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84. Tay-Uyboco JS, et al: Hypoxic airway constriction in infants of very low birth weight recovering from moderate to severe bronchopulmonary dysplasia. J Pediatr 115:456, 1989. 85. Smyth JA, et al: Pulmonary function and bronchial hyper-reactivity in longterm survivors of bronchopulmonary dysplasia. Pediatrics 68:336, 1981. 86. Northway WH, et al: Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 323:1793, 1990. 87. Greenspan JS, et al:Airway reactivity as determined by a cold air challenge in infants with bronchopulmonary dysplasia. J Pediatr 114:452, 1989. 88. Brundage KL, et al: Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia.Am Rev Respir Dis 142:1137, 1990. 89. Cabal LA, et al: Effects of metaproterenol on pulmonary mechanics, oxygenation, and ventilation in infants with chronic lung disease. J Pediatr 110:116, 1987. 90. Gomez-Del Rio M, et al: Effect of a beta-agonist nebulization on lung function in neonates with increased pulmonary resistance. Pediatr Pulmonol 2:287, 1986. 91. Kao LC, et al: Effect of isoproterenol inhalation on airway resistance in chronic bronchopulmonary dysplasia. Pediatrics 73:509, 1984. 92. Stefano JL, et al:A randomized placebo-controlled study to evaluate the effects of oral albuterol on pulmonary mechanics in ventilator-dependent infants at risk of developing BPD. Pediatr Pulmonol 10:183, 1991. 93. Wilkie RA, Bryan MH: Effect of bronchodilators on airway resistance in ventilator-dependent neonates with chronic lung disease. J Pediatr 111:278, 1987. 94. Kao LC, et al: Effects of inhaled metaproterenol and atropine on the pulmonary mechanics of infants with bronchopulmonary dysplasia. Pediatr Pulmonol 6:74, 1989. 95. Engelhardt B, et al: Short- and long-term effects of furosemide on lung function in infants with bronchopulmonary dysplasia. J Pediatr 109:1034, 1986. 96. Kao LC, et al: Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial. Pediatrics 74:37, 1984. 97. Kao LC, et al: Oral theophylline and diuretics improve pulmonary mechanics in infants with bronchopulmonary dysplasia. J Pediatr 111:439, 1987. 98. McCann EM, et al: Controlled trial of furosemide therapy in infants with chronic lung disease. J Pediatr 106:957, 1985. 99. Rush MG, et al: Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia. J Pediatr 117:112, 1990. 100. Weinstein MR, Oh W: Oxygen consumption in infants with bronchopulmonary dysplasia. J Pediatr 99:958, 1981. 101. Kurzner SI, et al: Growth failure in bronchopulmonary dysplasia: elevated metabolic rates and pulmonary mechanics. J Pediatr 112:73, 1988. 102. Yunis KA, Oh W: Effects of intravenous glucose loading on oxygen consumption, carbon dioxide production, and resting energy expenditure in infants with bronchopulmonary dysplasia. J Pediatr 115:127, 1989. 103. Mallory GB, et al: Longitudinal changes in lung function during the rst three years of premature infants with moderate to severe bronchopulmonary dysplasia. Pediatr Pulmonol 11:8, 1991. 104. Blayney M, et al: Bronchopulmonary dysplasia: improvement in lung function between 7 and 10 years of age. J Pediatr 118:201, 1991. 105. Harrod JR, et al: Long-term follow-up of severe respiratory distress syndrome treated with IPPB. J Pediatr 84:277, 1974. 106. Abman SH, et al: Pulmonary vascular response to oxygen in infants with severe bronchopulmonary dysplasia. Pediatrics 75:80, 1985. 107. Berman W, Jr, et al: Evaluation of infants with bronchopulmonary dysplasia using cardiac catheterization. Pediatrics 70:708, 1982. 108. Tomashefski JF, et al: BPD: a morphometric study with emphasis on the pulmonary vasculature. Pediatr Pathol 2:469, 1984. 109. Goodman G, et al: Pulmonary hypertension in infants with bronchopulmonary dysplasia. J Pediatr 112:67, 1988. 110. Halliday HL, et al: Effects of inspired oxygen on echocardiographic assessment of pulmonary vascular resistance and myocardial contractility in bronchopulmonary dysplasia. Pediatrics 65:536, 1980. 111. Abman SH, et al: Systemic hypertension in infants with bronchopulmonary dysplasia. J Pediatr 104:928, 1984. 112. Melnick G, et al: Normal pulmonary vascular resistance and left ventricular hypertrophy in young infants with bronchopulmonary dysplasia: an echocardiographic and pathologic study. Pediatrics 66:589, 1980. 113. Abman SH, et al: Pulmonary vascular extraction of circulating norepinephrine in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 3:386, 1987. 114. Brownlee JR, et al: Acute hemodynamic effects of nifedipine in infants with bronchopulmonary dysplasia and pulmonary hypertension. Pediatr Res 24:186, 1988. 115. Johnson CE, et al: Pharmacokinetics and pharmacodynamics of nifedipine in children with bronchopulmonary dysplasia and pulmonary hypertension. Pediatr Res 29:500, 1991. 116. Banks BA, et al: Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 103:610, 1999. 117. Lonnqvist PA, et al: Inhaled nitric oxide in infants with developing or established chronic lung disease.Acta Paediatr 84:118, 1995. 118. Clark PL, et al: Safety and efcacy of nitric oxide in chronic lung disease. Arch Dis Child 86:F41, 2002.

96

Jay S. Greenspan, Thomas H. Shaffer, William W. Fox, and Alan R. Spitzer

Assisted Ventilation: Physiologic Implications and Complications

lung injury includes attention to issues such as infection, uid management, patent ductus arteriosus, nutrition, anemia, and many other aspects of patient management. For the purposes of this chapter, however, the indications and implications of initiating mechanical ventilation are discussed, and some of the newer techniques of ventilation and lung protection are addressed.

Mechanical ventilation is used in the treatment of neonatal pulmonary insufciency. Since its introduction in the 1980s, it has been steadily rened, resulting in the successful treatment of many previously fatal diseases and dramatically improving the survival rate of many high-risk neonates. As with many other advances in medicine, however, this therapy has been accompanied by complications, particularly chronic lung injury or bronchopulmonary dysplasia (BPD).l This disease, unknown before the use of mechanical ventilation, has produced a population of patients who are ventilator or oxygen dependent, with serious accompanying morbidity and mortality.2, 3 A clear understanding of the physiology of mechanical ventilation is essential for the neonatologist to maximize the benets and reduce the problems associated with its use. This chapter provides a review of the physiologic and pathophysiologic processes in conventional mechanical ventilation of the neonate. Because acute and chronic neonatal lung disease is multifactorial in origin, virtually all aspects of neonatal care can be considered part of the ventilation strategy.The prevention of

PULMONARY PHYSIOLOGY AND PATHOPHYSIOLOGY: CONSIDERATIONS WITH ASSISTED VENTILATION

Although the design of the lung serves multiple functions, the primary structure and its placement within the thorax establish its main purpose as gas exchange. The respiratory system consists of a series of branching tubes that bring fresh gas from the atmosphere to the terminal air spaces, while allowing the elimination of respiratory byproducts of metabolism to ow from the alveoli back into the environment (Fig. 961). The diaphragm, the primary muscular force during quiet ventilation, contracts during inspiration, lowering intrapleural pressure.This

962

XII / The Lung

testing, aided by the use of computerized analysis (Fig. 962), has produced extensive data on compliance and resistance measurements during states of both health and disease.9 Compliance refers to the lung relationship that correlates a given change in volume to a change in pressure required to produce that volume change. In general, the smaller the lung is, the lower the compliance. If one compares compliance in the healthy newborn with FRC (specic compliance), values are comparable to those seen in older children and adults. Little contribution to total lung compliance is made by the newborn chest wall, especially in preterm infants, because thoracic compliances are extraordinarily high. The airways of young infants are small in caliber, highly distensible, and susceptible to injury during mechanical ventilation.1014 Resistance (related to the fourth power of the radius of the airway by Poiseuilles law) is rapidly elevated by any reduction in airway caliber. Increased secretions, airway edema, increased collapsibility of the airway, and other related phenomena may result from the use of mechanical ventilation in the small infant.15 Furthermore, assessment of ow-volume and pressure-volume loops provides important information about airway patency and chest wall distortion.16 Measurement of FRC, although somewhat more difcult, can also be performed with either a helium dilution method17 or the nitrogen washout technique.18 Finally, the lack of infant cooperation during forced expiratory volumes19 has been resolved by the use of external compression of the thorax (Fig. 963).These techniques enable the neonatologist to understand both normal infant ventilation and the alterations produced during mechanical ventilation. Certain features of the developing lung predispose it to injury during therapy with mechanical ventilation. Surface tension is relatively higher in the alveoli for all infants during the rst hours of life, and some degree of atelectasis is common until a monomolecular layer of phospholipids (and their accompanying proteins), collectively known as surfactant, is deposited at the air-liquid interface (Table 963). Surfactant, primarily composed of phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, and several other lipid-soluble moieties, decreases the surface tension in the lung at end-expiration.2025 The surfactant proteins (SP-A, SP-B, SP-C) play important roles in the stability and recycling of the lipid moieties. Surfactant reduces the tendency of the lung to collapse from increased surface active forces in the alveoli. Surface tension and structural immaturity appear to be the major factors in the premature lung that lead to respiratory insufciency and result in hyaline membrane disease or respiratory distress syndrome (RDS) (Fig. 964). Although primarily a disease of prematurity, RDS does occasionally occur in full-term births.When surfactant deciency and structural immaturity are present, lung compliance in the newborn is reduced, and ventilator support is frequently necessary. In addition to lung immaturity, numerous studies have suggested that the ventilatory muscles of newborns are more susceptible to fatigue than those of adults, a factor that may additionally contribute to the respiratory problems of preterm neonates.26 Studies of histochemical and physiologic properties of respiratory muscle bers reported age-related differences in human and baboon diaphragm. In comparison with bers in the full-term baby or adult, the diaphragm in the premature baboon has fewer contractile proteins per ber area and poorly developed sarcoplasmic reticulum; thus, the premature diaphragm contracts from progressively shorter lengths and develops less tension.When mechanical ventilation is used in infants with respiratory muscle weakness, the work of breathing is reduced, oxygen consumption is decreased, and respiratory muscle fatigue may be prevented. Other factors, such as the fragility of lung tissue, marginal energy reserves, limited ability to increase cardiac output, and lability of pulmonary perfusion from pulmonary hypertension, also may result in both a greater need for mechanical ventilation and additional problems during mechanical ventilation.

