Perioperative Management of Heart Transplantation: A Clinical Review

Abstract

Heart transplantation remains the treatment of choice for patients with end-stage heart failure, allowing high survival rates and improved quality of life.1 Worldwide, more than 6,000 heart transplantations are performed annually, with 1-yr posttransplant survival around 85% and median survival now exceeding 12 yr.2 The progressive improvement in posttransplant outcome that has been observed during these years is mostly driven by a dramatic drop in the early posttransplant mortality.2 However, the first weeks after heart transplantation remain critical, with an 8% 1-month mortality in contemporary cohorts.2 The perioperative period remains at very high risk due to the increasing proportion of candidates bridged to transplant with durable mechanical circulatory supports and an increasing number of sensitized patients.3,4 In addition, the prioritization of high-risk candidates on extracorporeal membrane oxygenation (ECMO) support and the broader eligibility for both recipient- and donor-related risk factors of primary graft dysfunction (older age, comorbidities) also contribute to increase the challenges of the perioperative period.2,5 The role of the cardiothoracic anesthesiologist–intensivist in the early management of heart transplant recipients is crucial both during surgery and in the intensive care unit (ICU).6 Guidelines focused on the perioperative management of heart transplant recipients are still lacking, and the area of knowledge required is vast. This includes the management of hemodynamic instability, transfusion and hemostatic disorders, immunosuppression, and infectious complications (prevention and treatment) in addition to acute kidney injury and renal replacement therapy. This review aims to summarize the latest knowledge in the field of perioperative management of heart transplant recipients in order to guide cardiothoracic anesthesiologist–intensivists.A refractory vasoplegic syndrome (a persistent low vascular resistance requiring intravenous vasopressors) is observed in 11 to 60% of heart transplantation patients.7,8 There is currently no standard consensus on the definition of vasoplegic syndrome after cardiac surgery or more specifically after heart transplantation, but hypotension occurring within 24 h of heart transplantation with a cardiac index greater than 2.2 l/kg/m2 and a systemic vascular resistance of less than 800 dyne.s/cm5 is generally considered characteristic of this situation.7,9 The pathophysiology of vasoplegic syndrome remains poorly understood, but it could be associated with cytokine release, adrenergic receptor desensitization, increased nitric oxide synthesis, relative deficiency of vasopressin, activation of adenosine triphosphate–sensitive potassium channels, vascular smooth muscle cell membrane hyperpolarization, dysfunction of the renin–angiotensin system, and endothelial glycocalyx alteration.10Age, history of thyroid disease or chronic kidney disease, ventricular-assist device before transplant, duration of cardiopulmonary bypass, and intraoperative blood products are associated with this condition.8,11,12 Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is associated with vasoplegia after cardiac surgery,13 although this is less well-documented after heart transplantation.8 Nevertheless, the presence of a vasoplegic syndrome may be associated with an unfavorable prognosis in heart transplantation patients,14 and the consequences of the vasoplegia do not appear to differ after heart transplantation and after standard cardiac surgery.15As highlighted in the recent guidelines of the International Society for Heart and Lung Transplantation (Chicago, Illinois), the first-line choice in the treatment of vasoplegia is norepinephrine16 (see figure in Supplemental Digital Content 1, https://links.lww.com/ALN/D159). However, the management of post–heart transplantation vasoplegia is most often extrapolated from the literature related to this condition after standard cardiac surgery, due to the lack of specific data. In a recent Brazilian single-center study, Hajjar et al. randomized 330 patients with vasoplegic shock after cardiac surgery to receive vasopressin or norepinephrine.17 Mortality or severe complications occurred in 32% of patients receiving vasopressin, compared with 49% receiving norepinephrine, but the extrapolation of these findings has been questioned. Moreover, acute renal failure occurred in only 10.3% of patients receiving vasopressin, compared with 35.8% of patients receiving norepinephrine.17 In heart transplantation patients with vasoplegia syndrome, vasopressin was shown to decrease norepinephrine requirements, but the level of evidence remains low.18 Similarly, the use of methylene blue, hydroxocobalamin, or angiotensin II could be of interest in this population but, up to now, efficacy of these therapies has only been substantiated by cases reports.10,19–23The International Society of Heart and Lung Transplant defined primary graft dysfunction after heart transplantation as a failure of the transplanted heart, necessitating high doses of catecholamines and/or temporary mechanical circulatory support to achieve an adequate cardiac index in the recipient, and diagnosed within 24 h of completion of surgery in the absence of a discernible alternate cause such as hyperacute rejection, pulmonary hypertension, or surgical complications.24,25 Primary graft dysfunction can be further characterized as predominantly left-sided or right-sided, as well as mild, moderate, or severe, depending on the level of cardiac dysfunction and the extent of inotrope and mechanical support required (table 1). The most recent data suggest an incidence of 10 to 36% with severe primary graft dysfunction occurring in 8 to 18% of heart transplantation patients. Primary