Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide

FETAL AND NEONATAL MEDICINE

Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide John P. Kinsella, MD, Steven R. Neish, MD, D. D u n b a r Ivy, MD, Elizabeth Shaffer, MD, a n d Steven H. A b m a n , MD From the Department of Pediatrics, Divisions of Neonatology, Cardiology, and Pulmonary Medicine, Children's Hospital and University of Colorado School of Medicine, Denver We studied the e f f i c a c y of low-dose nitric o x i d e inhalation in nine consecutive patients with severe persistent pulmonary hypertension of the newborn (PPHN) who were c a n d i d a t e s for e x t r a c o r p o r e a l m e m b r a n e o x y g e n a t i o n (ECMO). All patients had marked h y p o x e m i a despite aggressive ventilator m a n a g e m e n t and e c h o c a r d i o g r a p h i c e v i d e n c e of pulmonary hypertension. Associated diagnoses included m e c o n i u m aspiration syndrome (3 patients), sepsis (3 patients), and c o n g e n i t a l d i a p h r a g m a t i c hernia (2 patients). Infants were initially treated with inhaled nitric o x i d e at 20 ppm for 4 hours and then at 6 ppm for 20 hours. In all infants, o x y g e n a t i o n promptly improved (arterial/alveolar o x y g e n ratio, 0.077 _ 0.016 at baseline vs 0.193 • 0.030 at 4 hours; p <0.001) without a d e c r e a s e in systemic b l o o d pressure. Sustained improvement in o x y g e n a t i o n was a c h i e v e d in eight patients treated with inhaled nitric o x i d e for 24 hours at 6 ppm (arterial/alveolar o x y g e n ratio, 0.270 • 0.053 at 24 hours; p <0.001 vs baseline). One patient with overwhelming sepsis had an initial improvement of o x y g e n a t i o n with nitric o x i d e but required ECMO for multiorgan and c a r d i a c dysfunction. We c o n c l u d e that low doses of nitric o x i d e cause sustained clinical improvement in severe PPHN and may reduce the need for ECMO, However, i m m e d i a t e availability of ECMO is important in selected cases of PPHN complic a t e d by severe systemic h e m o d y n a m i c collapse. (J PEDIATR1993;123:103-8)

Vasodilator drug therapy in persistent pulmonary hypertension of the newborn has been limited by the lack of pharmacologic agents that cause selective and sustained pulmonary vasodilation without adverse systemic vascular effects.i, 2 Two recent reports have suggested the potential utility of inhaled nitric oxide in the management of severe Supported in part by grants HL-01932, HL-41012, and HL-46481 from the National Institutes of Health, Bethesda, Md., and the Bugtler Physician-Scientist Training Program. Submitted for publication Dec. 22, 1992; accepted March 3, 1993. Reprint requests: John P. Kinsella, MD, Divisionof Neonatology, Box B-070, Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218-1088. Copyright | 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/23/46917

PPHN. 3,4 Roberts et al. 3 found that brief exposure (30 minutes) to 80 ppm NO in infants with PPHN increased See commentary, p. 76.

CDH ECMO HFOV NO NO2 OI PPHN

Congenital diaphragmatic hernia Extracorporeal membrane oxygenation High-frequency oscillatory ventilation Nitric oxide Nitrogen dioxide Oxygenation index Persistent pulmonary hypertension of the newborn

arterial oxygen saturation; however, in all but one patient, this response was not sustained when therapy with NO was

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discontinued. Moreover, potential oxidant injury from the intrapulmonary production of toxic NO products in the immature lung warrants the use of the lowest effective concentration of NO. We previously reported acute improvement in oxygenation in severe PPHN with inhaled NO at doses as low as 10 ppm. 4 In a small number of patients, prolonged administration of low doses of NO (6 ppm) caused sustained improvement in oxygenation in infants with PPHN refractory to conventional therapy. 4 We now extend our previous report by examining the response to low-dose inhalational NO therapy (6 ppm) in nine consecutive patients with severe respiratory failure and PPHN refractory to conventional therapy. METHODS