Figure 96l. Negative pressure gradient produced on inspiration by descent of the diaphragm in spontaneously breathing infant. Pressures measured in interpleural space (Pip) and alveoli (Palv), and at opening of mouth or atmosphere (Patm). Pip < Palv < Patm. (From Harris TN: In Goldsmith JP, Karotkin EH [eds]:Assisted Ventilation of the Neonate, 2nd ed. Philadelphia,WB Saunders Co, 1988, p 24.) contraction, occurring against the anchoring ribcage, results in a pressure gradient that decreases from the mouth to the alveoli and leads to an inward ow of gas. Simultaneously, the increase in intra-abdominal pressure and the physical structure of the thorax limit inspiratory movement until rising intrathoracic pressure terminates ow. During inspiration, a series of elastic elementsthe chest wall muscles, diaphragm, airway connective tissue, pleurae, and blood vesselsstretch within the thorax. At the end of inspiration, the energy stored in these stretched elastic elements provides a recoil force that pumps gas out of the lung during expiration. Under normal circumstances, expiration is a passive process.When the respiratory workload is increased, the accessory muscles of the intercostal spaces and the abdominal musculature are recruited, so both inspiration and expiration may become active and require additional energy expenditure. The gas volume in the lungs at the point at which inspiratory effect again begins to oppose the expiratory recoil forces is known as the functional residual capacity (FRC). Neurochemical control of breathing in the newborn and its inuence on the process are only partially understood (Table 961). Compared with an adult, the brain stem centers of respiratory control in the neonate are immature and are more susceptible to failure, as seen in apnea of infancy.4 Chemoreceptor responsiveness also appears to be diminished, particularly with respect to hypoxemia.57 In addition, numerous reex responses present in very young infants disappear rapidly during the rst months and years of life.8 Finally, sleep state, which inuences respiratory control, is different in the newborn infant, with predominance of rapid eye movement (REM) sleep.6, 7 Numerous studies have attempted to establish values for ventilatory volumes in neonates (Table 962).9 Although values for tidal volume and minute ventilation change with growth, physiologic dead space remains relatively constant at about 0.3 throughout life in the healthy person. Pulmonary function

96 / Assisted Ventilation: Physiologic Implications and Complications 963

TABLE 961

Factors Affecting Control of Ventilation in the Spontaneously Breathing Neonate

Neurologic Factors Maturity of the CNS Degree of myelination, which largely determines speed of impulse transmission and response time to stimuli affecting ventilation Degree of arborization or dendritic interconnections (synapses) between neurons, allowing summation of excitatory potentials coming in from other parts of the CNS and largely setting the neuronal depolarization threshold and response level of the respiratory center Sleep state (i.e., REM sleep vs. quiet or non-REM sleep) REM sleep is generally associated with irregular respirations (both in depth and in frequency), distortion, and paradoxical motion of the rib cage during inspiration, inhibition of Hering-Breuer and glottic closure reexes, and blunted response to CO2 changes Quiet sleep is generally associated with regular respirations, a more stable rib cage, and a directly proportional relationship between PCO2 and degree of ventilation Reex responses Hering-Breuer reex, whereby inspiratory duration is limited in response to lung ination sensed by stretch receptors located in major airways. Not present in adult humans, this reex is active during quiet sleep of newborns but absent or weak during REM sleep Heads reex, whereby inspiratory effort is further increased in response to rapid lung ination.Thought to produce the frequently observed biphasic signs of newborns that may be crucial for promoting and maintaining lung ination (and therefore breathing regularity) after birth Intercostal-phrenic reex, whereby inspiration is inhibited by proprioception (position-sensing) receptors in intercostal muscles responding to distortion of the lower rib cage during REM sleep Trigeminal-cutaneous reex, whereby tidal volume increases and respiratory rate decreases in response to facial stimulation Glottic closure reex, whereby the glottis is narrowed through reex contraction of the laryngeal adductor muscles during respiration, thereby breaking exhalation and increasing subglottic pressure (as with expiratory grunting) Chemical Drive Factors (Chemoreexes) Response to hypoxemia (falling PaO2) or to decrease in O2 concentration breathed (mediated by peripheral chemoreceptors in carotid and aortic bodies) Initially, there is increase in depth of breathing (tidal volume), but subsequently if hypoxia persists or worsens, there is depression of respiratory drive, reduction in depth and rate of respiration, and eventual failure of arousal For the rst week of life at least, these responses are dependent on environmental temperature, i.e., keeping the baby warm Hypoxia is associated with an increase in periodic breathing and apnea Response to hyperoxia (increase in F IO concentration breathed): enriched O2 breathing causes a transient respiratory depression, stronger in term 2 than in preterm infants Response to hypercapnia (rising PaCO2 or [H+]) or to increase in CO2 concentration breathed (mediated by central chemoreceptors in the medulla) Increase in ventilation is directly proportional to inspired CO2 concentration (or, more accurately stated, to alveolar CO2 tension), as is the case in adults Response to CO2 is in large part dependent on sleep state: In quiet sleep, a rising PaCO2 causes increase in depth and rate of breathing, whereas during REM sleep, the response is irregular and reduced in depth and rate.The degree of reduction closely parallels the amount of rib cage deformity occurring during REM sleep Ventilatory response to CO2 in newborns is markedly depressed during behavioral activity such as feeding and easily depressed by sedatives and anesthesia
CNS = central nervous system; REM = rapid eye movement. Adapted from Harris TN: In Goldsmith JP, Karolkin EH (eds):Assisted Ventilation of the Neonate. Philadelphia,WB Saunders Co, 1988, p 28.

TABLE 962

Ventilatory Values in Normal Newborns

Authors Cook, et al Swyer, et al Strang Nelson, et al Koch Bancalari, et al Method Plethysmography Pneumotachography Plethysmography Nonrebreathing valve Nonrebreathing valve Plethysmography Weight (kg) 3.8 3.0 3.3 2.2 3.6 3.3 Respiratory Rate 38 37 41 38 44 (24 h) 39 (7 d) 48 VT (mL) 16.0 20.6 18.1 12.8 16.5 16.6 18.1 VE (mL/min) 750 480 703 632 868 VA (mL/min) 378 309 442 425 VD/VT 0.32* 0.50 0.25 0.25* 0.24*

* Physiologic. Anatomic. VT = tidal volume;VE = respiratory minute volume;VA = alveolar ventilation;VD/VT = physiologic dead space. Adapted from Bancalari E: In Thibeault DW, Gregory GA (eds): Neonatal Pulmonary Care. Norwalk, CT, Appleton-Century-Crofts, 1986, p 208.

ETIOLOGY OF LUNG INJURY WITH MECHANICAL VENTILATION

Mechanical ventilation enables the infant to maintain adequate gas exchange until the lung can heal. Although effective, this therapy can induce lung injury, thereby exacerbating the disease process as well as creating new iatrogenic disorders.The lung of the premature infant is more susceptible to injury than the more mature lung. Although the source of iatrogenic injury for the

ventilated preterm infant may be similar to that of the older infant, child, or adult, these mechanisms are exacerbated. Current concepts identify lung tissue injury from barotrauma (effect of pressure), volutrauma (effect of tidal volumes), atelectrauma (repetitive opening and closing of lung units from low lung volumes), and toxic reactive oxygen species as causative of this injury.2729 Studies of preterm lambs demonstrated alterations in lung function after brief exposure to high ventilation pressure at birth.30 Furthermore, the histopathology of controlled studies of

964

XII / The Lung

Figure 962. Computerized pulmonary function tests demonstrating ow-volume (A) and volume-pressure (B) loops for four consecutive breaths in an individual infant.The dotted line in each volume-pressure loop indicates the slope of the line for the calculated compliance. Ct = total lung compliance; Exp = expiration; Fpke = peak expiratory ow; Fpki = peak inspiratory ow; Insp = inspiration; Rt = total lung resistance;Wt = total work. preterm animals and infants with chronic lung disease suggests that lung development is arrested by prolonged mechanical ventilation.3133 Adult animal studies demonstrate an increase in proinammatory cytokines and induction of c-fos mRNA with mechanical ventilation, with the greatest increases occurring with high ination pressures and tidal volumes with zero endexpiratory pressure.34 In addition, studies have demonstrated that this lung injury could alter gene expression in the lung. Thus, noxious stimuli lead to another mechanism of lung injury called biotrauma. Nonsurvivors of adult/acute RDS (ARDS) have elevation of bronchoalveolar lavage uid (BALF) cytokines, suggesting a pulmonary origin for the plasma cytokines.35 Elevated levels of interleukin-8 in BALF are predictive of severe ARDS, and cytokines are released into the systemic circulation when the alveolar-endothelial barrier is disrupted.36, 37 This may be the mechanism by which ventilator-induced lung injury leads to multiorgan failure.38 Because the lung is in contact with the entire cardiac output, the release of active substances can act as a signicant attenuator of or contributor to systemic compromise. Although the circulating neutrophil pool and alveolar macrophage population increase with age,39, 40 both have been implicated in mechanisms of lung injury of preterm infants.The circulating neutrophil pool size decreases and lung neutrophils increase after the mechanical ventilation of preterm animals.4146 The increase in neutrophils in the pulmonary air space is directly related to the decrease in circulating neutrophils, clearance of protein and liquid from the lung, and extravascular lung water. Pulmonary neutrophils therefore play a role in the pathogenesis of lung injury and the creation of lung edema. Mechanotransduction, the conversion of a mechanical stimulus into structure and functional alterations of tissues, has been shown to affect the lung.47, 48 Prolonged mechanical gas ventilation of the preterm lamb results in increased elastin expression (mRNA tropoelastin) and abnormal lung development.49 Some of these alterations can be attenuated with ventilation strategies designed to reduce injury.5054 Once injury is initiated, many factors can contribute to ongoing damage. Pulmonary injury initiates and is accompanied by a series of responses that ultimately lead to varying degrees of residual damage, depending on the duration and level of ventilator support. Desquamation of the epithelial and ciliary apparatus, increased goblet cells and smooth muscle, bronchial necrosis

96 / Assisted Ventilation: Physiologic Implications and Complications 965

Figure 963. A, Infant partial expiratory ow volume (PEFV) by rapid thoracic compression set-up showing the compression bag wrapped around the infants thorax and abdomen and connected to the pressure reservoir. Flow is measured by a pneumotachograph (PNT), processed by computer (CPU), and displayed at a ow-volume loop. B, PEFV curves from infants with obstructive lung disease compared with a normal curve demonstrating ow limitation and concavity toward the volume axis. (From Bhutani VK, et al: Neonatal Pulmonary Function Testing. Ithaca, NY, Perinatology Press, 1988.)
TABLE 963

Roles of Surfactant in Pulmonary Physiology

Reduce alveolar surface tension Increase compliance Decrease work of breathing Increase alveolar stability Improve alveolar recruitment Reduce lung forces that result in pulmonary edema

that heals with brosis, increased interstitial lung uid, rupture of alveolar septa, and diffuse inammatory disease throughout the lung are some of the changes that are apparent with mechanical ventilation.5560 These sequelae of lung injury are most often seen in BPD, as evidenced by airway distention, shifting atelectasis on chest roentgenography, hyperination of other areas of the lung, ventilation/perfusion (V/Q) inequalities, and impaired cardiac function.11, 6164 The use of mechanical ventilation is therefore a two-edged sword: often, there is no other way to save an infants life, yet the therapy itself almost always produces some degree of lung and airway damage.

