Institutional Affiliations
Chair
Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA
Task Force 1
Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesù, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK
Task Force 2
Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria.
Task Force 3
Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruña, La Coruña, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA
Independent Reviewers
Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.
Abbreviations:
AAIR (atrium paced, atrium sensed inhibited rate modulation), ACC (American College of Cardiology), ACEI (angiotensin converting enzyme inhibitor), ACT (activated clotting time), ADA (American Diabetes Association), AHA (American Heart Association), AMR (antibody-mediated rejection), AP (aerosolized pentamidine), aPTT (activated partial thromboplastin time), ARB (angiotensin receptor blocker), ATG (anti-thymocyte globulin), AZA (azathioprine), BiV (biventricular), BMD (bone mass density), BNP (brain natriuretic peptide), CAV (cardiac allograft vasculopathy), CCB (calcium channel blocker), CEDIA (cloned enzyme donor immunoassay method), CI (cardiac index), CKD (chronic kidney disease), CO (cardiac output), CPB (cardiopulmonary bypass), CMV (cytomegalovirus), CNI (calcineurin inhibitor), CRP (C-reactive protein), CS (corticosteroid), CT (computed tomography), CVP (central venous pressure), CYA (cyclosporine), CYP3A (cytochrome P-450 3A4), DDDR (dual-paced, dual-sensed, dual-response to sensing, rate modulation), DEXA (dual energy x-ray absorptiometry), DSA (donor specific antibody), ECG (electrocardiogram), ED (erectile dysfunction), ECMO (extracorporeal membrane oxygenation), EMB (endomyocardial biopsy), EMIT (enzyme multiplied immunoassay technique), ESC (European Society of Cardiology), EVL (everolimus), FFP (fresh frozen plasma), GFR (glomerular filtration rate), Hgb (hemoglobin), HIT (heparin-induced thrombocytopenia), HLA (human leukocyte antigen), HPLC (high-performance liquid chromatography), HPV (human papillomavirus), HRS (Heart Rhythm Society), HSV (herpes simplex virus), HT (heart transplant), ICU (intensive care unit), Ig (immunoglobulin), IgG (immunoglobulin G), INR (international normalized unit), ISHLT (International Society for Heart and Lung Transplantation), IUD (intrauterine device), IV (intravenous), IVUS (intravascular ultrasound), LV (left ventricle), LVEF (left ventricular ejection fraction), LVH (left ventricular hypertrophy), MAOI (monoamine oxidase inhibitors), MCS (mechanical circulatory support), MDRD equation (modified diet in renal disease equation), MMF (mycophenolate mofetil), MPA (mycophenolic acid), mTOR (mammalian target of rapamycin), MVO2 (mixed venous oxygen), PAWP (pulmonary artery wedge pressure), PCC (prothrombin plasma concentrates), PFA-100 (platelets function assay 100), PGF (primary graft failure), PRA (panel reactive antibodies), PRES (posterior reversible leukoencephalopathy), PSI (proliferation signal inhibitor), PTLD (posttransplant lymphoproliferative disorder), PT (prothrombin time), PTT (partial thromboplastin time), PVR (pulmonary vascular resistance), RAP (right atrial pressure), rFVII (recombinant factor 7), RV (right ventricle), sCr (serum creatinine), SRL (sirolimus), STI (sexually transmitted infection), SVT (sustained ventricular tachycardia), TAC (tacrolimus), TEE (transesophageal echocardiogram), TMP/SMZ (trimethoprim/sulfamethoxazole), TTE (transthoracic echocardiogram), TV (tricuspid valve), VAD (ventricular assist device), VER (ventricular evoked responses), VT (ventricular tachycardia)Since the dawn of heart transplantation in the 1960s, the medical care of heart transplant recipients has been guided by the experience of individual clinicians and has varied from center to center. Despite many advances in surgical techniques, diagnostic approaches, and immunosuppressive strategies, survival after heart transplantation is limited by the development of cardiac allograft vasculopathy and by the adverse effects of immunosuppression. The International Society for Heart and Lung Transplantation (ISHLT) has made an unprecedented commitment to convene experts in all areas of heart transplantation to develop practice guidelines for the care of heart transplant recipients. After a vast effort involving 40 writers from 9 countries worldwide, the ISHLT Guidelines for the Care of Heart Transplant Recipients have now been completed and the Executive Summary of these guidelines is the subject of this article.
The document results from the work of 3 Task Force groups:
- •Task Force 1 addresses the peri-operative care of heart transplant recipients, including the surgical issues affecting early post-operative care; monitoring and treatment of early hemodynamic, metabolic, and infectious issues; evaluation and treatment of allosensitization; evaluation and treatment of early coagulopathies; the organization of a multidisciplinary care team; management of ABO “incompatible” pediatric heart transplantation; and the use of extracorporeal membrane oxygenation (ECMO) for the hemodynamic support of pediatric recipients.
- •Task Force 2 discusses the mechanisms, diagnosis, and treatment of heart transplant rejection; the mechanisms of action, dosing, and drug level monitoring of immunosuppressive drugs as well as their adverse effects and interactions with concomitantly used medications; and reviews the major clinical trials and the immunosuppressive strategies to be used in special clinical situations.
- •Task Force 3 covers the myriad of clinical issues occurring long-term after heart transplantation, including cardiac allograft vasculopathy, the chronic adverse effects of immunosuppression (neurotoxicity, renal insufficiency, hypertension, bone disease, diabetes and malignancy), as well as reproductive health, exercise, psychologic problems, return to work, and operation of motor vehicles after heart transplantation.
It is important to note that each task force was co-chaired by a pediatric heart transplant physician who had the specific mandate to highlight issues unique to the pediatric heart transplant population and to ensure their adequate representation.
As the reader will undoubtedly observe, most of the recommendations only achieve a Level of Evidence C, indicating that these recommendations are based on expert consensus and not on randomized controlled clinical trials. A concerted effort was also made to highlight the numerous gaps in evidence pertaining to many aspects of the care of heart transplant recipients. This lack of “evidence-based” recommendations is mostly due to the limited number of heart transplant recipients worldwide. However, it is the hope of all contributing writers and reviewers that the increased awareness of the “gaps in evidence” provided by these guidelines will spur further research in many important areas of heart transplantation.
Task Force 1: Peri-operative Care of the Heart Transplant Recipient
Chair: Maria Rosa Costanzo, MD; Co-Chairs: Anne Dipchand, MD; Randall Starling, MD
Contributing Writers: Allen Anderson, MD; Michael Chan, MD; Shashank Desai, MD; Savitri Fedson, MD; Patrick Fisher, MD; Gonzalo Gonzales-Stawinski, MD; Luigi Martinelli, MD; David McGiffin, MD; Jon Smith, MD
Topic 1: Surgical Issues Impacting Care in the Immediate Post-operative Period
Recommendations on Donor Heart Selection:1, 2
Class IIa
- 1Taking into consideration only the variable of “donor age,” the hearts of donors younger than 45 years will invariably have sufficient reserves to withstand the rigors of heart transplant (HT) even in settings of prolonged ischemic time, recipient comorbidities, and multiple previous recipient operations with hemodynamically destabilizing bleeding. Hearts from donors between the ages of 45 and 55 years should probably be used when the projected ischemic time is ≤ 4 hours and the potential recipient does not have comorbidities or surgical issues where anything less than robust donor heart performance could prove fatal. The use of donor hearts > 55 years should only be used if the survival benefit of HT for a recipient unequivocally exceeds the decrement in early HT survival due to transplantation of a heart with limited myocardial reserves.Level of Evidence: B.
