The International Society of Heart and Lung Transplantation Guidelines for the care of heart...

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PECIAL FEATURE

he International Society of Heart and Lung Transplantationuidelines for the care of heart transplant recipients

hair: Maria Rosa Costanzo, MDask Force 1: Chair: Maria Rosa Costanzo, MD; Co-Chairs: Anne Dipchand, MD; Randall Starling, MDontributing Writers: Allen Anderson, MD; Michael Chan, MD; Shashank Desai, MD; Savitri Fedson, MD;atrick Fisher, MD; Gonzalo Gonzales-Stawinski, MD; Luigi Martinelli, MD; David McGiffin, MD; Jon Smith, MDask Force 2: Chair: David Taylor, MDo-Chairs: Bruno Meiser, MD; Steven Webber, MDontributing Writers: David Baran, MD; Michael Carboni, MD; Thomas Dengler, MD; David Feldman, MD;aria Frigerio, MD; Abdallah Kfoury, MD; Daniel Kim, MD; Jon Kobashigawa, MD; Michael Shullo, PhD;

osef Stehlik, MD; Jeffrey Teuteberg, MD; Patricia Uber, PharmD; Andreas Zuckermann, MDask Force 3: Chair: Sharon Hunt, MDo-Chair: Michael Burchontributing Writers: Geetha Bhat, MD; Charles Canter, MD; Richard Chinnock, MD; Marisa Crespo-Leiro, MD;eynolds Delgado, MD; Fabienne Dobbels, PhD; Kathleen Grady, PhD; Kao W, MD; Jaqueline Lamour, MD;areth Parry, MD; Jignesh Patel, MD; Daniela Pini, MD; Jeffrey Towbin, MD; Gene Wolfel, MD

ndependent Reviewers: Diego Delgado, MD; Howard Eisen, MD; Lee Goldberg, MD; Jeff Hosenpud, MD;aryl Johnson, MD; Anne Keogh, MD; Clive Lewis, MD; John O’Connell, MD; Joseph Rogers, MD; Heather Ross, MD;

tuart Russell, MD; Johan Vanhaecke, MD

INSTITUTIONAL AFFILIATIONSChair: Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USATask 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 FairfaxHospital, 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 ofAlabama, Birmingham, Alabama, USA; Smith J: Freeman Hospital, Newcastle upon Tyne, UKTask Force 2: Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: Universityof 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: IntermountainMedical 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 ofPittsburgh, 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 StreetHospital, 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’sHospital, 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

Reprint requests: Amanda W. Rowe, International Society for Heart and Lung Transplantation, 14673 Midway Road, Suite 200, Addison, TX 75001.elephone: 804-873-2541. Fax: 817-912-1237.

E-mail address: [email protected]; [email protected]

053-2498/$ -see front matter © 2010 International Society for Heart and Lung Transplantation. All rights reserved.oi:10.1016/j.healun.2010.05.034

mailto:[email protected]

mailto:[email protected]

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915Costanzo et al. Guidelines for Heart Transplant Care

Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: Universityof 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, LosAngeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Towbin J: CincinnatiChildren’s Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USAIndependent Reviewers: Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: DrexlerUniversity 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 SouthWales, 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.J Heart Lung Transplant 2010;29:914–956© 2010 International Society for Heart and Lung Transplantation. All rights reserved.

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ince the dawn of heart transplantation in the 1960s, theedical care of heart transplant recipients has been

uided by the experience of individual clinicians and hasaried from center to center. Despite many advances inurgical techniques, diagnostic approaches, and immuno-uppressive strategies, survival after heart transplantations limited by the development of cardiac allograft vascu-opathy and by the adverse effects of immunosuppres-ion. The International Society for Heart and Lung Trans-lantation (ISHLT) has made an unprecedentedommitment to convene experts in all areas of heartransplantation to develop practice guidelines for the caref heart transplant recipients. After a vast effort involv-ng 40 writers from 9 countries worldwide, the ISHLTuidelines for the Care of Heart Transplant Recipientsave now been completed and the Executive Summary ofhese guidelines is the subject of this article.

The document results from the work of 3 Task Forceroups:

Task Force 1 addresses the peri-operative care of hearttransplant recipients, including the surgical issues affect-ing early post-operative care; monitoring and treatment ofearly hemodynamic, metabolic, and infectious issues;evaluation and treatment of allosensitization; evaluationand treatment of early coagulopathies; the organization ofa multidisciplinary care team; management of ABO “in-compatible” pediatric heart transplantation; and the use ofextracorporeal membrane oxygenation (ECMO) for thehemodynamic support of pediatric recipients.Task Force 2 discusses the mechanisms, diagnosis, andtreatment of heart transplant rejection; the mechanisms ofaction, dosing, and drug level monitoring of immunosup-pressive drugs as well as their adverse effects and inter-actions with concomitantly used medications; and re-views the major clinical trials and the immunosuppressivestrategies to be used in special clinical situations.Task Force 3 covers the myriad of clinical issues occurringlong-term after heart transplantation, including cardiac allograftvasculopathy, the chronic adverse effects of immunosuppres-sion (neurotoxicity, renal insufficiency, hypertension, bone dis-
ease, diabetes and malignancy), as well as reproductive health,
exercise, psychologic problems, return to work, and operationof motor vehicles after heart transplantation.

