Non-Ventilatory Co-Factors of Ventilator-Induced Lung Injury

Numerous experimental studies demonstrate key aspects of mechanical ventilation which initiate or exacerbate acute lung injury, characterized by proteinaceous edema, inflammation, and hemorrhage. The great majority of these investigations into Ventilator-Induced Lung Injury (VILI) have focused on the characteristics of mechanical ventilation directly regulated by the clinician, including the individual tidal cycle-tidal volume, inspiratory flow rate, driving Pressure and End-Expiratory airway Pressure (PEEP). More recently, the impact of frequency has been recognized by tracking the inflation energy expended per minute, an inclusive variable termed ‘power’ [1]. Although these mechanical features are of unquestioned importance, other characteristics of the clinical environment have been shown to modify the intensity and/or nature of any resulting damage. While most research has focused mainly on approaches to minimize VILI over the last decades, largely ignoring these other injury co-factors, we believe a renewed focus on these background characteristics will help improve patient outcomes. Indeed, many facets of the COVID pandemic highlighted the need for a more holistic approach to lung injury.

In the largest and perhaps the most widely cited clinical trial of ventilator strategy to prevent acute lung injury, smaller tidal volumes (6 ml/kg predicted body weight, PBW) were associated with reduced mortality as compared to unnaturally large ones (12 ml/kg PBW) [2]. This result was attributed to the generally lower peak alveolar pressures and reduced mechanical stresses associated with smaller tidal volumes. Analysis of the data pooled from both trial groups not only demonstrated a positive correlation between plateau pressure and mortality rate, but also revealed its monotonic, linear nature—without an obvious break point down to pressures that are considerably lower than those that are feasible to use in the management of Acute Respiratory Distress Syndrome (ARDS) [3]. Although such an association does not confirm plateau pressure as the sole causative variable, it implies that there may be no “safe” plateau pressure below which mortality cannot be influenced by further pressure reduction. Because this relationship seems unexplainable on the basis of trans-pulmonary pressure and stretch alone, it underscores the need to identify any cofactors that influence VILI expression.

Focusing on lower tidal volumes, lower plateau pressures, and higher PEEP settings during the early phase of injury has helped to decrease ARDS -associated length of Intensive Care Unit (ICU) stay and to curtail the mortality rate [4]. We raise awareness here to the potential for lung injury to be modified during mechanical ventilation by such non-ventilatory factors as body position, acid-base status, pulmonary vascular dynamics, body temperature, concomitant pathologies, and pharmacologic agents. In this discussion, we review a selected subset of these non-ventilatory factors and propose mechanisms for their actions, summarized in figure 1. Our objective is to focus on those amenable to modification at the bedside.

Figure 1: Modifiable factors which contribute to lung injury, and should be considered by the bedside clinician to minimize lung injury.

Although VILI is a complex process initiated and propagated through several mechanisms, generally speaking, damage that results from excessive mechanical stress can be classified into two broad categories: structural and inflammatory. The injury process is initiated by repeated cycles of intolerable mechanical stress that depend on the magnitude, frequency and cumulative effect of this stimulus. Repetitive over-stretching and cyclic recruitment-derecruitment of collapsed areas that are exposed periodically to high pressure favor injury that disrupts the integrity of the epithelial membrane [5].

Simultaneously, these mechanical forces activate intracellular signaling cascades within epithelial cells. This activation culminates in recruitment of polymorphonuclear leukocytes, production of pro-inflammatory cytokines, vasodilatation and alveolar edema—collectively a process termed ‘biotrauma’ [6]. Once formed, alveolar edema has two opposing effects. On one hand, completely flooded alveoli are theoretically subject to lower shearing stresses than atelectatic units, as the gas-liquid interface is eliminated and alveolar dimensions increase. On the other hand, the increased weight of the edematous lung may promote small airway compression and accentuate the tendency for tidal opening and closure of dependent units to occur [7]. Overt breaks in the blood-gas barrier may arise when the applied mechanical force is extreme. In experiments, these microscopic breaks, or “stress fractures”, may arise very quickly after high pressure ventilatory cycles are initiated and involve both the cellular membranes of individual cells as well as larger tears that traverse intracellular boundaries. The presence of alveolar hemorrhage implies breaks of sufficient size to allow erythrocyte passage through them.

