- Open Access
Unshrinking the baby lung to calm the VILI vortex
Critical Care volume 26, Article number: 242 (2022)
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.
The acute respiratory distress syndrome (ARDS) remains a significant clinical problem with primary management being supportive use of mechanical ventilation (MV) . However, inappropriate use of MV may result in ventilator-induced lung injury (VILI), which significantly increases ARDS mortality . The use of MV for ARDS patients must balance its life-preserving attributes against its potential for harm. Strategies for optimizing this balance may vary substantially across patients, and even within the same patient over a given clinical course.
The shrinking baby lung
The ARDS lung has been conceptualized as being composed of two distinct, gravitationally separated compartments: (1) dependent regions consisting atelectatic and/or edematous airspaces and (2) normally inflated tissue in less dependent regions comprising the so-called baby lung . This conceptualization led to the hypothesis that ventilating patients with ARDS using a reduced tidal volume (VT) would protect the baby lung from volutrauma caused by overdistension, while simultaneously allowing the atelectatic compartment to rest and [ideally] recover . It was also assumed that an appropriate level of positive end-expiratory pressure (PEEP), based on oxygenation, would avoid atelectrauma [4, 5]. This ARDSNet method was studied in a NIH clinical trial in 2000  and showed a significant reduction in ARDS mortality using volume control [assist-control] mode with a VT of 6 mL kg−1 compared to 12 mL kg−1 of ideal body weight. The use of 6 mL kg−1 soon became the standard of care for patients with ARDS.
Recent statistical analyses suggest, however, that this low VT (LVT) strategy has not lived up to its initial promise in reducing mortality in ARDS [6,7,8,9]. Deans et al.  analyzed data from 2587 patients that were screened but excluded from the ARDSNet Acute Respiratory Management Approach (ARMA) trial for technical reasons but were followed and treated with VT of ~ 10 mL kg−1, which was the standard of care for ventilation at the time. The group with VT ~ 10 mL kg had the same mortality as the LVT (6 mL kg1) group (Fig. 1A). Also, a VT greater than 6 mL kg−1 was not always associated with increased mortality, nor was LVT always associated with reduced mortality. Rather, in patients with lower respiratory system compliance (CRS), raising VT increased mortality compared to LVT (42% for LVT vs. 29% for high VT), while raising VT in patients with higher CRS reduced mortality (21% for high VT vs. 37% for LVT; p = 0.003; Fig. 1B) .
These findings demonstrate that a patient’s individual lung pathophysiology is critically important for clinical outcome. Thus, there cannot be a single weight-based value of VT that is best for all patients either at the initiation of MV or as their clinical course evolves. Appreciation of this fact is evidenced by the recent interest in driving pressure (ΔP), calculated as the difference between plateau and end-expiratory pressures. ΔP can evolve over a patient’s clinical course and is approximated by the ratio VT/CRS, which explains why letting VT be influenced by CRS has proven to be better at stratifying ARDS-related mortality risk compared to weight-based VT [7, 11,12,13,14,15].
These observations beg the question as to whether ΔP should replace VT as the key factor guiding protective ventilation strategies [7, 11,12,13,14,15,16]. Dramatic reductions in ΔP can be achieved with high-frequency oscillatory ventilation (HFOV), because it uses VT that are less than the anatomic dead space volume. However, when tested in randomized controlled trials [17,18,19], HFOV failed to reduce ARDS-related mortality below that in the ARMA study . Such a disappointing result may be related to the heterogeneous way that ventilation is distributed throughout the lung when cycled at high frequencies [20, 21] and the resultant heterogeneous distributions of parenchymal strain [20, 21]. Moreover, studies have shown that normal lung tissue, which is presumed to comprise the baby lung, is resistant to tissue damage induced by overdistension [22,23,24,25,26,27,28,29,30]. Also, although some studies suggest VILI occurs when a threshold of mechanical power applied to the lung is exceeded, studies in animal models suggest that VILI in the normal lung is only initiated when atelectrauma is allowed to occur regardless of VT [26, 31, 32].
The baby lung concept, which established the rationale for LVT, was originally based on CT imaging . However, more recent studies pairing CT with 3He or 129Xe magnetic resonance imaging (MRI) have shown that pathologic airspaces develop heterogeneously throughout the ARDS lung [33,34,35,36], contrary to the notion of a normal baby lung compartment. Furthermore, it has recently been shown that the principle mechanism of VILI at the tissue level is regional alveolar instability , defined as cyclic alveolar collapse causing scattered micro-atelectasis to develop throughout the lung [33,34,35,36,37,38]. In addition, Broche et al. using high-resolution synchrotron phase-contrast computerized tomography (CT) showed that acute lung injury significantly increased small airway (1.7–0.21 mm) closure and that this closure was time dependent. They suggest that the airway pressure release ventilation (APRV) mode, with a very short expiratory duration, may help to keep these small airways open . Since micro-atelectasis cannot be seen in conventional chest radiographs or CT images [32, 40], its importance as a VILI mechanism may not have been fully appreciated until recently.
An assumption of the current protective ventilation approach is that the injured lung can be easily compartmentalized into simple opened and closed components. However, several studies have demonstrated that the injured lung has a far more heterogeneous distribution of parenchymal mechanical properties. Techniques that may be used to further assess such intraparenchymal heterogeneity include electrical impedance tomography [39, 41], computed tomographic image registration [42, 43] and oscillometric measurements of respiratory impedance . How any of these approaches may be used to further refine the ventilation modality will of course require further investigation.
