- Email: [email protected]
Neonatal ECMO: Iron lung of the 1990s?
EDITOR'S COLUMN
Neonatal ECMO: Iron lung of the Neonatal extracorporeal membrane oxygenation became an established therapy in neonatal intensive care during the second half of the 1980s. As reviewed by Kanto in this issue of THE JOURNAL, many lives have been saved, while shortterm morbidity has been held at relatively low levels for such a high-risk population. 1 The number of neonates treated with ECMO in the United States during the current decade has stabilized, and probably peaked, at about 1300 cases per year. A new "growth spurt" in neonatal ECMO is therefore unlikely, and presumably the proliferation of new ECMO programs has halted. With ECMO as the ultimate "safety net" for patients with intractable respiratory failure, it has become possible to explore alternative, less invasive therapies such as high-frequency oscillation, as reported by Clark et al. 2 in this issue. However, the question remains: Will the need for neonatal ECMO be sustained at its current pace, or will this therapy be largely replaced by a combination of less invasive approaches? Persistent pulmonary hypertension of the newborn, also known as persistent fetal circulation, figures prominently as an indication for neonatal ECMO therapy. It is frequently the primary cause of respiratory failure in infants born at (or close to) term, and it may contribute substantially to the pathophysiology of congenital diaphragmatic hernia, meconium aspiration syndrome, neonatal sepsis, and respiratory distress syndrome. In all these instances the diagnosis of P P H N is suggested by lability in oxygenation or by hypoxemia disproportionate to the severity of parenchymal lung disease; echocardiographic confirmation is typically required. Because PPHN is the end result of such a broad spectrum of pathophysiologic states, rather than a single disease entity, therapy must be tailored individually and no single therapeutic regimen is likely to provide a cure for every patient. This concept has long been exemplified by the variable responses to the administration of tolazoline, which was (and still is) given in an attempt to induce selective pulmonary vasodilation and improve gas exchange. Despite the diagnostic diversity of infants with PPHN, two currently available therapeutic options, and one rapidly Reprint requests: Richard J. Martin, MD, Division of Neonatology, Rainbow Babies and Childrens Hospital, 2101 Adelbert Rd., Cleveland, OH 44106. THE JOURNAL OF PEDIATRICS 1994;124:427-30. Copyright ® 1994 by Mosby-Year Book, Inc. 0022-3476/94 $3.00 + 0 9/21/52717
990s?
emerging therapy, appear promising for decreasing the need for ECMO in this population. SURFACTANT
THERAPY
Respiratory distress syndrome, in association with surfactant deficiency, was previously the primary diagnosis in a significant number of ECMO-treated infants. 1Coincident with the widespread availability of surfactant therapy, the incidence of this diagnosis in ECMO-treated newborn infants appears to have declined. It is therefore a reasonable assumption that exogenous surfactant therapy has reduced the need for ECMO in many of these infants. However, the future role of surfactant therapy for respiratory failure in infants with meconium aspiration syndrome and neonatal pneumonia is less clear. In vitro data have revealed that even dilute meconium is capable of inhibiting the ability of surfactant to lower surface tension. 3 In contrast, studies of surfactant therapy in animal models of meconium aspiraSee related articles, pp. 335 and 447.
