Nitric oxide is superior to prostacyclin for pulmonary hypertension after cardiac operations

Nitric Oxide Is Superior to Prostacyclin for Pulmonary Hypertension After Cardiac Operations Allan P. Goldman, MRCP, Ralph E. Delius, MD, John E. Deanfield, FRCP, and D u n c a n J. Macrae, FRCA Cardiothoracic Unit, Great Ormond Street Hospital for Children, London, United Kingdom

Background. Severe pulmonary hypertension is still a cause of morbidity and mortality in children after cardiac operations. The objective of this study was to compare the vasodilator properties of inhaled nitric, oxide, a novel pulmonary vasodilator, and intravenous prostacyclin in the treatment of severe postoperative pulmonary hypertension. Methods. Thirteen children (aged 3 days to 12 months) with severe pulmonary hypertension after cardiac operations were given inhaled nitric oxide (20 ppm x 10 minutes) and intravenous prostacyclin (20 ng" kg -~ • rain x 10 minutes) in a prospective, randomized cross-over study. Results. Both nitric oxide and prostacyclin resulted in a

reduction in puhnonary arterial pressure, although the mean p u l m o n a r y arterial pressure was significantly lower during nitric oxide therapy (28.5 + 2.9 m m Hg) than during prostacyclin therapy (35.4 -+ 2.1 m m Hg; p < 0.05). The mean pulmonary to systemic arterial pressure ratio was also significantly lower during nitric oxide than prostacytin administration (0.46 -+ 0.04 versus 0.68 + 0.05; p < 0.01), due mainly to only prostacyclin lowering systemic blood pressure. Conclusions. Inhaled nitric oxide was a more effective and selective pulmonary vasodilator than prostacyclin and should be considered as the preferred treatment for severe postoperative pulmonary hypertension.

evere life-threatening reactive p u l m o n a r y h y p e r t e n sion is a significant cause of morbidity a n d m o r t a l i ~ in children after corrective operations for congenital heart disease [1]. This complication may occur despite technically successful operation and active conventional m a n a g e m e n t including the administration of a high fractional inspired oxygen concentration, hyperventilation, sedation, muscle paralysis, and support with inotropic and vasodilator drugs [1]. Intravenous vasodilator drugs are an important part of this m a n a g e m e n t protocol, with prostacyclin being considered one of the p u l m o n a r y vasodilators of choice for severe p u l m o n a r y h y p e r t e n sion. Unfortunately, the intravenous vasodilators lack specificity for the p u l m o n a r y circulation and their use is frequently limited by their systemic hypotensive effects. Inhaled nitric oxide (INO) has recently e m e r g e d as a novel and selective p u l m o n a r y vasodilator 12-7]. We [7l have previously d e m o n s t r a t e d a m a r k e d selective pulm o n a r y vasodilator response to very low dose INO in infants with p u l m o n a r y hypertension after cardiac operations. We now report a study comparing the effectiveness of INO and intravenous prostacyclin as p u l m o n a r y vasodilators in the treatment of severe p u l m o n a r y hypertension in children after corrective heart operations for congenital heart disease.

Material and Methods

S

Presented at the Thirty-first Annual Meeting of The Society of Thoracic Surgeons, Palm Springs, CA, Jan 30-Feb 1, 1995. Address reprint requests to Dr Goldman, Cardiac Intensive Care Unit, Great Ormond Street Hospital tor Children, Great Ormond St, London WCIN 3JH, United Kingdom. © 1995 by The Societv of Thoracic Surgeons

(Ann Thorac Surg 1995;60:300-6)

