Ventilator strategies to reduce lung injury and duration of mechanical ventilation

Introduction

Despite appropriate emphasis on noninvasive respiratory support when feasible, mechanical ventilation (MV) remains a mainstay of therapy in many extremely preterm infants. Although frequently life-saving, invasive MV has many untoward effects on the brain and the lungs, especially in the most immature infants. The endotracheal tube (ETT) acts as a foreign body, quickly becoming colonized with nosocomial organisms and acting as a portal of entry for pathogens, potentially leading to ventilator-associated pneumonia and late-onset sepsis. For these reasons, avoidance of MV in favor of noninvasive respiratory support is considered one of the most important steps in preventing neonatal morbidity. When MV is required, the goal is to wean the patient from invasive ventilation as soon as feasible in order to minimize ventilator-associated lung injury (VALI). While VALI is a key element in the pathogenesis of bronchopulmonary dysplasia (BPD), many other factors play an important role in its pathogenesis, including the intrauterine environment (inflammation and infection), postnatal infection, oxidative stress, impaired intrauterine and postnatal nutrition, and excessive fluid administration. The long-accepted causative role of patent ductus arteriosus (PDA) has more recently been brought into question. While there is clearly an association between PDA and BPD, there is no clear evidence that medical or surgical closure of the ductus reduces the incidence of BPD, other complication of prematurity, or that it shortens the duration of MV.

Ventilator-associated lung injury

Many terms have been used to describe the mechanism of injury in VALI. Barotrauma refers to damage caused by inflation pressure. The conviction that pressure is the major determinant of lung injury has caused clinicians to focus on limiting inflation pressure, often to the point of precluding adequate support. However, available evidence indicates that high inflation pressure by itself, without correspondingly high tidal volume (V _T ), does not result in lung injury. Rather, injury related to high inflation pressure is mediated through tissue stretch resulting from excessive V _T or from regional overdistention when ventilating lungs with extensive atelectasis results in maldistribution of the tidal volume. Dreyfuss and colleagues demonstrated more than 30 years ago that severe acute lung injury occurred in small animals ventilated with large V _T , regardless of whether that volume was generated by positive or negative pressure. In contrast, animals exposed to the same high inflation pressure but with an elastic bandage over the chest and abdomen to limit chest wall excursion and thus V _T had much less evidence of lung injury. Similarly, Hernandez et al. demonstrated that animals exposed to pressure as high as 45 cm H ₂ O did not show evidence of acute lung injury when their chest and abdomen were enclosed in a plaster cast. Volutrauma refers to injury caused by overdistention and excessive stretch of tissues, which leads to disruption of alveolar and small airway epithelium resulting in acute edema, outpouring of protein-rich exudate that inactivates surfactant, and release of proteases, cytokines, and chemokines. This in turn leads to activation of macrophages and invasion of activated neutrophils. Collectively, this latter process is referred to as biotrauma . Another important concept is that of atelectrauma or lung damage caused by tidal ventilation in the presence of atelectasis. Atelectrauma causes lung injury via several mechanisms. The portion of the lungs that remains atelectatic experiences increased surfactant turnover and has high critical opening pressure. There are shear forces at the boundary between the aerated and atelectatic parts of the lung, leading to structural tissue damage. Ventilation of injured lungs using inadequate end-expiratory pressure results in repeated alveolar collapse and expansion and rapidly injures the immature lungs. Perhaps most importantly, when a portion of the lungs is atelectatic, any gas entering the lungs will preferentially distend the aerated portion of the lung, which is more compliant than the atelectatic lung with its high critical opening pressure. This fact is evident from Laplace’s law (pressure = 2 × surface tension/radius) and corroborated by experimental evidence, showing that the most injured portion of the lung was the aerated nondependent lung. This maldistribution of V _T leads to overdistention of that portion of the lungs and regional volutrauma. Thus, VALI is initiated by some form of biophysical injury, which in turn triggers a release of proinflammatory mediators from activated leukocytes leading to biotrauma and initiates the complex cascade of lung injury and eventual repair. A schematic representation of the cycle of VALI is illustrated in Fig. 10.1 .

How can we reduce VALI?

As is evident from the prior discussion, the process of lung damage from MV is multifactorial and cannot be linked to any single variable. Consequently, any approach to reducing lung injury and minimizing the length of MV must be comprehensive and begin with the initial stabilization of the infant in the delivery room. Because some degree of impairment of normal pulmonary development (i.e., arrest of alveolarization) is probably inevitable when an extremely preterm fetus is suddenly thrust into what by fetal standards is a very hyperoxic environment and must initiate air breathing with lungs that are incompletely developed, it is unlikely that improved respiratory support can completely prevent impairment of lung structure and function. However, optimal respiratory and general supportive care can minimize the superimposition of VALI on this developmental arrest and together with optimal nutrition can facilitate lung growth and repair.

Delivery room stabilization

The time immediately after birth when air breathing is initiated in structurally immature surfactant deficient lungs is known to be a critical time during which the process of lung injury and subsequent repair may be triggered in a matter of minutes. Moments after birth, the newborn infant must rapidly clear lung fluid from the airways and terminal air spaces, aerate their lungs, and sustain a functional residual capacity (FRC), thus facilitating a dramatic increase in pulmonary blood flow. Vigorous full-term infants achieve this critical transition quickly and effectively, but this is a much greater challenge for the very preterm infants who may be unable to generate sufficient critical opening pressure to achieve adequate lung inflation because of their limited muscle strength, excessively compliant chest wall, limited surfactant pool, and incomplete lung development. The excessively compliant chest wall of the preterm infant fails to sustain the lung aeration that may have been achieved spontaneously or with positive pressure ventilation. For the same reasons, these infants may be unable to generate sufficient negative intrathoracic pressure to effectively move lung fluid from the air spaces to the interstitium, lymphatics, and veins. Subsequent tidal breathing, both spontaneous and that generated by positive pressure ventilation, occurs in lungs that are still partially fluid-filled and incompletely expanded. This situation leads to maldistribution of tidal volume to a fraction of the preterm lung, a phenomenon that can generate excessive tissue stretch even when a tidal volume generally thought to be safe is used.

