Brief Update: Status of Pediatric Heart Transplantation

By Eckehard Alfred Stuth, MD
Professor of Anesthesiology
Medical College of Wisconsin
Director, Cardiac Anesthesia Service
Children’s Hospital of Wisconsin

and

John Paul Scott, MD
Assistant Professor of Anesthesiology and Pediatrics
Medical College of Wisconsin
Co-director, Pediatric Intensive Care Unit
Children’s Hospital of Wisconsin
Milwaukee, Wisconsin

Center Volumes
In 2012, our team performed 23 pediatric heart transplants at the Children’s Hospital of Wisconsin (CHW) in Milwaukee, placing the pediatric heart transplant program within a subset of 21 (= 14% of worldwide centers in registry) “high” volume programs (defined as having performed at least 10 transplants per year). Half of North American pediatric heart transplant centers fall in this group, which is responsible for 56% of all pediatric cardiac transplants performed from 2006-2011. Another 21 medium volume centers performed between 5-9 transplants per year during the same time period. However, worldwide 111 of 153 reporting centers (73%) are considered low volume (less than 5 transplants annually) accounting for less than 25% of all pediatric heart transplants. There has been a slight decrease (from 139 to 111, i.e. 20%) in low volume centers and a moderate increase (from 14 to 21, i.e. 50%) in high volume centers compared to the previous five years. For detailed graphs and statistics we refer the interested reader to 1(Kirk et al. 2012).

Recipient age distribution
According to the 15th annual report of the registry of the International Society for Heart and Lung Transplantation (IHSLT) each year over 500 pediatric (age < 18 years) heart transplants have been performed worldwide in the current era (2006-2011) 1(Kirk et al. 2012). Due to severely limited donor availability for all pediatric age ranges (infants age < 1 year, 1-10 years and 11 to 17 years) this number has remained relatively static over the past decade 1(Kirk et al. 2012). North American centers perform roughly similar numbers of pediatric heart transplants in the two age groups of patients older than 1 year, but nearly three times as many infant transplants compared to centers worldwide (28% of North American total). This discrepancy in infant transplants is probably a complex function of universal availability of staged palliation of single ventricle heart disease (i.e. HLHS) in North America, different cultural attitudes toward organ donation and different societal attitudes towards prenatally diagnosed severe congenital heart disease in various parts of the world. While median pediatric waiting times are typically shorter than in adults more small children < 15 kg die on the waiting list compared to older children because of limited donor organ availability 2(Almond et al 2009).

Recipient diagnosis
The two main groups for the 23 transplantations in 2012 at our center were non congenital heart disease associated with end stage heart failure (e.g. mainly various cardiomyopathies, especially the dilated forms 3(Kipps et al. 2007)) (n=11), and end stage disease after surgical palliation of congenital heart disease (e.g. s/p staged palliation for hypoplastic left heart syndrome and s/p palliation for biventricular congenital heart disease) (n=12). Our data mirror the ISHLT registry data with about half of the pediatric recipients in North America being transplanted for cardiomyopathy and the other half for congenital heart disease 1. However, a diagnosis of congenital heart disease was more common in infants < 1 year (60%), especially in North America, while a diagnosis of cardiomyopathy was slightly more common in the older age groups, especially outside North America. The diagnosis in the pediatric age group contrasts with the adult indications. While cardiomyopathies are most common in adults (about 57%), end stage ischemic heart disease is second (37%), but congenital heart diseases remain a rare indication (3%) 4(Stehlik et al. 2012).

Primary neonatal transplantation for hypoplastic left heart syndrome (HLHS), which was more common in the 1980’s, is now rare due to critical limitations of donor organ availability 5(Chinnock et al 2011). For example, Loma Linda University Medical Center performed more than 300 neonatal/infant heart transplants from 1985 to 2010, but now also primarily pursues a staged single ventricle palliation pathway for HLHS, because staged palliation results have improved markedly in the past decade, while donor heart availability for neonatal transplants has remained below 100/year in North America 5(Chinnock et al. 2011).