Subjects. Nine consecutive patients with severe PPHN who were candidates for extracorporeal membrane oxygenation were enrolled in this study. Patients were eligible if they had severe respiratory failure and echocardiographic evidence of PPHN and met criteria for ECMO therapy. The prerequisite for ECMO in our institution is either a combination of factors (including birth weight >2000 gm, gestational age >34 weeks, absence of congenital heart defect or central nervous system disease, and severe refractory hypoxemia [sustained oxygenation index >40] [OI = Mean airway pressure x Fractional inspired oxygen X 100/Arterial oxygen tension]) or an acute clinical deterioration, with arterial oxygen tension <40 despite maximal medical management. These criteria are similar to those of other ECMO centers. 5 Study design. The study was approved by the institutional review board of Children's Hospital and, under a sponsorinvestigator Investigational New Drug exemption, by the U.S. Food and Drug Administration. Patients were enrolled after informed consent was obtained from the parents. At enrollment, baseline echocardiographic measurements and postductal arterial blood samples were drawn for determination of pH, blood gas tensions, and methemoglobin saturation immediately before treatment with NO. Two-dimensional, M-mode, and Doppler echocardiographic studies were performed with a Sonos 1000 system (HewlettPackard Co., Palo Alto, Calif.) by using a 5 M H z phasedarray transducer. The diagnosis of pulmonary hypertension was based on standard echocardiographic criteria. 6 The NO gas (Airco Inc., Riverton, N.J.) used in this study was certified at a concentration of 450 ppm NO (chemiluminescence method, balance N2) with <1% contamination by other oxides of nitrogen. The NO gas was introduced into the afferent limb of the ventilator circuit by using a specially designed adapter fitted within 25 cm of the endotracheal tube, thus mixing the NO gas with the fixed flow rate of circuit gas. The resulting concentrations of in-

The Journal o f Pediatrics July 1993

haled N O were verified on line by using chemiluminescence (Thermo Environmental Instruments, Franklin, Mass.). In some patients, NO was delivered during high-frequency oscillatory ventilation with minor modifications of the ventilator circuit. Nitric oxide was initially administered at 20 ppm for 4 hours; the dose was decreased to 6 ppm for the following 20 hours. Arterial blood gas tensions, methemoglobin levels, and systemic arterial blood pressure were recorded at baseline, at 15, 30, 60, and 90 minutes, and at 4, 12, and 24 hours. At 24 hours, therapy with NO was discontinued. If adequate oxygenation was not sustained after discontinuation of NO (arterial/alveolar oxygen ratio, <0.10), administration of NO was started again for another 12- to 24-hour period. Study variables (e.g., arterial blood gas values, systemic arterial pressure) were analyzed by using analysis of variance for repeated measures. The Fisher least significant difference test was employed for post hoc comparisons. The level of statistical significance was set at p <0.05. Data are expressed as mean _+ SEM. RESULTS Each infant had severe hypoxemia and echocardiographic evidence of pulmonary hypertension at enrollment despite aggressive treatment with mechanical ventilation and 100% inspired 02. Mean gestational age and birth weight were 38 _+ 1 weeks and 3221 ___ 188 gins, respectively. In addition to severe PPHN, three patients had meconium aspiration syndrome, three patients had evidence of severe sepsis, and two patients had congenital diaphragmatic hernia. Five patients had acute deterioration of clinical status with arterial oxygen tensions ~<37 mm Hg before treatment with NO. One patient had severe perinatal asphyxia associated with uterine rupture before delivery. All patients were treated with catecbolamines (dopamine, dobutamine) before treatment with NO; two patients had previous trials of pulmonary vasodilator drugs (sodium nitroprusside, tolazoline). The response to these vasodilators was characterized by only transient improvement in oxygenation (two of two), systemic hypotension (one of two), or both. Five patients were initially treated with HFOV (model 3100A ventilator; Sensormedics Corp., Yorba Linda, Calif.) and had transient improvement in oxygenation, but subsequently they met ECMO criteria and were candidates for treatment with NO. Marked improvements in oxygenation occurred with the start of NO inhalation, and this improvement was sustained for the entire 24-hour period at NO concentrations of only 6 ppm (Fig. 1). The O1 at the beginning of treatment with NO was 77 +_ 25. Inhalation of NO (20 ppm) decreased OI by 58% after 30 minutes (32 + 8; p <0.001). The Table

