416 SECTION IV Pediatric Critical Care Cardiovascular The initial signal is T cell receptor binding of antigen on the sur face of an APC The APC is derived from the donor in the form of a monocyte, or[.]
416 S E C T I O N I V Pediatric Critical Care: Cardiovascular The initial signal is T-cell receptor binding of antigen on the surface of an APC The APC is derived from the donor in the form of a monocyte, or a tissue macrophage Interaction of the APC and T-cell receptor causes release of interleukin (IL)-1 from the APC, which activates the T cell Activated T cells secrete IL-2 and other lymphokines that induce proliferation of activated T cells, which migrate to the allograft and cause tissue damage Immunosuppression protocols are similar from center to center with generally only small variations Initial immunosuppression protocols typically include high-dose corticosteroids, induction with IL-2 receptor blockade (e.g., basiliximab) or antithymocyte globulin (ATG), followed within approximately 48 hours by introduction of a calcineurin inhibitor (CNI), such as cyclosporine or tacrolimus (Table 37.1) TABLE Immunosuppression in the Intensive Care Unit 37.1 Agent Mechanism of Action Dose Monitoring Major Side Effect(s) Induction Immunosuppression Corticosteroids Redistribution of peripheral lymphocytes, inhibition of lymphokine IL-2 production, impairment of macrophage response to lymphocyte signals Center specific: Generally high-dose steroids followed by taper Glucose Infection, cushingoid appearance, hypertension, hyperlipidemia, glucose intolerance Basiliximab Monoclonal antibody binds to IL-2 receptor 20 mg 35 kg 10 mg ,35 kg, administer days and CBC Anaphylaxis Antithymocyte globulin Nonspecific T-cell lysis 1.5 mg/kg/day for 3–7 days (1/2 dose for platelet count 50,000–75,000, WBC 2000– 3000; hold for platelets ,50,000, WBC ,2,000) T-lymphocyte subsets, platelets Thrombocytopenia, anaphylaxis, infection, PTLD, localized pain with RATG administration, serum sickness Cyclosporine Calcineurin inhibitor, inhibition of T-cell receptor lymphokine production and T-cell proliferation IV: 2.5-5 mg/kg/day Oral: 5–10 mg/kg/day divided q12h (may need q8h in infants) Monoclonal whole blood assay 100–400 ng/mL, depending on time since transplantation Nephrotoxicity, central nervous system seizures, decreased magnesium, hypertension, hirsutism, gingival hyperplasia Tacrolimus Calcineurin inhibitor, inhibition of T-cell receptor lymphokine production and T-cell proliferation Oral: 0.5–1.0 mg (or 0.1–0.3 mg/ kg) q12h and increase the dose to therapeutic level 10–15 ng/mL, whole blood Nephrotoxicity, anemia/ neutropenia, headache, tremors, insomnia, glucose intolerance Maintenance Immunosuppression Cyclosporine IV: 2.5-5 mg/kg/day Oral: 5–10 mg/kg/day divided q12h (may need q8h in infants) Tacrolimus Oral: 0.5–1.0 mg (or 0.1–0.3 mg/ kg) q12h and increase the dose to therapeutic level Sirolimus Inhibition of T-cell activation and proliferation by preventing translation of mRNA mg/m2 daily Triglycerides, platelets, level 5–10 mg/mL Nephrotoxicity, hyperlipidemia, thrombocytopenia, leukopenia, gastrointestinal intolerance, mouth sores Azathioprine Antimetabolite inhibits purine and DNA synthesis 1–2 mg/kg/day WBC ,4000 ANC 1500 Bone marrow suppression Mycophenolate mofetil Inhibits proliferation of T and B cells Mycophenolate mofetil or mycophenolic acid 30–60 mg/kg/ day or 300–600 mg/m2/day WBC ,4000 ANC 1500 Bone marrow suppression, gastrointestinal intolerance Prednisone Variable Acute Cellular Rejection Methylprednisolone Antithymocyte globulin 1.5 mg/kg/day for 5–7 days Peripheral lymphocyte count, platelet count ANC, Absolute neutrophil count; CBC, complete blood cell count; IL-2, interleukin-2; IV, intravenous; mRNA, messenger ribonucleic acid; PTLD, posttransplant lymphoproliferative disease; RATG, rabbit antithymocyte globulin; WBC, whole blood cell count CHAPTER 37 Cardiac Transplantation Induction protocols using IL-2 receptor antagonists or ATG are effective in delaying the time to first allograft rejection episode and the time needed to initiate CNI medications, which is especially useful when there is significant renal dysfunction Induction therapy also reduces the risk of death due to rejection, although it does not appear to have a long-term survival benefit, except possibly in those with a PRA greater than 50% or diagnosis of congenital heart disease.2,29–31 Induction therapy may also be useful in steroid avoidance protocols.32 