View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 44, No. - 4,Publisher 2004 Connector © 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.05.047 Hemodynamic Effects of Inhaled Nitric Oxide in Right Ventricular Myocardial Infarction and Ignacio Inglessis, MD,* Jordan T. Shin, MD,*† John J. Lepore, MD,* Igor F. Palacios, MD, FACC,* Warren M. Zapol, MD,‡ Kenneth D. Bloch, MD,*† Marc J. Semigran, MD* Boston, Massachusetts

OBJECTIVES We sought to determine whether or not inhaled nitric oxide (NO) could improve hemodynamic function in patients with right ventricular myocardial infarction (RVMI) and cardiogenic shock (CS). BACKGROUND Inhaled NO is a selective pulmonary vasodilator that can decrease right ventricular . METHODS Thirteen patients (7 males and 6 females, age 65 Ϯ 3 years) presenting with electrocardio- graphic, echocardiographic, and hemodynamic evidence of acute inferior myocardial infarc- tion associated with RVMI and CS were studied. After administration of supplemental ϭ oxygen (inspired oxygen fraction [FiO2] 1.0), hemodynamic measurements were recorded ϭ before, during inhalation of NO (80 ppm at FiO2 0.90) for 10 min, and 10 min after NO ϭ inhalation was discontinued (FiO2 1.0). RESULTS NO decreased the mean by 12 Ϯ 3%, mean pulmonary arterial pressure by 13 Ϯ 2%, and pulmonary by 36 Ϯ 8% (all p Ͻ 0.05). Nitric oxide inhalation increased the by 24 Ϯ 11% and the index by 23 Ϯ 12% (p Ͻ 0.05). The NO administration did not change systemic arterial or pulmonary capillary wedge pressures. Contrast identified three patients with a patent ϭ foramen ovale and right-to-left shunt flow while breathing at FiO2 1.0. Breathing NO decreased shunt flow by 56 Ϯ 5% (p Ͻ 0.05) and was associated with markedly improved systemic oxygen saturation. CONCLUSIONS Nitric oxide inhalation results in acute hemodynamic improvement when administered to patients with RVMI and CS. (J Am Coll Cardiol 2004;44:793–8) © 2004 by the American College of Cardiology Foundation

Right ventricular myocardial infarction (RVMI) is observed in therapy including supplemental oxygen. Overall, RVMI pa- up to 50% of patients with acute left ventricular (LV) inferior- tients with CS have in-hospital mortality similar to that of LV posterior wall infarction (1), many of whom manifest signifi- myocardial infarction (MI) patients with CS (4,8). cant hemodynamic abnormalities, including cardiogenic shock Afterload reduction therapy for the failing RV with a (CS) characterized by increased venous pressure, a low cardiac selective pulmonary vasodilator might be expected to lead to output, and systemic hypotension (2,3). The current treatment improved cardiac performance without producing systemic of RVMI patients includes optimization of right ventricular and hypotension (9,10). Pulmonary vasodilation (RV) and LV with intravenous fluids, coronary reper- can occur when inhaled nitric oxide (NO) diffuses to smooth fusion, maintenance of atrioventricular synchrony, administra- muscle cells in lung arterioles and activates soluble guanylate tion of inotropic agents, and intra-aortic balloon pump coun- cyclase to generate cyclic 3=,5=-monophosphate (11,12). This terpulsation (2,4–6). Many RVMI patients with impaired intracellular messenger leads to a reduction in the intracellular cardiac function improve with these therapies, particularly after concentration of calcium and inhibition of myosin light chain early percutaneous coronary intervention (PCI) (4). Dobut- kinase, producing smooth muscle cell relaxation and vasodila- amine and have been infused to improve the tion (13). The vasodilator effects of inhaled NO are restricted cardiac index (CI) of patients with CS complicating RVMI to the pulmonary circulation, as NO is readily bound to (6), but their utility is limited by arrhythmias, systemic vaso- hemoglobin in circulating erythrocytes and inactivated (14). dilation, and hypotension. Furthermore, RVMI patients with a Breathing NO has been shown to decrease pulmonary vascular patent foramen ovale may develop hypoxemia as a result of tone in adults and children with pulmonary hypertension of right-to-left shunting (7) that is resistant to conventional diverse etiology without causing systemic vasodilation, includ- ing patients with congenital disease (15), primary pul- From the *Cardiology Division, †Cardiovascular Research Center, and the ‡De- monary hypertension (9), and pulmonary hypertension second- partment of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard ary to a variety of etiologies (10). Inhaled NO has also been Medical School, Boston, Massachusetts. Supported by grants HL-42397 (Dr. Zapol), HL-70896 (Dr. Bloch), and HL-04021 (Dr. Semigran) from the National Heart, shown to improve oxygenation and reduce the need for Lung, and Blood Institute.Massachusetts General Hospital holds a patent for the extracorporeal membrane oxygenation in newborns with per- therapeutic use of inhaled nitric oxide and may receive royalties. Dr. Bloch has a sistent pulmonary hypertension and hypoxic respiratory failure sponsored research agreement with iNO Therapeutics. Manuscript received February 4, 2004; revised manuscript received April 30, 2004, (16,17). Furthermore, inhaled NO has been observed to accepted May 4, 2004. decrease RV afterload in a porcine model of RVMI (18). 794 Inglessis et al. JACC Vol. 44, No. 4, 2004 NO in Right Ventricular Infarction August 18, 2004:793–8

