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J Thorac Cardiovasc Surg 2008;136:529-531
© 2008 The American Association for Thoracic Surgery
Brief Communication |
a Division of Pediatric Cardiothoracic Surgery, Saint Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo
b Division of Pediatric Cardiology, Saint Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo
Received for publication November 14, 2007; accepted for publication January 9, 2008. * Address for reprints: Sanjiv K. Gandhi, MD, Division of Cardiothoracic Surgery, Saint Louis Children's Hospital, Suite 5S50, 1 Children's Place, St Louis, MO 63110. (Email: gandhis{at}wustl.edu).
Severe pulmonary hypertension unresponsive to acute pulmonary vasodilators—"fixed" or "irreversible" pulmonary hypertension—has traditionally been regarded as a contraindication to an orthotopic heart transplant. We report a novel strategy of combining mechanical biventricular assist device (BiVAD) support provided by the Berlin Heart EXCOR device (Berlin Heart AG, Berlin, Germany) with medical pulmonary vasodilator therapy in the cases of 2 children initially referred to our institution for a heart–lung transplant because of heart failure and presumed irreversible pulmonary hypertension. In both cases, our approach significantly improved the pulmonary hypertension, permitting an orthotopic heart transplant alone, a procedure with a much better long-term prognosis than a heart–lung transplant.
Patient 1
Patient 1 was a 2-year-old boy with congenitally corrected transposition of the great arteries, congenital heart block, and a small ventricular septal defect. He had undergone implantation of a single-chamber epicardial pacemaker as a neonate. He was seen at 2 years with worsening ventricular failure. Cardiac catheterization at that time demonstrated a pulmonary vascular resistance (PVR) of 15 Woods units/m2 and a transpulmonary gradient of 40 mm Hg, unresponsive to oxygen or inhaled nitric oxide (
Table 1).
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Patient 2
The second patient was a 10-month-old girl with a presentation of failure to thrive who was discovered to have a restrictive cardiomyopathy and severe pulmonary hypertension. Anatomically, she had a very small left ventricle, probably representing a forme fruste of hypoplastic left heart syndrome. Cardiac catheterization demonstrated a PVR of 11 Wood units/m2 and a transpulmonary gradient of 42 mm Hg, minimally responsive to a combination of oxygen and inhaled nitric oxide (
Table 2). The patient was started on a regimen of intravenous epoprostenol (initiated at 1 ng/[kg · min] and titrated to 15 ng/[kg · min] over 2 weeks), milrinone (1 µg/[kg · min]), and oral sildenafil citrate (3 mg four times daily) and was also maintained on inhaled nitric oxide (20 ppm by nasal cannula). Repeat cardiac catheterization 2 weeks after the initiation of medical therapy demonstrated only minimal improvement in the pulmonary hypertension. The decision was made to implant EXCOR BiVADs. In addition to maintenance of inhaled nitric oxide therapy, the epoprostenol was aggressively upwardly titrated (to a maximum dose of 40 ng/[kg · min]) and the sildenafil dosing was increased (7 mg by mouth four times daily). At 6 postoperative weeks, the PVR had dropped to 4.6 Woods units/m2 and the transpulmonary gradient had declined to 14 mm Hg. At 10 postoperative weeks, a successful orthotopic heart transplant was performed. The patient's immediate postoperative course was uneventful. Epoprostenol was tapered over 3 weeks, and she was discharged on postoperative day 25. Sildenafil citrate was tapered over 2 months. The patient's posttransplant hemodynamics normalized, and she remains clinically well 6 months after her heart transplant.
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Severe pulmonary hypertension, especially associated with congenital heart disease, has traditionally been regarded as an absolute contraindication to a cardiac transplant alone because of the prohibitive risk of right ventricular failure in the allograft.1 The outlook for these patients has changed, however, with the advent of potent pulmonary vasodilators. Patients with heart failure and pulmonary hypertension responsive to such agents acutely in the cardiac catheterization laboratory are considered to have reversible lung disease and are thus possible candidates for a heart transplant alone. Those patients whose pulmonary pressures do not respond are considered to have "fixed" or "irreversible" lung disease and are not considered eligible for a heart transplant alone. The traditional tenets of PVR with regard to a heart transplant are brought into question by the 2 cases in this report. Acute irreversibility in the catheterization laboratory may not equate to irreversibility over the course of weeks to months with pulmonary vasodilator therapy, mechanical ventricular assistance, or both. In these 2 cases, we reversed what was initially designated as irreversible pulmonary hypertension by using a combined surgical and medical approach. This strategy ultimately allowed a successful isolated orthotopic heart transplant. Our results suggest that the classification of who is eligible for a heart transplant should be broadened.