It is important to note that each task force was co-chaired bypediatric heart transplant physician who had the specificandate to highlight issues unique to the pediatric heart trans-

lant population and to ensure their adequate representation.As the reader will undoubtedly observe, most of the

ecommendations only achieve a Level of Evidence C,ndicating that these recommendations are based on expertonsensus and not on randomized controlled clinical trials.

concerted effort was also made to highlight the numerousaps in evidence pertaining to many aspects of the care ofeart transplant recipients. This lack of “evidence-based”ecommendations is mostly due to the limited number ofeart transplant recipients worldwide. However, it is theope of all contributing writers and reviewers that the in-reased awareness of the “gaps in evidence” provided byhese guidelines will spur further research in many impor-ant areas of heart transplantation.

ask Force 1: Peri-operative Care of the Heartransplant Recipient

hair: Maria Rosa Costanzo, MD; Co-Chairs: Anne Dipc-and, MD; Randall Starling, MD

Contributing Writers: Allen Anderson, MD; Michaelhan, MD; Shashank Desai, MD; Savitri Fedson, MD; Patrickisher, MD; Gonzalo Gonzales-Stawinski, MD; Luigi Mar-

inelli, MD; David McGiffin, MD; Jon Smith, MD

opic 1: Surgical Issues Impacting Care in themmediate Post-operative Period

ecommendations on Donor Heart Selection:1,2

lass IIa:

. Taking into consideration only the variable of “donor age,”the hearts of donors younger than 45 years will invariablyhave sufficient reserves to withstand the rigors of hearttransplant (HT) even in settings of prolonged ischemictime, recipient comorbidities, and multiple previous recip-
ient operations with hemodynamically destabilizing bleed-

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916 The Journal of Heart and Lung Transplantation, Vol 29, No 8, August 2010

ing. Hearts from donors between the ages of 45 and 55years should probably be used when the projected ischemictime is � 4 hours and the potential recipient does not havecomorbidities or surgical issues where anything less thanrobust donor heart performance could prove fatal. The useof donor hearts � 55 years should only be used if thesurvival benefit of HT for a recipient unequivocally exceedsthe decrement in early HT survival due to transplantation ofa heart with limited myocardial reserves.

Level of Evidence: B.

ecommendation on the Transplantation of Hearts fromonors with Infection3:lass IIa:

. Hearts from donors with severe infection can be usedprovided that (1) the donor infection is community ac-quired and donor death occurs rapidly (within 96 hours);(2) repeat blood cultures before organ procurement arenegative; (3) pathogen-specific anti-microbial therapy isadministered to the donor; (4) donor myocardial functionis normal; and (5) there is no evidence of endocarditis bydirect inspection of the donor heart. If such hearts areused for transplantation, the recipient should undergosurveillance blood cultures on the first post-operativeday and pathogen-specific anti-biotic therapy should beadministered for an appropriate duration of time.

Level of Evidence: C.

ecommendation on the Transplantation of Hearts fromonors with Potential Drug Toxicities:4–8

lass IIa:

. Hearts from donors with a history of past or current non-intravenous (IV) cocaine abuse can be used for transplantationprovided cardiac function is normal and LVH is absent.

Level of Evidence: C.. In light of current information, the use of hearts from

donors with a history of “alcohol abuse” remains uncer-tain, but is should probably be considered unwise.

Level of Evidence: C.. The use of hearts from donors who have died of carbon

monoxide intoxication can be recommended with cau-tion, although the safety has not been completely estab-lished. It is recommended that these hearts be used pro-vided there is a normal donor electrocardiogram (ECG)and echocardiogram, minimal elevation of cardiac mark-ers, minimal inotropic requirements, a relatively short isch-emic time, a favorable donor to recipient weight ratio and arecipient with normal pulmonary vascular resistance.


ecommendations on the Use of Donors with Pre-existingardiac Abnormalities:9,10

lass I:

. As far as the function is concerned, a donor heart shouldnot be used in the presence of intractable ventriculararrhythmias, the need for excessive inotropic support
(dopamine at a dose of 20 �g/kg/min or similar doses of
other adrenergic agents despite aggressive optimizationof pre-load and after-load), discreet wall motion abnor-malities on echocardiography or left ventricular ejectionfraction (LVEF) � 40% despite optimization of hemo-dynamics with inotropic support.

Level of Evidence: B.. A donor heart with a normally functioning bicuspid

aortic valve can be used for HT. Anatomically and he-modynamically abnormal aortic and mitral valves mayundergo bench repair or replacement with subsequenttransplantation of the heart.


lass IIa:

. The use of donor hearts with obstructive disease in anymajor coronary artery should be avoided unless the heartis being considered for the alternate list recipients withconcomitant coronary bypass surgery.

Level of Evidence: C.. It would seem appropriate to use hearts from donors with left

ventricular hypertrophy (LVH) provided it is not associatedwith ECG findings of LVH and LV wall thickness is � 14mm.


ecommendations on Donor Cardiac Function:lass I:

. As far as the function is concerned, a donor heart should notbe used in the presence of intractable ventricular arrhyth-mias, the need for excessive inotropic support (dopamine ata dose of 20 mcg/kg/min or similar doses of other adren-ergic agents despite aggressive optimization of preload andafter load), discreet wall motion abnormalities on echocar-diography or LV ejection fraction � 40% despite optimi-zation of hemodynamics with inotropic support.


ecommendations on Donor-Recipient Size Matching:11,12

lass I:

. As a general rule, the use of hearts from donors whosebody weight is no greater than 30% below that of therecipient is uniformly safe. Furthermore, a male donor ofaverage weight (70 kg) can be safely used for any sizerecipient irrespective of weight. Use of a female donorwhose weight is more than 20% lower than that of a malerecipient should be viewed with caution.


ecommendations on Ischemic Times10:lass I:

. As a general rule the ischemic time should be less than4 hours. However, there are situations in which ischemictimes longer than 4 hours are anticipated. Donor heartswith ischemic times longer than 4 hours should only be
accepted when other factors interacting with ischemic

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time are ideal, including donor young age, normal car-diac function, and absence of inotropic support.


opic 2: Early Post-operative Care of the Heartransplant Recipient

ecommendations on the Post-operative Monitoring ofeart Transplant Recipients:13–31

lass I:

. Peri-operative monitoring of heart transplant recipientsshould include (1) continuous ECG monitoring; (2) post-operative 12-lead ECG; (3) invasive arterial pressuremonitoring; (4) direct measurement of right atrial pres-sure (RAP) or central venous pressure (CVP); (5) mea-surement of left atrial or pulmonary artery wedge pres-sure (PAWP); (6) intermittent measurement of cardiacoutput (CO); (7) continuous measurement of arterialoxygen saturation; (8) intraoperative transesophagealechocardiogram (TEE); (9) continuous assessment ofurinary output.


