84. Tay-Uyboco JS, et al: Hypoxic airway constriction in infants of very low birthweight recovering from moderate to severe bronchopulmonary dysplasia.J Pediatr 115:456, 1989.

85. Smyth JA, et al: Pulmonary function and bronchial hyper-reactivity in long-term survivors of bronchopulmonary dysplasia. Pediatrics 68:336, 1981.

86. Northway WH, et al: Late pulmonary sequelae of bronchopulmonary dyspla-sia. N Engl J Med 323:1793, 1990.

87. Greenspan JS, et al:Airway reactivity as determined by a cold air challenge ininfants with bronchopulmonary dysplasia. J Pediatr 114:452, 1989.

88. Brundage KL, et al: Bronchodilator response to ipratropium bromide ininfants with bronchopulmonary dysplasia.Am Rev Respir Dis 142:1137,1990.

89. Cabal LA, et al: Effects of metaproterenol on pulmonary mechanics, oxygena-tion, 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 functionin neonates with increased pulmonary resistance. Pediatr Pulmonol 2:287,1986.

91. Kao LC, et al: Effect of isoproterenol inhalation on airway resistance inchronic bronchopulmonary dysplasia. Pediatrics 73:509, 1984.

92. Stefano JL,et al:A randomized placebo-controlled study to evaluate the effectsof oral albuterol on pulmonary mechanics in ventilator-dependent infants atrisk 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 pul-monary mechanics of infants with bronchopulmonary dysplasia. PediatrPulmonol 6:74, 1989.

95. Engelhardt B,et al:Short- and long-term effects of furosemide on lung functionin infants with bronchopulmonary dysplasia. J Pediatr 109:1034, 1986.

96. Kao LC, et al: Effect of oral diuretics on pulmonary mechanics in infants withchronic bronchopulmonary dysplasia: results of a double-blind crossoversequential trial. Pediatrics 74:37, 1984.

97. Kao LC, et al: Oral theophylline and diuretics improve pulmonary mechanicsin infants with bronchopulmonary dysplasia. J Pediatr 111:439, 1987.

98. McCann EM, et al: Controlled trial of furosemide therapy in infants withchronic lung disease. J Pediatr 106:957, 1985.

99. Rush MG, et al: Double-blind, placebo-controlled trial of alternate-dayfurosemide therapy in infants with chronic bronchopulmonary dysplasia.J Pediatr 117:112, 1990.

100. Weinstein MR, Oh W: Oxygen consumption in infants with bronchopul-monary dysplasia. J Pediatr 99:958, 1981.

96 / Assisted Ventilation: Physiologic Implications and Complications 961

101. Kurzner SI, et al: Growth failure in bronchopulmonary dysplasia: elevatedmetabolic rates and pulmonary mechanics. J Pediatr 112:73, 1988.

102. Yunis KA, Oh W: Effects of intravenous glucose loading on oxygen consump-tion, carbon dioxide production, and resting energy expenditure in infantswith bronchopulmonary dysplasia. J Pediatr 115:127, 1989.

103. Mallory GB, et al: Longitudinal changes in lung function during the first threeyears of premature infants with moderate to severe bronchopulmonary dys-plasia. Pediatr Pulmonol 11:8, 1991.

104. Blayney M, et al: Bronchopulmonary dysplasia: improvement in lung functionbetween 7 and 10 years of age. J Pediatr 118:201, 1991.

105. Harrod JR, et al: Long-term follow-up of severe respiratory distress syndrometreated with IPPB. J Pediatr 84:277, 1974.

106. Abman SH, et al: Pulmonary vascular response to oxygen in infants withsevere bronchopulmonary dysplasia. Pediatrics 75:80, 1985.

107. Berman W, Jr, et al: Evaluation of infants with bronchopulmonary dysplasiausing cardiac catheterization. Pediatrics 70:708, 1982.

108. Tomashefski JF, et al: BPD: a morphometric study with emphasis on the pul-monary vasculature. Pediatr Pathol 2:469, 1984.

109. Goodman G, et al: Pulmonary hypertension in infants with bronchopul-monary dysplasia. J Pediatr 112:67, 1988.

110. Halliday HL, et al: Effects of inspired oxygen on echocardiographic assess-ment of pulmonary vascular resistance and myocardial contractility in bron-chopulmonary dysplasia. Pediatrics 65:536, 1980.

111. Abman SH, et al: Systemic hypertension in infants with bronchopulmonarydysplasia. J Pediatr 104:928, 1984.

112. Melnick G, et al: Normal pulmonary vascular resistance and left ventricularhypertrophy in young infants with bronchopulmonary dysplasia: an echocar-diographic and pathologic study. Pediatrics 66:589, 1980.

113. Abman SH,et al:Pulmonary vascular extraction of circulating norepinephrinein infants with bronchopulmonary dysplasia. Pediatr Pulmonol 3:386, 1987.

114. Brownlee JR, et al:Acute hemodynamic effects of nifedipine in infants withbronchopulmonary dysplasia and pulmonary hypertension. Pediatr Res24:186, 1988.

115. Johnson CE, et al: Pharmacokinetics and pharmacodynamics of nifedipine inchildren with bronchopulmonary dysplasia and pulmonary hypertension.Pediatr Res 29:500, 1991.

116. Banks BA, et al: Changes in oxygenation with inhaled nitric oxide in severebronchopulmonary dysplasia. Pediatrics 103:610, 1999.

117. Lonnqvist PA, et al: Inhaled nitric oxide in infants with developing or estab-lished chronic lung disease.Acta Paediatr 84:118, 1995.

118. Clark PL,et al: Safety and efficacy of nitric oxide in chronic lung disease. ArchDis Child 86:F41, 2002.

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

Assisted Ventilation: Physiologic Implications and Complications

Mechanical ventilation is used in the treatment of neonatal pul-monary insufficiency. Since its introduction in the 1980s, it hasbeen steadily refined, resulting in the successful treatment ofmany previously fatal diseases and dramatically improving thesurvival rate of many high-risk neonates. As with many otheradvances in medicine, however, this therapy has been accompa-nied by complications, particularly chronic lung injury or bron-chopulmonary dysplasia (BPD).l This disease, unknown beforethe use of mechanical ventilation, has produced a population ofpatients who are ventilator or oxygen dependent, with seriousaccompanying morbidity and mortality.2,3 A clear understandingof the physiology of mechanical ventilation is essential for theneonatologist to maximize the benefits and reduce the problemsassociated with its use.

This chapter provides a review of the physiologic and patho-physiologic processes in conventional mechanical ventilation ofthe neonate. Because acute and chronic neonatal lung disease ismultifactorial in origin, virtually all aspects of neonatal care canbe considered part of the ventilation strategy.The prevention of

lung injury includes attention to issues such as infection, fluidmanagement, patent ductus arteriosus, nutrition, anemia, andmany other aspects of patient management. For the purposes ofthis chapter, however, the indications and implications of initiat-ing mechanical ventilation are discussed, and some of the newertechniques of ventilation and lung protection are addressed.

PULMONARY PHYSIOLOGY AND PATHOPHYSIOLOGY:CONSIDERATIONS WITH ASSISTED VENTILATIONAlthough the design of the lung serves multiple functions, theprimary structure and its placement within the thorax establishits main purpose as gas exchange. The respiratory system con-sists of a series of branching tubes that bring fresh gas from the atmosphere to the terminal air spaces, while allowing theelimination of respiratory byproducts of metabolism to flowfrom the alveoli back into the environment (Fig. 96–1). Thediaphragm, the primary muscular force during quiet ventilation,contracts during inspiration, lowering intrapleural pressure.This

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contraction, occurring against the anchoring ribcage, results in apressure gradient that decreases from the mouth to the alveoliand leads to an inward flow of gas. Simultaneously, the increasein intra-abdominal pressure and the physical structure of thethorax limit inspiratory movement until rising intrathoracicpressure terminates flow. During inspiration, a series of elasticelements—the chest wall muscles,diaphragm,airway connectivetissue, pleurae, and blood vessels—stretch within the thorax.Atthe end of inspiration, the energy stored in these stretchedelastic elements provides a recoil force that pumps gas out of thelung during expiration. Under normal circumstances, expirationis a passive process.When the respiratory workload is increased,the accessory muscles of the intercostal spaces and the abdomi-nal musculature are recruited, so both inspiration and expirationmay become active and require additional energy expenditure.The gas volume in the lungs at the point at which inspiratoryeffect again begins to oppose the expiratory recoil forces isknown as the functional residual capacity (FRC).

Neurochemical control of breathing in the newborn and its influence on the process are only partially understood (Table 96–1). Compared with an adult, the brain stem centers ofrespiratory control in the neonate are immature and are moresusceptible to failure, as seen in apnea of infancy.4 Chemo-receptor responsiveness also appears to be diminished, particu-larly with respect to hypoxemia.5–7 In addition, numerous reflexresponses present in very young infants disappear rapidly duringthe first months and years of life.8 Finally, sleep state, whichinfluences 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 forventilatory volumes in neonates (Table 96–2).9 Although valuesfor 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

962 XII / The Lung

testing, aided by the use of computerized analysis (Fig. 96–2), hasproduced extensive data on compliance and resistance measure-ments during states of both health and disease.9 Compliancerefers to the lung relationship that correlates a given change involume to a change in pressure required to produce that volumechange. In general, the smaller the lung is, the lower the compli-ance. If one compares compliance in the healthy newborn withFRC (specific compliance), values are comparable to those seenin older children and adults. Little contribution to total lung com-pliance is made by the newborn chest wall, especially in preterminfants, because thoracic compliances are extraordinarily high.