Unshrinking the baby lung
Marini and Gattinoni recently described the progression of VILI as a shrinking of the baby lung whereby tissue moves from the open to the atelectatic compartment, a process labeled the ‘VILI vortex’ (Fig. 2) . They hypothesize that as the baby lung continues to lose normal tissue as a result of alveolar instability and collapse, increasing stress and strain from a fixed VT will be placed on the remaining open tissue, amplify existing lung injury. The VILI vortex concept was recently supported in a clinical study showing COVID-19-induced ARDS (CARDS) resulted in progressive lung collapse over a 3-week period .
Unfortunately, fixing the VILI vortex is unlikely to be achieved solely with the use of a LVT strategy because the parenchymal tissues at the interfaces between normal and atelectatic regions experience particularly high distortional forces. These forces predispose the interfacial tissues to being the site of VILI pathogenesis through a permeability-originated obstruction response (POOR) that is self-reinforcing (Fig. 3) . This means that VILI will continue to progress at the interfacial regions even if the baby lung as a whole is not over-inflated. It also leads to the conjecture that the only way of preventing VILI progression is through a substantial reduction in the total burden of POOR regions, something that requires the immediate mitigation of alveolar instability followed by steps to progressively and safely reopen densely atelectatic lung tissue (Fig. 2) .
The above supposition is not new, and indeed, it motivated the open lung approach (OLA) to protective MV. The OLA attempts to open the majority of collapsed lung by applying high levels of PEEP, either with or without periodic recruitment maneuvers (RM) [47,48,49,50]. Several large clinical trials using the OLA, however, failed to show a reduction in ARDS-related mortality [47,48,49,50] despite preliminary data suggesting that opening the ARDS lung reduces VILI. While this might seem puzzling given that the OLA has an apparently well-founded physiologic rationale, there are two critical factors that potentially account for its lack of success. First, while recruitment/derecruitment (R/D) is a process normally associated with excursions in lung volume over the lower end of its functional range, these processes can manifest at increasingly elevated volumes as the lung becomes progressively more injured and may eventually even extend over the entire lung volume range [51, 52]. Thus, in some ARDS cases there may be no safe level of PEEP at which R/D is eliminated during MV.
The second factor not addressed by the OLA is that recruitment is not solely determined by the amount of airway pressure applied but also depends on inspiratory and expiratory time. Indeed, lung reopening may take a long time, sometimes hours or days, to occur . The OLA uses RMs that rely on high inspiratory pressure applied transiently (seconds to minutes) to achieve rapid reopening, but lung recruitment can be challenging to achieve quickly even with very high pressures due to accumulation of surfactant deactivation and edema in the airspaces [38, 54]. Also, the nondurable recruitment produced by the OLA has the potential for increasing the number of unstable airspaces if adequate PEEP is not applied.
Similarly, reducing airway pressure may not cause immediate derecruitment because collapse also takes time to occur. The timescale for alveolar collapse is typically much faster than the timescale for alveolar reopening, and the delay before collapse begins may be < 0.5 s . If PEEP is set too low and/or expiratory time too long, the resulting progressive lung collapse is reflected in transient increases in lung elastance (i.e., reductions in CRS) observed immediately following a RM . Furthermore, the rates at which both alveolar opening and collapse occur are functions of the nature and severity of lung injury , as well as the level of airway pressure applied . In general, the more severe the lung injury, the more rapid and extensive derecruitment will be at a given pressure . As conventionally practiced, the administration of a RM does not consider how rapidly the lung derecruits following each maneuver. If atelectatic regions are recruited but not stabilized, then cyclic R/D will continue to cause atelectrauma .
The above considerations suggest that a non-injurious ventilation strategy for the ARDS lung must first be able to halt ongoing derecruitment and then progressively pull the lung out of the VILI vortex by gradually opening atelectatic lung (Fig. 2). To do this, such a strategy must have the following two key attributes:
It must rapidly stabilize alveoli that are actively undergoing atelectrauma, such that susceptible airspaces do not have enough time to close during expiration and thus are prevented from having to reopen again during the subsequent inspiration. This prevents the accumulation of breath-to-breath atelectrauma and so pulls the lung from the VILI vortex.
It must progressively recruit atelectatic lung tissue in a sustained manner over a period of hours or even days. This minimizes the amount of excessively distorted parenchyma at the interfaces between patent and atelectatic regions of the lung that are frequently the sites of VILI initiation . Once gradual airspace opening begins, it can spread to adjacent collapsed regions via the forces of parenchymal tethering and interdependence .
Neither attribute is likely to be realized in the injured lung during conventional MV because expiration is usually long enough to allow rapidly closing lung units sufficient time to derecruit unless very high PEEP is applied, and inspiration is too brief to recruit collapsed alveoli that open slowly over time (Figs. 4A, 5A). The above two attributes can be realized, however, if the pattern of ventilation is allowed to depart from traditional mechanical ventilation in the following two ways (Figs. 4B, 5B):
Expiration must be sufficiently brief that derecruitment does not have enough time to occur prior to the beginning of the next inspiration (Fig. 4B, Release Phase).