ecommendations on the Management of Peri-operativericuspid Valve Regurgitation:32,33

lass I:

. Tricuspid valve regurgitation identified intraoperativelyand estimated to be moderate or severe (� 2�), shouldbe re-evaluated by transthoracic echocardiogram (TTE)or TEE within 24 hours of HT and closely monitored forthe first few post-operative days. The frequency of sub-sequent follow-up should be guided by clinical and he-modynamic variables.


lass II:

. DeVega annuloplasty of the donor tricuspid valve (TV)can be considered to maintain the normal size of the TVannulus.


ecommendations on the Management of Peri-operative

Table 1 Properties of Intravenous Vasoactive Drugs Used afte

Peripheralvasoconstriction

Cardiaccontrac

Isoproterenol 0 ��Dobutamine 0 ��Dopamine �� Epinephrine �� Milrinone/enoximone 0 ��Norepinephrine �� Phenylephrine �� 0Vasopressin �� 0

Adapted and reprinted with permission from Kirklin JK, et al.46

ericardial Effusions:34,35 (

lass I:

. Pericardial effusions occurring after HT should be mon-itored by echocardiogram.

. Percutaneous or surgical drainage should be done when thepericardial effusion causes hemodynamic compromise.


lass IIa:

. Pericardial effusions that are not hemodynamically com-promising do not require drainage unless there is a strongsuspicion of an infectious etiology.


ecommendations for Peri-operative Vasoactive Drugs Usen Heart Transplant Recipients36–46:See Table 1)lass I:

. Continuous infusion of an inotropic agent should be usedto maintain hemodynamic stability post-operatively. Ino-tropic agents should be weaned as tolerated over the first3 to 5 days. The lowest effective dose should be used.

Level of Evidence: C.. The following therapies are suggested:

a. isoproterenol, 1 to 10 �g/min, orb. dobutamine, 1 to 10 �g/kg/min � dopamine 1 to 10

�g/kg/min, orc. isoproterenol, 1 to 10 �g/min � dopamine 1 to 10

�g/kg/min, ord. milrinone, 0.375 to 0.75 �g/kg/min


. Continuous infusion of �-adrenergic agonists includingphenylephrine, norepinephrine, or epinephrine can beused to maintain adequate mean arterial pressure.

Level of Evidence: C.. Low dose vasopressin (0.03–0.1 U/min) or methylene

blue can be added to �-agonist for vasodilatory shock.Level of Evidence: B.

ecommendations for the Medical Management of Rightentricular Dysfunction and Pulmonary Vascular Hyperten-ion After Heart Transplantation36–45,47:

t Transplantation

Peripheralvasodilation

Chronotropiceffect

Arrhythmiarisk

�� 0 � �0 0 00 0 0

r Hear

tility

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lass I:

. Inotropic agents that can be used to augment right ven-tricle (RV) function include isoproterenol, milrinone,enoximone, dobutamine, and epinephrine.


lass IIa:

. Systemic vasodilators with pulmonary vasodilatingproperties, including nitroglycerine and sodium nitro-prusside, can be used in the absence of systemic hypo-tension.

Level of Evidence: C.. Selective pulmonary vasodilators that can be used in the

management of peri-operative RV dysfunction include(1) prostaglandins (prostaglandin E1 [alprostadil], pros-taglandin I2 [epoprostenol or prostacyclin], inhaled ilo-prost); (2) inhaled nitric oxide; (3) sildenafil.


ecommendations on the Peri-operative Use of Mechanicalirculatory Support After Heart Transplantation:48–52

lass I:

. Mechanical circulatory support (MCS) should be initi-

igure 1 Management of right ventricular dysfunction. AV,yocardial infarction; PE, pulmonary embolism; PEEP, positive

ermission from Haddad F, et al.47

ated early if there is failure to wean from cardiopulmo-

nary bypass (CPB) or other evidence of heart allograftfailure such as the requirement for multiple high-doseinotropic agents to permit separation from CPB.

Level of Evidence: B.. MCS should be considered if there is continued or wors-

ening hemodynamic instability, such as decreasing car-diac index (CI) and a falling MVO2 or MVO2 � 50%that is not corrected by appropriate resuscitation.

Level of Evidence: B.. Support for either LV or RV failure should escalate from

pharmacotherapy to IABP to MCS.Level of Evidence: B.

. Small ventricular assist devices (VADs) such as theTandemHeart and Levitronix Centrimag can provide ad-equate support for RV, LV, or biventricular (BiV) fail-ure, and have benefits of ease of implantation, manage-ment, and explant.


lass IIa:

. In the presence of hemodynamic instability, cardiac tam-ponade should be excluded by direct surgical explora-tion. The presence of hyperacute/antibody-mediated re-

entricular; CVVH, continuous venovenous hemofiltration; MI,piratory pressure; SR, sinus rhythm. Adapted and reprinted with

atriovend-ex

jection should also be excluded. If hemodynamic

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instability persists in the absence of cardiac tamponade,MCS should be considered.

Level of Evidence: C.. The timing MCS discontinuation should be guided by

evidence of graft recovery. If there is no evidence ofgraft functional recovery within 3 to 4 days, hyperacuteand antibody-mediated rejection should be excluded andthe option of listing for repeat HT may be considered.


lass IIb:

. Use of ECMO support in adults requires consideration ofthe risk of infection, immobility, and need for anti-coagulation.


ecommendations for the Management of Early Heart Al-ograft Dysfunction in Pediatric Recipients:53–60

lass IIb:

. The increased risk of post-operative RV dysfunctionmust be carefully evaluated in children, although evi-dence suggests that children can safely undergo HT de-spite elevation of pulmonary vascular resistance (PVR)above values considered unsafe in adults.

