Comparison of Inhaled Nitric Oxide Versus Oxygen on Hemodynamics in Patients With Mitral Stenosis and Severe Pulmonary Hypertension After Mitral Valve Surgery

Pulmonary hypertension represents an important cause of morbidity and mortality in patients with mitral stenosis who undergo cardiac surgery, especially in the postoperative period. The aim of this study was to test the hypothesis that inhaled nitric oxide (iNO) would improve the hemodynamic effects and short-term clinical outcomes of patients with mitral stenosis and severe pulmonary hypertension who undergo cardiac surgery in a randomized, controlled study. Twenty-nine patients (4 men, 25 women; mean age 46 ± 2 years) were randomly allocated to receive iNO (n = 14) or oxygen (n = 15) for 48 hours immediately after surgery. Hemodynamic data, the use of vasoactive drugs, duration of stay, and short-term complications were assessed. No differences in baseline characteristics were observed between the groups. After 24 and 48 hours, patients receiving iNO had a significantly greater increase in cardiac index compared to patients receiving oxygen (p <0.0001). Pulmonary vascular resistance was also more significantly reduced in patients receiving iNO versus oxygen (−117 dyne/s/cm5, 95% confidence interval −34 to −200, vs 40 dyne/s/cm5, 95% confidence interval −34 to 100, p = 0.005) at 48 hours. Patients in the iNO group used fewer systemic vasoactive drugs (mean 2.1 ± 0.14 vs 2.6 ± 0.16, p = 0.046) and had a shorter intensive care unit stay (median 2 days, interquartile range 0.25, vs median 3 days, interquartile range 7, p = 0.02). In conclusion, iNO immediately after surgery in patients with mitral stenosis and severe pulmonary hypertension improves hemodynamics and may have short-term clinical benefits. Pulmonary hypertension represents an important cause of morbidity and mortality in patients with mitral stenosis who undergo cardiac surgery, especially in the postoperative period. The aim of this study was to test the hypothesis that inhaled nitric oxide (iNO) would improve the hemodynamic effects and short-term clinical outcomes of patients with mitral stenosis and severe pulmonary hypertension who undergo cardiac surgery in a randomized, controlled study. Twenty-nine patients (4 men, 25 women; mean age 46 ± 2 years) were randomly allocated to receive iNO (n = 14) or oxygen (n = 15) for 48 hours immediately after surgery. Hemodynamic data, the use of vasoactive drugs, duration of stay, and short-term complications were assessed. No differences in baseline characteristics were observed between the groups. After 24 and 48 hours, patients receiving iNO had a significantly greater increase in cardiac index compared to patients receiving oxygen (p <0.0001). Pulmonary vascular resistance was also more significantly reduced in patients receiving iNO versus oxygen (−117 dyne/s/cm5, 95% confidence interval −34 to −200, vs 40 dyne/s/cm5, 95% confidence interval −34 to 100, p = 0.005) at 48 hours. Patients in the iNO group used fewer systemic vasoactive drugs (mean 2.1 ± 0.14 vs 2.6 ± 0.16, p = 0.046) and had a shorter intensive care unit stay (median 2 days, interquartile range 0.25, vs median 3 days, interquartile range 7, p = 0.02). In conclusion, iNO immediately after surgery in patients with mitral stenosis and severe pulmonary hypertension improves hemodynamics and may have short-term clinical benefits. It has been shown that the pulmonary vasoconstriction present in clinical pulmonary hypertension can be alleviated in the short term using inhaled nitric oxide (iNO) through a mechanism involving vascular smooth muscle relaxation.1Griffiths M.J. Evans T.W. Inhaled nitric oxide therapy in adults.N Engl J Med. 2005; 353: 2683-2695Crossref PubMed Scopus (286) Google Scholar In humans, the ability of iNO to reduce pulmonary vascular resistance (PVR) while sparing systemic resistance by selective pulmonary vasodilatation has been exploited in patients with right ventricular dysfunction,2Bhorade S. Christenson J. O'Connor M. Lavoie A. Pohlman A. Hall J.B. Response to inhaled nitric oxide in patients with acute right heart syndrome.Am J Respir Crit Care Med. 1999; 159: 571-579Crossref PubMed Scopus (134) Google Scholar, 3Knothe C. Scholz S. Zickmann B. Marquart B. Dapper F. Hempelmann G. NO inhalation in heart surgery procedures: relevance for right heart function?.Anaesthesist. 