Inspiratory duration and pressure must be sufficient to progressively recruit atelectatic lung over an extended period of time, but not so high as to be injurious to the parenchyma or have adverse hemodynamic consequences (Fig. 4B, CPAP Phase). Pressure must be sustained in a manner that is capable of recruiting lung units gradually, and this pressure must be applied for hours or days until the lung is fully open and stable (Fig. 5B–D).
A mode of MV that potentially meets the above two requirements is APRV, although it must be administered in a very particular manner (Fig. 4B). The most critical APRV parameter is the duration of the expiratory Release Phase (TLow), which must be brief enough to prevent collapse of even the most rapidly closing alveoli, thereby attending to the first requirement. It is important to realize, however, that extending TLow from its optimal value by even a fraction of a second can increase expiratory derecruitment dramatically, with potentially disastrous results for the lung (Fig. 6A, B—APRV 10%) .
The second requirement can be met by an appropriate level of inspiratory airway pressure (PHigh) applied for an extended duration (THigh) (Fig. 4B, CPAP Phase). This effectively applies CPAP to the lung, initiating a gradual and sustained alveolar reopening over a prolonged period of time (Fig. 5B–D). Since the time required to recruit some regions of the lung can be extremely long, the benefits of opening the lung in this manner may not be evident for hours or even days (Fig. 5B–D) [32,33,34,35]. The level of pressure applied during expiration (PLow) is less critical to the derecruitment process because the brief TLow prevents the lungs from completely emptying by the end of expiration, resulting in a degree of time-controlled PEEP (Fig. 4B, TC-PEEP). Setting PLow to 0 cmH2O maximizes expiratory flow and facilitates CO2 elimination with each breath, thus helping to maintain normocarbia. At the exhalation termination point (TLow), the lung is rapidly re-inflated to the CPAP Phase (Fig. 4B, Gas Flow/Time curve, red arrowhead).
The values of PHigh, THigh, PLow, and TLow thus collectively define how APRV is administered. Using appropriate values for these parameters will mitigate some of the adverse effects of ventilating a baby lung. The question remains, however, as to how these values should be chosen, particularly TLow. Figure 7 shows: (A) normal expiratory flow/time curve, (B) the changes caused by ARDS, and (C) how this information can be used to set TLow necessary to stabilize alveoli and maintain a normal functional residual capacity (FRC). Passive exhalation in the normal lung is slow (~ 2 s) due a high CRS and low lung recoil (Fig. 7A—thin springs). A functioning pulmonary surfactant system maintains a normal FRC at atmospheric pressure. ARDS-induced surfactant deactivation reduces lung CRS and increases recoil (thick springs) causing a rapid exhalation (~ 1 s) of gas during expiration (Fig. 7B—ARDS). The FRC can decrease by up to 45% in lungs with severe ARDS . Thus, allowing the injured lung to collapse to atmospheric pressure will result in a much lower FRC than in the normal lung. Experience in both the animal laboratory and the intensive care unit (ICU) has demonstrated that the expiratory gas flow curve using the APRV mode can be used in a patient-targeted and adaptable approach to predict the TLow duration necessary to stabilize alveoli.
Using this approach, TLow is set such that expiration terminates when the magnitude of expiratory flow has fallen to a fixed percentage (75%) of its peak value at the start of expiration (Fig. 5C) [65, 66]. This results in TLow values that vary across patients and disease states. For example, patients with severe ARDS typically have less compliant lungs that empty quickly, thus reaching their expiratory termination points (Fig. 7C, 0.3 s) earlier than patients with more compliant lungs (Fig. 7C, 0.5 s). This effect can be appreciated by examining the slope of the expiratory gas flow/time curve (SlopeEF) from lungs with differing CRS (Fig. 7C—ARDS and NORMAL) . As lung health improves and CRS increases, TLow may be increased accordingly (Fig. 5C—ARDS = 0.3 s; NORMAL = 0.5 s). Thus, setting TLow according to the SlopeEF affords a personalized approach to ventilating the injured lung that adapts to a patient’s changing physiology. Finally, similar to normalizing VT to CRS (i.e., driving pressure) to reduce mortality (Fig. 1B), TLow adjusted to 75% of peak expiratory flow produces VTs (Fig. 5B 6.2 mL/kg and Fig. 5C 9.2 mL/kg) that is proportional to CRS (Fig. 5B = CRS low; 5D = CRS high).
Applying APRV in the above manner requires continuous monitoring of intra-breath expiratory flow as well as the ability to control the termination of expiration. This precise method of setting the APRV mode using the SlopeEF is termed the time-controlled adaptive ventilation (TCAV) method (Fig. 7C). The TCAV method has been shown to enhance lung protection [63, 66, 68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83] by stabilizing alveoli  (Fig. 6A, B—APRV 75%) and progressively reopening recalcitrant regions of atelectasis (Fig. 5 B–D). TCAV rapidly pulls the lung out of the VILI vortex and then gradually reopens collapsed tissue (Fig. 2) [63, 70, 84].
