Nitric oxide inhalation therapy for newborn infants

Nitric Oxide Inhalation Therapy for Newborn Infants Jeffrey W. Skimming, MD itric oxide (NO) is a colorless gas that readily dissolves in water. Endogenously produced NO mediates numerous physiologic processes (Table 1). Exogenously produced NO has effects similar to those of endogenously produced NO. These similarities become clear on realizing that both alveolar (exogenous) and endothelial (endogenous) sources of NO relax the contractile elements of pulmonary vascular smooth muscle cells. The inhalation of commercially produced NO has recently become a popular method to relax pulmonary vascular tone in a manner that mimics the normal passive relaxation that occurs with endogenous NO. Two physiologic responses to NO inhalation have caused widespread interest in its possible therapeutic properties. First, unlike the systemic hypotension that limits the usefulness of intravenously administered pulmonary vasorelaxants, inhaled NO relaxes preconstricted pulmonary blood vessels without causing concomitant systemic hypotension. 1-5 The selectivity of NO for pulmonary vasorelaxation relates to its direct action on pulmonary vascular smooth muscle and its rapid inactivation by hemoglobin. 5,6 Second, NO inhalation increases the blood oxygen content of selected subjects who have ventilation-perfusion disorders. 2,5,7,8 The improvement in ventilation-perfusion matching relates to selective deposition of NO into well-ventilated lung regions, which decreases alveolar deadspace and thereby increases oxygen uptake into the blood. 7 Both of these physiologic responses occur within seconds of exposure. NO can be easily titrated and is free of tachyphylaxis. Because increased pulmonary vascular tone and ventilation-perfusion mismatching frequently compromise the health of critically ill neonates, many investigators believe that palliative NO therapy warrants investigation. The purpose of this article is to

Jeffrey W. Skimming, MD, is a member of the Departments of Pediatrics and Anesthesiology, University of Florida College of Medicine, PO Box 100296, JHMHC, Gainesville, FL 32610-0296. Curr Probl Pediatr 1998;27:253-64. Copyright © 1998 by Mosby, Inc. 0045-9380/98/$6.00 + 0 53/1/91963

Curr Probl Pediatr, September 1998

critically review current concepts of NO inhalation therapy for neonates.

Nitric Oxide Biochemistry NO is produced in vivo enzymatically from the guanidino group on L-arginine.9 The reactions that result in NO production are catalyzed by a class of enzymes termed NO synthases. These enzymes exist in many cell types; most notably neurons, macrophages, and endothelial cells. Each NO synthase isoform is expressed to varying degrees within the different cell types. Although the isoforms of NO synthase differ in their molecular weights, all structurally resemble cytochrome P450 reductase. 1°,11 Moreover, all of the isoforms rely on cofactors such as nicotinamide adenine dinucleotide phosphate, 12 flavin-adenine dinucleotide, 13 tetrahydrobiopterin, 14 and calmodulin. 15 After enzymatic production by the endothelial cells, NO causes both local and remote physiologic actions. NO can diffuse directly into nearby smooth muscle cells, causing them to relax. Relaxation of remote smooth muscle cells can occur after NO is carried through the vascular system as an adduct of albumin. 16 NO produced by blood vessels that line the nasopharynx can pass in gaseous form through the airways and modulate vascular tone within the lungs. 17 NO causes many of its effects by binding with heavy metal-containing proteins, such as myoglobin, hemoglobin, cytochrome C, and guanylyl cyclase. The mechanism by which NO mediates relaxation of vascular smooth muscle cells remains controversial. The most popular theory is that smooth muscle relaxation occurs when NO begins its activation of guanylyl cyclase. Iron contained within the porphyrin ring of guanylyl cyclase actively binds NO. An isomeric change in guanylyl cyclase caused by NO binding is believed to catalyze formation of the nucleotide cyclic guanosine monophosphate (cGMP). cGMP is believed to decrease sarcoplasmic calcium concentrations by inducing sequestration of calcium into intracellular stores and by augmenting extrusion of calcium from the sarcoplasm. 18 The decrease in sarcoplasmic calcium concentrations is believed to slow phosphorylation of myosin filaments and thereby attenuate muscular contraction. 19 253