1996; 45 ([article in German]): 240-248Crossref PubMed Scopus (4) Google Scholar acute lung injury,4Taylor R.W. Zimmerman J.L. Dellinger R.P. Straube R.C. Criner G.J. Davis Jr, K. Kelly K.M. Smith T.C. Small R.J. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.JAMA. 2004; 291: 1603-1609Crossref PubMed Scopus (431) Google Scholar and lung transplantation.5Khan T.A. Schnickel G. Ross D. Bastani S. Laks H. Esmailian F. Marelli D. Beygui R. Shemin R. Watson L. Vartapetian I. Ardehali A. A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients.J Thorac Cardiovasc Surg. 2009; 138: 1417-1424Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Specifically in patients with mitral stenosis, in whom chronic left-sided underfilling is prominent, the use of iNO has not been studied thoroughly. Most studies were not randomized or controlled, did not look specifically at clinical outcomes but only focused on the immediate hemodynamic effects of iNO,6Girard C. Lehot J.J. Pannetier J.C. Filley S. Ffrench P. Estanove S. Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension.Anesthesiology. 1992; 77: 880-883Crossref PubMed Scopus (204) Google Scholar used iNO during brief periods only,7Santini F. Casali G. Franchi G. Auriemma S. Lusini M. Barozzi L. Favaro A. Messina A. Mazzucco A. Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults.Int J Cardiol. 2005; 103: 156-163Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Fattouch K. Sbraga F. Bianco G. Speziale G. Gucciardo M. Sampognaro R. Ruvolo G. Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement.J Card Surg. 2005; 20: 171-176Crossref PubMed Scopus (91) Google Scholar or were restricted to children9Atz A.M. Adatia I. Jonas R.A. Wessel D.L. Inhaled nitric oxide in children with pulmonary hypertension and congenital mitral stenosis.Am J Cardiol. 1996; 77: 316-319Abstract Full Text PDF PubMed Scopus (47) Google Scholar or women.10Mahoney P.D. Loh E. Blitz L.R. Herrmann H.C. Hemodynamic effects of inhaled nitric oxide in women with mitral stenosis and pulmonary hypertension.Am J Cardiol. 2001; 87: 188-192Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Fattouch et al11Fattouch K. Sbraga F. Sampognaro R. Bianco G. Gucciardo M. Lavalle C. Vizza C.D. Fedele F. Ruvolo G. Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, double-blind study.J Cardiovasc Med (Hagerstown). 2006; 7: 119-123Crossref PubMed Scopus (56) Google Scholar compared the use of iNO in mitral stenosis with inhaled prostacyclin and intravenous nitroprusside but did not include a control group not using vasodilators. This is the first randomized controlled study of patients with severe mitral stenosis and pulmonary hypertension using iNO compared to a control group receiving only oxygen. We observed not only the hemodynamic effects of each treatment but also the associated short-term clinical outcomes in these patients. The study was approved by the institutional research committee, and all subjects gave written informed consent. Patients were consecutively selected at an outpatient cardiac valve disease clinic of a tertiary cardiology referral hospital. Men and women aged ≥18 years were selected if they met all the following inclusion criteria: mitral stenosis with a valve area <1.5 cm2; severe pulmonary hypertension, defined as pulmonary artery systolic pressure (PASP) >60 mm Hg; and symptomatic disease with New York Heart Association functional class ≥II. Patients were excluded if they presented with concomitant valvular disease other than mitral stenosis (specifically moderate or important mitral regurgitation as defined by preoperative quantitative echocardiography) or had severe left or right ventricular dysfunction, defined as an ejection fraction <40% by preoperative echocardiography. Nineteen screened patients were excluded before randomization because of concomitant mitral regurgitation (15 patients) or severe left ventricular dysfunction (3 patients). Central computerized randomization of the treatment assignments was performed. Concealment was interrupted only when the patient was weaned from cardiopulmonary bypass and started to receive the designated therapy. Before surgery, baseline 2-dimensional echocardiography and Doppler echocardiography were performed using commercially available equipment (Sonos 5500; Philips Medical Systems, Andover, Massachusetts). The ejection fraction, transmitral valve gradient, valve area calculated using the pressure half-time method, mitral valve echocardiographic score,12Wilkins G.T. Weyman A.E. Abascal V.M. Block P.C. Palacios