ECMO NO PPHN RDS
Extracorporeal membrane oxygenation Nitric oxide Persistent pulmonary hypertension of the newborn Respiratory distress syndrome
tion syndrome have had inconsistent results 4 (also: Wiswell TE, Davis JM, Merritt TA: unpublished observations). Several years ago Auten et al. 5 documented a beneficial effect of calf lung surfactant extract on the oxygenation of 14 term infants, 50% with meconium aspiration syndrome and 50% with pneumonia. These data were encouraging, but there was no separate control group from whom surfactaut therapy was withheld. Meanwhile, there are rapidly increasing numbers of reports that are somewhat conflicting with regard to the role of surfactant proteins and lipids in pulmonary immune regulation.6, 7Alveolar macrophages, the primary immunologic cells in the lung, are important in surfactant metabolism, and therefore concern exists that therapeutic doses of surfactant may modify alveolar macrophage function. Thus, on the basis of this laboratory evidence, the role of exogenous surfactant in term infants in whom the diagnosis of pneumonia is suspected remains unclear. As suggested by Kanto, this group of infants with early-onset neonatal pneumonia complicated by PPHN may be prime candidates for ECMO because of the poten-
427
428
Walsh-Sukys, Stork, and Martin
tial for rapid clinical decompensation. 1 Therefore if surfactant therapy is to obviate the need for ECMO in such infants, it must produce a rapid improvement, which is more likely to occur with a protein-containing (or natural) surfactant product. A significant number of ECMO candidates have nonspecific pulmonary infiltrates radiographically, for which a precise diagnosis is never made. Some of these infants may have a form of adult RDS related to perinatal asphyxia; however, in the absence of a clear diagnosis, a focused therapeutic approach to their lung disease is difficult. Available data indicate that use of exogenous surfactant therapy may significantlyshorten the duration of ECMO support in term infants with respiratory failure of various causes. 8 A multicenter clinical trial is currently under way to identify the role of surfactant therapy in eliminating the need for ECMO in patients with respiratory failure caused by PPHN, sepsis, or meconium aspiration syndrome, but not by RDS. HIGH-FREQUENCY
VENTILATION
Hyperventilation to induce respiratory alkalosis appears to be declining as the primary management for PPHN. However, in the early 1980s clinicians extended the concept of hyperventilation to include high-frequency ventilation and raised the hope that it might be a useful therapy in many patients with PPHN. This initial enthusiasm was somewhat dampened in a retrospective review in which we were unable to document a decreased use of ECMO among eligible neonates treated with high-frequencyjet ventilation compared with conventional ventilation.9 At that time the strategy among many investigators who were using high-frequency ventilation was to lower mean airway pressure as much as possible in an effort to reduce barotrauma. This was also the strategy largely used in the multicenter high-frequency ventilation trial for preterm infants with respiratory distress. 1° Subsequently it has been suggested that raising mean airway pressure (while lowering pressure excursions) may produce less barotrauma, and it has been argued that the multicenter trial may have failed to demonstrate any benefit from high-frequency ventilation because of the low mean airway pressure strategy used, rather than because of any inherent flaw in high-frequency ventilation. The current study by Clark et al. 2 describes a prospective, randomized trial of high-frequency oscillatory ventilation that uses a high mean airway strategy, which builds on their previous extensive experience with this therapy. 2' l l These authors demonstrate three important points. First, highfrequency oscillatory ventilation can be an effective and safe rescue technique for neonates in whom conventional mechanical ventilation has failed, with acceptable pulmonary outcomes. Second, high-frequency ventilation was no more
The Journal of Pediatrics March 1994
effective in avoiding the need for ECMO than conventional mechanical ventilation when used as a first-line treatment of respiratory failure. The third important point was not intentionally a component of the trial. In the original power analysis the authors projected a sample size of 250 patients. However, the study had to be terminated when patient enrollment plummeted as referral patterns at the three centers changed, which the authors speculate was related to the dissemination of high-frequency technology beyond academic centers. Therefore, although it is possible that the availability of high-frequency ventilation may avoid the need for ECMO in some patients, this has been impossible to prove, even in this well-designed multicenter trial. NITRIC OXIDE During the past two decades investigators have searched for the so-called magic bullet, that is, a selective pulmonary