The airways of young infants are small in caliber, highly dis-tensible, and susceptible to injury during mechanical ventila-tion.10–14 Resistance (related to the fourth power of the radius ofthe airway by Poiseuille’s law) is rapidly elevated by any reduc-tion in airway caliber. Increased secretions, airway edema,increased collapsibility of the airway, and other related phenom-ena may result from the use of mechanical ventilation in thesmall infant.15 Furthermore, assessment of flow-volume and pres-sure-volume loops provides important information about airwaypatency and chest wall distortion.16 Measurement of FRC,although somewhat more difficult, can also be performed witheither a helium dilution method17 or the nitrogen washouttechnique.18 Finally, the lack of infant cooperation during forcedexpiratory volumes19 has been resolved by the use of externalcompression of the thorax (Fig. 96–3).These techniques enablethe neonatologist to understand both normal infant ventilationand the alterations produced during mechanical ventilation.

Certain features of the developing lung predispose it to injuryduring therapy with mechanical ventilation. Surface tension isrelatively higher in the alveoli for all infants during the first hoursof life, and some degree of atelectasis is common until amonomolecular layer of phospholipids (and their accompanyingproteins), collectively known as surfactant, is deposited at theair-liquid interface (Table 96–3). Surfactant, primarily composedof phosphatidylcholine, phosphatidylglycerol, phosphatidylinosi-tol, and several other lipid-soluble moieties,decreases the surfacetension in the lung at end-expiration.20–25 The surfactant proteins(SP-A, SP-B, SP-C) play important roles in the stability and recy-cling of the lipid moieties.Surfactant reduces the tendency of thelung to collapse from increased surface active forces in thealveoli. Surface tension and structural immaturity appear to bethe major factors in the premature lung that lead to respiratoryinsufficiency and result in hyaline membrane disease or respira-tory distress syndrome (RDS) (Fig. 96–4). Although primarily adisease of prematurity, RDS does occasionally occur in full-termbirths.When surfactant deficiency and structural immaturity arepresent, lung compliance in the newborn is reduced, and venti-lator support is frequently necessary.

In addition to lung immaturity, numerous studies have sug-gested that the ventilatory muscles of newborns are more sus-ceptible to fatigue than those of adults, a factor that mayadditionally contribute to the respiratory problems of pretermneonates.26 Studies of histochemical and physiologic propertiesof respiratory muscle fibers reported age-related differences inhuman and baboon diaphragm. In comparison with fibers in thefull-term baby or adult, the diaphragm in the premature baboonhas fewer contractile proteins per fiber area and poorly devel-oped sarcoplasmic reticulum; thus, the premature diaphragmcontracts from progressively shorter lengths and develops lesstension.When mechanical ventilation is used in infants with res-piratory muscle weakness, the work of breathing is reduced,oxygen consumption is decreased, and respiratory musclefatigue may be prevented. Other factors, such as the fragility oflung tissue, marginal energy reserves, limited ability to increasecardiac output, and lability of pulmonary perfusion from pul-monary hypertension, also may result in both a greater need formechanical ventilation and additional problems during mech-anical ventilation.

Figure 96–l. Negative pressure gradient produced on inspirationby 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, KarotkinEH [eds]:Assisted Ventilation of the Neonate, 2nd ed.Philadelphia,WB Saunders Co, 1988, p 24.)

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ETIOLOGY OF LUNG INJURY WITH MECHANICAL VENTILATIONMechanical ventilation enables the infant to maintain adequategas exchange until the lung can heal. Although effective, thistherapy can induce lung injury, thereby exacerbating the diseaseprocess as well as creating new iatrogenic disorders.The lung ofthe premature infant is more susceptible to injury than the moremature lung. Although the source of iatrogenic injury for the

96 / Assisted Ventilation: Physiologic Implications and Complications 963

ventilated preterm infant may be similar to that of the olderinfant,child,or adult, these mechanisms are exacerbated.Currentconcepts identify lung tissue injury from barotrauma (effect ofpressure), volutrauma (effect of tidal volumes), atelectrauma(repetitive opening and closing of lung units from low lungvolumes), and toxic reactive oxygen species as causative of thisinjury.27–29 Studies of preterm lambs demonstrated alterations inlung function after brief exposure to high ventilation pressure atbirth.30 Furthermore, the histopathology of controlled studies of

TABLE 96–1

Factors Affecting Control of Ventilation in the Spontaneously Breathing Neonate

Neurologic FactorsMaturity of the CNS

Degree of myelination, which largely determines speed of impulse transmission and response time to stimuli affecting ventilationDegree 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 centerSleep 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 reflexes, 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 anddegree of ventilation

Reflex responsesHering-Breuer reflex, whereby inspiratory duration is limited in response to lung inflation sensed by stretch receptors located in major airways.

Not present in adult humans, this reflex is active during quiet sleep of newborns but absent or weak during REM sleepHead’s reflex, whereby inspiratory effort is further increased in response to rapid lung inflation.Thought to produce the frequently observed

biphasic signs of newborns that may be crucial for promoting and maintaining lung inflation (and therefore breathing regularity) after birthIntercostal-phrenic reflex, whereby inspiration is inhibited by proprioception (position-sensing) receptors in intercostal muscles responding to

distortion of the lower rib cage during REM sleepTrigeminal-cutaneous reflex, whereby tidal volume increases and respiratory rate decreases in response to facial stimulationGlottic closure reflex, whereby the glottis is narrowed through reflex contraction of the laryngeal adductor muscles during respiration, thereby

breaking exhalation and increasing subglottic pressure (as with expiratory grunting)

Chemical Drive Factors (Chemoreflexes)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 arousalFor the first week of life at least, these responses are dependent on environmental temperature, i.e., keeping the baby warmHypoxia is associated with an increase in periodic breathing and apnea

Response to hyperoxia (increase in FIO2concentration breathed): enriched O2 breathing causes a transient respiratory depression, stronger in term

than in preterm infantsResponse 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 96–2

Ventilatory Values in Normal Newborns

Authors Method Weight (kg) Respiratory Rate VT (mL) VE (mL/min) VA (mL/min) VD/VT

Cook, et al Plethysmography 3.8 38 16.0 — — 0.32*Swyer, et al Pneumotachography 3.0 37 20.6 — — —Strang Plethysmography 3.3 41 18.1 750 378 0.50†

Nelson, et al Nonrebreathing valve 2.2 38 12.8 480 309 0.25†

Koch Nonrebreathing valve 3.6 44 (24 h) 16.5 703 442 0.25*39 (7 d) 16.6 632 425 0.24*

Bancalari, et al Plethysmography 3.3 48 18.1 868 — —

* 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.

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preterm animals and infants with chronic lung disease suggeststhat lung development is arrested by prolonged mechanicalventilation.31–33 Adult animal studies demonstrate an increase inproinflammatory cytokines and induction of c-fos mRNA withmechanical ventilation, with the greatest increases occurringwith high inflation pressures and tidal volumes with zero end-expiratory pressure.34 In addition, studies have demonstratedthat this lung injury could alter gene expression in the lung.Thus, noxious stimuli lead to another mechanism of lung injurycalled biotrauma. Nonsurvivors of adult/acute RDS (ARDS) haveelevation of bronchoalveolar lavage fluid (BALF) cytokines, sug-gesting a pulmonary origin for the plasma cytokines.35 Elevatedlevels of interleukin-8 in BALF are predictive of severe ARDS, andcytokines are released into the systemic circulation when thealveolar-endothelial barrier is disrupted.36, 37 This may be themechanism by which ventilator-induced lung injury leads to mul-tiorgan failure.38 Because the lung is in contact with the entirecardiac output, the release of active substances can act as asignificant attenuator of or contributor to systemic compromise.

Although the circulating neutrophil pool and alveolarmacrophage population increase with age,39, 40 both have been

964 XII / The Lung

implicated in mechanisms of lung injury of preterm infants.Thecirculating neutrophil pool size decreases and lung neutrophilsincrease after the mechanical ventilation of preterm animals.41–46

The increase in neutrophils in the pulmonary air space is directlyrelated to the decrease in circulating neutrophils, clearance ofprotein and liquid from the lung, and extravascular lung water.Pulmonary neutrophils therefore play a role in the pathogenesisof lung injury and the creation of lung edema.

Mechanotransduction, the conversion of a mechanical stimu-lus into structure and functional alterations of tissues, has beenshown to affect the lung.47, 48 Prolonged mechanical gas ventila-tion of the preterm lamb results in increased elastin expression(mRNA tropoelastin) and abnormal lung development.49 Some ofthese alterations can be attenuated with ventilation strategiesdesigned to reduce injury.50–54

Once injury is initiated, many factors can contribute toongoing damage. Pulmonary injury initiates and is accompaniedby a series of responses that ultimately lead to varying degrees ofresidual damage, depending on the duration and level of ventila-tor support. Desquamation of the epithelial and ciliary appara-tus, increased goblet cells and smooth muscle,bronchial necrosis

Figure 96–2. Computerized pulmonary function testsdemonstrating flow-volume (A) and volume-pressure (B) loops for four consecutive breaths in an individualinfant.The dotted line in each volume-pressure loopindicates the slope of the line for the calculatedcompliance. Ct = total lung compliance;Exp = expiration; Fpke = peak expiratory flow;Fpki = peak inspiratory flow; Insp = inspiration;Rt = total lung resistance;Wt = total work.