"I'AI31.1Z1. Some physiologic processes mediated by NO Smooth muscle relaxation Neural signal transmission Inhibition of p!atelet aggregation Microbial cytotoxicity Tumor cell destruction Apoptosis (programmed cell death)

Relaxation of vascular smooth muscle cells corresponds with increased sarcoplasmic cGMP concentrations. Hydrolysis of cGMP to guanosine 5"monophosphate by cyclic nucleotide phosphodiesterases may limit the effects of cGMR Evidence to support this idea comes from studies that demonstrate smooth muscle relaxation by inhibition of the cGMP phosphodiesterases. Inhibitors of cGMP phosphodiesterases, such as dipyridamole, zaprinast, MY-5445, and vinpocetine, relax vascular smooth muscle both in isolated tissue preparations 2°-22 and in whole animal preparations. 23-27 If NO causes vascular muscle relaxation through a mechanism that is limited by sarcoplasmic cGMP concentrations, then inhibitors of cGMP phosphodiesterase should dramatically potentiate the effects of NO. Experiments performed using isolated tissues reveal that cGMP phosphodiesterase inhibitors can potentiate vascular smooth muscle relaxation caused by N O 26 and by NO-releasing drugs. 28 Despite the efforts of numerous investigators, inhibition of cGMP phosphodiesterase by NO has not been demonstrated consistently in intact animals or humans. Mechanisms have been proposed for smooth muscle relaxation by NO, which are independent of cGMR One such mechanism involves hyperpolarization of the sarcolemma by activation of potassium channels, which causes subsequent vasodilation, at least in some instances, by cyclic nucleotide-independent mechanisms. Drugs that activate potassium channels, such as kromakalim, cause smooth muscle relaxation without affecting sarcoplasmic cyclic nucleotide concentrations. 29-31 Both NO 32-35 and NO-releasing drugs activate potassium channels. 35-39 Bolotina and coworkers 4° reported that NO activates potassium channels of explanted smooth muscle cells by cGMP-independent mechanisms. Therefore, cyclic nucleotide-independent activation of potassium channels could, at least partially, account for NOinduced vasodilation. Another mechanism that may mediate NO-induced vasodilation involves inhibition of mitochondrial respiration. 26 In vitro studies have shown that heme pros-

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thetic groups of electron transport chain cytochromes reversibly bind N O 41'42 and that this reversibly inhibits electron transport activity. 43 Interestingly, congenitally acquired impairment of cytochrome function results in conditions characterized by generalized muscle hypotonia. 42,43 Inhibition of mitochondrial respiration could, at least partially, account for NO-induced vasodilation. However, this mechanism is less popular than others--perhaps because the idea conjures up undesirable thoughts of NO relaxing vascular tone by reversibly "poisoning" the smooth muscle.

Special Considerationsfor Neonates Developing NO therapy for neonates involves many issues that distinguish their care. NO inhalation is regarded as a palliative rather than a curative therapy. By decreasing the impediment to blood flow through the lungs and improving blood oxygen content, NO may palliate selected patient populations. In general, neonates are more apt than adults to recover from ailments that are transiently complicated by life-threatening hypoxemia, increased pulmonary vascular tone, or both. Palliative therapy using NO should therefore be expected to decrease the mortality rate more in neonates than in adults. Although a dose-response relationship to NO has been described in animals 3,5,44-46 and human adults, 47-49 such a relationship remains poorly characterized in neonates. The dose-response relationships in newborn infants are difficult to predict; intuitively, they should be different from those in adults. One might expect neonates to be particularly sensitive to NO inhalation because their resistance vessels are relatively small in diameter. Alternatively, one might expect neonates to be relatively insensitive to NO inhalation because their pulmonary vascular smooth muscle is underdeveloped. Other relevant features of newborn infants include their high proportion of fetal hemoglobin, relative polycythemia, and extrapulmonary shunting. Premature neonates possess additional distinguishing features such as surfactant deficiencies, immature respiratory control centers, and excessively compliant chest walls. Choosing a dosing indicator for dose-response studies in neonates can be complicated. Most researchers have used NO concentrations measured in samples of homogenous inspired gas as a dosing indicator. Infant and adult mechanical ventilation systems are different; therefore, special considerations for NO delivery to neonates must be observed to ensure that the inspired