vasodilator that could improve blood flow to the lungs without adversely affecting systemic blood pressure. Nitric oxide has recently been nominated for this honor. Only 5 years ago NO was revealed to be the so-called endotheliumderived relaxing factor. Previously recognized as a toxic gas contributing to air pollution, NO is now known to be the endogenous mediator of multiple physiologic processes, including regulation of pulmonary vascular tone. 12 Endogenous NO is synthesized within the endothelium from its precursor arginine and diffuses into the underlying vascular smooth muscle. There it stimulates guanyl cyclase to increase intracellular levels of cyclic guanosine monophosphate, which in turn produces smooth muscle relaxation. Exogenous NO delivered to the alveoli through inspired gas rapidly diffuses across the alveolar membrane to effect vasorelaxation, presumably through this same pathway. In contrast to other vasodilators administered intravenously, inhaled NO has virtually no effect on systemic vascular tone, because it is rapidly taken up and inactivated by hemoglobin, which limits its access to the systemic circulation. Inhalation of NO reverses pulmonary hypertension in various animal models of PPHN. 13, ~4 The first published reports of the use of NO in neonates with PPHN appeared in December 1992.15, 16 Roberts et al. 15 administered 80 ppm NO for 30 minutes to six patients with PPHN. During this short-term exposure, oxygen saturation improved in all six patients, whereas systemic blood pressure was unaffected. The authors suggested that the excessive pulmonary vasoconstriction associated with PPHN in these infants resulted from inadequate endogenous NO levels in their pulmonary vascular endothelial cells. Kinsella et al. 16 administered 10 to 20 ppm NO to nine infants with PPHN and also reported significantly improved oxygenation without change in systemic pressure; all infants in this series recovered without the need for ECMO. In a more recent article,
The Journal of Pediatrics Volume 124, Number 3
Kinsella et al. 17 reported sustained improvement in oxygenation in eight of nine infants with P P H N treated with inhaled NO for 24 hours at only 6 ppm. Will NO fulfill our expectations as a therapeutic agent for PPHN? This question will be answered only by rigorous prospective trials comparing this agent with conventional treatment strategies. The optimal dose and duration of therapy are still unknown. Nitric oxide is toxic at higher concentrations; the frequency of its potential side effects, including methemoglobinemia, pulmonary edema, and platelet dysfunction, must be carefully studied, particularly with regard to long-term exposure. Finally, we should not lose sight of the potential benefit of administering other vasodilating agents directly to the pulmonary circulation via the airway. In a newborn lamb model, Curtis et a l l s showed that tolazoline administered by means of an endotracheal tube produced a more selective pulmonary vascular response than intravenous administration of tolazoline. Similarly, Walmrath et a1.19 reported improved oxygenation and a 30% decrease in pulmonary vascular resistance in three adult patients with adult RDS who were treated with prostacyclin administered in an aerosolized form; systemic vascular resistance and blood pressure were only marginally affected. These and other vasodilators administered directly to the airway may compare favorably with NO in producing selective pulmonary vasodilation. Ironically, the pathway of action for many of these agents may ultimately involve stimulating endogenous NO production and release. A more novel approach to the delivery of vasodilators may include instillation of these medications by perfluorochemical liquid ventilation. These inert heavy liquids reduce ventilation-perfusion mismatch by homogenously inflating the lungs, and they provide a unique vehicle for delivering oxygen, biologically active agents, or both to the alveolar level. This was recently demonstrated by Wolfson et al., 2° who showed a greater pulmonary versus systemic response to tolazoline delivered in this manner to 13 lambs with hypoxia-induced pulmonary hypertension. In summary, the future of selective modulation of pulmonary vascular tone appears more promising then ever. CONCLUSION How does one sort through the crowded field of therapeutic options to select a "best" treatment strategy for an individual patient who appears to be a candidate for ECMO? Although there is no current resolution of this dilemma, the presumptive underlying abnormalities will necessitate an individualized therapeutic approach in each case. The expansion of available therapies ultimately should benefit patients by reducing the need for ECMO. However, it is critical that long-term follow-up studies be performed
Walsh-Sukys, Stork, and Martin
429
