Principles of Lung-Protective Ventilation


Respiratory failure is a common and serious clinical condition in newborn infants that is associated with an increased risk of neonatal morbidity and mortality. Although respiratory failure occurs in both term and preterm infants, it is especially common in the latter group. Despite the fact that many of the very low birth-weight infants can initially be managed on noninvasive respiratory support, such as nasal continuous positive airway pressure, historically almost 70% of them have needed to be supported by invasive mechanical ventilation at some point during their admission. Unfortunately, in its goal to correct gas exchange, mechanical ventilation often results in secondary lung damage, also referred to as ventilator-induced lung injury (VILI). VILI is considered one of the major risk factors for the development of chronic pulmonary morbidity in newborn infants, that is, bronchopulmonary dysplasia (BPD). Studies in both animal models and humans have provided valuable insight into the mechanisms of VILI, and this knowledge has been used to develop so-called lung-protective ventilation strategies, aiming to minimize the risk of (respiratory) morbidity and mortality. This chapter will summarize the basic principles of VILI and the basic concepts of lung-protective ventilation strategies.

Neonatal Respiratory Failure

As noted previously, preterm infants are most at risk of respiratory failure. This is to a large extent explained by the fact that their lungs are both structurally and biochemically immature. This is reflected by surfactant deficiency (neonatal respiratory distress syndrome, i.e., RDS), which results in an increase in elastic recoil forces of the lung due to the higher surface tension at the alveolar/saccular air–liquid interface and a concomitant reduction in lung compliance. In addition, the end-expiratory lung volume (EELV) or functional residual capacity is reduced and unstable, because the excessively high compliance of the chest wall of the preterm infant is unable to counteract the increased recoil forces. A low EELV will lead to a further reduction in lung compliance, an increase in airway resistance, and an increase in work of breathing. Furthermore, collapse of saccules will increase intrapulmonary left-to-right shunting, leading to (severe) hypoxia and to uneven distribution of tidal volume. These physiologic concepts are also applicable to term infants although the immaturity of the respiratory system is much less compared with the preterm infant and the surfactant dysfunction is not caused by surfactant deficiency but surfactant inactivation (meconium aspiration syndrome or pneumonia) or loss of type 2 cell function (e.g., status post asphyxia neonatorum). Understanding these physiologic concepts is essential when designing and applying so-called lung-protective ventilation strategies.

Ventilator-Induced Lung Injury

Although BPD is considered a multifactorial disease, VILI remains an important determinant in its pathophysiology. Animal studies conducted since 1974 have greatly improved our knowledge about the mechanisms of VILI. These studies have identified the most important risk factors for VILI and its pulmonary and systemic consequences.

Risk Factors for VILI


In 1974 Webb and Tierney showed that the application of high peak inflation pressures during conventional mechanical ventilation resulted in alveolar and perivascular edema, leading to deteriorating lung mechanics and ultimately death in healthy rats. Additional experiments showed that application of high peak inflation pressures will damage the lung only if the thorax can freely expand and volume can enter the lungs. Preventing this expansion by thoracic strapping (low volume, high pressure) will protect the lung against VILI. These results clearly indicate that the volume entering the lungs (volutrauma) and not the pressure applied to the lungs causes VILI. The importance of volutrauma in the development of VILI has also been confirmed in preterm animal models.

Volutrauma is often thought to be equivalent to high tidal volume ventilation. Although this is true in most cases, it is important to realize that even low tidal volumes can induce volutrauma. First of all and explained in more detail in the next paragraph, low tidal volumes provided at the airway opening can result in regional overdistention if part of the lung is atelectatic. Second, if low tidal volumes are superimposed on a high EELV, the end-inspiratory lung volume can still exceed total lung capacity and result in volutrauma.


As previously discussed, neonatal respiratory failure is often accompanied by surfactant deficiency or inhibition, resulting in collapse of small airways and alveoli/saccules (atelectasis). Owing to the heterogeneous nature of lung disease and gravitational effects on the lung, the distribution and behavior of unstable lung units differ at the regional level. Roughly three zones can be identified ( Fig. 19-1 ): (1) alveoli that remain open during the entire ventilatory cycle, (2) alveoli that are recruitable during the inspiration phase but collapse during expiration, and (3) alveoli that remain collapsed during the entire ventilatory cycle. Alveoli in zone 2 will be subjected to repetitive opening and collapse during conventional (tidal) ventilation. Animal experiments in both adult and preterm models have shown that the repetitive tidal recruitment and collapse are injurious to the lung. As alveoli in zone 3 do not participate in tidal ventilation, the tidal volume administered to the lung during conventional ventilation is redistributed to the alveoli in the other two zones. This may increase the risk of regional overdistention (volutrauma) and subsequent VILI.