The TCAV method has been extensively studied by several groups [63, 66, 68, 71,72,73,74,75,76,77,78,79,80,81,82,83, 85, 86]. It has been shown to recruit subpleural alveoli in a rat model of ARDS (Fig. 6, APRV 75%) [63, 71, 86] and reduce tissue damage compared to ARDSNet LVT strategy in a clinically applicable porcine sepsis and gut ischemia/reperfusion-induced ARDS model [72, 79]. The TCAV method has also been shown to reduce ARDS incidence and mortality in trauma patients . These findings suggest the physiologic principles upon which TCAV is based represent a successful method to balancing the benefits of positive pressure ventilation against the harm it may cause to an already injured lung.
It must be noted that in patients with expiratory flow limitations (EFL) the TCAV method must be modified. Since flow/time is an integral of volume, airflow limitations are easily depicted with changes in peak expiratory flow rates and can be readily seen at the bedside with flow graphics using the TCAV method. The pattern of airflow limitations results in the following characteristics: (a) The peak expiratory flow rate decreases as expected in diseases with obstructed airways and (b) an uneven pattern of incomplete and sequential gas emptying that greatly increases the deceleration angle of the expiratory flow curve, which is a hallmark of obstructive lung disease. Once EFL is identified, the TCAV protocol is modified to increase the expiratory duration, since more time is needed for the same volume of gas to be exhaled. The TCAV protocol for patients with EFL is beyond the scope of this paper.
Insight into the mechanism by which the TCAV method opens collapsed lung tissue can be gained by analyzing the method the newborn infant uses to open their collapsed lung at birth (Fig. 8) . Spontaneously breathing newborns recruit collapsed lung with a rapid inspiration (Fig. 8—Inflation and aeration) and prevent re-collapse of the newly opened tissue by partially closing the glottis to act as a ‘brake’ on expiratory flow (Fig. 8—Slowing of expiratory flow). Thus, the method by which nature opens the lung at birth is to inflate a small amount of tissue with each breath and then apply a ‘brake’ to prevent the newly opened tissue from re-collapsing. When a force causes a strain in one direction and some type of ‘brake’ prevents strain in the opposite direction it is termed a ratchet. Therefore, nature’s strategy is to ratchet open lung tissue with each breath until the lung is fully inflated.
We postulate that the TCAV method uses the ratchet mechanism to open collapsed lung in the ARDS patient. There is a rapid lung inflation from the termination point of expiration (Fig. 4B, Gas Flow/Time curve) that recruits a small portion of collapsed lung, combined with a brief Release Phase to ‘brake’ expiratory flow preventing derecruitment during expiration. In addition, the prolonged CPAP Phase accelerates recruitment of alveoli with long opening time constants (Fig. 4B, CPAP Phase). Addition of CPAP has been shown to significantly increase FRC in premature infants .
If our hypothesis is correct, the ratchet approach is a novel and innovative method of lung recruitment. Unlike the OLA, which attempts to open the entire lung in a seconds or minutes , the TCAV method ratchets open small volumes of lung with each breath that will progressively open the entire lung over hours or days. As described above a ratchet is a device (ventilator) that causes an object to strain in one direction (alveolar recruitment during inspiration), while applying a ‘brake’ (very short expiratory duration) necessary to prevent strain in the opposite direction (prevent alveolar collapse during exhalation). An example of the ratcheting approach on progressive lung recruitment is shown in Fig. 5.
Low tidal volumes and airway pressures using the ARDSNet method can push the lung with mild ARDS into the VILI vortex. To prevent progressive lung collapse, the time-dependent nature of alveolar opening and collapse must be taken into account. The TCAV method to set APRV uses: (i) the ratchet approach combined with an extended inspiratory duration necessary to recruit alveoli and (ii) a brief expiratory duration to ‘brake’ the derecruitment of rapidly collapsing alveoli. The TCAV method is personalized and adaptable and has shown promising results in animal models of ARDS and has yielded positive clinical outcomes in the ICU. Whether TCAV, or a similar strategy, can significantly reduce ARDS-related mortality when implemented in a large-scale clinical trial remains to be seen, but it is clear that a new approach to MV in ARDS is needed. We propose that ventilating patients with ARDS in a manner that specifically addresses the time dependence of R/D is a logical strategy for interrupting and reversing the VILI vortex. Accordingly, we believe consideration should be given to the design of a clinical trial comparing the TCAV method to the current standard of care in ARDS patients.
Availability of data and materials
Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, Herridge M, Randolph AG, Calfee CS. Acute respiratory distress syndrome. Nat Rev Dis Prim. 2019;5(1):18.
Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126–36.
Gattinoni L, Pesenti A. The concept of “baby lung.” Intensive Care Med. 2005;31(6):776–84.
Acute Respiratory Distress Syndrome N, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301–8.
Schiller HJ, McCann UG 2nd, Carney DE, Gatto LA, Steinberg JM, Nieman GF. Altered alveolar mechanics in the acutely injured lung. Crit Care Med. 2001;29(5):1049–55.
Caser EB, Zandonade E, Pereira E, Gama AM, Barbas CS. Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: prospective evaluation of 7133 patients*. Crit Care Med. 2014;42(3):574–82.
Laffey JG, Bellani G, Pham T, Fan E, Madotto F, Bajwa EK, Brochard L, Clarkson K, Esteban A, Gattinoni L, et al. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42(12):1865–76.
Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA. 2018;319(7):698–710.
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800.
