The introduction of cyclosporine, as well as the progress in critical care and operative management of transplant patients, has significantly improved early and thus overall postheart transplantation survival.1 A recent review of the 21 year experience with pediatric heart transplantation at Texas Children’s Hospital, however, demonstrated that the mortality rate for patients surviving the first posttransplant year has not changed in two decades.2 This has also been observed in the Pediatric Heart Transplant Registry of the International Society for Heart and Lung Transplantation.3 Cardiac graft rejection remains a leading cause of long-term morbidity and mortality in pediatric heart transplant recipients, necessitating the development and use of novel therapies.
Over the past two decades, clinicians and researchers have sought to bring mechanical circulatory support (MCS) to pediatric patients with heart failure.4 The use of MCS to manage children with cardiac failure caused by myopathy, postcardiotomy shock, and myocarditis is now being established.5–9 Mechanical circulatory support in these children can stabilize hemodynamics, provide improved perfusion, and allow recovery of end-organ function. This has resulted in hundreds of children being successfully bridged to recovery of function or transplant.10–16 The use of MCS to treat cardiac failure caused by acute graft rejection has been reported in small series in adults but not in the pediatric population except from an earlier report from this institution.17–24 When patients with graft rejection and hemodynamic instability are mechanically supported, the circulation is secured, allowing for aggressive immunosuppressive strategies.25
This manuscript reports the use of MCS at Texas Children’s Hospital in patients with severe acute cardiac allograft rejection causing hemodynamic instability.
Materials and Methods
Between July 1995 and December 2006, 117 patients received 132 orthotopic heart transplants (OHT). During that time, 7 of 117 heart transplant patients (6%) underwent MCS placement in 8 cases of acute graft rejection with hemodynamic instability. During this time period, MCS was used 82 times in the Texas Children’s Hospital heart center. Ten percent (8 of 82) of this usage was for presumed acute rejection (AR): 8 devices in 7 patients. Mean age at MCS was 12 ± 6.6 years. Mean weight was 33 ± 17 kg (range, 5.4–53.5 kg). Five of eight applications (63%) were in women. Two patients (25%) had a pretransplant diagnosis of cardiomyopathy and six (75%) had a history of congenital heart disease. Mean age at time of transplant was 10 ± 5.9 years. Age ranges at transplant were 13% (n = 1) less than 1 year old, 37% (n = 3) 1–10 years old, and 50% (n = 4) 10–20 years old.
Before being placed on MCS, all patients were managed with two or more inotropes, four patients (50%) were mechanically ventilated, and three patients (38%) received CPR. Five patients (63%) were put on MCS within 24 hours of admission. The median time interval from admission to placement on MCS was 1 day, with a range of 0–12 days. Median age of graft at time of MCS was 1 year (range, 1.2 months to 8.4 years). Four patients (50%) underwent cardiac catheterizations before placement of MCS, two with biopsy scores of 3 R, one with a score of 1 R, and one with 0 R, using the International Society for Heart and Lung Transplantation Heart Biopsy Grading Scale.26
There were six left ventricular assist devices (LVADs) [five Biomedicus centrifugal pumps (Medtronic Biomedical, Prairie, MN) and one Thoratec system (Thoratec Lab., Berkeley, CA)]; one BiVAD (two Thoratec pumps), and one extracorporeal membrane oxygenator (ECMO) [Biomedicus centrifugal pump/affinity oxygenator (Medtronic Biomedical)]. Myocardial biopsies were taken at the time of device placement. In four of the five Biomedicus pumps, the ascending aorta and the left atrium were cannulated via repeat sternotomy. One patient with a Biomedicus was cannulated via a left thoracotomy in the descending aorta and left atrium. The right and left atria were cannulated for the Thoratec BiVAD and the left atrium for the Thoratec LVAD; all outflow grafts were sewn to the ascending aorta. The child on ECMO was cannulated via the right atrium and the aorta. Patients on ECMO or the Biomedicus pump were monitored continuously by the perfusion staff for the duration of their time on the device. The two patients placed on the Thoratec system were monitored continuously for the first 24 hours; thereafter, the perfusion staff remained on call should any problems arise.
Biopsy revealed evidence of cellular rejection in three patients, humoral rejection in one, both cellular and humoral rejection in two, and nonconfirmatory biopsies in two. One of the patients with a nonspecific graft biopsy, which was done at time of device placement, demonstrated only mild cellular rejection (1 R) and negative viral studies [i.e., cultures, polymerase chain reaction (PCR)]. This level of cellular rejection is usually not associated with severe hemodynamic compromise. The other patient categorized as a nonspecific biopsy and graft failure had evidence of plasma cell infiltration but no specific signs of cellular or humoral rejection. This patient was retransplanted after 29 days of support and the explanted heart demonstrated posttransplant lymphoproliferative disease with Epstein-Barr virus and 1 R cellular rejection.