attending cardiologist. The success of PCI was assessed Abbreviations and Acronyms using both the Thrombolysis In Myocardial Infarction CI ϭ cardiac index (TIMI) study criteria for successful reperfusion (Ͻ50% CS ϭ cardiogenic shock residual stenosis and restoration of TIMI flow grade 3 in the ϭ FiO2 inspired oxygen fraction distal right coronary [19]) and the more stringent HR ϭ LV ϭ left /ventricular criteria of Bowers et al. (4) requiring complete reperfusion MI ϭ myocardial infarction of the right coronary artery and all RV marginal branches NO ϭ nitric oxide Ͼ1 mm in diameter. Transthoracic echocardiography and PA ϭ /arterial right heart catheterization were then performed. Patients ϭ PCI percutaneous coronary intervention received intravenous normal saline if their pulmonary cap- PCWP ϭ pulmonary capillary wedge pressure Ͻ PVR ϭ pulmonary vascular resistance illary wedge pressure (PCWP) was 15 mm Hg. Patients RA ϭ right /atrial were then included for further study if their right atrial (RA) RV ϭ right ventricle/ventricular pressure was Ͼ10 mm Hg, their PCWP was no Ͼ5mmHg RVMI ϭ right ventricular myocardial infarction higher than the RA pressure, and their CI was Ͻ2.5 ϭ SAP systemic arterial pressure l/min/m2. Patients were excluded from study if they had TIMI ϭ Thrombolysis In Myocardial Infarction severe pulmonary edema (PCWP Ͼ25 mm Hg; n ϭ 4), mechanical complications of MI requiring urgent surgical correction (n ϭ 0), severe mitral or aortic valvular disease (n The objective of this study was to assess whether or not ϭ 1), persistent hemodynamically significant tachyarrhyth- NO inhalation could improve cardiac performance in pa- mias (n ϭ 1), or a history of clinically significant pulmonary tients with RVMI and CS. disease (n ϭ 0). Thirteen patients underwent further study. METHODS Study procedure. To minimize hypoxic pulmonary vaso- constriction and to standardize the concentration of oxygen This protocol was approved by the Massachusetts General administered to patients participating in the study, the

Hospital Subcommittee on Human Studies. inspired oxygen fraction (FiO2) was increased to 1.0 in Study population. Patients with acute inferior MI (defined patients who were intubated with an endotracheal tube (n ϭ as an episode of chest pain lasting Ͼ30 min and electrocardio- 10), and 100% oxygen was administered via a tight-fitting graphic evidence of Ն1 mm ST elevation in inferior leads face mask to patients who were not intubated (n ϭ 3) (Table within the past 7 days) presenting to the Massachusetts 1). After 10 min, the following parameters were recorded: General Hospital were prospectively screened for electrocar- RA, pulmonary arterial (PA), PCWP, and mean systemic diographic (Ն1 mm ST-segment elevation on right precordial arterial pressure (SAP), as well as heart rate (HR). Cardiac leads V3RorV4R) or echocardiographic (RV dilation and free output was determined by the Fick oxygen technique. The wall akinesis or dyskinesis) evidence of RVMI. CI, stroke volume index, pulmonary vascular resistance Informed consent was obtained from 19 patients meeting (PVR), and systemic vascular resistance were calculated these criteria. Diagnostic coronary angiography was per- using standard formulas. Patients then breathed 80 ppm ϭ formed, and PCI was carried out at the discretion of the NO at FiO2 0.90 for 10 min, and hemodynamic