Deans KJ, Minneci PC, Cui X, Banks SM, Natanson C, Eichacker PQ. Mechanical ventilation in ARDS: one size does not fit all. Crit Care Med. 2005;33(5):1141–3.
Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747–55.
Yehya N, Hodgson CL, Amato MBP, Richard JC, Brochard LJ, Mercat A, Goligher EC. Response to ventilator adjustments for predicting acute respiratory distress syndrome mortality. Driving pressure versus oxygenation. Ann Am Thorac Soc. 2021;18(5):857–64.
Costa ELV, Slutsky A, Brochard LJ, Brower R, Serpa-Neto A, Cavalcanti AB, Mercat A, Meade M, Morais CCA, Goligher E, et al. Ventilatory variables and mechanical power in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2021;204:303–11.
Aoyama H, Pettenuzzo T, Aoyama K, Pinto R, Englesakis M, Fan E. Association of driving pressure with mortality among ventilated patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2018;46(2):300–6.
Chen Z, Wei X, Liu G, Tai Q, Zheng D, Xie W, Chen L, Wang G, Sun JQ, Wang S, et al. Higher versus lower DP for ventilated patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Emerg Med Int. 2019;2019:4654705.
Goligher EC, Costa ELV, Yarnell CJ, Brochard LJ, Stewart TE, Tomlinson G, Brower RG, Slutsky AS, Amato MPB. Effect of lowering tidal volume on mortality in ARDS varies with respiratory system elastance. Am J Respir Crit Care Med. 2021;203:1378–85.
Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD, Lamontagne F, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368(9):795–805.
Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K, Cuthbertson BH, Group OS. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368(9):806–13.
Malhotra A, Drazen JM. High-frequency oscillatory ventilation on shaky ground. N Engl J Med. 2013;368(9):863–5.
Herrmann J, Lilitwat W, Tawhai MH, Kaczka DW. High-frequency oscillatory ventilation and ventilator-induced lung injury: size does matter. Crit Care Med. 2020;48(1):e66–73.
Kaczka DW. Oscillatory ventilation redux: alternative perspectives on ventilator-induced lung injury in the acute respiratory distress syndrome. Curr Opin Physiol. 2021;21:36–43.
Protti A, Andreis DT, Monti M, Santini A, Sparacino CC, Langer T, Votta E, Gatti S, Lombardi L, Leopardi O, et al. Lung stress and strain during mechanical ventilation: any difference between statics and dynamics? Crit Care Med. 2013;41(4):1046–55.
Protti A, Andreis DT, Iapichino GE, Monti M, Comini B, Milesi M, Zani L, Gatti S, Lombardi L, Gattinoni L. High positive end-expiratory pressure: only a dam against oedema formation? Crit Care. 2013;17(4):R131.
Protti A, Maraffi T, Milesi M, Votta E, Santini A, Pugni P, Andreis DT, Nicosia F, Zannin E, Gatti S, et al. Role of strain rate in the pathogenesis of ventilator-induced lung edema. Crit Care Med. 2016;44(9):e838-845.
Jain SV, Kollisch-Singule M, Satalin J, Searles Q, Dombert L, Abdel-Razek O, Yepuri N, Leonard A, Gruessner A, Andrews P, et al. The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model. Intensive Care Med Exp. 2017;5(1):25.
Seah AS, Grant KA, Aliyeva M, Allen GB, Bates JHT. Quantifying the roles of tidal volume and PEEP in the pathogenesis of ventilator-induced lung injury. Ann Biomed Eng. 2011;39(5):1505–16.
Wilson MR, Patel BV, Takata M. Ventilation with “clinically relevant” high tidal volumes does not promote stretch-induced injury in the lungs of healthy mice. Crit Care Med. 2012;40(10):2850–7.
Syring RS, Otto CM, Spivack RE, Markstaller K, Baumgardner JE. Maintenance of end-expiratory recruitment with increased respiratory rate after saline-lavage lung injury. J Appl Physiol. 2007;102(1):331–9.
Hamlington KL, Smith BJ, Dunn CM, Charlebois CM, Roy GS, Bates JHT. Linking lung function to structural damage of alveolar epithelium in ventilator-induced lung injury. Respir Physiol Neurobiol. 2018;255:22–9.
Otto CM, Markstaller K, Kajikawa O, Karmrodt J, Syring RS, Pfeiffer B, Good VP, Frevert CW, Baumgardner JE. Spatial and temporal heterogeneity of ventilator-associated lung injury after surfactant depletion. J Appl Physiol. 2008;104(5):1485–94.
Cressoni M, Gotti M, Chiurazzi C, Massari D, Algieri I, Amini M, Cammaroto A, Brioni M, Montaruli C, Nikolla K, et al. Mechanical power and development of ventilator-induced lung injury. Anesthesiology. 2016;124(5):1100–8.
Albert K, Krischer JM, Pfaffenroth A, Wilde S, Lopez-Rodriguez E, Braun A, Smith BJ, Knudsen L. Hidden microatelectases increase vulnerability to ventilation-induced lung injury. Front Physiol. 2020;11:530485.
Cressoni M, Chiurazzi C, Gotti M, Amini M, Brioni M, Algieri I, Cammaroto A, Rovati C, Massari D, di Castiglione CB, et al. Lung inhomogeneities and time course of ventilator-induced mechanical injuries. Anesthesiology. 2015;123(3):618–27.