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Kinsella et al.

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T a b l e . Arterial pH, partial pressure of arterial oxygen and carbon dioxide, arterial/alveolar oxygen ratio, oxygenation index, mean arterial blood pressure, and heart rate

Study period Baseline At 24 hr (6 ppm NO)

Pa02 (mm Hg)

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43 _+ 9 0.077 ___0.016 111_+15" 0.270_+0.053*

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174 _+ 8 152+ 12:~

58 _+ 7 56•

Values expressed as mean • SEM; n = 8. Pao2, Partial pressure of arterial oxygen;a/A02, arterial/alveolar oxygenratio; Fro2,fractional inspired oxygen;Pac02, partial pressure of arterial carbon dioxide; BP~t, mean arterial blood pressure.

*p <0.001 compared with baseline. tp <0.01 compared with baseline. ~:p <0.05 compared with baseline.

shows arterial blood gas values, arterial/alveolar oxygen ratio, OI, fractional inspired oxygen, mean arterial blood pressure, and heart rate at baseline and at 24 hours of treatment with N O . Improvements in oxygenation were noted with an increase in arterial/alveolar O2 ratio >350% during the 24-hour treatment period. Systemic arterial blood pressure did not change during treatment. Heart rate decreased from 174 + 8 to 152 _+ 12 beats/rain (p <0.05). Baseline echoeardiographic measurements were performed within 30 minutes of institution of treatment with N O . Five patients had high-velocity tricuspid insufficiency jets, and five patients had connections between the pulmonary and systemic circulations that allowed estimation of relative resistances; in these patients, predominantly rightto-left shunting was observed. In most patients, the tricuspid insufficiency jet was not quantifiable after 24 hours of

treatment with NO; however, in three patients the ductus arteriosus was patent, and Doppler measurements showed predominantly left-to-right shunting. Five patients had adequate resolution of P P H N and sustained improvement in oxygenation after only 24 hours of low-dose therapy with N O . However, one patient had severe sepsis associated with progressive deterioration of left ventricular performance. Despite initial improvement in oxygenation with inhalational NO, this patient required E C M O for cardiac support and had a prolonged E C M O course complicated by severe myocardial stun syndrome. Two other patients with sepsis had sustained improvement during treatment with N O and progressive improvement in hemodynamic status leading to complete recovery. The patient with severe asphyxia responded to N O with marked improvement in oxygenation and resolution of P P H N ;

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Kinsella et al.

The Journal of Pediatrics July 1993

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Fi9. 2. Changes in OI in responseto discontinuingand restarting NO inhalation therapy in a patient with congenital diaphragmatic hernia. By 72 hours, NO could be discontinuedwithout significant worseningof oxygenation, suggesting resolution of reactive pulmonary hypertension.