Because stresses severe enough to disrupt structural elements of the matrix are most likely to be amplified at the junctions of aerated and non-aerated tissues, hemorrhagic edema due to materials failure tends to form preferentially in gravitationally dependent regions. In such zones, inflammation may be a secondary epi-phenomenon to physical disruption of the barrier, rather than a primary event initiated by repetitive mechanical signaling. Whatever the stimulus, the potential for mechanical ventilation to induce systemic cytokine release and for a protective lung ventilation strategy to attenuate this response have been well demonstrated in the clinical context [8].

The trans-pulmonary pressure that determines tissue stress is not only a function of plateau pressure but also of the local (interstitial) pressure that surrounds the alveolus. Although interstitial pressure undoubtedly varies from site to site, by convention it is approximated by the local pleural pressure along any given transverse plane [9]. Pleural pressure, in turn, is a function of the relative elastances of the lung and chest wall (and in the prone position, of the surface against which the thorax rests, as well). The conformations of the chest wall and lung influence regional pleural pressures, and these are affected by body position. Edema from acute injury imposes lung tissue weight upon more gravitationally dependent zones, accentuating the gradient of pleural pressure (and inversely of transpulmonary pressure) that exists in the supine healthy subject [10]. Computed tomography has made clear that lung collapse is most prevalent in the dependent lung zones, whatever the body position [11]. When supine, the weight of the heart and mediastinal contents makes an important contribution to atelectasis, as they are cradled by the lower lobes that partially support them [12]. Conceptually, tissue forces (stresses) are focused at the interface between open and closed lung units. Judged solely on this basis, the tendency for VILI should be greatest in the most dependent and mid-positioned lung zones. In fact, when high plateau pressures are used with insufficient PEEP to keep the high-risk dependent units continually patent, VILI does prevail in the dorsal regions of large, supine experimental animals—even of those with initially healthy lungs [13,14]. Other co-factors, such as secretion retention and microvascular pressure (discussed below) may also contribute to this regional predilection for injury, but these are likely to be of secondary importance.

Although the supine position has traditionally been favored for the care of the critically ill, there are important reasons to question this practice in patients with ARDS. The great majority of mammals—including our closest primate relatives—orient themselves in the prone position, and healthy humans normally spend only a small fraction of their time supine. Anatomically, the shapes of the lung and the chest wall are more closely matched in the prone position, so that the gradients of pleural and transpulmonary pressure are attenuated. Overall, the resting aerated lung volume changes little after proning, while the distribution of that volume is markedly affected. Moreover, the airways drain more effectively in the prone position, and the weight of the heart is borne by the anterior chest wall rather than by the lungs, reducing further the tendency for dependent atelectasis to form. Less tissue collapse and reduced heterogeneity of regional transpulmonary pressures is likely to account for improved ventilation-perfusion matching in the prone position [14]. To a lesser degree, these observations apply to normal lungs as well as to acutely injured ones.

Experimental studies demonstrate that injurious ventilatory patterns produce less damage when the animal is oriented prone [13,14] and the positional reduction in injury is experienced primarily in the gravitationally dependent regions. Early clinical trials suggested advantages from prone positioning despite relatively short durations of application per day. These included improved oxygenation [15,16] and improved efficiency of carbon dioxide elimination [17], likely due to the combination of better ventilation/perfusion matching and reduced atelectasis. Initial studies showed non-statistically significant declines in mortality for those with severe ARDS [18]. However, the first trial to demonstrate improved mortality (both 28 and 90 day) was that of Guerin, et al. [19] who utilized prone positioning early in the course of severe ARDS for at least 16 consecutive hours per day, along with accepted ‘lung protective ventilation’ (6 mg/kg PBW and targeted plateau pressure< 30 cmH2O). The COVID-19 pandemic provided additional support for the benefits of prone positioning, including reduced need for intubation in non-ventilated patients [20] and reduced mortality in proned, intubated ones [21].