INITIATION OF NEONATAL LUNG DISEASE AND THE DECISION TO INITIATE NEONATAL MECHANICAL VENTILATION
Given the risk of injury associated with mechanical ventilation, the decision to place an infant on respiratory support, with the selection of appropriate ventilator settings, is one of the most critical decisions made in medicine. The clinician must understand the reasons behind this decision and the strategy that will be employed. This decision has been made more difcult over the past several years, because a large body of work has begun to redesign the ventilation targets for neonates and to elucidate the ramications of the decision to ventilate the patient me-

Figure 964. The pathogenesis of respiratory distress syndrome. (From Polin RA, Burg MD [eds]:Workbook in Practical Neonatology. Philadelphia,WB Saunders Co, 1983, p. 106.) chanically.The process that determines the need for mechanical ventilation begins in utero, with the initiation of maternal steroid or tocolytic therapy, and proceeds in the delivery room. The development of adequate pulmonary blood ow, FRC, and V/Q matching, with uniform distribution of lung surfactant, can be affected by the management of these issues in the rst few minutes of life. Animal studies demonstrate that airway and lung parenchymal injury can occur with only a few large breaths at the time of birth.6568 In addition, tidal breathing in the delivery room can cause alterations in surfactant function.These changes

966

XII / The Lung

TABLE 964

may result from parenchymal disruption with protein leak and surfactant inactivation.69, 70 Hence, tidal breaths in the delivery room can reduce the efcacy of exogenous surfactant administration while simultaneously disrupting the integrity of the airway structure and the pulmonary parenchyma. As a result, from even shortly after birth, the physician attempting to reduce pulmonary trauma in the neonate may be ghting a losing battle. Once in the intensive care nursery, the infant who is managed on mechanical ventilator support must be monitored closely. The relatively recent addition of on-line, ventilator-generated lung mechanics measurements allows for rapid assessment, alteration, and sculpting of ventilator breaths. The goal of any strategy is to provide the necessary gas exchange while minimizing lung injury. Dening adequate gas exchange in the newborn infant is no longer clear. Providing for arterial carbon dioxide pressure (PaCO2) and pH values that are normal for adult humans may constitute relative overventilation for the newborn. Decreasing PaCO2 may result in unnecessary lung injury, and low levels of PaCO2 may be detrimental. Permitting higher levels of PaCO2, or allowing time for these levels to diminish over time in the newborn, may alleviate the need to initiate mechanical ventilation. Increasingly, programs are evaluating the use of early continuous positive airway pressure (CPAP) and are permitting PCO2 levels to be relatively elevated to avoid the lung injury associated with mechanical ventilation. Similarly, a high requirement for supplemental oxygen to maintain a level of arterial oxygen pressure (PaO2) that would be considered normal in a human adult may also not be necessary.71 The newborn infants oxygen requirement is in transition from the hypoxemic levels of the fetus to that of the adultlike human. If the expense of achieving higher levels of oxygen is lung injury, perhaps lower levels can be tolerated. Recent work has suggested that tolerating lower blood hemoglobin saturation levels may be benecial. Hence, understanding the gas-exchange targets not only will affect ventilator management but may eliminate the need to initiate or maintain mechanical ventilator support.

Modes of Ventilatory Assistance in the Newborn

Oxygen therapy CPAP Nasal CPAP Endotracheal CPAP Face-mask CPAP Negative end distending pressure Negative-pressure ventilation Positive-pressure ventilation Pressure limited Time-cycle limited Volume limited High-frequency positive pressure ventilation Oscillatory Flow interrupter Jet High-frequency negative pressure ventilation Extracorporeal membrane oxygenation Liquid ventilation
CPAP = continuous positive airway pressure.

CONVENTIONAL ASSISTED VENTILATION IN THE NEWBORN INFANT

Several different modes of ventilator assistance exist for the treatment of neonatal lung disease (Table 964). All types of ventilator support basically serve the same function: to assist in gas exchange to reduce pulmonary insufciency, an inability of the lung to exchange gas adequately to meet the demands of aerobic

metabolism. Common causes of pulmonary insufciency and respiratory distress in the newborn period are listed in Table 965. Virtually all assisted ventilation currently used in the United States is some variant of positive-pressure ventilation. Negativepressure ventilators disappeared from most nurseries as very low birth weight infants (<1500 g) increased in number in the nursery population. Although some recent efforts with negativepressure ventilation in pulmonary hypertension appear to be interesting, this therapy is still uncommon.72, 73 In contrast to spontaneous ventilation, positive-pressure mechanical ventilation generates gas ow in a different manner. With positive-pressure breathing, a gradient down the airway is again established by raising pressure in the proximal airway (usually through an endotracheal [ET] tube, occasionally a tracheostomy), compared with the decrease in intrapleural pressure that occurs with spontaneous breathing. Gas still ows in the direction of decreasing pressure, although the mechanism for producing this ow differs signicantly. As shown in Figure 965, although there is a transpulmonary pressure gradient of a similar direction in both spontaneous and assisted ventilation, the pressure throughout the lung, from the atmosphere

TABLE 965

Differential Diagnosis of Respiratory Distress in the Newborn Period*

Respiratory Common Respiratory distress syndrome (hyaline membrane disease) Transient tachypnea Meconium aspiration Primary pulmonary hypertension (persistent fetal circulation) Pneumonia, especially caused by group B streptococci Less Common Pulmonary hemorrhage Pneumothorax Immature lung syndrome Rare Airway obstruction (upper), e.g., choanal atresia Space-occupying lesion e.g., diaphragmatic hernia, lung cysts Hypoplasia of the lung Heart Congenital heart disease Patent ductus arteriosus (acquired) Extrapulmonary Metabolic Metabolic acidosis Hypoglycemia Hypothermia Septicemia Brain Hemorrhage Edema Drugs Trauma Hyperviscosity Blood Acute blood loss Hypovolemia Twin-twin transfusion

* Presentation with or without cyanosis, grunting, retractions, tachypnea, apnea, shock, lethargy. Data from Martin RJ, et al: In Klaus MH, Fanaroff AV (eds): Care of the High Risk Neonate. 3rd ed. Philadelphia,WB Saunders Co, 1986.

96 / Assisted Ventilation: Physiologic Implications and Complications 967

TABLE 966

Control Variables in Assisted Ventilation

Oxygen therapy Continuous positive airway pressure Peak inating pressure Frequency Inspiratory/expiratory ratio Inspiratory time Expiratory time Mean airway pressure

variable has both physiologic advantages and disadvantages that must be considered.

Oxygen Therapy
Maintenance of adequate tissue oxygenation is one of the primary goals of therapy during mechanical ventilation.The simplest way to achieve adequate oxygenation is to increase the fraction of oxygen in inspired gas. Oxygen must be considered a drug, however, with potential harmful side effects such as retinopathy of prematurity (ROP)8183 and BPD.64 Retinopathy is believed to occur, at least in part, from varying oxygen concentrations in the blood that result in vasoconstriction and subsequent proliferation and abnormal vascular growth in the retina of the immature infants eye. Other factors, such as prematurity itself, carbon dioxide levels, apnea, blood pressure, and vitamin E levels, as well as some additional (possibly unknown) factors, also appear to be important in the development of this condition.82 Genetic tendency may also play a role. BPD appears to be a result of prolonged exposure to high inspired oxygen concentrations and positive-pressure ventilation. It is thought that this condition may have an underlying inherited tendency in some families84 and is also multifactorial in origin. Generation of superoxide anions from oxygen may be one of the inammatory processes that initiates the lung response that later results in BPD (Fig. 966). Superoxide dismutase (SOD), catalase, glutathione peroxidase, and other enzymes important in the catalytic reduction of these anions are reduced in the premature infant. As a result, the premature lung may be at increased risk from the effects of this oxygen byproduct. Studies with SOD have suggested a therapeutic role for this agent in preventing BPD. Mammalian cells contain two types of SOD molecules, namely CuZnSOD and MnSOD. Human CuZnSOD, which resides in the cytoplasm of the cell, is a dimeric metalloprotein composed of identical noncovalently lined 16-kDa subunits, each containing one atom of copper and one atom of zinc. An extracellular glycosylated tetrameric form of CuZnSOD also exists. Human MnSOD is localized in the mitochondria and is a homotetramer composed of 22-kDa subunits, each possessing one manganese atom. Developmental up-regulation of antioxidant enzyme expression occurs in various mammalian species during the last 10 to 15% of gestation and parallels the increase in surfactant levels.85 In vitro and in vivo hyperoxic exposure of the lungs of normal immature animals results in a rapid increase in pulmonary SOD activity.86 In humans, SOD activity in the lung also increases with age; it is lowest in fetal life, increases in term infants, and is highest in adults.87 Most premature infants without RDS show the expected hyperoxic increase in SOD activity, whereas most infants with RDS do not.88 This nding suggests that antioxidant deciency may play a role in neonatal lung disease. In a prior study, recombinant human (r-h) CuZnSOD was well tolerated, with an adverse experience prole generally comparable to that of placebo. In addition, no between-group differences

Figure 965. Positive pressure gradient produced by ventilator. Pressures measured in airway (Paw) and as in Figure 961. Paw > Palv > Pip > Patm. (From Goldsmith JP, Karothin EH [eds]: Assisted Ventilation of the Neonate. Philadelphia,WB Saunders Co, 1988, p 25.) to the pleural cavity, is higher with mechanical ventilation. As a result, the airways and lungs receive higher pressures than normal. In the young infant with decreased connective tissue and cartilage, the airway becomes distended,11, 15 and gas ow, which depends partly on rigidity of the airway, may become more turbulent. With increasing turbulence, gas distribution throughout the lung is altered, gas exchange is reduced, and one often has to compensate by further increasing ventilator pressure support.74, 75 This process, occurring over several days, may lead to progressive airway and lung injury. Although positive pressure applied to the fragile preterm pulmonary airway and parenchyma produces lung injury, the specic ventilator variable that induces the greatest injury has remained controversial. Attempts to eliminate lung injury completely in the neonate have been less than successful, and it has become increasingly clear that the process of tidal breathing itself is sufcient to induce injury in the preterm infant. Animal studies suggest that even short-term and limited tidal breathing (volutrauma), as well as ventilation of the atelectatic lung (atelectrauma), causes injury.71, 7680 The size of the breath may therefore be more important than the inating pressure in determining the risk of chronic lung disease. In the atelectatic lung, adequate minute ventilation is achieved by overinating already expanded lung regions, thereby causing damage to those ventilated regions. Hence, using an adequate amount of end-expiratory pressure, or mean airway pressure (MAP), to optimize alveolar volume recruitment may diminish lung injury. The goal of therapy therefore is to maximize the benets of ventilation while minimizing its negative effects. Understanding the controls available with mechanical ventilation can assist in this end.