The use of positive end-expiratory pressure (PEEP) and/or continuous positive airway pressure (CPAP) during the initial stabilization of preterm infants compensates for the excessively compliant chest wall and surfactant deficiency by stabilizing alveoli during the expiratory phase and has been shown to facilitate establishment of FRC. Both NRP and ILCOR guidelines give a qualified endorsement to the use of PEEP/CPAP, but cite lack of high-quality randomized controlled trials (RCTs) to make a stronger recommendation. However, the physiologic rationale and experimental evidence from preclinical studies is so persuasive that this practice has become the de facto standard of care in much of the developed world and thus an RCT would be very difficult to undertake. Although there are no data on the optimal end-expiratory pressure level to maintain FRC without inducing lung injury, there is a strong rationale for continuous application of the end-expiratory pressure and avoidance of any disconnection that results in loss of FRC. Provision of the usual level of end-expiratory pressure alone may not sufficiently address the inadequate muscle strength of the preterm infant or help clear lung fluid rapidly enough to avoid regional volutrauma and atelectrauma. Owing to the much greater viscosity of liquid compared to air, resistance to moving liquid through small airways is much greater than that for air, making the time constants required to move fluid through the airways much longer. These considerations support the concept that a prolonged (AKA “sustained”) inflation applied soon after birth should be more effective in clearing lung fluid in the first minutes of life than the typical short inflations used during positive pressure ventilation. It has been proposed that rapid and effective lung recruitment that results in even distribution of V _T immediately after birth should reduce VALI. Early evidence supported the theoretical advantages of sustained inflation in preterm infants, ^, but the potential for harm from overdistention was also evident. Subsequent studies did not offer evidence that sustained inflation reduces VALI. The largest RCT to date failed to substantiate any benefit of sustained inflation in the most vulnerable infants < 27 weeks’ gestation and was terminated early because of an increase in early neonatal mortality in the intervention arm. A subsequent meta-analysis concluded that there is no evidence to support the routine use of sustained inflation in the care of extremely low-birth-weight (ELBW) infants. A novel approach to the effort to facilitate uniform lung expansion soon after birth in preterm infants is being tested in a large multicenter trial, which compares the use of standard static PEEP to a titrated PEEP strategy that seeks to tailor the level of distending pressure to each infant’s need based on initial response (Australian New Zealand Clinical Trials Registry ACTRN12618001686291).

Noninvasive respiratory support

Avoiding MV reduces iatrogenic lung injury, though the magnitude of this benefit is much more modest than early cohort comparisons of CPAP versus MV suggested. A meta-analysis of four large trials that enrolled nearly 2800 preterm infants showed that BPD rates alone were not significantly different between infants randomized to MV and those assigned to nasal CPAP (32.4% vs. 34.0%). However, the more important combined outcome of death or BPD (death and BPD are competing outcomes) showed a nearly 10% reduction (RR, 0.91; 95% CI, 0.84–0.99) with a number needed to treat of 25. There was also a significant decrease in the duration of MV and a trend toward shorter duration of supplemental oxygen with early CPAP in two of the trials. ^,

Nasal intermittent positive-pressure ventilation (NIPPV), if delivered effectively, may be able to augment an immature infant’s inadequate respiratory effort without the complications associated with endotracheal intubation. This approach has the benefit of avoiding the use of an ETT, thus reducing the incidence of VALI and ventilator-associated pneumonia, and avoiding the contribution of postnatal inflammatory response to the development of BPD. A meta-analysis of several small single-center studies concluded that NIPPV was superior to CPAP in preventing extubation failure, especially when NIPPV was synchronized with the infant’s respiratory effort, but a subsequent large multinational randomized trial in ELBW infants failed to show any benefits with no reduction in BPD, mortality, or the combined outcome. Current evidence suggests that unsynchronized NIPPV rarely generates a measurable tidal volume, likely because the vocal cords are closed except when the infant is actively breathing in. The cyclic inflation, however, does result in a higher mean airway pressure and it is likely that this higher distending pressure accounts for some of the observed benefits of NIPPV (primarily in reducing postextubation failure) in the most recent Cochrane Review. Buzzella et al. demonstrated that the use of higher, as opposed to lower CPAP level following extubation significantly reduced CPAP failure, providing the explanation for the apparent superiority of NIPPV over CPAP. Studies are underway to test the hypothesis that CPAP and NIPPV are equivalent when used at the same mean airway pressure. Nasal high-frequency oscillatory ventilation (HFOV) has also been explored by several groups, but as of this writing, the suggestion of efficacy is only based on case reports and small series. Noninvasive neurally adjusted ventilatory assist (NIV-NAVA) uses the electrical activity of the diaphragm (EAdi) to trigger ventilator inflations and is thus not affected by leakage of a noninvasive interface; it may thus be the best tool to deliver noninvasive ventilation in small preterm infants. However, definitive studies are still lacking.