Patient Population Patients in w h o m severe postoperative p u l m o n a r y hypertension d e v e l o p e d within 5 days of corrective operation for congenital heart disease were recruited to this study. The b r o a d catagories of congenital heart lesions included left-to-right shunt lesions and lesions causing obstruction to p u l m o n a r y venous drainage. Severe postoperative pulmonary, hypertension was defined either as a mean p u l m o n a r y arterial pressure (PAP) greater than two thirds the systemic arterial pressure (SAP) or p u l m o nary hypertension severe enough to cause c a r d i o p u l m o nary c o m p r o m i s e as reflected by either hypoxia, hypotension, or one or more p u l m o n a r y hypertensive crises (mean PAP > SAP). Between D e c e m b e r 1993 a n d D e c e m b e r 1994 t h i r t e e n children, 8 girls a n d 5 boys, fulfilled the a b o v e criteria for severe p u l m o n a r y h y p e r t e n s i o n after r e c e i v i n g high i n s p i r e d oxygen h y p e r v e n t i l a t i o n , s e d a t i o n with m o r p h i n e (20 to 40 g g / k g p e r hour) a n d m i d a z o l a m (2 to 6 /~g/kg p e r minute), a n d m u s c l e p a r a l y s i s with v e c u r o n i u m . The use of i n o t r o p i c a g e n t s a n d i n t r a v e nous vasodilators, o t h e r t h a n prostacyclin, was not r e s t r i c t e d p r i o r to trial entry. The preoperative cardiac diagnoses and d e m o g r a p h i c details are shown in Table 1. The study was a p p r o v e d by our Research Ethics Committee in D e c e m b e r 1993, a n d informed consent was obtained from the parents of the patients. 0003-4975/95159.50 0003-4975(95)00408-D

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Table 1. Baseline Characteristics and Outcome o f the 13 Patients Studied

Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13

Age

Diagnosis

Medication

Outcome

2 mo 3 days 3 mo 2 mo 5 mo 9 mo 7 mo 1 mo 12 mo 3 days 4 mo 9 mo 10 mo

VSD TAPVD AVSD, Down syndrome TAPVD AVSD, hypoplastic LV, AVV AVSD, Down syndrome AVSD TAPVD Mitral stenosis TAPVD AVSD, Down syndrome VSD AVSD, Down syndrome

Dop, Norepi, Enox Dop, NTG Dop, NTG, Enox Dop, Dob, NTG Dob, Epi, Enox Dop, NTG Dop, Epi, NTG NTG Dob, Epi, Norepi, Enox Dob Isop, Enox Enox, NTG, Dop Dop, Epi, NTG, Enox

Survived Survived Survived Survived Died Died Survived Died Died Survived Survived Survived Survived

AVSD = atrioventricular septal defect; A~v*' atrioventricularvalve; Dob dobutarnine; Dop - dopamine; Enox= enoximone; Epi = epinephrine; Iso = isoprenaline; LV left ventricle; Norepi= norepinephrine; NTG nitroglycerin; TAPVD totalanomalous pulmonary venous drainage; VSD ventricular septal defect.

I n t e n s i v e Care

Patients were recruited at the time w h e n the attending physician r e q u e s t e d intravenous prostacyclin therapy for severe postoperative p u l m o n a r y hypertension. After recruitment, patients were r a n d o m l y assigned to receive either INO (20 p p m × 10 minutes) or intravenous prostacyclin (20 ng/kg per minute × 5 minutes). This was followed by a 10-minute period in which both agents were administered simultaneously, and a final 10 minutes in which the alternative agent was administered alone (Fig 1). T r e a tm e n t other than INO or prostacyclin was not altered during the course of the study. Muscle paralysis and deep sedation were continued during the period of the study and during the early course of INO therapy (for at least 24 hours). Each patient was contin-

IntravenousProstacyclinI st (n=8) 2O Pr°stacyclin ' O~ ~]~C I PC I O1~_~0 INO (ng/kg/min) I~1O IN (ppm)

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Inhalednitricoxide1st (n=5) INO ~ 0

10

I 20

31

PC

Time(minutes)

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40

Fig 1. The study protocol consisted of 3 phases: in phase 1, patients were randomly assigned to either inhaled nitric oxide ([NO) or in travenous prostacyclin (PC). In phase ~,9 both/NO and PC were administered simultaneously. In phase 3, the alternate agent was administered alone. Arrows indicate times when measurements were recorded.

ued on the agent providing the greatest h e m o d y n a m i c i m p r o v e m e n t during the study.

