Symposium. Post-operative Management Of Pediatric Heart Transplantation : A Brief Review

Transcription

1 DOI / Symposium Post-operative Management Of Pediatric Heart Transplantation : A Brief Review Balakrishnan KR*, Suresh KG**, Muralikrishna T***, Suresh Kumar R **** *Director, Cardiac Science, Fortis Malar hospital, Chennai, **Head, Cardiac critical care, Fortis Malar hospital, Chennai ***Consultant, Cardiac anesthesia, Fortis Malar hospital, Chennai, ****Transplant co-ordinator, Physician assistant, Fortis Malar hospital, Chennai, India Received: 10-Jun-18/Accepted: 25-Jun-18/Published online: 30-Jun-18 ABSTRACT Post-operative care in pediatric heart transplantation involves specialized intensive care support. The common anticipated issues in this scenario include right ventricular dysfunction, pulmonary hypertension, graft related issues (dysfunction, rejection etc), infection & other organ dysfunction. This review describes the post -operative management of pediatric heart transplantation with special emphasis on the above anticipated problems. Key Words: Pediatric heart transplant, right ventricle dysfunction, graft survival, cardiac intensive care unit Introduction Pediatric heart transplantation is for children with end-stage heart failure refractory to medical management. The diverse age range, diagnoses, and practice variations continue to challenge the development of evidence-based practices and new technologies. Outcomes in the most recent era are excellent, especially with the more widespread use of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). Waitlist mortality remains high and knowledge of risk factors for death while waiting and following transplantation contributes to decision-making around transplant candidacy and timing of listing. Knowledge about the issue they face in the postoperative period is important to have good outcomes. Authors at Fortis Malar experience with 60 patients ranged from age 2 years to 18 years and weight- 7 kg to 80 kg. Once heart transplantation is complete, patient will be shifted from operating room (OR) to cardiac intensive care unit (ICU) with inotropes, ventilator and nitric oxide support. Common issues faced in the post-operative period in children are : RV dysfunction Pulmonary artery hypertension (PAH) Primary graft dysfunction Correspondence: Dr K.R. Balakrishnan. MS, Mch (CTVS) Director, Cardiac Science, Fortis Malar hospital, Chennai, India id: cvskrb@gmail.com Rejection Infection Other organ dysfunction (liver and kidney). Right Ventricular Dysfunction Right ventricular dysfunction is prevalent following orthotopic heart transplantation. The sequential insults of brain dead donor, cardioplegia, ischemia, reperfusion injury and CPB interact together with raised recipient pulmonary vascular resistance to produce this complication. Early recognition is important to have good outcomes; management principles include avoiding volume overload, maintaining adequate coronary pressure and appropriate inotropic support. With improved understanding, availability of selective pulmonary vasodilator and advances in mechanical circulatory support currently satisfactory outcomes are seen in cases with severe RV dysfunction. Management of RV dysfunction in post heart transplantation Appropriate Fluid management Diuretics Inodilators & inotropes Mechanical ventilation Continuous renal replacement therapy (CRRT) Mechanical assist device Pulmonary Artery Hypertension (PAH) Pulmonary artery hypertension in post heart transplantation is a complex pathophysiological and hemodynamic condition due to dysregulation 75

