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Ann Thorac Surg 1995;60:300-305
© 1995 The Society of Thoracic Surgeons
Cardiothoracic Unit, Great Ormond Street Hospital for Children, London, United Kingdom
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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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-1 • min-1 x 10 minutes) in a prospective, randomized cross-over study.
Results. Both nitric oxide and prostacyclin resulted in a reduction in pulmonary arterial pressure, although the mean pulmonary arterial pressure was significantly lower during nitric oxide therapy (28.5 ± 2.9 mm Hg) than during prostacyclin therapy (35.4 ± 2.1 mm Hg; p < 0.05). The mean pulmonary to systemic arterial pressure ratio was also significantly lower during nitric oxide than prostacylin 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.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Severe life-threatening reactive pulmonary hypertension is a significant cause of morbidity and mortality in children after corrective operations for congenital heart disease [1]. This complication may occur despite technically successful operation and active conventional management 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 management protocol, with prostacyclin being considered one of the pulmonary vasodilators of choice for severe pulmonary hypertension. Unfortunately, the intravenous vasodilators lack specificity for the pulmonary circulation and their use is frequently limited by their systemic hypotensive effects.
Inhaled nitric oxide (INO) has recently emerged as a novel and selective pulmonary vasodilator [2–7]. We [7] have previously demonstrated a marked selective pulmonary vasodilator response to very low dose INO in infants with pulmonary hypertension after cardiac operations.
We now report a study comparing the effectiveness of INO and intravenous prostacyclin as pulmonary vasodilators in the treatment of severe pulmonary hypertension in children after corrective heart operations for congenital heart disease.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Between December 1993 and December 1994 thirteen children, 8 girls and 5 boys, fulfilled the above criteria for severe pulmonary hypertension after receiving high inspired oxygen hyperventilation, sedation with morphine (20 to 40 µg/kg per hour) and midazolam (2 to 6 µg/kg per minute), and muscle paralysis with vecuronium. The use of inotropic agents and intravenous vasodilators, other than prostacyclin, was not restricted prior to trial entry.
The preoperative cardiac diagnoses and demographic details are shown in Table 1
. The study was approved by our Research Ethics Committee in December 1993, and informed consent was obtained from the parents of the patients.
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). Treatment 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 continued on the agent providing the greatest hemodynamic improvement during the study.
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. Nitric oxide gas, obtained in a mixture of nitrogen at 1,000 ppm NO (BOC-Special Gases, Surrey, England), was delivered via a calibrated N2 flow meter (KDG Instruments, Surrey, England) into the inspiratory limb of an infant ventilator as previously described [8]. The concentrations of inspired NO and its toxic oxidative product nitrogen dioxide were analyzed by chemiluminescence (model 42; Thermo Environmental 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 ppm NO and 0 and 4 ppm NO2 before each study.
Patients who responded more favorably to INO were left on continuous INO therapy. Daily reverse dose–response studies were conducted allowing the INO dose to be reduced gradually as clinical improvement progressed.
The muscle paralysis and deep sedation were weaned after the patients had had at least a 24-hour period of stability (no cardiopulmonary compromise or pulmonary hypertensive crises) on low-dose INO therapy (<10 ppm). The dose of INO and sedation were then weaned simultaneously as tolerated, at the discretion of the attending physician. All the patients were, however, weaned from the INO therapy before tracheal extubation.
Methemoglobin levels were measured after 30 minutes of exposure to INO. Subsequent levels were monitored every 12 hours during ongoing INO therapy or more frequently if levels rose to more than 4%.
Prostacyclin Dosage and Administration
Prostacyclin was infused continuously into a central vein at an initial dose of 5 ng • kg • min-1, increasing incrementally in steps of 5 ng/kg per minute to a dose of 20 ng • kg-1 • min-1. Hemodynamic 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.
Outcome Measurements
The following variables were recorded at baseline and after each therapy: PAP, SAP, mean PAP/SAP ratio, and PaO2. The PAP was monitored continuously in 9 of the 13 patients studied via an indwelling pulmonary artery catheter (3F), which had been inserted under direct vision into the proximal main pulmonary artery at the completion of the surgical repair. The SAP was continuously monitored via an indwelling catheter. Both the pulmonary 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.
Statistical Analysis
Data are presented as means ± 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 between INO alone and INO and prostacyclin administered simultaneously. A p value less than 0.05 was taken as significant. To avoid using multiple t tests, means and 95% confidence intervals (CI) were used to summarize changes between baseline and INO, and between baseline and prostacyclin.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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and for individual patients in Figure 4.