Curr Probl Pediatr, September 1998

gases are homogenous. Several investigations5°-53 have demonstrated that subtle inhomogeneities can appear in some NO delivery systems. Choosing a response indicator that is a relevant clinical marker for treating neonates can be just as complicated. To facilitate choosing NO doses, clinical researchers have used many different response indicators, such as blood oxygen tension, oxyhemoglobin saturations, pulmonary vascular resistances, pulmonary arterial pressures, and tricuspid valve regurgitation velocities. Some response indicators are age-sensitive. For example, those obtained via intrapulmonary catheters (such as pulmonary arterial pressure) are more practical for adults, whereas those obtained by ultrasound (such as the peak tricuspid valve regurgitation velocity) are more practical for neonates. The methods used to titrate NO dose in neonates may therefore differ from those used in adults. Deciding how to use these physiologic doseresponse relationships in the design of therapeutic trials is continuously growing more complex. For example, all of the response indicators exhibit their own unique sensitivity to NO. This was clearly demonstrated by Gerlach and coworkers,4s who studied adults with respiratory distress syndrome (RDS; Fig. 1). Using EDso estimates (the smallest dose necessary to cause 50% of the maximum effect), they showed that blood oxygen tensions were about twentyfold more sensitive than pulmonary arterial pressures to NO inhalation. Whether NO inhalation therapy in neonates should be directed toward decreasing pulmonary vascular tone, increasing blood oxygen content, or increasing the efficiency of carbon dioxide elimination is unclear. All of the aforementioned complexities underscore the need to establish therapeutic and physiologic dose-response relationships that are specific for neonates. For neonates, the risks associated with NO inhalation are likely as unique as the therapeutic responses; for premature neonates, the risks are especially concerning because of their susceptibility to intracranial hemorrhages and sudden shifts in systemic blood flow. For those with a patent ductus arteriosus, the risks associated with decreasing pulmonary vascular resistance with NO are unclear. Rosenberg and colleagues 54 studied fetal sheep and demonstrated that NO inhalation caused negligible effects on cerebral blood flow despite causing dramatic changes in blood flow through the ductus arteriosus. Whether

Curr Probl Pediatr, September 1998

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FI6, 1, Dose-response of inhaled NO for systemic arterial blood oxygen tension (Pao2; upper plot) and mean pulmonary arterial pressure (PAP; Iowerplot). Values are shown as mean + standard deviation for 12 adults with acute respiratory distress syndrome and are expressed as a percentage of maximal change. The estimated EDs0 of NO for increases in Paos and decreases in PAP are indicated on the abscissa. (Reproduced with permission from Gerlach H, Rossaint R, Pappert D, Falke KJ. Eur J Clin Invest 1993;23:499-502.)

these shifts in blood flow will affect the risks of developing cerebral hemorrhages or necrotizing enterocolitis is unknown.

Diseases in Neonates Affected by Nitric Oxide Therapy RDS RDS is a common illness of premature neonates. The illness involves respiratory signs, such as tachypnea, dyspnea, retractions, grunting, hypoxemia, and a characteristic reticulogranular pattern on the chest radiograph. RDS is frequently complicated by pulmonary hypertension.55-6° Severe pulmonary hypertension can cause "right-to-left" shunting of blood across the foramen ovale and the ductus arteriosus, exacerbating hypoxemia. 59,61Walther and colleagues 6° reported that right-to-left shunting across the ductus arteriosus and the foramen ovale is common among preterm neonates. They suggested that large right-to-left shunts are a risk factor for early death from RDS. RDS is also complicated by intrapulmonary shunting of blood caused by regional atelectasis and hyaline membrane formation. 61-68 In animal models of RDS, NO inhalation decreased the impediment to pulmonary blood flow and increased the blood oxygen content. 2,69 In a randomized, prospective trial on neonates with RDS, NO

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inhalation increased the blood oxygen tension. 7° In this study, the response to NO inhalation, in the range of 5 to 20 ppm, was relatively dose-independent (Fig. 2). These results are similar to those of others, which show the effects of NO inhalation in adults with acute R D S . 47-49 Determining whether NO can decrease the morbidity or mortality rates associated with RDS requires further study.