Not only does the stress associated with high pressure ventilatory cycles incite injury, but also an association of hyperventilation and hypocapnia with worsened lung injury has been suggested. In fact, hypocapnia appears to mediate parenchymal injury by altering surfactant function and by increasing permeability in airway and parenchymal microvessels [22]. Accepting a lower minute ventilation level reduces the energy and power delivered by mechanical ventilation, but invariably results in more carbon dioxide (Co₂) retention and hypercapnia relative to baseline. Doing so may reduce VILI risk simply by reducing cumulative stress and strain. Indeed, the obligate hypoventilation associated with lung protective strategies of ventilation has been termed “permissive” hypercapnia for this reason. It has been proposed, however, that hypercapnia and resultant acidosis itself may promote increased survival in ARDS [23,24].

If this contention proves true, is it hypercapnia or any associated acidosis that confers benefit? Laboratory data indicate that acidosis may confer protective adaptation in the context of cellular stress, thereby benefitting acute organ injury [25]. In the setting of ARDS, hypercapnic acidosis may alter the activity of polymorphonuclear phagocytes and influence numerous subcellular mechanisms [26-30]. The bulk of current evidence suggests that any beneficial effects of hypercapnic acidosis in acute lung injury more closely relate to the acidosis, rather than to the elevated partial pressure of Co₂ per se. Although benefit-confirming clinical evidence remains sparse, laboratory data suggest that lower pH may favor cellular functioning, down-regulate inflammatory responses, improve cardiac function, and maintain or reactivate hypoxic pulmonary vasoconstriction to improve ventilation/perfusion matching [26,31-36].

In some clinical work, patients with ARDS (both ventilated and non-ventilated) have been reported to have higher mortality rates in moderate ARDS after experiencing sustained early hypocapnia (study days 1-2). Importantly, those with normocapnia and hypocapnia were less likely to have protective mechanical ventilatory strategies employed than the hypercapnic group [24]. The hypercapnic group was found to experience neither harm nor benefit with regards to mortality. It is noteworthy that other clinical work indicates that severe hypercapnia (>50mmHg), rather than being protective, has been associated with higher ICU mortality in ARDS patients [37].

In summary, it remains unsettled whether hypercapnia in isolation exerts therapeutic benefit for inflamed tissue when dissociated from the low tidal volume and ventilating frequencies that simultaneously reduce cumulative tissue stress while promoting atelectasis.

The pulmonary vascular tree can be considered as a series of three segments: arterial, intermediate or middle (which includes alveolar capillaries and contiguous microvessels), and venous, as visualized in figure 2. Under normal conditions the arterial and venous segments (which are extra-alveolar) contribute most to overall pulmonary vascular resistance, while the compliant intermediate segment is influenced primarily by alveolar pressures. As a consequence, it undergoes the greatest change in overall vascular resistance during the ventilation cycle [38].

Figure 2: Mechanical interaction at the airspace-capillary boundary during inflation. As blood proceeds along the pathway from pre-capillary to post-capillary zones, the conducting vessels experience different stresses during the inflation cycle (insert). Note that during inflation, interstitial small vessels expand while capillaries embedded with alveoli are compressed.

Different animal model experiments collectively underscore the potential for deleterious interactions to occur between lung volumes and pulmonary hemodynamics [39-42]. Increased blood flows and vascular pressures within the intermediate segment influence the gradient of trans-alveolar vascular pressure and result in greater severity of VILI that result from an unchanging downstream pressure and an adverse pattern of ventilation. In keeping with this concept, ventilation with negative pressure may cause lung damage more severe than equivalent ventilation by positive pressure, implicating involvement of increased blood flow in ventilation-related damage [43]. Moreover, experimental rats given dopamine to increase cardiac output suffer increased albumin leak when ventilated with high pressure, suggesting that a major portion of the protective effect of PEEP in the setting of high pressure ventilation may be due to its reduction of pulmonary perfusion [44].