Although the pathophysiology of pulmonary hypertension in patients with heart failure is complex and multifactorial, it is in large part related to elevated left atrial filling pressures, which are a consequence of impaired left (systemic) ventricular systolic and diastolic function and, in many cases, systemic atrioventricular valve pathology. Left atrial hypertension translates into increased postcapillary pressure in the pulmonary circulation, which unleashes a cascade of biochemical responses, resulting in endothelial dysfunction, intimal thickening, and smooth muscle cell proliferation and thrombosis.2 Whereas in idiopathic pulmonary hypertension these derangements are seemingly progressive and unalterable, our patients and other data suggest that in patients whose lung disease is secondary to heart failure, this process can be halted or even reversed.
Continuous unloading of the left ventricle, thereby lowering left atrial pressure, is the theoretic basis for ventricular assist device implantation in these patients as a mechanism of improving their pulmonary hypertension. There is information in adults that this unloading of the left ventricle, accomplished by left ventricular assist device insertion, reduces elevated PVR over time.3 Most of these previously described adult patients have had a modest (5–6 Woods units/m2) elevation of PVR, unlike the extreme pulmonary hypertension present in the children in this report. In addition, most have not had severe right heart failure and have thus undergone isolated left ventricular assist device implantation. As recent technologic advancements have made ventricular assist devices applicable even to infants, even the smallest child with end-stage heart failure and lung disease may benefit from their use.
We combined the use of mechanical ventricular assistance with aggressive use of pulmonary vasodilators. Animal and human studies have implicated several molecular mechanisms in the development of pulmonary hypertensive changes.4 Such medications as inhaled nitric oxide, phosphodiesterase 5 inhibitors, endothelin receptor antagonists, and epoprostenol analogs have been shown not only to reduce pulmonary arterial pressure acutely but also to reverse some of the pathologic remodeling that has already occurred in the pulmonary vascular bed. The clinical application of combination medical pulmonary vasodilator therapy to affect chronic pulmonary hypertension is becoming more widespread5 and may be particularly effective in children, in whom the chronicity of vascular changes is relatively short relative to adults. This pharmacotherapy is also an important adjunct in the immediate posttransplant period, when allograft function may be compromised by even mildly elevated pulmonary arterial pressures.
Our results suggest that patients with end-stage heart disease and severe pulmonary hypertension may be successful candidates for a heart transplant alone, instead of a heart–lung transplant. When evaluating children for a heart transplant in situations where fixed pulmonary hypertension is apparently present, consideration should be given to an aggressive trial of medical pulmonary vasodilators. If these prove ineffective, implantation of BiVADs in concert with medical therapy may resurrect the potential of a heart transplant for a patient previously considered ineligible.
References
This article has been cited by other articles:
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  A. Z. Gazit, S. C. Sweet, R. M. Grady, and C. B. Huddleston First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension J. Thorac. Cardiovasc. Surg., June 1, 2011; 141(6): e48 - e50. [Full Text] [PDF]
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 G. Brancaccio, A. Amodeo, Z. Ricci, S. Morelli, M. G. Gagliardi, R. Iacobelli, G. Michielon, S. Picardo, F. Parisi, G. Pongiglione, et al. Mechanical Assist Device as a Bridge to Heart Transplantation in Children Less Than 10 Kilograms Ann. Thorac. Surg., July 1, 2010; 90(1): 58 - 62. [Abstract] [Full Text] [PDF]
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A. Hoskote, C. Carter, P. Rees, M. Elliott, M. Burch, and K. Brown Acute right ventricular failure after pediatric cardiac transplant: Predictors and long-term outcome in current era of transplantation medicine J. Thorac. Cardiovasc. Surg., January 1, 2010; 139(1): 146 - 153. [Abstract] [Full Text] [PDF]
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M. Imamura, A. M. Dossey, P. Prodhan, M. Schmitz, E. Frazier, U. Dyamenahalli, A. Bhutta, W. R. Morrow, and R. D.B. Jaquiss Bridge to Cardiac Transplant in Children: Berlin Heart versus Extracorporeal Membrane Oxygenation Ann. Thorac. Surg., June 1, 2009; 87(6): 1894 - 1901. [Abstract] [Full Text] [PDF]
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