VARIABLES IN ASSISTED VENTILATION

Several different controls for mechanical ventilation can be manipulated in the care of individual infants (Table 966). Each

968

XII / The Lung

Figure 966. Schematic representation of the source and generation of free radicals and reactive intermediates and the enzymatic and nonenzymatic protective systems available to the cell.Additional details are provided in the text. (Adapted from Roberts RJ: Nucleic Acid Res 12[Suppl]:167, 1984.)

in growth parameters or physical or neurologic examination ndings were seen at 1 year of corrected age. There were no signicant differences between treatment groups in the shortterm end-points of BPD, death, or the combined end-point of BPD or death. However, fewer patients who were previously treated with r-h CuZnSOD compared with those patients who were previously treated with placebo used respiratory medications between 6 and 12 months of corrected age. Further, fewer infants in the r-h CuZnSOD group required home nebulizer use. Thus, results from these studies support further prospective evaluation of the long-term effects of r-h CuZnSOD in preterm infants with RDS.89

Because of the substantial morbidity from these conditions, oxygen therapy must be cautiously administered and monitored during the neonatal period. Frequent assessment of inspired oxygen concentration, as well as blood oxygen saturation and tension, is recommended. If hyperoxia leads to major morbidity in the newborn, hypoxia can produce even greater problems. Hypoxemia, if prolonged, results in a change from aerobic to anaerobic metabolism, increased lactic acid production, and, ultimately, cellular and organ demise. Death usually follows soon afterward. These effects are unquestionably time related. A shorter duration of hypoxemia, however, may result in organ injury that can be

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permanent.90 The effects of hypoxemia on central nervous system function and development are a constant concern for the neonatologist.The effects of hypoxemia on the developing brain are discussed in more detail elsewhere in this book. Since the mid-1990s, there has been a gradual change in the approach to oxygen use and acceptable hemoglobin oxygen saturations in the newborn. In the process of resuscitation of the newborn, it is no longer believed that even brief exposures to 100% oxygen are harmless.91 The risks of high oxygen levels may occur at relatively normal oxygen saturations. The fear of low oxygen tensions includes increase in pulmonary vascular and airway resistance and decreased growth and enzymatic activity. Several studies suggest that normal levels of oxygen saturation (96 to 99%) in preterm infants with chronic disease may increase the risk of pneumonia or exacerbation of chronic lung disease or ROP and may prolong the oxygen requirement.9294 The optimal arterial oxygen saturation varies with the disease state, but it will probably be lowered over the next several years.91, 95 pressure is increased by CPAP and is directly related to the amount of CPAP applied as well as compliance of the lungs.108 With increased lung compliance, more pressure is transmitted to the cardiovascular system, resulting in a rise in central venous pressure and intracranial pressure. Cerebral perfusion pressure, however, can decrease with application of end-distending pressure, because venous pressure rises and arterial pressure decreases initially. Some compensation is likely to occur over time; however, these changes in intracranial pressure may lead to an increased risk of intracranial hemorrhage, especially in the preterm baby.90 Some effects of CPAP on renal function have been documented.109 These include a decrease in glomerular ltration rate, reduction of urinary sodium excretion, and diminished urinary output.110, 111 These ndings also appear to be mediated through transmission of pressure to the cardiovascular system with reduction in renal blood ow. As renal blood ow decreases, there may be some redistribution of intrarenal blood ow to the inner renal cortex and outer medulla.112 Aldosterone appears to increase with application of CPAP,113 and antidiuretic hormone secretion may increase as well,114 although there have also been reports of decreased antidiuretic hormone with CPAP. These contradictory ndings may again be a reection of the nding that CPAP may improve or worsen lung compliance, resulting in either increase or decrease in intracranial perfusion (Table 967).115 One trend in respiratory support of the premature newborn is the use of noninvasive ventilation strategy. At the forefront of this approach is permissive hypercapnia and the early use of CPAP in lieu of mechanical ventilation. Reports in the 1980s showed that units that accepted higher values for arterial PCO2 and used CPAP aggressively had a lower rate of chronic lung disease.116 The concept of gentle ventilation with permissive hypercapnia and the aggressive use of CPAP illustrates one of the most confusing aspects of managing respiratory distress in the newborn, namely, when, and to what degree, to intervene.The introduction of mechanical ventilation is potentially detrimental, and deciding to place an infant on mechanical ventilator support remains a difcult decision. In addition, determining what measurements (e.g., blood gases, graphics monitoring) should guide ventilator changes remains unclear. Permissive hypercapnia in preterm infants seems safe and may reduce the duration of assisted ventilation.This strategy has particular appeal in that hypocarbia may be related to brain injury. However, severe hypercarbia may also cause brain injury, a nding strongly suggesting that nature has excellent physiologic reasons to establish eucapnic ventilation as the normal range.When using a strategy or permissive hypercapnia, it is important to minimize atelectasis, because the recruitment and de-recruitment of lung regions is not optimal. In addition, although data look promising when this strategy is implemented, long-term follow-up of infants managed with high carbon dioxide levels has not been explored.

Continuous Positive Airway Pressure

Since its introduction by Gregory and colleagues in 1971,96 the use of CPAP has become a standard part of ventilator care. CPAP is also referred to as positive end-expiratory pressure (PEEP) when used in conjunction with a mechanical ventilator (that is supplying a ventilator rate for the infant) or continuous distending pressure.The full effects of this form of therapy are not fully understood, and part of the difculty may be that CPAP may have variable results in different clinical situations. CPAP is believed to result in progressive alveolar recruitment, inating collapsed alveoli96 and reducing intrapulmonary shunt.97100 From Laplaces law: Pressure = 2 tension radius [1]

However, one could expect that collapsed alveoli would remain collapsed, and inated or partially inated alveoli would become increasingly inated or overdistended. These ndings have never been clearly documented. Some of the effects of CPAP, however, have been measured. CPAP increases gas volume in the lung, including FRC.97 Initially, as FRC increases, gas exchange improves; arterial PO2 (PaO2) increases and arterial PCO2 (PaCO2) decreases. With additional CPAP, however, the volume of the lung increases excessively, and the lung becomes overdistended. In such cases, PaO2 remains high,but PaCO2 also begins to increase as tidal volume diminishes and physiologic dead space is increased. Continued excessive CPAP may ultimately lead to very serious consequences, such as air leak syndromes: pneumomediastinum, pneumothorax, or pneumopericardium.101 Excessive CPAP may also increase dead space ventilation, leading to a rise in PaCO2. Furthermore, although low levels of CPAP may be useful in decreasing pulmonary edema or left-to-right cardiac shunting, high levels of CPAP can lead to a reduction in cardiac output, reduced pulmonary perfusion, and enhanced V/Q mismatching, resulting in a lower PaO2.102104 Depending on levels of CPAP applied and lung compliance, pulmonary vascular resistance may be increased with CPAP, although its use early in the course of RDS may lead to decreased pulmonary vascular resistance.105 CPAP has some nonspecic effects on neonatal ventilation as well. Application of CPAP appears to produce a more regular breathing pattern in preterm neonates106 and has been thought to be mediated through chest wall stabilization and reduction of thoracic distortion. Obstructive apnea is also reduced with CPAP,107 even when it is applied by nasopharyngeal route. Furthermore, it has been shown that both inspiratory and expiratory times are increased with CPAP. Finally, it is thought that surfactant release may be enhanced by CPAP in RDS. Intracranial

Peak Inating Pressure

Peak inating pressure (PIP) is the primary ventilator variable that determines tidal volume on most time-cycled or pressurelimited ventilators. Since the introduction of neonatal mechanical ventilation, controversy has raged over the optimal approach to the administration of PIP. Many of the effects of PIP are similar to those described previously in the section on CPAP. The introduction of a peak pressure, unlike the constant pressure application of CPAP, may have additional physiologic effects on the neonatal airways and lungs. Once one begins cycling a ventilator and providing a PIP, physiologic changes occur.Tidal volume and minute ventilation increase. Depending on the type of waveform generated by the ventilator and the duration of inspiratory to expiratory time (I/E ratio) selected, mean airway pressure (MAP) may be altered (Fig. 967). Airways expand, and, as noted with CPAP, alveolar distention is

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TABLE 967

Continuous Positive Airway Pressure

Low (23 cm H2O) Use Maintenance of lung volume in very low birth weight infants During weaning During hyperventilation for PPHN Side Effects May be too low to maintain adequate lung volume or adequate oxygenation CO2 retention Medium (47 cm H2O) Use Increasing lung volume in surfactant deciency, such as RDS Stabilizing areas of atelectasis Stabilizing obstructed airways Side Effects If lungs have normal CL: May overdistend May impede venous return Air leak

High (810 cm H2O) Use Preventing alveolar collapse with poor CL and poor lung volume Improving distribution of ventilation Side Effects Pulmonary air leak Decreased CL if overdistended May impede venous return (metabolic acidosis) May increase PVR CO2 retention

Ultrahigh (1115 cm H2O) Use Tracheal or bronchial collapse Markedly decreased CL or severe obstruction Preventing white-out or reestablishing lung volume during ECMO Side Effects Same as High levels, depending on CL

CL = lung compliance; ECMO = extracorporeal membrane oxygenation; PPHN = persistent pulmonary hypertension of the newborn; PVR = pulmonary vascular resistance; RDS = respiratory distress syndrome.

Figure 967. Five different ways to increase mean airway pressure: (1) increase inspiratory ow rate, producing more of a square-wave inspiratory pattern; (2) increase peak inspiratory pressure; (3) reverse the inspiratory/expiratory (I/E) ratio or prolong inspiratory time without changing the rate; (4) increase positive end-expiratory pressure; and (5) increase ventilator rate by reducing expiratory time without changing inspiratory time. (Modied from Reynolds EOR: In Goldsmith JP, Karotkin EH [eds]:Assisted Ventilation of the Neonate. Philadelphia,WB Saunders Co, 1988, p 61.) increased. One of the primary goals of all mechanical ventilation is to achieve the optimal gas exchange at the lowest positive pressure. The neonatologist must constantly examine the benets derived by the patient versus the risk of pulmonary injury (Table 968) with different ventilator approaches. These approaches have become even more complicated with the newer modes of ventilation, all innovated to decrease pulmonary iatrogenic injury. The causes of injury with mechanical ventilation were previously outlined. No clear data suggest a specic level of PIP that will invariably damage an individual infant. Some infants demonstrate barotrauma at low levels of PIP, whereas other infants may not have any injury even at higher levels of PIP. Size and gestational age clearly inuence the response of mechanical ventilation, although babies of equal gestational age, weight, and severity of disease may have different responses to mechanical ventilation. A study of the incidence of chronic lung disease in

perinatal centers in academic institutions conrmed this highly variable incidence of BPD in infants treated with mechanical ventilation.116 It cannot be overemphasized that one should not attempt to limit PIP to some predetermined pressure value in an attempt to reduce barotrauma while ignoring the importance of adequate gas exchange. In many instances, high peak pressures are necessary to achieve adequate ventilation and oxygenation. Inadequate gas exchange is invariably either fatal or injurious to the central nervous system and must never be ignored while one tries to limit pressure below some arbitrary level. Additional factors become more important in mechanical ventilation when one adjusts ventilator peak pressure. The length and caliber of an ET tube signicantly inuence airway resistance. Longer, narrower ET tubes have higher airway resistance. Because of the added resistance, gas trapping can occur because the recoil of the lung does not have sufcient time to evacuate gas from the air spaces. As a result, the lung expands to a higher FRC. Although this increase in lung volume may be of value early in the course of neonatal lung diseases complicated by atelectasis (i.e., RDS), in most cases, air trapping adds to the likelihood of air leaks and pulmonary injury. It has been demonstrated, in studies by Wall,117 that if one shortens a 2.5-mm inner-diameter (ID) ET tube from 14.8 to 4.8 cm (tracheostomy length), the measured in vitro resistance is reduced to that of a full-length 3.0-mm ID ET tube. Therefore, one must select the appropriate size tube for an individual infant to maximize ow and decrease resistance to a minimum. ET tubes are usually supplied in excessive lengths and should be cut to remove any unnecessary dead space after ideal placement has been secured.The effect of the diameter of the ET tube is somewhat surprising in the neonate, given that airways rapidly decrease in caliber to a size far smaller than the ET tube within one or two bronchial divisions. One would consequently expect that the smaller airways of the tracheobronchial tree would contribute far more to resistance than the ET tube. Resistance within the lung is primarily dependent on the total cross-sectional area of all airway branches. Because the total cross-sectional area of the airways of the lung increases rapidly with bronchial subdivisions, these smaller airways contribute far less to resistance than expected. As a result, the larger airways and the ET tube in the newborn infant become the major contributors to resistance, a nding that is especially important in the baby with chronic lung disease who often demonstrates bronchospasm or tracheobronchomalacia.

