Practice Variation, Costs and Outcomes Associated with the Use of Inhaled Nitric Oxide in Pediatric Heart Transplant Recipients
- 82 Downloads
Right ventricular (RV) failure is a potentially fatal complication following heart transplantation (HTx). Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that is used to decrease pulmonary vascular resistance immediately post-HTx to reduce the risk of RV failure. The aim of this study was to describe utilization patterns, costs, and outcomes associated with post-transplant iNO use in children. All pediatric HTx recipients (2002–2016) were identified from a unique linked PHIS/SRTR dataset. Post-HTx iNO use was determined based on hospital billing data. Utilization patterns and associated costs were described. The association of iNO support with post-HTx survival was assessed using the Kaplan–Meier method and a multivariable Cox proportional hazards model was used to adjust for risk factors. A total of 2833 pediatric HTx recipients from 28 centers were identified with 1057 (36.5%) receiving iNO post-HTx. Post-HTx iNO use showed significant increase overall (17.2–54.7%, p < 0.001) and wide variation among centers (9–100%, p < 0.001). Patients with congenital heart disease (aOR 1.4, 95% CI 1.2, 1.6), requiring mechanical ventilation at HTx (aOR 1.3, 95% CI 1.1, 1.6), and pre-transplant iNO (aOR 9.3, 95% CI 5.4, 16) were more likely to receive iNO post-HTx. The median daily cost of iNO was $2617 (IQR $1843–$3646). Patients who required > 5 days of iNO post-HTx demonstrated inferior 1-year post-HTx survival (p < 0.001) and iNO use > 5 days was independently associated with worse post-HTx survival (AHR 1.6, 95% CI 1.2, 2.1; p < 0.001). There is wide variation in iNO use among centers following pediatric HTx with use increasing over time despite significant incremental cost. Prolonged iNO use post-HTx is associated with worse survival, likely serving as a marker of residual illness severity. Further research is needed to define the populations that derive the greatest benefit from this costly therapy.
KeywordsChild Heart transplantation Nitric oxide Heart failure Vasodilator agents
This project was supported through internal funding from the Katherine Dodd Faculty Scholar Program at Vanderbilt University (JG). Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL123938 (Bethesda, MD) (JS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
The data reported here have been supplied by the Minneapolis Medical Research Foundation as the contractor for the SRTR. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy of or interpretation by the SRTR or the U.S. Government.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
For this type of study formal consent is not required.
- 2.Huang J, Trinkaus K, Huddleston CB, Mendeloff EN, Spray TL, Canter CE (2004) Risk factors for primary graft failure after pediatric cardiac transplantation: importance of recipient and donor characteristics. J Heart Lung Transplant 23(6):716–722. https://doi.org/10.1016/j.healun.2003.08.001 CrossRefPubMedGoogle Scholar
- 3.Hoskote A, Carter C, Rees P, Elliott M, Burch M, Brown K (2010) Acute right ventricular failure after pediatric cardiac transplant: predictors and long-term outcome in current era of transplantation medicine. J Thorac Cardiovasc Surg 139(1):146–153. https://doi.org/10.1016/j.jtcvs.2009.08.020 CrossRefPubMedGoogle Scholar
- 4.Davies RR, Russo MJ, Mital S, Martens TM, Sorabella RS, Hong KN, Gelijns AC, Moskowitz AJ, Quaegebeur JM, Mosca RS, Chen JM (2008) Predicting survival among high-risk pediatric cardiac transplant recipients: an analysis of the United Network for Organ Sharing database. J Thorac Cardiovasc Surg 135(1):147–155, 155 e141–142. https://doi.org/10.1016/j.jtcvs.2007.09.019.