Cereda M, Xin Y, Meeder N, Zeng J, Jiang Y, Hamedani H, Profka H, Kadlecek S, Clapp J, Deshpande CG, et al. Visualizing the propagation of acute lung injury. Anesthesiology. 2016;124(1):121–31.
Cereda M, Xin Y. Alveolar recruitment and lung injury: an issue of timing and location? Crit Care Med. 2013;41(12):2837–8.
Cereda M, Emami K, Kadlecek S, Xin Y, Mongkolwisetwara P, Profka H, Barulic A, Pickup S, Mansson S, Wollmer P, et al. Quantitative imaging of alveolar recruitment with hyperpolarized gas MRI during mechanical ventilation. J Appl Physiol. 2011;110(2):499–511.
Gaver DP 3rd, Nieman GF, Gatto LA, Cereda M, Habashi NM, Bates JHT. The POOR Get POORer: a hypothesis for the pathogenesis of ventilator-induced lung injury. Am J Respir Crit Care Med. 2020;202(8):1081–7.
Nakahashi S, Imai H, Shimojo N, Magata Y, Einama T, Hayakawa M, Wada T, Morimoto Y, Gando S. Effects of the prone position on regional neutrophilic lung inflammation according to 18F-FDG pet in an experimental ventilator-induced lung injury model. Shock. 2022;57(2):298–308.
Broche L, Pisa P, Porra L, Degrugilliers L, Bravin A, Pellegrini M, Borges JB, Perchiazzi G, Larsson A, Hedenstierna G, et al. Individual airway closure characterized in vivo by phase-contrast CT imaging in injured rabbit lung. Crit Care Med. 2019;47(9):e774–81.
Cereda M, Xin Y, Goffi A, Herrmann J, Kaczka DW, Kavanagh BP, Perchiazzi G, Yoshida T, Rizi RR. Imaging the injured lung: mechanisms of action and clinical use. Anesthesiology. 2019;131:716–49.
Sang L, Zhao Z, Lin Z, Liu X, Zhong N, Li Y. A narrative review of electrical impedance tomography in lung diseases with flow limitation and hyperinflation: methodologies and applications. Ann Transl Med. 2020;8(24):1688.
Kaczka DW, Cao K, Christensen GE, Bates JH, Simon BA. Analysis of regional mechanics in canine lung injury using forced oscillations and 3D image registration. Ann Biomed Eng. 2011;39(3):1112–24.
Herrmann J, Gerard SE, Shao W, Hawley ML, Reinhardt JM, Christensen GE, Hoffman EA, Kaczka DW. Quantifying regional lung deformation using four-dimensional computed tomography: a comparison of conventional and oscillatory ventilation. Front Physiol. 2020;11:14.
Kaczka DW, Hager DN, Hawley ML, Simon BA. Quantifying mechanical heterogeneity in canine acute lung injury: impact of mean airway pressure. Anesthesiology. 2005;103(2):306–17.
Marini JJ, Gattinoni L. Time course of evolving ventilator-induced lung injury: the “Shrinking Baby Lung.” Crit Care Med. 2020;48(8):1203–9.
Rossi S, Palumbo MM, Sverzellati N, Busana M, Malchiodi L, Bresciani P, Ceccarelli P, Sani E, Romitti F, Bonifazi M, et al. Mechanisms of oxygenation responses to proning and recruitment in COVID-19 pneumonia. Intensive Care Med. 2022;48(1):56–66.
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial I, Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, Guimaraes HP, Romano ER, Regenga MM, Taniguchi LNT, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) versus low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):1335–45.
Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646–55.
Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637–45.
Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT, Natl Heart Lung Blood Inst AC. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327–36.
Hickling KG. The pressure–volume curve is greatly modified by recruitment. A mathematical model of ARDS lungs. Am J Respir Crit Care Med. 1998;158(1):194–202.
Hickling KG. Reinterpreting the pressure–volume curve in patients with acute respiratory distress syndrome. Curr Opin Crit Care. 2002;8:32–8.
Gaver D, Samsel RW, Solway J. Effects of surface tension and viscosity on airway reopening. J Appl Physiol. 1990;69:74–85.
Fraser RS, Paré PD. Fraser and Paré’s diagnosis of diseases of the chest. 4th ed. Philadelphia: W.B. Saunders; 1999.
Cassidy KJ, Halpern D, Ressler BG, Grotberg JB. Surfactant effects in model airway closure experiments. J Appl Physiol. 1999;87(1):415–27.
Allen G, Lundblad LK, Parsons P, Bates JH. Transient mechanical benefits of a deep inflation in the injured mouse lung. J Appl Physiol. 2002;93(5):1709–15.
Allen G, Bates JH. Dynamic mechanical consequences of deep inflation in mice depend on type and degree of lung injury. J Appl Physiol. 2004;96(1):293–300.
Massa CB, Allen GB, Bates JH. Modeling the dynamics of recruitment and derecruitment in mice with acute lung injury. J Appl Physiol. 2008;105(6):1813–21.
Allen GB, Leclair T, Cloutier M, Thompson-Figueroa J, Bates JH. The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration. Am J Physiol. 2007;292(6):L1580-1589.