2 of vascular smooth muscle tone and structural remodelling. These abnormalities related to pulmonary vascular, endothelial dysfunction with lack of sensitivity to endogenus and exogenous vasodilatation released from pulmonary vascular endothelial. This can lead to post operative RV failure, difficulty in weaning patients from ventilator support. Management Diuretics Phosphodiesterase inhibitors, endothelial receptor antagonists All factors that will aggravate pulmonary vascular resistance (pain, hypoxia, hypercapnia, and hypothermia) should be controlled aggressively. Inodilators and inotropes Mechanical ventilation Nitric oxide Mechanical assist device Primary Graft Dysfunction Primary graft dysfunction (PGD) is a life-threatening complication of heart transplantation that presents as left, right, or biventricular dysfunction occurring within the first 24 hours after transplant surgery for which there is no identifiable secondary cause. Myocardial injury caused by acute catecholamine toxicity and the release of multiple proinflammatory mediators in the donor, followed by ischaemia-reperfusion injury sustained during retrieval, have been considered the predominant cause of pathogenetic processes leading to PGD. The incidence of PGD described in literature varies from 7 to 30%. 1 Donor, recipient, and procedural factors contribute to the development of this clinical syndrome. PGD is graded from mild to severe depending on the extent of circulatory support that is required to maintain haemodynamic stability and vital organ function. Potential causes of primary graft failure after pediatric heart transplantation can be as follows: a) Donor issues Poor donor organ preservation Poor donor quality Diminished echocardiographic ejection fraction Requirement for high inotropic support Elevated blood troponin I level Prolonged ischemic time Large donor (donor-to-recipient weight ratio > 2.0) Small donor (donor-to-recipient weight ratio < 1.0) Prolonged donor cardiopulmonary resuscitation times Anoxia as cause of death Non-identical blood type Donor age b) Recipient issues Pre-transplantation diagnosis of congenital heart disease Previous sternotomy Elevated pulmonary vascular resistance Pre-transplantation need for extracorporeal membrane oxygenator Pre-transplantation need for ventilatory support Management includes inotropic support & mechanical assist device. Immunosuppression & Rejection The standard immunosuppression therapy includes induction therapy (optional) and maintenance therapy. Induction therapy is with drugs like anti-thymocyte globulin, basiliximab. Maintenance therapy is with triple drug regimen viz steroid, antimetabloic agent (mycophenolate / azathioprine) and a calcineurin inhibitor (tacrolimus / cyclosporine). Drug levels have to be monitored at regular intervals to adjust drug dosage. Rejection surveillance should be done by regular echocardiogram and endo-myocardial biopsy. The recipient s body may reject a donor organ through hyperacute rejection, acute cellular rejection, or antibody-mediated rejection. The risk for developing rejection is the highest in the first six months following heart transplantation, with a decrease as the time from transplantation increases. Sex and age are both linked to rejection risk, with females and younger individuals being at higher risk. Similarly, patients of black race are also at a higher risk of rejection. A higher rate of 76

3 rejection one-year post-transplant has been reported in patients who received induction therapy; however, this may represent selection bias with higher risk patients receiving induction. Hyperacute rejection During the immediate post-transplant phase, after cross clamp removal, hyperacute rejection may occur when the recipient has pre-existing donor directed human leukocyte antigen (HLA) antibodies. In a 1991 study of 463 heart transplant patients, 18 patients were diagnosed with hyperacute rejection (approximately 4%). 2 Fortunately, hyperacute rejection is now uncommon as a result of both antibody screening prior to transplantation (panel reactive antibodies (PRA), & blood type matching. Acute cellular rejection This remains a frequent complication post-transplant. It involves recipient T-cells recognizing donor HLA molecules by means of antigen-presenting cells. Around 20 to 40% of patients will experience acute cellular rejection between 6 and 12 months posttransplant, though most patients are asymptomatic without allograft dysfunction. Antibody-mediated rejection This type of rejection is characterized by an antibodydriven immune response to vascular endothelial antigens in the allograft, involving both B-cells and T-cells. Though not as common as acute cellular rejection, antibody-mediated rejection has an estimated incidence of 10 to 20% in the first year post-transplant. Mixed rejection that has features of both acute cellular rejection and antibody mediated rejection-can be seen in as many as 25% of acute rejection cases. 3 An important risk factor for antibody-mediated rejection is sensitization to HLA molecules prior to transplantation. Sensitized patients have pre-existing antibodies against HLA molecules, which can be quantified by their calculated PRA (cpra). The cpra is calculated based on HLA antigen profile of the population of potential donors. The cpra represents the probability that a recipient will have an unacceptable donor based on the presence of incompatible antigens (a probability of 10% means that one in ten donors will be unacceptable for that particular recipient). Risk factors for sensitization include infection, pregnancy, blood transfusion, ventricular assist device (VAD), or previous transplant. A United Network for Organ Sharing/ Organ Procurement and Transplantation Network (UNOS/OPTN) database study reported that patients with a most recent pre-transplant PRA greater than 25% had a higher risk of treated rejection in their first year post-transplant versus patients with a 0% PRA (OR 1.4, 95% CI = ). Donor-specific antibodies are also associated with increased risk of rejection. Donor-specific antibodies can develop after transplant. Rejection can present as deterioration in cardiac function, acute cardiac failure, arrhythmias or asymptomatic (diagnosed on surveillance endomyocardial biopsy). Treatment includes supporting the heart and circulation with appropriate inotropes, inodilators and specific treatment for handling rejection episode. The guidelines suggested by International Society of Heart and Lung Transplantation (ISHLT) for the treatment of cellular and antibody rejection are mentioned in table 1 & 2. 4 Cardiac Allograft Vasculopathy Cardiac allograft vasculopathy is an accelerated form of intimal hyperplasia that occurs in the coronaries of the transplanted heart. It has historically been a limiting factor for the long-term survival of heart transplantation, responsible for 32% of deaths after 5 years. According to the 2015 ISHLT report, cardiac allograft vasculopathy was detectable by angiography in 8% of survivors within the first year, 30% by 5 years, and 50% by 10 years after transplant. The diffuse and progressive nature of cardiac allograft vasculopathy explains some of the challenges associated with interventional therapies. The pathophysiology of cardiac allograft vasculopathy involves both immune and non-immune mediated endothelial damage with changes that can be seen as early as 6 months post-transplant. The earliest changes are characterized by intimal thickening of the proximal arteries followed by fibro fatty atheromatous plaque and ultimately diffuse fibrous thickening of the intima which can have overlying atheromatous plaques. Unlike the focal and proximal nature of nontransplant coronary artery disease, cardiac allograft 77