At our institution, patients admitted with clinical findings consistent with graft rejection are presumed to have cellular-mediated rejection and are treated with pulse steroids, until biopsy results are available (Table 1). When hemodynamics allow, catheterization and endomyocardial biopsy are performed. Steroid-resistant cellular rejection or hemodynamically unstable patients are treated with antithymocyte immunoglobulin (ATGAM) or OKT3. Biopsy-demonstrated humoral rejection, defined as complement or immunoglobulin deposition within the endothelium as detected by immunohistochemistry staining, is treated with plasmapheresis (six treatments), intravenous immunoglobulin (IVIG), and rituximab, an anti-CD20 monoclonal antibody.
Seven of eight patients (88%) weaned from MCS (Table 2). Sixty-three percent (five of eight) were weaned to recovery and 25% (two of eight) were bridged to retransplant. Median duration of support was 7.5 days, with a range of 3–28 days. The patient who failed to wean was an 11-year-old girl who had undergone transplantation for hypertrophic cardiomyopathy. She was admitted 9 months posttransplant with heart failure and poor biventricular function. She underwent aggressive antirejection therapy, including plasmapheresis for presumed cellular and humoral rejections. Her ventricular function progressively deteriorated, necessitating an escalation of inotropes and placement of a Thoratec LVAD. She subsequently developed septic shock and severe coagulopathy with little improvement of her heart function or multiple organ system failure. On the 10th day of support, the device and other therapies were electively discontinued and she died that day.
Seven of eight patients had significant postoperative complications. Hemorrhage was the most common, with five patients experiencing postoperative bleeding requiring mediastinal re-exploration. Four of these five patients had undergone plasmapheresis before re-exploration. Four patients had impaired renal function requiring dialysis (e.g., continuous veno-venous hemodailysis). Two patients developed sepsis during device support. There were no clinically apparent neurologic events. Embolic infarcts were found on a computerized tomographic scan of the brain in one patient, although the timing of these infarcts in relation to VAD support was unclear. There were no focal neurologic deficits found on examination. Five of the seven patients weaned (71%) from MCS were discharged home, all with normal systolic ventricular function. Median hospital length of stay was 34 days (range, 21–57 days). Time from MCS wean to discharge was 18 days (range, 16–50 days). Overall hospital survival was 62% (five of eight).
Two patients weaned from MCS but subsequently died in hospital. One patient was a 20-year-old girl who underwent transplant for a failing Fontan circulation. She had two episodes of rejection caused by noncompliance, one cellular and one cellular and humoral, 2 years apart. Both episodes led to hemodynamic instability requiring Biomedicus LVADs. After her second episode of MCS, she had cardiac recovery allowing the device to be explanted 8 days after device placement. She developed multisystem organ failure, including renal and respiratory failure requiring dialysis and tracheostomy. Two months after MCS, she developed a massive bleed from her tracheostomy site from which she did not recover. The other patient was a 7-month-old infant who underwent OHT for dilated cardiomyopathy. Five weeks after transplantation, the patient developed humoral rejection requiring increasing inotropic support accompanied by renal insufficiency with severe fluid retention and worsening hypoxemia. On posttransplant day 36, she was placed emergently on ECMO and was aggressively treated for AR with no cardiac recovery. She underwent repeat transplant 15 days after initiation of ECMO, but had primary graft failure at retransplantation and died.
Median follow-up for those patients discharged was 3.0 years, with a range of 4.5 months to 3.5 years. The 1 year patient survival post-MCS is 50% and the 3 year survival is 38%. Three of the five patients discharged died. One patient, an 8-year-old boy, underwent repair of tetralogy of Fallot at an outside hospital that was complicated by remote ventricular failure necessitating transplantation, done at our institution. Fourteen months posttransplant, he was admitted with graft failure assumed to be AR and was placed on a Biomedicus LVAD for 3 days. He was discharged home with normal cardiac function. He had a cardiac arrest at home and died at 3.2 years post-MCS and 3.4 years posttransplant. His explanted heart at autopsy was PCR parvovirus positive and had evidence of coronary vasculopathy. One patient, a 7-year-old boy, had OHT for a failing Fontan circulation. He was noted to have significant left ventricular dysfunction and poor perfusion during a clinic visit. He was admitted and treated for his biopsy-proven humoral rejection, but because of progressive hemodynamic compromise, he required support (a Biomedicus LVAD) for 4 days. He responded well to treatment and was discharged after 23 days, but died suddenly at home 4.5 months post-MCS; 2.7 years post-OHT. One patient, mentioned previously, had multiple rejection episodes caused by noncompliance. Although she weaned and was later discharged after her first 7 day placement on a Biomedicus LVAD, she died in the hospital 2 years later, 2 months after being weaned from her second device for acute cardiac rejection.