Level of Evidence: C.. Contrary 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.

lass IIa, Level of Evidence C.

ecommendations for the Peri-operative Management ofardiac Arrhythmias in Heart Transplant Recipients:61–67

lass I:

. Pharmacologic chronotropic agents, including isoproter-enol and theophylline can be used in the peri-operativesetting to increase heart rate.

Level of Evidence: B.. Atrial and ventricular temporary epicardial pacing wires

should be placed at the time of HT even if the initialrhythm is sinus.

Level of Evidence: B.. After HT, temporary pacing should be initiated in the

setting of relative bradycardia to maintain heart rates of� 90 beats/min.

Level of Evidence: B.. Pacing guidelines of the American College of Cardiol-

ogy (ACC)/American Heart Association (AHA)/HeartRhythm Society (HRS) and the European Society ofCardiology (ESC) lack recommendations specific fortemporary pacing early after HT. Recommendations forpermanent pacing exist for inappropriate chronotropicresponse 3 weeks after HT. Standard atrium-paced, atri-um-sensed, inhibited-rate modulation (AAIR) or dual-paced, dual-sensed, dual-response to sensing, rate mod-ulation (DDDR) pacemakers are preferable.


. Treatment of tachyarrhythmias should be aimed at ratecontrol.

Level of Evidence: B.. Persistent tachyarrhythmias, whether atrial or ventricu-

lar, should prompt investigation of possible rejection andelectrophysiological evaluation if rejection is absent.

Level of Evidence: B.. Sustained ventricular tachycardia (SVT) should be eval-

uated with both an angiogram and an endomyocardialbiopsy (EMB).


lass IIa:

. The Class III anti-arrhythmics sotalol and amiodaronecan be safely used in HT recipients and have minimalinteraction with immunosuppressive agents.

Level of Evidence: C.. Non-dihydropyridine calcium channel blockers (CCBs)

and �-blockers may be used in HT recipients for ratecontrol.


ecommendations for Peri-operative Renal Function andluid Status Management in Heart Transplant Recipients:8–71

lass I:

. The CVP should be maintained between 5 and 12 mmHg, a level that provides adequate cardiac filling pres-sures without causing RV overload.

Level of Evidence: C.. Colloid replacement is generally preferred in the first 24

hours after HT; blood, if indicated, is the first choice.Level Evidence: C.

. Compatible blood products may be safely administeredafter HT without increasing the risk for rejection. In thesetting of ABO incompatible pediatric HT special caremust be taken in the selection of compatible products toaccount for both donor and recipient blood types.

Level of Evidence: B.. Blood products should be leukocyte-depleted. Blood

products should be cytomegalovirus (CMV) negative ifdonor and recipient are CMV negative.

Level of Evidence: B.. IV loop diuretics are used to decrease volume overload.

In addition to intermittent IV bolus, continuous IV infu-sion of loop diuretics with or without sequential nephro-nal blockade using thiazide diuretics or aldosterone an-tagonists may be necessary.

Level of Evidence: C.. Hemodialysis for renal failure should be initiated early

for both volume management and renal replacement. Ifthe recipient is anuric, oliguric, or has a sharp rise in sCrwithin 2 to 4 hours after HT, then hemodialysis may benecessary.


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lass IIa:

. Ultrafiltration should be considered if RAP remains ele-vated (� 20 mm Hg) despite pharmacologic interventions.


lass IIb:

. Delay of initiation of calcineurin inhibitor (CNI) therapyshould be considered if there is significant pre-operativerenal insufficiency or deterioration of kidney function inthe first 2 post-operative days.


ecommendations for the Peri-operative Management ofyperglycemia in Heart Transplant Recipient:72,73

lass I:

. Oral hypoglycemic agents should be discontinued pre-operatively.

Level Evidence: C.

lass IIa:

. A continuous infusion insulin regimen should be used tomaintain blood glucose below 200 mg/dL during theintensive care unit (ICU) stay.

Level of Evidence: B.. Aggressive management of hyperglycemia should be

continued for the duration of hospitalization.Level of Evidence: C.

ecommendations for Anti-bacterial Prophylaxis/Treat-ent74:

lass I:

. Pre-operative anti-biotic prophylaxis should be used be-fore the transplant operation.

Level of Evidence: B.. Drugs should be selected based upon their activity

against usual skin flora, specifically Staphylococcus spe-cies.

Level of Evidence: B.. If a chronically infected device such as a VAD or a

pacemaker is present, then peri-operative anti-bioticsshould be selected based on microbiologic sensitivities.

Level of Evidence: B.. In the event that the donor had an ongoing bacterial

infection, a course of suitable anti-biotics should beconsidered.


ecommendations for Peri-operative Anti-viral Prophylaxisn Heart Transplant Recipients75:See Table 2)lass I:

. Prophylaxis against CMV should be initiated within 24to 48 hours after HT.

Level of Evidence: A.. The CMV serologic status of the donor and recipient

may be used to stratify the patient as low-risk, interme-
diate-risk, or high-risk for developing a CMV infection.
Level of Evidence: A.. Intravenous ganciclovir may be administered to interme-

diate and high-risk patients, whereas patients at low-riskfor CMV infection may only receive anti-herpes simplexvirus prophylaxis with acyclovir. (See Table 3.)