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TABLE 968

Waveforms in Neonatal Mechanical Ventilation

Sine Wave Advantages Smoother increase of pressure More like normal breathing pattern Side Effects Lower mean airway pressure Advantages Higher mean airway pressure for equivalent PIP Longer time at peak pressure may open up atelectasis or improve distribution of ventilation Square Wave Side Effects With high ow, the ventilator may be applying higher pressure to normal alveoli, resulting in barotrauma Could impede venous return if inverse I/E ratio is used

I/E = inspiratory/expiratory; PIP = peak inspiratory pressure. Adapted from Fox WW, et al: In Goldsmith J Karotkin E (eds):Assisted Ventilation of the Neonate. Philadelphia,WB Saunders Co, 1988.

TABLE 969

Peak Inspiratory Pressure

Low (<30 cm H2O) Advantages Fewer side effects, especially BPD, PAL Normal lung development may occur more rapidly Side Effects Insufcient ventilation; may not control PaCO2 May have low PaO2, if too low Generalized atelectasis may occur (may be desirable in some cases of air leaks) High (30 cm H2O) Advantages May reexpand atelectasis Increase PaO2 Decrease PaCO2 Decrease pulmonary vascular resistance Side Effects Associated with PAL, BPD May impede venous return May decrease cardiac output

BPD = bronchopulmonary dysplasia; PAL = pulmonary air leaks.

Furthermore, because work of breathing, or the force needed to expand the lung (pressure times volume displacement), is so closely related to resistance, small changes in airway caliber markedly increase resistance and, in turn, work of breathing. Such problems are important in the consideration of optimal approaches to mechanical ventilation. In many cases of BPD, for example, initial respiratory failure may be related to the nding that the contribution of resistance factors to work of breathing is excessive for the infant over a certain period, although it may not be immediately apparent when one performs pulmonary function testing. Energy expenditure ultimately exceeds limited energy stores, and ventilator failure ensues. Subsequent ventilator management may be complicated by the problems created during ventilator cycling (Table 969).

Rate Effects
Respiratory rate is one of the primary determinants of minute ventilation.Minute ventilation equals the product of tidal volume and respiratory rate (or frequency). Several schools of thought exist concerning the optimal ventilator frequency for neonatal mechanical ventilation, although these can be divided into two primary modes of therapy: rapid-rate ventilation (>60 breaths/minute)118 and slower-rate ventilation (<40 breaths/minute).119 In both instances, the goal has been to try to reduce the complications associated with high inating pressures. Advantages and disadvantages exist with all forms of treatment (Table 9610). In attempting to understand the physiologic consequences of rate on ventilation, the concept of time constant must be addressed.The time constant of the lung is a measure of how rapidly equilibration between proximal and alveolar pressures occurs, and it

expresses how quickly an infant can move air into or out of the lung. The time constant is expressed by the following equation: time constant = compliance resistance. Time constants can be determined for both inspiration and expiration, although the neonatologist is particularly interested in the expiratory time constant with mechanical ventilation, because it is very important to have some idea of how rapidly the lung empties after a mechanical breath. Bancalari120 determined that, in the normal newborn, with a compliance of 0.005 L/cm H2O and a resistance of 30 cm H2O/L/second, one time constant equals about 0.15 second. A single time constant is dened as the time required by the lung to discharge 63% of the tidal volume that was delivered to the terminal air spaces.Three time constants equal the time required for the alveolus to discharge 95% of gas delivered and would therefore be approximately 0.45 second in the normal, spontaneously breathing infant. In diseased lung states, the effects of changes in compliance and resistance must be considered in applying mechanical ventilation. For an infant with RDS who has markedly reduced compliance in the early stages of the disease, the time constant of the lung may be exceedingly short. During that disease stage, one can readily use high rates to ventilate an infant, because the exit time of gas from the lung is so rapid, or one can use a slower rate with a prolonged inspiratory phase,again relying on the short time constant of a very stiff lung to allow gas exit during the short expiratory phase. Difculty arises, however, with both these therapeutic modalities when the lung begins to heal. During the recovery period, compliance begins to increase as surfactant release is enhanced and structural maturity occurs, whereas the effects of ventilator therapy, as noted previously, tend to narrow the airway lumen and increase resistance. In these circumstances, the time constant of the lung tends to

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TABLE 9610

Positive End-Expiratory Pressure

Low (23 cm H2O) Advantages Used during weaning Maintenance of lung volume in premature infants with low FRC Side Effects May be too low to maintain adequate lung volume CO2 retention Medium (47 cm H2O) Advantages Stabilizes lung volume Recruit lung volume with surfactant deciency states (e.g., RDS) Improve ventilation/ perfusion matching Side Effects May overdistend lungs with normal compliance High (8 cm H2O) Advantages Prevents alveolar collapse in surfactant deciency states with severely decreased CL Improves distribution of ventilation Side Effects PAL Decreases compliance if lung overdistends May impede venous return to the heart May increase PVR CO2 retention

CL = lung compliance; FRC = functional residual capacity; PAL = pulmonary air leaks; PVR = pulmonary vascular resistance; RDS = respiratory distress syndrome.

become increasingly prolonged, and if the rate of ventilation is not changed from the initial approach, gas trapping occurs, leading to a situation referred to as inadvertent PEEP.129 Although some inadvertent PEEP may be of value in maintaining lung volume during periods of atelectasis, progressive air trapping may lead to air dissection and air-leak syndromes and may also be one of the important initiating factors in the development of BPD. Furthermore, as demonstrated by Boros and colleagues,121 the use of very high ventilator rates with conventional mechanical ventilation at xed ow rates is limited by the nding that in vitro minute ventilation decreases beyond a certain maximum rate for individual ventilators (Fig. 968). Highfrequency ventilators, which generate inspiratory ow in a different manner from conventional ventilators, are not affected by these rate limitations to the same extent.The high-frequency ventilator, however, can also produce air trapping or inadvertent PEEP when it is used at rates beyond its optimal frequency. In neonatal ventilation, the introduction of continuous-ow circuitry,122 rather than intermittent ow of gas, permits the use of slow ventilator rates. Before the introduction of this modication, an infant breathing between respirator cycles would simply rebreathe exhaled gas in the breathing circuit, thus increasing work of breathing and raising the PaCO2. With the addition of constant ow, periodic ventilator breaths could be combined with spontaneous ventilation in a mode of therapy referred to as intermittent mandatory ventilation (IMV).123 This therapy enables the physician to supply a ventilator rate in the midrange (40 to 60 breaths/minute), thus providing sufcient ventilatory support for the infant while avoiding some of the complications of either high or low rate ventilation. At these midrange rates, the likelihood of air trapping and injury appears to be reduced for most infants. Again, the management of neonatal ventilator assistance cannot be carried out by following simple rules. Although the guidelines indicated are helpful in initiating treatment, each child must have care individualized to some degree. Newer ventilators have permitted the use of modalities such as assist/control (A/C) ventilation and pressure-support ventilation that allow the infant to set rate parameters. These techniques generally result in faster respiratory rates and greater synchrony. A comparative evaluation of the benets of these modalities has not been completed. Experience is therefore an essential ingredient in successful ventilator treatment of neonates.

1000

900

800 Minute volume (ml/min)

700

600

500

25 50 75 100 125 150 Figure 968. Minute volume effects of increasing ventilator rates from 25 to 150 breaths/minute (bpmhorizontal axis). Ventilators examined: BB 1, Babybird 1; BB 2, Babybird 2; BP, Bourns BP200; HD, Healthdyne; SC, Sechrist.Ventilator settings: peak inspiratory pressure = 25 cm H2O; positive end-expiratory pressure = 5 cm H2O; inspiration to expiration ratio (I/E) = 1:2 (after 75 bpm, ventilator BB 1 minute volumes were measured at 1:1 I/E ratio); ow = 10 Vain. (From Boros SJ, et al: Pediatrics 74:487, 1984.)

Mean Airway Pressure

Studies have demonstrated the signicance of MAP in the physiology of neonatal mechanical ventilation. MAP is dened as the

mean of instantaneous readings of proximal airway pressure during a single respiratory cycle. In waveform terminology, MAP is equal to the integration of the area under the pressure curve during a respiratory cycle.When one compares the two types of waveforms generated by ventilators, sine waves and square waves, it is obvious that MAP is higher in square wave ventilation compared with sine wave ventilation if inspiratory time (Ti) and PIP are equal (Fig. 969). Increasing MAP has been shown to increase oxygenation in neonates with RDS.124 However, this relationship may not hold true for all methods of increasing MAP (see Fig. 967). For example, if MAP is increased by raising the PIP, but with a very short Ti, that increase may be dissipated rapidly in the upper airways and ET tube, thus negating its effect.

96 / Assisted Ventilation: Physiologic Implications and Complications 973

Figure 969. Comparison of ventilator waveforms. A, Sine wave (relative). B, Square wave (relative). (From Goldsmith JP, Karotkin EH [eds]:Assisted Ventilation of the Neonate. Philadelphia,WB Saunders Co, 1988, p 148.)