Some centers not use induction therapy in particular circumstances owing to concerns for risk of infection or viral reactivation, although that has not been borne out in recent studies.33 Corticosteroids have been part of standard protocols since the early days of solid-organ transplantation High-dose methylprednisolone (5–10 mg/kg) is administered at the time of aortic crossclamp removal and continued in tapering doses over the first several days after surgery Corticosteroids have immunosuppressive properties and benefit the allograft because of membranestabilizing and antioxidant effects on the graft Steroid-sparing/ steroid-avoidance protocols exist for other solid-organ transplants and are in development for heart transplantation.32 More controversial is the timing of the introduction of the CNIs cyclosporine and tacrolimus A major complication in the early perioperative course after heart transplantation is renal dysfunction; in the past, CNIs were major contributors The APC and lymphocyte receptor interaction occurs within hours of the transplant; therefore, early introduction of CNIs is important Because oral bioavailability of these drugs is so variable, continuous IV administration of these drugs is sometimes more desirable However, IV administration of these drugs can be associated with acute renal failure in the posttransplant setting Because of these factors, there is variation in CNI protocols among centers Some, for instance, use IV cyclosporine until oral tacrolimus can be delivered reliably Others wait until an oral CNI can be started Most protocols have some delay in starting a CNI until renal function is stable, depending on whether induction therapy was used Most protocols are based on oral/nasogastric administration of a standard dose of tacrolimus within 48 hours of transplantation Target levels of this drug are reached to days after transplantation if subsequent doses are based on the trough level obtained each morning (see Table 37.1) The high-risk period for acute cellular rejection (ACR) is the first month after transplantation ACR is a phenomenon that rarely occurs in the first week after transplantation Hyperacute rejection is uncommon but can occur when a heart transplant recipient has preformed HLA antibody that reacts with a donor who has those specific HLA antigens A positive crossmatch will be reported at the time of transplantation, which means that the recipient’s serum causes lysis of donor T cells obtained from lymph nodes from the donor at the time of organ procurement (in the case of cytotoxic testing) or that there is binding of recipient immunoglobulin G after exposure to donor lymphocytes (in the case of flow cytometry crossmatch) Heart transplant recipients at risk for hyperacute rejection are identified by measuring the presence of HLA antibody in their serum pretransplant Specificity and quantification of these HLA antibodies can be measured by Luminex beads, which enable a virtual crossmatch (comparison of recipient HLA antibodies to donor HLA antigens) to be done between potential donors and recipients at the time of an offer Children with palliated congenital heart disease are at particular risk for HLA sensitization because of exposure to blood products at the time of their previous surgical procedures Institution of plasmapheresis immediately after implantation and 417 continuing through the first several days after the operation is the preferred way to clear the offending antibody causing heart allograft dysfunction The diagnosis of ACR is made by endomyocardial biopsy Histopathology of cardiac tissue obtained by endomyocardial biopsy remains the gold standard for diagnosis of acute cardiac allograft rejection The amount of infiltrating lymphocytes and the presence of myocyte injury are used to grade rejection (International Society for Heart and Lung Transplantation Grade 0R-3R) and to guide allograft rejection therapy Surveillance endomyocardial biopsies are generally performed within the first weeks after transplantation and then at strategic times depending on age and size of the child, available access, and technical difficulty of obtaining tissue Follow-up protocols vary by center Clinical recognition of acute allograft rejection can be subtle but is obviously important because tissue diagnosis is not always possible and surveillance techniques using peripheral blood, electrocardiography, and echocardiography have limitations ACR can be present in the allograft without any