FIG 19-1

Schematic drawing of the zones of alveolar instability during conventional mechanical ventilation. Zone 1: alveoli that remain open during the entire ventilatory cycle. Zone 2: alveoli that are recruitable during the inspiration phase but collapse during expiration. Zone 3: alveoli that remain collapsed during the entire ventilatory cycle. exp , Expiration phase; insp , inspiration phase.

Oxygen Toxicity

Ventilation with high fractions of inspiratory oxygen concentrations can result in excessive production of oxygen radicals, overwhelming the normal antioxidant-detoxifying capacity of the cell and leading to VILI. Both animal and human studies have indicated that prematurity impairs the ability to increase antioxidant enzymes in response to hyperoxia, making this group of patients extremely vulnerable to oxidative stress often present after preterm birth. Low EELV results in high oxygen requirement due to poor ventilation/perfusion matching and intrapulmonary right-to-left shunt, thus contributing to oxidative stress.

Pulmonary and Systemic Consequences of VILI

Structural Injury

Volutrauma can cause direct structural injury to the alveolar–capillary unit. Coexistence of atelectatic and open alveoli may further increase this risk owing to so-called shear forces that exceed transpulmonary pressures. Finally, hyperoxia can have a direct cytotoxic effect on alveolar endothelial and epithelial cells. This loss of structural integrity will increase endothelial and epithelial permeability, leading to pulmonary edema and hemorrhage.


In vitro studies have shown that cyclic stretch of alveolar epithelial cells and alveolar macrophages stimulates the production of proinflammatory cytokines such as tumor necrosis factor α and interleukin-8 (IL-8). Ex vivo and in vivo animal studies showed that volutrauma, atelectrauma, and especially the combination of these risk factors result in a significant inflammatory response in the lung. Pulmonary inflammation is further upregulated by hyperoxia, which stimulates neutrophil migration into the alveoli and enhances proinflammatory cytokine response of alveolar macrophages.

One of the changes induced by the production of proinflammatory mediators like IL-8 is the recruitment of polymorphonuclear (PMN) white blood cells in the lung. PMN cells can inflict tissue damage through the release of proteases, the production of reactive oxygen species, and the release of cytokines. The importance of PMN cells in the development of VILI has been shown by Kawano et al., who found little evidence of VILI in rabbits depleted of granulocytes prior to initiation of injurious conventional ventilation.

In addition to upregulation of local inflammation in the lung, there is now also evidence from both experimental and human data that injurious ventilation will also lead to a decompartmentalization of inflammatory mediators into the systemic circulation, possibly leading to multiple organ failure.

Surfactant Dysfunction

Although surfactant dysfunction is often already present at the start of invasive respiratory support, conventional mechanical ventilation may further compromise its function.

As previously mentioned, VILI is often accompanied by an increased permeability of both the endothelial and the epithelial barriers, promoting an influx of plasma proteins in to the alveolar space. It has been shown that these proteins result in a dose-dependent inhibition of surfactant.

Studies investigating the alveolar metabolism of pulmonary surfactant have shown that surfactant exists in different subfractions. The two major subfractions of surfactant obtained from lung lavage material are large aggregates (LA) and small aggregates (SA). LA surfactant is able to lower alveolar surface tension, but SA surfactant is not surface active and is the metabolic product of the LA fraction. Animal experiments have shown that the conversion from LA to SA surfactant is increased when high tidal volumes are applied during ventilation of the injured lung. The increased conversion of surfactant has also been documented in newborn and adult patients with acute lung injury.

Animal experiments have shown that ventilation can enhance the secretion of endogenous surfactant by the type 2 cells. This surfactant can subsequently be squeezed out of the alveolar space into the small airways as a result of compression of the surfactant film when the surface of the alveolus becomes smaller. Ex vivo experiments in rat lungs showed that this movement of surfactant into the airways is directly related to the tidal volume and inversely related to the end-expiratory pressure. Hyperoxia results in both inactivation and decreased synthesis of pulmonary surfactant, resulting in a deterioration of lung mechanics.

Lung Development

Experimental studies in preterm animal models have shown that mechanical ventilation and hyperoxia are able to arrest the normal alveolarization process during lung development. This arrest in lung development is considered one of the histologic hallmarks of the “new” BPD and highlights the link between mechanical ventilation, VILI, and the development of BPD.