to evaluate the risks of "avoiding" ECMO. Neonatal outcome may not be improved by swapping the risks of ECMO for potentially greater risks of profound pulmonary morbidity related to prolonged ventilatory support. The expansion of therapeutic alternatives raises another problem: Must every neonatal intensive care unit be able to provide every conceivable therapy? In the past high-priced but glamorous rescue techniques have been used as marketing tools by hospitals, leading to a costly medical "arms race." As the debate surrounding health care reform has highlighted, the nation can no longer afford this practice. The financial implications are considerable, but there are other dangers to the diffusion of rescue techniques. As the experience of Clark and associates underscores, the dispersion of a small pool of patients among multiple centers and multiple therapies may deplete the number of patients at any one center below that which is critical to maintain expertise (let alone support research) with that technique. Further, individual patients may be jeopardized if they "respond" to one rescue therapy, only to have their condition deteriorate again later, to the extent that they are too critically ill to survive transport for ECMO. We believe that ECMO is a lifesaving therapeutic tool for neonates with respiratory failure and that its use will continue in the foreseeable future. However, surfactant therapy will, and high-frequency ventilation may, decrease the need for neonatal ECMO. The early reports of inhaled NO are encouraging, hut the history of neonatology dictates restraint until this promising therapy is supported by well-designed clinical trials. With regard to the long-term future of neonatal ECMO, one cannot help but speculate whether history will repeat itself. In the 1940s the development of the iron lung ventilator was a major therapeutic advance that certainly saved thousands of lives during the poliomyelitis epidemics that preceded development of the Salk and Sabin vaccines. If and when neonatal ECMO meets the same fate as the iron lung ventilator, we will have reached another important milestone in neonatal intensive care. Michele Walsh-Sukys, MD Eileen K. Stork, M D Richard J. Martin, M D Division o f Neonatology Rainbow Babies and Childrens Hospital Cleveland, OH 44106 EDITOR'S NOTE: A Medical Progress review of high-frequency ventilation will soon appear in THE JOURNAL.--J.M.G. REFERENCES
1. Kanto WP Jr. A decade of experience with neonatal extracorporeal membrane oxygenation. J PEDIATR1994;124:335-47. 2. Clark RH, Yoder BA, Sell MS. Prospective randomized corn-
430
3.
4.
5.
6.
7.
8.
9.
10.
11.
Walsh-Sukys, Stork, and Martin
parison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. J PEDIATR 1994;124:447-54. Moses D, Holm BA, Spitale P, Liu M, Enhorning G. Inhibition of pulmonary surfactant function by meconium. Am J Obstet Gynecol 1991;164:477-81. Sun B, Curstedt T, Song G-W, Robertson B. Surfactant improves lung function and morphology in newborn rabbits with meconium aspiration. Biol Neonate 1993;63:96-104. Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991;87:101-7. Thomassen M J, Meeker DP, Antal JM, Connors M J, Wiedemann HP. Synthetic surfactant (Exosurf) inhibits endotoxinstimulated cytokine secretion by human alveolar macrophages. Am J Respir Cell Mol Biol 1992;7:257-60. Wright JR, Youmans DC. Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophage. Am J Physiol 1993;264:L338-L344. Lotze A, Knight GR, Martin GR, et at. Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J PEDIATR 1993;122:261-8. Carlo WA, Beoglos A, Chatburn RL, Walsh MC, Martin RJ. High-frequency jet ventilation in neonatal pulmonary hypertension. Am J Dis Child 1989;143:233-8. HiFi Study Group. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N Engl J Med 1989;320:88-93. Carter JM, Gerstmann DR, Clark RH, Snyder G, Cornish JD, Null DM Jr, deLemos RA. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the
The Journal of Pediatrics March 1994
12.
13.
14.
15.
16.
17.
18.
19.
20.
treatment of acute neonatal respiratory failure. Pediatrics 1990;85:159-64. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43:109-42. Zayek M, Cleveland D, Morin FC III. Treatment of persistent pulmonary hypertension in the newborn lamb by inhaled nitric oxide. J PEDIATR 1993;122:743-50. Berger JI, Gibson RL, Redding G J, Standaert TA, Clarke WR, Truog WE. Effect of inhaled nitric oxide during group B streptococcal sepsis in piglets. Am Rev Respir Dis 1993; 147:1080-6. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-20. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical response to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J PEDIATR 1993;123:103-8. Curtis J, O'Neill JT, Pettett G. Endotracheal administration of tolazoline in hypoxia-induced pulmonary hypertension. Pediatrics 1993;92:403-8. Walmrath D, Schneider T, Pilch J, Grimminger F, Seeger W. Aerosolised prostacyclin in adult respiratory distress syndrome. Lancet 1993;342:961-2. Wolfson MR, Greenspan JS, Shaffer TH. Pulmonary administration of priscoline by perfluorochemical liquid ventilation: reversal of induced-pulmonary hypertension and hypoxemia [Abstract]. Pediatr Res 1992;31:229A.