Table 1. Patient Characteristics at the Time of Study Enrollment Time to

Patient Age PCI Enrollment‡ Mechanical SaO2 No. (yrs) Gender Success* (h) IABP Vasopressors§ Dobutamine Ventilation FiO2 (%) 1 66 M N/A 30 ϩϪ ϩ ϩ1.0 82 2 74 F No 5 ϩϩ ϩ ϩ0.8 92 3 65 F Yes† 96 ϩϩ ϩ ϩ0.4 100 4 62 M N/A 48 Ϫϩ Ϫ Ϫ0.8ʈ 83 5 49 M Yes 12 ϩϩ ϩ ϩ1.0 71 6 66 M Yes 5 ϪϪ Ϫ ϩ0.4 97 7 48 M Yes† 44 ϩϩ Ϫ ϩ0.6 98 8 62 F No 68 ϩϩ ϩ ϩ0.5 95 9 48 M Yes 16 ϩϩ Ϫ ϩ0.7 88 10 73 F Yes† 96 Ϫϩ Ϫ Ϫ0.4ʈ 100 11 84 F Yes 72 ϪϪ Ϫ ϩ0.4 97 12 65 F Yes† 120 ϩϩ ϩ ϩ0.9 95 13 86 M Yes† 20 ϩϩ Ϫ Ϫ0.3ʈ 100 Mean 65 Ϯ 349Ϯ 11 0.6 Ϯ 0.1 92 Ϯ 2

*Successful percutaneous coronary intervention (†indicates patients in whom PCI did not result in restoration of right ventricular ). ‡Time from onset of symptoms to study enrollment. §Norepinephrine or phenylephrine administration. ʈOxygen delivered by face mask or nasal prongs. Values expressed as mean Ϯ SEM. ϭ ϭ ϭ ϭ ϭ FiO2 inspired oxygen fraction; IABP intraaortic balloon counterpulsation; N/A PCI not attempted; PCI percutaneous coronary intervention; SaO2 systemic arterial oxygen saturation as measured by oximetry. JACC Vol. 44, No. 4, 2004 Inglessis et al. 795 August 18, 2004:793–8 NO in Right Ventricular Infarction

Table 2. Hemodynamic Parameters at the Time of Study Enrollment Patient RAP PAP PCWP SAP CI PVR SVR ؊ ؊ No. (mm Hg) (mm Hg) (mm Hg) (mm Hg) (l/min/m2) (dynes·s·cm 5) (dynes·s·cm 5) LVEF 1 20 26 12 80 1.1 599 2567 0.40 2 25 28 20 68 1.9 216 1161 0.30 3 18 25 18 78 1.4 224 1920 0.30 4 27 31 24 78 1.3 190 1383 0.70 5 24 33 20 59 1.2 347 933 0.35 6 18 20 14 75 1.3 169 1609 0.45 7 20 34 23 90 2.5 152 966 0.70 8 17 27 19 78 2.0 211 1605 0.31 9 22 28 20 62 1.6 221 1103 0.30 10 13 25 15 50 2.3 179 663 0.45 11 16 31 18 59 2.0 236 782 0.45 12 18 24 19 80 0.8 267 3307 0.42 13 21 26 19 74 2.1 147 1116 0.35 Mean 20 Ϯ 128Ϯ 119Ϯ 172Ϯ 3 1.7 Ϯ 0.1 243 Ϯ 34 1,470 Ϯ 210 0.42 Ϯ 0.04

