PEDIATRICS Vol. 105 No. 1 January 2000, pp. 112-114

COMMENTARY:
Lung Protective Strategies of Ventilation in the Neonate: What Are They?

In the July 1999 issue of the Journal of the American Medical Association, Dr Leonard Hudson proclaims that "the concept of ventilator-induced lung injury (VILI) has come of age."¹ His comments were derived from a report by Ranieri et al² which shows that a "lung-protective strategy" of respiratory support reduces cytokine levels in both the bronchoalveolar lavage fluid and serum of adult patients with acute respiratory distress syndrome (ARDS). Dr Hudson's enthusiasm is increased by the recent press release from the National Institutes of Health (NIH) ARDS Network Study, reporting positive results of a study evaluating a "lung-protective strategy" in >800 adults with ARDS. The NIH study was stopped early, when the safety monitoring committee noted "25% fewer deaths" among patients receiving small (6 mL/kg) rather than large (12 mL/kg) tidal volumes to support gas exchange.

The importance of these observations is that they provide data in support of the hypothesis that VILI can cause biotrauma associated with a "mediator storm" (perhaps cytokines) that is responsible for distal organ dysfunction, subsequent multiorgan failure, and death.³ These adult data unequivocally prove that how we support gas exchange in patients with lung disease markedly affects outcome.

Although it has been shown that pulmonary cytokine levels also appear to be elevated in some neonates on assisted ventilation, an exact relationship to neonatal lung injury has not yet been well defined.^4-7 Proinflammatory mediators may be elevated because of fetal exposure to maternal inflammatory mediators, postnatal infection, or by release from preterm lungs attributable to ventilator-induced injury.⁵ The neonatal lung is still in stages of development and growth, therefore cytokine responses and effects may be immature and different from what is seen in adults. Indeed, data from Kwong et al^8,9 suggests a possible relationship between cytokine signaling and lung generation. However, these data do not minimize the compelling evidence establishing the presence of VILI in the neonate.^510-16

The most common reason neonates need respiratory support is because of respiratory distress syndrome (RDS). In this disease, the pathophysiology is one of progressive loss of lung volume, intrapulmonary shunt, and deflation instability. Animal models of RDS clearly show that ventilator strategy alters the clinical and pathologic evolution of RDS. In addition, it is well known that neonates with RDS are susceptible to lung injury and the subsequent development of chronic lung disease.

In 1989, Meredith et al¹⁵ reported the landmark observation that lung injury caused by a commonly used but inappropriate ventilatory strategy (in this case: large tidal volumes and insufficient positive end-expiratory pressure [PEEP]) contributed to the development of RDS in premature baboons. Use of high-frequency ventilation (HFV) with small tidal volumes prevented the development of hyaline membrane disease, the pathologic correlate of RDS. These experiments in the baboon model of RDS showed striking pathologic differences between animals supported with conventional ventilation and those supported with low tidal volume, oscillatory ventilation.

A sentinel point often missed in Dr Meredith's paper is that tidal volume was limited but not at the expense of lung recruitment. The ventilatory strategy used by Meredith et al¹⁵ was to maximally recruit the lung with a high mean airway pressure and then use oscillatory ventilation to maintain a normal PaCO₂. Although this approach improved oxygenation and ventilation, there were clinical signs of cardiac compromise. In a subsequent study, Kinsella et al¹⁴ showed that the problems with cardiac compromise could be avoided if, after the lung was recruited, the mean airway pressure was gradually decreased as dictated by chest radiograph and oxygenation (PaO₂/PAO₂). This strategy exploits the concept of lung pressure-volume hysteresis; namely once the lung is recruited, surfactant and alveolar interdependence act to keep it inflated. Mean airway pressure can be decreased without a great loss of lung volume, so long as the pressure is not decreased below the critical closing pressure of the lung. This approach is in accord with the pioneering work of Dr Bryan's group that demonstrated the protective effects of HFV if the lung was recruited.^13,17

When we consider the possible variables that can be adjusted (inspiratory time, PEEP, peak inspiratory pressure, volume limited, pressure limited assist control, synchronized, high-frequency oscillation, high-frequency jet ventilation, high-frequency flow interruption, rate) and the broad diversity of the diseases we treat (meconium aspiration syndrome, pneumonia, RDS, air leak, congenital diaphragmatic hernia, etc), it may appear that defining a "lung protective strategy" for the neonate will be extremely difficult. As in the experimental RDS model, providing lung protection during assisted ventilation for neonatal lung disease is entirely dependent on strategies that are individualized to the primary or underlying pathophysiology. For example, failure to define the mechanisms causing hypoxemia can lead to unsafe application of what would be life-saving respiratory support under different conditions. Use of higher levels of end-expiratory pressure will not help a patient who has idiopathic pulmonary hypertension and clear lung fields. In fact, the resultant lung overinflation will make gas exchange and hemodynamics worse. Increasing peak inspiratory pressures or tidal volumes to recruit the lung in a patient with RDS while using no end-expiratory pressure to maintain functional residual capacity is equally incorrect.