The two survivors both had normal left ventricular function at last echocardiography. One is a 19-year-old girl who is asymptomatic 3.5 years after MCS and retransplant and the other is an 18-year-old boy who is asymptomatic 5.3 years after MCS and 6.1 years after original OHT.
The leading cause of death in the first 5 years post-OHT is AR.27 The rate is higher in children, in fact, than in adults. Two-thirds of children have at least one episode of AR by the end of their first year posttransplant. Most AR episodes are, however, not associated with severe ventricular dysfunction and hemodynamic instability. If AR is hemodynamically significant, requiring inotropic support, the 1 year mortality post-AR is 30%–50%.27–29 Acute rejection with hemodynamic compromise can usually be managed in a critical care setting with inotropic agents and antirejection therapy. The combination of marginal perfusion on inotropic support and aggressive antirejection therapy is often not tolerated.8,28–30 In these patients, early use of MCS should be considered. Indications for MCS posttransplant include right heart failure postimplant, primary graft failure, and rejection.8,30 Mechanical support for AR is intended as a bridge to recovery, whereas for heart failure caused by chronic rejection, it is instituted as a bridge to retransplant. Mechanical circulatory support during treatment of AR also may have advantages. If perfusion is stabilized by MCS, one can be more aggressive with rejection therapy. Patients on MCS can tolerate large volume shifts often required in aggressive rejection therapies such as IVIG or plasmapheresis because volume can be easily removed. Also, antirejection therapies may be more effective in MCS patients, whose hearts may be undergoing less detrimental remodeling because they are decompressed, well-perfused, and not under the strain of attempting to provide adequate perfusion.
The literature on MCS for AR, adult or pediatric, is sparse. We were unable to find a manuscript on pediatric VAD support for acute heart rejection from another institution.24 However, we speculate that other pediatric programs have been applying VADs for this indication. The adult literature on this subject is discouraging, with weaning rates from MCS for AR of 15%–20%.20–23 This current series demonstrates that this difficult cohort can be well supported by MCS and treated for their severe rejection with acceptable weaning rates (88%) and discharge rates (63%). The 1 year survival post-MCS for this cohort is 50% and by 3 years survival is 38%. This mortality rate is accelerated when compared with the general heart transplant cohort,3 even though these patients were discharged home with normal ventricular function.
Even though this is a small case series, there do seem to be trends. All patients discharged home were placed on MCS within 24 hours of admission. The early institution of support in these patients perhaps allowed end-organ function to be preserved, the heart to be rested, and an aggressive medical strategy to be instituted early. An example of the latter is that IVIG, which is a large volume load and often avoided in these AR patients with marginal hemodynamics, can be given with less concern and even before biopsy results if on MCS. This is particularly important because the incidence of a humoral component to AR in this series of patients requiring MCS was 38%. This high incidence of symptomatic humoral rejection in this series may be explained by another observation in the current series.31 The incidence of patients with AR requiring MCS who were transplanted for end-stage congenital heart disease (75%) is twice the incidence of congenital patients in the overall transplant cohort (36%). Perhaps congenital patients who undergo heart transplant are more likely to have severe humoral rejection because of their exposure in the past during surgical palliation to homograft material and multiple transfusions, which can increase their panel-reactive antibodies as well as undetectable donor-specific antibodies.31
Options for MCS in pediatric patients with cardiac failure remain limited and a critical unmet need in the United States. Recently, several pediatric VAD initiatives have begun, both in the United States and abroad. Advancements continue to be made in VADs in children, including improvements in decision-making, device technology, implantation techniques, coagulation monitoring, and anticoagulation.32,33 Mechanical circulatory support is particularly challenging in children, because of the wide range of patient sizes and anatomy as well as the variety of differences in their coagulation cascades that do not allow the lessons learned in adult VADs to be directly translated to the pediatric population.4–6 Despite these challenges, the comfort in supporting pediatric patients with MCS is increasing, which has lead to a trend toward earlier application. A more aggressive use of pediatric MCS may allow patients with hemodynamically significant AR to receive earlier and more aggressive antirejection therapies and to preserve end-organ function. This will hopefully lead to improving the outcomes of this difficult patient cohort.
Mechanical circulatory support can be applied in patients with acute cardiac graft rejection causing hemodynamic instability with acceptable weaning and discharge rates. Unfortunately, late survival for this cohort remains poor. A better understanding of the factors predicting the long-term outcomes of these patients is needed. Despite these shortcomings, MCS may be an important therapeutic adjunct in supporting the circulation of these critically ill patients and allowing the heart to rest while aggressively treating their severe acute myocardial rejection. As our understanding of AR expands and thus the tools to effectively treat it, the proficient use of MCS to support patients with acute cardiac rejection causing hemodynamic instability may well lead to better outcomes for this growing and difficult patient population.
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