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that heals with fibrosis, increased interstitial lung fluid, ruptureof alveolar septa, and diffuse inflammatory disease throughoutthe lung are some of the changes that are apparent with mechan-ical ventilation.55–60 These sequelae of lung injury are most oftenseen in BPD, as evidenced by airway distention, shifting atelec-tasis on chest roentgenography, hyperinflation of other areas ofthe lung, ventilation/perfusion (V/Q) inequalities, and impairedcardiac function.11, 61–64 The use of mechanical ventilation istherefore a two-edged sword:often, there is no other way to savean infant’s life, yet the therapy itself almost always producessome degree of lung and airway damage.

INITIATION OF NEONATAL LUNG DISEASE AND THE DECISION TO INITIATE NEONATALMECHANICAL VENTILATIONGiven the risk of injury associated with mechanical ventilation,the decision to place an infant on respiratory support, with theselection of appropriate ventilator settings, is one of the mostcritical decisions made in medicine. The clinician must under-stand the reasons behind this decision and the strategy that willbe employed. This decision has been made more difficult overthe past several years,because a large body of work has begun toredesign the ventilation targets for neonates and to elucidate the ramifications of the decision to ventilate the patient me-

96 / Assisted Ventilation: Physiologic Implications and Complications 965

chanically.The process that determines the need for mechanicalventilation begins in utero, with the initiation of maternalsteroid or tocolytic therapy, and proceeds in the delivery room.

The development of adequate pulmonary blood flow,FRC,andV/Q matching, with uniform distribution of lung surfactant, canbe affected by the management of these issues in the first fewminutes of life. Animal studies demonstrate that airway and lungparenchymal injury can occur with only a few large breaths atthe time of birth.65–68 In addition, tidal breathing in the deliveryroom can cause alterations in surfactant function.These changes

Figure 96–3. A, Infant partial expiratory flowvolume (PEFV) by rapid thoracic compressionset-up showing the compression bag wrappedaround the infant’s thorax and abdomen andconnected to the pressure reservoir. Flow ismeasured by a pneumotachograph (PNT),processed by computer (CPU), and displayed ata flow-volume loop. B, PEFV curves from infantswith obstructive lung disease compared with anormal curve demonstrating flow limitation andconcavity toward the volume axis. (FromBhutani VK, et al: Neonatal Pulmonary FunctionTesting. Ithaca, NY, Perinatology Press, 1988.)

TABLE 96–3

Roles of Surfactant in Pulmonary Physiology

Reduce alveolar surface tensionIncrease complianceDecrease work of breathingIncrease alveolar stabilityImprove alveolar recruitmentReduce lung forces that result in pulmonary edema

Figure 96–4. The pathogenesis of respiratory distress syndrome.(From Polin RA, Burg MD [eds]:Workbook in PracticalNeonatology. Philadelphia,WB Saunders Co, 1983, p. 106.)

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may result from parenchymal disruption with protein leak andsurfactant inactivation.69, 70 Hence, tidal breaths in the deliveryroom can reduce the efficacy of exogenous surfactant adminis-tration while simultaneously disrupting the integrity of the air-way structure and the pulmonary parenchyma. As a result, fromeven shortly after birth, the physician attempting to reduce pul-monary trauma in the neonate may be fighting a losing battle.

Once in the intensive care nursery, the infant who is managedon mechanical ventilator support must be monitored closely.The relatively recent addition of on-line, ventilator-generatedlung mechanics measurements allows for rapid assessment,alteration, and sculpting of ventilator breaths. The goal of anystrategy is to provide the necessary gas exchange while mini-mizing lung injury. Defining adequate gas exchange in thenewborn infant is no longer clear. Providing for arterial carbondioxide pressure (PaCO2) and pH values that are normal for adulthumans may constitute relative overventilation for the newborn.Decreasing PaCO2 may result in unnecessary lung injury, and lowlevels of PaCO2 may be detrimental. Permitting higher levels ofPaCO2, or allowing time for these levels to diminish over time inthe newborn, may alleviate the need to initiate mechanical ven-tilation. Increasingly, programs are evaluating the use of earlycontinuous positive airway pressure (CPAP) and are permittingPCO2 levels to be relatively elevated to avoid the lung injury asso-ciated with mechanical ventilation. Similarly, a high requirementfor supplemental oxygen to maintain a level of arterial oxygenpressure (PaO2) that would be considered normal in a humanadult may also not be necessary.71 The newborn infant’s oxygenrequirement is in transition from the hypoxemic levels of thefetus to that of the adultlike human. If the expense of achievinghigher levels of oxygen is lung injury, perhaps lower levels canbe tolerated. Recent work has suggested that tolerating lowerblood hemoglobin saturation levels may be beneficial. Hence,understanding the gas-exchange targets not only will affect ven-tilator management but may eliminate the need to initiate ormaintain mechanical ventilator support.

CONVENTIONAL ASSISTED VENTILATION IN THE NEWBORN INFANTSeveral different modes of ventilator assistance exist for the treat-ment of neonatal lung disease (Table 96–4).All types of ventila-tor support basically serve the same function: to assist in gasexchange to reduce pulmonary insufficiency, an inability of thelung to exchange gas adequately to meet the demands of aerobic

966 XII / The Lung

metabolism.Common causes of pulmonary insufficiency and res-piratory distress in the newborn period are listed in Table 96–5.

Virtually all assisted ventilation currently used in the UnitedStates is some variant of positive-pressure ventilation. Negative-pressure ventilators disappeared from most nurseries as verylow birth weight infants (<1500 g) increased in number in thenursery population. Although some recent efforts with negative-pressure ventilation in pulmonary hypertension appear to beinteresting, this therapy is still uncommon.72,73

In contrast to spontaneous ventilation, positive-pressuremechanical ventilation generates gas flow in a different manner.With positive-pressure breathing, a gradient down the airway isagain established by raising pressure in the proximal airway(usually through an endotracheal [ET] tube, occasionally a tra-cheostomy), compared with the decrease in intrapleural pres-sure that occurs with spontaneous breathing. Gas still flows inthe direction of decreasing pressure, although the mechanismfor producing this flow differs significantly. As shown in Figure 96–5, although there is a transpulmonary pressure gradi-ent of a similar direction in both spontaneous and assisted ven-tilation, the pressure throughout the lung, from the atmosphere

TABLE 96–5

Differential Diagnosis of Respiratory Distress in the Newborn Period*

Respiratory Extrapulmonary

Common Less Common Rare Heart Metabolic Brain BloodRespiratory distress Pulmonary Airway obstruction Congenital Metabolic Hemorrhage Acute blood

syndrome (hyaline hemorrhage (upper), e.g., heart acidosis Edema lossmembrane disease) Pneumothorax choanal atresia disease Hypoglycemia Drugs Hypovolemia

Transient tachypnea Immature lung Space-occupying lesion Patent ductus Hypothermia Trauma Twin-twinMeconium aspiration syndrome e.g., diaphragmatic arteriosus Septicemia Hyperviscosity transfusionPrimary pulmonary hernia, lung cysts (acquired)

hypertension Hypoplasia of the lung(persistent fetalcirculation)

Pneumonia, especially caused by group B streptococci

* 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.

TABLE 96–4

Modes of Ventilatory Assistance in the Newborn

Oxygen therapyCPAP

Nasal CPAPEndotracheal CPAPFace-mask CPAP

Negative end distending pressureNegative-pressure ventilationPositive-pressure ventilation

Pressure limitedTime-cycle limitedVolume limited

High-frequency positive pressure ventilationOscillatoryFlow interrupterJet

High-frequency negative pressure ventilationExtracorporeal membrane oxygenationLiquid ventilation

CPAP = continuous positive airway pressure.

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to the pleural cavity, is higher with mechanical ventilation. As aresult, the airways and lungs receive higher pressures thannormal. In the young infant with decreased connective tissueand cartilage, the airway becomes distended,11, 15 and gas flow,which depends partly on rigidity of the airway, may becomemore turbulent. With increasing turbulence, gas distributionthroughout the lung is altered, gas exchange is reduced, and oneoften has to compensate by further increasing ventilator pres-sure support.74,75 This process, occurring over several days, maylead to progressive airway and lung injury. Although positivepressure applied to the fragile preterm pulmonary airway andparenchyma produces lung injury, the specific ventilator variablethat induces the greatest injury has remained controversial.Attempts to eliminate lung injury completely in the neonatehave been less than successful, and it has become increasinglyclear that the process of tidal breathing itself is sufficient toinduce injury in the preterm infant.Animal studies suggest thateven short-term and limited tidal breathing (volutrauma), as wellas ventilation of the atelectatic lung (atelectrauma), causesinjury.71, 76–80 The size of the breath may therefore be moreimportant than the inflating pressure in determining the risk ofchronic lung disease. In the atelectatic lung, adequate minuteventilation is achieved by overinflating already expanded lungregions, thereby causing damage to those ventilated regions.Hence, using an adequate amount of end-expiratory pressure, ormean airway pressure (MAP), to optimize alveolar volumerecruitment may diminish lung injury.

The goal of therapy therefore is to maximize the benefits of ven-tilation while minimizing its negative effects. Understanding thecontrols available with mechanical ventilation can assist in this end.

VARIABLES IN ASSISTED VENTILATIONSeveral different controls for mechanical ventilation can bemanipulated in the care of individual infants (Table 96–6). Each

96 / Assisted Ventilation: Physiologic Implications and Complications 967

variable has both physiologic advantages and disadvantages thatmust be considered.