Recommendation on the Transplantation of Hearts from Donors with Infection3
Class IIa
- 1Hearts from donors with severe infection can be used provided that (1) the donor infection is community acquired and donor death occurs rapidly (within 96 hours); (2) repeat blood cultures before organ procurement are negative; (3) pathogen-specific anti-microbial therapy is administered to the donor; (4) donor myocardial function is normal; and (5) there is no evidence of endocarditis by direct inspection of the donor heart. If such hearts are used for transplantation, the recipient should undergo surveillance blood cultures on the first post-operative day and pathogen-specific anti-biotic therapy should be administered for an appropriate duration of time.Level of Evidence: C.
Recommendation on the Transplantation of Hearts from Donors with Potential Drug Toxicities:4, 5, 6, 7, 8
Class IIa
- 1Hearts from donors with a history of past or current non-intravenous (IV) cocaine abuse can be used for transplantation provided cardiac function is normal and LVH is absent.Level of Evidence: C.
- 2In light of current information, the use of hearts from donors with a history of “alcohol abuse” remains uncertain, but is should probably be considered unwise.Level of Evidence: C.
- 3The use of hearts from donors who have died of carbon monoxide intoxication can be recommended with caution, although the safety has not been completely established. It is recommended that these hearts be used provided there is a normal donor electrocardiogram (ECG) and echocardiogram, minimal elevation of cardiac markers, minimal inotropic requirements, a relatively short ischemic time, a favorable donor to recipient weight ratio and a recipient with normal pulmonary vascular resistance.Level of Evidence: C.
Recommendations on the Use of Donors with Pre-existing Cardiac Abnormalities:9, 10
Class I
- 1As far as the function is concerned, a donor heart should not be used in the presence of intractable ventricular arrhythmias, the need for excessive inotropic support (dopamine at a dose of 20 μg/kg/min or similar doses of other adrenergic agents despite aggressive optimization of pre-load and after-load), discreet wall motion abnormalities on echocardiography or left ventricular ejection fraction (LVEF) < 40% despite optimization of hemodynamics with inotropic support.Level of Evidence: B.
- 2A donor heart with a normally functioning bicuspid aortic valve can be used for HT. Anatomically and hemodynamically abnormal aortic and mitral valves may undergo bench repair or replacement with subsequent transplantation of the heart.Level of Evidence: C.
Class IIa
- 1The use of donor hearts with obstructive disease in any major coronary artery should be avoided unless the heart is being considered for the alternate list recipients with concomitant coronary bypass surgery.Level of Evidence: C.
- 2It would seem appropriate to use hearts from donors with left ventricular hypertrophy (LVH) provided it is not associated with ECG findings of LVH and LV wall thickness is < 14 mm.Level of Evidence: C.
Recommendations on Donor Cardiac Function
Class I
- 1As far as the function is concerned, a donor heart should not be used in the presence of intractable ventricular arrhythmias, the need for excessive inotropic support (dopamine at a dose of 20 mcg/kg/min or similar doses of other adrenergic agents despite aggressive optimization of preload and after load), discreet wall motion abnormalities on echocardiography or LV ejection fraction < 40% despite optimization of hemodynamics with inotropic support.Level of Evidence: B.
Recommendations on Donor-Recipient Size Matching:11, 12
Class I
- 1As a general rule, the use of hearts from donors whose body weight is no greater than 30% below that of the recipient is uniformly safe. Furthermore, a male donor of average weight (70 kg) can be safely used for any size recipient irrespective of weight. Use of a female donor whose weight is more than 20% lower than that of a male recipient should be viewed with caution.Level of Evidence: C.
Recommendations on Ischemic Times10
Class I
- 1As a general rule the ischemic time should be less than 4 hours. However, there are situations in which ischemic times longer than 4 hours are anticipated. Donor hearts with ischemic times longer than 4 hours should only be accepted when other factors interacting with ischemic time are ideal, including donor young age, normal cardiac function, and absence of inotropic support.Level of Evidence: C.
Topic 2: Early Post-operative Care of the Heart Transplant Recipient
Recommendations on the Post-operative Monitoring of Heart Transplant Recipients:13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31
Class I
- 1Peri-operative monitoring of heart transplant recipients should include (1) continuous ECG monitoring; (2) post-operative 12-lead ECG; (3) invasive arterial pressure monitoring; (4) direct measurement of right atrial pressure (RAP) or central venous pressure (CVP); (5) measurement of left atrial or pulmonary artery wedge pressure (PAWP); (6) intermittent measurement of cardiac output (CO); (7) continuous measurement of arterial oxygen saturation; (8) intraoperative transesophageal echocardiogram (TEE); (9) continuous assessment of urinary output.Level of Evidence: C.
Recommendations on the Management of Peri-operative Tricuspid Valve Regurgitation:32, 33
Class I
- 1Tricuspid valve regurgitation identified intraoperatively and estimated to be moderate or severe (> 2+), should be re-evaluated by transthoracic echocardiogram (TTE) or TEE within 24 hours of HT and closely monitored for the first few post-operative days. The frequency of subsequent follow-up should be guided by clinical and hemodynamic variables.Level of Evidence: C.
Class II
- 1DeVega annuloplasty of the donor tricuspid valve (TV) can be considered to maintain the normal size of the TV annulus.Level of Evidence: C.
Recommendations on the Management of Peri-operative Pericardial Effusions:34, 35
Class I
- 1Pericardial effusions occurring after HT should be monitored by echocardiogram.
- 2Percutaneous or surgical drainage should be done when the pericardial effusion causes hemodynamic compromise.Level of Evidence: C.
Class IIa
- 1Pericardial effusions that are not hemodynamically compromising do not require drainage unless there is a strong suspicion of an infectious etiology.Level of Evidence: C.
Recommendations for Peri-operative Vasoactive Drugs Use in Heart Transplant Recipients36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46
(See Table 1)
Table 1Properties of Intravenous Vasoactive Drugs Used after Heart Transplantation
Adapted and reprinted with permission from Kirklin JK, et al.