Susceptibility of Newborn Lungs to VILI

Animal experiments have shown that the magnitude of VILI is highly dependent on the condition of the lung at the start of mechanical ventilation. Exposing the preterm lungs antenatally to intra-amniotic endotoxin before starting mechanical ventilation after birth results in a more pronounced inflammatory response compared to subjecting the lungs to either of these insults alone. The same is true when exposing the lungs to postnatal inflammation by systemic injection of endotoxin. These experiments strongly suggest that the inflammatory status of the lungs is an important mediator in the effect of mechanical ventilation on lung injury. In addition to inflammation, the surfactant status of the lungs also seems to be an important mediator of VILI. Applying high-pressure ventilation to surfactant-deficient lungs results in more VILI compared to similar ventilation given to surfactant-sufficient lungs.

These experimental results suggest that preterm lungs are highly susceptible to VILI, as antenatal inflammation (chorioamnionitis), postnatal inflammation (sepsis, pneumonia), and surfactant deficiency (RDS) are often present in the preterm population and are reasons for starting invasive mechanical ventilation.

Studies in preterm animal models also suggest that just a few injurious inflations administered immediately after birth are sufficient to trigger the cascade of VILI.

Lung-Protective Ventilation: Basic Principles

The basic goal of lung-protective ventilation is to establish an acceptable level of gas exchange while minimizing VILI as much as possible. Based on the experimental data on the pathogenesis of VILI, the cornerstones of a lung-protective ventilation strategy are (1) minimizing end-inspiratory (alveolar) overdistention (volutrauma) and (2) optimizing EELV by reversing atelectasis (recruitment) and stabilizing lung units throughout the ventilatory cycle (avoiding atelectrauma). Applying such a strategy will often improve oxygenation and allow for a reduction in the fraction of inspired oxygen (less oxygen toxicity). A lung-protective ventilation strategy based on these principles is often referred to as an optimal lung volume strategy or open lung ventilation strategy .

Minimizing Volutrauma

Minimizing volutrauma has mainly been associated with reducing tidal volume during mechanical ventilation. Indeed, animal studies have shown that reducing alveolar overdistention by limiting tidal volumes during mechanical ventilation will attenuate VILI. However, it is important to realize that it is equally important to distribute the tidal volume evenly into optimally inflated and adequately recruited lungs; small tidal volumes can still result in (regional) volutrauma if superimposed on a relatively high EELV or administered during heterogeneous lung disease with significant atelectasis.

Minimizing Atelectrauma

It is essential to realize that in a diseased lung, the reduction of atelectasis is based on two principles. First, already collapsed alveoli/saccules need to be reopened or recruited by applying sufficient inflation pressure. Second, after recruitment, sufficient (end-expiratory) airway pressure should be applied to stabilize the lung volume and prevent subsequent collapse during expiration. Figure 19-2 shows the pressure–volume (P/V) relationship of an individual alveolus. Staub and colleagues proposed that the behavior of alveoli is quantal in nature. After reaching a critical opening pressure the collapsed alveolus pops open, immediately resulting in a large volume (radius) increase. As follows from the law of LaPlace, which states that the pressure (P) necessary to keep a spherical structure opened is two times the surface tension (γ) divided by the radius (r), the critical closing pressure of the alveolus will be lower than the opening pressure.

FIG 19-2

Schematic drawing of the pressure–volume relationship of a single alveolus during inspiration and expiration ( solid line ). At the start of the inflation (A) the alveolus is collapsed. At point B, the pressure increase has reached the critical opening pressure (Po), leading to an immediate volume increase ( dashed line ) as the alveolus is recruited (D). As the pressure is slowly decreased there is little volume loss until the critical closing pressure (Pc) is reached at point C. The alveolus immediately collapses to point A. Note that Pc is lower than Po owing to the law of LaPlace.

The P/V curve of the entire lung, as shown in Figure 19-3 , will be the cumulative relationship of all alveoli/saccules of the lung, each with a different severity of lung disease and thus a different opening and closing pressure. The inflation limb of the P/V curve shows the changes in lung volume during incremental airway pressures and usually contains a so-called lower inflection point above which lung volume suddenly increases in a linear fashion. As lung volume approaches total lung capacity (TLC) the inflation limb flattens off. The deflation limb represents the changes in lung volume during decremental airway pressure steps starting at TLC. Again, as explained by the law of LaPlace, lung volume is initially maintained as pressures are lowered but eventually decreases owing to progressive alveolar collapse as the distending pressure drops below the critical closing pressure. The clear difference in lung volume at identical airway pressures between the inflation and the deflation limb of the P/V relationship is called lung hysteresis . Studies in newborn infants have shown that lung hysteresis is present in preterm infants with RDS and term infants with more heterogeneous causes of lung disease.