4 vasculopathy affects distal vessels as well. Intimal progression is accompanied by fibrosis of the media; whereas the capillaries remain relatively unaffected due to a lack of smooth muscle cells. Table 1: Treatment of acute cellular rejection DRUGS Corticosteroids Methylprednisolone Prednisone Thymoglobulin B ATGAMb ATG-Freseniusb DOSAGE mg/day IV 3 days 1 3 mg/kg/day PO 3 5 days mg/kg/day 5 14 days 10 mg/kg/day 5 14 days 3 mg/kg/day 5 14 days Monoclonal antibody 5 mg/day 5 14 days ATG, anti-thymocyte gamma-globulin-fresenius; ATGAM, anti-thymocyte gamma-globulin; IV, intravenous; PO, oral (per os). Premedicate with CS, anti-histamine and anti-pyretic. Table 2: Treatment of antibody mediated rejection Plasmapheresis 1 2 plasma exchanges Daily 3 5 days Every other day 1 2 weeks 3 times per week 1 4 weeks Once weekly 2 4 weeks IV Ig 100 1,000 mg/kg 1 3 times per week, often given after each plasmapheresis,1 4 weeks Rituximab 375 mg/m2 Once weekly 1 4 weeks Identification of Rejection Routine echocardiogram Sudden rhythm abnormalities Acute breathlessness Infection Immunosuppression therapy can lead to an increased risk of infection due to the suppression of the hosts immune response. Many heart transplant patients will develop an infection following transplant, with a cumulative incidence of 85% after 5 years. In particular, immunocompromised individuals are at an increased risk of opportunistic viral and bacterial infections. Most infections involve the respiratory system, urinary tract, and the skin. Commonly reported infections include cytomegalovirus, herpes simplex virus, Epstein-Barr virus, varicella zoster virus, tuberculosis, and pneumonia. Invasive fungal infections, such as Aspergillus and Candida, are less common in heart-transplant recipients; however, they are associated with significant morbidity and mortality. Infections are common in the first 6 months after transplant with decreasing risk as immunosuppression (IS) is reduced over time and upon a better understanding of an individual patient s risk of rejection. Specifically, there are 8.78 infectious episodes/1000 transplant days in the first month following heart transplant and 2.33 in months 2-6, but only 0.34 episodes after 6 months. Both active and latent infections can be transmitted from the donor or derived/acquired from the recipient. Generally, the mode of infection follows a common pattern. In the first month, infections tend to be nosocomial, from months 1-6, opportunistic infections or previously latent infections tend to dominate, and infections after 6 months tend to be acquired in the community. While much progress has been made in reducing the risks and consequences of infection, it remains a significant cause of morbidity, mortality, and hospital readmissions in post-heart transplant patients. Infection is one of the leading causes of death in the first year after transplant, being the primary cause of death in 25-32% of patients. The risk of death due to infection is highest between 1 month and 1 year following transplant and then decreases significantly after the first year post-transplant. Infection is also associated with 17% of hospital readmissions in the first year following heart transplant. These patients are at increased risk for bacterial infections in the postoperative period due to immunosuppression, pre transplant hospital admissions, frail status and invasive lines. Appropriate therapy should be based on the site of infection, culture sensitivity report and antibiotic resistance pattern in the unit. Bacterial sepsis (both gram positive and gram negative) is one of the causes for postoperative morbidity and mortality. Early identification and appropriate treatment will result in good outcomes. Cytomegalovirus is an important infection in hearttransplant patients, affecting 47% of patients in the first year post-transplant despite pre-emptive and 78

