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Cardiac Transplantation Dr. Muhammad Usman Shams
Indications for Cardiac Transplantation• Cardiogenic shock requiring mechanical assistance.• Refractory heart failure with continuous inotropic infusion.• Progressive symptoms with maximal therapy.• Severe symptomatic hypertrophic or restrictive cardiomyopathy.• Medically refractory angina with unsuitable anatomy for revascularization.• Life-threatening ventricular arrhythmias despite aggressive medical and device interventions.• Cardiac tumors with low likelihood of metastasis.• Hypoplastic left heart and complex congenital heart disease.
Indications of Cardiac Transplantation• Patients should receive maximal medical therapy before being considered for transplantation. They should also be considered for alternative surgical therapies including CABG, valve repair / replacement, cardiac septalplasty, etc.• VO2 (oxygen carrying capacity) has been used as a reproducible way to evaluate potential transplant candidates and their long term risk. Generally a peak VO2 >14ml/kg/min has been considered “too well” for transplant as transplantation has not been shown to improve survival over conventional medical therapy. Peak VO2 10 to 14 ml/kg/min had some survival benefit, and peak VO2 <10 had the greatest survival benefit.
Evaluation of Cardiac Transplantation Recipient• Right and Left Heart Catheterization.• Cardiopulmonary testing.• Labs including BMP, CBC, LFT, UA, coags., TSH, UDS, ETOH level, HIV, Hepatitis panel, PPD, CMV IgG, RPR / VDRL, PRA (panel of reactive antibodies), ABO and Rh blood type, lipids.• CXR, PFT’s including DLCO, EKG.• Substance abuse history and evidence of abstinence for at least 6 months and enrollment in formal rehabilitation.• Mental health evaluation including substance abuse hx and social support.• Financial support.• Weight no more than 140% of ideal body weight.
Cardiac Donor• Brain death is necessary for any cadaveric organ donation. This is defined as absent cerebral function and brainstem reflexes with apnea during hypercapnea in the absence of any central nervous system depression.• There should be no hypothermia, hypotension, metabolic abnormalities, or drug intoxication.• If brain death is uncertain, confirmation tests using EEG, cerebral flow imaging, or cerebral angiography are indicated.
Cardiac Donor – Exclusion Criteria• Age older than 55 years.• Serologic results (+) for HIV, Hepatitis B or C.• Systemic Infection.• Malignant tumors with metastatic potential (except primary brain tumors)• Systemic comorbidity (diabetes mellitus, collagen vascular disease)• Cardiac disease or trauma• Coronary artery disease• Allograft ischemic time estimated to be > than 4-5 hours• LVH or LV dysfunction on echocardiography• Death of carbon monoxide poisoning• IV drug abuse.
Matching Donor and Recipient• Because ischemic time during cardiac transplantation is crucial, donor recipient matching is based primarily not on HLA typing but on the – severity of illness – ABO blood type (match or compatible), – response to PRA – donor weight to recipient ratio (must be 75% to 125%) – geographic location relative to donor – length of time at current status.
Surgical Transplantation Techniques• Orthotopic implantation is the most common – it involves complete explantation of the native heart.• Heterotopic implantation is an alternative technique in which the donor heart functions in parallel with the recipient’s heart.
Physiologic concerns of Transplant• Biatrial connection means less atrial contribution to stroke volume.• Resting heart rate is faster (95 to 110 bpm) and acceleration of heart rate is slower during exercise because of denervation.• Diurnal changes in blood pressure are abolished.• Diastolic dysfunction is very common because the myocardium is stiff from some degree of rejection and possibly from denervation.
Postoperative Complications• Surgical – Aortic pseudoaneurysm or rupture at cannulation site – Hemorrhagic pericardial effusion due to bleeding or coagulopathy• Medical – Severe tricuspid regurgitation – RV failure • Pulmonary artery compression • Pulmonary hypertension – LV failure • Ischemia • Operative Injury • Acute rejection
Postoperative Complications• Rhythm disturbances • Asystole • Complete heart block. • Sinus node dysfunction with bradyarrhythmias (25% permanent but most resolve within 1-2 weeks). • Atrial fibrillation. • Ventricular tachycardia.• Coagulopathy induced by cardiopulmonary bypass• Respiratory failure • Cardiogenic pulmonary edema. • Noncardiogenic pulmonary edema. • Infection.• Renal or hepatic insufficiency • Drugs. • CHF.
Postoperative Management• Initiation of medications, particularly immunosuppressive agents begins on the day of the operation. – Cyclosporin – Azathioprine – Solumedrol – +/- Muromonab-CD3 (OKT3)
Postoperative Management• Pneumocystis carinii prophylaxis is started within the first week after transplant.• If patient or donor is CMV positive then ganciclovir is started on postop day 2.• Endomyocardial biopsy is performed on postop day 4 and steroids can begin to be tapered if there is no rejection greater than grade 2b.• Anticoagulation is started if heterotopic transplantation has been performed.• Amylase and lipase are measured on day 3 to detect pancreatitis.• ECG’s are obtained every day.