Oxygen TherapyMaintenance of adequate tissue oxygenation is one of theprimary goals of therapy during mechanical ventilation.The sim-plest way to achieve adequate oxygenation is to increase thefraction of oxygen in inspired gas. Oxygen must be considered adrug, however, with potential harmful side effects such asretinopathy of prematurity (ROP)81–83 and BPD.64 Retinopathy isbelieved to occur, at least in part, from varying oxygen concen-trations in the blood that result in vasoconstriction and subse-quent proliferation and abnormal vascular growth in the retinaof the immature infant’s eye. Other factors, such as prematurityitself, carbon dioxide levels, apnea, blood pressure, and vitamin Elevels, 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 ventila-tion. It is thought that this condition may have an underlyinginherited tendency in some families84 and is also multifactorial inorigin. Generation of superoxide anions from oxygen may beone of the inflammatory processes that initiates the lungresponse that later results in BPD (Fig. 96–6). Superoxide dismu-tase (SOD), catalase, glutathione peroxidase, and other enzymesimportant in the catalytic reduction of these anions are reducedin the premature infant. As a result, the premature lung may beat increased risk from the effects of this oxygen byproduct.Studies with SOD have suggested a therapeutic role for this agentin preventing BPD.

Mammalian cells contain two types of SOD molecules, namelyCuZnSOD and MnSOD. Human CuZnSOD, which resides in thecytoplasm of the cell, is a dimeric metalloprotein composed ofidentical noncovalently lined 16-kDa subunits, each containingone atom of copper and one atom of zinc.An extracellular gly-cosylated tetrameric form of CuZnSOD also exists. HumanMnSOD is localized in the mitochondria and is a homotetramercomposed of 22-kDa subunits, each possessing one manganeseatom.

Developmental up-regulation of antioxidant enzyme expres-sion occurs in various mammalian species during the last 10 to15% of gestation and parallels the increase in surfactant levels.85

In vitro and in vivo hyperoxic exposure of the lungs of normalimmature animals results in a rapid increase in pulmonary SODactivity.86 In humans, SOD activity in the lung also increases withage; it is lowest in fetal life, increases in term infants, and ishighest in adults.87 Most premature infants without RDS showthe expected hyperoxic increase in SOD activity, whereas mostinfants with RDS do not.88 This finding suggests that antioxidantdeficiency may play a role in neonatal lung disease.

In a prior study, recombinant human (r-h) CuZnSOD was welltolerated, with an adverse experience profile generally compara-ble to that of placebo. In addition, no between-group differences

TABLE 96–6

Control Variables in Assisted Ventilation

Oxygen therapyContinuous positive airway pressurePeak inflating pressureFrequencyInspiratory/expiratory ratio

Inspiratory timeExpiratory time

Mean airway pressure

Figure 96–5. Positive pressure gradient produced by ventilator.Pressures measured in airway (Paw) and as in Figure 96–1. Paw> Palv > Pip > Patm. (From Goldsmith JP, Karothin EH [eds]:Assisted Ventilation of the Neonate. Philadelphia,WB SaundersCo, 1988, p 25.)

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in growth parameters or physical or neurologic examinationfindings were seen at 1 year of corrected age. There were nosignificant differences between treatment groups in the short-term end-points of BPD, death, or the combined end-point ofBPD or death. However, fewer patients who were previouslytreated with r-h CuZnSOD compared with those patients whowere previously treated with placebo used respiratory medica-tions between 6 and 12 months of corrected age. Further, fewerinfants in the r-h CuZnSOD group required home nebulizer use.Thus, results from these studies support further prospective eval-uation of the long-term effects of r-h CuZnSOD in preterminfants with RDS.89

968 XII / The Lung

Because of the substantial morbidity from these conditions,oxygen therapy must be cautiously administered and monitoredduring the neonatal period. Frequent assessment of inspiredoxygen concentration, as well as blood oxygen saturation andtension, is recommended.

If hyperoxia leads to major morbidity in the newborn,hypoxiacan produce even greater problems. Hypoxemia, if prolonged,results in a change from aerobic to anaerobic metabolism,increased lactic acid production, and, ultimately, cellular andorgan demise. Death usually follows soon afterward. Theseeffects are unquestionably time related. A shorter duration ofhypoxemia, however, may result in organ injury that can be

Figure 96–6. Schematic representation of the source and generation of free radicals and reactive intermediates and the enzymaticand 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.)

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permanent.90 The effects of hypoxemia on central nervoussystem function and development are a constant concern for theneonatologist.The effects of hypoxemia on the developing brainare discussed in more detail elsewhere in this book.

Since the mid-1990s, there has been a gradual change in theapproach to oxygen use and acceptable hemoglobin oxygen sat-urations in the newborn. In the process of resuscitation of thenewborn, it is no longer believed that even brief exposures to100% oxygen are harmless.91 The risks of high oxygen levels mayoccur at relatively “normal” oxygen saturations.The fear of lowoxygen tensions includes increase in pulmonary vascular andairway 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 increasethe risk of pneumonia or exacerbation of chronic lung disease orROP and may prolong the oxygen requirement.92–94 The optimalarterial oxygen saturation varies with the disease state,but it willprobably be lowered over the next several years.91,95

Continuous Positive Airway PressureSince its introduction by Gregory and colleagues in 1971,96 theuse of CPAP has become a standard part of ventilator care. CPAPis also referred to as positive end-expiratory pressure (PEEP)when used in conjunction with a mechanical ventilator (that issupplying a ventilator rate for the infant) or continuous distend-ing pressure.The full effects of this form of therapy are not fullyunderstood,and part of the difficulty may be that CPAP may havevariable results in different clinical situations.CPAP is believed toresult in progressive alveolar recruitment, inflating collapsedalveoli96 and reducing intrapulmonary shunt.97–100

From Laplace’s law:

Pressure = 2 × tensionradius

However,one could expect that collapsed alveoli would remaincollapsed, and inflated or partially inflated alveoli would becomeincreasingly inflated or overdistended.These findings have neverbeen 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 increasesexcessively, and the lung becomes overdistended. In such cases,PaO2 remains high,but PaCO2 also begins to increase as tidal volumediminishes and physiologic dead space is increased. Continuedexcessive CPAP may ultimately lead to very serious consequences,such as air leak syndromes: pneumomediastinum, pneumothorax,or pneumopericardium.101 Excessive CPAP may also increase deadspace ventilation, leading to a rise in PaCO2. Furthermore, althoughlow levels of CPAP may be useful in decreasing pulmonary edemaor left-to-right cardiac shunting, high levels of CPAP can lead to areduction in cardiac output, reduced pulmonary perfusion,and enhanced V/Q mismatching, resulting in a lower PaO2.102–104

Depending on levels of CPAP applied and lung compliance, pul-monary vascular resistance may be increased with CPAP, althoughits use early in the course of RDS may lead to decreased pul-monary vascular resistance.105

CPAP has some nonspecific effects on neonatal ventilation aswell. Application of CPAP appears to produce a more regularbreathing pattern in preterm neonates106 and has been thoughtto be mediated through chest wall stabilization and reduction ofthoracic distortion. Obstructive apnea is also reduced withCPAP,107 even when it is applied by nasopharyngeal route.Furthermore, it has been shown that both inspiratory and expi-ratory times are increased with CPAP. Finally, it is thought thatsurfactant release may be enhanced by CPAP in RDS. Intracranial

96 / Assisted Ventilation: Physiologic Implications and Complications 969

pressure is increased by CPAP and is directly related to theamount of CPAP applied as well as compliance of the lungs.108

With increased lung compliance, more pressure is transmitted tothe cardiovascular system, resulting in a rise in central venouspressure and intracranial pressure. Cerebral perfusion pressure,however, can decrease with application of end-distendingpressure, because venous pressure rises and arterial pressuredecreases initially. Some compensation is likely to occur overtime;however, these changes in intracranial pressure may lead toan increased risk of intracranial hemorrhage, especially in thepreterm baby.90

Some effects of CPAP on renal function have been docu-mented.109 These include a decrease in glomerular filtration rate,reduction of urinary sodium excretion, and diminished urinaryoutput.110, 111 These findings also appear to be mediated throughtransmission of pressure to the cardiovascular system with reduc-tion in renal blood flow. As renal blood flow decreases, there maybe some redistribution of intrarenal blood flow to the inner renalcortex and outer medulla.112 Aldosterone appears to increase withapplication of CPAP,113 and antidiuretic hormone secretion mayincrease as well,114 although there have also been reports ofdecreased antidiuretic hormone with CPAP. These contradictoryfindings may again be a reflection of the finding that CPAP mayimprove or worsen lung compliance, resulting in either increaseor decrease in intracranial perfusion (Table 96–7).115 One trend inrespiratory support of the premature newborn is the use of non-invasive ventilation strategy. At the forefront of this approach ispermissive hypercapnia and the early use of CPAP in lieu ofmechanical ventilation. Reports in the 1980s showed that unitsthat accepted higher values for arterial PCO2 and used CPAP aggres-sively had a lower rate of chronic lung disease.116 The concept of“gentle ventilation” with permissive hypercapnia and the aggres-sive use of CPAP illustrates one of the most confusing aspects ofmanaging respiratory distress in the newborn, namely, when, andto what degree, to intervene.The introduction of mechanical ven-tilation is potentially detrimental, and deciding to place an infanton mechanical ventilator support remains a difficult decision. Inaddition, determining what measurements (e.g., blood gases,graphics monitoring) should guide ventilator changes remainsunclear.Permissive hypercapnia in preterm infants seems safe andmay reduce the duration of assisted ventilation.This strategy hasparticular appeal in that hypocarbia may be related to brain injury.However, severe hypercarbia may also cause brain injury, a findingstrongly suggesting that nature has excellent physiologic reasonsto establish eucapnic ventilation as the normal range.When usinga strategy or permissive hypercapnia, it is important to minimizeatelectasis, because the recruitment and de-recruitment of lungregions is not optimal. In addition, although data look promisingwhen this strategy is implemented, long-term follow-up of infantsmanaged with high carbon dioxide levels has not been explored.