5 prophylactic therapies. Clinical manifestations of cytomegalovirus can range from flu-like symptoms to organ infiltration and damage. Furthermore, cytomegalovirus can indirectly lead to cardiac allograft vasculopathy, post-transplant lymphoproliferative disorder, and suppression of the immune system, which can further predispose individuals to opportunistic infections and malignancy. While cytomegalovirus infection is still associated with mortality (up to 0.7% of all deaths), the prognosis has improved over time. This is likely due to implementation of donor/recipient serology testing, prophylactic use of ganciclovir in high-risk patients, and regular monitoring of viral load following transplant. During an acute infectious episode, clinicians should consider decreasing the doses of IS as deemed necessary by the severity of the infection. In the case of patients at a high risk of cytomegalovirus, everolimus is an option for IS therapy. This is due to its ability to reduce the odds of cytomegalovirus infection and cytomegalovirus disease compared to both standard IS and prophylactic drugs. Finally, every attempt should be made to gradually taper doses of IS drugs following transplant. Typical Recommendations for the Prevention of Cytomegalovirus in Heart Transplant Recipients Oral ganciclovir (1000 g PO TID) or valganciclovir (900 mg PO/day) for 3 months or IV ganciclovir (5 10 mg/kg/day) for 1 3 months. Preemptive therapy generally not preferred dueto high risk of disease. Some HT centers will add CMV immune globulin for high risk patients. Other Organ Dysfunction (Liver And Kidney) Liver : Children can have liver dysfunction secondary to pre op congestive hepatitis, low cardiac output, sepsis and post op RV dysfunction. Renal: Renal dysfunction in these patients can be secondary to pre transplant CCF, pre transplant low cardiac output, diuretics and post op calcineurin inhibitors induced toxicity. Renal dysfunction can present from mild derangement of renal parameters to acute renal shutdown. Management includes avoiding nephrotoxic drugs, maintaining calcineurin inhibitors within therapeutic range, maintaining adequate cardiac output and considering renal replacement therapy at an appropriate point of time. These patients can have other issues like postoperative bleeding, effusions. Postoperative bleeding can be secondary to congestive coagulopathy, pre-op anticoagulants, and multiple suture lines. Treatment should be based on guidance from point of care tests for coagulation. Effusions can be due to disparity in the size between the pericardial cavity and the new heart from recipient. Recipients who had received hearts from bigger donors (donor to recipient weight > 3) have the risk of developing neurological complications due to hypertension (big heart syndrome). Neurological complications can range from headache to coma; to avoid this complication blood pressure should be aggressively controlled in the post-operative period. Key Messages 1. For successful treatment, or at least to improve the probability of success and to reduce the risks of morbidity and mortality of transplantation, timely referral is essential. 2. The success of cardiac transplant programme is attributed to using team-based, patient-centred care including multidisciplinary staff and specialists across programmes and departments. Source of Funding: Nil Conflict of Interest: Nil References 1. Vamsidhar BD, Chris AR, Nicholas RB. Primary Cardiac Allograft Dysfunction Validation of a Clinical Definition. Transplantation 2015;99: Lavee J, Kormos RL, Duquesnoy RJ, Zerbe TR, Armitage JM, et al. (1991) Influence of panel-reactive antibody and lymphocytotoxic crossmatch on survival after heart transplantation. J Heart Lung Transplant 10: Kfoury AG Hammond ME. Controversies in defining cardiac antibody-mediated rejection: need for updated criteria. J Heart Lung Transplant 2010; 29: Colvin MM, Cook JL, Chang P, et al, Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation 2015;131:

6 How to cite this article: Balakrishnan KR, Suresh KG, Muralikrishna T, Suresh Kumar R. : A brief review. J Pediatr Crit Care 2018;5(3): How to cite this URL: Balakrishnan KR, Suresh KG, Muralikrishna T, Suresh Kumar R. : A brief review. J Pediatr Crit Care 2018;5(3): Available from: 80