The critical issue that is highlighted by our increased understanding of VILI in the neonate is that each change in ventilatory strategy has a consequence. Small tidal volume ventilation at low lung volumes, even in normal lungs, is associated with progressive loss of lung volume and surfactant dysfunction. Physiologic levels of end-expiratory pressure must be applied to prevent the development of hypoxemia. This problem is made worse by diseases that cause surfactant dysfunction and make the lung prone to collapse. Limiting tidal volume requires higher levels of end-expiratory pressure and/or fraction of inspired oxygen (FIO₂) to maintain adequate oxygenation. Higher levels of FIO₂ can contribute to oxidant-induced lung injury. Defining lung protective strategies requires compromises between gas exchange goals and potential toxicities associated with overdistention, recruitment/derecruitment of lung units, and high oxygen concentrations.

Although the variety of ventilator choices is limitless, the underlying principles of neonatal lung protection are relatively straightforward. The most important issue is not the specific mode of ventilation, or the specific ventilator used, but rather a matching of a ventilatory strategy to the patient's underlying physiology. Current evidence strongly supports the following concepts:

1. Antecedent lung inflammation or injury makes the lung more susceptible to volutrauma and oxidant-induced lung injury.⁵
2. Lung injury promotes a cycle of inflammation that is not limited to the lung, but may also affect distant organs.²
3. Oxygen, when used at high concentration, can be toxic.^18,19
4. A major factor causing VILI is regional overdistension of lung units or airwaysincreased lung volume (stretch), and not pressure per se, promotes lung injury.^20-25 Compared with adults, neonates have compliant chest walls, so that at a given airway pressure, the relative degree of lung distension is greater than in the adult.
5. In patients with ARDS, the distribution of the underlying pathology is such that only a small portion of the lung is available for ventilation (usually the nondependent or anterior aspect in the supine position). The implication of this so called "baby lung"^26,27 concept to the neonate with RDS is that if only 1/3 of the lung is available for ventilation, then for a tidal volume of 10 mL/kg the ventilated portion of the lung would be stretched to an extent equivalent to 30 mL/kg in a healthy lung. Although the NIH ARDS trial data suggests targeting a tidal volume of 6 mL/kg, the appropriate value to avoid injury of the "baby, baby lung" of the neonate with RDS is unclear, and indeed depends on the degree of underlying injury.
6. Another major factor causing VILI relates to the concept of atelectrauma.²⁸ In patients with ARDS or RDS, in which there is surfactant dysfunction, alveolar units are prone to collapse. The cycle of recruitment and subsequent derecruitment of these units on each breath causes lung injury.²⁹ This mechanism of injury explains the observation that lung recruitment protects against VILI and also reduces the need for high levels of FIO₂. Using a lung recruitment maneuver and maintaining lung volume with PEEP, surfactant, liquid ventilation, or oscillatory ventilation at a mean airway pressure that is higher than that used on conventional support can reduce VILI, promote more normal lung inflation, and reduce lung inflammation.
7. Targeting of PaCO₂ is important. The NIH ARDS study used a strategy of permissive hypercapnia, allowing PaCO₂ to rise to higher than normal levels rather than increasing tidal volume, ie, minute ventilation (within certain limits). In neonates there is insufficient data addressing this trade-off between higher tidal volume (or pressures) and hence propensity to VILI, versus the detrimental effects of high PaCO₂s. In general, however, HFV as a ventilation tool in the neonate is very effective at normalizing PaCO₂ levels using very small, noninjurious tidal volume. In addition, avoiding hypocarbia is important because there is evidence that it is associated with brain injury.^30-32

Lung injury in the neonate develops rapidly and can begin right from the first breath, in the delivery room where we often ignore the tidal volume and the end-expiratory pressure we use to support gas exchange. In our adrenalin-driven desire to save life, we can easily deliver very large tidal volumes while applying no PEEP. This is the fastest way to create lung injury. Using lung protective strategies in the neonate requires proactive decisions that must be specific for disease pathophysiology, lung maturity and involve compromises between gas exchange goals and potential toxicities. When you make rounds today, see if your walk matches your talk. Look at whether the ventilator strategies you have chosen are protective, because VILI has also come of age for the neonate and it can alter the very frame on which future lung growth and development occur.

Reese H. Clark, MD
Pediatrix Medical Group
Weston, FL 33326

Arthur S. Slutsky, MD
Departments of Medicine, Surgery, and Biomedical Engineering
Respiratory Division
University of Toronto
Toronto, Ontario, Canada

Dale R. Gerstmann, MD
Neonatal Research
Division of Neonatology
Utah Valley Regional Medical Center
Provo, UT

FOOTNOTES

Received for publication Aug 23, 1999; accepted Aug 23, 1999.

Reprint requests to (R.H.C.) Pediatrix Medical Group, 1455 North Park Dr, Weston, FL 33326. E-mail: reese  clark{at}mail.pediatrix.com

ABBREVIATIONS

VILI, ventilator-induced lung injury; ARDS, acute respiratory distress syndrome; NIH, National Institutes of Health; RDS, respiratory distress syndrome; PEEP, positive end-expiratory pressure; HFV, high-frequency ventilation; EEP, end-expiratory pressure; FIO₂, fraction of inspired oxygen.

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