Mechanical Circulatory Support (MCS)
Since 2006, 24% of CHW heart transplant recipients required mechanical circulatory support (MCS) prior to transplantation, including 4 (17%) of our 23 patients in 2012. The IHSLT registry reports similar numbers, with slightly less than 25% of children bridged with MCS in the 2005-2010 period compared to about 36% of adults. Not surprisingly, extracorporeal membrane oxygenation (ECMO) was the predominant MCS support modality in infants, while single or biventricular assist devices were more common in patients older than 1 year 1(Kirk et al 2012).

Ongoing resource limitation and significant waiting list attrition of infants and children has increased the use of MCS as a bridge to transplant. Mechanical assist devices help stabilize failing circulations and thus significantly improve multi-organ dysfunction until a donor heart becomes available 6(Gazit et al 2011). ECMO represents the most commonly utilized form of perioperative rescue and short-term mechanical support. However, protracted waiting list times have stimulated the development of miniaturized ventricular assist devices (e.g. Berlin heart 7, 8) and centrifugal pumps more suitable for long term MCS in infants and children. Pediatric ventricular assist devices (VADs) are associated with thrombotic and embolic complications as well as increased rates of allosensitization from repeated blood transfusions. Thus, the use of VADs such as the Berlin heart continues to be limited in the pediatric population and rescue ECMO remains much more frequent, especially in infants.

Allosensitization of Recipients
A growing number of pediatric heart transplant patients have had multiple previous palliative surgeries for congenital heart disease, which exposed them to significant blood product transfusions. Thus the number of pediatric transplant candidates that have become highly sensitized has considerably increased over the years compared to adults 9(Mahle et al 2011). Panel reactive antibodies (PRA) of > 10% are now present in almost a third of pediatric patients which is more than double the percentage of sensitized patients in the adult patients. There is also a slowly growing number of highly sensitized pediatric patients (PRA >40%) 10(Feingold et al. 2007). The problem of sensitization is likely to grow, because patients with failing Fontan circulations, who have undergone multiple major staged palliation procedures with multiple blood product transfusions, are one of the largest and most rapidly growing subgroup of patients with palliated congenital heart disease in North America 11,12(Davies et al. 2011 and 2012).

ABO incompatible transplants in infancy
Infants <1 year often do not have significant levels of isohemagglutinins present in their blood, which would cause hyperacute rejection after transplantation of an ABO incompatible donor heart. This immunological immaturity is a window of opportunity that allows ABO-incompatible transplantation in the neonatal and infant period and thus increases the potential donor pool. In fact survival after ABO-incompatible neonatal/infant transplantation is non-inferior to ABO compatible transplantation 5(Chinnock et al. 2011). Some of this survival advantage seems to be related to a markedly reduced T-cell receptor diversity in infancy, which reduces the risk of rejection and cardiac allograft vasculopathy, but increases the risk of infections.

We as well as many others have successfully transplanted ABO incompatible hearts in infants 13(Urschel et al. 2013). In order to minimize the risk of rejection these patients, similar to allosensitized patients, typically receive several blood volume exchanges immediately with initiation of CPB.

Survival after transplant
One-year post transplant survival at our center for the period of 2006-2011 was 86%. The IHSLT registry data shows that the risk of early death was slightly higher in infants, especially in the first 6 months after transplant. However, Kaplan-Meier survival curves for all pediatric transplants performed from 1982 to 2010 show median survival was the highest for the youngest, i.e., infants < 1 year at transplant had a median survival of 19.2 years compared to the two older age groups 15.6 years (for 1-10 year olds) and 11.9 years (11-17 year olds)(for detailed curves see 1(Kirk et al. 2012)). This reduction in median survival with increasing recipient age at transplant continues throughout the adult age range. For those patients surviving the high risk first year after transplant (i.e. conditional survival) median survival is even better (> 20 years for infants and 19.2 and 15.9 years for the two older pediatric groups). There has been also improved survival for each era with best survival in the most recent era, which appears to be entirely due to better survival in the first 6 months after transplant.