Neonatal ECMO: Iron lung of the Neonatal extracorporeal membrane oxygenation became an established therapy in neonatal intensive care during the second half of the 1980s. As reviewed by Kanto in this issue of THE JOURNAL, many lives have been saved, while shortterm morbidity has been held at relatively low levels for such a high-risk population. 1 The number of neonates treated with ECMO in the United States during the current decade has stabilized, and probably peaked, at about 1300 cases per year. A new "growth spurt" in neonatal ECMO is therefore unlikely, and presumably the proliferation of new ECMO programs has halted. With ECMO as the ultimate "safety net" for patients with intractable respiratory failure, it has become possible to explore alternative, less invasive therapies such as high-frequency oscillation, as reported by Clark et al. 2 in this issue. However, the question remains: Will the need for neonatal ECMO be sustained at its current pace, or will this therapy be largely replaced by a combination of less invasive approaches? Persistent pulmonary hypertension of the newborn, also known as persistent fetal circulation, figures prominently as an indication for neonatal ECMO therapy. It is frequently the primary cause of respiratory failure in infants born at (or close to) term, and it may contribute substantially to the pathophysiology of congenital diaphragmatic hernia, meconium aspiration syndrome, neonatal sepsis, and respiratory distress syndrome. In all these instances the diagnosis of P P H N is suggested by lability in oxygenation or by hypoxemia disproportionate to the severity of parenchymal lung disease; echocardiographic confirmation is typically required. Because PPHN is the end result of such a broad spectrum of pathophysiologic states, rather than a single disease entity, therapy must be tailored individually and no single therapeutic regimen is likely to provide a cure for every patient. This concept has long been exemplified by the variable responses to the administration of tolazoline, which was (and still is) given in an attempt to induce selective pulmonary vasodilation and improve gas exchange. Despite the diagnostic diversity of infants with PPHN, two currently available therapeutic options, and one rapidly Reprint requests: Richard J. Martin, MD, Division of Neonatology, Rainbow Babies and Childrens Hospital, 2101 Adelbert Rd., Cleveland, OH 44106. THE JOURNAL OF PEDIATRICS 1994;124:427-30. Copyright ® 1994 by Mosby-Year Book, Inc. 0022-3476/94 $3.00 + 0 9/21/52717
990s?
emerging therapy, appear promising for decreasing the need for ECMO in this population. SURFACTANT
THERAPY
Respiratory distress syndrome, in association with surfactant deficiency, was previously the primary diagnosis in a significant number of ECMO-treated infants. 1Coincident with the widespread availability of surfactant therapy, the incidence of this diagnosis in ECMO-treated newborn infants appears to have declined. It is therefore a reasonable assumption that exogenous surfactant therapy has reduced the need for ECMO in many of these infants. However, the future role of surfactant therapy for respiratory failure in infants with meconium aspiration syndrome and neonatal pneumonia is less clear. In vitro data have revealed that even dilute meconium is capable of inhibiting the ability of surfactant to lower surface tension. 3 In contrast, studies of surfactant therapy in animal models of meconium aspiraSee related articles, pp. 335 and 447.