however, because of severe, persistent central nervous system injury after cardiopulmonary recovery, the infant later died after support ~vas withdrawn. To assess the need for continued treatment with NO, we discontinued administration of NO at 24 hours of treatment in all patients. In three patients, PPHN persisted as evidenced by acute deterioration in oxygenation on discontinuation of NO. When NO was started again, oxygenation rapidly improved and OI returned to the baseline level. Two patients with CDH were treated. Before treatment with NO, the highest postductal values for arterial oxygen tension were 52 mm Hg for the first patient and 57 mm Hg for the second patient, despite maximal mechanical ventilation with 100% oxygen. The effects of low-dose treatment with NO for one patient are shown in Fig. 2; the OI decreased during 72 hours of treatment, causing stable oxygenation for the entire preoperative and postoperative course. Discontinuation of NO therapy at 24 and at 48 hours resulted in marked worsening of oxygenation, which responded well to the reinstitution of therapy with NO (Fig. 2). Metbemoglobin levels increased from the baseline level of 0.87% + 0.03% at baseline to 1.44% _+ 0.09% at 4 hours of NO inhalation (p <0.001). However, as the concentration

of inhaled NO was reduced, the percentage of methemoglobin fell. Methemoglobin concentration did not differ from baseline at the 24-hour time point (0.98% +_ 0.07%). One patient with meconium aspiration syndrome had radiographic changes of chronic lung disease and required supplemental oxygen at 30 days of age (~<0.1 L 02 per minute by nasal cannula to achieve arterial oxygen saturation >~92%). This patient was successfully weaned from supplemental oxygen at 2 months of age. The two patients with CDH also required supplemental oxygen at 30 days of age (0.l L 02 per minute by nasal cannula) and continue to receive supplemental oxygen at 2 and 6 months of age. DISCUSSION This study extends the findings of our preliminary report of improved oxygenation in infants with PPHN during treatment with NO 4 and provides the rationale for further study of the role of NO in the treatment of PPHN. Most patients in this study recovered after 24 hours of inhalational NO treatment; oxygenation in the absence of NO was adequate with conventional treatment alone. However, it is possible that extending therapy in all patients to 48 to 72 hours would lead to even more rapid resolution of PPHN. All patients treated with NO in this study had marked

The Journal of Pediatrics Volume 123, Number 1

improvement in oxygenation in response to very low doses of NO. However, one patient required ECMO for cardiac support because of progressive cardiac failure associated with overwhelming sepsis. This finding emphasizes the importance of immediate availability of ECMO for patients treated with alternative therapies and highlights the role of cardiac dysfunction in severe neonatal pulmonary hypertension. 6 The response shown by infants with CDH suggests the utility of this therapy for perioperative management of this defect. The use of low-dose NO therapy improved oxygenation and likely attenuated the lability that characterizes the postoperative course in many patients with CDH. More experience is needed in the use of NO in CDH, but this strategy may prove useful in the preoperative differentiation of lethal puhnonary hypoplasia versus reactive pulmonary hypertensi0n. 7, s Previous studies have shown that inhaled NO lowers pulmonary vascular resistance in adult animals during acute pulmonary vasoconstriction induced by hypoxia, U44619 (a thromboxane analog), or heparin-protamine. 9,1~ Inhalational NO is als0 a potent dilator of the immature pulmonary circulation in the ovine fetus. 11 Recently recognized as the endothelium-derived relaxing factor, NO directly stimulates cyclic guanosine monophosphate in vascular smooth muscle, causing relaxation. 12, 23 Endogenous production of NO plays a major role in regulation of vascular tone in the adult pulmonary circulation.~4 Recently, enhanced activity of the endothelium-derived relaxing factor (i.e., NO) has been shown to contribute to the normal decline in pulmonary vascular resistance at birth. 15 Although causal mechanisms of P P H N are poorly understood, we speculate that decreased production of endogenous NO Contributes to the failure of postnatal pulmonary vascular adaptation. Severe hypoxia or hypertension may directly impair release of the endothelium-derived releasing factor, NO.16 Alternatively, endogenous production of NO may be normal; increased pulmonary vascular resistance may be caused by the production of vasoconstrictor mediators (e.g., leukotrienes, platelet-acfivating factor, or endothelinl7), and the effects of pharmacologic doses of exogenous NO in the treatment of PPHN may be unrelated to decreased endogenous production of N O . When administered by inhalation, NO diffuses to vascular smooth muscle from the alveolar side. Rapid and avid binding of N O by hemoglobin decreases its availability for causing systemic vasodilation, allowing for selective pulmonary vasodilation.9, 18 In our patients, selective lowering of pulmonary vascular resistance decreased right-to-left shunting, thereby increasing pulmonary blood flow and improving oxygenation. In addition, because NO is administered by inhalation, it will most effectively dilate pulmonary