symptoms or clinical findings When ACR has progressed to hemodynamically significant allograft dysfunction, then symptoms of abdominal pain and vomiting are prevalent, and findings of systemic venous congestion, liver enlargement, and low cardiac output predominate Symptoms of pulmonary venous congestion/pulmonary edema are rare findings Graft dysfunction can be severe enough that cardiogenic shock is present, requiring inotropes or mechanical circulatory support When ACR is suspected, histologic confirmation is always desirable if it can be safely performed The principles of management are to acutely augment immunosuppression with methylprednisolone or a lympholytic agent depending on the histologic and clinical severity of the heart allograft dysfunction Following acute treatment, increases in maintenance of immunosuppression agents are prescribed and a follow-up endomyocardial biopsy is scheduled In addition to ACR, humoral or antibody-mediated rejection (AMR) may also present in similar fashion Acute AMR is treated as in ACR, with the addition of plasmapheresis to reduce the presence of any DSA In severe cases of graft dysfunction, therapy may be initiated prior to biopsy or results of antibody testing Complications of Immunosuppression in Heart Transplant Recipients That Occur in the Pediatric Intensive Care Unit Infection Infections are a major cause of mortality and morbidity in the early period after heart transplantation.2,34 Factors that predispose to infection can be divided into preexisting factors related to the donor and recipient and factors secondary to events in the intraoperative and postoperative periods For example, the site of the organ transplanted provides a clue to the site of infection Renal transplant recipients acquire urinary tract infections, whereas heart transplant recipients are exposed to chest cavity infections The type and severity of the underlying illness leading to organ failure can increase the risk for rejection Children with cardiomyopathy can be severely malnourished, require prolonged mechanical respiratory or circulatory support, and have chronic indwelling venous catheters, all of which predispose to infection Pretransplant ventricular assist devices or ECMO can also increase risk of infection at cannulation and driveline sites The 418 S E C T I O N I V Pediatric Critical Care: Cardiovascular presence of a pretransplant pulmonary infarction is associated with lung abscess in the posttransplant recovery period.35 Neonates may experience severe sepsis from coagulase-positive staphylococci more often than older children The herpes virus family plays a significant role in infections occurring after transplantation The clinical expression of cytomegalovirus (CMV) and Epstein-Barr virus infection in the young patient is more severe because it is often a primary exposure.36 Clinical infections related to these viruses rarely present before month following organ transplantation and are most common in the first months after heart transplantation However, the presence of a CMV mismatch (donor and recipient CMV status differ) can place the recipient at risk of significant CMV illness and requires prophylactic therapy with ganciclovir/ valganciclovir Herpes simplex virus (HSV) can also be an issue posttransplant in the presence of immunosuppression Currently, the donor’s HSV status is usually not known and recommendation is for universal prophylaxis with acyclovir/valaciclovir or ganciclovir/valganciclovir Antibiotic management of the heart transplant recipient in the ICU can be guided by clinical suspicion, timing of infection after transplantation, and predisposing factors Immunosuppression is selective and targets T cells Neutrophil function is normal except for the effect of high-dose corticosteroids Neutropenia can occasionally be a problem because of bone marrow suppression caused by antimetabolites and tacrolimus Prophylactic antibiotics, in the form of third-generation cephalosporins, are used for patients after sternotomy and generally are continued until chest tubes and central lines are removed The strategy to prevent infection also includes initial isolation, routine surveillance cultures, and regular replacement of indwelling catheters In the early setting after transplantation, temperature elevation should indicate active infection and serious complication until proven otherwise If an infection is suspected, early and aggressive investigation is necessary and broad-spectrum