The primary factors that control MAP are PEEP, I/E ratio, PIP, and waveform. Reynolds119 demonstrated that prolonging inspiration (increased Ti) during slow-rate ventilation with a square wave increased oxygenation. Additional work by Boros and associates124 conrmed the value of increasing MAP to improve oxygenation in RDS. As MAP increases, right-to-left shunt and the alveolar-arterial oxygen gradient are progressively reduced. Although high MAP may improve oxygenation during acute phases of neonatal lung disease (which is usually accompanied by decreased compliance), as infants recover and compliance improves, high MAP may cause venous obstruction similar to that seen with high CPAP. In addition, airways may become overdistended, leading to the complication of pulmonary injury described previously. Because MAP is a function of numerous variables and is not specically set on any conventional ventilator (this control is available on some high-frequency oscillators), one must again be cautious in selecting the optimal ventilatory pattern for this disease state to maximize the effect of MAP on oxygenation while attempting to reduce the negative effects of excessive levels. In general, the greatest effect on oxygenation can be achieved by increasing PEEP, because MAP will increase in direct proportion to the increase in PEEP (depending on the I/E ratio). If one does not simultaneously change PIP, however, in such circumstances, PaCO2 may rise because tidal volume will decrease (secondary to the decrease in the difference between PIP and PEEP). Furthermore, one must consider that oxygenation may paradoxically decrease as one attempts to raise MAP, if one begins to impede venous return to the heart, thereby impairing venous return and cardiac output, while also compressing the pulmonary vasculature. In such cases, the clinician has usually exceeded the optimal level of PEEP for the clinical situation.

ventilator rate is slowed during recovery. For example, an I/E ratio equal to 1.0 at a rate of 60 breaths/minute produces a Ti of 0.5 second, but the Ti becomes prolonged to 1.0 second when the rate is slowed to 30 beats/minute. Prolonged Ti may predispose patients to air leaks and BPD if the time constant of the lung is exceeded.

APPROACHES TO RESPIRATORY SUPPORT

As noted previously, the effects of injury associated with neonatal mechanical ventilation can result in substantial morbidity and mortality. Because of the continuing high incidence of BPD, ranging from approximately 10 to 40% at major university medical centers,116 several alternative approaches to ventilator support have been investigated (see Tables 964 and 966 through 969). We are concentrating on conventional ventilation, although modalities such as high-frequency ventilation, inhalational nitric oxide, and extracorporeal life support remain important tools in the intensive care nursery. These modalities are discussed elsewhere in this book.

Advances in Conventional Ventilation

Many improvements in conventional ventilators have been introduced into the intensive care nursery.The addition of ow sensors permitted on-line respiratory function measurements and more complex monitoring systems. Miniaturization of technologies, available for adult ventilation including pressuresupport,A/C, and volume ventilation, are now available for even the smallest neonates. For the infant receiving intermittent mandatory ventilation (IMV), spontaneous respiratory effort that is not in synchrony with the mechanical breath can be detrimental. The active expiration of the asynchronous breath may diminish tidal volume and may result in barotrauma.125 Attempts at achieving synchrony have included pharmacologic paralysis, sedation, and the use of a rapid respiratory rate and a short Ti.Variable results have been demonstrated in multiple studies, but, in general, synchronous ventilation diminishes barotrauma and alterations in cerebral blood ow and increases tidal volume and minute ventilation.126, 127 Synchrony on IMV can be achieved with rapid rates.128 Maintaining synchrony in these infants, in the healthier infant, or during weaning is difcult. Patient-triggered ventilation addresses some of these limitations and has now become a standard

Inspiratory/Expiratory Ratio
Many of the effects of I/E ratio have been discussed in sections related to CPAP, PIP, ventilator rate, and MAP. Some of the effects of varying I/E ratio are noted in Table 9611.Again, it is not possible simply to set an I/E ratio at the onset of ventilator treatment that will maximize oxygenation and ventilation throughout the clinical course of the disease. One must reevaluate the clinical course frequently in this regard. In fact, it may be better to select a Ti as a variable rather than selecting an I/E ratio, because, with an I/E ratio selection, the Ti may become excessively long as the

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TABLE 9611

Neonatal Mechanical Ventilatory Rates

Slow (< 40 breaths/min) Advantages Increased PaO2 with increased MAP Useful in weaning Used with square wave ventilation Used when I/E ratio is inverted Side Effects Must increase PIP to maintain ventilation Increased PIP may cause barotrauma Patient may require paralysis Medium (4060 breaths/min) Advantages Mimics normal ventilatory rate Effectively treats most neonatal lung diseases Usually does not exceed time constant of lung, so air trapping is unlikely Side Effects May not provide adequate ventilation in some cases Rapid (>60 breaths/min) Advantages Higher PaO2 (may be the result of air trapping) May allow decreased PIP and VT Hyperventilation may be useful in PPHN May reduce atelectasis (? air trapping) Side Effects May exceed time constant and produce air trapping May cause inadvertent PEEP May result in change in compliance (frequency dependence of compliance) Inadequate VT and minute ventilation if only dead space is ventilated

I/E = inspiratory/expiratory; MAP = mean airway pressure; PEEP = positive end-expiratory pressure; PIP = peak inspiratory pressure; PPHN = persistent pulmonary hypertension of the neonate;VT = tidal volume.

part of the neonatologists repertoire. In general, patienttriggered ventilation consists of two forms of mechanical ventilation: synchronized IMV (SIMV) and A/C ventilation. With SIMV, the ventilator is synchronized to the infants breathing pattern. If the patient-triggering threshold is met within a specic time (depending on the preset ventilator rate), a ventilator breath is not delivered, and the infant breathes spontaneously.A ventilator breath is delivered if the infant fails to breathe. Examination of the babys breathing pattern with SIMV will reveal both spontaneous breaths and ventilator breaths. The value of this form of support is that pressures within the airway are not stacked, so injury to the airway and the lung is theoretically reduced, and gas is not inadvertently dumped from the ventilator because airway pressures are reached prematurely.Although many neonatologists use SIMV as their primary mode of ventilator support for neonates, this technique appears to have greater benet as a weaning tool or if overdistention is present with A/C ventilation, particularly in the extremely low birth weight infant with either RDS or pulmonary insufciency of prematurity. A/C ventilation is also a form of patient-triggered support.With A/C ventilation, each infant breath that reaches the trigger threshold initiates a full ventilator breath. If the infant is apneic, or if the effort is inadequate to trigger a ventilator breath, the ventilator will deliver a preset back-up rate to the baby. All breaths in this form of ventilation appear similar and are entirely ventilator derived, and no spontaneous infant breaths ever occur on A/C support (unless the generated pressure is so low that it fails to trigger the ventilator). With A/C ventilation, the infant is fully synchronized to the ventilator.With the use of termination sensitivity as an adjunct, Ti will be limited to a percentage of maximum ow, and air trapping can usually be reduced or eliminated. A/C ventilation is a very effective form of initial treatment for many babies with various neonatal lung diseases in the early stages of their illness.The use of A/C ventilation limits pressure exposure for the infants, and they often spontaneously select a rate that is optimal for gas exchange, with a lower pressure than would usually be set on SIMV. Minute ventilation is higher on A/C than on SIMV.129 It is more difcult, however, to wean babies on A/C ventilation; occasionally, some overdistention will occur if there is excessive neural drive to breathe, and prolonged use of A/C ventilation may lead to some diaphragmatic muscle atrophy and further weaning difculty. Consequently, we often move

infants from A/C to SIMV when they begin to show signs of recovery from their lung disease.With A/C ventilation, one must also be cautious of autocycling of the ventilator. This problem can occur when there is erroneous triggering of the ventilator from leaks in the system, build-up of humidity in the circuit, or sensing of the cardiac pulsations as breaths. Frequent breaths are delivered unnecessarily to the baby. We have also seen an occasional infant on A/C support who does well while awake, with good gas exchange, but who has inadequate blood gases while sleeping or if sedated. In such cases, it would be helpful to have the capability of using two separate ventilator settings, one for waking periods and one during apneic support when slightly more pressure may be necessary for gas exchange. To date, however, no neonatal ventilator allows for the selection of multiple ventilator settings simultaneously that could automatically trigger under certain conditions. An adjunct therapy during patient-triggered ventilation is pressure-support ventilation, in which spontaneous infant breaths are partially or fully augmented by an inspiratory pressure assist higher than baseline end-distending pressure. This approach eases the work of breathing by allowing additional pressure delivery to overcome the elastic and resistive loads. This form of therapy may be used alone or in association with SIMV ventilation. Because it is synchronized with the infants ventilation, it can be used in babies who are becoming fatigued from work of breathing, in sedated infants, and in infants in a weaning phase of ventilation who are rst beginning to reuse their respiratory musculature. When this technique is used in conjunction with SIMV, it is important that the SIMV rate is not set too high, or the baby will have no impetus to breathe, and one of the primary purposes of pressure support will be nullied. Tidal volumeguided ventilation or volume-guarantee ventilation is a newer approach to therapy in which the clinician sets a mean tidal volume to be delivered by the ventilator while still allowing management of ventilator pressures. It is a variation of pressure-support ventilation in which volume, not pressure, guides the delivery of an augmented breath.The goal is to minimize variation in delivery of tidal volume, thought to be the cause of pulmonary injury in infants.Volume guarantee is used in conjunction with patient-triggered modalities. When the operator sets the inspiratory pressure limit during patient-triggered support, the ventilator attempts to deliver the set guaranteed