Andrews PL, Shiber JR, Jaruga-Killeen E, Roy S, Sadowitz B, O’Toole RV, Gatto LA, Nieman GF, Scalea T, Habashi NM. Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature. J Trauma Acute Care Surg. 2013;75(4):635–41.
Cereda M, Xin Y, Hamedani H, Bellani G, Kadlecek S, Clapp J, Guerra L, Meeder N, Rajaei J, Tustison NJ, et al. Tidal changes on CT and progression of ARDS. Thorax. 2017;72(11):981–9.
Ryans JM, Fujioka H, Gaver DP 3rd. Microscale to mesoscale analysis of parenchymal tethering: the effect of heterogeneous alveolar pressures on the pulmonary mechanics of compliant airways. J Appl Physiol. 2019;126(5):1204–13.
Kollisch-Singule M, Emr B, Smith B, Roy S, Jain S, Satalin J, Snyder K, Andrews P, Habashi N, Bates J, et al. Mechanical breath profile of airway pressure release ventilation: the effect on alveolar recruitment and microstrain in acute lung injury. JAMA Surg. 2014;149(11):1138–45.
Rylander C, Hogman M, Perchiazzi G, Magnusson A, Hedenstierna G. Functional residual capacity and respiratory mechanics as indicators of aeration and collapse in experimental lung injury. Anesth Analg. 2004;98(3):782–9, table of contents.
Habashi NM. Other approaches to open-lung ventilation: airway pressure release ventilation. Crit Care Med. 2005;33(3 Suppl):S228-240.
Nieman GF, Al-Khalisy H, Kollisch-Singule M, Satalin J, Blair S, Trikha G, Andrews P, Madden M, Gatto LA, Habashi NM. A physiologically informed strategy to effectively open, stabilize, and protect the acutely injured lung. Front Physiol. 2020;11:227.
Herrmann J, Gerard SE, Shao W, Xin Y, Cereda M, Reinhardt JM, Christensen GE, Hoffman EA, Kaczka DW. Effects of lung injury on regional aeration and expiratory time constants: insights from four-dimensional computed tomography image registration. Front Physiol. 2021;12:707119.
Albert SP, DiRocco J, Allen GB, Bates JH, Lafollette R, Kubiak BD, Fischer J, Maroney S, Nieman GF. The role of time and pressure on alveolar recruitment. J Appl Physiol. 2009;106(3):757–65.
Emr B, Gatto L, Roy S, Satalin J, Ghosh A, Snyder K, Andrews P, Habashi N, Marx W, Ge L, et al. Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs. JAMA Surg. 2013;148:1005–12.
Kollisch-Singule M, Emr B, Smith B, Ruiz C, Roy S, Meng Q, Jain S, Satalin J, Snyder K, Ghosh A, et al. Airway pressure release ventilation reduces conducting airway micro-strain in lung injury. J Am Coll Surg. 2014;219(5):9.
Kollisch-Singule M, Jain S, Andrews P, Smith BJ, Hamlington-Smith KL, Roy S, DiStefano D, Nuss E, Satalin J, Meng Q, et al. Effect of airway pressure release ventilation on dynamic alveolar heterogeneity. JAMA Surg. 2015;151:1–9.
Kollisch-Singule M, Emr B, Jain SV, Andrews P, Satalin J, Liu J, Porcellio E, Kenyon V, Wang G, Marx W, et al. The effects of airway pressure release ventilation on respiratory mechanics in extrapulmonary lung injury. Intensive Care Med Exp. 2015;3(1):35.
Smith BJ, Lundblad LK, Kollisch-Singule M, Satalin J, Nieman G, Habashi N, Bates JH. Predicting the response of the injured lung to the mechanical breath profile. J Appl Physiol. 2015;118(7):932–40.
Kollisch-Singule M, Jain SV, Satalin J, Andrews P, Searles Q, Liu Z, Zhou Y, Wang G, Meier AH, Gatto LA, et al. Limiting ventilator-associated lung injury in a preterm porcine neonatal model. J Pediatr Surg. 2017;52(1):50–5.
Nieman GF, Satalin J, Kollisch-Singule M, Andrews P, Aiash H, Habashi NM, Gatto LA. Physiology in medicine: understanding dynamic alveolar physiology to minimize ventilator-induced lung injury. J Appl Physiol. 2017;122(6):1516–22.
Nieman GF, Satalin J, Andrews P, Aiash H, Habashi NM, Gatto LA. Personalizing mechanical ventilation according to physiologic parameters to stabilize alveoli and minimize ventilator induced lung injury (VILI). Intensive Care Med Exp. 2017;5(1):8.
Nieman GF, Gatto LA, Habashi NM. Impact of mechanical ventilation on the pathophysiology of progressive acute lung injury. J Appl Physiol. 2015;119(11):1245–61.
Silva PL, Cruz FF, Samary CDS, Moraes L, de Magalhaes RF, Fernandes MVS, Bose R, Pelegati VB, Carvalho HF, Capelozzi VL, et al. Biological response to time-controlled adaptive ventilation depends on acute respiratory distress syndrome etiology. Crit Care Med. 2018;46(6):e609–17.
Roy S, Habashi N, Sadowitz B, Andrews P, Ge L, Wang G, Roy P, Ghosh A, Kuhn M, Satalin J, et al. Early airway pressure release ventilation prevents ARDS—a novel preventive approach to lung injury. Shock. 2013;39(1):28–38.
