory flow rate (E_PF) on simulated mucus movement within the ETT. Mechanical ventilation was randomized into 6 groups (n = 10 runs/group): group 1—TCAV protocol settings with an end-expiratory pressure (P_Low) of 0 cmH₂O and P_High 25 cmH₂O, group 2—modified TCAV protocol with increased P_Low 5 cmH₂O and P_High 25 cmH₂O, group 3—modified TCAV with P_Low 10 cmH₂O and P_High 25 cmH₂O, group 4—ARDSnet protocol using low tidal volume (LTV) and PEEP 0 cmH₂O, group 5—ARDSnet protocol using LTV and PEEP 10 cmH₂O, and group 6—ARDSnet protocol using LTV and PEEP 20 cmH₂O. PEEP of ARDSnet is analogous to P_Low of TCAV. Proximal (towards the ventilator) mucus movement distance was recorded after 1 min of ventilation in each group.

The TCAV protocol groups 1, 2, and 3 generated significantly greater peak expiratory flow (E_PF 51.3 L/min, 46.8 L/min, 36.8 L/min, respectively) as compared to the ARDSnet protocol groups 4, 5, and 6 (32.9 L/min, 23.5 L/min, and 23.2 L/min, respectively) (p < 0.001). The TCAV groups also demonstrated the greatest proximal mucus movement (7.95 cm/min, 5.8 cm/min, 1.9 cm/min) (p < 0.01). All ARDSnet protocol groups (4–6) had zero proximal mucus movement (0 cm/min).

The TCAV protocol groups promoted the greatest proximal movement of simulated mucus as compared to the ARDSnet protocol groups in this excised lung model. The TCAV protocol settings resulted in the highest E_PF and the greatest proximal movement of mucus. Increasing P_Low reduced proximal mucus movement. We speculate that proximal mucus movement is driven by E_PF when E_PF is greater than I_PF, creating a net force in the proximal direction.

• ARDSnet ventilation
• Airway pressure release ventilation (APRV) mode
• Expiratory flow rate
• Mucus
• Mucus removal
• Time-controlled adaptive ventilation (TCAV)
• Ventilator-associated pneumonia (VAP)
• Volume assist control (VAC) mode

• Over-distension
• acute respiratory distress syndrome (ARDS)
• computational model
• recruitment and derecruitment
• surfactant function

• R00 HL128944 NHLBI NIH HHS
• R01 HL124052 NHLBI NIH HHS

• Acute lung injury
• Injurious mechanical ventilation
• TCAV protocol

• Acute respiratory distress syndrome
• Alveolar epithelial injury
• Lung function measurement
• Mechanical ventilation
• Scanning electron microscopy

• Ventilator-induced lung injury
• acute respiratory distress syndrome
• atelectrauma
• protective mechanical ventilation
• volutrauma

Application of continuous positive airway pressure (CPAP) helps to recruit collapsed areas of the lung, which improves the oxygen reserve.

To compare the time to desaturate to 90% during apnea following preoxygenation and apneic ventilation with tidal volume breathing for 3 min with and without the application of CPAP.

This prospective randomized study was conducted in a tertiary care institution.

Twenty adult surgical patients were allocated into two groups. Group C patients were preoxygenated with 100% oxygen with CPAP of 20 cm H₂O for 3 min. Group P patients were preoxygenated for 3 min without CPAP. In Group C, apneic oxygenation was initiated following induction and neuromuscular blockade with CPAP of 20 cm H₂O. In Group P, no CPAP was applied. The study was terminated when the patient desaturated to 90%.

Chi-square test and Mann–Whitney test.

Group C had a significantly longer apnea time as compared to Group P (816.00 ± 30.98 vs. 348.00 ± 122.64 s). Three patients in Group P desaturated to <90% by 3 min and the remaining soon after 6 min. No patient in Group C desaturated till 12 min of apnea. PaO₂ was significantly higher in Group C at 3 and 6 min of apnea. At 3 and 6 min, Group P had significantly lower saturation as compared to Group C.

Preoxygenation with CPAP significantly delayed desaturation during apnea with significantly higher arterial partial pressure of oxygen as compared to preoxygenation without CPAP.

• Apneic ventilation
• PaO2
• continuous positive airway pressure
• oxygenation
• tidal volume breathing

• ARDS
• Open lung ventilation
• PEEP
• Personalizing mechanical ventilation
• VILI

• R01 HL131143 NHLBI NIH HHS
• National Heart, Lung, and Blood Institute

• Acute respiratory distress syndrome
• Extracorporeal membrane oxygenation
• High-frequency oscillatory ventilation
• Lung protective ventilation
• Neuromuscular blockade
• Physical conditioning
• Prone positioning
• Pulmonary vasodilators

• acute lung injury
• acute respiratory distress syndrome
• mechanical ventilation
• positive end-expiratory pressure
• ventilator-induced lung injury

• Humans
• Pulmonary Alveoli/physiology
• Pulmonary Ventilation/physiology
• Respiration, Artificial/adverse effects
• Respiration, Artificial/methods
• Respiratory Distress Syndrome/etiology
• Respiratory Distress Syndrome/physiopathology
• Respiratory Distress Syndrome/prevention & control
• Ventilator-Induced Lung Injury/etiology
• Ventilator-Induced Lung Injury/physiopathology
• Ventilator-Induced Lung Injury/prevention & control

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

• CD39
• CD73
• Diffuse alveolar damage
• Extracellular ATP
• Purinergic signalling
• Ventilation-induced lung injury

• Acute lung injury
• Acute respiratory distress syndrome (ARDS)
• Alveolar collapse and reexpansion
• Alveolar over-distension
• Atelectasis
• Dynamic strain
• Heterogeneous lung
• Heterogeneous lung inflation
• Over-distension
• Static strain
• Strain
• Stress
• Ventilator-induced lung injury (VILI)

• Airway pressure release ventilation
• Respiratory distress syndrome
• Ventilator-induced injury