Risk factors for early post transplant death
The risk factors for one-year mortality after transplant are largely predictable, i.e., the sicker the patient pre-transplant the higher the early post transplant mortality risk. Risk factors for early mortality are ECMO, especially in infants, re-transplant, renal replacement therapy, ventilator dependence and previous sternotomy. Additional factors that impact early survival are the pre-transplant diagnosis. Infants who had a diagnosis of cardiomyopathy had greater survival than those with a diagnosis of congenital heart disease. Primary graft failure (28%) represents the leading cause of early demise, followed by multi-organ failure (16%), infection (14%) and rejection (14%). After the 3rd year cardiac allograft vasculopathy leading to graft failure becomes the dominant cause of death.

Contraindications to transplant
Severe multi-organ failure (especially complete renal and severe hepatic failure) is a relative contraindication to transplant. Interestingly, with the advent of more age appropriate VADs, inhaled NO and other pulmonary vasodilator therapy the acceptable upper limits for pre-transplant pulmonary vascular resistance values have steadily increased 14(Chiu et al. 2012). Severe social and psychosocial problems are relative contraindications given the complexity of modern immunosuppressive therapy. Malignancy, systemic infections, and HIV are considered by many centers an absolute contraindication. Genetic syndromes with only mild learning disabilities are not considered absolute contraindications and there are case reports of heart transplantation in patients with Down’s syndrome.

Considerations for Anesthetic Management-Individualized written plans
Prospective studies evaluating anesthetic risks and optimal anesthetic management are lacking. Available literature mainly consists of expert opinions in form of review articles or retrospective chart reviews that attempt to highlight anesthetic management concerns in these high risk cardiac patients 3,15,16(Schure et al. 2011, Kipps et al. 2007, Pratap et al 2010). These are complex patients with complex problems and no uniform, “cook-book” style approach to anesthetizing them can be recommended.

Several years ago, Dr Michael Mitchell, one of our pediatric cardiovascular surgeons, started distributing his detailed written surgical plans, that explained stepwise what he was going to do, to the entire cardiac OR team by e-mail. Over time we have refined this unique communication tool further at CHW. Thus, in addition to the customary direct verbal briefings between the various caretakers, nowadays both the (transplant) cardiac surgeon as well as the (transplant) attending cardiac anesthesiologist exchange detailed written preoperative surgical and anesthesia plans with the entire care team by e-mail. Importantly, the recipient list is not limited to the immediate intraoperative caretakers assigned to the particular operation (i.e., perfusion technicians, scrub technicians, cardiovascular physician assistants and cardiac OR nurses and fellows) but also the transplant cardiologists and the cardiac intensivists as well as other cardiac anesthesia and cardiac surgical staff indirectly involved in the particular patient’s care. This allows the entire perioperative team at the Herma Heart Center of the Children’s Hospital of Wisconsin to be well prepared and work ”in sync”. It further facilitates additional timely and valuable feedback from experienced senior colleagues and caretakers that are available as consultants.

“The good”, the “not so good” and “the ugly”.
“The Good”: Even seasoned senior cardiac anesthesiologists may actually volunteer to provide an anesthetic for transplantation of a patient with a pristine dilated cardiomyopathy, i.e. a patient who has had no prior surgical interventions. Such patients tend to tolerate a carefully planned and conducted cardiac anesthetic induction relatively well and typically exhibit improved hemodynamics with transition to anesthesia and positive pressure ventilation as evidenced by an almost universal improvement in the somato-renal and cerebral regional saturations (i.e. increased regional oxygenation suggestive of a narrowed arterio-venous oxygen difference). These patients also tend to present relatively few vascular access challenges and rarely experience excessive perioperative bleeding.

“The not so good”: A Patient requiring MCS prior to transplantation (VAD, e.g. Berlin heart) tends to be more challenging, because such a patient typically had several previous sternotomies, numerous previous vascular access procedures and multiple blood transfusions. Changes in preload and afterload with anesthetic induction may significantly impact VAD function and have to be anticipated 16(Pratap 2010 et al.). Vascular access even with the help of current ultrasound technology may be quite challenging and time consuming. Significant amounts of early and continued intraoperative blood loss are likely and have to be planned for. A busy and long day and night in the OR are likely.