graft dysfunction is associated with increased 30-day and 1-yr mortality.25The risk factors for primary graft dysfunction include factors related to the donor, the recipient, and the surgical procedure itself (table 2). The Right atrial pressure, recipient Age, Diabetes mellitus, Inotrope dependence, donor Age, Length of ischemic time (RADIAL) score was developed from a cohort of 621 heart transplantation patients in which six risk factors were identified using multivariable analysis: (1) recipient risk factors include right atrial pressure 10 mmHg or greater, age 60 yr or greater, diabetes mellitus, and dependence toward inotropes, and (2) donor risk factors are age 30 yr or greater, and length of ischemic time 240 min or greater.26 The RADIAL score allows heart transplantation patients to be stratified into groups with an incremental incidence of primary graft dysfunction.27 In patients bridged to heart transplantation with continuous-flow left ventricular assist devices, the RADIAL score did not accurately predict severe primary graft dysfunction. In this group, the risk factors for primary graft dysfunction included mechanical support duration more than 1 yr, elevated pre–heart transplantation creatinine plasma levels, elevated central venous pressure or pulmonary capillary wedge pressure ratio, and use of amiodarone before heart transplantation.28Despite the lack of high-level evidence supporting their efficacy, inotropic drugs and vasopressors (including dobutamine, dopamine, milrinone, epinephrine, and norepinephrine) remain the first-line treatment for primary graft dysfunction. These medications may potentially be combined with vasopressin and inhaled nitric oxide8 (see figure in Supplemental Digital Content 1, https://links.lww.com/ALN/D159). The use of milrinone as a bridge to transplantation has been reported in a few cohort studies, but the data regarding the treatment of primary graft dysfunction using this medication are extremely limited.29,30 Weis et al. assessed the effect of levosimendan in 12 heart transplantation patients with primary graft dysfunction, with good results on hemodynamic parameters such as cardiac index, mean arterial pressure, or mean pulmonary artery pressure.31 In this cohort of patients with primary graft dysfunction, survival at day 30 was 93%. When cardiac output remains inadequate despite high doses of inotropes and/or vasopressors, the use of temporary mechanical circulatory support is needed to provide systemic perfusion and oxygenation, allowing the graft to recover and maintaining the other organs. For patients needing a temporary mechanical circulatory support, venoarterial ECMO seems to be associated with shorter assistance duration, lower incidence of major bleeding, lower incidence of renal failure requiring renal replacement therapy, and reduced mortality compared with patients supported with a continuous-flow external ventricular assist device.32 The ideal timing for ECMO implantation in patients with primary graft dysfunction is not known. However, as with the timing for ECMO implantation in postcardiotomy cardiogenic shock, it can be assumed that early implantation is beneficial. Thus, in a cohort of 347 patients assisted with postcardiotomy venoarterial ECMO, including 59 primary graft dysfunction patients, postoperative implantation of venoarterial ECMO was independently associated with an increased risk of Kidney Disease Improving Global Outcomes stage 3 acute kidney injury.33 In a retrospective study involving 135 primary graft dysfunction patients including 66 assisted with venoarterial ECMO, delayed initiation of venoarterial ECMO was independently associated with in-hospital mortality.34 Thus, venoarterial ECMO implantation appears to be an efficient strategy for the management of severe primary graft dysfunction, in spite of a significant impact on long-term quality of life.35 Finally, although there are data pointing to a beneficial effect of left ventricle unloading in patients assisted by venoarterial ECMO, there is little specific evidence in transplant patients.36 Indeed, in a recent study from the Extracorporeal Life Support Organization (Ann Arbor, Michigan) registry on the association between left ventricle unloading and in-hospital mortality, transplantation was an exclusion criterion.36Right heart failure remains a frequent and potentially severe complication after heart transplantation and contributes significantly to morbidity and mortality. When a discernible cause can be identified, right heart failure is related to a secondary graft dysfunction. Usual etiologies include hyperacute rejection (see Treatment of Cardiac Allograft Rejection section), known surgical complication, or pulmonary hypertension. As the presence of pretransplant pulmonary hypertension in heart recipients increases the risk of posttransplant right heart failure, the selection of transplant recipients and their pretransplant hemodynamic optimization is essential. A single-center retrospective study reported an incidence of 5.9% for severe right heart failure after heart transplantation, while increased pulmonary capillary wedge pressure and mean pulmonary arterial pressure were identified as risk factors.37 The International Society for Heart and Lung Transplantation suggests that a pulmonary vasodilator challenge with inhaled (nitric oxide or prostacyclins) or intravenous (nitroglycerin or nitroprusside) vasoactive agents should be administered when the systolic pulmonary artery pressure is 50 mmHg or greater and when the transpulmonary gradient is 15 mmHg or greater or the pulmonary vascular resistance is greater than 3 Wood units. Meanwhile, systolic arterial blood pressure should be maintained greater than 85 mmHg. Although the right and left filling pressures decrease within weeks after heart transplantation, an elevated mean