Intriguing experiments indicate that lowering post-capillary pressure increases the edema and filtration coefficient resulting from a fixed pattern of ventilation and upstream pre-capillary pressure [45]. In other words, vascular pressures as well as the characteristics of the tidal cycle appear to be fundamental to the genesis of VILI. In addition, the minute ventilation, the number of the stress cycles of a potentially damaging character that occur per unit time, or their cumulative number, might be important from the viewpoint of small vessel trauma as well as the airspace energy per minute (‘power’) already discussed [39-41]. The effects of respiratory frequency and vascular pressures on VILI are not mediated primarily by pulsatile vascular pressure in the absence of lung motion, but rather by a phenomenon related to cyclic modulation of the vascular microenvironment induced by ventilation itself [40-42].

At first consideration, the fact that lowering post-capillary pressure might accentuate the edema resulting from VILI might seem paradoxical; in other disease settings reducing capillary pressure often confers benefit on lung functioning. Lower capillary and venous pressures limit exudation of protein-rich fluid, which may inactivate surfactant and further alter membrane permeability by increasing surface tension. Furthermore, edematous lungs tend to collapse under their own weight and to develop dependent atelectasis. When tidal airway pressures are high enough, such compression may lead to cyclic opening and collapse, and amplified shear stresses. Such conditions could account for the preferentially dependent distribution of VILI, as discussed above [44]. At the same time, flooding the alveoli of dependent regions can reduce regional mechanical stress by preventing their tidal expansion and collapse. In fact, excessive reduction of capillary pressure may promote vascular de-recruitment, alter ventilation-perfusion matching, and contribute to vascular stress, as during positive pressure ventilation it tends to impose the ‘zone two’ conditions under which alveolar pressure exceeds pulmonary venous pressure [46]. This extension of zone two can amplify the increase in vascular resistance caused by inflation and augment tidal intramural pressure changes and stresses within the vessels located upstream from the narrowed and/or collapsed vessels. Consequently, alveolar collapse that occurs in the course of mechanical inflation tends to redistribute flow toward extra-alveolar vessels, thereby increasing their transmural pressure and rates of fluid filtration.

During positive pressure ventilation, the majority of capillaries embedded within the alveolar wall are compressed by the expansion of adjoining alveoli. At the same time, lung expansion decreases interstitial pressure, which increases the transmural pressure of the vessels in the intermediate segment of small, fragile vessels (Figure 2). Raising pre-capillary and/or reducing post-capillary microvascular pressures simultaneously, increases the pressure gradient and energy dissipated across this middle segment of the pulmonary microvasculature. These actions appear to worsen edema and/or accentuate barrier injury when airway mechanical stresses are sufficiently high [40]. On the other hand, cyclic opening and closure of the microvessels may amplify shearing forces and stretching of the vascular endothelium (similar to that undergone by the alveolar wall), with the potential to initiate inflammation-mediated tissue breakdown. By promoting alveolar vascular collapse and amplifying extra-alveolar vascular stress, excessive reductions in lung volume and microvascular pressure have the potential to contribute to VILI [39].

If raising pre-capillary microvascular pressure and reducing post-capillary pressure might both amplify VILI, how can pre-capillary microvascular pressure be reduced without compromising systemic organ perfusion or lowering pulmonary post-capillary pressures excessively? Blood flow and oxygen consumption are linked variables. It follows that reducing tissue demands for oxygen also reduces the blood flow through the lung, which apart from lowering the ventilating power need also decreases both upstream microvascular pressure and the luminal transcapillary pressure gradient. Although more studies are clearly necessary to determine the exact relationship between vascular pressure and lung injury, it would seem prudent to diminish unnecessary demands for ventilation and cardiac output; the direct clinical implication is that conditions of agitation, high fever, pain and elevated work of breathing should be avoided if potentially damaging alveolar pressures must be applied.