Peak Inflating PressurePeak inflating pressure (PIP) is the primary ventilator variablethat determines tidal volume on most time-cycled or pressure-limited ventilators. Since the introduction of neonatal mechani-cal ventilation, controversy has raged over the optimal approachto the administration of PIP. Many of the effects of PIP are similarto those described previously in the section on CPAP. The intro-duction of a peak pressure, unlike the constant pressure appli-cation of CPAP, may have additional physiologic effects on theneonatal airways and lungs.

Once one begins cycling a ventilator and providing a PIP, physi-ologic changes occur.Tidal volume and minute ventilation increase.Depending on the type of waveform generated by the ventilatorand the duration of inspiratory to expiratory time (I/E ratio)selected, mean airway pressure (MAP) may be altered (Fig. 96–7).Airways expand, and, as noted with CPAP, alveolar distention is

[1]

FNP3e-Sect XII (0942-0978) 9/6/03 9:55 AM Page 969

increased.One of the primary goals of all mechanical ventilation isto achieve the optimal gas exchange at the lowest positive pres-sure. The neonatologist must constantly examine the benefitsderived by the patient versus the risk of pulmonary injury (Table 96–8) with different ventilator approaches. Theseapproaches have become even more complicated with the newermodes of ventilation, all innovated to decrease pulmonary iatro-genic injury.

The causes of injury with mechanical ventilation were previ-ously outlined. No clear data suggest a specific level of PIP thatwill invariably damage an individual infant. Some infants demon-strate barotrauma at low levels of PIP, whereas other infants maynot have any injury even at higher levels of PIP. Size and gesta-tional age clearly influence the response of mechanical ventila-tion, although babies of equal gestational age, weight, andseverity of disease may have different responses to mechanicalventilation. A study of the incidence of chronic lung disease in

970 XII / The Lung

perinatal centers in academic institutions confirmed this highlyvariable incidence of BPD in infants treated with mechanicalventilation.116 It cannot be overemphasized that one should notattempt to limit PIP to some predetermined pressure value in anattempt to reduce barotrauma while ignoring the importance ofadequate gas exchange. In many instances, high peak pressuresare necessary to achieve adequate ventilation and oxygenation.Inadequate gas exchange is invariably either fatal or injurious tothe central nervous system and must never be ignored while onetries to limit pressure below some arbitrary level.

Additional factors become more important in mechanical ven-tilation when one adjusts ventilator peak pressure. The lengthand caliber of an ET tube significantly influence airway resist-ance. Longer, narrower ET tubes have higher airway resistance.Because of the added resistance, gas trapping can occur becausethe recoil of the lung does not have sufficient time to evacuategas from the air spaces. As a result, the lung expands to a higherFRC. Although this increase in lung volume may be of value earlyin the course of neonatal lung diseases complicated by atelecta-sis (i.e.,RDS), in most cases, air trapping adds to the likelihood ofair leaks and pulmonary injury. It has been demonstrated, instudies 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), themeasured in vitro resistance is reduced to that of a full-length3.0-mm ID ET tube.Therefore, one must select the appropriatesize tube for an individual infant to maximize flow and decreaseresistance to a minimum. ET tubes are usually supplied in exces-sive lengths and should be cut to remove any unnecessary deadspace after ideal placement has been secured.The effect of thediameter of the ET tube is somewhat surprising in the neonate,given that airways rapidly decrease in caliber to a size far smallerthan the ET tube within one or two bronchial divisions. Onewould consequently expect that the smaller airways of the tra-cheobronchial tree would contribute far more to resistance thanthe ET tube. Resistance within the lung is primarily dependenton the total cross-sectional area of all airway branches. Becausethe total cross-sectional area of the airways of the lung increasesrapidly with bronchial subdivisions, these smaller airwayscontribute far less to resistance than expected. As a result,the larger airways and the ET tube in the newborn infantbecome the major contributors to resistance, a finding that isespecially important in the baby with chronic lung disease whooften demonstrates bronchospasm or tracheobronchomalacia.

TABLE 96–7

Continuous Positive Airway Pressure

Low (2–3 cm H2O) Medium (4–7 cm H2O)

Use Side Effects Use Side EffectsMaintenance of lung volume in May be too low to maintain Increasing lung volume in If lungs have normal CL:

very low birth weight infants adequate lung volume or surfactant deficiency, such as May overdistendDuring weaning adequate oxygenation RDS May impede venous returnDuring hyperventilation for CO2 retention Stabilizing areas of atelectasis Air leak

PPHN Stabilizing obstructed airways

High (8–10 cm H2O) Ultrahigh (11–15 cm H2O)

Use Side Effects Use Side EffectsPreventing alveolar collapse Pulmonary air leak Tracheal or bronchial collapse Same as “High” levels, depending on

with poor CL and poor lung Decreased CL if overdistended Markedly decreased CL or CL

volume May impede venous return severe obstructionImproving distribution of (metabolic acidosis) Preventing white-out or

ventilation May increase PVR reestablishing lung volume CO2 retention during ECMO

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

Figure 96–7. Five different ways to increase mean airwaypressure: (1) increase inspiratory flow rate, producing more ofa square-wave inspiratory pattern; (2) increase peak inspiratorypressure; (3) reverse the inspiratory/expiratory (I/E) ratio orprolong inspiratory time without changing the rate;(4) increase positive end-expiratory pressure; and (5) increaseventilator rate by reducing expiratory time without changinginspiratory time. (Modified from Reynolds EOR: In GoldsmithJP, Karotkin EH [eds]:Assisted Ventilation of the Neonate.Philadelphia,WB Saunders Co, 1988, p 61.)

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Furthermore, because work of breathing, or the force needed toexpand the lung (pressure times volume displacement), is soclosely related to resistance, small changes in airway calibermarkedly increase resistance and, in turn, work of breathing.Such problems are important in the consideration of optimalapproaches to mechanical ventilation. In many cases of BPD, forexample, initial respiratory failure may be related to the findingthat the contribution of resistance factors to work of breathingis excessive for the infant over a certain period, although it maynot be immediately apparent when one performs pulmonaryfunction testing. Energy expenditure ultimately exceeds limitedenergy stores, and ventilator failure ensues. Subsequent ventila-tor management may be complicated by the problems createdduring ventilator cycling (Table 96–9).

Rate EffectsRespiratory rate is one of the primary determinants of minute ven-tilation.Minute ventilation equals the product of tidal volume andrespiratory rate (or frequency). Several schools of thought existconcerning the optimal ventilator frequency for neonatal mechan-ical ventilation, although these can be divided into two primarymodes of therapy: rapid-rate ventilation (>60 breaths/minute)118

and slower-rate ventilation (<40 breaths/minute).119 In bothinstances, the goal has been to try to reduce the complicationsassociated with high inflating pressures. Advantages and disadvan-tages exist with all forms of treatment (Table 96–10). In attempt-ing to understand the physiologic consequences of rate onventilation, the concept of time constant must be addressed.Thetime constant of the lung is a measure of how rapidly equilibra-tion between proximal and alveolar pressures occurs, and it

96 / Assisted Ventilation: Physiologic Implications and Complications 971

expresses how quickly an infant can move air into or out of thelung. The time constant is expressed by the following equation:time constant = compliance × resistance.Time constants can bedetermined for both inspiration and expiration, although theneonatologist is particularly interested in the expiratory time con-stant with mechanical ventilation, because it is very important tohave some idea of how rapidly the lung empties after a mechani-cal breath. Bancalari120 determined that, in the normal newborn,with a compliance of 0.005 L/cm H2O and a resistance of 30 cmH2O/L/second, one time constant equals about 0.15 second. Asingle time constant is defined as the time required by the lung todischarge 63% of the tidal volume that was delivered to the termi-nal air spaces.Three time constants equal the time required for thealveolus to discharge 95% of gas delivered and would therefore beapproximately 0.45 second in the normal, spontaneously breath-ing infant. In diseased lung states, the effects of changes in com-pliance and resistance must be considered in applying mechanicalventilation. For an infant with RDS who has markedly reducedcompliance in the early stages of the disease, the time constant ofthe lung may be exceedingly short. During that disease stage, onecan readily use high rates to ventilate an infant, because the exittime of gas from the lung is so rapid, or one can use a slower ratewith a prolonged inspiratory phase,again relying on the short timeconstant of a very stiff lung to allow gas exit during the short expi-ratory phase. Difficulty arises, however, with both these therapeu-tic modalities when the lung begins to heal.