ECMO NO PPHN RDS
Extracorporeal membrane oxygenation Nitric oxide Persistent pulmonary hypertension of the newborn Respiratory distress syndrome
tion syndrome have had inconsistent results 4 (also: Wiswell TE, Davis JM, Merritt TA: unpublished observations). Several years ago Auten et al. 5 documented a beneficial effect of calf lung surfactant extract on the oxygenation of 14 term infants, 50% with meconium aspiration syndrome and 50% with pneumonia. These data were encouraging, but there was no separate control group from whom surfactaut therapy was withheld. Meanwhile, there are rapidly increasing numbers of reports that are somewhat conflicting with regard to the role of surfactant proteins and lipids in pulmonary immune regulation.6, 7Alveolar macrophages, the primary immunologic cells in the lung, are important in surfactant metabolism, and therefore concern exists that therapeutic doses of surfactant may modify alveolar macrophage function. Thus, on the basis of this laboratory evidence, the role of exogenous surfactant in term infants in whom the diagnosis of pneumonia is suspected remains unclear. As suggested by Kanto, this group of infants with early-onset neonatal pneumonia complicated by PPHN may be prime candidates for ECMO because of the poten-
427
428
Walsh-Sukys, Stork, and Martin
tial for rapid clinical decompensation. 1 Therefore if surfactant therapy is to obviate the need for ECMO in such infants, it must produce a rapid improvement, which is more likely to occur with a protein-containing (or natural) surfactant product. A significant number of ECMO candidates have nonspecific pulmonary infiltrates radiographically, for which a precise diagnosis is never made. Some of these infants may have a form of adult RDS related to perinatal asphyxia; however, in the absence of a clear diagnosis, a focused therapeutic approach to their lung disease is difficult. Available data indicate that use of exogenous surfactant therapy may significantlyshorten the duration of ECMO support in term infants with respiratory failure of various causes. 8 A multicenter clinical trial is currently under way to identify the role of surfactant therapy in eliminating the need for ECMO in patients with respiratory failure caused by PPHN, sepsis, or meconium aspiration syndrome, but not by RDS. HIGH-FREQUENCY
VENTILATION
Hyperventilation to induce respiratory alkalosis appears to be declining as the primary management for PPHN. However, in the early 1980s clinicians extended the concept of hyperventilation to include high-frequency ventilation and raised the hope that it might be a useful therapy in many patients with PPHN. This initial enthusiasm was somewhat dampened in a retrospective review in which we were unable to document a decreased use of ECMO among eligible neonates treated with high-frequencyjet ventilation compared with conventional ventilation.9 At that time the strategy among many investigators who were using high-frequency ventilation was to lower mean airway pressure as much as possible in an effort to reduce barotrauma. This was also the strategy largely used in the multicenter high-frequency ventilation trial for preterm infants with respiratory distress. 1° Subsequently it has been suggested that raising mean airway pressure (while lowering pressure excursions) may produce less barotrauma, and it has been argued that the multicenter trial may have failed to demonstrate any benefit from high-frequency ventilation because of the low mean airway pressure strategy used, rather than because of any inherent flaw in high-frequency ventilation. The current study by Clark et al. 2 describes a prospective, randomized trial of high-frequency oscillatory ventilation that uses a high mean airway strategy, which builds on their previous extensive experience with this therapy. 2' l l These authors demonstrate three important points. First, highfrequency oscillatory ventilation can be an effective and safe rescue technique for neonates in whom conventional mechanical ventilation has failed, with acceptable pulmonary outcomes. Second, high-frequency ventilation was no more
The Journal of Pediatrics March 1994
effective in avoiding the need for ECMO than conventional mechanical ventilation when used as a first-line treatment of respiratory failure. The third important point was not intentionally a component of the trial. In the original power analysis the authors projected a sample size of 250 patients. However, the study had to be terminated when patient enrollment plummeted as referral patterns at the three centers changed, which the authors speculate was related to the dissemination of high-frequency technology beyond academic centers. Therefore, although it is possible that the availability of high-frequency ventilation may avoid the need for ECMO in some patients, this has been impossible to prove, even in this well-designed multicenter trial. NITRIC OXIDE During the past two decades investigators have searched for the so-called magic bullet, that is, a selective pulmonary