atrioventricular canals, and patent ductus arteriosus, are complicated by high pulmonary blood flow and pressure that gradually, over months to years, cause irreversible pulmonary vascular disease. Whether prophylactic inhalation of NO by neonates with cardiac shunts will affect their long-term outcome is difficult to predict. It could hasten the development of irreversible pulmonary vascular disease by increasing pulmonary blood flow and concomitant shear forces on the pulmonary endothelium. Occasionally, some physicians attempt prophylactic treatment of these neonates using oxygen, which is a selective pulmonary vasodilator that is less potent than NO. Ironically, this therapy is controversial, whereas treatment of patients who have Eisenmenger's complex, a severe pulmonary vascular disease associated with pulmonary-to-systemic shunting and hypoxemia, as a result of congenital cardiac shunting, is well accepted. 72 It seems reasonable, however, that inhalation of NO would cause responses similar to oxygen in individuals with cardiac shunts. Neonates with congenital heart disease that is complicated by pulmonary venous hypertension represent a special population that is likely to benefit from oxygen or NO inhalation therapy (Table 2). The increased pulmonary venous pressure of these neonates is believed to cause severe reflexive arteriolar hypertension that is particularly sensitive to pulmonary vasodilator therapy. Whether long-term NO inhalation therapy will be useful in these patients will depend partly on whether they can undergo surgery to correct their underlying congenital malformation. For neonates treated with cardiopulmonary bypass surgery, pulmonary hypertension is a common complication; the mechanistic explanation may relate to disturbed endothelial cell function. % The form of pulmonary hypertension that complicates surgery for congenital heart disease is, therefore, probably related to impaired endogenous production of NO. Inhalation of NO by these patients may be helpful in the postoperative period. 74-77

Congenital Heart Disease

PersistentPulmonary Hypertension

Estimates of the prevalence of congenital heart disease range from about 2 to 10 per 1000 live births. 71 Although many forms of congenital heart disease are associated with pulmonary hypertension, relatively few seem likely to benefit from selective pulmonary vasodilator therapy in the newborn period. Structural abnormalities associated with cardiac shunts, such as ventricular septal defects,

Many of the inconsistencies that exist in the medical literature regarding diagnostic criteria for persistent pulmonary hypertension (PPHN) are caused by ambiguities in terminology. Unfortunately, the expression PPHN, which includes an ambiguous temporal concept ("persistent") and a discrete physiologic concept ("pulmonary h ypertension " ), poorly describes the intended population.

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Inhaled NO Concentration (ppm) FIG, 2, Inhaling either 5 ppm or 20 ppm NO increases arterial blood oxygen tensions (Pan2) of preterm newborns with respiratory distress syndrome. Analysis of variance with repeated measures revealed that the effect of NO treatment was significant (P < .01 ). Values are shown as mean + standard error. (Produced using data from reference 70.)

TABLE 2. Cardiac pathologic conditions associated with pulmonary venous hypertension in neonates Anomalous pulmonary venous drainage Pulmonary venous stenosis Cot triatriatum Mitral stenosis Severe mitral insufficiency Congenital cardiomyopathies Left ventricular outflow obstructions* *The ductus arteriosus of many affected neonates remains patent, and pulmonary vasorelaxation may worsen the pulmonary congestion. NO inhalation therapy should therefore be used with extreme caution in neonates with this form of pulmonary venous hypertension.

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Curr Probl Pediatr, September 1998