Nitric Oxide Dosage and Administration

Dose and sequence of INO administration are shown in Figure 1. Nitric oxide gas, obtained in a mixture of nitrogen at 1,000 p p m N O (BOC-Special Gases, Surrey, England), was delivered via a calibrated N 2 flow m e t e r (KDG Instruments, Surrey, England) into the inspiratory limb of an infant ventilator as previously described [8]. The concentrations of inspired N O and its toxic oxidative product nitrogen dioxide were analyzed by chemiluminescence (model 42; T h e r m o En v i r o n m en t al Instruments, Franklin, MA) from samples of circuit gas obtained from a point 25 cm distal to the patient. The analyzer was calibrated at 0 and 10 p p m N O and 0 and 4 p p m N O 2 before each study. Patients who r e s p o n d e d more favorably to INO were left on continuous I N O therapy. Daily reverse d o s e response studies were conducted allowing the INO dose to be reduced gradually as clinical i m p r o v e m e n t progressed. The muscle paralysis and deep sedation were w e a n e d after the patients had had at least a 24-hour period of stability (no car d i o p u l m o n ar y c o m p r o m i s e or p u l m o n a r y hypertensive crises) on low-dose INO therapy (<10 ppm). The dose of INO and sedation were then w e a n e d simultaneously as tolerated, at the discretion of the attending physician. All the patients were, however, weaned from the I N O therapy before tracheal extubation. M e t h e m o g l o b i n levels were m e a s u r e d after 30 minutes of exposure to INO. S u b s e q u e n t levels were m o n i t o r e d every 12 hours during ongoing INO therapy or more frequently if levels rose to more than 4%.

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Prostacyclin Dosage and A d n l i n i s t r a t i o n

Prostacyclin was infused continuously into a central vein at an initial dose of 5 n g . k g , rain ~, increasing incrementally in steps of 5 ng/kg per m i n u t e to a dose of 20 n g ' k g l ' m i n 1. H e m o d y n a m i c variables were measured after 5 minutes at this dose, both alone and together with INO administration. The infusion of prostacylin was stopped if the mean systemic arterial pressure fell by more than 25% despite the administration of 15 mL/kg of colloid.

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Statistical A n a l y s i s

Data are presented as m e a n s = standard errors. The paired Student's t test was used to compare the hemodynamic and arterial oxygen tension (PaO2) differences between INO therapy and intravenous prostacyclin therapy, as well as betw'een INO alone and 1NO and prostacyclin administered simultaneously. A p value less than 0.05 was taken as significant. To avoid using multiple t tests, means and 95'Y confidence intervals (CI) were used to summarize changes between baseline and INO, and between baseline and prostacyclin. Results

In this study, only INO led to selective p u l m o n a ~ , vasodilatation with an associated i m p r o v e m e n t in oxygenation. H e m o d y n a m i c and oxygenation data are shown for grouped data in Figures 2 and 3 a n d for individual patients in Figure 4. Hemodynamics

Both drugs caused a reduction in mean PAP from baseline, INO by 33°/i, (95% CI, 24% to 51%) and prostacyclin by 16% (95% CI, - 4 % to 38%) (see Fig 3). Mean PAP was significantly lower with INO than prostacyclin (28.2 + 2.9 versus 35.4 ÷ 2.1 m m Hg; p < 0.01) (see Fig 2). Only intravenous prostacyclin resulted in a reduction in the m e a n SAP (95% C1 for the changes in SAP from baseline with prostacyclin, 4 to 10 m m Hg; and with INO, 2 to +7 m m Hg) (see Fig 3). The systemic hypotensive effect of prostacyclin was so marked in 1 patient (>25% reduction in m e a n SAP from 42 to 28 m m Hg with 10 n g . k g ~ . m i n ~ prostacyclin, u n r e s p o n s i v e to a

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The following variables were recorded at baseline and after each therapy: PAP, SAP, m e a n PAP/SAP ratio, and PaO 2. The PAP was monitored continuously in 9 of the 13 patients studied via an indwelling p u l m o n a r y artery catheter (3F), which had b e e n inserted u n d e r direct vision into the proximal main p u l m o n a r y artery, at the completion of the surgical repair. The SAP was continuously monitored via an indwelling catheter. Both the p u l m o n a r y and systemic catheters were connected to high-pressure tubing, fluid-filled transducers, and the Merlin Component Monitoring System (Hewlett-Packard, Boeblingen, Germany). Arterial samples for blood gas analysis were withdrawn from the indwelling arterial catheters.