Level of Evidence: A.

ecommendations for Peri-operative Anti-Fungal Prophy-axis in Heart Transplant Recipients76:lass I:

. Anti-fungal prophylaxis to prevent mucocutaneous can-didiasis should be initiated once the recipient is extu-bated. The agents most commonly used are nystatin(4–6 mL [400,000 to 600,000 units] 4 times daily, swishand swallow) or clotrimazole lozenges (10 mg).


ecommendations for Anti-Protozoal Prophylaxis in Heartransplant Recipients77:lass I:

. Prophylaxis against Pneumocystis jiroveci (formerlyPneumocystis carinii) pneumonia and Toxoplasma gon-dii (in indicated cases) should also be initiated in theearly post-operative period. Trimethoprim/sulfamethox-azole (80 mg TMP/160 mg SMZ, 1 single- or double-strength tablet per day) is the most commonly usedmedication. In the setting of a sulfa allergy or glucose-6-phosphate dehydrogenase deficiency, alternative regi-mens can be used, including: (1) Aerosolized pentami-dine (AP) isethionate (300 mg every 3–4 weeks). (2)Dapsone (diaminodiphenylsulfone) with or without TMPor pyrimethamine (50–100 mg/day). Pyrimethaminemay be administered weekly (25 or 50 mg) to supple-

Table 2 Typical Recommendations for the Prevention ofCytomegalovirus in Heart Transplant Recipients

Group Recommendations/Options

D�/R– Oral ganciclovir (1000 g PO TID) or valganciclovir(900 mg PO/day) for 3 months

orIV ganciclovir (5–10 mg/kg/day) for 1–3 monthsPreemptive therapy generally not preferred due

to high risk of diseaseSome HT centers will add CMV immune globulin

for high risk patientsR� Oral ganciclovir (1000 g PO TID) or valganciclovir

(900 mg PO/day) for 3 monthsorIV ganciclovir (5–10 mg/kg/day) for 1–3 monthsorPreemptive therapy. Monitor with nucleic acid

testing or CMV antigenemia assayTherapy with IV ganciclovir or oral valganciclovir

CMV, cytomegalovirus; D, donor; HT, heart transplant; IV, intrave-nous; PO, oral (per os); R, recipient; TID, 3 times daily.

ment dapsone (50–100 mg/day). Dapsone is metabolized

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via the hepatic cytochrome P-450 system (CYP3A). (3)Atovaquone (1500 mg PO QD). (4) Clindamycin andpyrimethamine.


ecommendations for Peri-operative Infection Prophylaxisnd Treatment in Pediatric Heart Transplant Recipients:74–77

lass IIb:

. IV anti-fungal prophylaxis should be considered for in-fants (� 1 year of age) with an open chest and/or requir-ing ECMO support in the peri-operative period.

Level of Evidence: C.. Prophylaxis for Pneumocystis jiroveci should be insti-

tuted for a minimum of 3 months up to a maximum of 24months after HT.


opic 3: Evaluation of Allosensitization,pproaches to Sensitized Heart Transplantecipients, and Hyperacute and Delayedntibody-Mediated Rejection

ecommendations for the Evaluation of Donor/Recipientistocompatibility:78–84

lass I:

. Screening panel reactive antibodies (PRA) should beperformed in all HT candidates. When the PRA is ele-vated (�10%) further evaluation is recommended.

Level of Evidence: C.. The specificity of circulating antibodies should be deter-

Table 3 Examples of Desensitization Therapies

Therapy Dose

Plasmapheresis (A, F) 1.5 volume exchanges

Intravenous immunoglobulin(IV Ig)

(A, B) 2g/kg IV divided over 2

(C) 2–3 g/kg IV divided over 4(D) 0.1 mg/kg IV(E) 100 mg/kg IV(F) 20 g (of 10% IV Ig)(G) 150 g (of 10% IV Ig) divid

Rituximab (A) 1 g IV(C, E) 375 mg/m2

(G) 500 mg

Cyclophosphamide(used in the past)

(A) 1 mg/kg orally

(C) 0.5 �g/m2

(D) 1 mg/kg orally

(A) UCLA; (B) Stanford University; (C) University of Maryland; (D) Un(G) University of Berlin.

Adapted from Kobashigawa J, et al.80

mined with a solid-phase assay such as flow-cytometry,

if possible, in a regional certified human leukocyte an-tigen (HLA) laboratory.

Level of Evidence: C.. The complement fixation capability of detected antibod-

ies should be reported.Level of Evidence: C.

. The anti-HLA class I and II specificities (ie, any HLAantibody directed against HLA-A, HLA-B, HLA-Cw,HLA-DR, and HLA-DQ antigens) should be defined. Inthe absence of international standards, each transplantcenter must define the threshold of antibody levels usedto define which specific donor HLA antigens confer anunacceptable rejection risk.

Level of Evidence: C.. The virtual crossmatch, which compares recipient anti-

HLA antibody specificities with donor HLA antigens,should be routinely used to increase the donor pool forsensitized recipients.


ecommendations for the Risk-Assessment and Prophy-axis Strategies for Allosensitized Heart Transplant Candi-ates80,85:See Table 3)lass IIa:

. A complete patient sensitization history, including pre-vious PRA determinations, blood transfusions, pregnan-cies, implant of homograft materials, previous transplan-tation, and use of a VAD is required to assess the risk ofheart allograft anti-body-mediated rejection.

Frequency

(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(A) Every 2–4 weeks

(D) Every 2–4 weeks(E) Every 4 weeks

er 3 rounds (G) Every 4 weeks(A) Weekly � 4(C) �2 doses(E) Weekly � 4(G) Every 2 weeks(A) Daily

of Toronto; (E) University of Wisconsin; (F) Loyola University Chicago;

days

days

ed ov

iversity


2

3

C

1

2

3

Rt(C

1

2

3

4

5

6

7

RRC

1

2

3

RPC

1

T


. A PRA � 10% indicates significant allosensitization and itshould raise the question of whether therapies aimed atreducing allosensitization should be instituted to minimizethe need for a prospective donor/recipient crossmatch.

Level of Evidence: C.. The results of the retrospective donor recipient cross-

match may be considered to make decisions regardingimmunosuppressive therapy.


lass IIb:

. Desensitization therapy should be considered when thecalculated PRA is considered by the individual trans-plant center to be high enough to significantly decreasethe likelihood for a compatible donor match or to de-crease the likelihood of donor heart rejection where un-avoidable mismatches occur.

Level of Evidence: C.. Choices to consider as desensitization therapies include

IV immunoglobulin (Ig) infusion, plasmapheresis, eitheralone or combined, rituximab, and in very selected cases,splenectomy.