Many physicians consider PPHN to be a disease that characteristically involves persistence of fight-to-left shunting through the ductus arteriosus from birth. Persistence of this shunt is frequently attributed to failure of the pulmonary resistance vessels to relax normally after birth. The idea that the pulmonary resistance vessels "fail to relax" suggests that the infants in whom PPHN is diagnosed had a prenatal abnormality. Others believe that PPHN can also develop within the first few hours or days of life, despite an initial normal adaptation to extrauterine life. Distinguishing those infants who transiently adapt to extrauterine life normally from those who are maladapted from birth may be important. Neonates who exhibit volatile changes in blood oxygen content after birth seem more likely to respond favorably to NO inhalation therapy than those who exhibit persistent pulmonary hypertension after birth. The expression PPHN is usually used with the expectation that not only is the pulmonary arterial pressure abnormally high, but that the pulmonary arterial pressure is at least as high as the systemic arterial pressure. Unfortunately, pulmonary arterial pressure is difficult to measure in newborns. The existence of pulmonary hypertension in neonates is ordinarily inferred from sonographic or oximetric indexes. As a result, the existence of suprasystemic pulmonary arterial hypertension is infrequently diagnosed with absolute certainty. In addition, infrasystemic pulmonary hypertension may be a common, yet poorly recognized, abnormality in neonates. The term PPHN in this review is used to refer to disorders of term and near-term neonates who are hypoxemic, have evidence of suprasystemic pulmonary vascular resistance, and have grossly normal cardiovascular morphologic features. PPHN has been estimated to affect about 1 in 1500 live newborns, which corresponds to approximately 2300 to 2600 cases per year in the United States. 78,79 Despite recent advances in the treatment of PPHN, morbidity and death are common. Less than half of the infants with PPHN who are treated with extracorporeal membrane oxygenation (ECMO) have a normal outcome. 8° NO inhalation increases blood oxygen levels in infants with PPHN (Fig. 3). 81 The effects of this therapy on long-term outcome, however, remain somewhat unclear. Some investigators recently reported that the use of ECMO decreased in infants who received NO inhalation therapy for PPHN. 81-83 The risks associated with ECMO seem much greater than the risks of NO therapy; this assessment alone may justify approving

Curr Probl Pediatr, September 1998

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FIG. 3. Inhaled NO causesan acute increasein postductal arterial blood oxygen tension (Pa%) in newborns with severe hypoxemia associated with persistentpulmonary hypertensionof the newborn (P < .001 ). Values are shown as mean _+standard deviation. (Reproduced with permission from RobertsJD, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. N Engl J Med 1997;336:605-10.)

NO therapy for PPHN. This necessarily unscientific assessment has been argued to be so evident that many have suggested that the FDA approve the use of NO inhalation without requiring compelling statistics to show that it improves the mortality rate. Unfortunately, the treatment of PPHN has grown so complex that the large number of confounding variables that exist in current management strategies may prohibit costeffective studies of the effects of NO on death associated with PPHN. Recognizing that cardiopulmonary bypass grafting and ECMO are nearly identical interventions offers some insight into the treatment of PPHN. Many health care providers view cardiopulmonary bypass grafting as a palliative procedure that can induce pulmonary vascular disease and view ECMO as a therapy for some forms of pulmonary vascular disease. ECMO treatment of newborn infants is effective because it allows specific causes of pulmonary hypertension to resolve, such that iatrogenic pulmonary vascular disease is adequately tolerated at the time of decannulation. Therefore, it should not be surprising that neonates who do not respond to NO before ECMO often do respond immediately afterwardf 4

Congenital Diaphragmatic Hernia Each year, congenital diaphragmatic hernia (CDH) is diagnosed in approximately 1100 newborns in the

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United States. 85 Incomplete fetal development of the diaphragm causes migration of the abdominal viscera into the chest. Expansion of the abdominal viscera within the chest causes the lungs to be hypoplastic and compressed. Despite recent advances in the medical and surgical treatment of CDH, current survival rates in tertiary care centers are about 40% to 60%. 85-87 Some investigators speculate that the survival rate among those who do not receive tertiary medical care is even lower, s8 About one third of neonates with CDH have an associated congenital abnormality, which worsens the prognosis. 89 Whether high pulmonary vascular tone contributes to the mortality risk associated with CDH is unclear. Some neonates with CDH exhibit extrapulmonary right-to-left shunting, which suggests that pulmonary vascular tone is high. Lamb models of CDH suggest that the pulmonary vascular tone decreases during NO inhalation, especially when combined with Surfactant9° or liquid ventilation. 91 Rats with experimentally induced diaphragmatic hernias survive more often if they breathe supplemental NO. 92 NO inhalation increases blood oxygen tension of some neonates with CDH. 86 However, in one study of neonates with CDH, the result of NO inhalation did not affect whether the physicians ultimately treated their patients with ECMO, nor did it affect the mortality rate. 93