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Outcome Measurements

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15 mL/kg colloid challenge) that it necessitated the termination of therapy. Only INO resulted in selective p u l m o n a r y vasodilation, as demonstrated by a marked fall in the m e a n PAP/SAP ratio of 38% (95% CI, -31% to -45%) from baseline (see Fig 3). Prostacyclin alone did not lower the mean PAP/SAP ratio from baseline (95°/',, CI for the changes in the PAP/SAP ratio from baseline with prostacyclin, 0.3 to +0.16) (see Fig 3). The m e a n PAP/SAP ratio was significantly lower with INO compared with prostacyclin (0.46 _+ 0.04 versus 0.68 _~ 0.05; p < 0.01), but not significantly different from that of INO and prostacyclin administered simultaneously (0.53 _+ 0.06) (see Figs 2, 4). The fall in the PAP/SAP ratio with INO was not d e p e n d e n t on the continuation of the prostacyclin administration in those patients who received prostacyclin first. Oxygenation

Inhaled nitric oxide improved the m e a n PaO 2 by 70% from baseline (95% CI, 39% to 101%) (see Fig 3). Prostacyclin was not associated with an i m p r o v e m e n t in oxygenation (95% CI for the changes in PaO 2 from baseline with prostacyclin, - 2 to +3 m m Hg). The m e a n PaO2

GOLDMANET AL NITRIC OXIDEVERSUSPROSTACYCLIN

Ann Thorac Surg 1995;60:300-6

measured during 1NO administration was significantly greater than d u r i n g the prostacyclin infusion (20.1 ÷ 2.9 versus 13 + 2.0 m m Hg; p < 0.01) (see Fig 2).

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I n h e r e n t in the design of this study was that each patient would be continued on the treatment providing the greatest benefit to the patient. All 13 patients studied had a more favorable h e m o d y n a m i c response to INO than prostacyclin a n d were therefore continued on this treatm e n t for 1 to 17 days (median, 6 days). Nine of the 13 patients continued to improve with INO a n d survived to discharge from hospital. Four patients died even though they had also demonstrated an initial i m p r o v e m e n t with INO. Only 1 patient died of acute p u l m o n a r y hypertension. The patient had u n d e r g o n e a mitral valve replacement for severe mitral stenosis and had been successfully weaned from INO after 5 days of treatment. Unfortunately she died of a delayed-onset p u l m o n a r y hypertensive crisis 2 days later before INO therapy could be recommenced. The cause of death in the remaining 3 patients was not a result of ongoing pulmonary, hypertension. One patient died of an u n d e r l y i n g lung disease, the second of multiorgan failure, and the third of left ventricular failure due

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Paralysis and Sedation

Inhaled nitric oxide therapy did not appear to alter the dose or the duration of deep sedation required during the treatment of the patient's postoperative p u l m o n a r y hypertension. In all of the patients who were successfully weaned from INO, this was achieved before extubation. Toxicity

No toxic effects were noted during the INO therapy, except in 1 patient in whom the methemoglobin level transiently rose to 8%. This rapidly fell to less than 4% when the INO dose was reduced to 15 ppm. The NO 2 concentrations did not exceed 1.2 ppm. Comment The results of this study support the hypothesis that INO is a more selective p u l m o n a r y vasodilator than intravenous prostacyclin w h e n treating children with severe p u l m o n a r y hypertension after congenital heart operation. Oxygenation improved only with INO, despite both drugs reducing p u l m o n a r y artery pressures. This may be