46
| Peripheral vasoconstriction | Cardiac contractility | Peripheral vasodilation | Chronotropic effect | Arrhythmia risk | |
|---|---|---|---|---|---|
| Isoproterenol | 0 | ++++ | +++ | ++++ | ++++ |
| Dobutamine | 0 | +++ | ++ | + | + |
| Dopamine | ++ | +++ | + | + | + |
| Epinephrine | +++ | ++++ | + | ++ | +++ |
| Milrinone/enoximone | 0 | +++ | + | ++ | ++ |
| Norepinephrine | ++++ | +++ | 0 | + | + |
| Phenylephrine | ++++ | 0 | 0 | 0 | 0 |
| Vasopressin | ++++ | 0 | 0 | 0 | 0 |
Class I
- 1Continuous infusion of an inotropic agent should be used to maintain hemodynamic stability post-operatively. Inotropic agents should be weaned as tolerated over the first 3 to 5 days. The lowest effective dose should be used.Level of Evidence: C.
- 2The following therapies are suggested:
- aisoproterenol, 1 to 10 μg/min, or
- bdobutamine, 1 to 10 μg/kg/min ± dopamine 1 to 10 μg/kg/min, or
- cisoproterenol, 1 to 10 μg/min ± dopamine 1 to 10 μg/kg/min, or
- dmilrinone, 0.375 to 0.75 μg/kg/minLevel of Evidence: C.
- a
- 3Continuous infusion of α-adrenergic agonists including phenylephrine, norepinephrine, or epinephrine can be used to maintain adequate mean arterial pressure.Level of Evidence: C.
- 4Low dose vasopressin (0.03–0.1 U/min) or methylene blue can be added to α-agonist for vasodilatory shock.Level of Evidence: B.
Recommendations for the Medical Management of Right Ventricular Dysfunction and Pulmonary Vascular Hypertension After Heart Transplantation36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47
(See Figure 1)
Figure 1Management of right ventricular dysfunction. AV, atrioventricular; CVVH, continuous venovenous hemofiltration; MI, myocardial infarction; PE, pulmonary embolism; PEEP, positive end-expiratory pressure; SR, sinus rhythm.
Adapted and reprinted with permission from Haddad F, et al.47
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Class I
- 1Inotropic agents that can be used to augment right ventricle (RV) function include isoproterenol, milrinone, enoximone, dobutamine, and epinephrine.Level of Evidence: C.
Class IIa
- 1Systemic vasodilators with pulmonary vasodilating properties, including nitroglycerine and sodium nitroprusside, can be used in the absence of systemic hypotension.Level of Evidence: C.
- 2Selective pulmonary vasodilators that can be used in the management of peri-operative RV dysfunction include (1) prostaglandins (prostaglandin E1 [alprostadil], prostaglandin I2 [epoprostenol or prostacyclin], inhaled iloprost); (2) inhaled nitric oxide; (3) sildenafil.Level of Evidence: C.
Recommendations on the Peri-operative Use of Mechanical Circulatory Support After Heart Transplantation:48, 49, 50, 51, 52
Class I
- 1Mechanical circulatory support (MCS) should be initiated early if there is failure to wean from cardiopulmonary bypass (CPB) or other evidence of heart allograft failure such as the requirement for multiple high-dose inotropic agents to permit separation from CPB.Level of Evidence: B.
- 2MCS should be considered if there is continued or worsening hemodynamic instability, such as decreasing cardiac index (CI) and a falling MVO2 or MVO2 < 50% that is not corrected by appropriate resuscitation.Level of Evidence: B.
- 3Support for either LV or RV failure should escalate from pharmacotherapy to IABP to MCS.Level of Evidence: B.
- 4Small ventricular assist devices (VADs) such as the TandemHeart and Levitronix Centrimag can provide adequate support for RV, LV, or biventricular (BiV) failure, and have benefits of ease of implantation, management, and explant.Level of Evidence: C.
Class IIa
- 1In the presence of hemodynamic instability, cardiac tamponade should be excluded by direct surgical exploration. The presence of hyperacute/antibody-mediated rejection should also be excluded. If hemodynamic instability persists in the absence of cardiac tamponade, MCS should be considered.Level of Evidence: C.
- 2The timing MCS discontinuation should be guided by evidence of graft recovery. If there is no evidence of graft functional recovery within 3 to 4 days, hyperacute and antibody-mediated rejection should be excluded and the option of listing for repeat HT may be considered.Level of Evidence: C.
Class IIb
- 1Use of ECMO support in adults requires consideration of the risk of infection, immobility, and need for anti-coagulation.Level of Evidence: C.
Recommendations for the Management of Early Heart Allograft Dysfunction in Pediatric Recipients:53, 54, 55, 56, 57, 58, 59, 60
Class IIb
- 1The increased risk of post-operative RV dysfunction must be carefully evaluated in children, although evidence suggests that children can safely undergo HT despite elevation of pulmonary vascular resistance (PVR) above values considered unsafe in adults.Level of Evidence: C.
- 2Contrary to the experience and practice in adults, the first choice for support in the setting of primary graft failure (PGF) in the pediatric setting should be ECMO.
Class IIa
Level of Evidence C.
Recommendations for the Peri-operative Management of Cardiac Arrhythmias in Heart Transplant Recipients:61, 62, 63, 64, 65, 66, 67
Class I
- 1Pharmacologic chronotropic agents, including isoproterenol and theophylline can be used in the peri-operative setting to increase heart rate.Level of Evidence: B.
- 2Atrial and ventricular temporary epicardial pacing wires should be placed at the time of HT even if the initial rhythm is sinus.Level of Evidence: B.
- 3After HT, temporary pacing should be initiated in the setting of relative bradycardia to maintain heart rates of > 90 beats/min.Level of Evidence: B.
- 4Pacing guidelines of the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) and the European Society of Cardiology (ESC) lack recommendations specific for temporary pacing early after HT. Recommendations for permanent pacing exist for inappropriate chronotropic response 3 weeks after HT. Standard atrium-paced, atrium-sensed, inhibited-rate modulation (AAIR) or dual-paced, dual-sensed, dual-response to sensing, rate modulation (DDDR) pacemakers are preferable.Level of Evidence: C.
- 5Treatment of tachyarrhythmias should be aimed at rate control.Level of Evidence: B.
- 6Persistent tachyarrhythmias, whether atrial or ventricular, should prompt investigation of possible rejection and electrophysiological evaluation if rejection is absent.Level of Evidence: B.
- 7Sustained ventricular tachycardia (SVT) should be evaluated with both an angiogram and an endomyocardial biopsy (EMB).Level of Evidence: B.
Class IIa
- 1The Class III anti-arrhythmics sotalol and amiodarone can be safely used in HT recipients and have minimal interaction with immunosuppressive agents.Level of Evidence: C.
- 2Non-dihydropyridine calcium channel blockers (CCBs) and β-blockers may be used in HT recipients for rate control.Level of Evidence: B.
Recommendations for Peri-operative Renal Function and Fluid Status Management in Heart Transplant Recipients:68, 69, 70, 71
Class I
- 1The CVP should be maintained between 5 and 12 mm Hg, a level that provides adequate cardiac filling pressures without causing RV overload.Level of Evidence: C.
- 2Colloid replacement is generally preferred in the first 24 hours after HT; blood, if indicated, is the first choice.Level Evidence: C.