FIG 19-3

Pressure–volume relationship of the lung showing the inflation ( red line ) and the deflation limb ( green line ). Note the clear difference in lung volume between the limbs at identical pressures ( hysteresis ).

It was initially assumed that lung recruitment occurred primarily around the lower inflection point of the P/V curve. However, observations in adults and newborn infants have indicated that recruitment occurs along the entire inflation limb of the P/V curve. Although sometimes stated differently, the inflation pressures or volumes, and not positive end-expiratory pressure (PEEP), are responsible for alveolar recruitment during conventional ventilation. PEEP is an expiratory phenomenon, and its main purpose is to stabilize the previously opened alveoli and thereby prevent subsequent collapse during expiration. Failing to recruit the lungs prior to or concomitant with increasing PEEP will not prevent VILI. On the other hand, recruiting the lungs but applying insufficient PEEP to prevent subsequent collapse will augment rather than reduce lung injury.

It was also believed that the optimal PEEP levels preventing alveolar collapse should be above the lower inflection point of the P/V curve. However, experimental and human data have shown that the critical closing pressure of the lungs is not related to the lower inflection point.

Both mathematical models and animal experiments have shown that adequate recruitment of collapsed alveoli, followed by optimal stabilization with adequate levels of PEEP, will place ventilation on the deflation limb of the P/V curve. This position will improve compliance and reduce VILI compared to ventilation on, or close to, the inflation limb of the P/V curve.

As most underlying lung diseases causing neonatal respiratory failure are heterogeneous in nature, regional overdistention of relatively healthy lung parts has been a major concern during recruitment. Although this concern seems valid, there is little evidence that recruitment maneuvers actually damage the lungs if accompanied by sufficient PEEP. More importantly, to date most experiments have indicated that derecruitment is more injurious than recruitment.

One of the difficulties of practical implementation of lung recruitment is the lack of tools that can assess changes in EELV in ventilated newborn infants at the bedside. Although often used in clinical practice, chest radiography provides only general information on lung aeration at one point in time and does not seem to correlate well with actual lung volumes. This may in part be caused by suboptimal technique in terms of centering of the film and the difficulty in timing exposure at a particular point in the respiratory cycle at rapid respiratory rates. Tracer gas washout techniques can be used to measure changes in EELV, but they do not provide continuous information and are not applicable during high-frequency ventilation. Respiratory inductive plethysmography has been successfully used in newborn infants to measure changes in EELV and to reconstruct the P/V relationship of the lung. However, its application is hampered by signal instability over time, especially in unsedated non-muscle-relaxed infants. Another disadvantage that applies to all of the aforementioned techniques is the inability to differentiate between lung volume changes caused by alveolar recruitment (which is the aim of volume optimization) and those caused by alveolar distention (of already open alveoli). A more recent imaging technique called electrical impedance tomography does provide regional information on changes in lung aeration and has been successfully used in (preterm) infants. However, the hardware, software, and patient interface of this technique need to be improved before it can be used in daily clinical practice.

Owing to these limitations of the currently available monitoring tools, most clinicians use oxygenation as an indirect tool to measure changes in lung volume at the bedside. The basic principle is illustrated in Figure 19-4 . In a collapsed alveolus, blood flowing through the alveolar–capillary unit will not be able to take up oxygen before returning to the left atrium. This is called intrapulmonary right-to-left shunting, which results in hypoxemia. If the alveolus is recruited with sufficient airway pressure, gas exchange will be restored at the alveolar level, resulting in an improvement of the ventilation/perfusion ratio reflected by improved oxygenation. Increasing the airway pressure further will increase the volume of the alveolus (distention) but will not affect the ventilation/perfusion ratio. In the case of overdistention, the capillaries will be compressed, resulting in increased alveolar dead space and hypercarbia. The same concepts also apply when reducing the airway pressure once the alveolus is recruited. This means that oxygenation is able to differentiate between volume changes based on alveolar recruitment and distention.