antibiotics/antifungal agents should be initiated until the source of the fever is identified Renal Function Acute kidney injury is a major complication following orthotopic heart transplantation It is often multifactorial in etiology, as the premorbid risk factors of heart transplant recipients cannot necessarily be controlled One must monitor and control use of CNI immunosuppression agents, especially when renal dysfunction is present or expected Therapeutic strategies include delaying the initiation of cyclosporine and tacrolimus by using ATG or IL-2 receptor blockade for induction of immunosuppression The other option is to use a modified oral/nasogastric protocol for tacrolimus administration.37 This protocol targets tacrolimus levels to below ng/mL in the first days after transplantation, followed by rapid increases in dosing and target level over the next days It is important to avoid early IV administration of these agents because they invariably lead to renal afferent arteriolar vasoconstriction and oliguria If renal dysfunction is complicating the posttransplant course, it is still difficult to withdraw CNIs completely, but lowering the target level to ,6 ng/L and substituting higher doses of mycophenolate mofetil and adding sirolimus are reasonable options.38 Other medications, such as diuretics and CMV prophylaxis, can contribute to posttransplant renal dysfunction Often, all of these medications are started at approximately the same time, thus increasing the risk for renal dysfunction Diabetes Mellitus Hyperglycemia is common after heart transplantation with highdose steroid and tacrolimus-based immunosuppression The combination of decreased insulin production from islet cells caused by tacrolimus and decreased peripheral utilization related to highdose corticosteroids results in nonketotic hyperglycemia Insulin therapy is commonly used early posttransplant until the point at which steroid dosing can be reduced and tacrolimus adjusted Future Management Strategies for Critical Care of Infants and Children With Cardiopulmonary Failure Heart transplantation in children has gained wide acceptance as an important adjunct to treatment of children with end-stage cardiomyopathic function from cardiomyopathy and palliated congenital heart disease Successful transplantation has produced greater longevity and better quality of life for many infants and children Ten-year survival free of malignancy and coronary vasculopathy is now the expected outcome.2 Although the future appears to be moving toward fewer transplant procedures in children owing to better surgical options for patients with congenital heart disease, the total number of transplants yearly continues to grow There are many possible reasons for this, including better wait list survival to transplant, more retransplants, and increased numbers of children unable to complete intended staged palliations Also, children who in the past were failing palliation and were not transplant candidates owing to their high risk are now undergoing transplants with reasonable results The use of ventricular assist devices has also allowed patients to get to transplant that may not have in the past The natural history of cardiomyopathy is changing because of our understanding of the cellular mechanisms of myocardial function New treatment strategies using angiotensin receptor blockers, neprilysin inhibitors, and b-adrenergic blockade therapy are delaying or replacing the need for heart transplantation Circulatory support is being miniaturized with the development of the extracorporeal Berlin Heart and with ongoing trials of implantable pediatric ventricular assist devices Current adult devices continue to be used in ever smaller pediatric patients These devices can cause reversed ventricular modeling, allowing discontinuation of support without heart replacement therapy (bridge to recovery) The other major benefit of circulatory support is that, if initiated early, it can rehabilitate the child, recover end-organ function, and reduce the risks of heart transplantation surgery Cardiac failure and ventricular assist devices are covered in greater detail in Chapter 28 Other strategies are under investigation that would expand the donor pool and potentially reduce wait times and wait list mortality These include novel methods of organ transport to allow continued perfusion of the beating heart This allows procurement of hearts from greater distances and allows for observation of a heart that may be