- 3Compatible blood products may be safely administered after HT without increasing the risk for rejection. In the setting of ABO incompatible pediatric HT special care must be taken in the selection of compatible products to account for both donor and recipient blood types.Level of Evidence: B.
- 4Blood products should be leukocyte-depleted. Blood products should be cytomegalovirus (CMV) negative if donor and recipient are CMV negative.Level of Evidence: B.
- 5IV loop diuretics are used to decrease volume overload. In addition to intermittent IV bolus, continuous IV infusion of loop diuretics with or without sequential nephronal blockade using thiazide diuretics or aldosterone antagonists may be necessary.Level of Evidence: C.
- 6Hemodialysis for renal failure should be initiated early for both volume management and renal replacement. If the recipient is anuric, oliguric, or has a sharp rise in sCr within 2 to 4 hours after HT, then hemodialysis may be necessary.Level of Evidence: B.
Class IIa
- 1Ultrafiltration should be considered if RAP remains elevated (> 20 mm Hg) despite pharmacologic interventions.Level of Evidence: B.
Class IIb
- 1Delay of initiation of calcineurin inhibitor (CNI) therapy should be considered if there is significant pre-operative renal insufficiency or deterioration of kidney function in the first 2 post-operative days.Level of Evidence: C.
Recommendations for the Peri-operative Management of Hyperglycemia in Heart Transplant Recipient:72, 73
Class I
- 1Oral hypoglycemic agents should be discontinued pre-operatively.Level Evidence: C.
Class IIa
- 1A continuous infusion insulin regimen should be used to maintain blood glucose below 200 mg/dL during the intensive care unit (ICU) stay.Level of Evidence: B.
- 2Aggressive management of hyperglycemia should be continued for the duration of hospitalization.Level of Evidence: C.
Recommendations for Anti-bacterial Prophylaxis/Treatment74
Class I
- 1Pre-operative anti-biotic prophylaxis should be used before the transplant operation.Level of Evidence: B.
- 2Drugs should be selected based upon their activity against usual skin flora, specifically Staphylococcus species.Level of Evidence: B.
- 3If a chronically infected device such as a VAD or a pacemaker is present, then peri-operative anti-biotics should be selected based on microbiologic sensitivities.Level of Evidence: B.
- 4In the event that the donor had an ongoing bacterial infection, a course of suitable anti-biotics should be considered.Level of Evidence: B.
Recommendations for Peri-operative Anti-viral Prophylaxis in Heart Transplant Recipients75
(See Table 2)
Table 2Typical Recommendations for the Prevention of Cytomegalovirus in Heart Transplant Recipients
| Group | Recommendations/Options |
|---|---|
| D+/R– | 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 due to high risk of disease | |
| Some HT centers will add CMV immune globulin for high risk patients | |
| R+ | 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 | |
| or | |
| Preemptive therapy. Monitor with nucleic acid testing or CMV antigenemia assay | |
| Therapy with IV ganciclovir or oral valganciclovir |
CMV, cytomegalovirus; D, donor; HT, heart transplant; IV, intravenous; PO, oral (per os); R, recipient; TID, 3 times daily.
Class I
- 1Prophylaxis against CMV should be initiated within 24 to 48 hours after HT.Level of Evidence: A.
- 2The CMV serologic status of the donor and recipient may be used to stratify the patient as low-risk, intermediate-risk, or high-risk for developing a CMV infection.Level of Evidence: A.
- 3Intravenous ganciclovir may be administered to intermediate and high-risk patients, whereas patients at low-risk for CMV infection may only receive anti-herpes simplex virus prophylaxis with acyclovir. (See Table 3.)Table 3Examples of Desensitization TherapiesAdapted from Kobashigawa J, et al.80
Therapy Dose Frequency Plasmapheresis (A, F) 1.5 volume exchanges (A) 5 consecutive days (B) 5 times, every other day (C) 2–3 times/week until transplant (D) 5 times, every other day, every 2–4 weeks Intravenous immunoglobulin (IV Ig) (A, B) 2g/kg IV divided over 2 days (A) Every 2–4 weeks (C) 2–3 g/kg IV divided over 4 days (D) 0.1 mg/kg IV (D) Every 2–4 weeks (E) 100 mg/kg IV (E) Every 4 weeks (F) 20 g (of 10% IV Ig) (G) 150 g (of 10% IV Ig) divided over 3 rounds (G) Every 4 weeks Rituximab (A) 1 g IV (A) Weekly × 4 (C, E) 375 mg/m2 (C) ×2 doses (G) 500 mg (E) Weekly × 4 (G) Every 2 weeks Cyclophosphamide (used in the past) (A) 1 mg/kg orally (A) Daily (C) 0.5 μg/m2 (D) 1 mg/kg orally (A) UCLA; (B) Stanford University; (C) University of Maryland; (D) University of Toronto; (E) University of Wisconsin; (F) Loyola University Chicago; (G) University of Berlin.Level of Evidence: A.
Recommendations for Peri-operative Anti-Fungal Prophylaxis in Heart Transplant Recipients76
Class I
- 1Anti-fungal prophylaxis to prevent mucocutaneous candidiasis should be initiated once the recipient is extubated. The agents most commonly used are nystatin (4–6 mL [400,000 to 600,000 units] 4 times daily, swish and swallow) or clotrimazole lozenges (10 mg).Level of Evidence: C.
Recommendations for Anti-Protozoal Prophylaxis in Heart Transplant Recipients77
Class I
- 1Prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia and Toxoplasma gondii (in indicated cases) should also be initiated in the early post-operative period. Trimethoprim/sulfamethoxazole (80 mg TMP/160 mg SMZ, 1 single- or double-strength tablet per day) is the most commonly used medication. In the setting of a sulfa allergy or glucose-6-phosphate dehydrogenase deficiency, alternative regimens can be used, including: (1) Aerosolized pentamidine (AP) isethionate (300 mg every 3–4 weeks). (2) Dapsone (diaminodiphenylsulfone) with or without TMP or pyrimethamine (50–100 mg/day). Pyrimethamine may be administered weekly (25 or 50 mg) to supplement dapsone (50–100 mg/day). Dapsone is metabolized via the hepatic cytochrome P-450 system (CYP3A). (3) Atovaquone (1500 mg PO QD). (4) Clindamycin and pyrimethamine.Level of Evidence: B.
Recommendations for Peri-operative Infection Prophylaxis and Treatment in Pediatric Heart Transplant Recipients:74, 75, 76, 77
Class IIb
- 1IV anti-fungal prophylaxis should be considered for infants (< 1 year of age) with an open chest and/or requiring ECMO support in the peri-operative period.Level of Evidence: C.
- 2Prophylaxis for Pneumocystis jiroveci should be instituted for a minimum of 3 months up to a maximum of 24 months after HT.Level of Evidence: C.