Mean values expressed as mean Ϯ SEM. CI ϭ cardiac index; LVEF ϭ left ventricular ; PAP ϭ mean pulmonary arterial pressure; PCWP ϭ mean pulmonary capillary wedge pressure; PVR ϭ pulmonary vascular resistance; RAP ϭ mean right atrial pressure; SAP ϭ mean systemic arterial pressure; SVR ϭ systemic vascular resistance. measurements were repeated. Nitric oxide administration ples were assessed for equal variance before analysis of variance. ϭ Ͻ was stopped, patients resumed breathing at FiO2 1.0, and A value of p 0.05 was considered significant. a third set of hemodynamic measurements was recorded 10 min later. We chose an inhaled concentration of 80 ppm RESULTS NO because this dose has been reported to provide a greater pulmonary vasodilator response than lower doses (20). Baseline characteristics. The characteristics of the study Moreover, breathing 80 ppm NO for 10 min is not population are summarized in Table 1. There were seven men associated with adverse effects such as methemoglobinemia and six women, age 65 Ϯ 3 years. The right coronary artery in adults (20). was dominant in all patients. Two patients (#9 and #11) In patients with a systemic oxygen saturation Յ95% despite received thrombolytic therapy before coronary angiography. ϭ Ͼ breathing at FiO2 1.0, contrast echocardiography was used Two patients (#6 and #11) had a 95% proximal stenosis of to identify the presence of right-to-left shunting via a patent the right coronary artery with TIMI grade 2 distal flow, and foramen ovale. The magnitude of right-to-left shunt flow was the nine remaining patients had total occlusion of the proximal assessed by oximetry (21). The pulmonary venous oxygen right coronary artery. The PCI was successful, as assessed by content was calculated using the alveolar gas equation (22), as the TIMI criteria, in 9 of the 11 patients in whom it was there were no patients with significant pulmonary disease, and attempted. However, PCI resulted in complete reperfusion of ϭ the right coronary artery and all RV marginal branches Ͼ1mm all patients were breathing at FiO2 1.0. in only four patients. The elapsed time from the onset of NO administration. Nitric oxide gas was supplied in tanks Ϯ containing 800 ppm NO in N (INO Therapeutics Inc., symptoms to the PCI procedure was 21 10 h (median: 8 h). 2 In two patients (#1 and #4), PCI was not attempted. Clinton, New Jersey) and was administered using an INO- At the time of enrollment in the study, 9 patients vent (Datex-Ohmeda Inc., Andover, Massachusetts) to required intra-aortic balloon pump counterpulsation, 10 supply NO at a concentration of 80 ppm to the inspiratory patients required treatment with norepinephrine or phenyl- limb of a ventilator circuit or a tight-fitting mask. A flow ephrine, and 6 patients required treatment with dobut- rate of Ն30 l/min of NO gas mixed with oxygen was amine. Ten patients required via an maintained to meet the inspiratory flow demands of the endotracheal tube, including a positive end-expiratory pres- patient and to minimize the transit time of the inspired gas Ն sure 5cmH2O. Five patients (#2, #3, #5, #8, and #10) and hence the formation of higher nitrogen oxides. Nitric had bradyarrhythmias requiring ventricular pacing. The oxide, NO2, and FiO2 were monitored continuously; in all elapsed time from the onset of chest pain to initiation of the Ͻ cases, NO2 was 2 ppm. NO inhalation study was 49 Ϯ 11 h. Statistical analysis. Continuous variables are expressed as The hemodynamic parameters of the patients at the time Ϯ mean standard error, with median values provided where the of enrollment are presented in Table 2. The mean RA, PA, data were not normally distributed as assessed by the Wilk- and PCWPs were elevated, as were the PVR and systemic Shapiro test. Hemodynamic and gas exchange alterations in vascular resistance. The mean PA systolic pressure was 36 Ϯ response to NO breathing and its discontinuation were ana- 2 mm Hg. The CI was low (1.7 Ϯ 0.1 l/min/m2). All lyzed using repeated measures analysis of variance followed by patients had RV dilation and systolic dysfunction by echo- the Neuman-Keuls procedure, when appropriate. Data sam- cardiography. The LV ejection fraction was 0.42 Ϯ 0.04. 796 Inglessis et al. JACC Vol. 44, No. 4, 2004 NO in Right Ventricular Infarction August 18, 2004:793–8

Figure 1. Hemodynamic parameters in right ventricular myocardial infarction patients before (Pre-nitric oxide [NO]), during (NO), and 10 min after the discontinuation of NO inhalation (Post-NO). RAP ϭ mean right atrial pressure; PAP ϭ mean pulmonary arterial pressure; PVR ϭ pulmonary vascular resistance; CI ϭ cardiac index; PCWP ϭ mean pulmonary capillary wedge pressure; SAP ϭ mean systemic arterial pressure; SVR ϭ systemic vascular resistance; HR ϭ heart rate. *p Ͻ 0.05 versus Pre-NO and Post-NO; †p Ͻ 0.05 versus Pre-NO.