borderline for use in transplantation In addition, heart procurement in donation after circulatory death is an approach that may allow for an expanded donor pool As technology continues to advance, so the possibilities for in vitro growth of a complete organ or partial replacement of a diseased heart with healthy tissue CHAPTER 37 Cardiac Transplantation Key References Almond CS, Morales DL, Blackstone EH, et al Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children Circulation 2013;127:1702-1711 Butts R, Davis M, Savage A, et al Effect of induction therapy on graft survival in primary pediatric heart transplantation: a propensity score analysis of the UNOS database Transplantation 2017;101(6): 1228-1233 Del Nido PJ, Bailey L, Kirklin JK Surgical techniques in pediatric heart transplantation In: Canter CE, Kirklin JK, eds ISHLT Monograph Series: Pediatric Heart Transplantation Vol Philadelphia: Elsevier; 2007:83-102 Green M, Michaels MG Infections in pediatric solid organ transplant recipients J Pediatric Infect Dis Soc 2012;1:144-151 Hoffman TM, Wernovsky G, Atz AM, et al Prophylactic intravenous use of milrinone after cardiac operations in pediatrics (PRIMACORP) study Am Heart J 2002;143:15 Kirshborn PM, Bridges ND, Myung RJ, et al Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation J Thorac Cardiovasc Surg 2002;1223:130 419 Rossano JW, Cherikh WS, Chambers DC, et al The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first pediatric heart transplantation report; Focus them: multiorgan transplantation J Heart Lung Transplant 2018;37:1184-1195 Rossano JW, Lorts A, VanderPluym CJ, et al Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) J Heart Lung Transplant 2016;35(5): 585-590 Wessel DL Managing low cardiac output syndrome after congenital heart surgery Crit Care Med 2001;29:S220 West LJ, Pollock-Barziv SM, Dipchand, AI, et al ABO-incompatible (ABOi) heart transplantation in infants N Engl J Med 2001;344: 793-800 The full reference list for this chapter is available at ExpertConsult.com e1 References Baum D, Stinson EB, Shumway NE The place for heart transplantation in children In: Godman MJ, ed Pediatric Cardiology Vol London: Churchill Livingstone; 1981 Rossano JW, Cherikh WS, Chambers DC, et al The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first pediatric heart transplantation report; Focus them: multiorgan transplantation J Heart Lung Transplant 2018;37:1184-1195 Ringewald JM, Gidding SS, Crawford SE, et al Non-adherence is associated with late rejection in pediatric heart transplant recipients J Pediatr 2001;139:75 Lawrence KS, Fricker FJ Pediatric heart transplantation: quality of life J Heart Lung Transplant 1987;6:329 Canter CE, Shaddy RE, Berstein D Indications for heart transplantation Circulation 2007;115:658 Gajarksi RJ, Bennett Pearce F Recipient evaluation: medical and psychological morbidities In: Canter CE, Kirklin JK, eds ISHLT Monograph Series: Pediatric Heart Transplantation Philadelphia: Elsevier; 2007:19-32 Hoffman TM, Wernovsky G, Atz AM, et al Prophylactic intravenous use of milrinone after cardiac operations in pediatrics (PRIMACORP) study Am Heart J 2002;143:15 Wessel DL Managing low cardiac output syndrome after congenital heart surgery Crit Care Med 2001;29:S220 Almond CS, Thiagarajan RR, Piercey GE, et al Waiting list mortality among children listed for heart transplantation in the United States Circulation 2009;119(5):717-727 10 Kirshborn PM, Bridges ND, Myung RJ, et al Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation J Thorac Cardiovasc Surg 2002;1223:130-136 11 Mehta U, Laks H, Sadeghi A, et al Extracorporeal membrane oxygenation for cardiac support in pediatric patients Am Surg 2000;66:879-886 12 Almond CS, Morales DL, Blackstone EH, et al Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children Circulation 2013;127:1702-1711 13 Rossano JW, Lorts A, VanderPluym CJ, et al Outcomes of pediatric patients supported with continuous-flow ventricular assist devices: a report from the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) J Heart Lung Transplant 2016;35(5): 585-590 14 Reinhartz O, Keith FM, EL-Banayosy A, et al Multicenter experience with the Thoratec ventricular assist device in children and adolescents J Heart Lung Transplant 2001;20:439 15 Conway J, Miera O, Adachi I, et al Worldwide experience of a durable centrifugal flow pump in pediatric patients Semin Thorac Cardiovasc Surg 2018;30:327-335 16 Blume ED, Naftel DC, Bastardi HJ, et al Pediatric