Delivery of Nitric Oxide to Neonates NO is commonly used in industry and is therefore readily available. NO is manufactured by reacting sodium nitrite with sulfuric acid and is typically stored as a compressed gas within aluminum alloy cylinders. NO in concentrations suitable for therapy (typically 100 to 10,000 ppm) can be purchased from commercial sources. Manufacturers usually report NO cylinder contents as volumetric ratios of NO gas to diluent gas, in units as parts per billion (ppb) or parts per million (ppm). NO cylinder content is analyzed using chemiluminescence analyzers that have been calibrated using standard methods that refer to gas samples at the National Institute of Standards and Technology. Most manufacturers use nitrogen, argon, or another inert gas as the diluent. Oxygen cannot be used as a diluent because it rapidly reacts with NO to form nitrogen dioxide. The toxicity of NO necessitates meticulous attention to the details of administration. This is complicated by the wide variety of administration techniques currently used. 50,52,94-99 During mechanical ventilation, the contact time of NO and oxygen should be minimized to avoid the possibility of damaging elastomeric ventila-

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tor components. 1°° This has led to mixing NO with other inhaled gases within the breathing circuit. Various infusion sites within the breathing circuit have been suggested, such as between the Y-piece and endotracheal tube 1°1 or further upstream (toward the ventilator) to ensure better mixing of the gases. 5°,96,97 Inhaled NO concentrations ([NO]inh) can be calculated by assuming that all gases mix thoroughly and by using the following equation:

[NO]inh = [Qstock NO + (Qmain + Qstock NO)] X [NO]stock in which Qstoc~NO represents the flow of gas (ml/min) from the stock NO cylinder, Qmainrepresents the mainstream flow of gas (ml/min) from the mechanical ventilator, and [NO]stoc~ represents the concentration (ppm) of NO in the stock cylinder. In instances that involve gas flow rates that are not constant, time-averaged estimates of flow rates yield values that roughly approximate time-averaged [NO]inh estimates. 52 Thorough gas mixing is easier to achieve with ventilation systems that maintain constant flow rates (ie, Baby Bird, Healthdyne 105, BP-200, BP-2001 "Bear Cub," and Sechrist IV-100) than with ventilation systems that allow mainstream flow rates to vary (ie, Siemens 900C, Babylog 8000, Infant Star, and VIP Bird). Infusing NO at a constant rate into a mainstream gas that flows at a constant rate yields a predictable NO concentration once radial homogeneity (loss of streaming) is achieved. Gas mixing devices have been used to facilitate the establishment of radial homogeneity in conjunction with the (infant) ventilation systems that involve constant mainstream gas flow rates. 5° The difficulties associated with achieving longitudinal gas homogeneity in ventilation systems with variable mainstream flow rates have been discussed by others. 51,1°2 In ventilation systems that are ordinarily used on adults, mainstream flow varies periodically in association with the breathing cycle. In addition, the timeaveraged mainstream flow (minute-flow) of these systems may vary in response to unpredictable physiologic changes. Infusing NO at a constant rate into the inspiratory limb of ventilation systems with pulsatile mainstream flow will therefore result in the formation of NO pools that accumulate periodically within the inspiratory limb during the low-flow (exhalation) phases. Breath-to-breath variations in mainstream flow will result in breath-to-breath variations in the pool sizes. Two strategies can be used to address variations in mainstream flow of mechanical breathing systems. One strategy involves ensuring that the gases are thoroughly