I.F. Percutaneous balloon dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation.Br Heart J. 1988; 60: 299-308Crossref PubMed Scopus (975) Google Scholar and PASP estimated using the modified Bernoulli equation were determined. Before anesthesia induction in the operating room, a pulmonary artery catheter was placed in the right internal jugular vein or right subclavian vein, and pulmonary capillary wedge pressure, PASP, cardiac output calculated by thermodilution, and PVR were established. Cardiac output measurements were obtained from the mean of 3 consecutive end-expiratory readings. Patients were operated on using standard surgical procedures, and the choice of valve repair or replacement was left to the surgeons' discretion. Immediately before weaning off cardiopulmonary bypass, patients randomized to the iNO arm had the NO delivery equipment attached to the anesthesia breathing circuit. The surgical team was not aware of the patient randomization allocation until this moment. Inhaled NO was delivered using NO tanks connected to the inspiratory limb of the airflow tubes at a concentration of 10 ppm, a dose with the best cost/benefit ratio according to previous dosing studies.13Solina A.R. Ginsberg S.H. Papp D. Grubb W.R. Scholz P.M. Pantin E.J. Cody R.P. Krause T.J. Dose response to nitric oxide in adult cardiac surgery patients.J Clin Anesth. 2001; 13: 281-286Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Concentrations of iNO and NO2 were measured continuously with a dedicated monitoring device (NOxBox; Bedfont Instruments, Rochester, United Kingdom). Patients randomized to the oxygen control group continued to receive standard anesthesia care to maintain oxygen saturation >95%. All patients were then transferred to a surgical intensive care unit (ICU) and continued the assigned treatment for up to 48 hours, in the ICU or in the ward. The criteria for ICU discharge were prespecified as hemodynamic stability (defined by a mean systemic arterial pressure >65 mm Hg), mechanical ventilation weaning with no signs of respiratory distress (as evaluated by the attending physician, who was blind to the outcomes of the study), urinary output >0.5 ml/kg/hour, and no significant bleeding from surgical sites. No patient was held in the ICU because of the protocol if he or she was considered apt for discharge and achieved the mentioned criteria. After extubation, patients received iNO or oxygen through a facial mask, keeping the aforementioned parameters. In all patients, an airtight sealed nonrebreathing cushioned face mask was used, allowing minimum leakage of either iNO or oxygen. Inhaled NO concentration was measured through a sampling line adjacent to the mask to guarantee a precise reading of the delivered concentration. The use of any vasoactive drugs was permitted throughout the study and was left to the choice of the attending physician in the ICU, blinded to the outcomes of the study. At 24 and 48 hours after the initiation of iNO or control oxygen, a new reading of the pulmonary artery catheter was carried out, with the determination of the same parameters obtained before surgery. After 48 hours, patients withdrew oxygen therapy unless contraindicated by the assisting physician. Patients receiving iNO were progressively weaned, with total switch to room air or oxygen by mask as needed in 1 hour. All patients were followed during the total hospital stay for the assessment of predefined complications (acute renal insufficiency, infections, need for reintubation, liver failure, and death). The primary outcomes of this study were the differences at 48 hours compared to the baseline cardiac index and PVR in each treatment group. These primary end points were chosen to allow a more accurate sample size calculation as well as to provide a more relevant link to the clinical effects. Secondary outcomes included clinical variables regarding postoperative complications, total days in the ICU, total hospital stay, and number and dosing of systemic intravenous vasoactive drugs. Complications were defined as acute renal insufficiency (renal output <0.3 ml/kg/hour), need for reintubation, sepsis according to standardized definitions,14Levy M.M. Fink M.P. Marshall J.C. Abraham E. Angus D. Cook D. Cohen J. Opal S.M. Vincent J.L. Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med. 2003; 31: 1250-1256Crossref PubMed Scopus (4657) Google Scholar cardiogenic shock, and need for urgent reoperation. Data are presented as mean ± SD, except for total hospital and ICU length of stay, which were not normally distributed and are presented as median and interquartile range. Comparisons among absolute values of the hemodynamic parameters preoperatively and at 24 and 48 hours were done using analysis of variance for repeated measures on ranks with Tukey's and profile tests for time and group differences. Analyses of the differences as well as other comparisons regarding the iNO and control groups were made using unpaired Student's t tests for continuous variables, Mann-Whitney or chi-square tests for proportions, and Fisher's exact tests as needed. Sample size was calculated on the basis of an α error of 0.05 and power of 80% to detect a 40% difference in PVR between the 2 groups. We calculated the number of subjects needed for the study to be 30 (15 in each group) on the basis of previous studies.10Mahoney P.D. Loh E. Blitz L.R. Herrmann H.C. Hemodynamic effects of inhaled nitric oxide in women with mitral stenosis and pulmonary hypertension.Am J Cardiol. 2001; 87: 188-192Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar All calculations were done using intention-to-treat analysis and were performed in SAS version 9.1.3 (SAS Institute Inc., Cary, North Carolina). Significance was assumed at a 2-tailed p value <0.05. Twenty-nine patients (86% women, mean age 46 ± 2 years) were enrolled in the study, with a total evaluation of 48 patients. One patient withdrew consent on the morning of the surgery and was not included in the final analysis. The baseline clinical characteristics of the 2 groups are listed in Table 1. No significant differences between the groups were observed. Patients enrolled were characterized by significant mitral stenosis (mean valve area 0.89 ± 0.04 cm2) with severe pulmonary hypertension (mean PASP 73 ± 3 mm Hg, mean PVR 303 ± 31 dyne/s/cm5). Only 1 death occurred; a patient in the oxygen group died 22 days after surgery with sepsis and multiple-organ failure. All randomized patients received the assigned treatment with iNO or oxygen during the full duration of the planned intervention, with no crossovers. Patients in the iNO group were mechanically ventilated for 7.5 ± 8.5 hours, while patients receiving oxygen were ventilated for 15.1 ± 21.8 hours (p = 0.23). No patient developed significant mitral valve regurgitation as assessed by echocardiography 7 days after surgery (data not shown).Table 1Baseline characteristicsiNOOxygenVariable(n = 14)(n = 15)p ValueAge (years)48 ± 1144 ± 130.43Women13 (93%)12 (80%)0.60Body mass index (kg/m2)23 ± 422 ± 40.69New York Heart Association functional class0.39 II3 (21%)6 (40%) III10 (72%)7 (47%) IV1 (7%)2 (13%)Atrial fibrillation8 (57%)8 (53%)0.99Left ventricular ejection fraction (%)71 ± 870 ± 60.48Mitral valve echocardiographic score10.1 ± 1.710.6 ± 1.00.55Mitral valve area (cm2)0.92 ± 0.180.85 ± 0.210.35Mitral valve mean diastolic gradient (mm Hg)14.9 ± 3.716.4 ± 5.80.48PASP (echocardiography) (mm Hg)80 ± 2180 ± 170.71Pulmonary capillary wedge pressure (mm Hg)26.3 ± 10.527.9 ± 10.50.87PASP (pulmonary artery catheterization) (mm Hg)73 ± 1073 ± 140.99Cardiac index (L/min/m2)2.35 ± 0.62.89 ± 0.90.10PVR (dyne/s/cm5)341 ± 183264 ± 1330.38Bypass time (minutes)88 ± 3194 ± 340.59Valve replacement6 (43%)3 (20%)0.25Reoperation4 (29%)3 (20%)0.91Intensive care unit stay (days)2.0 (0.25)3.0 (7.0)0.02Data are expressed as mean ± SD, number (percentage), or median (interquartile range). Open table in a new tab Data are expressed as mean ± SD, number (percentage), or median (interquartile range). Changes in hemodynamic parameters after surgery are presented in Figure 1, Figure 2. After 24 and 48 hours, the 2 groups had significant reductions in pulmonary capillary wedge pressure, with no differences between patients receiving iNO or oxygen. Significant decreases also occurred in PASP at 24 and 48 hours compared to that at baseline in the 2 groups, with no differences between them. However, the cardiac index increased significantly in patients receiving iNO at 24 and 48 hours (p <0.0001 for both). Moreover, although the cardiac index increased significantly compared to that at baseline in the 2 groups after 24 hours, this increase was sustained at 48 hours only in patients who received iNO, with a mean increase of 1.58 L/min/m2 (95% confidence interval [CI] 1.0 to 2.16, p <0.0001) versus 0.4 L/min/m2 (95% CI 0.01 to 0.82, p = 0.06) in patients receiving oxygen. PVR changes