vasodilator that could improve blood flow to the lungs without adversely affecting systemic blood pressure. Nitric oxide has recently been nominated for this honor. Only 5 years ago NO was revealed to be the so-called endotheliumderived relaxing factor. Previously recognized as a toxic gas contributing to air pollution, NO is now known to be the endogenous mediator of multiple physiologic processes, including regulation of pulmonary vascular tone. 12 Endogenous NO is synthesized within the endothelium from its precursor arginine and diffuses into the underlying vascular smooth muscle. There it stimulates guanyl cyclase to increase intracellular levels of cyclic guanosine monophosphate, which in turn produces smooth muscle relaxation. Exogenous NO delivered to the alveoli through inspired gas rapidly diffuses across the alveolar membrane to effect vasorelaxation, presumably through this same pathway. In contrast to other vasodilators administered intravenously, inhaled NO has virtually no effect on systemic vascular tone, because it is rapidly taken up and inactivated by hemoglobin, which limits its access to the systemic circulation. Inhalation of NO reverses pulmonary hypertension in various animal models of PPHN. 13, ~4 The first published reports of the use of NO in neonates with PPHN appeared in December 1992.15, 16 Roberts et al. 15 administered 80 ppm NO for 30 minutes to six patients with PPHN. During this short-term exposure, oxygen saturation improved in all six patients, whereas systemic blood pressure was unaffected. The authors suggested that the excessive pulmonary vasoconstriction associated with PPHN in these infants resulted from inadequate endogenous NO levels in their pulmonary vascular endothelial cells. Kinsella et al. 16 administered 10 to 20 ppm NO to nine infants with PPHN and also reported significantly improved oxygenation without change in systemic pressure; all infants in this series recovered without the need for ECMO. In a more recent article,
The Journal of Pediatrics Volume 124, Number 3
Kinsella et al. 17 reported sustained improvement in oxygenation in eight of nine infants with P P H N treated with inhaled NO for 24 hours at only 6 ppm. Will NO fulfill our expectations as a therapeutic agent for PPHN? This question will be answered only by rigorous prospective trials comparing this agent with conventional treatment strategies. The optimal dose and duration of therapy are still unknown. Nitric oxide is toxic at higher concentrations; the frequency of its potential side effects, including methemoglobinemia, pulmonary edema, and platelet dysfunction, must be carefully studied, particularly with regard to long-term exposure. Finally, we should not lose sight of the potential benefit of administering other vasodilating agents directly to the pulmonary circulation via the airway. In a newborn lamb model, Curtis et a l l s showed that tolazoline administered by means of an endotracheal tube produced a more selective pulmonary vascular response than intravenous administration of tolazoline. Similarly, Walmrath et a1.19 reported improved oxygenation and a 30% decrease in pulmonary vascular resistance in three adult patients with adult RDS who were treated with prostacyclin administered in an aerosolized form; systemic vascular resistance and blood pressure were only marginally affected. These and other vasodilators administered directly to the airway may compare favorably with NO in producing selective pulmonary vasodilation. Ironically, the pathway of action for many of these agents may ultimately involve stimulating endogenous NO production and release. A more novel approach to the delivery of vasodilators may include instillation of these medications by perfluorochemical liquid ventilation. These inert heavy liquids reduce ventilation-perfusion mismatch by homogenously inflating the lungs, and they provide a unique vehicle for delivering oxygen, biologically active agents, or both to the alveolar level. This was recently demonstrated by Wolfson et al., 2° who showed a greater pulmonary versus systemic response to tolazoline delivered in this manner to 13 lambs with hypoxia-induced pulmonary hypertension. In summary, the future of selective modulation of pulmonary vascular tone appears more promising then ever. CONCLUSION How does one sort through the crowded field of therapeutic options to select a "best" treatment strategy for an individual patient who appears to be a candidate for ECMO? Although there is no current resolution of this dilemma, the presumptive underlying abnormalities will necessitate an individualized therapeutic approach in each case. The expansion of available therapies ultimately should benefit patients by reducing the need for ECMO. However, it is critical that long-term follow-up studies be performed
Walsh-Sukys, Stork, and Martin
429