Topic 3: Evaluation of Allosensitization, Approaches to Sensitized Heart Transplant Recipients, and Hyperacute and Delayed Antibody-Mediated Rejection
Recommendations for the Evaluation of Donor/Recipient Histocompatibility:78, 79, 80, 81, 82, 83, 84
Class I
- 1Screening panel reactive antibodies (PRA) should be performed in all HT candidates. When the PRA is elevated (≥10%) further evaluation is recommended.Level of Evidence: C.
- 2The specificity of circulating antibodies should be determined with a solid-phase assay such as flow-cytometry, if possible, in a regional certified human leukocyte antigen (HLA) laboratory.Level of Evidence: C.
- 3The complement fixation capability of detected antibodies should be reported.Level of Evidence: C.
- 4The anti-HLA class I and II specificities (ie, any HLA antibody directed against HLA-A, HLA-B, HLA-Cw, HLA-DR, and HLA-DQ antigens) should be defined. In the absence of international standards, each transplant center must define the threshold of antibody levels used to define which specific donor HLA antigens confer an unacceptable rejection risk.Level of Evidence: C.
- 5The virtual crossmatch, which compares recipient anti-HLA antibody specificities with donor HLA antigens, should be routinely used to increase the donor pool for sensitized recipients.Level of Evidence: C.
Recommendations for the Risk-Assessment and Prophylaxis Strategies for Allosensitized Heart Transplant Candidates80, 85
(See Table 3)
Class IIa
- 1A complete patient sensitization history, including previous PRA determinations, blood transfusions, pregnancies, implant of homograft materials, previous transplantation, and use of a VAD is required to assess the risk of heart allograft anti-body-mediated rejection.Level of Evidence: C.
- 2A PRA ≥ 10% indicates significant allosensitization and it should raise the question of whether therapies aimed at reducing allosensitization should be instituted to minimize the need for a prospective donor/recipient crossmatch.Level of Evidence: C.
- 3The results of the retrospective donor recipient cross-match may be considered to make decisions regarding immunosuppressive therapy.Level of Evidence: C.
Class IIb
- 1Desensitization therapy should be considered when the calculated PRA is considered by the individual transplant center to be high enough to significantly decrease the likelihood for a compatible donor match or to decrease the likelihood of donor heart rejection where unavoidable mismatches occur.Level of Evidence: C.
- 2Choices to consider as desensitization therapies include IV immunoglobulin (Ig) infusion, plasmapheresis, either alone or combined, rituximab, and in very selected cases, splenectomy.Level of Evidence: C.
- 3A large randomized controlled clinical trial is needed to assess the effectiveness of desensitization strategies and their impact on outcomes after HT.Level of Evidence: C.
Recommendations for Monitoring of Allosensitization Status of Heart Transplant Candidates and Recipients78, 80, 85
(Table 4)
Table 4Panel-Reactive Antibody Screening Frequency After Original Assessment
Adapted from Betkowski AS, et al.
78
| PRA | Number of heart transplant centers screening at each interval | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| 1 mon | 2 mon | 3 mon | 4–6 mon | 1 year | Variable | SE | Other | Total | |
| Negative | 10 | 2 | 8 | 16 | 7 | 4 | 16 | 2 | 65 |
| Positive | 33 | 8 | 6 | 2 | … | … | … | … | 65 |
PRA, panel reactive antibody; SE, sensitizing events.
Class IIb
- 1The presence of anti-HLA antibodies should be regularly monitored in allosensitized patients undergoing desensitizing therapies until a compatible heart allograft becomes available.Level of Evidence: C.
- 2In ambulatory, non-sensitized HT candidates it is reasonable to measure anti-HLA antibodies every 6 months.Level of Evidence: C.
- 3In HT candidates requiring blood transfusions, anti-HLA antibodies determination should be repeated 2 to 4 weeks later and prospective donor/recipient crossmatch is required in the interim period if a suitable donor organ becomes available.Level of Evidence: C.
- 4No uniform recommendations exist as to the frequency of anti-HLA antibody determinations after an infection or during MCS.Level of Evidence: C.
- 5Circulating immunoglobulins should be measured before and after plasmapheresis or immunoabsorption.Level of Evidence: C.
- 6Lymphocyte sub-populations should be measured before and after the use of rituximab.Level of Evidence: C.
- 7In addition to the post-operative retrospective crossmatch, donor-specific antibodies levels should be obtained when antibody-mediated rejection (AMR) is suspected or confirmed by EMB.Level of Evidence: C.
Recommendations for the Treatment of Antibody-Mediated Rejection:80, 86
Class IIa
- 1Initial therapy of AMR can include immunoadsorption and corticosteroid (CS) or plasmapheresis/low dose of IV Ig and CS.Level of Evidence: C.
- 2Rituximab can be added to reduce the risk of recurrent rejection.Level of Evidence: C.
- 3Changes in therapy, which can be considered for maintenance immunosuppression in patients who experience AMR, can include switch to tacrolimus (TAC) in patients receiving cyclosporine (CYA)-based immunosuppression, increased doses of mycophenolate mofetil (MMF), and CS.Level of Evidence: C.
Recommendations for the Approach to Allosensitization in Pediatric Heart Transplant Recipients:76, 77, 87
Class IIb
- 1The HT can be carried out in highly sensitized pediatric patients without a prospective crossmatch or virtual crossmatch at centers experienced in pediatric HT across a positive crossmatch.Level of Evidence: C.
Topic 4: Management of ABO “Incompatible” Heart Transplant Recipients
Recommendations for the Selection of Candidates for ABO “Incompatible” Heart Transplant:88, 89
Class IIa
- 1The upper limit of age or isohemagglutinin titer for ABO-incompatible pediatric HT remains unclear.Level of Evidence: C.
- 2ABO-incompatible HT can be safely performed in the pediatric population in the presence of positive isohemagglutinin titers against the donor organ.Level of Evidence: C.
- 3ABO-incompatible HT, especially in the presence of donor-specific isohemagglutinins > 1:4, should be performed in an experienced center.Level of Evidence: C.
Recommendation for the Intraoperative Care of ABO “Incompatible” Heart Transplant Recipients:88, 89
Class IIa
- 1ABO-incompatible HT can be undertaken by performing plasma exchange using the CPB circuit to remove donor specific isohemagglutinins.Level of Evidence: C.
- 2Plasma exchange using the CPB circuit allows the safe transplantation of ABO-incompatible organs without the need of aggressive pre-operative immunosuppressive therapies or splenectomy.Level of Evidence: C.
Recommendations for the Monitoring of Isohemagglutinin Levels in ABO “Incompatible” Heart Transplant Recipients:88, 90
Class IIa
- 1Serial measurements of isohemagglutinin titers should be done in the post-operative period. Decisions about whether immunosuppressive therapy must be modified should be based not only on the change in isohemagglutinin titers but also on clinical or pathologic evidence of rejection.Level of Evidence: C.