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blood vessels that are associated with the best-ventilated lung units, enhancing ventilation-perfusion matching. Although marked right-to-left shunting is the major cause of hypoxemia in PPHN, some newborn infants also can have altered ventilation-perfusion as a result of parenchymal lung disease (e.g., meconium aspiration). Lg,20 In this study, we used <20 ppm doses of NO because of the demonstrated efficacy of low-doses of inhaled NO in animal experiments, 9 preliminary observations of efficacy in treating PPHN at this dose, 4 and the recommended exposure limit set by the National Institute for Occupational Safety and Health (25 ppm). 21 Although this study was designed to investigate the hemodynamic effects o f inhaled NO within "nontoxic" concentrations, concerns regarding potential toxicity remain. The major toxic effects include methemoglobinemia, conversion to nitrogen dioxide, and increased oxidant stress from the production of peroxynitrite. 22 Despite the absence of increased methemoglobin concentrations in these patients, longer treatment at higher concentrations may increase this risk. Although we monitored for NO2 formation in delivered gas, formation of NO2 and peroxynitrite within the lung remains a potential problem. However, rabbits exposed to 43 ppm of NO and 3.6 ppm of NOz for 6 days had no histopathologic lung lesions.23 More in vivo studies examining potential toxicities of NO and defining safe time and dosage ranges are needed, not only in healthy animals but also in immature animals with decreased host antioxidant defenses or with lung inflammation. Unlike the effects in primary pulmonary hypertension in adults, in neonates lowering pulmonary vascular resistance for relatively brief periods (hours to a few days) is often sufficient for successful resolution of pulmonary hypertension. in five patients, we combined HFOV with inhalational NO therapy because of the failure of HFOV alone to sustain clinical improvement. When HFOV has been used to recruit atelectatic lung and sustain lung volume, marked improvements in oxygenation have been demonstrated in infants with severe respiratory failure. 24, 25 In one study, 24 46% of ECMO candidates treated with HFOV recovered without the need for ECMO. Although the respective roles of HFOV and NO are unclear, some patients appear to benefit from combination treatment. The treatment of PPHN and severe respiratory failure demands meticulous attention to the nature of the underlying pulmonary parenchymal disease in addition to the hemodynamic perturbations that characterize PPHN. Further studies are required to better define the roles of HFOV and N O in the treatment of PPHN. Our cumulative experience now includes 15 patients with severe PPHN who were treated with low-dose NO therapy as an alternative to ECMO. Of this group, 13 patients re-

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covered without E C M O , and 9 patients required only 24 hours of therapy with N O . However, two patients required E C M O because of severe cardiac dysfunction associated with sepsis, and four patients (including both patients with C D H ) required >24 hours of treatment with NO. W e conclude that inhaled N O improves oxygenation in newborn infants with severe P P H N . These preliminary findings begin to define physiologic responses and optimal strategies for the use of inhaled NO, and provide the rationale for controlled clinical trials using this unique vasodilator. However, follow-up studies are important to identify potential long-term toxic effects. Moreover, the prudent application of this therapy requires vigilant attention to labile hemodynamic status in patients with sepsis, with immediate availability of E C M O in cases complicated by severe disturbances in cardiac performance. We are grateful for the support of Adam A. Rosenberg, MD, J. Schmidt, RRT, J. Griebel, RRT, D. Swanton, RRT, and the neonatology section of the University of Colorado School of Medicine. REFERENCES