Level of Evidence: C.. A large randomized controlled clinical trial is needed to

assess the effectiveness of desensitization strategies andtheir impact on outcomes after HT.


ecommendations for Monitoring of Allosensitization Sta-us of Heart Transplant Candidates and Recipients78,80,85:Table 4)lass IIb:

. The presence of anti-HLA antibodies should be regularlymonitored in allosensitized patients undergoing desensi-tizing therapies until a compatible heart allograft be-comes available.

Level of Evidence: C.. In ambulatory, non-sensitized HT candidates it is rea-

sonable to measure anti-HLA antibodies every 6 months.Level of Evidence: C.

. In HT candidates requiring blood transfusions, anti-HLAantibodies determination should be repeated 2 to 4 weekslater and prospective donor/recipient crossmatch is re-quired in the interim period if a suitable donor organbecomes available.

Table 4 Panel-Reactive Antibody Screening Frequency After O

PRA

Number of heart tra

1 mon 2 mon 3 mon 4–6 mo

Negative 10 2 8 16Positive 33 8 6 2

PRA, panel reactive antibody; SE, sensitizing events.Adapted from Betkowski AS, et al.78

Level of Evidence: C. H

. No uniform recommendations exist as to the frequencyof anti-HLA antibody determinations after an infectionor during MCS.

Level of Evidence: C.. Circulating immunoglobulins should be measured before

and after plasmapheresis or immunoabsorption.Level of Evidence: C.

. Lymphocyte sub-populations should be measured beforeand after the use of rituximab.

Level of Evidence: C.. In addition to the post-operative retrospective cross-

match, donor-specific antibodies levels should be ob-tained when antibody-mediated rejection (AMR) is sus-pected or confirmed by EMB.


ecommendations for the Treatment of Antibody-Mediatedejection:80,86

lass IIa:

. Initial therapy of AMR can include immunoadsorptionand corticosteroid (CS) or plasmapheresis/low dose ofIV Ig and CS.

Level of Evidence: C.. Rituximab can be added to reduce the risk of recurrent

rejection.Level of Evidence: C.

. Changes in therapy, which can be considered for mainte-nance immunosuppression in patients who experienceAMR, can include switch to tacrolimus (TAC) in patientsreceiving cyclosporine (CYA)-based immunosuppression,increased doses of mycophenolate mofetil (MMF), and CS.


ecommendations for the Approach to Allosensitization inediatric Heart Transplant Recipients:76,77,87

lass IIb:

. The HT can be carried out in highly sensitized pediatricpatients without a prospective crossmatch or virtualcrossmatch at centers experienced in pediatric HT acrossa positive crossmatch.


opic 4: Management of ABO “Incompatible”

Assessment

t centers screening at each interval

1 year Variable SE Other Total

7 4 16 2 65. . . . . . . . . . . . 65

riginal

nsplan

n

eart Transplant Recipients

R“C

1

2

3

RpC

1

2

RtRC

1

Ri(C

1

2

3

RpC

1

2

RpC

1


ecommendations for the Selection of Candidates for ABOIncompatible” Heart Transplant:88,89

lass IIa:

. The upper limit of age or isohemagglutinin titer forABO-incompatible pediatric HT remains unclear.

Level of Evidence: C.. ABO-incompatible HT can be safely performed in the

pediatric population in the presence of positive isohem-agglutinin titers against the donor organ.

Level of Evidence: C.. ABO-incompatible HT, especially in the presence of

donor-specific isohemagglutinins � 1:4, should be per-formed in an experienced center.


ecommendation for the Intraoperative Care of ABO “Incom-atible” Heart Transplant Recipients:88,89

lass IIa:

. ABO-incompatible HT can be undertaken by performingplasma exchange using the CPB circuit to remove donorspecific isohemagglutinins.

Level of Evidence: C.. Plasma exchange using the CPB circuit allows the safe

transplantation of ABO-incompatible organs without theneed of aggressive pre-operative immunosuppressivetherapies or splenectomy.


ecommendations for the Monitoring of Isohemagglu-inin Levels in ABO “Incompatible” Heart Transplantecipients:88,90

lass IIa:

. Serial measurements of isohemagglutinin titers shouldbe done in the post-operative period. Decisions aboutwhether immunosuppressive therapy must be modifiedshould be based not only on the change in isohemagglu-tinin titers but also on clinical or pathologic evidence ofrejection.

Table 5 Match of Blood Products to Specific ABO-Incompatib

Blood groupRed blood cells(plasma depleted)

FreplaRecipient’s Donor’s

O A O AO B O BO AB O ABA B A ABA AB A ABB A B ABB AB B AB

aSecond choice.


ecommendations for the Administration of Blood Productsn ABO “Incompatible” Heart Transplant Recipients88–90:See Table 5)lass IIa:

. Whole blood products should never be administered to achild who has received an ABO-incompatible HT, andthe families should be educated to communicate this factto other caregivers in the case of any future medicalemergency or surgery. Group O red blood cells andgroup AB blood elements are safe for every blood groupcombination.

Level of Evidence: C.. If red blood cells transfusions are given to any ABO-

incompatible HT recipient, red blood cell units should bematched based on the HT recipient’s ABO blood type.

Level of Evidence: C.. If platelets and/or plasma preparations are needed in

ABO-incompatible HT recipients, these blood productsshould be matched based on the donor’s ABO bloodtype.


ecommendations for Immunosuppression in ABO “Incom-atible” Heart Transplant Recipients:88,89,91

lass IIa:

. Standard (triple) immunosuppression with a CNI, ananti-proliferative agent, and CS can be used in childrenundergoing ABO-incompatible HT without an increasedrisk of rejection.