pulmonary arterial pressure after transplantation is an independent prognostic factor for long-term mortality.38,39The management of right heart failure relies on the preservation of coronary perfusion through the maintenance of an adequate mean arterial pressure using norepinephrine infusion, optimization of the right ventricle preload with careful monitoring to avoid congestion, reduction of the right ventricle afterload by decreasing pulmonary vascular resistance, and limitation of pulmonary vasoconstriction through ventilator settings (avoiding hypoxia and hypercarbia)40 (see figure in Supplemental Digital Content 1, https://links.lww.com/ALN/D159). Inhaled nitric oxide is unique in that it allows selective pulmonary vasodilatation and is effective in improving stroke volume as a result of right ventricle afterload reduction.41 However, there is currently no clear evidence that this medication may improve long-term outcome in patients, and the cost/benefit ratio is questioned.42 Finally, it was recently suggested, in a retrospective cohort of cardiac surgical patients with pulmonary hypertension or right ventricular failure, that the combination of inhaled milrinone and epoprostenol was associated with beneficial effects on hemodynamics.43The severe forms of primary graft dysfunction are traditionally managed with venoarterial ECMO, but up to 45% of patients with primary graft dysfunction have isolated right ventricular dysfunction.27 In these patients, percutaneous right ventricular support, for example through the Protek Duo cannula (CardiacAssist Inc., USA) or with the Abiomed Impella RP device (ABIOMED, USA), could be particularly useful, allowing mechanical support of the right ventricle without the detrimental effects of venoarterial ECMO (nonphysiologic circulation with reduced pulmonary flow, risk of intravascular pulmonary thrombosis, increased left ventricular afterload).44,45The mechanisms for arrhythmogenesis in heart transplant patients are related to several factors including surgical technique, graft ischemia duration, autonomic denervation, immune rejection, cardiac allograft vasculopathy, and graft dysfunction. The loss of parasympathetic input from the vagus nerve results in a higher resting heart rate for transplant patients (90 to 100 beats/min) and a significantly reduced heart rate variability. Graft ischemia exceeding 240 min and the biatrial surgical technique are associated with increased rates of postoperative atrial fibrillation. Atrial fibrillation, atrial flutter, and supraventricular tachycardia are the most common posttransplant arrhythmias and are associated with decreased long-term survival.46,47 Despite their frequency, atrial arrhythmias occur in heart transplant recipients at a much lower rate (2 to 4%) than in other post–cardiac surgery patients (overall incidence of 26.7%, from 22.9% for coronary artery bypass graft to 45.2% for combined procedures).46,48 The majority of atrial fibrillation episodes occur within 2 weeks of transplantation, whereas atrial flutter most commonly presents after the first 2 weeks. Atrial fibrillation and flutter may be associated with acute rejection and/or cardiac allograft vasculopathy, particularly when arrhythmias the postoperative arrhythmias and cardiac of after heart transplantation, with an incidence of 100 rejection and cardiac allograft were as risk factors for cardiac in heart transplant The management of atrial fibrillation after heart transplantation is to that of other cardiac surgery patients. A treatment strategy of rate is by the presence of and the effect of atrial fibrillation on systolic may be with with drugs at the of treatment in this to may in or should be that treatment of the recipient with amiodarone before heart transplantation is a factor for primary graft Finally, as these patients are on inotropes, it may be to decrease the inotropes and to for other for rate or There are no specific guidelines for after heart transplantation, and a should be after the heart failure, Age, Diabetes mellitus, or ischemic disease, Age, score to dysfunction and requiring implantation are in 2 to of heart transplant In addition to the biatrial surgical technique, risk factors for early implantation than 3 are donor age, ischemic rejection, and amiodarone use before heart implantation than 3 risk factors include donor age and cardiac allograft is the most common after heart transplantation to and has been associated with increased morbidity and The risk of mortality is greater in of due to primary graft dysfunction or the effects of remain the more severe forms could be associated with chronic congestion, lower congestion, and renal there may be other factors that could be for a rejection, transpulmonary and vascular the risk factor seems to be the biatrial surgical et al. observed a higher incidence of patients a biatrial surgical technique patients a at 1 and at 24 at 1 and at 24 can also be the of the of the performed to allograft rejection, is a procedure particularly at risk of Although the majority of patients are to severe can progressive right ventricle elevated and of right heart remain the treatment for patients with However, a surgical could be in refractory cases to ventricular failure and the systemic consequences of severe rejection remains an cause of graft dysfunction, mortality, and morbidity after heart The the risk between allograft rejection and the complications of particularly infectious complications occurring early after heart of an is to a and to lower the risk of are by the level of (1) no therapy, (2) using receptor and with The is and study a survival of strategy at the population The ratio of should be for at the time of 3 the and monitoring of a major to heart The presence of to is associated with increased risk of mortality. 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