Hemodynamic effects of inhaled NO administra- tion of NO, the RA pressure, PVR, and CI had returned to tion. The effects of breathing 80 ppm NO for 10 min are values similar to those measured immediately before NO shown in Figure 1. When compared with breathing at FiO2 administration. The mean PA pressure, however, remained ϭ 1.0, the addition of NO decreased the RA pressure by 12 5 Ϯ 2% lower than before NO administration (p Ͻ 0.05). Ϯ 3%, mean PA pressure by 13 Ϯ 2%, and PVR by 36 Ϯ Inhaled NO was well tolerated in all patients without any 8% (all p Ͻ 0.05). The NO administration increased CI by side effects. 24 Ϯ 11% and stroke volume index by 23 Ϯ 12% (both p Ͻ Four patients had a systemic oxygen saturation Յ95% ϭ 0.05) but did not change SAP and PCWP, systemic despite breathing at FiO2 1.0 and underwent contrast vascular resistance, or HR. Ten minutes after discontinua- echocardiography. In three patients (#1, #4, and #5), right-to- left shunting of bubble contrast medium through a patent foramen ovale was observed, and a shunt flow of 0.67 Ϯ 0.08 L/min was measured by oximetry. Inhaled NO decreased right-to-left shunting by 56 Ϯ 5% (p Ͻ 0.05) associated with an increase of systemic arterial oxygen saturation to Ͼ95% in all three patients (Fig. 2). In one patient (#2) with a systemic oxygen saturation Յ95%, transthoracic echocardiography was technically limited, precluding identification of a patent fora- men ovale. Nonetheless, breathing NO increased the systemic oxygen saturation in this patient.