Extensive acute lung injury occurring in the COVID-19 pandemic has renewed interest in the role of the pulmonary vasculature in its pathogenesis. SARS-CoV-2 promotes endothelial dysfunction, vasoregulatory dysfunction, vascular leak, and microthrombi [47]. Ackermann, et al. [48] reviewed autopsy findings in COVID-19 ARDS lungs and compared them to those of influenza associated respiratory failure. They found COVID-19 infected lungs were unique in the extensive presence of intracellular SARS-CoV-2 and disruption of endothelial cell membranes. These findings were associated with widespread vascular thrombosis with microangiopathy and ‘intussusceptive angiogenesis’. Interestingly, the lung weight of COVID-ARDS was significantly less than influenza-related ARDS. Moreover, significantly increased numbers of inflammatory CD3+ t-cells within the pre-and post-capillary vessel walls suggested ‘angiocentric inflammation’. Also notable, COVID-19 lungs revealed nine times the alveolar capillary microthrombi compared to influenza. The occlusion of alveolar capillaries appears to have contributed to profound hypoxia and hypercarbia of COVID-19 ARDS, irrespective of the level of parenchymal injury [48].

Maintenance of appropriate thermoregulation is essential for normal cellular functioning. Beyond certain defined physiologic limits, enzymatic performance may be either induced or impaired, distorting the mechanisms of normal homeostasis. Extremes of temperature may culminate in protein degradation or overt cellular disruption. The pace at which temperature aberrations are accomplished strongly impacts their ultimate physiologic effects. Slowly cooling into the range of tolerable hypothermia slows metabolic processes sufficiently to allow tolerance to certain high risk surgical procedures. It has also been demonstrated that induced hypothermia of modest proportions may improve the prognosis of cardiac arrest [49].

Preconditioning is a process whereby cells or tissues exposed to a sub-lethal stimulus are transiently protected from a subsequent noxious stress. When preconditioning is conducted using a stressful stimulus (e.g. high temperatures) applied for a tolerable interval, Heat Shock Proteins (HSP) are elaborated [50-52]. These HSPs act as molecular chaperones against injury for certain classes of vital intracellular proteins, preventing their premature folding and denaturation and allowing normal protein assembly and interactions to proceed under otherwise adverse environmental conditions. Thermal preconditioning attenuates VILI-associated decreases in lung compliance, reduces the production of inflammatory cytokines, and increases the percentage of large surfactant aggregates (the active form) [53]. Following thermal exposure, full expression of HSP requires hours to develop. It has been demonstrated that experimental animals that have been pre-stressed by heat exposure are more resistant to the adverse effects of such noxious influences as endotoxin when later exposed to it [54]. In this context, the protective effects of pre-stressing could theoretically attenuate VILI, as well. This possibility, however, currently remains unproven.

This concept of preconditioning has been beneficial in other aspects of lung injury. Gradual imposition of a purely mechanical ventilation stress may improve tolerance to it. This principle has been convincingly shown experimentally for recruiting maneuvers [55], large tidal volumes [56], increments of PEEP [57] and higher frequency [58].

In this context, the pace and timing of non-ventilatory interventions may also influence their actions. Although appropriate heat pre-conditioning may be lung protective, heat exposure occurring simultaneously with high pressure ventilation accentuates rather than attenuates VILI [59]. Presumably, the heat shock class of proteins has not yet been elaborated during simultaneous exposure to heat and mechanical stress, whereas destructive inflammatory enzymes are up-regulated, edema clearance mechanisms are overwhelmed, and/or metabolic demands outstrip the delivery of vital energy substrates. Moderate cooling of experimental animals also appears to afford a VILI-protective effect when the mechanical stress is applied simultaneously with the cooling challenge [59].