- 6.Sabato LA, Salerno DM, Moretz JD, Jennings DL (2017) Inhaled pulmonary vasodilator therapy for management of right ventricular dysfunction after left ventricular assist device placement and cardiac transplantation. Pharmacotherapy 37(8):944–955. https://doi.org/10.1002/phar.1959 CrossRefPubMedGoogle Scholar
- 8.Ofori-Amanfo G, Hsu D, Lamour JM, Mital S, O’Byrne ML, Smerling AJ, Chen JM, Mosca R, Addonizio LJ (2011) Heart transplantation in children with markedly elevated pulmonary vascular resistance: impact of right ventricular failure on outcome. J Heart Lung Transplant 30(6):659–666. https://doi.org/10.1016/j.healun.2010.12.007 CrossRefPubMedGoogle Scholar
- 9.Daftari B, Alejos JC, Perens G (2010) Initial experience with sildenafil, bosentan, and nitric oxide for pediatric cardiomyopathy patients with elevated pulmonary vascular resistance before and after orthotopic heart transplantation. J Transplant 2010:656984. https://doi.org/10.1155/2010/656984 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Godown J, Thurm C, Dodd DA, Soslow JH, Feingold B, Smith AH, Mettler BA, Thompson B, Hall M (2017) A unique linkage of administrative and clinical registry databases to expand analytic possibilities in pediatric heart transplantation research. Am Heart J 194:9–15. https://doi.org/10.1016/j.ahj.2017.08.014 CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Paniagua MJ, Crespo-Leiro MG, Rodriguez JA, Fojon S, Pastor J, Castro MJ, Hermida LF, Cuenca JJ, Juffe-Stein A, Castro-Beiras A (1999) Usefulness of nitric oxide inhalation for management of right ventricular failure after heart transplantation in patients with pretransplant pulmonary hypertension. Transplant Proc 31(6):2505–2506CrossRefPubMedGoogle Scholar
- 20.Richmond ME, Law YM, Das BB, Everitt MD, Kukreja M, Naftel DC et al (2015) Elevated pre-transplant pulmonary vascular resistance is not associated with mortality in children without congenital heart disease: a multicenter study. J Heart Lung Transplant 34(3):448–456. https://doi.org/10.1016/j.healun.2014.04.021 CrossRefPubMedGoogle Scholar
- 21.Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ et al (2017) The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant 36(10):1037–1046. https://doi.org/10.1016/j.healun.2017.07.019 CrossRefPubMedGoogle Scholar
- 23.Tsukashita M, Takayama H, Takeda K, Han J, Colombo PC, Yuzefpolskaya M, Topkara VK, Garan AR, Mancini DM, Kurlansky PA, Naka Y (2015) Effect of pulmonary vascular resistance before left ventricular assist device implantation on short- and long-term post-transplant survival. J Thorac Cardiovasc Surg 150(5):1352–1360, 1361 e1351–1352. https://doi.org/10.1016/j.jtcvs.2015.07.012
- 24.Egbe AC, Connolly HM, Miranda WR, Ammash NM, Hagler DJ, Veldtman GR, Borlaug BA (2017) Hemodynamics of Fontan failure: the role of pulmonary vascular disease. Circ Heart Fail. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004515 PubMedPubMedCentralGoogle Scholar
- 25.Mitchell MB, Campbell DN, Ivy D, Boucek MM, Sondheimer HM, Pietra B, Das BB, Coll JR (2004) Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. J Thorac Cardiovasc Surg 128(5):693–702. https://doi.org/10.1016/j.jtcvs.2004.07.013 CrossRefPubMedGoogle Scholar
- 29.Brown AT, Gillespie JV, Miquel-Verges F, Holmes K, Ravekes W, Spevak P et al (2012) Inhaled epoprostenol therapy for pulmonary hypertension: improves oxygenation index more consistently in neonates than in older children. Pulm Circ 2(1):61–66. https://doi.org/10.4103/2045-8932.94835 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, Zanaboni PB, Moazami N, Smith JR (2004) Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg 127(4):1058–1067. https://doi.org/10.1016/j.jtcvs.2003.11.035 CrossRefPubMedGoogle Scholar
- 32.Rimensberger PC, Spahr-Schopfer I, Berner M, Jaeggi E, Kalangos A, Friedli B, Beghetti M (2001) Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms. Circulation 103(4):544–548CrossRefPubMedGoogle Scholar
- 34.Theodoraki K, Tsiapras D, Tsourelis L, Zarkalis D, Sfirakis P, Kapetanakis E, Alivizatos P, Antoniou T (2006) Inhaled iloprost in eight heart transplant recipients presenting with post-bypass acute right ventricular dysfunction. Acta Anaesthesiol Scand 50(10):1213–1217. https://doi.org/10.1111/j.1399-6576.2006.01139.x CrossRefPubMedGoogle Scholar
- 36.Khan TA, Schnickel G, Ross D, Bastani S, Laks H, Esmailian F, Marelli D, Beygui R, Shemin R, Watson L, Vartapetian I, Ardehali A (2009) A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. J Thorac Cardiovasc Surg 138(6):1417–1424. https://doi.org/10.1016/j.jtcvs.2009.04.063 CrossRefPubMedGoogle Scholar