DISCUSSION We observed that short-term administration of inhaled NO to a group of patients with RVMI and CS resulted in Figure 2. Right-to-left shunt flow and systemic arterial oxygen saturation beneficial hemodynamic effects, as reflected by a decrease of in three right ventricular myocardial infarction patients before (Pre-nitric RA and PA pressures and an increase of CI. Nitric oxide oxide [NO]), during (NO), and 10 min after the discontinuation of NO inhalation (Post-NO). Diamonds ϭ Patient #1; squares ϭ Patient #5; inhalation produced pulmonary vasodilation but did not triangles ϭ Patient #4. alter SAP and PCWP or the HR. In three patients with JACC Vol. 44, No. 4, 2004 Inglessis et al. 797 August 18, 2004:793–8 NO in Right Ventricular Infarction significant right-to-left shunting through a patent foramen systemic venous congestion seen in RVMI patients with ovale that was refractory to oxygen administration, NO CS, improving cardiac performance without producing inhalation reduced shunt flow and improved systemic oxy- adverse myocardial effects. genation. Short-term administration of inhaled NO was In this study, PCWP did not change during NO inha- well tolerated by all patients without significant side effects. lation by RVMI patients, as has been previously observed All of the patients with RVMI and CS that were studied during its administration to patients with severe LV systolic had an abnormally elevated PVR. The elevation in PA pressure dysfunction (20,31). In patients with severe LV systolic observed in our patients was similar to that reported by Jacobs dysfunction, which is usually accompanied by poor diastolic et al. (8) in their registry of patients with RVMI and CS. The ventricular compliance, breathing NO is thought to increase increased pulmonary vascular tone in our patients with RVMI pulmonary venous return, resulting in an increase in LV and CS is likely multifactorial in etiology. A low filling pressure (32). The RVMI patients in this study had results in a decreased mixed venous blood oxygen content, primarily RV systolic and diastolic function, and the degree which enhances PA (23). The intravenous of LV dysfunction was not as severe as in those patients in infusion of alpha-adrenergic vasoconstrictors can contribute to whom the PCWP has been reported to increase during NO pulmonary vasoconstriction, as has been reported in animal inhalation. Furthermore, RVMI patients have been ob- models (24,25). Mechanical ventilation with positive end- served to have a shift of the interventricular septum towards Ͼ expiratory pressure 5cmH2O, as was used in five of the the left ventricle, impairing LV diastolic compliance and patients in this study, can increase the PVR through compres- increasing LV filling pressure. In our patient population, sion of the pulmonary vasculature (26). Finally, interstitial NO inhalation decreased RV filling pressure, which may pulmonary edema, which may have occurred in some of our have decreased the deleterious effect of the RV on LV patients with an elevated PCWP, can also cause pulmonary compliance, counterbalancing any effect that increased LV constriction (27). Our observations of a selective pulmonary filling might have had on the PCWP. vasodilator effect of breathing NO are consistent with previous Right-to-left shunt flow through a patent foramen ovale studies of patients with pulmonary hypertension secondary to a caused by elevation of RV filling pressure is a well-described variety of etiologies in which pulmonary vasomotor tone is complication of patients with RVMI and can produce increased (9,10,15), suggesting that the increased PVR in our refractory systemic hypoxemia (7). Systemically adminis- patients is related to an increase in pre-capillary vasomotor tone tered vasodilator or inotropic therapy has limited efficacy in rather than compressive effects on pulmonary capillaries. decreasing shunt flow, as agents that decrease RA pressure The increase of CI and reduction of RA pressure ob- simultaneously reduce the left atrial pressure, leaving the served in RVMI patients breathing NO are likely due to transatrial pressure gradient unchanged. Attempts to me- selective pulmonary vasodilation, resulting in a reduction of chanically close a patent foramen ovale to decrease inter- RV afterload and subsequent improvement in RV perfor- atrial shunting in RVMI patients have had variable success mance. These effects are in agreement with those reported (33,34). In our study, we observed that 3 of 13 RVMI in two previous case reports of RVMI patients treated with patients had significant right-to-left shunting through a ϭ inhaled NO (28,29). patent foramen ovale despite breathing at FiO2 1.0, The selectivity of inhaled NO for the pulmonary circu- whereas breathing NO consistently reduced the shunt flow lation offers a significant advantage over non-selective pul- and improved systemic oxygenation. monary and systemic vasodilators, such as nitroprusside, Our study expands upon the previous report of Bowers et for the treatment of RVMI patients. Dell’Italia et al. (6) al. (4), who observed that failure to achieve early, successful reported that systemic administration of nitroprusside to reperfusion of the RV myocardium in RVMI patients RVMI patients increased CI without augmenting stroke resulted in a high incidence of refractory hypotension, CS, volume index, and was associated with decreased SAP and and death. In our group of RVMI patients with severe PCWP and an increased HR. The nitroprusside-induced hemodynamic compromise, the majority of whom did not increase of HR suggests that nonselective vasodilation in obtain prompt reperfusion of their RV myocardium, breath- RVMI patients can increase sympathetic tone, which may ing 80 ppm NO increased the CI and stroke volume index. augment ischemia, arrhythmias, and promote infarct expan- If this effect can be sustained, inhaled NO therapy offers the sion. Dell’Italia et al. (6) also reported that administration of potential to improve cardiac performance in patients who the beta-adrenergic agonist dobutamine to RVMI patients fail to benefit from early revascularization and who remain increased CI and stroke volume index but was associated critically ill despite the use of intra-aortic and/or pharma- with arrhythmias and recurrent ischemia. In contrast, we cologic circulatory support. observed that breathing NO for 10 min increased CI and The prognosis for most RVMI patients who survive their stroke volume index without decreasing SAP or PCWP or initial hospitalization is excellent, even when their course is increasing the HR in our patients with RVMI and CS. complicated by CS (35), and significant improvement of Previous studies have shown that inhaled NO does not indices of RV systolic function have been measured at affect RV or LV contractility (9,30) and therefore may prove long-term follow-up (36). Bowers et al. (4) reported that in superior to currently available therapies for the low CI and RVMI patients with unsuccessful early perfusion and he- 798 Inglessis et al. JACC Vol. 44, No. 4, 2004 NO in Right Ventricular Infarction August 18, 2004:793–8 modynamic compromise who survive their initial hospital- 15. Rimensberger PC, Spahr-Schopfer I, Berner M, et al. Inhaled nitric ization, RV systolic wall motion at one month is similar to oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and patients in whom early, successful RV myocardial reperfu- cellular mechanisms. Circulation 2001;103:544–8. sion was achieved. Further study is necessary to ascertain if 16. Roberts JD Jr., Fineman JR, Morin FC, et al. Inhaled nitric oxide and the beneficial hemodynamic effects observed with short- persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 1997;336:605–10. term inhaled NO in our study of RVMI patients with CS or 17. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide refractory hypoxemia can reduce early mortality, permitting in full-term and nearly full-term infants with hypoxic respiratory the eventual recovery of RV function. failure. N Engl J Med 1997;336:597–604. 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