compared to those at baseline were also observed only in the group with iNO at 24 hours (−103 dyne/s/cm5, 95% CI −14 to −192, p = 0.04) and 48 hours (−117 dyne/s/cm5, 95% CI −34 to −200, p = 0.02), with significant differences between the 2 groups at 48 hours (p = 0.005). Partial pressure of oxygen was not significantly different between the groups at baseline or at 24 and 48 hours (baseline iNO group 92 ± 7 vs 93 ± 9 mm Hg in the oxygen group, p = 0.90; 24 hours 190 ± 72 vs 221 ± 97 mm Hg, p = 0.40; 48 hours 158 ± 67 vs 193 ± 102 mm Hg, p = 0.50). Although we did not invasively monitor the hemodynamic status of patients after weaning of iNO or oxygen, no patient in the study experienced any clinically relevant hemodynamic symptoms after withdrawal of either therapy.Figure 2Changes compared to baseline of hemodynamic data in patients using oxygen (white bars) and iNO (black bars). Cardiac index increased much more significantly in patients receiving iNO at 24 and 48 hours (p <0.01 for both) compared to preoperative values.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Patients who received iNO had significantly shorter ICU stays compared to patients who received oxygen (Table 1). However, total hospital stay was similar in the 2 groups (median 10 days, interquartile range 6.0 in iNO group vs median 13 days, interquartile range 16.25 in the oxygen group, p = 0.14). The use of concurrent vasoactive drugs might have interfered with the results regarding the previous hemodynamic measurements. Table 2 lists systemic intravenous vasoactive drugs used in the 2 groups during ICU and hospital stay. Although no significant differences were observed regarding the percentage of patients using each drug or the maximum dose used in each patient, the mean number of systemic vasoactive drugs used during hospital stay was significantly smaller in the iNO group (2.1 ± 0.14) compared to that in patients receiving only oxygen (2.6 ± 0.16) (p = 0.046). There were a nonsignificant smaller proportion of patients receiving nitroprusside and milrinone in the iNO group compared to controls. Other drugs known to significantly affect pulmonary pressure were not used by any patient in our study either during ICU or ward stay.Table 2Concurrent vasoactive drugs used in each group during intensive care unit and hospital stayiNOOxygenDrug(n=14)(n=15)p ValueDobutamine Percentage of patients86%87%0.90 Maximum dose (μg/kg/min)7.7 ± 3.88.7 ± 4.90.37Nitroprusside Percentage of patients43%73%0.08 Maximum dose (μg/kg/min)0.68 ± 0.670.86 ± 1.390.49Dopamine Percentage of patients21%27%0.37 Maximum dose (μg/kg/min)4.2 ± 1.56.7 ± 1.40.99Norepinephrine Percentage of patients14%40%0.28 Maximum dose (μg/min)1.77 ± 0.42.55 ± 4.70.19Milrinone Percentage of patients29%60%0.06 Maximum dose (μg/kg/min)0.15 ± 0.280.29 ± 0.320.14Maximum number of systemic vasoactive drugs used2.1 ± 0.142.6 ± 0.160.046 Open table in a new tab The percentage of patients with any of the predefined complications was similar in the 2 groups (9 of 15 [60%] in the oxygen group vs 4 of 14 [29%] in the iNO group, p = 0.14). According to the definitions of complications previously mentioned, 3 patients in the iNO group needed urgent reoperation due to bleeding complications (1 for cardiac tamponade and 2 for >500 ml of sanguineous drainage in the first hour postoperatively), and 1 patient developed sepsis. In the oxygen group, 2 patients needed reintubation, 2 patients underwent urgent reoperation (1 for cardiac tamponade and 1 for high blood drainage), 1 patient developed acute renal failure, and 4 patients were diagnosed with sepsis. Although we did not find any significant differences between the groups regarding complications, we could determine that patients who presented with complications after surgery had significantly fewer change in PVR values compared to patients with no complications at 24 and 48 hours. The mean change in PVR in patients with complications was 4 ± 42 dyne/s/cm5 compared to −124 ± 34 dyne/s/cm5 in patients with no complications at 24 hours (p = 0.02) and −31 ± 41 and −98 ± 37 dyne/s/cm5, respectively, at 48 hours (p = 0.03). We have demonstrated that treatment with iNO immediately after surgery in patients with significant mitral stenosis and severe pulmonary hypertension is associated with increased cardiac output and reduced PVR. This in turn translated into shorter ICU stays and less need for systemic vasoactive drug use. Different therapies for the postoperative