Heart Transplant Study Investigators outcomes of children bridged to heart transplantation with ventricular assist devices: a multi-institutional study Circulation 2006;113(19):2313-2319 17 West LJ, Pollock-Barziv SM, Dipchand, AI, et al ABO-incompatible (ABOi) heart transplantation in infants N Engl J Med 2001;344: 793-800 18 West LJ, Karamlou T, Dipchand AI, et al Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood groupincompatible donor hearts for neonates and infants J Thorac Cardiovasc Surg 2006;131:455-461 19 Everitt MD, Donaldson AE, Casper TC, et al Effect of ABO-incompatible listing on infant heart transplant waitlist outcomes: analysis of the United Network for Organ Sharing (UNOS) database J Heart Lung Transplant 2009;28:1254-1260 20 Almond CSD, Gauvreau K, Thiagarajan RR, et al Impact of ABOincompatible listing on wait-list outcomes among infants listed for heart transplantation in the United States: a propensity analysis Circulation 2010;121:1926-1933 21 Shumway NE Heart transplantation 1958-1995 J Ir Coll Physicians Surg 1995;24:7-8 22 Mayer JE, Perry S, O’Brien P Orthotopic heart transplantation for complex congenital heart disease J Thorac Cardiovasc Surg 1990;99:484 23 Del Nido PJ, Bailey L, Kirklin JK Surgical techniques in pediatric heart transplantation In: Canter CE, Kirklin JK, eds ISHLT Monograph Series: Pediatric Heart Transplantation Vol Philadelphia: Elsevier; 2007:83-102 24 Tsilimingas NB Modification of bicaval anastomosis: an alternative technique for orthotopic cardiac transplantation Ann Thorac Surg 2003;75:1333 25 Kirklin JK, McGriffin DC, Pinderski LJ, et al Selection of patients and techniques of heart transplantation Surg Clin North Am 2004;84:257 26 Razzouk AJ, Johnston JK, Larsen RL, et al Effect of over-sizing cardiac allografts on survival in pediatric patients with congenital heart disease J Heart Lung Transplant 2005;24:195 27 Stover EP, Siegel LC Physiology of the transplanted heart Int Anesthesiol Clin 1995;33:11 28 Kulkarni A, Singh TP, Sarniak A, et al Sildenaphil for pulmonary hypertension after heart transplantation J Heart Lung Transplant 2004;23:1441 29 Di Filippo S, Boissonnat P, Sassolas F, et al Rabbit antithymocyte globulin as induction immunotherapy in pediatric heart transplantation Transplantation 2003;75(3):354-358 30 Grundy N, Simmonds J, Dawkins H, et al Pre-implantation basiliximab reduces incidence of early acute rejection in pediatric heart transplantation J Heart Lung Transplant 2009;28:1279 31 Butts R, Davis M, Savage A, et al Effect of induction therapy on graft survival in primary pediatric heart transplantation: a propensity score analysis of the UNOS database Transplantation 2017;101(6): 1228-1233 32 Singh TP, Faber C, Blume ED, et al Safety and early outcomes using a corticosteroid-avoidance immunosuppression protocol in pediatric heart transplant recipients J Heart Lung Transplant 2010;29(5):517-522 33 Gajarski RJ, Blume ED, Urschel S, et al Infection and malignancy after pediatric heart transplantation: the role of induction therapy J Heart Lung Transplant 2011;30(3):299-308 34 Rostad CA, Wehrheim K, Kirklin JK, et al Bacterial infections after pediatric heart transplantation: epidemiology, risk factors and outcomes J Heart Lung Transplant 2017;36:996-1003 35 Hsu DT, Addonizio LJ, Hordof AJ, et al Acute pulmonary embolism in pediatric patients awaiting heart transplantation J Am Coll Cardiol 1991;17:1621 36 Green M, Michaels MG Infections in pediatric solid organ transplant recipients J Pediatric Infect Dis Soc 2012;1:144-151 37 Baran DA, Galin I, Sandle D, et al Tacrolimus in cardiac transplantation: efficacy and safety of a novel dosing protocol Transplantation 2002;74:1136 38 Lobach NE, Pollock-Barziv SM, West LJ, Dipchand AI Sirolimus immunosuppression in pediatric heart transplant recipients: a singlecenter experience J Heart Lung Transplant 2005;24:184-189 ... on oral/nasogastric administration of a standard dose of tacrolimus within 48 hours of transplantation Target levels of this drug are reached to days after transplantation if subsequent doses... in the past, CNIs were major contributors The APC and lymphocyte receptor interaction occurs within hours of the transplant; therefore, early introduction of CNIs is important Because oral bioavailability... guide allograft rejection therapy Surveillance endomyocardial biopsies are generally performed within the first weeks after transplantation and then at strategic times depending on age and size