“The Ugly”: Only a very energetic junior cardiac anesthesiologist with an excellent coronary circulation will volunteer for a heart transplant in a patient with failing hypoxemic Fontan physiology and elevated end-diastolic ventricular pressures leading to multi-organ impairment (e.g. plastic bronchitis, pleural effusions, ascites and protein losing enteropathy). Most seasoned, battle scared anesthesiologists (e.g. Dr Stuth) will have to be conscripted to provide anesthesia for such a patient, if they can be found. These patients pose ongoing extreme challenges to the anesthesiologist throughout the intra- and perioperative period. The transition from spontaneous breathing to positive pressure ventilation needs to be handled with great skill, as loss of optimal airway patency and air exchange during induction will not only lead to inadequate gas exchange but with the resulting reduction or complete loss of functional residual capacity (FRC) pulmonary perfusion will decrease or even cease, and single ventricular preload will be acutely and severely compromised. In our experience, if loss of significant FRC occurs, fairly high airway pressures (recruitment maneuvers) may be required to reestablish an adequate FRC and pulmonary blood flow. In addition to meticulous airway management, inotropes and vasopressor drugs should be available or even infusing before induction (e.g. epinephrine/milrinone) in a dedicated intravascular line and the anesthesiologist needs to be ready for escalating these infusions as dictated by the circumstances. Vascular access will likely be challenging and it helps to recruit a second experienced cardiac anesthesiologist to assist with this task while the primary anesthesiologist focuses on maintaining overall cardiopulmonary stability. Copious bleeding during redo-sternotomy and an increased likelihood for transitioning to groin or neck vascular access for cardiopulmonary bypass can be expected and needs to be anticipated. Post CPB bleeding will likely be also large and post CPB lung ventilation and management of elevated PVR (with NO and milrinone) may prove challenging.

In general, acute right heart failure is more common following pediatric heart transplantation and may be exacerbated by elevated recipient pulmonary artery pressures, pulmonary vein pressures, and interstitial lung disease. The transplanted right ventricle may exhibit restrictive physiology with preload dependence and require vasoconstrictor therapy to maintain adequate right coronary artery perfusion pressure.

In all our cardiac surgery patients we have found continuous two site NIRS monitoring (cerebral and in particular somato-renal) very helpful and will not proceed without it. While not yet universally embraced by all centers in North America, our center has found multi-site NIRS monitoring indispensible and it is standard monitoring for all our cardiac patients system-wide. Especially during the induction phase and before invasive hemodynamic monitoring is established multi-site NIRS monitoring may provide an early warning of a deteriorating circulation and thus allow for earlier intervention 17(Tweddell et al. 2010).

In summary, pediatric cardiac transplantation is not for the faint of heart. We need to face these challenges head on and be well prepared, in particular because patients with failing Fontan circulation presenting for cardiac transplantation are becoming an increasing fraction of our pediatric transplant population.

References:

Kirk R, Dipchand AI, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbles F, Rahmel AO, Stehlik J, Hertz MI: The Registry of the International Society for Heart and Lung Transplantation: fifteenth pediatric heart transplantation report--2012. J Heart Lung Transplant 2012; 31: 1065-72
Almond CS, Thiagarajan RR, Piercey GE, Gauvreau K, Blume ED, Bastardi HJ, Fynn-Thompson F, Singh TP: Waiting list mortality among children listed for heart transplantation in the United States. Circulation 2009; 119: 717-27
Kipps AK, Ramamoorthy C, Rosenthal DN, Williams GD: Children with cardiomyopathy: complications after noncardiac procedures with general anesthesia. Paediatr Anaesth 2007; 17: 775-81
Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, Dobbels F, Kirk R, Rahmel AO, Hertz MI: The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report--2012. J Heart Lung Transplant 2012; 31: 1052-64
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