304

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G O L D M A N ET AL NITRIC OXIDE VERSUS PROSTACYCLIN

explained by INO counteracting hypoxia-induced pulm o n a r y vasoconstriction and improving ventilationperfusion mismatch, which intravenous vasodilators have been shown to aggravate [4]. The improvements in hemodynamics and oxygenation observed with INO therapy were not augmented by the simultaneous administration of INO and prostacyclin, nor were they dependent on the continuation of prostacyclin administration in the patients who received prostacyclin first. Furthermore, no tolerance to the INO developed in the patients treated with long-term INO, nor was there any evidence of significant clinical toxicity at the doses used in this study. The precise etiology of acute increases in PAP and pulmonary vascular resistance after operation for congenital heart disease remains uncertain and the treatment empirical [1, 9-11]. Pulmonary hypertension complicating congenital heart disease is associated with both structural [12, 13] and functional impairment of the endothelium, with loss of local endothelium-derived relaxing factor-NO vasodilator activity [14]. Endothelial dysfunction is further exacerbated by the effects of cardiopulmonary bypass [15]. Prostacyclin and nitric oxide are both naturally occuring endogenous vasodilators produced by the endothelium. Prostacyclin leads to an elevation in cyclic adenosine monophosphate in the vascular smooth muscle cell [16], and nitric oxide activates guanylate cyclase [17, 18], both of which lead to vascular relaxation. Exogenous prostacyclin administered intravenously is accepted as one of the pulmonary vasodilators of choice for patients with severe pulmonary hypertension after heart operations [11]. Like all intravenous pulmonary vasodilators, however, it is limited in its use by its lack of specificity for the pulmonary vasculature and may result in systemic hypotension. Furthermore, the association of atrial or ventricular right-to-left shunt during pulmonary hypertensive crises leads to shunting of increased levels of intravenous vasodilators toward the systemic circulation, exacerbating the systemic hypotension [1]. Inhaled nitric oxide has the unusual property of being a selective pulmonary vasodilator. Inhaled nitric oxide exerts its action on the abluminal side of the arteriolar vascular smooth muscle, causing specific vasodilatation in ventilated areas of the lung, diffuses into the blood, and is then rapidly inactivated by avid binding to hemoglobin. The selectiv e pulmonary vasodilatory properties of INO have been demonstrated in adults with primary pulmonary hypertension [3] and acute respiratory distress syndrome I4], neonates with persistent pulmonary hypertension of the newborn [5], and children with corrected [71 and uncorrected [6] congenital heart disease. To compare these two agents we performed a randomized cross-over design study in which each patient received both drugs. Although a washout period between the two drugs would have been ideal, it was not thought to be ethically acceptable in patients with severe pulmonary hypertension. Furthermore, we have previously shown [7], in a similar group of patients, that the hemo-

dynamic responses of INO return rapidly to baseline when INO administration is discontinued. Bush and associates [11] have similarly demonstrated rapid dissipation of the vasodilator effects of prostacyclin with discontinuation of this therapy. The results of this study strongly support the hypothesis that INO is a selective p u l m o n a r y vasodilator whereas intravenous prostacyclin, although an effective pulmonary vasodilator, also causes systemic hypotension at the doses required to produce pulmonary vasodilatation. We believe this is principally due to the different routes of administration. Recently there have been reports of the selective pulmonary vasodilator properties of inhaled prostacyclin [19] in adults with acute respiratory distress syndrome and inhaled tolazoline [20] in sheep with hypoxiainduced pulmonary hypertension. The clin!cal potential of inhalational administration of these agents in the management of severe postoperative pulmonary hypertension after cardiac operations has, however, not been tested. It also remains to be seen whether these benefits from inhalational administration are sustained with continuous administration and whether there will be accumulation in the lung with systemic absorption, resulting in similar side effects to those observed with the intravenous route of administration.