During the recovery period, compliance begins to increase assurfactant 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. Inthese circumstances, the time constant of the lung tends to

TABLE 96–8

Waveforms in Neonatal Mechanical Ventilation

Sine Wave Square Wave

Advantages Side Effects Advantages Side EffectsSmoother increase of pressure Lower mean airway pressure Higher mean airway pressure With high flow, the ventilator may be More like normal breathing for equivalent PIP applying higher pressure to

pattern Longer time at peak pressure normal alveoli, resulting in may open up atelectasis or barotraumaimprove distribution of Could impede venous return ifventilation 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 96–9

Peak Inspiratory Pressure

Low (<30 cm H2O) High (≥30 cm H2O)

Advantages Side Effects Advantages Side EffectsFewer side effects, especially Insufficient ventilation; may May reexpand atelectasis Associated with PAL, BPD

BPD, PAL not control PaCO2 Increase PaO2 May impede venous returnNormal lung development May have low PaO2, if too low Decrease PaCO2 May decrease cardiac output

may occur more rapidly Generalized atelectasis may Decrease pulmonary vascularoccur (may be desirable in resistancesome cases of air leaks)

BPD = bronchopulmonary dysplasia; PAL = pulmonary air leaks.

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become increasingly prolonged, and if the rate of ventilation isnot 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 maintaininglung volume during periods of atelectasis, progressive air trap-ping may lead to air dissection and air-leak syndromes and mayalso be one of the important initiating factors in the develop-ment of BPD. Furthermore, as demonstrated by Boros andcolleagues,121 the use of very high ventilator rates with conven-tional mechanical ventilation at fixed flow rates is limited by thefinding that in vitro minute ventilation decreases beyond acertain maximum rate for individual ventilators (Fig. 96–8).High-frequency ventilators, which generate inspiratory flow in a dif-ferent manner from conventional ventilators, are not affected bythese rate limitations to the same extent.The high-frequency ven-tilator, however, can also produce air trapping or inadvertentPEEP when it is used at rates beyond its optimal frequency. Inneonatal ventilation, the introduction of continuous-flow cir-cuitry,122 rather than intermittent flow of gas, permits the use ofslow ventilator rates. Before the introduction of this modifi-cation, an infant breathing between respirator cycles wouldsimply rebreathe exhaled gas in the breathing circuit, thusincreasing work of breathing and raising the PaCO2. With theaddition of constant flow, periodic ventilator breaths could becombined with spontaneous ventilation in a mode of therapyreferred to as intermittent mandatory ventilation (IMV).123Thistherapy enables the physician to supply a ventilator rate in themidrange (40 to 60 breaths/minute), thus providing sufficientventilatory support for the infant while avoiding some of thecomplications of either high or low rate ventilation. At thesemidrange rates, the likelihood of air trapping and injury appears to be reduced for most infants.Again, the managementof neonatal ventilator assistance cannot be carried out by fol-lowing simple rules. Although the guidelines indicated arehelpful in initiating treatment, each child must have care indi-vidualized to some degree.Newer ventilators have permitted theuse of modalities such as assist/control (A/C) ventilation andpressure-support ventilation that allow the infant to set rateparameters. These techniques generally result in faster respira-tory rates and greater synchrony. A comparative evaluation ofthe benefits of these modalities has not been completed.Experience is therefore an essential ingredient in successful ven-tilator treatment of neonates.

Mean Airway PressureStudies have demonstrated the significance of MAP in the phy-siology of neonatal mechanical ventilation. MAP is defined as the

972 XII / The Lung

mean of instantaneous readings of proximal airway pressureduring a single respiratory cycle. In waveform terminology, MAPis equal to the integration of the area under the pressure curveduring a respiratory cycle.When one compares the two types ofwaveforms generated by ventilators, sine waves and squarewaves, it is obvious that MAP is higher in square wave ventilationcompared with sine wave ventilation if inspiratory time (Ti) andPIP are equal (Fig. 96–9). Increasing MAP has been shown toincrease oxygenation in neonates with RDS.124 However, thisrelationship may not hold true for all methods of increasing MAP(see Fig. 96–7). For example, if MAP is increased by raising thePIP, but with a very short Ti, that increase may be dissipatedrapidly in the upper airways and ET tube, thus negating its effect.

TABLE 96–10

Positive End-Expiratory Pressure

Low (2–3 cm H2O) Medium (4–7 cm H2O) High (≥8 cm H2O)

Advantages Side Effects Advantages Side Effects Advantages Side EffectsUsed during May be too low to Stabilizes lung May overdistend Prevents alveolar PAL

weaning maintain volume lungs with collapse in Decreases compliance if Maintenance of lung adequate lung Recruit lung volume normal surfactant lung overdistends

volume in volume with surfactant compliance deficiency states May impede venouspremature infants CO2 retention deficiency states with severely return to the heartwith low FRC (e.g., RDS) decreased CL May increase PVR CO2

Improve ventilation/ Improves retentionperfusion distributionmatching of ventilation

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

Figure 96–8. Minute volume effects of increasing ventilator ratesfrom 25 to 150 breaths/minute (bpm—horizontal 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-expiratorypressure = 5 cm H2O; inspiration to expiration ratio (I/E) = 1:2(after 75 bpm, ventilator BB 1 minute volumes were measuredat 1:1 I/E ratio); flow = 10 Vain. (From Boros SJ, et al: Pediatrics74:487, 1984.)

Min

ute

volu

me

(ml/m

in)

1000

900

800

700

600

500

25 50 75 100 125 150

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The primary factors that control MAP are PEEP, I/E ratio, PIP,and waveform. Reynolds119 demonstrated that prolonging inspi-ration (increased Ti) during slow-rate ventilation with a squarewave increased oxygenation. Additional work by Boros and asso-ciates124 confirmed the value of increasing MAP to improve oxy-genation in RDS. As MAP increases, right-to-left shunt and thealveolar-arterial oxygen gradient are progressively reduced.Although high MAP may improve oxygenation during acutephases of neonatal lung disease (which is usually accompaniedby decreased compliance), as infants recover and complianceimproves, high MAP may cause venous obstruction similar tothat seen with high CPAP. In addition, airways may becomeoverdistended, leading to the complication of pulmonary injurydescribed previously. Because MAP is a function of numerousvariables and is not specifically set on any conventional ventila-tor (this control is available on some high-frequency oscillators),one must again be cautious in selecting the optimal ventilatorypattern for this disease state to maximize the effect of MAP onoxygenation while attempting to reduce the negative effects ofexcessive levels.

In general, the greatest effect on oxygenation can beachieved by increasing PEEP, because MAP will increase indirect proportion to the increase in PEEP (depending on theI/E ratio). If one does not simultaneously change PIP, however,in such circumstances,PaCO2 may rise because tidal volume willdecrease (secondary to the decrease in the difference betweenPIP and PEEP). Furthermore, one must consider that oxygena-tion may paradoxically decrease as one attempts to raise MAP,if one begins to impede venous return to the heart, therebyimpairing venous return and cardiac output, while also com-pressing the pulmonary vasculature. In such cases, the clinicianhas usually exceeded the optimal level of PEEP for the clinicalsituation.

Inspiratory/Expiratory RatioMany of the effects of I/E ratio have been discussed in sectionsrelated to CPAP, PIP, ventilator rate, and MAP. Some of the effectsof varying I/E ratio are noted in Table 96–11.Again, it is not pos-sible simply to set an I/E ratio at the onset of ventilator treatmentthat will maximize oxygenation and ventilation throughout theclinical course of the disease. One must reevaluate the clinicalcourse frequently in this regard. In fact, it may be better to selecta Ti as a variable rather than selecting an I/E ratio, because, withan I/E ratio selection, the Ti may become excessively long as the

96 / Assisted Ventilation: Physiologic Implications and Complications 973

ventilator rate is slowed during recovery. For example, an I/Eratio equal to 1.0 at a rate of 60 breaths/minute produces a Ti of0.5 second, but the Ti becomes prolonged to 1.0 second whenthe rate is slowed to 30 beats/minute. Prolonged Ti may predis-pose patients to air leaks and BPD if the time constant of thelung is exceeded.

APPROACHES TO RESPIRATORY SUPPORTAs noted previously, the effects of injury associated with neona-tal mechanical ventilation can result in substantial morbidity andmortality. Because of the continuing high incidence of BPD,ranging from approximately 10 to 40% at major universitymedical centers,116 several alternative approaches to ventilatorsupport have been investigated (see Tables 96–4 and 96–6through 96–9). We are concentrating on conventional ventila-tion, although modalities such as high-frequency ventilation,inhalational nitric oxide, and extracorporeal life support remainimportant tools in the intensive care nursery. These modalitiesare discussed elsewhere in this book.

Advances in Conventional VentilationMany improvements in conventional ventilators have beenintroduced into the intensive care nursery.The addition of flowsensors permitted on-line respiratory function measurementsand more complex monitoring systems. Miniaturization of tech-nologies, available for adult ventilation including pressure-support,A/C, and volume ventilation, are now available for eventhe smallest neonates.

For the infant receiving intermittent mandatory ventilation(IMV), spontaneous respiratory effort that is not in synchronywith the mechanical breath can be detrimental. The activeexpiration of the asynchronous breath may diminish tidalvolume and may result in barotrauma.125 Attempts at achievingsynchrony have included pharmacologic paralysis, sedation, andthe use of a rapid respiratory rate and a short Ti.Variable resultshave been demonstrated in multiple studies, but, in general, syn-chronous ventilation diminishes barotrauma and alterations incerebral blood flow and increases tidal volume and minuteventilation.126,127

Synchrony on IMV can be achieved with rapid rates.128

Maintaining synchrony in these infants, in the healthier infant, orduring weaning is difficult. Patient-triggered ventilation add-resses some of these limitations and has now become a standard

Figure 96–9. 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.)