Curr Prob] Pediatr, September 1998

mixed before they are inhaled. This could be accomplished by both ensuring that the gases are infused far enough upstream to avoid inadvertent streaming and simultaneously linking the NO infusion rate to the mainstream gas flow rate. 95 Another strategy simply allows inhalation of inhomogeneous gas. This could be accomplished by allowing pools of NO to accumulate in the downstream end of the breathing circuit. Estimating an inhaled concentration of NO under these circumstances is virtually impossible; however, monitoring NO delivery remains possible. Rather than monitoring NO doses as inhaled concentrations, consumed amounts of NO can be estimated. These estimates can be determined by simultaneously measuring the amount of NO infused into the breathing circuit and the amount leaving the breathing circuit. Simpler methods of monitoring the dose of NO involve measurements of methemoglobin or other sensitive indicators of NO consumption. Dose-response relationships should be more reliable if the responses are correlated with consumed NO rather than inhaled concentrations. Consumed NO can be affected by mechanical ventilation variables that are independent of the inhaled concentration, 103 which is not surprising because changing mechanical ventilation pressures while maintaining the inspired oxygen fraction constant causes analogous effects on blood oxygen levels. Breathing inhomogeneous exogenous NO seems more reasonable because inhalation of endogenous NO also involves gas inhomogeneity. Because the nasopharynx contains higher concentrations of NO than ambient and exhaled gas, pools of NO from the nasopharynx must normally pass deeply into the lungs at the end of inhalation. Mimicking this normal process can be performed by allowing pools of NO gas to accumulate at the downstream end of a mechanical breathing circuit during exhalation, which forces the NO pools to be delivered deeply within the lungs. Advantages of this strategy over those involving delivery of homogenous gases to the lungs include avoiding unnecessary exposure of the conducting airways to toxic NO byproducts and improving the efficiency of NO consumption.

Effects of Nitric Oxide on Respiration In a study of premature infants with RDS, inhaling either 5 ppm or 20 ppm NO seemed to decrease spontaneous breathing frequencies (Fig. 4). 70 NO inhalation might have caused this change by improving the efficiency of respiration by affecting the neurochemi-

CurT Probl Pediatr, September 1998

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cal mediators of respiration. This effect should apply to neonates and older patients.

Arterial Carbon Dioxide Tension (Paco2) Affects Respiration Maintaining normal concentrations of oxygen, carbon dioxide, and hydrogen ions in the blood are basic functions of respiration. Oxygen exerts its influence on respiration through peripheral chemoreceptors found on the carotid and aortic bodies. Carbon dioxide and hydrogen ions both exert their influence on respiration through central chemoreceptors within the medulla. 104 The medulla's chemoreceptors are sensitive to acute changes in blood carbon dioxide tensions and hydrogen ion concentrations. Although the chemoreceptors may be more sensitive to hydrogen ions than to carbon dioxide, blood carbon dioxide levels are believed to affect the central chemoreceptors more than blood hydrogen levels. 1°5 This belief is supported by the finding that carbon dioxide crosses the blood brain barrier faster than both hydrogen ions and bicarbonate ions. Acute changes in carbon dioxide tensions cause peak changes in respiration within minutes. These effects decrease over 1 to 2 days. Although the mechanisms that underlie this gradual decrease remain somewhat unclear, the active transport of

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bicarbonate from the blood into the cerebrospinal fluid may be involved. 1°6 Oxygen usually affects respiration less than either carbon dioxide or hydrogen. The effects of hypoxemia on respiration are evident only after the blood oxygen tension falls below about 60 mm Hg.

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The term deadspace refers to ventilated areas that do not participate in gas exchange. Physiologic (or total) deadspace (VD) is comprised of anatomic and alveolar deadspace. The conducting airways leading to alveoli are termed anatomic deadspace; the alveoli that are ventilated but not perfused are termed alveolar deadspace. In regard to NO inhalation, the anatomic deadspace can be considered a fixed portion of physiologic deadspace, whereas alveolar deadspace can be considered a variable portion. Physiologic deadspace was originally described algebraically by Bohr in 1891 using the equation:

where PEco 2 represents the partial pressure of carbon dioxide in mixed exhaled gas. Close inspection of Enghoff's equation reveals how alveolar deadspace volumes are closely related to Paco 2. Consider the effects of an acute change in alveolar deadspace in a paralyzed subject whose lungs are ventilated mechanically. In such a subject, tidal volume (VT) and breathing frequency (f) can be maintained constant. The Paco 2 is determined by a combination of V T, f, and the metabolic rate of carbon dioxide production. If both the metabolic rate of carbon dioxide production and the anatomic portion of V D remain constant, then changes in alveolar deadspace must be directly proportional to changes in Paco 2. On the other hand, if neurologic modulation of respiration o ccu r s, V T andfwill change so that the Paco 2 will shift toward normal.