Recommendations for the Administration of Blood Products in ABO “Incompatible” Heart Transplant Recipients88, 89, 90
(See Table 5)
Table 5Match of Blood Products to Specific ABO-Incompatible Heart Transplant Scenario
| Blood group | Red blood cells (plasma depleted) | Fresh frozen plasma | Cryoprecipitate | Platelets (managed similarly to plasma) | ||
|---|---|---|---|---|---|---|
| Recipient's | Donor's | 2nd choice | ||||
| O | A | O | A | A | A | O concentrate |
| O | B | O | B | B | B | O concentrate |
| O | AB | O | AB | AB, A or B | AB | A or B concentrate |
| A | B | A | AB | AB, or B | AB | B concentrate |
| A | AB | A | AB | AB, A or B | AB | A or B concentrate |
| B | A | B | AB | AB, or A | AB | A concentrate |
| B | AB | B | AB | AB, A or B | AB | A or B concentrate |
a Second choice.
Class IIa
- 1Whole blood products should never be administered to a child who has received an ABO-incompatible HT, and the families should be educated to communicate this fact to other caregivers in the case of any future medical emergency or surgery. Group O red blood cells and group AB blood elements are safe for every blood group combination.Level of Evidence: C.
- 2If red blood cells transfusions are given to any ABO-incompatible HT recipient, red blood cell units should be matched based on the HT recipient's ABO blood type.Level of Evidence: C.
- 3If platelets and/or plasma preparations are needed in ABO-incompatible HT recipients, these blood products should be matched based on the donor's ABO blood type.Level of Evidence: C.
Recommendations for Immunosuppression in ABO “Incompatible” Heart Transplant Recipients:88, 89, 91
Class IIa
- 1Standard (triple) immunosuppression with a CNI, an anti-proliferative agent, and CS can be used in children undergoing ABO-incompatible HT without an increased risk of rejection.Level of Evidence: B.
- 2Immunosuppression management beyond the peri-operative period is similar to that of the ABO-compatible pediatric HT population.Level of Evidence: B.
Recommendation for Rejection Surveillance in ABO “Incompatible” Heart Transplant Recipients:88, 89, 90
Class IIa
- 1Rejection surveillance in ABO-incompatible HT recipients is the same as that of the ABO-compatible HT population.Level of Evidence: C.
Topic 5: Coagulopathies in Heart Transplant Surgery
Recommendations for the Evaluation of Hemostasis in Heart Transplant Recipients92
Class I
- 1A history of bleeding (including details of family history, previous excessive post-traumatic or post-surgical bleeding) and of the use of any medications that alter coagulation should be obtained from the patient.Level of Evidence: C.
- 2Screening coagulation tests of prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelets counts should be measured immediately before HT surgery.Level of Evidence: C.
- 3The activated clotting time (ACT) should be obtained at multiple points during the HT surgery to gauge the activity of heparin during each phase of the HT surgery.Level of Evidence: C.
Class IIa
- 1Thromboelastography may be useful during the HT surgery to further elucidate the status of the patient's hemostasis.Level of Evidence: C.
- 2Platelet function can be measured either by platelet aggregometry or by a point of care assay such as the platelets function assay 100 (PFA-100) during the HT surgery.Level of Evidence: C.
- 3Fibrinogen levels and D-Dimer values should be measured post-operatively because these are tests of fibrinolysis and correlate with the risk of bleeding after HT surgery.Level of Evidence: C.
- 4Thromboelastography may be repeated after HT surgery to monitor patients' hemostasis.Level of Evidence: C.
Recommendations for the Reversal of Anti-coagulation before Heart Transplantation:93, 94, 95, 96
Class I
- 1Pre-operatively, the international normalized ratio (INR) should be reduced to ≤ 1.5.Level of Evidence: C.
- 2Low doses of vitamin K (2.5–5.0 mg) given IV are preferable to high doses because they are associated with a lower risk of anaphylaxis.Level of Evidence: C.
- 3Given the need for rapid normalization of the INR, chronically anti-coagulated patients about to undergo HT should receive vitamin K in conjunction with fresh frozen plasma (FFP), prothrombin plasma concentrates (PCCs), or recombinant factor VII (rFVII), depending on their availability and the patient's renal and hepatic functions.Level of Evidence: C.
Recommendations for Anti-coagulation in Heart Transplant Recipients:97, 98, 99
Class IIa
- 1The absence of platelet factor 4/heparin antibodies should be confirmed.Level of Evidence: C.
- 2The use of unfractionated heparin should be restricted to the operative procedure itself. Low-molecular-weight heparin is not recommended, due to a longer half-life than unfractionated heparin and the inability to fully reverse its effect with protamine.Level of Evidence: C.
- 3Alternative anti-coagulants can be used pre-operatively and post-operatively in patients with history of heparin-induced thrombocytopenia (HIT) in whom the platelet count has recovered but immunoglobulin G (IgG) antibodies to the platelet factor 4/heparin complex are still present.Level of Evidence: C.
- 4Patients with abnormal hepatic and normal renal function can be treated with lepirudin, danaparoid, or fondaparinux, whereas those with abnormal renal and normal hepatic function can receive argatroban at standard doses or lepirudin at reduced doses.Level of Evidence: C.
- 5Patients with both renal and hepatic dysfunction can be treated with argatroban or bivalirudin at reduced doses.Level of Evidence: C.
Gaps in Evidence:
Transfusion strategies are not well studied. Consensus opinion drives the decision of when to transfuse blood products. Expert opinions on which clinical situations require transfusions are highly variable. Recombinant factor VIIa has not been tested in controlled clinical trials and therefore there is little evidence to support its use in a bleeding cardiac surgery patient. Tranexamic acid and aminocaproic acid have not been evaluated in a definitive randomized study. Very few studies have been performed specifically in HT recipients. Thus, the recommendations for HT are extrapolated from evidence regarding achievement of hemostasis in general cardiac surgery.
Recommendations for the Pharmacologic Management of Coagulopathies in Heart Transplant Recipients:100, 101, 102, 103, 104, 105
Class I
- 1Transfusion of coagulation factors is necessary for adequate hemostasis. Thus, fresh frozen plasma and platelets should be transfused based on measured levels. Fibrinogen infusion for massive bleeding and inadequate fibrinogen levels is needed to control blood loss.Level of Evidence: C.
Class IIa
- 1Tranexamic acid and epsilon-aminocaproic acid both have anti-fibrinolytic activity and can be used before CPB to reduce the risk of bleeding in selected patients.Level of Evidence: B.
Class IIb
- 1Recombinant factor VIIa may be used in cases of intractable or excessive bleeding with HT surgery.Level of Evidence: C.
Class III
- 1Although aprotinin can reduce bleeding during HT surgery, its routine use is not recommended due to an increased risk of adverse clinical events.Level of Evidence: B.
- 2Desmopressin is not recommended for routine use because its modest reduction in bleeding has been associated with adverse clinical events.Level of Evidence: A.
Topic 6: Documentation and Communication with the Multidisciplinary Team
Recommendations for the Documentation and Communication with the Multidisciplinary Team:106, 107, 108
Class I
- 1Transplant centers must have a multidisciplinary approach to patient management.Level of Evidence: C.