Clinical studies have demonstrated that moderate to extreme hypothermia attenuates the adverse response in models of VILI induced purely by mechanical forces and in models characterized by pre-existing inflammation [59]. In animal models, rats undergoing high pressure ventilation showed less expression of systemic inflammatory markers (serum chemokines and cytokines) when performed under hypothermia than normo or hyperthermia [60]. Additional animal models have shown lower inflammatory markers (neutrophil counts and IL-1beta levels) in bronchoalveolar lavage fluid as well as lower lung weight ratios and histologic acute lung injury scores when ventilated under hypothermic conditions (27°C) [61].

While awaiting confirmation in patients, such observations illustrate the potential for thermal manipulation to reduce the risk of VILI. Although clearly of unproven benefit and certainly not yet advocated for clinical application, preventing hyperthermia when high alveolar pressures are necessary or even inducing mild hypothermia may eventually prove viable options to reinforce our approach to lung protective ventilation.

Inactivation of pre-formed surfactant results from exposure to the proteinaceous and often mediator-rich edema fluid that forms after breakdown of the alveolar-capillary barrier. Resulting alveolar instability predisposes to creation of high-stress parenchymal foci and to VILI. Seen from this vantage point, preventing transfer of noxious fluids to well-functioning lung units should help to preserve gas exchange and limit the injury process.

Perhaps in part for this reason, the lung has evolved as a segmented structure organized as parallel compartments connected by a branching common corridor. Because of this compartmentalized nature, the lung is well designed to confine regional damage to isolated lobes or segments. Furthermore, the spiraling array of segmental openings ensures that at any given time the feeder channels of some lung sectors are less gravitationally dependent than others, whatever the spatial orientation of the lung might be. Such geometry offers advantages when attempting to confine potentially damaging bio-fluids to their sites of origin and impede propagation of an initially regionalized injury [62,63].

In ARDS, bio-fluids initially fill the interstitial compartment and the alveolar airspaces once occupied by air (percentages of each depend on severity and phase of the inflammatory process). The edematous phase of biofluid mobility is short lived; however, in the initial hours of ARDS development the sheer volume of such fluid can potentially overwhelm anatomic defenses. Indeed, most experienced clinicians have occasionally encountered rapid and poorly explained patient deterioration shortly after intubation. One might speculate that in such cases deep breathing and forceful exhalation are coupled with ineffective airway clearance just prior to initiating ventilator support. Post-intubation, deeper sedation, endotracheal intubation and adverse gravitational biases associated with unfavorable body positioning encourage propagation of injury via the airway passages.

While the resting functional residual capacity of an adult normally exceeds 2000 mL, the tracheo-bronchial tree accommodates little more than 150 mL, with only a minor fraction of that capacity residing in conducting airways <2 mm in diameter. Although liquid secretions are not commonly seen to enter the endotracheal tube (especially when PEEP is applied), it is not difficult to envision how the acutely flooded alveoli could extend injury rapidly, sector to sector by distributing mobile proteinaceous fluids through the airway network to previously unaffected lung units, as illustrated in figure 3.

Figure 3: Rapid evolution of ARDS in lobar pneumonia. Left panel reveals a spontaneously breathing patient, with left lower lobe consolidation and infiltrates in that zone. The right panel illustrates radiograph taken within 24 hours. Frontal radiograph has evolved in typical pattern of ARDS after intubation and initiation of mechanical ventilation. There was no other clinical explanation for such rapid progression (ie heart failure, flash pulmonary edema, aspiration, etc.)

VILI is undoubtedly a dynamic and complex process that depends on considerably more than the augmented mechanical ventilation strategies targeting ‘safe’ airway pressures, tidal volumes, and mechanical power, which justifiably have received the most investigative attention over the last several decades. Yet, many laboratory experiments and observations have helped us to better understand the multiple cofactors that modulate VILI expression and have suggested novel therapeutic options. This review highlights those aspects of lung injury which may be readily modified by a bedside clinician. Not described are other factors which deserve further investigation regarding vulnerability to VILI development, such as the roles of age and gender [64,65]. Renewed research interest and closer attention to such non-mechanical co-factors of lung injury may further reduce the iatrogenic morbidity associated with the ventilation of patients with acute respiratory failure.

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