Curr Probl Pediatr, September 1998

Nitric Oxide Inhalation Affects Alveolar Deadspace Preliminary evidence, using sheep with acutely injured lungs, suggests that alveolar deadspace decreases as a result of NO inhalation 7,47,1°9,11° (Fig. 5). Changes in alveolar deadspace caused by NO inhalation predict changes in intrapulmonary shunt fractions (Fig. 6). 7 Because decreases in alveolar deadspace result in improved efficiency of carbon dioxide elimination, NO inhalation may decrease spontaneous minute ventilation via neuroregulatory responses intended to maintain normal blood carbon dioxide tensions. Decreases in breathing frequenc!es 09, decreases in V T, or both are associated with decreases in minute ventilation because minute ventilation is defined as the product o f f and V T. Decreases in minute ventilation due to NO inhalation are manifested by decreases in f, VT, or both (Fig. 4). 7o

Relevance of the Effects of Nitric Oxide Inhalation on Respiration Treatment with NO inhalation may benefit neonates who have ventilation-perfusion disorders by decreasing their work of breathing. This conservation of calories may lead to improved growth. Moreover, enhancing carbon dioxide elimination may permit the use of lower mechanical inflation pressures, inflation volumes, and breathing frequencies. At present, this rationale is perhaps the best one that supports palliative NO inhalation treatment for patients whose existing therapy involves breathing less-thanpure oxygen.

Foodand DrugAdministrationEndorsement Whether the Food and Drug Administration (FDA) will eventually endorse NO inhalation therapy for neonates is uncertain. Commercial biases will certainly favor securing an endorsement for treating adults over one for treating newborns. FDA endorsement of NO inhalation therapy for patients of any age rests partly on whether the favorable outcomes of clinical trials outweigh the unfavorable outcomes. Balancing these outcomes necessarily involves choices that are subject to incessant criticism.

Summary Binding of NO to heavy metal-containing proteins probably accounts for many of its physiologic actions. NO inhalation is a promising new treatment for vari-

Curr P~obl Pediatr, September 1998

ous disorders of neonates. The therapy is most likely to benefit premature neonates who are hypoxemic despite breathing pure oxygen and those who suffer from impaired carbon dioxide elimination. Newborn infants who have congenital heart disease may benefit from inhaled NO therapy if their disease involves some form of pulmonary venous hypertension or if they have recently undergone surgery involving cardiopulmonary bypass grafting. The use of NO in infants with PPHN might obviate the need for ECMO or other invasive treatment methods. Neonates with CDH seem likely to benefit marginally from NO therapy. Minimizing the toxicities of NO inhalation therapy requires that the physicians understand the nuances of infant care. The therapeutic value of increasing carbon dioxide elimination with NO inhalation warrants further investigation. References 1. Pepke Zaba J, Higenbottam TW, Dinh Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991 ;338:1173-4. 2. Skimming JW, DeMarco VG, Cassin S. The effects of nitric oxide inhalation on the pulmonary circulation of preterm lambs. Pediatr Res 1995;37:35-40. 3. Fratacci MD, Frostell CG, Chen TY, Wain JC Jr, Robinson DR, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology i991;75:990-9. 4. DeMarco V, Skimming J, Ellis TM, Cassin S. Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations. Chest 1994;105:91S-2S. 5. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991 ;83:2038-47. 6. Gibson QH, Roughton FJW. The kinetics and equilibria of the reactions of nitric oxide with sheep haemoglobin. J Physiol 1957;136:507-26. 7. Skimming JW, Banner MJ, Blanch PB. Nitric oxide inhalation decreases alveolar deadspace in an ovine lung injury model [abstract]. Crit Care Med 1997;25:97. 8. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405. 9. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991 ;43:109-42. 10. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:714-8. 11. White KA, Bancroft JB, Mackie GA. Mutagenesis of a hexanucleotide sequence conserved in potexvirus RNAs. Virology 1992;189:817-20. 12. Palmer RM, Moncada S. A novel citmlline-fomaing enzyme implicated in the formation of nitric oxide by vascular endothelial cells. Biochem Biophys Res Commun 1989;158:348-52.

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