- 2The HT team should have regularly scheduled meetings of all disciplines involved.Level of Evidence: C.
Class IIa
- 1Social work and psychiatry specialists should be integrated into the patient management team.Level of Evidence: B.
- 2Transplant centers should strive to have specialty-trained pharmacists or physicians with expertise in pharmacology as part of the multidisciplinary team.Level of Evidence: B.
Class IIb
- 1Integration of input from pharmacists and infectious disease specialists is important during the development of treatment protocols for HT recipients.Level of Evidence: B.
- 2Dieticians should be involved in the care of HT recipients to provide input regarding prevention of weight gain and maintenance of glucose control.Level of Evidence: C.
Topic 7: Use of Extracorporeal Membrane Oxygenation for the Management of Primary Graft Failure in Pediatric Heart Transplant Recipients
Recommendations on the Indications for Extracorporeal Membrane Oxygenation in Pediatric Heart Transplant Recipients109, 110, 111, 112, 113, 114
(See Table 6)
Table 6Potential Causes of Primary Graft Failure After Pediatric Heart Transplantation
Adapted from Huddleston CB, et al.
114
| Donor issues |
|
| Recipient issues |
|
Class IIa
- 1The use of ECMO should be considered when there is failure to separate from CPB after all correctable causes of such failure have been excluded.Level of Evidence: C.
- 2ECMO should be promptly instituted when progressive heart allograft dysfunction occurs post-operatively.Level of Evidence: C.
Recommendations for the Conduct of ECMO Support in Pediatric Heart Transplant Recipients:115, 116
Class IIa
- 1The amount of circulatory support provided by ECMO should be sufficient to achieve adequate systemic perfusion and oxygen delivery while waiting for the myocardium to recover.Level of Evidence: C.
- 2Left heart distension during ECMO support should be aggressively treated because it will compromise pulmonary function and impede LV recovery.Level of Evidence: C.
Recommendations for the Timing of Discontinuation of ECMO Support in the Setting of Primary Graft Failure117
Class IIa
- 1Clinical and echocardiographic variables should be serially assessed to determine if myocardial recovery is occurring.Level of Evidence: C.
- 2Objective signs of recovery should lead to weaning and discontinuation of ECMO support.Level of Evidence: C.
Class IIb
- 1Lack of objective evidence of myocardial recovery within 3 to 5 days should prompt consideration of either institution of long term MCS as a bridge to recovery or HT or withdrawal of life-sustaining therapy.Level of Evidence: C.
Gaps in Evidence:
- 1The optimal modality for surveillance of adverse neurologic events during ECMO support for PGF is unknown.
- 2Optimal infection prophylaxis in the immunosuppressed patient receiving ECMO support for PGF is unknown.
- 3Optimal renal-sparing immunosuppression protocol(s) in patients receiving ECMO support for PGF is unknown.
- 4The duration of time waiting for recovery of myocardial function in the setting of PGF beyond which recovery is unlikely is unknown.
- 5The role of more intermediate and long-term MCS in patients with myocardial recovery insufficient to allow separation from ECMO within 5 to 7 days is unknown.
- 6Risk factors for poor outcomes after retransplantation in ECMO-supported HT recipients are unknown.
Task Force 2: Immunosuppression and Rejection
Chair: David Taylor, MD; Co-Chairs: Bruno Meiser, MD; Steven Webber, MD
Contributing Writers: David Baran, MD; Michael Carboni, MD; Thomas Dengler, MD; David Feldman, MD; Maria Frigerio, MD; Abdallah Kfoury, MD; Daniel Kim, MD; Jon Kobashigawa, MD; Michael Shullo, PhD; Josef Stehlik, MD; Jeffrey Teuteberg, MD; Patricia Uber, PharmD; Andreas Zuckermann, MD
Topic 1: Rejection Surveillance
Recommendations for Rejection Surveillance by Endomyocardial Biopsy in Heart Transplant Recipients:118- Cooper L.T.
- Baughman K.L.
- Feldman A.M.
- et al.
The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.J Am Coll Cardiol. 2007; 50: 1914-1931, 119, 120
- Cooper L.T.
- Baughman K.L.
- Feldman A.M.
- et al.
The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology.
J Am Coll Cardiol. 2007; 50: 1914-1931
Class IIa
- 1It is reasonable to utilize EMB in a HT candidate suspected of having an infiltrative cardiomyopathy or an inflammatory process, such as giant cell myocarditis, amyloidosis, or sarcoidosis.Level of Evidence: C.
- 2The standard of care for adult HT recipients is to perform periodic EMB during the first 6 to 12 post-operative months for surveillance of HT rejection.Level of Evidence: C.
- 3The standard of care in adolescents should be similar to that in adults, including surveillance EMB for heart allograft rejection for 6 to 12 months after HT. In younger children, especially infants, it is reasonable to utilize echocardiography as a screening tool to reduce the frequency of EMB.Level of Evidence: C.
- 4After the first post-operative year, EMB surveillance for an extended period of time (eg, every 4–6 months) is recommended in HT recipients at higher risk for late acute rejection, to reduce the risk for rejection with hemodynamic compromise, and to reduce the risk of death in African-American recipients.Level of Evidence: C.
Class IIb
- 4The use of routine EMB later than 5 years after HT is optional in both adults and children, depending on clinical judgment and the risk for late allograft rejection.Level of Evidence: C.
Recommendations for the Non-Invasive Monitoring of Acute Heart Transplant Rejection:120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135
Class IIa
- 1In centers with proven expertise in ventricular evoked potentials (VER) monitoring, intramyocardial electrograms recorded non-invasively with telemetric pacemakers can be used for rejection surveillance in patients at low risk for rejection.Level of Evidence: C.
- 2Gene Expression Profiling (Allomap) can be used to rule out the presence of ACR of grade 2R or greater in appropriate low-risk patients, between 6 months and 5 years after HT.Level of Evidence: B.
Class IIb
- 1Use of echocardiography as primary monitoring modality for acute heart allograft rejection in infants can be considered as an alternative to surveillance EMB.Level of Evidence: C.
Class III
- 1The routine clinical use of electrocardiographic parameters for acute heart allograft rejection monitoring is not recommended.Level of Evidence: C.
- 2The use of echocardiography as an alternative to EMB for rejection monitoring is not recommended.Level of Evidence: C.
- 3The routine clinical use of MRI for acute allograft rejection monitoring is not recommended.Level of Evidence: C.
- 4The use of brain natriuretic peptide (BNP), troponin I or T, or C-reactive protein (CRP) levels for acute heart allograft rejection monitoring is not recommended.Level of Evidence: C.
- 5The use of systemic inflammatory markers for acute heart allograft rejection monitoring is not recommended.Level of Evidence: C.
- 6Routine use of non-invasive testing modalities (ECG, imaging, or biomarkers) is not recommended as the primary method for acute heart allograft rejection surveillance in older children and adolescents.Level of Evidence: C.