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part of the neonatologist’s repertoire. In general, patient-triggered ventilation consists of two forms of mechanical venti-lation: synchronized IMV (SIMV) and A/C ventilation. WithSIMV, the ventilator is synchronized to the infant’s breathingpattern. If the patient-triggering threshold is met within a spe-cific time (depending on the preset ventilator rate), a ventilatorbreath is not delivered, and the infant breathes spontaneously.Aventilator breath is delivered if the infant fails to breathe. Exam-ination of the baby’s breathing pattern with SIMV will revealboth spontaneous breaths and ventilator breaths. The value ofthis form of support is that pressures within the airway are notstacked, so injury to the airway and the lung is theoreticallyreduced, and gas is not inadvertently “dumped” from the ventila-tor because airway pressures are reached prematurely.Althoughmany neonatologists use SIMV as their primary mode of ventila-tor support for neonates, this technique appears to have greaterbenefit as a weaning tool or if overdistention is present with A/Cventilation, particularly in the extremely low birth weight infantwith either RDS or pulmonary insufficiency of prematurity.

A/C ventilation is also a form of patient-triggered support.WithA/C ventilation, each infant breath that reaches the triggerthreshold initiates a full ventilator breath. If the infant is apneic,or if the effort is inadequate to trigger a ventilator breath, theventilator will deliver a preset back-up rate to the baby. Allbreaths in this form of ventilation appear similar and are entirelyventilator derived, and no spontaneous infant breaths ever occuron A/C support (unless the generated pressure is so low that itfails to trigger the ventilator).With A/C ventilation, the infant isfully synchronized to the ventilator.With the use of terminationsensitivity as an adjunct, Ti will be limited to a percentage ofmaximum flow, and air trapping can usually be reduced oreliminated.

A/C ventilation is a very effective form of initial treatment formany babies with various neonatal lung diseases in the earlystages of their illness.The use of A/C ventilation limits pressureexposure for the infants, and they often spontaneously select arate that is optimal for gas exchange, with a lower pressure thanwould usually be set on SIMV.Minute ventilation is higher on A/Cthan on SIMV.129 It is more difficult, however, to wean babies onA/C ventilation; occasionally, some overdistention will occur ifthere is excessive neural drive to breathe, and prolonged use ofA/C ventilation may lead to some diaphragmatic muscle atrophyand further weaning difficulty. Consequently, we often move

974 XII / The Lung

infants from A/C to SIMV when they begin to show signs ofrecovery from their lung disease.With A/C ventilation, one mustalso be cautious of autocycling of the ventilator. This problemcan occur when there is erroneous triggering of the ventilatorfrom leaks in the system, build-up of humidity in the circuit, orsensing of the cardiac pulsations as breaths.Frequent breaths aredelivered unnecessarily to the baby.We have also seen an occa-sional infant on A/C support who does well while awake, withgood gas exchange, but who has inadequate blood gases whilesleeping or if sedated. In such cases, it would be helpful to havethe capability of using two separate ventilator settings, one forwaking periods and one during apneic support when slightlymore pressure may be necessary for gas exchange. To date,however, no neonatal ventilator allows for the selection of mul-tiple ventilator settings simultaneously that could automaticallytrigger under certain conditions.

An adjunct therapy during patient-triggered ventilation is pressure-support ventilation, in which spontaneous infantbreaths are partially or fully augmented by an inspiratory pres-sure assist higher than baseline end-distending pressure. Thisapproach eases the work of breathing by allowing additionalpressure delivery to overcome the elastic and resistive loads.This form of therapy may be used alone or in association withSIMV ventilation. Because it is synchronized with the infant’sventilation, it can be used in babies who are becoming fatiguedfrom work of breathing, in sedated infants, and in infants in aweaning phase of ventilation who are first beginning to reusetheir respiratory musculature. When this technique is used inconjunction with SIMV, it is important that the SIMV rate is notset too high, or the baby will have no impetus to breathe, andone of the primary purposes of pressure support will benullified.

Tidal volume–guided ventilation or volume-guarantee ven-tilation is a newer approach to therapy in which the cliniciansets a mean tidal volume to be delivered by the ventilator whilestill allowing management of ventilator pressures. It is a variationof pressure-support ventilation in which volume, not pressure,guides the delivery of an augmented breath.The goal is to mini-mize variation in delivery of tidal volume, thought to be thecause of pulmonary injury in infants.Volume guarantee is used inconjunction with patient-triggered modalities. When the opera-tor sets the inspiratory pressure limit during patient-triggeredsupport, the ventilator attempts to deliver the set guaranteed

TABLE 96–11

Neonatal Mechanical Ventilatory Rates

Slow (< 40 breaths/min) Medium (40–60 breaths/min) Rapid (>60 breaths/min)

Advantages Side Effects Advantages Side Effects Advantages Side EffectsIncreased PaO2 Must increase PIP Mimics normal May not provide Higher PaO2 (may be May exceed time constant

with increased to maintain ventilatory rate adequate the result of air and produce airMAP ventilation Effectively treats ventilation in trapping) trapping

Useful in weaning Increased PIP most neonatal some cases May allow decreased May cause inadvertent Used with square may cause lung diseases PIP and VT PEEP

wave ventilation barotrauma Usually does not Hyperventilation May result in change in Used when I/E Patient may require exceed time may be useful in compliance (frequency

ratio is inverted paralysis constant of lung, PPHN dependence ofso air trapping is May reduce compliance)unlikely atelectasis (? air Inadequate VT and minute

trapping) 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 pulmonaryhypertension of the neonate;VT = tidal volume.

FNP3e-Sect XII (0942-0978) 9/6/03 9:56 AM Page 974

tidal volume using the lowest airway pressure possible.When theexpired tidal volume exceeds the upper pressure limit, the ven-tilator will use a lower PIP on the next breath. If the set tidalvolume cannot be delivered within the set pressure limit, analarm alerts the operator to reset the pressure limit to a higherlevel or to adjust the guaranteed tidal volume to a lower level.Although available data on this technique are limited, it doesappear that volume guarantee can achieve similar levels of gasexchange with slightly lower mean levels of inspiratory pres-sure.130 Additional modifications may occur in the future, such asguaranteed minute ventilation, in which a desired minute venti-lation is designated, with the ventilator providing a mix of guar-anteed tidal volume and frequency to provide the desired minuteventilation.

Proportional assist ventilation (PAV) and respiratory muscleunloading (RMU) require even more sophisticated computerassistance to achieve their effects.These innovative approacheswork to control ventilator pressure throughout inspiration (inthe case of PAV) or throughout the entire cycle (during RMU).With both forms of ventilator support, the infant’s respiratoryeffort is continuously monitored. During inspiration, as withpressure support ventilation, pressure rises to more than base-line to produce the desired inspiratory resistive unloading,thereby easing work of breathing. During exhalation, the circuitpressure falls to less than the baseline end-distending pressure,facilitating elastic and resistive unloading throughout that phaseof the respiratory cycle.With this form of support, the resultingairway pressure is a variable that changes with the needs of theinfant at any point during the respiratory cycle and is a weightedsummation of a combination of airflow and tidal volume abovebaseline pressure. Although infant studies with PAV and RMU arelimited at present, the initial work appears very encouraging.131,

132 In a trial that examined the relative effects of low birth weightinfants treated with IMV,A/C, and PAV, PAV appeared to maintainequivalent arterial oxygenation at lower airway and transpul-monary pressures than the other two modalities. During PAV, theoxygenation index was also reduced by 28%, with no evidenceof more frequent apnea or other complications.There was also adecrease in both systolic and diastolic beat-to-beat variabilitywith PAV, suggesting that there is additional overall cardiovascu-lar stability offered to infants treated with this form of support.Another study indicated that there was less thoracoabdominalsynchrony during PAV in preterm infants.133 Currently, fewcenters use this form of ventilator support, because it is still inearly trials, yet the concepts appear very promising. Additionallarger scale trials will unquestionably be seen in the near future.

The additional space required by the ventilator adapter and bythe ET tube adds a significant amount of anatomic dead spaceduring mechanical ventilation, particularly to the airway of anextremely low birth weight (<1000 g) infant.Through a mecha-nism of tracheal gas insufflation, fresh gas is delivered to themore distal part of the ET tube and aids in washing out carbondioxide from the airway.Peak inspiratory pressure can usually bedecreased as well as tidal volume.134 These factors may reducebarotrauma and volutrauma in these infants, and early trialsappear promising.

Adjuncts to Mechanical VentilationThe care of infants with respiratory failure during the newbornperiod has been helped immeasurably by additional approachesincluding the measurement of pulmonary functions and lungvolumes by computer, the administration of synthetic or naturalsurfactant, and early trials of antioxidants such as SOD for theprevention of BPD.

Pulmonary function testing, which enables the determinationof such factors as tidal volume, dynamic or static lung compli-

96 / Assisted Ventilation: Physiologic Implications and Complications 975

ance, resistance, work of breathing, FRC, and others, has elimi-nated much of the guesswork that once was standard in neona-tal intensive care units. Furthermore, pulmonary function testshave altered our understanding of the management of some dis-eases.135 Increased use of pulmonary function testing can betterdefine therapy and should be a standard part of newborn inten-sive care.

Few therapeutic adjuncts have had the impact of surfactant inthe intensive care nursery. Since its widespread introduction,surfactant has significantly decreased the severity and incidenceof RDS during the neonatal period while reducing the likeli-hood of BPD.