Patient Outcome This study was not designed to compare the differences in clinical outcome between the two agents. Nonetheless, every patient studied had a more favorable hemodynamic response to INO and was therefore continued on this therapy for ongoing treatment of pulmonary hypertension. Nine of these critically ill patients showed a sustained clinical response to INO and recovered. No patients died of pulmonary hypertension while receiving INO. Although the n u m b e r of patients recruited to this study is small (n - 13), any advances in therapeutic strategies for treating this condition are important because severe postoperative pulmonary hypertension remains a life-threatening problem, which is paroxysmal in nature and potentially curable. A large, prospective, randomized, multicenter trial comparing INO with present conventional therapy is needed to assess the influence of INO on clinical outcome. This may, however, not be feasible because of the potential difficulty in recruiting sufficient numbers of patients and the ethical question of withholding a potentially life-saving treatment.

Toxicity Nitric oxide has potentially toxic effects related to its conversion to NO2, peroxynitrite, and methemoglobin. It appears to be safe in h u m a n s exposed to continuous administration of INO for periods of up to 2 months [4, 5, 7]. In this study the NO2 levels did not rise to more than 1.2 ppm. These levels are well within the recommendations of the Centers for Disease Control guidelines [211 for occupational exposure in healthy adults (NO2 less

Ann Thorac Surg 1995;60:300-6

t h a n 5 p p m for 8 hours). T h e r e are no g u i d e l i n e s for m a x i m a l e x p o s u r e limits of N O a n d N O 2 in children. W e h a v e t h e r e f o r e a d o p t e d a policy of titrating I N O levels to the m i n i m u m r e q u i r e d for effective t r e a t m e n t . In a prev i o u s s t u d y [7] w e s h o w e d this could be a c h i e v e d with I N O d o s e s as low as 2 p p m , a n d in the c u r r e n t s t u d y s o m e p a t i e n t s c o u l d be m a i n t a i n e d on doses as low as 300 ppb. O n e p a t i e n t h a d a t r a n s i e n t i n c r e a s e in m e t h e m o g l o b i n to 8%, w h i c h r e s p o n d e d to a r e d u c t i o n in the I N O dose. Levels of up to 10% to 20% are t o l e r a t e d by p a t i e n t s with congenital methemoglobinemia [221, w h e r e a s l e v e l s g r e a t e r t h a n 80% are i n v a r i a b l y fatal [23]. M e t h e m o g l o bin is not itself directly toxic, but it d o e s r e d u c e the o x y g e n c a r r y i n g capacity of the blood. T h u s a safe level of m e t h e m o g l o b i n in p a t i e n t s r e c e i v i n g I N O is at p r e s e n t e m p i r i c and d e p e n d e n t on the b a l a n c e b e t w e e n the benefit of p u l m o n a r y v a s o d i l a t a t i o n a n d the d e t r i m e n t of d e c r e a s i n g the o x y g e n - c a r r y i n g capacity of the blood. O u r policy is to aim to k e e p the m e t h e m o g l o b i n level less t h a n 4% a n d the h e m a t o c r i t g r e a t e r t h a n 40%. It is also i m p o r t a n t to n o t e that certain p o p u l a t i o n g r o u p s m a y be at g r e a t e r risk of this c o m p l i c a t i o n by virtue of h a v i n g a h i g h e r i n c i d e n c e of m e t h e m o g l o b i n r e d u c t a s e deficiency [24]. W e b e l i e v e it is essential to m o n i t o r m e t h e m o g l o b i n levels e v e n d u r i n g l o w - d o s e I N O therapy.

Summary and Conclusion I n h a l e d nitric oxide, u n l i k e i n t r a v e n o u s prostacyclin, p r o v e d to be an effective selective p u l m o n a r y vasodilator, i m p r o v e d oxygenation, did not cause s y s t e m i c h y p o t e n sion, was associated w i t h g o o d clinical o u t c o m e , and a p p e a r e d to lack significant toxicity at the doses and d u r a t i o n of a d m i n i s t r a t i o n u s e d in the p r e s e n t study. T h e s e findings s u g g e s t that I N O s h o u l d be c o n s i d e r e d as the p u l m o n a r y v a s o d i l a t o r of choice for c h i l d r e n with s e v e r e p o s t o p e r a t i v e p u l m o n a D, h y p e r t e n s i o n w h o do not r e s p o n d a d e q u a t e l y to c o n v e n t i o n a l therapy. We thank the nursing staff and the ventilator technicians of the cardiac intensive care unit, who helped make this study possible, and Angela Wade, University of London, for her advice on the statistical analysis. Doctor Goldman is supported bv a grant from The British Heart Foundation.