management of pulmonary hypertension are available and include intravenous nitroprusside, inhaled prostacyclin, and intravenous phosphodiesterase inhibitors.15Zamanian R.T. Haddad F. Doyle R.L. Weinacker A.B. Management strategies for patients with pulmonary hypertension in the intensive care unit.Crit Care Med. 2007; 35: 2037-2050Crossref PubMed Scopus (175) Google Scholar In contrast with these therapies, iNO is rapidly inactivated through a hemoglobin-mediated process while still in the pulmonary circulation,16Creagh-Brown B.C. Griffiths M.J. Evans T.W. Bench-to-bedside review: Inhaled nitric oxide therapy in adults.Crit Care. 2009; 13: 221Crossref PubMed Scopus (71) Google Scholar with clinical studies showing no effect on systemic circulation17Pepke-Zaba J. Higenbottam T.W. Dinh-Xuan A.T. Stone D. Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.Lancet. 1991; 338: 1173-1174Abstract PubMed Scopus (959) Google Scholar, 18George I. Xydas S. Topkara V.K. Ferdinando C. Barnwell E.C. Gableman L. Sladen R.N. Naka Y. Oz M.C. Clinical indication for use and outcomes after inhaled nitric oxide therapy.Ann Thorac Surg. 2006; 82: 2161-2169Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and an established safety profile even up to 40 ppm.19Hugod C. Effect of exposure to 43 ppm nitric oxide and 3.6 ppm nitrogen dioxide on rabbit lung A light and electron microscopic study.Int Arch Occup Environ Health. 1979; 42: 159-167Crossref PubMed Scopus (76) Google Scholar In our patients, also not statistically significant, there was a smaller proportion of patients in the iNO group receiving nitroprusside as well as milrinone, and no differences were found in the use of other systemic vasoactive drugs. This reinforces the benefits of iNO use, because these patients exhibited a significant decrease in PVR while using, at most, the same doses of vasoactive drugs. In our study, we chose to use a dose of 10 ppm of iNO to further minimize any toxic risks associated with the drug and due to previous dose-response studies showing no benefits of increased doses.13Solina A.R. Ginsberg S.H. Papp D. Grubb W.R. Scholz P.M. Pantin E.J. Cody R.P. Krause T.J. Dose response to nitric oxide in adult cardiac surgery patients.J Clin Anesth. 2001; 13: 281-286Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar The 34% reduction in PVR seen in patients using iNO is in accordance with previous reports indicating reductions of PVR up to 27% to 45% with iNO, with more significant reductions being obtained with 20 than at 10 ppm.7Santini F. Casali G. Franchi G. Auriemma S. Lusini M. Barozzi L. Favaro A. Messina A. Mazzucco A. Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults.Int J Cardiol. 2005; 103: 156-163Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Fattouch K. Sbraga F. Bianco G. Speziale G. Gucciardo M. Sampognaro R. Ruvolo G. Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement.J Card Surg. 2005; 20: 171-176Crossref PubMed Scopus (91) Google Scholar, 20Sitbon O. Brenot F. Denjean A. Bergeron A. Parent F. Azarian R. Herve P. Raffestin B. Simonneau G. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension A dose-response study and comparison with prostacyclin.Am J Respir Crit Care Med. 1995; 151: 384-389Crossref PubMed Scopus (290) Google Scholar We also observed an increase in cardiac output after surgery in the 2 groups, but the increase with iNO was significantly greater and sustained. This finding has also been reported by others but was not reproduced in all iNO studies.10Mahoney P.D. Loh E. Blitz L.R. Herrmann H.C. Hemodynamic effects of inhaled nitric oxide in women with mitral stenosis and pulmonary hypertension.Am J Cardiol. 2001; 87: 188-192Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 21Hayward C.S. Kalnins W.V. Rogers P. Feneley M.P. MacDonald P.S. Kelly R.P. Effect of inhaled nitric oxide on normal human left ventricular function.J Am Coll Cardiol. 1997; 30: 49-56Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This apparent discrepancy can be attributed to differences in preoperative cardiac function or hemodynamic conditions, all of which might influence the final cardiac output observed with the treatment. In fact, in the presence of ventricular dysfunction, an increase in left atrial end-diastolic pressure with increased pulmonary blood flow with iNO may lead to pulmonary edema and reduced cardiac output.22Loh E. Stamler J.S. Hare J.M. Loscalzo J. Colucci W.S. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction.Circulation. 1994; 90: 2780-2785Crossref PubMed Google Scholar It is also interesting to point out that despite the reductions in pulmonary hypertension observed in the study, the values of the mean PASP were still elevated in the 2 groups. Part of this is due to the vast and complex pathophysiology of pulmonary hypertension, in which a variety of arterial abnormalities play a role at different stages in the same patient.23McLaughlin V.V. Archer S.L. Badesch D.B. Barst R.J. Farber H.W. Lindner J.R. Mathier M.A. McGoon M.D. Park M.H. Rosenson R.S. Rubin L.J. Tapson V.F. Varga J. Harrington R.A. Anderson J.L. Bates E.R. Bridges C.R. Eisenberg M.J. Ferrari V.A. Grines C.L. Hlatky M.A. Jacobs A.K. Kaul S. Lichtenberg R.C. Moliterno D.J. Mukherjee D. Pohost G.M. Schofield R.S. Shubrooks S.J. Stein J.H. Tracy C.M. Weitz H.H. Wesley D.J. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association.Circulation. 2009; 119: 2250-2294Crossref PubMed Scopus (888) Google Scholar Therefore, acute interventions in the postoperative setting may revert only part of the functional and structural changes represented by intimal hyperplasia, medial hypertrophy, adventitial proliferation, thrombosis, and inflammation. The increase in cardiac output and reduced PVR observed in the iNO group in this study was associated with an improvement in several clinical parameters that may result in improved management of these patients after surgery. First, the total ICU stay was reduced using iNO, a finding also reported by others recently.11Fattouch K. Sbraga F. Sampognaro R. Bianco G. Gucciardo M. Lavalle C. Vizza C.D. Fedele F. Ruvolo G. Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: a randomized, prospective, double-blind study.J Cardiovasc Med (Hagerstown). 2006; 7: 119-123Crossref PubMed Scopus (56) Google Scholar We also found that the use of iNO permitted a more judicious use of systemic vasoactive drugs, with a better hemodynamic profile in these patients despite the use of a reduced number of these agents. Interestingly, a trend was noted toward fewer complications in patients receiving iNO compared to controls, with a shorter total hospital stay. Patients with no complications had significantly higher reductions in PVR postoperatively than did patients presenting with any complications. This may reflect the baseline reversibility of pulmonary hypertension in these patients, but the role of iNO in this reduction cannot be disregarded. Moreover, patients enrolled in this study represented a very high risk population, with a mean PASP of 73 ± 3 mm Hg, much higher than the 39 to 61 mm Hg reported in other studies.7Santini F. Casali G. Franchi G. Auriemma S. Lusini M. Barozzi L. Favaro A. Messina A. Mazzucco A. Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults.Int J Cardiol. 2005; 103: 156-163Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Fattouch K. Sbraga F. Bianco G. Speziale G. Gucciardo M. Sampognaro R. Ruvolo G. Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement.J Card Surg. 2005; 20: 171-176Crossref PubMed Scopus (91) Google Scholar, 24Schmid E.R. Burki C. Engel M.H. Schmidlin D. Tornic M. Seifert B. Inhaled nitric oxide versus intravenous vasodilators in severe pulmonary hypertension after cardiac surgery.Anesth Analg. 1999; 89: 1108-1115Crossref PubMed Scopus (47) Google Scholar, 25Yurtseven N. Karaca P. Kaplan M. Ozkul V. Tuygun A.K. Aksoy T. Canik S. Kopman E. Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery.Anesthesiology. 2003; 99: 855-858Crossref PubMed Scopus (37) Google Scholar Therefore, any degree of reduction in PVR that would mitigate complications in these patients would be desirable. Limitations of this study include the hemodynamic readings at 24 and 48 hours in the ICU setting, while the patients were taking other vasoactive drugs that might have confounded our results, although no significant differences were observed in terms of frequency and maximum doses of these drugs in the 2 groups. The use of right ventricular parameters as outcomes of the study would also have enhanced our results, but we believe that other variables studied already give independent and prognostic information regarding the right-sided cardiac chambers to allow the conclusions presented here. Last, although it could be desirable to blind the effective treatment, because we needed to monitor the values of NO2 for safety reasons, this approach would not seem possible.