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). Mean PAP was significantly lower with INO than prostacyclin (28.2 ± 2.9 versus 35.4 ± 2.1 mm Hg; p < 0.01) (see Fig 2).
Only intravenous prostacyclin resulted in a reduction in the mean SAP (95% CI for the changes in SAP from baseline with prostacyclin, -4 to -10 mm Hg; and with INO, -2 to +7 mm Hg) (see Fig 3). The systemic hypotensive effect of prostacyclin was so marked in 1 patient (>25% reduction in mean SAP from 42 to 28 mm Hg with 10 ng • kg-1 • min-1 prostacyclin, unresponsive to a 15 mL/kg colloid challenge) that it necessitated the termination of therapy.
Only INO resulted in selective pulmonary vasodilation, as demonstrated by a marked fall in the mean 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 mean 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 dependent on the continuation of the prostacyclin administration in those patients who received prostacyclin first.
Oxygenation
Inhaled nitric oxide improved the mean PaO2 by 70% from baseline (95% CI, 39% to 101%) (see Fig 3). Prostacyclin was not associated with an improvement in oxygenation (95% CI for the changes in PaO2 from baseline with prostacyclin, -2 to +3 mm Hg). The mean PaO2 measured during INO administration was significantly greater than during the prostacyclin infusion (20.1 ± 2.9 versus 13 ± 2.0 mm Hg; p < 0.01) (see Fig 2).
Patient Outcome
Inherent 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 hemodynamic response to INO than prostacyclin and were therefore continued on this treatment for 1 to 17 days (median, 6 days).
Nine of the 13 patients continued to improve with INO and survived to discharge from hospital. Four patients died even though they had also demonstrated an initial improvement with INO. Only 1 patient died of acute pulmonary hypertension. The patient had undergone 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 pulmonary 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 underlying lung disease, the second of multiorgan failure, and the third of left ventricular failure due to severe left ventricular hypoplasia, which had been underestimated on the preoperative echocardiogram.
Muscle 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 pulmonary 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 NO2 concentrations did not exceed 1.2 ppm.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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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 selective pulmonary vasodilatory properties of INO have been demonstrated in adults with primary pulmonary hypertension [3] and acute respiratory distress syndrome [4], neonates with persistent pulmonary hypertension of the newborn [5], and children with corrected [7] 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 hemodynamic 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 pulmonary 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 hypoxia-induced pulmonary hypertension. The clinical 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 number 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 humans 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 [21] for occupational exposure in healthy adults (NO2 less than 5 ppm for 8 hours). There are no guidelines for maximal exposure limits of NO and NO2 in children. We have therefore adopted a policy of titrating INO levels to the minimum required for effective treatment. In a previous study [7] we showed this could be achieved with INO doses as low as 2 ppm, and in the current study some patients could be maintained on doses as low as 300 ppb.
One patient had a transient increase in methemoglobin to 8%, which responded to a reduction in the INO dose. Levels of up to 10% to 20% are tolerated by patients with congenital methemoglobinemia [22], whereas levels greater than 80% are invariably fatal [23]. Methemoglobin is not itself directly toxic, but it does reduce the oxygen carrying capacity of the blood. Thus a safe level of methemoglobin in patients receiving INO is at present empiric and dependent on the balance between the benefit of pulmonary vasodilatation and the detriment of decreasing the oxygen-carrying capacity of the blood. Our policy is to aim to keep the methemoglobin level less than 4% and the hematocrit greater than 40%. It is also important to note that certain population groups may be at greater risk of this complication by virtue of having a higher incidence of methemoglobin reductase deficiency [24]. We believe it is essential to monitor methemoglobin levels even during low-dose INO therapy.
Summary and Conclusion
Inhaled nitric oxide, unlike intravenous prostacyclin, proved to be an effective selective pulmonary vasodilator, improved oxygenation, did not cause systemic hypotension, was associated with good clinical outcome, and appeared to lack significant toxicity at the doses and duration of administration used in the present study. These findings suggest that INO should be considered as the pulmonary vasodilator of choice for children with severe postoperative pulmonary hypertension who do not respond adequately to conventional therapy.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Doctor Goldman is supported by a grant from The British Heart Foundation.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Goldman, Cardiac Intensive Care Unit, Great Ormond Street Hospital for Children, Great Ormond St, London WC1N 3JH, United Kingdom.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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