References 1. Hopkins RA, Bull C, Haworth SG, de Leval MR, Stark J. Pulmonary hypertensive crises following surge D, for congenital heart defects in young children. Eur J Cardiothorac Surg 1991;5:628-34. 2. Frostell CG, Fratacci MD, Wain JC, Zapol WM. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:2038-47. 3. Pepke-Zaba J, Higenbottam TW, Tuan Dinh-Xuan A, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173-4.

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4. Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993;328:399-405. 5. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 1993;123:103-8. 6. Roberts JD, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM. Inhaled nitric oxide in congenital heart disease. Circulation 1993;87:447-53. 7. Miller Of, Celemajer DS, Deanfield JE, Macrae DJ. Very-lowdose inhaled nitric oxide: a selective pulmonary vasodilator after operations for congenital heart disease. J Thorac Cardiovasc Surg 1994;108:487-94. 8. Miller OI, Celemajer DS, Deanfield JE, Macrae DJ. Guidelines for the safe administration of inhaled nitric oxide. Arch Dis Child 1994;70:F47-9. 9. Jones ODH, Shore DF, Rigby ML, et al. The use of tolazoline hydrochloride as a pulmonary vasodilator in potentially fatal episodes of pulmonary vasoconstriction after cardiac surgery in children. Circulation 1981;64(Suppl 2):134-9. 10. Wheller J, George BL, Mulder DG, Jarmakani JM. Diagnosis and management of postoperative pulmonary hypertensive crises. Circulation 1980;60:1640-4. 11. Bush A, Busst CM, Knight WB, Shinebourne EA. Comparison of the haemodynamic effects of epoprostenol (prostacyclin) and tolazoline. Br Heart J 1988;60:141-8. 12. Haworth SG. Pulmonary vascular remodeling in neonatal puhnonary hypertension. Chest 1988;93:133S-8S. 13. Hall SM, Haworth SG. Onset and evolution of pulmonary vascular disease in young children: abnormal postnatal remodeling studied in lung biopsies. J Pathol 1992;166: 183-93. 14. Celermajer DS, Cullen S, Deanfield JE. Impairment of endothelial dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993;87:440-6. 15. Smith EEJ, Naftel DC, Blackstone EH, Kirklin JW. Microvascular permaebility after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1987;94:225-33. 16. Vane JR. Adventures and excursions in bioassay--the stepping stones to prostacyclin. Postgrad Med J 1983;59: 743-58. 17. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6. 18. Waldman SA, Murad F. Biochemical mechanism underlying vascular smooth muscle relaxation: the guanylate cyclasecyclic GMP system. J Cardiovasc Pharmacol 1988;12(Suppl 5):$115-8. 19. Walmrath D, Schneider 1-, Pilch J, Grimminger F, Seeger W. Aerolised prostacyclin in adult respiratoDT distress syndrome. Lancet 1993;342:961-2. 20. Curtis J, O'Neill JT, Pettett G. Endotracheal administration of tolazoline in hypoxia-induced pulmonary hypertension. Pediatrics 1993;92:403-8. 21. Centers for Disease Control. Recommendations for occupational safety and health standard. MMWR 1988;37(Suppl 7):1-29. 22. Borgese N, Pietrini G, Gaetani S. Concentration of NADHcytochrome b5 reductase in erythrocytes of normal and methemoglobinemic individuals measured with a quantitative radioimmunoblotting assay. J Clin Invest 1987;80: 1296 -302. 23. Caudill L, Wallbridge J, Kuhn G. Methemoglobinemia as a cause of coma. Ann Emerg Med 1990;19:677-9. 24. Scott EM, Hoskins DD. Hereditary methemoglobinemia in Alaskan Eskimos and Indians. Blood 1958;13:795-802.