Level of Evidence: B.. Immunosuppression management beyond the peri-oper-

ative period is similar to that of the ABO-compatiblepediatric HT population.


ecommendation for Rejection Surveillance in ABO “Incom-atible” Heart Transplant Recipients:88–90

lass IIa:

. Rejection surveillance in ABO-incompatible HT recipients

rt Transplant Scenario

enCryoprecipitate

Platelets (managed similarlyto plasma)

2nd choice

A A O concentrateB B O concentrateAB, A or B AB A or B concentrateAB, or Ba AB B concentrateAB, A or Ba AB A or B concentrateAB, or Aa AB A concentrateAB, A or Ba AB A or B concentrate

le Hea

sh frozsma

is the same as that of the ABO-compatible HT population.

TS

RHC

1

2

3

C

1

2

3

4

RfC

1

2

3

RRC

1

2

3

4

5

opqVtbndcHo

RCC

1

C

1



opic 5: Coagulopathies in Heart Transplanturgery

ecommendations for the Evaluation of Hemostasis ineart Transplant Recipients92:lass I:

. A history of bleeding (including details of family history,previous excessive post-traumatic or post-surgical bleed-ing) and of the use of any medications that alter coagu-lation should be obtained from the patient.

Level of Evidence: C.. Screening coagulation tests of prothrombin time (PT),

activated partial thromboplastin time (aPTT), and plate-lets counts should be measured immediately before HTsurgery.

Level of Evidence: C.. The activated clotting time (ACT) should be obtained at

multiple points during the HT surgery to gauge theactivity of heparin during each phase of the HT surgery.


lass IIa:

. Thromboelastography may be useful during the HT surgeryto further elucidate the status of the patient’s hemostasis.

Level of Evidence: C.. Platelet function can be measured either by platelet aggre-

gometry or by a point of care assay such as the plateletsfunction assay 100 (PFA-100) during the HT surgery.

Level of Evidence: C.. Fibrinogen levels and D-Dimer values should be measured

post-operatively because these are tests of fibrinolysis andcorrelate with the risk of bleeding after HT surgery.

Level of Evidence: C.. Thromboelastography may be repeated after HT surgery

to monitor patients’ hemostasis.Level of Evidence: C.

ecommendations for the Reversal of Anti-coagulation be-ore Heart Transplantation:93–96

lass I:

. Pre-operatively, the international normalized ratio (INR)should be reduced to � 1.5.

Level of Evidence: C.. Low doses of vitamin K (2.5–5.0 mg) given IV are

preferable to high doses because they are associated witha lower risk of anaphylaxis.

Level of Evidence: C.. Given the need for rapid normalization of the INR, chron-

ically anti-coagulated patients about to undergo HT shouldreceive vitamin K in conjunction with fresh frozen plasma(FFP), prothrombin plasma concentrates (PCCs), or recom-binant factor VII (rFVII), depending on their availabilityand the patient’s renal and hepatic functions.


ecommendations for Anti-coagulation in Heart Transplantecipients:97–99

lass IIa:

. The absence of platelet factor 4/heparin antibodiesshould be confirmed.

Level of Evidence: C.. The use of unfractionated heparin should be restricted to

the operative procedure itself. Low-molecular-weightheparin is not recommended, due to a longer half-lifethan unfractionated heparin and the inability to fullyreverse its effect with protamine.

Level of Evidence: C.. Alternative anti-coagulants can be used pre-operatively

and post-operatively in patients with history of heparin-induced thrombocytopenia (HIT) in whom the plateletcount has recovered but immunoglobulin G (IgG) anti-bodies to the platelet factor 4/heparin complex are stillpresent.

Level of Evidence: C.. Patients with abnormal hepatic and normal renal func-

tion can be treated with lepirudin, danaparoid, orfondaparinux, whereas those with abnormal renal andnormal hepatic function can receive argatroban at stan-dard doses or lepirudin at reduced doses.

Level of Evidence: C.. Patients 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

pinion drives the decision of when to transfuse bloodroducts. Expert opinions on which clinical situations re-uire transfusions are highly variable. Recombinant factorIIa has not been tested in controlled clinical trials and

herefore there is little evidence to support its use in aleeding cardiac surgery patient. Tranexamic acid and ami-ocaproic acid have not been evaluated in a definitive ran-omized study. Very few studies have been performed spe-ifically in HT recipients. Thus, the recommendations forT are extrapolated from evidence regarding achievementf hemostasis in general cardiac surgery.

ecommendations for the Pharmacologic Management ofoagulopathies in Heart Transplant Recipients:100–105

lass I:

. Transfusion of coagulation factors is necessary for ade-quate hemostasis. Thus, fresh frozen plasma and plate-lets should be transfused based on measured levels. Fi-brinogen infusion for massive bleeding and inadequatefibrinogen levels is needed to control blood loss.


lass IIa:

. Tranexamic acid and epsilon-aminocaproic acid bothhave anti-fibrinolytic activity and can be used beforeCPB to reduce the risk of bleeding in selected patients.


C

1

C

1

2

Tt

RtC

1

2

C

1

2

C

1

2

TOF

RMc(C

1

2

RdC

1

2

REC

1

2


lass IIb:

. Recombinant factor VIIa may be used in cases of intrac-table or excessive bleeding with HT surgery.


lass III:

. Although aprotinin can reduce bleeding during HT sur-gery, its routine use is not recommended due to anincreased risk of adverse clinical events.

Level of Evidence: B.. Desmopressin is not recommended for routine use be-

cause its modest reduction in bleeding has been associ-ated with adverse clinical events.

Level of Evidence: A.

opic 6: Documentation and Communication withhe Multidisciplinary Team

ecommendations for the Documentation and Communica-ion with the Multidisciplinary Team:106–108

lass I:

. Transplant centers must have a multidisciplinary ap-proach to patient management.

Level of Evidence: C.. The HT team should have regularly scheduled meetings

of all disciplines involved.Level of Evidence: C.

lass IIa:

. Social work and psychiatry specialists should be inte-grated into the patient management team.

Level of Evidence: B.. Transplant centers should strive to have specialty-trained

pharmacists or physicians with expertise in pharmacol-ogy as part of the multidisciplinary team.


lass IIb:

. Integration of input from pharmacists and infectious dis-ease specialists is important during the development oftreatment protocols for HT recipients.