Roy SK, Emr B, Sadowitz B, Gatto LA, Ghosh A, Satalin JM, Snyder KP, Ge L, Wang G, Marx W, et al. Preemptive application of airway pressure release ventilation prevents development of acute respiratory distress syndrome in a rat traumatic hemorrhagic shock model. Shock. 2013;40(3):210–6.
Jain SV, Kollisch-Singule M, Sadowitz B, Dombert L, Satalin J, Andrews P, Gatto LA, Nieman GF, Habashi NM. The 30-year evolution of airway pressure release ventilation (APRV). Intensive Care Med Exp. 2016;4(1):11.
Nieman GF, Andrews P, Satalin J, Wilcox K, Kollisch-Singule M, Madden M, Aiash H, Blair SJ, Gatto LA, Habashi NM. Acute lung injury: how to stabilize a broken lung. Crit Care. 2018;22(1):136.
Kollisch-Singule M, Satalin J, Blair SJ, Andrews PL, Gatto LA, Nieman GF, Habashi NM. Mechanical ventilation lessons learned from alveolar micromechanics. Front Physiol. 2020;11:233.
Kollisch-Singule M, Jain S, Andrews P, Smith BJ, Hamlington-Smith KL, Roy S, DiStefano D, Nuss E, Satalin J, Meng Q, et al. Effect of airway pressure release ventilation on dynamic alveolar heterogeneity. JAMA Surg. 2016;151(1):64–72.
Emr B, Gatto LA, Roy S, Satalin J, Ghosh A, Snyder K, Andrews P, Habashi N, Marx W, Ge L, et al. Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs. JAMA Surg. 2013;148(11):1005–12.
Kollisch-Singule M, Emr B, Smith B, Ruiz C, Roy S, Meng Q, Jain S, Satalin J, Snyder K, Ghosh A, et al. Airway pressure release ventilation reduces conducting airway micro-strain in lung injury. J Am Coll Surg. 2014;219(5):968–76.
Tingay DG, Farrell O, Thomson J, Perkins EJ, Pereira-Fantini PM, Waldmann AD, Ruegger C, Adler A, Davis PG, Frerichs I. Imaging the respiratory transition at birth: unraveling the complexities of the first breaths of life. Am J Respir Crit Care Med. 2021;204(1):82–91.
Lam R, Schilling D, Scottoline B, Platteau A, Niederhausen M, Lund KC, Schelonka RL, MacDonald KD, McEvoy CT. The effect of extended continuous positive airway pressure on changes in lung volumes in stable premature infants: a randomized controlled trial. J Pediatr. 2020;217:66-72.e61.
Cui Y, Cao R, Wang Y, Li G. Lung recruitment maneuvers for ARDS patients: a systematic review and meta-analysis. Respiration. 2020;99(3):264–76.
Roy S, Sadowitz B, Andrews P, Gatto LA, Marx W, Ge L, Wang G, Lin X, Dean DA, Kuhn M, et al. Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury. J Trauma Acute Care Surg. 2012;73(2):391–400.
Nieman GF, Gatto LA, Andrews P, Satalin J, Camporota L, Daxon B, Blair SJ, Al-Khalisy H, Madden M, Kollisch-Singule M, et al. Prevention and treatment of acute lung injury with time-controlled adaptive ventilation: physiologically informed modification of airway pressure release ventilation. Ann Intensive Care. 2020;10(1):3.
NIH R01HL142702—Support for Bates, Gaver, Nieman, Satalin, Blair. Office of the Assistant Secretary of Defense for Health Affairs, Peer Reviewed Medical Research Program, Award W81XWH-20-1-0696—Support for Nieman, Satalin, Blair, Kaczka, Habashi. Office of the Assistant Secretary of Defense for Health Affairs, Peer Reviewed Medical Research Program, Award W81XWH-20-1-0507—Support for Kaczka. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.
Ethics approval and consent to participate
Consent for publication
MKS has received a Research Grant and GF an Unrestricted Educational Grant from Dräger Medical Systems, Inc. PLA, GFN, MKS, and NMH have presented and received honoraria and/or travel reimbursement at event(s) sponsored by Dräger Medical Systems, Inc., outside of the published work. PLA, GFN, MKS, and NMH have lectured for Intensive Care Online Network, Inc. (ICON). NMH is the founder of ICON, of which PLA is an employee. NMH holds patents on a method of initiating, managing and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same, but these patents are not commercialized, licensed, or royalty-producing. The authors maintain that industry had no role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; nor the preparation, review, or approval of the manuscript. Dr. Kaczka is a co-founder and shareholder of OscillaVent, Inc., and is a co-inventor on a patent involving multi-frequency oscillatory ventilation. Dr. Kaczka also receives research support from ZOLL Medical Corporation and is a paid consultant for Lungpacer Medical, Inc. Dr. Bates is a consultant to and sharehold in OscillaVent, Inc., and has two patents pending in the field of MV.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nieman, G., Kollisch-Singule, M., Ramcharran, H. et al. Unshrinking the baby lung to calm the VILI vortex. Crit Care 26, 242 (2022). https://doi.org/10.1186/s13054-022-04105-x
- Acute respiratory distress syndrome (ARDS)
- Ventilator-induced lung injury (VILI)
- Protective mechanical ventilation