FIG 19-4

Basic principle of oxygenation-guided recruitment illustrated by one alveolar–capillary unit. A, Collapsed but perfused alveolus with no uptake of oxygen in the bloodstream. Blood returns to the left atrium in a hypoxic state. This is called intrapulmonary right-to-left shunting . B, The increased airway pressure exceeds the critical opening pressure of the alveolus, resulting in opening of the alveolus, a (rapid) volume increase, and an uptake of oxygen owing to the optimal ventilation/perfusion match. This process is called recruitment. C, A further increase in pressure will distend the already open alveolus, resulting in an increase in volume but no change in the optimal ventilation/perfusion match. This process is called distention. D, A further increase in pressure will result in overdistention of the alveolus, resulting in absent perfusion owing to compression of the alveolar blood vessels. This will result in an increase in (alveolar) dead space and rising P co 2 .

Lung-Protective Ventilation: Conventional Mechanical Ventilation

Conventional mechanical ventilation is the most frequently used modality in newborn infants. It is a broad term for various modalities that all use the concept of tidal ventilation. In this section we will focus on the various elements of lung protection during conventional mechanical ventilation without going into the specifics of the available conventional ventilation modes. For these details the reader is referred to other chapters in this textbook.

Low Tidal Volume Ventilation

Based on the experimental evidence that higher tidal volumes can lead to VILI, experts have advocated targeting a tidal volume between 4 and 7 mL/kg during conventional mechanical ventilation in (preterm) infants. The evidence to support this recommendation, however, is limited. As of this writing, there are no large randomized controlled trials comparing higher and lower tidal volumes and their impact on clinically relevant outcomes, such as BPD. A small clinical trial comparing a tidal volume of 3 mL/kg with 5 mL/kg in preterm infants with RDS showed an increased inflammatory response in the tracheal aspirates of infants treated with 3 mL/kg. This study seems to suggest that tidal volumes below 4 mL/kg combined with a relatively low PEEP of 3 to 4 cm H 2 O may cause lung injury, probably due to alveolar collapse. Other studies have indicated that the optimal tidal volume in terms of gas exchange is probably not a fixed number but instead a dynamic parameter that changes over time.

Tidal Volume Stabilization

Pressure-limited ventilation, the most widely used mode in neonatology, delivers a preset inflation pressure above PEEP during each mechanical inflation. Although the inflation pressure is initially set to target an appropriate tidal volume, the actual delivered tidal volume is dependent on the compliance and resistance of the respiratory system and the patient’s own effort. As these variables change, delivered tidal volumes may become too high or too low, thereby increasing the risk of VILI. Applying volume-targeted ventilation will result in a more stable tidal volume and less VILI. A systematic review of the (small) randomized controlled trials comparing volume-targeted to pressure-limited ventilation in preterm infants suggests that this approach also translates into a reduced risk of BPD.

Permissive Hypercarbia

In an attempt to reduce tidal volume as much as possible, some clinicians accept higher carbon dioxide levels during mechanical ventilation, a strategy also referred to as permissive hypercarbia. Despite the fact that experimental evidence suggests a protective effect on the lungs, studies in ventilated preterm infants did not show a clear benefit in terms of BPD-free survival. Of concern, one of these studies suggested that permissive hypercarbia was associated with worse neurodevelopmental outcome at 2 years’ corrected age.

Open Lung Ventilation

As previously mentioned, an open lung ventilation strategy aims to optimize lung volume by recruiting and stabilizing unstable lung units and by ventilating the lungs with low tidal volumes. Animal studies have shown that such an open lung ventilation strategy is feasible during positive-pressure ventilation using relatively high peak inflation pressures and PEEP to, respectively, recruit and stabilize the lung. Open lung positive-pressure ventilation (PPV) improves gas exchange and attenuates VILI compared to more conventional ventilation strategies. These beneficial effects are similar during open lung PPV and open lung high-frequency ventilation, suggesting that the open lung ventilation strategy is probably more important than the ventilation mode.

Despite these promising animal data, studies on open lung PPV in human infants are limited. As of this writing, only one study has assessed the short-term benefits of open lung PPV in preterm infants with RDS. This study reported better oxygenation and shorter oxygen dependency.

Several studies explored the short-term effects of various levels of PEEP without a recruitment procedure during conventional mechanical ventilation in preterm infants. Higher levels of PEEP improved functional residual capacity and oxygenation but also resulted in a reduction in lung compliance and higher carbon dioxide levels. These findings may reflect failure to achieve lung recruitment before increasing PEEP. Unfortunately, the effects on markers of VILI or the incidence of BPD were not reported. Another study explored the effects of a higher versus a lower PEEP in term infants on extracorporeal membrane oxygenation and showed that lung function was better preserved by using higher PEEP levels, resulting in a more rapid recovery.

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Jan 30, 2019 | Posted by in PEDIATRICS | Comments Off on Principles of Lung-Protective Ventilation
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