Long-term ManagementEndomycardial biopsy is performed once a week for the first month and then less frequently depending on the presence or absence of rejection (usual regimen is qweek x 4 weeks, qmonth x 3 months, q3months in 1st year, q4months in 2nd year, 1 to 2 times per year subsequently).
Long-term Management• Cyclosporine levels are checked periodically by individual center protocols.• Echocardiography is useful periodically and as an adjunct to endomyocardial biopsy.• Cardiac catheterization is performed annually for early detection of allograft vasculopathy.• There is probably no need for routine exercise or nuclear stress testing.
Complications - Rejection• Avoidance with preoperative therapy with cyclosporin, corticosteroids, and azathioprine.• If rejection is suspected then workup should include: measurement of cyclosporine level CKMB level, echocardiography for LV function, and endomyocardial biopsy.• Signs and symptoms of rejection only manifest in the late stages and usually as CHF (rarely arrhythmias). Due to close surveillance, most rejection is picked up in asymptomatic patients.
Complications - Rejection• Hyperacute Rejection: Caused by preformed antibodies against the donor in the recipient. It occurs within minutes to hours and is uniformly fatal. PRA screening is the best method in avoiding hyperacute rejection.• Acute Cellular Rejection: Most common form and occurs at least once in about 50% of cardiac transplant recipients. Half of all episodes occur within the first 2 to 3 months. It is rarely observed beyond 12 months unless immunosuppression has been decreased.
Complications - Rejection• Vascular (Humoral) Rejection: not well defined. – Characterized by immunoglobulin and complement in the microvasculature with little cellular infiltrate. – It is associated with positive cross match, sensitization to OKT3, female sex, and younger recipient age. – It is more difficult to treat than acute cellular rejection, is associated with hemodynamic instability, and carries a worse prognosis.
Staging of Acute Rejection• If acute rejection is found, histologic review of endomyocardial biopsy is performed to determine the grade of rejection. • Grade 0 — no evidence of cellular rejection • Grade 1A — focal perivascular or interstitial infiltrate without myocyte injury. • Grade 1B — multifocal or diffuse sparse infiltrate without myocyte injury. • Grade 2 — single focus of dense infiltrate with myocyte injury. • Grade 3A — multifocal dense infiltrates with myocyte injury. • Grade 3B — diffuse, dense infiltrates with myocyte injury. • Grade 4 — diffuse and extensive polymorphous infiltrate with myocyte injury; may have hemorrhage, edema, and microvascular injury.
Complications - Infection• There are two peak infection periods after transplantation: • The first 30 days postoperatively: nosocomial infections related to indwelling catheters and wound infections. • Two to six months postoperatively: opportunistic immunosuppresive-related infections.• There is considerable overlap, however as fungal infections and toxoplasmosis can be seen during the first month.• It is important to remember that immunosuppressed transplant patients can develop severe infections in unusual locations and remain afebrile.
Complications - Malignancy• Transplant recipients have a 100-fold increase in the prevalence of malignant tumors as compared with age-matched controls.• Most common tumor is posttransplantation lymphoproliferative disorder (PTLD), a type of non-Hodgkin’s lymphoma believed to be related to EBV. • The incidence is as high as 50% in EBV-negative recipients of EBV-positive hearts. • Treatment involves reduction of immunosuppressive agents, administration of acyclovir, and chemotherapy for widespread disease.• Skin cancer is common with azathioprine use.• Any malignant tumor present before transplantation carries the risk for growth once immunosuppresion is initiated because of the negative effects on the function of T-cells.
Complications - Hypertension• As many as 75% of transplant recipients treated with cyclosporine or corticosteroids eventual develop hypertension.• Treatment is empiric with a diuretic added to a calcium channel blocker, B-blocker, or Ace inhibitor.• If either diltiazem or verapamil is used, the dosage of cyclosporin should be reduced.
Complications - Dyslipidemia• As many as 80% of transplant recipients eventually have lipid abnormalities related to immunosuppression medications.• These dyslipidemias have been linked to accelerated allograft arteriopathy.• These disorders should be treated aggressively with statins and fibrates to hopefully alleviate transplant coronary vasculopathy.
Outcomes• The survival rate according to the United States Scientific Registry for Organ Transplantation reports the 1-year survival rate to be 82% and 3 year survival rate to be 74%.• The most common cause of mortality was cardiac allograft vasculopathy.• The UNOS data suggested some group differences with 3- year survival rate for white persons 75%, Hispanics 71%, and African Americans 68%• Similar survival rates between men and women.
Outcomes• Poor outcomes are associated with the following risk factors: • Age less than 1 year or approaching age 65. • Ventilator use at time of transplant. • Elevated pulmonary vascular resistance. • Underlying pulmonary disease. • Diffuse atherosclerotic vascular disease. • Small body surface area. • The need for inotropic support pre-transplant. • Diabetes mellitus. • Ischemic time longer than 4 hours of transplanted heart. • Sarcoidosis or amyloidosis as reason for transplant (as they may occur in the transplanted heart).