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DISCUSSION DR LESLIE HAMILTON (Newcastle-Upon-Tyne, United Kingdom): I am pleased to see that the search for the "Holy Grail" of a selective pulmonary vasodilator continues, and I congratulate Goldman and associates on what is obviously another step down this road. I do not have access to nitric oxide at the moment, so I am limited to prostacyclin, and you have demonstrated very. well the difficulty with systemic hypotension. There have been some suggestions in the literature recently of giving prostacyclin via the endotracheal tube. Do you have any comments on that? Second, I still have major concerns about the safety, both in the short term (although you have commented on that) and in the long term regarding the use of nitric oxide. Do you have any comments on toxicity, and do you feel comfortable recommending nitric oxide for prophylactic use in patients you would consider at high risk of pulmonary, hypertension postoperatively? DR LUDWIG K. YON SEGESSER (Zurich, Switzerland): You have told us that hypoxia is one of the vasoconstrictor agents too, and therefore I wanted to know if there was any difference between groups with regard to hypoxia before application of the specific agent. DR HILLEL LAKS (Los Angeles, CA): 1 very, much enjoyed this report documenting your extensive experience. Some people have postulated that there may be a rebound phenomenon seen after stopping nitric oxide administration, resulting in an acute pulmonary hypertensive crisis. Have you seen that? You had one death in which this may have happened. Do you recommend therefore that one proceeds to a more long-acting, more conventional pulmonary vasodilator after you have stopped nitric oxide administration? DR GOLDMAN: I thank the discussants for their questions. In response to Dr Hamilton's first question with regard to the inhalational administration of prostacyclin (PC), there are at present only sporadic reports on the administration of PC by this route. The clinical potential in the management of children with postoperative pulmonary hypertension has yet to be tested. Although we had originally considered comparing inhaled nitric oxide (INO) with inhaled PC, this appeared premature. In addition, a personal communication with one of the au-

thors who has administered inhaled PC revealed that severe coughing was a major side effect in a n u m b e r of the awake adults studied. This side effect may, however, be abolished by the use of deep sedation and the administration of PC via a jet nebulizer to keep the inhaled particle size down to a minimum. It also remains to be seen w h e t h e r the acute benefits described from the inhalational administration of PC are sustained with continuous administration and w h e t h e r there will be accumulation in the lung with systemic absorption resulting in similar side effects to those observed with the intravenous route of administration. With respect to Dr Hamilton's second question on nitric oxide toxicity, I think the potential long-term side effects of INO are of concern to everybody administering this therapy. At the present time the safe administration of INO requires the monitoring of nitrogen dioxide and methemoglobin. Although we meticulously monitor NO2, we do not, however, know what the toxic dose of NO 2 is for sick children--we only have safety guidelines for healthy adults working in industry. It is for this reason that we have moved toward administering the lowest effective dose of INO by conducting regular reverse dose-response studies. As far as Dr Hamilton's third question on the potential prophylactic use of INO for high-risk patients is concerned, I would personally recommend against this for two reasons: First, there may be unknown toxic side effects of INO, and second, we have noticed that a number of patients do become extremely dependent on the INO during the first few days of therapy. This may lengthen their ventilatory and intensive care course. The dependence on INO brings me to Dr Laks' question of a possible rebound p h e n o m e n o n when the INO administration is stopped. Patients in whom a dependence on INO develops during its early course of administration would obviously be at risk of a serious rebound effect and an acute crisis if this therapy was suddenly withdrawn. In our experience such a situation can be avoided by gradually weaning the dose of INO as is tolerated. In this way most patients should be able to be successfully weaned from the INO within a week. In the patient in question who died 2 days after the discontinuation of INO administration, a secondary, pneumonia had developed in the interim, which had precipitated her late-onset pulmonary hypertensive crisis. This was therefore not thought to be a rebound crisis caused by stopping INO administration 2 days earlier.