96 / Assisted Ventilation: Physiologic Implications and Complications 975

tidal volume using the lowest airway pressure possible.When the expired tidal volume exceeds the upper pressure limit, the ventilator will use a lower PIP on the next breath. If the set tidal volume cannot be delivered within the set pressure limit, an alarm alerts the operator to reset the pressure limit to a higher level or to adjust the guaranteed tidal volume to a lower level. Although available data on this technique are limited, it does appear that volume guarantee can achieve similar levels of gas exchange with slightly lower mean levels of inspiratory pressure.130 Additional modications may occur in the future, such as guaranteed minute ventilation, in which a desired minute ventilation is designated, with the ventilator providing a mix of guaranteed tidal volume and frequency to provide the desired minute ventilation. Proportional assist ventilation (PAV) and respiratory muscle unloading (RMU) require even more sophisticated computer assistance to achieve their effects. These innovative approaches work to control ventilator pressure throughout inspiration (in the case of PAV) or throughout the entire cycle (during RMU). With both forms of ventilator support, the infants respiratory effort is continuously monitored. During inspiration, as with pressure support ventilation, pressure rises to more than baseline to produce the desired inspiratory resistive unloading, thereby easing work of breathing. During exhalation, the circuit pressure falls to less than the baseline end-distending pressure, facilitating elastic and resistive unloading throughout that phase of the respiratory cycle.With this form of support, the resulting airway pressure is a variable that changes with the needs of the infant at any point during the respiratory cycle and is a weighted summation of a combination of airow and tidal volume above baseline pressure. Although infant studies with PAV and RMU are limited at present, the initial work appears very encouraging.131, 132 In a trial that examined the relative effects of low birth weight infants treated with IMV,A/C, and PAV, PAV appeared to maintain equivalent arterial oxygenation at lower airway and transpulmonary pressures than the other two modalities. During PAV, the oxygenation index was also reduced by 28%, with no evidence of more frequent apnea or other complications.There was also a decrease in both systolic and diastolic beat-to-beat variability with PAV, suggesting that there is additional overall cardiovascular stability offered to infants treated with this form of support. Another study indicated that there was less thoracoabdominal synchrony during PAV in preterm infants.133 Currently, few centers use this form of ventilator support, because it is still in early trials, yet the concepts appear very promising. Additional larger scale trials will unquestionably be seen in the near future. The additional space required by the ventilator adapter and by the ET tube adds a signicant amount of anatomic dead space during mechanical ventilation, particularly to the airway of an extremely low birth weight (<1000 g) infant.Through a mechanism of tracheal gas insufation, fresh gas is delivered to the more distal part of the ET tube and aids in washing out carbon dioxide from the airway. Peak inspiratory pressure can usually be decreased as well as tidal volume.134 These factors may reduce barotrauma and volutrauma in these infants, and early trials appear promising. ance, resistance, work of breathing, FRC, and others, has eliminated much of the guesswork that once was standard in neonatal intensive care units. Furthermore, pulmonary function tests have altered our understanding of the management of some diseases.135 Increased use of pulmonary function testing can better dene therapy and should be a standard part of newborn intensive care. Few therapeutic adjuncts have had the impact of surfactant in the intensive care nursery. Since its widespread introduction, surfactant has signicantly decreased the severity and incidence of RDS during the neonatal period while reducing the likelihood of BPD. The respiratory system inuences cardiovascular function through its effects on venous return and pulmonary vascular resistance. Return of venous blood to the heart depends primarily on the gradient between extrathoracic and intrathoracic pressures or transpulmonary pressure. Normally, because intrapleural pressure is subatmospheric (because of the effects of lung recoil and thoracic retraction), there is a favorable pressure gradient for the ow of blood back to the right side of the heart. With the application of positive-pressure ventilation, there is an increase in intrathoracic pressures, thereby reducing venous return and cardiac output. Ventricular performance of the heart may also become compromised owing to compression. The increase in intrapleural pressure that occurs with the introduction of mechanical ventilation depends on the degree of pressure transmitted from the airway to the intrapleural space. Pressure transmission is primarily a factor of lung compliance in infants. Thoracic compliance, important in adults, is relatively insignicant during the neonatal period because it is so high compared with lung compliance. In the patient with RDS, reduction in lung compliance allows signicantly less pressure transmission to the intrapleural space. Extrathoracic to intrathoracic pressures are not dramatically altered, so venous return and cardiac output are maintained. Patients with reduced compliance can tolerate signicant levels of PIP and PEEP with a minimal decrease in cardiac output. Sudden increase in intrathoracic pressure, however, as seen in a tension pneumothorax, may reduce venous return, even with a poorly compliant lung.This situation, encountered in the very premature infant with surfactant deciency, may result in an increase in venous pressure in the central nervous system and intraventricular hemorrhage. Furthermore, increasing compliance during RDS recovery may lead to a rapid increase in intrapleural pressure transmission over several hours, as seen during the diuretic phase of RDS. These ndings suggest that maintenance of high ventilator pressures may lead to an increased risk of intraventricular hemorrhage and air leaks. In addition to its effects on venous return and cardiac output, airway pressure during mechanical ventilation is also transmitted to intraparenchymal vessels.This effect is complex and depends on several factors in the newborn infant. Lung compliance again plays an important role, and in neonates there is less transmission of positive pressure with reduced compliance. In RDS, the disease process itself produces a decrease in FRC.This decrease results in an increase in pulmonary vascular resistance, offsetting the benecial effect of reduced pressure transmission from the airway. In contrast, lung overdistention, as seen in ventilation with large tidal volumes or modes of treatment that lead to gas trapping (i.e., high rate positive-pressure breathing) may pose problems. In these instances, overdistention of the air spaces compresses arterioles and capillaries, leading to increased pulmonary vascular resistance. Maintenance of FRC at near normal levels appears to be optimal for maintaining pulmonary perfusion. In addition to gas volumes, it is evident that another signicant part of the equation for pulmonary perfusion must include blood volume. When blood volume is reduced (e.g., in hemorrhage, postasphyxia capillary leak, or sepsis), the inuence

Adjuncts to Mechanical Ventilation

The care of infants with respiratory failure during the newborn period has been helped immeasurably by additional approaches including the measurement of pulmonary functions and lung volumes by computer, the administration of synthetic or natural surfactant, and early trials of antioxidants such as SOD for the prevention of BPD. Pulmonary function testing, which enables the determination of such factors as tidal volume, dynamic or static lung compli-

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situations, hyperventilation may not be necessary.142 In many cases, injury occurs early, leading to a need for an alternative therapeutic approach such as high-frequency ventilation or extracorporeal membrane oxygenation (ECMO). Of additional concern are ndings that indicate that continued hyperventilation to avoid ECMO may be a primary cause of neurologic injury, cerebral palsy, and developmental delay.145 In contrast to pulmonary hypoperfusion, pulmonary hyperperfusion may also have a signicant physiologic impact on optimal positive-pressure ventilation. In infants with a ventricular septal defect or in preterm infants with RDS and a patent ductus arteriosus, lung compliance may be adversely affected during ventilation by the excess pulmonary blood volume.With left-to-right shunting at a high rate, the pulmonary lymphatics may not maintain normal rates of uid reabsorption. Interstitial uid increases, and alveolar-capillary diffusion of gases may be reduced.These factors invariably lead to a need to increase ventilator support during mechanical ventilation. Failure to intervene by either pharmacologic means or surgery may lead to greater lung injury and may increase the probability of chronic lung disease.146 An additional concern in infants receiving mechanical ventilation is that of V/Q mismatching. During the application of CPAP or positive-pressure ventilation, areas of the lung that are atelectatic tend to remain so, whereas inated or partly inated regions of the lung tend to become further distended.The circulation generally responds to this situation with improved perfusion to lung segments that are inated, whereas areas of the lung that are collapsed receive less perfusion. These effects are thought to be locally mediated. When atelectasis is present, the arteriolar bed in that region becomes partially constricted. Although this vasoconstriction is somewhat benecial, there is still some lung tissue that is not receiving any signicant ventilation. V/Q mismatching is then present and is a common phenomenon in neonatal lung disease. With pulmonary interstitial emphysema, air dissects along distal bronchioles, interfering with circulation and gas exchange in affected segments of the lung that, however, may still be ventilated, resulting in a redistribution of pulmonary blood ow. As the situation progresses, gas exchange worsens, and ventilator support is commonly increased in an attempt to improve gas exchange.Too often, this response produces further overdistention of the already ventilated regions of the lung and increased pulmonary interstitial emphysema and ultimately results in the redistribution of pulmonary perfusion to less distended regions of the lung, owing to local vascular resistance changes in these regions.V/Q mismatching in such situations is often progressive, leading in some instances to tension pneumothorax. In such cases, one has maximum V/Q mismatching. Ventilation is now escaping into the pleural cavity, where no gas exchange can occur, while the perfusion remains conned within the lung, which is being progressively compressed from without by the pneumothorax. Subsequently, the heart may also be constricted as intrathoracic pressure increases. V/Q mismatching under any of the foregoing conditions therefore results in an increase in physiologic dead space and wasted ventilation. To compensate, the clinician must provide additional ventilatory support as well as alternate therapy (e.g., chest tube) in an attempt to reestablish more normal V/Q relationships. REFERENCES
1. Northway WH Jr, et al: Pulmonary disease following respirator therapy of hyaline membrane disease: bronchopulmonary dysplasia. N Engl J Med 276:368, 1967. 2. Philip AG: Oxygen plus pressure plus time: the etiology of bronchopulmonary dysplasia. Pediatrics 55:44, 1975. 3. Taghezadech A, Reynolds EO: Pathogenesis of bronchopulmonary dysplasia following hyaline membrane disease.Am J Pathol 82:241, 1976.

of mechanical ventilator pressures on pulmonary perfusion is magnied. Other complications associated with the effects of mechanical ventilation on cardiovascular performance during the neonatal period need further investigation. Investigators have shown that mechanical ventilation may alter relative tone in the autonomic nervous system; levels of various neurohumoral substances, referred to collectively as eicosanoids, may have wide-ranging effects in certain disease states, such as persistent pulmonary hypertension of the newborn (PPHN).136 In PPHN, there is a persistent elevation of pulmonary vascular resistance (PVR) of unknown etiology. Some evidence suggests that the increase in PVR may be partly mediated through either elevated or decreased amounts of these substances, which have very potent vasodilating and vasoconstricting capabilities. Other noneicosanoids, such as bradykinin, histamine, various hormones, and acetylcholine, as well as numerous other (perhaps some undiscovered) factors, also may have signicant inuence on pulmonary vascular tone and therefore perfusion. Furthermore, hypoxemia produces some degree of pulmonary arteriolar vasoconstriction, acting either through these vasoactive substances or through some alternative mechanism. Ultimately, a delicate balance emerges in which the infants blood volume, thoracic gas volume, autonomic control, and humoral factors produce a condition in which effective pulmonary blood ow is controlled. One of the most complicated diseases in which pulmonary hypoperfusion plays an important role is PPHN, or persistent fetal circulation. This syndrome, rst characterized during the 1970s by Gersony and other investigators,137, 138 is a disease primarily of full-term infants.The pathophysiology is notable in that the infant fails to demonstrate the normal decrease in PVR that typically occurs after birth. Pulmonary artery pressure is often higher than systemic blood pressure, which results in right-to-left shunting of blood across the foramen ovale and/or the ductus arteriosus. Infants with this syndrome often demonstrate signicant differential cyanosis, with high preductal oxygen saturation, whereas postductal saturation may be very low, depending on the degree of shunting.The syndrome is most commonly associated with postdate infants, sepsis, meconium aspiration, small for gestational age infants, pulmonary hypoplasia, and diaphragmatic hernias. In many cases, no specic etiology is discernible. Evidence suggests that some infants may have pulmonary vascular hypoplasia. Additionally, several new syndromes have been described that previously were thought to be PPHN. These syndromes include partial or complete surfactant protein B deciency in which the synthesis of surfactant-associated proteins is abnormal, resulting in a picture of alveolar proteinosis and chronic respiratory failure, and alveolar-capillary dysplasia, a syndrome diagnosed post mortem by ndings. At present, lung transplantation offers the only potential cure for these entities. Since 1978, when Fox introduced the hyperventilation technique for the treatment of PPHN,139 mechanical ventilator therapy has been an important part of the care given to these babies. Hyperventilation has been demonstrated to decrease PVR in this syndrome. 136, 139, 140 It is not entirely clear whether the response is a nonspecic pulmonary vasodilatation caused by a reduction of PaCO2, an increase in pH, a mechanical effect of ventilation, or some combination of factors. Subsequent work has demonstrated that hyperventilation does not provide better outcomes than other ventilation schemes in this population. Most likely, the lung injury associated with hyperventilation outweighs the benet of transient decreases in PVR with hypocarbia. In addition, drugs such as inhaled nitric oxide have replaced hyperventilation as a means of increasing pulmonary blood ow. The disease also has a series of stages through which the baby progresses to a more physiologic circulatory pattern, at which time the ventilatory approach must be altered to avoid ventilatorinduced lung injury.141144 In milder cases and in some clinical