The respiratory system influences cardiovascular functionthrough its effects on venous return and pulmonary vascularresistance.Return of venous blood to the heart depends primarilyon the gradient between extrathoracic and intrathoracic pres-sures or transpulmonary pressure. Normally, because intrapleuralpressure is subatmospheric (because of the effects of lung recoiland thoracic retraction), there is a favorable pressure gradient forthe flow of blood back to the right side of the heart. With theapplication of positive-pressure ventilation, there is an increase inintrathoracic pressures, thereby reducing venous return andcardiac output. Ventricular performance of the heart may alsobecome compromised owing to compression. The increase inintrapleural pressure that occurs with the introduction ofmechanical ventilation depends on the degree of pressure trans-mitted from the airway to the intrapleural space. Pressure trans-mission is primarily a factor of lung compliance in infants.Thoracic compliance, important in adults, is relativelyinsignificant during the neonatal period because it is so high com-pared with lung compliance. In the patient with RDS, reductionin lung compliance allows significantly less pressure transmissionto the intrapleural space. Extrathoracic to intrathoracic pressuresare not dramatically altered, so venous return and cardiac outputare maintained. Patients with reduced compliance can toleratesignificant levels of PIP and PEEP with a minimal decrease incardiac output. Sudden increase in intrathoracic pressure,however, as seen in a tension pneumothorax, may reduce venousreturn, even with a poorly compliant lung.This situation, encoun-tered in the very premature infant with surfactant deficiency,mayresult in an increase in venous pressure in the central nervoussystem and intraventricular hemorrhage. Furthermore, increasingcompliance during RDS recovery may lead to a rapid increase inintrapleural pressure transmission over several hours, as seenduring the diuretic phase of RDS. These findings suggest thatmaintenance of high ventilator pressures may lead to anincreased 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 transmittedto intraparenchymal vessels.This effect is complex and dependson several factors in the newborn infant. Lung compliance againplays an important role, and in neonates there is less transmis-sion of positive pressure with reduced compliance. In RDS, thedisease process itself produces a decrease in FRC.This decreaseresults in an increase in pulmonary vascular resistance,offsettingthe beneficial effect of reduced pressure transmission from theairway. In contrast, lung overdistention, as seen in ventilationwith large tidal volumes or modes of treatment that lead to gastrapping (i.e., high rate positive-pressure breathing) may poseproblems. In these instances, overdistention of the air spacescompresses arterioles and capillaries, leading to increased pul-monary vascular resistance. Maintenance of FRC at near normallevels appears to be optimal for maintaining pulmonary perfu-sion. In addition to gas volumes, it is evident that anothersignificant part of the equation for pulmonary perfusion mustinclude blood volume. When blood volume is reduced (e.g., inhemorrhage,postasphyxia capillary leak,or sepsis), the influence

FNP3e-Sect XII (0942-0978) 9/6/03 9:56 AM Page 975

of mechanical ventilator pressures on pulmonary perfusion ismagnified.

Other complications associated with the effects of mechanicalventilation on cardiovascular performance during the neonatalperiod need further investigation. Investigators have shown thatmechanical ventilation may alter relative tone in the autonomicnervous system; levels of various neurohumoral substances,referred to collectively as eicosanoids, may have wide-rangingeffects in certain disease states, such as persistent pulmonaryhypertension of the newborn (PPHN).136 In PPHN, there is a per-sistent elevation of pulmonary vascular resistance (PVR) ofunknown etiology. Some evidence suggests that the increase inPVR may be partly mediated through either elevated ordecreased amounts of these substances, which have very potentvasodilating and vasoconstricting capabilities. Other none-icosanoids, such as bradykinin, histamine, various hormones, andacetylcholine, as well as numerous other (perhaps some undis-covered) factors, also may have significant influence on pul-monary vascular tone and therefore perfusion. Furthermore,hypoxemia produces some degree of pulmonary arteriolar vaso-constriction, acting either through these vasoactive substancesor through some alternative mechanism. Ultimately, a delicatebalance emerges in which the infant’s blood volume,thoracic gasvolume, autonomic control, and humoral factors produce a con-dition in which effective pulmonary blood flow is controlled.One of the most complicated diseases in which pulmonaryhypoperfusion plays an important role is PPHN, or persistentfetal circulation. This syndrome, first characterized during the1970s by Gersony and other investigators,137, 138 is a disease pri-marily of full-term infants.The pathophysiology is notable in thatthe infant fails to demonstrate the normal decrease in PVR thattypically occurs after birth. Pulmonary artery pressure is oftenhigher than systemic blood pressure,which results in right-to-leftshunting of blood across the foramen ovale and/or the ductusarteriosus. Infants with this syndrome often demonstratesignificant differential cyanosis, with high preductal oxygen sat-uration, whereas postductal saturation may be very low, depend-ing on the degree of shunting.The syndrome is most commonlyassociated with postdate infants, sepsis, meconium aspiration,small for gestational age infants, pulmonary hypoplasia, anddiaphragmatic hernias. In many cases, no specific etiology is dis-cernible. Evidence suggests that some infants may have pul-monary vascular hypoplasia. Additionally, several new syndromeshave been described that previously were thought to be PPHN.These syndromes include partial or complete surfactant proteinB deficiency in which the synthesis of surfactant-associated pro-teins is abnormal, resulting in a picture of alveolar proteinosisand chronic respiratory failure, and alveolar-capillary dysplasia, asyndrome diagnosed post mortem by findings. At present, lungtransplantation offers the only potential cure for these entities.

Since 1978, when Fox introduced the hyperventilation tech-nique for the treatment of PPHN,139 mechanical ventilatortherapy has been an important part of the care given to thesebabies.Hyperventilation has been demonstrated to decrease PVRin this syndrome. 136, 139, 140 It is not entirely clear whether theresponse is a nonspecific pulmonary vasodilatation caused by areduction of PaCO2, an increase in pH, a mechanical effect of ven-tilation, or some combination of factors. Subsequent work hasdemonstrated that hyperventilation does not provide better out-comes than other ventilation schemes in this population. Mostlikely, the lung injury associated with hyperventilation out-weighs the benefit of transient decreases in PVR with hypocar-bia. In addition, drugs such as inhaled nitric oxide have replacedhyperventilation as a means of increasing pulmonary blood flow.The disease also has a series of stages through which the babyprogresses to a more physiologic circulatory pattern, at whichtime the ventilatory approach must be altered to avoid ventilator-induced lung injury.141–144 In milder cases and in some clinical

976 XII / The Lung

situations, hyperventilation may not be necessary.142 In manycases, injury occurs early, leading to a need for an alternativetherapeutic approach such as high-frequency ventilation orextracorporeal membrane oxygenation (ECMO). Of additionalconcern are findings that indicate that continued hyperventila-tion to avoid ECMO may be a primary cause of neurologic injury,cerebral palsy, and developmental delay.145

In contrast to pulmonary hypoperfusion, pulmonary hyper-perfusion may also have a significant physiologic impact onoptimal positive-pressure ventilation. In infants with a ventricu-lar septal defect or in preterm infants with RDS and a patentductus arteriosus, lung compliance may be adversely affectedduring ventilation by the excess pulmonary blood volume.Withleft-to-right shunting at a high rate, the pulmonary lymphaticsmay not maintain normal rates of fluid reabsorption. Interstitialfluid increases, and alveolar-capillary diffusion of gases may bereduced.These factors invariably lead to a need to increase ven-tilator support during mechanical ventilation. Failure to inter-vene by either pharmacologic means or surgery may lead togreater lung injury and may increase the probability of chroniclung disease.146

An additional concern in infants receiving mechanical ventila-tion is that of V/Q mismatching. During the application of CPAPor positive-pressure ventilation, areas of the lung that areatelectatic tend to remain so, whereas inflated or partly inflatedregions of the lung tend to become further distended.The circu-lation generally responds to this situation with improved perfu-sion to lung segments that are inflated, whereas areas of the lungthat are collapsed receive less perfusion. These effects arethought to be locally mediated.When atelectasis is present, thearteriolar bed in that region becomes partially constricted.Although this vasoconstriction is somewhat beneficial, there isstill some lung tissue that is not receiving any significant ven-tilation. V/Q mismatching is then present and is a commonphenomenon in neonatal lung disease.

With pulmonary interstitial emphysema, air dissects alongdistal bronchioles, interfering with circulation and gas exchangein affected segments of the lung that, however, may still be ven-tilated, resulting in a redistribution of pulmonary blood flow.Asthe situation progresses, gas exchange worsens, and ventilatorsupport is commonly increased in an attempt to improve gasexchange.Too often, this response produces further overdisten-tion of the already ventilated regions of the lung and increasedpulmonary interstitial emphysema and ultimately results in theredistribution of pulmonary perfusion to less distended regionsof the lung, owing to local vascular resistance changes in theseregions.V/Q mismatching in such situations is often progressive,leading in some instances to tension pneumothorax. In suchcases, one has maximum V/Q mismatching. Ventilation is nowescaping into the pleural cavity, where no gas exchange canoccur, while the perfusion remains confined within the lung,which is being progressively compressed from without by thepneumothorax. Subsequently, the heart may also be constrictedas intrathoracic pressure increases.V/Q mismatching under anyof the foregoing conditions therefore results in an increase inphysiologic dead space and wasted ventilation.To compensate,the clinician must provide additional ventilatory support as wellas alternate therapy (e.g., chest tube) in an attempt to reestablishmore normal V/Q relationships.

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