to evaluate the risks of "avoiding" ECMO. Neonatal outcome may not be improved by swapping the risks of ECMO for potentially greater risks of profound pulmonary morbidity related to prolonged ventilatory support. The expansion of therapeutic alternatives raises another problem: Must every neonatal intensive care unit be able to provide every conceivable therapy? In the past high-priced but glamorous rescue techniques have been used as marketing tools by hospitals, leading to a costly medical "arms race." As the debate surrounding health care reform has highlighted, the nation can no longer afford this practice. The financial implications are considerable, but there are other dangers to the diffusion of rescue techniques. As the experience of Clark and associates underscores, the dispersion of a small pool of patients among multiple centers and multiple therapies may deplete the number of patients at any one center below that which is critical to maintain expertise (let alone support research) with that technique. Further, individual patients may be jeopardized if they "respond" to one rescue therapy, only to have their condition deteriorate again later, to the extent that they are too critically ill to survive transport for ECMO. We believe that ECMO is a lifesaving therapeutic tool for neonates with respiratory failure and that its use will continue in the foreseeable future. However, surfactant therapy will, and high-frequency ventilation may, decrease the need for neonatal ECMO. The early reports of inhaled NO are encouraging, hut the history of neonatology dictates restraint until this promising therapy is supported by well-designed clinical trials. With regard to the long-term future of neonatal ECMO, one cannot help but speculate whether history will repeat itself. In the 1940s the development of the iron lung ventilator was a major therapeutic advance that certainly saved thousands of lives during the poliomyelitis epidemics that preceded development of the Salk and Sabin vaccines. If and when neonatal ECMO meets the same fate as the iron lung ventilator, we will have reached another important milestone in neonatal intensive care. Michele Walsh-Sukys, MD Eileen K. Stork, M D Richard J. Martin, M D Division o f Neonatology Rainbow Babies and Childrens Hospital Cleveland, OH 44106 EDITOR'S NOTE: A Medical Progress review of high-frequency ventilation will soon appear in THE JOURNAL.--J.M.G. REFERENCES
1. Kanto WP Jr. A decade of experience with neonatal extracorporeal membrane oxygenation. J PEDIATR1994;124:335-47. 2. Clark RH, Yoder BA, Sell MS. Prospective randomized corn-
430
3.
4.
5.
6.
7.
8.
9.
10.
11.
Walsh-Sukys, Stork, and Martin
parison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. J PEDIATR 1994;124:447-54. Moses D, Holm BA, Spitale P, Liu M, Enhorning G. Inhibition of pulmonary surfactant function by meconium. Am J Obstet Gynecol 1991;164:477-81. Sun B, Curstedt T, Song G-W, Robertson B. Surfactant improves lung function and morphology in newborn rabbits with meconium aspiration. Biol Neonate 1993;63:96-104. Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics 1991;87:101-7. Thomassen M J, Meeker DP, Antal JM, Connors M J, Wiedemann HP. Synthetic surfactant (Exosurf) inhibits endotoxinstimulated cytokine secretion by human alveolar macrophages. Am J Respir Cell Mol Biol 1992;7:257-60. Wright JR, Youmans DC. Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophage. Am J Physiol 1993;264:L338-L344. Lotze A, Knight GR, Martin GR, et at. Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J PEDIATR 1993;122:261-8. Carlo WA, Beoglos A, Chatburn RL, Walsh MC, Martin RJ. High-frequency jet ventilation in neonatal pulmonary hypertension. Am J Dis Child 1989;143:233-8. HiFi Study Group. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants. N Engl J Med 1989;320:88-93. Carter JM, Gerstmann DR, Clark RH, Snyder G, Cornish JD, Null DM Jr, deLemos RA. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the
The Journal of Pediatrics March 1994
12.
13.
14.
15.
16.
17.
18.
19.
20.
treatment of acute neonatal respiratory failure. Pediatrics 1990;85:159-64. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991; 43:109-42. Zayek M, Cleveland D, Morin FC III. Treatment of persistent pulmonary hypertension in the newborn lamb by inhaled nitric oxide. J PEDIATR 1993;122:743-50. Berger JI, Gibson RL, Redding G J, Standaert TA, Clarke WR, Truog WE. Effect of inhaled nitric oxide during group B streptococcal sepsis in piglets. Am Rev Respir Dis 1993; 147:1080-6. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-20. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical response to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J PEDIATR 1993;123:103-8. Curtis J, O'Neill JT, Pettett G. Endotracheal administration of tolazoline in hypoxia-induced pulmonary hypertension. Pediatrics 1993;92:403-8. Walmrath D, Schneider T, Pilch J, Grimminger F, Seeger W. Aerosolised prostacyclin in adult respiratory distress syndrome. Lancet 1993;342:961-2. Wolfson MR, Greenspan JS, Shaffer TH. Pulmonary administration of priscoline by perfluorochemical liquid ventilation: reversal of induced-pulmonary hypertension and hypoxemia [Abstract]. Pediatr Res 1992;31:229A.