1. Stevenson DK, Kasting DS, Darnall RA, et al. Refractory hypoxemia associated with neonatal pulmonary disease: the use and limitations of tolazoline. J PEDtATR 1979;95:595-9. 2. Drummond WH, Gregory G, Heymann MA, et al. The independent effects of hyperventilation, tolazoline, and dopamine on infants with persistent pulmonary hypertension. J PEDIATR 1981;98:603-11. 3. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9. 4. Kinsella JP, Neish SR, Shaffer E, Abman AH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-20. 5. Bartlett RH, Gazzaniga AB, Toomasian J. Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failu r e - 1 0 0 cases. Ann Surg 1986;204:236-45. 6. Kinsella JP, McCurnin DC, Clark RH, et al. Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO. J Pediatr Surg 1992;27:44-7. 7. O'Rourke PP, Vacanti JP, Crone RK, Fellows K, Lillehei C, Hougen TL Use of the postductal PAO2 as a predictor of pulmonary vascular hypoplasia in infants with congenital diaphragmatic hernia. J Pediatr Surg 1988;23:904-7. 8. Newman KD, Anderson KD, Van Meurs K, Parson S, Loe W, Short B. Extracorporeal membrane oxygenation and congenital diaphragmatic hernia: should any infant be excluded? J Pediatr Surg 1990;25:1048-53. 9. Frostell C, Fratacci M, Wain JC, et al. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47.

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10. Fratacci MD, Frostell CG, Chen TY, Wain JC, Robinson DR, Zapol WM, Inhaled nitric oxide: a selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep. Anesthesiology 1991;75:990-9. 11. Kinsella JP, McQueston J, Rosenberg A A, Abman SH, Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. Am J Physiol 1992;32:H87580. 12. Ignarro LJ. Biological actions and properties of endothelialderived nitric oxide formed and released from artery and vein. Circ Res 1989;65:1-21. 13. Palmer RMJ, Ferrige AG, Moncada SA. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6. 14. Cremona G, Dinh Xuan AT, Higgenbottam TW. EDRF and the pulmonary circulation. Lung 1991 ;169:185-202. 15. Abman SH, Chatfield BA, Hall SL, McMurtry IF. Role of EDRF during transition of pulmonary circulation at birth. Am J Physiol 1990;259:H1921-7. 16. Rodman DM, Yamaguchi T, Hasanuma K, O'Brien RF, McMurtry IF. Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery. Am J Physiol 1990;258 :L20714. 17. Rosenberg AA, Kennaugh J, Koppenhafer SL, Loomis M, Abman SH. Elevated immunoreactive endothelin-1 levels in infants with persistent pulmonary hypertension of the newborn. J PEDIATR(in press). 18. Borland CDR, Higenbottam TW. A simultaneous single breath measurement of pulmonary diffusing capacity with nitric oxide and carbon monoxide. Eur Respir J 1989;2:56-63. 19. Krauss AN, Soodalter J, Auld PAM. Adjustment of ventilation and perfusion in the full-term normal and distressed neonate as determined by urinary alveolar nitrogen gradients. Pediatrics 1971;47:865-9. 20. Truog WE, Lyrene RK, Standaert TA, et al. Effects of PEEP and tolazoline infusion on respiratory and inert gas exchange in experimental meconium aspiration. J PEDIATR 1982;100: 284-90. 21. Centers for Disease Control. Recommendations for occupational safety and health standards. MMWR 1988;37:$7-21. 22. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by pcroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990;87:1620-4. 23. Hugod C. Effect of exposure to 43 ppm nitric oxide and 3.6 ppm nitrogen dioxide on rabbit lung. Int Arch Occup Environ Health 1979;42:159-67. 24. Carter JM, Gerstmann DR, Clark RH, et al. High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the treatment of neonatal respiratory failure. Pediatrics 1990;85:159-64. 25. Kinsella JP, Gerstmann DR, Clark RH, et al. HFOV vs. IMV: early hemodynamic effects in the premature baboon with HMD. Pediatr Res 1991;29:160-6.