96 / Assisted Ventilation: Physiologic Implications and Complications 977

4. Gibson E: Apnea. In Spitzer A (ed): Intensive Care of the Fetus and Neonate. St. Louis, MosbyYear Book, 1996, pp. 470481. 5. Rigatto H: A critical analysis of the development of peripheral and central respiratory chemosensitivity during the neonatal period. In von Euler C, Lagercrantz H (eds): Central Nervous Control Mechanisms in Breathing. New York, Pergamon Press, 1979. 6. Rigatto H, et al: Ventilatory response to 100% and 15% oxygen during wakefulness and sleep in preterm infants. Early Hum Dev 7:1, 1982. 7. Rigatto H: Control of breathing in the fetus and newborn. In Spitzer A (ed): Intensive Care of the Fetus and Neonate. St. Louis, MosbyYear Book, 1996, pp 458469. 8. Harris TN: Physiological principles. In Goldsmith JP, Karothers EH (eds): Assisted Ventilation of the Neonate. Philadelphia, WB Saunders Co, 1988, p 28. 9. Antunes MJ, Greenspan JS: Pulmonary function testing. In Spitzer A (ed): Intensive Care of the Fetus and Neonate. St. Louis, MosbyYear Book, 1996, pp. 517530. 10. Bhutani VK, et al: Pressure-induced deformation in immature airways. Pediatr Res 15:829, 1981. 11. Bhutani VK, et al:Acquired tracheomegaly in very preterm neonates.Am J Dis Child 140:449, 1986. 12. Penn RB, et al: Effect of tracheal smooth muscle tone on the collapsibility of extremely immature airways. J Appl Physiol 65:863, 1988. 13. Panitch HB, et al:A comparison of preterm and adult airway smooth muscle mechanics. J Appl Physiol 66:1760, 1989. 14. Antunes MJ, et al: Decreased functional residual capacity predates requirement for ECMO and lung opacication during ECMO. Pediatr Res 31:192A, 1992. 15. Deoras KS, et al: Structural changes in the tracheae of preterm lambs induced by ventilation. Pediatr Res 26:434, 1989. 16. Allen JL, et al:Thoracoabdominal asynchrony in infants with airow obstruction.Am Rev Respir Dis 141:337, 1990. 17. Fox WW, et al: Effects of endotracheal tube leaks on functional residual capacity determination in intubated neonates. Pediatr Res 13:60, 1979. 18. Gerhardt T, et al:A simple method for measuring functional residual capacity by N2 washout in small animals and newborn infants. Pediatr Res 19:1165, 1985. 19. Morgan WJ, et al: Partial expiratory ow-volume curves in infants and young children. Pediatr Pulmonol 5:232, 1988. 20. Notter RH, Morrow PE: Pulmonary surfactant: a surface chemistry viewpoint. Am Biomed Eng 3:119, 1975. 21. Notter RN, Shapiro DL: Lung surfactant in an era of replacement therapy. Pediatrics 68:781, 1981. 22. Notter RN, Finkelstein JN: Pulmonary surfactant: an interdisciplinary approach. J Appl Physiol 57:1613, 1984. 23. Raju TK, et al: Double-blind controlled trial of single-dose treatment with bovine surfactant in severe hyaline membrane disease. Lancet 1:651, 1987. 24. Jobe A, et al: Duration and characteristics of treatment of premature levels with natural surfactant. J Clin Invest 67:370, 1981. 25. Vermont-Oxford Neonatal Network: A multicenter, randomized trial comparing synthetic surfactant with modied bovine surfactant extract in the treatment of neonatal respiratory distress syndrome. Pediatrics 97:1, 1996. 26. Wolfson MR, et al: Respiratory muscle function. In Tecklin J (ed): Cardiopulmonary Physical Therapy. St. Louis, CV Mosby, 1989. 27. Northway WH: An introduction to bronchopulmonary dysplasia. Clin Perinatol 19:489, 1999. 28. Troug WE, Jackson JC:Alternative Modes of Ventilation in the Prevention and Treatment of Bronchopulmonary Dysplasia. Philadelphia, WB Saunders Co, 1992, pp 621. 29. Slutsky AS: Lung injury caused by mechanical ventilation. Chest 116:9S, 1999. 30. Bjorklund LJ, et al: Manual ventilation with a few large breaths at rst compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res 42:348, 1998. 31. Jobe AJ:The new BPD: an arrest of lung development. Pediatr Res 4:641, 2000. 32. Coalson JJ, et al: Decreased alveolarization in baboon survivors with bronchopulmonary dysplasia.Am J Respir Crit Care Med 152:640, 2000. 33. Albertine KH, et al: Chronic lung injury in preterm lambs. Disordered respiratory tract development.Am J Respir Crit Care Med 159:945, 1999. 34. Tremblay L, et al: Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944, 1997. 35. Meduri GU, et al: Inammatory cytokines in the BAL of patients with ARDS: persistent elevation over time predicts poor outcome. Chest 108:1303, 1995. 36. Tutor JD, et al: Loss of compartmentalization of alveolar tumor necrosis factor after lung injury.Am J Respir Crit Care Med 149:1107, 1994. 37. Donnelly SC, et al: Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet 341:643, 1993. 38. Slutsky AS,Tremblay LN: Multiple system organ failure: is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 157:1721, 1998. 39. Jacobs RF, et al: Factors related to the appearance of alveolar macrophages in the developing lung.Am Rev Respir Dis 131:548, 1985. 40. Christensen RD, et al: Blood and marrow neutrophils during experimental group streptococcal infection: quantication of the stem cell, proliferative, storage and circulating pools. Pediatr Res 16:549, 1982. 41. Carlton DP, et al: Role of neutrophils in lung vascular injury and edema after premature birth in lambs. J Appl Physiol 83:1307, 1997. 42. Merritt TA, et al: Elastase and alpha 1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome: role of inammation in the pathogenesis of bronchopulmonary dysplasia. J Clin Invest 72:656, 1983. 43. Ogden BE, et al: Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance.Am Rev Respir Dis 130:817, 1984. 44. Ogden BE, et al: Lung lavage of newborns with respiratory distress syndrome: prolonged neutrophil inux is associated with bronchopulmonary dysplasia. Chest 83:31S, 1983. 45. Arnon S, et al: Pulmonary inammatory cells in ventilated preterm infants: effect of surfactant treatment.Arch Dis Child 69:44, 1993. 46. Groneck P, et al: Association of pulmonary inammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inammatory mediators in respiratory uids of high-risk preterm neonates. Pediatrics 93:712, 1994. 47. Rannels DE: Role of physical forces in compensatory growth of the lung.Am J Physiol 257:L179, 1989. 48. Wirtz HR, Dobbs LG: Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 250:1266, 1990. 49. Pierce RA, et al: Chronic lung injury in preterm lambs: disordered pulmonary elastin deposition.Am J Physiol 272:L452, 1997. 50. Jackson JC, et al: Effect of high-frequency ventilation on the development of alveolar edema in premature monkeys at risk for hyaline membrane disease. Am Rev Respir Dis 143:865, 1991. 51. Kinsella JP, et al: Independent and combined effects of inhaled nitric oxide, liquid peruorochemical and high-frequency oscillatory ventilation in premature lambs with respiratory distress syndrome.Am J Respir Crit Care Med 159:1220, 1999. 52. Jackson JC, et al: Reduction in lung injury after combined surfactant and highfrequency ventilation.Am J Respir Crit Care Med 150:534, 1994. 53. Ikegami M, et al: Lung injury and surfactant metabolism after hyperventilation of premature lambs. Pediatr Res 47:398, 2000. 54. Naik A, et al: Effects of different styles of ventilation on cytokine expression in the preterm lamb lung. Pediatr Res 4:372A, 2000. 55. Thurlbeck WM: Morphologic aspects of bronchopulmonary dysplasia. J Pediatr 95:842, 1979. 56. 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Pediatrics 66:589, 1980. 63. Berman W Jr, et al: Evaluation of infants with bronchopulmonary dysplasia using cardiac catheterization. Pediatrics 70:708, 1982. 64. Walsh WF, Hazinski TA: In Spitzer A (ed): Intensive Care of the Fetus and Neonate. St. Louis, MosbyYear Book, 1996, pp 641656. 65. Panitch HB, et al: Maturational changes in airway smooth muscle structurefunction relationships. Pediatr Res 31:151, 1992. 66. Bhutani VK, et al: Pressure-induced deformation in immature airways. Pediatr Res 15:829, 1981. 67. Shaffer TH, et al: In-vivo mechanical properties of the developing airway. Pediatr Res 25:143, 1989. 68. Bjorklund LJ, et al: Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs. Pediatr Res 42:348, 1997. 69. Berry D, et al: Leakage of macromolecules in ventilated and unventilated segments of preterm lamb lungs. J Appl Physiol 70:423, 1991. 70. 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112. Hall SV, et al: Renal hemodynamics and function with continuous positive pressure ventilation in dogs.Anesthesiology 41:452, 1974. 113. Annat G, et al: Effect of PEEP ventilation on renal function, plasma renin, aldosterone, neurophysins and urinary ADP, and prostaglandins. Anesthesiology 58:136, 1983. 114. Bark H, et al: Elevation in plasma ADH levels during PEEP ventilation in the dog: mechanisms involved.Am J Physiol 239:E474, 1980. 115. Fox WW, et al: Positive pressure ventilation of the neonate. In Goldsmith JP, Karotkin EH (eds): Assisted Ventilation of the Neonate. Philadelphia, WB Saunders Co, 1988, p 146. 116. Avery ME, et al: Is chronic lung disease in low birth weight infants preventable? A survey of eight centers. Pediatrics 79:26, 1987. 117. Wall NM: Infant endotracheal tube resistance: effects of changing length, diameter, and gas density. Crit Care Med 8:38, 1980. 118. 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Johnson LH, et al:Vitamin E and ROP: the continuing challenge. In Klaus MH, Fanaroff AA (eds): Yearbook of Neonatal-Perinatal Medicine. St. Louis, MosbyYear Book, 1993, pp xvxxiv. 85. Frank L, Sosenko IR: Prenatal development of lung antioxidant enzymes in four species. J Pediatr 110:106, 1987. 86. Sosenko IR, et al: Failure of premature rabbits to increase lung antioxidant enzyme activities after hyperoxic exposure: antioxidant enzyme gene expression and pharmacologic intervention with endotoxin and dexamethasone. Pediatr Res 137:469, 1995. 87. Autor AP, et al: Developmental characteristics of pulmonary superoxide dismutase: relationship to idiopathic respiratory distress syndrome. Pediatr Res 10:154, 1976. 88. Frank L, et al: Oxygen therapy and hyaline membrane disease: the effect of hyperoxia on pulmonary superoxide dismutase activity and the mediating role of plasma or serum. J Pediatr 90:105, 1997. 89. 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