Topic 2: Monitoring of Immunosuppressive Drug Levels
Recommendations for the Monitoring of Immunosuppressive Drug Levels136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149
(See Table 7)
Table 7Drugs That Affect the Levels of Tacrolimus, Cyclosporine, Sirolimus, and Everolimus
| Decrease immunosuppression levels | Increase immunosuppression levels |
|---|---|
| Anti-epileptics | Anti-microbials |
| Carbamazepine | Clarithromycin |
| Fosphenytoin | Erythromycin |
| Phenobarbital | Metronidazole and tinidazole |
| Phenytoin | Quinupristin/dalfopristin |
| Levofloxacin | |
| Anti-microbials | Anti-fungals |
| Caspofungin | Clotrimazole |
| Nafcillin | Itraconazole |
| Rifabutin | Ketoconazole |
| Rifampin | Fluconazole |
| Rifapentine | Posaconazole |
| Voriconazole | |
| Anti-retroviral Therapy | Anti-retroviral therapy |
| Efavirenz | Protease inhibitors (general) |
| Etravirine | Amprenavir |
| Nevirapine | Atazanavir |
| Darunavir | |
| Fosamprenavir | |
| Indinavir | |
| Nelfinavir | |
| Ritonavir | |
| Saquinavir | |
| Tipranavir | |
| Others | Cardiovascular |
| Antacids containing magnesium, calcium, or aluminum (tacrolimus only) | Amiodarone |
| Deferasirox | Diltiazem |
| Modafinil | Verapamil |
| St. John's wort | |
| Thalidomide | |
| Ticlopidine | |
| Troglitazone | |
| Nutraceuticals | |
| Bitter orange | |
| Grapefruit juice | |
| Others | |
| Rilonacept | |
| Theophylline | |
| Cimetidine | |
| Fluvoxamine | |
| Glipizide | |
| Glyburide | |
| Imatinib | |
| Nefazodone |
Class I
- 1The use of the microemulsion formulation of CYA is recommended because it is associated with more favorable pharmacokinetic features compared with the oil-based compound.Level of Evidence: B.
Class IIa
- 1At present, 2-hour post-dose (C2) levels should not replace 12-hour trough (C0) concentrations for routine monitoring of CYA exposure in most patients, but may be useful in selected patients in whom a better characterization of the pharmacokinetic profile of CYA is desired.Level of Evidence: B.
- 2Measurement of 12-hour trough CYA concentration is the recommended form of therapeutic drug monitoring for routine clinical use. The target levels are dependent on the method used (high-performance liquid chromatography [HPLC] vs enzyme multiplied immunoassay technique [EMIT] vs cloned enzyme donor immunoassay method [CEDIA]), concomitant immunosuppression, toxicity risks, and time after HT. In general, when used in conjunction with azathioprine (AZA) or a mycophenolic acid (MPA) preparation, the average CYA trough concentration target using the Abbot TDX assay (or equivalent) is 325 ng/ml (range, 275–375 ng/ml) for the first 6 post-operative weeks, 275 ng/ml (range 200–350 ng/ml) for Weeks 6 to 12, 225 ng/ml (range 150–300 ng/mL) for Month 3 to Month 6, and 200 ng/ml (range 150–250 ng/mL) from Month 6 onwards.Level of Evidence: C.
- 3At present, CYA trough concentration targets when CYA is used in combination with proliferation signal inhibitor (PSI; mammalian target of rapamycin [mTOR] inhibitors) agents have not been adequately determined.Level of Evidence: C.
- 4Measurement of 12-hour trough concentration for twice-daily TAC and a 24-hour trough concentration for once-daily TAC is the recommended drug monitoring method for routine clinical use. The therapeutic range of TAC levels varies depending on concomitant drugs, toxicity concerns, and time after HT. In general, when used in conjunction with AZA or a MPA preparation, TAC trough concentration targets range between 10 and 15 ng/ml during the early post-operative period (Days 0–60), between 8 and 12 ng/ml for the next 3 to 6 months, and between 5 and 10 ng/ml in stable patients 6 months after HT.Level of Evidence: C.
- 5At this time, target therapeutic TAC trough concentrations when TAC is used in combination with PSI (mTOR inhibitors) agents have not been adequately determined.Level of Evidence: C.
- 6Therapeutic drug monitoring for PSIs using trough concentration levels is recommended for sirolimus (SRL) and everolimus (EVL). Levels should be measured at least 5 days after adjustment of the dose, when a new steady state is achieved. When used in combination with CYA, the optimal trough target level for EVL is between 3 and 8 ng/ml. The corresponding optimal trough level for SRL is 4 to 12 ng/ml.Level of Evidence: B.
- 7In pediatric HT recipients, TAC and CYA should be monitored using C0 levels when twice-daily dosing is used. Target levels are comparable to those in adults, but slightly lower targets may be used in low-risk patients such as non-sensitized infant HT recipients.Level of Evidence: C.
- 8There are insufficient data to support routine monitoring of MPA levels in pediatric recipients. However, intermittent monitoring is reasonable when there is ongoing rejection, doubts about adequacy of dosing (eg, infants and young children), and to assess medical compliance.Level of Evidence: C.
Class IIb
- 1At this time replacement of twice-daily TAC with once-daily TAC dosing cannot be recommended in HT recipients. Should a patient require the once-daily formulation, appropriate monitoring should be used to ensure maintenance of appropriate levels and preserved heart allograft function.Level of Evidence: C.
- 2In patients with a therapeutic 12-hour trough concentration for twice daily TAC but evidence of potential drug-related toxicity or reduced efficacy (rejection), a 3-hour post-dose level (C3) may help to adjust TAC doses.Level of Evidence: C.
- 3In selected situations (rejection, infection, renal failure, malnutrition, and certain ethnic populations) where it is suspected that altered MMF exposure contributes to heart allograft dysfunction, measurement of trough MPA levels may be used to guide drug dosing. In such cases, a MPA level of < 1.5 mg/liter is considered to be sub-therapeutic.Level of Evidence: C.
- 4Dose adjustments and frequency of therapy with polyclonal antibodies (eg, anti-thymocyte globulin) used as induction therapy can be monitored with daily measurement of CD3 or CD2 counts with the goal of maintaining the CD2 or CD3 count between 25 and 50 cells/mm3 or absolute total lymphocyte counts < 100 to 200 cells/mm3.Level of Evidence: C.
- 5In pediatric HT recipients CYA C2 monitoring may be performed instead of C0 in centers with extensive experience with this form of monitoring.Level of Evidence: C.
- 6As in adults, routine monitoring of SRL and EVL at C0 is recommended also in children.Level of Evidence: C.
Class III
- 1Routine therapeutic drug monitoring of MPA levels to adjust MMF doses cannot be recommended at this time.Level of Evidence: C.
- 2Measuring CD 25 saturation to adjust the dose of anti-interleukin-2 receptor antibodies remains experimental and its routine clinical use cannot be recommended.Level of Evidence: C.