Level of Evidence: B.. Dieticians should be involved in the care of HT recipi-

ents to provide input regarding prevention of weight gainand maintenance of glucose control.


opic 7: Use of Extracorporeal Membranexygenation for the Management of Primary Graftailure in Pediatric Heart Transplant Recipients

ecommendations on the Indications for Extracorporealembrane Oxygenation in Pediatric Heart Transplant Re-ipients109–114:See Table 6)
lass IIa: C
. The use of ECMO should be considered when there isfailure to separate from CPB after all correctable causesof such failure have been excluded.

Level of Evidence: C.. ECMO should be promptly instituted when progressive

heart allograft dysfunction occurs post-operatively.Level of Evidence: C.

ecommendations for the Conduct of ECMO Support in Pe-iatric Heart Transplant Recipients:115,116

lass IIa:

. The amount of circulatory support provided by ECMOshould be sufficient to achieve adequate systemic perfu-sion and oxygen delivery while waiting for the myocar-dium to recover.

Level of Evidence: C.. Left heart distension during ECMO support should be

aggressively treated because it will compromise pulmo-nary function and impede LV recovery.


ecommendations for the Timing of Discontinuation ofCMO Support in the Setting of Primary Graft Failure117:lass IIa:

. Clinical and echocardiographic variables should be seri-ally assessed to determine if myocardial recovery isoccurring.

Level of Evidence: C.. Objective signs of recovery should lead to weaning and

discontinuation of ECMO support.Level of Evidence: C.

Table 6 Potential Causes of Primary Graft Failure AfterPediatric Heart Transplantation

Donor issues● Poor donor organ preservation● Poor donor quality

● Diminished echocardiographic ejection fraction● Requirement for high inotropic support● Elevated blood troponin I level

● Prolonged ischemic time● Large donor (donor-to-recipient weight ratio � 2.0)● Small donor (donor-to-recipient weight ratio � 1.0)● Prolonged donor cardiopulmonary resuscitation times● Anoxia as cause of death● Non-identical blood type● Donor ageRecipient issues● Pre-transplantation diagnosis of congenital heart disease● Previous sternotomy● Elevated pulmonary vascular resistance● Pre-transplantation need for extracorporeal membrane

oxygenator● Pre-transplantation need for ventilatory support

Adapted from Huddleston CB, et al.114

lass IIb:

1

1

2

3

4

5

6

T

CS

bMMSP

T

RcC

1

2

3

4

C

4

RAC

1

2

C

1

C

1

2

3

4

5

6

T


. Lack of objective evidence of myocardial recoverywithin 3 to 5 days should prompt consideration of eitherinstitution of long term MCS as a bridge to recovery orHT or withdrawal of life-sustaining therapy.


Gaps in Evidence:

. The optimal modality for surveillance of adverse neuro-logic events during ECMO support for PGF is unknown.

. Optimal infection prophylaxis in the immunosuppressedpatient receiving ECMO support for PGF is unknown.

. Optimal renal-sparing immunosuppression protocol(s) inpatients receiving ECMO support for PGF is unknown.

. The duration of time waiting for recovery of myocardialfunction in the setting of PGF beyond which recovery isunlikely is unknown.

. The role of more intermediate and long-term MCS inpatients with myocardial recovery insufficient to allowseparation from ECMO within 5 to 7 days is unknown.

. Risk factors for poor outcomes after retransplantation inECMO-supported HT recipients are unknown.

ask Force 2: Immunosuppression and Rejection

hair: David Taylor, MD; Co-Chairs: Bruno Meiser, MD;teven Webber, MD

Contributing Writers: David Baran, MD; Michael Car-oni, MD; Thomas Dengler, MD; David Feldman, MD;aria Frigerio, MD; Abdallah Kfoury, MD; Daniel Kim,D; Jon Kobashigawa, MD; Michael Shullo, PhD; Josef

tehlik, MD; Jeffrey Teuteberg, MD; Patricia Uber,harmD; Andreas Zuckermann, MD

opic 1: Rejection Surveillance

ecommendations for Rejection Surveillance by Endomyo-ardial Biopsy in Heart Transplant Recipients:118–120

lass IIa:

. It is reasonable to utilize EMB in a HT candidate sus-pected of having an infiltrative cardiomyopathy or aninflammatory process, such as giant cell myocarditis,amyloidosis, or sarcoidosis.

Level of Evidence: C.. The standard of care for adult HT recipients is to perform

periodic EMB during the first 6 to 12 post-operativemonths for surveillance of HT rejection.

Level of Evidence: C.. The standard of care in adolescents should be similar to

that in adults, including surveillance EMB for heart al-lograft rejection for 6 to 12 months after HT. In youngerchildren, especially infants, it is reasonable to utilizeechocardiography as a screening tool to reduce the fre-quency of EMB.

Level of Evidence: C.. After the first post-operative year, EMB surveillance for

an extended period of time (eg, every 4–6 months) isrecommended in HT recipients at higher risk for late
acute rejection, to reduce the risk for rejection with L
hemodynamic compromise, and to reduce the risk ofdeath in African-American recipients.


lass IIb:

. The use of routine EMB later than 5 years after HT isoptional in both adults and children, depending on clin-ical judgment and the risk for late allograft rejection.


ecommendations for the Non-Invasive Monitoring ofcute Heart Transplant Rejection:120–135

lass IIa:

. In centers with proven expertise in ventricular evokedpotentials (VER) monitoring, intramyocardial electro-grams recorded non-invasively with telemetric pacemak-ers can be used for rejection surveillance in patients atlow risk for rejection.

Level of Evidence: C.. Gene Expression Profiling (Allomap) can be used to rule

out the presence of ACR of grade 2R or greater inappropriate low-risk patients, between 6 months and 5years after HT.


lass IIb:

. Use of echocardiography as primary monitoring modal-ity for acute heart allograft rejection in infants can beconsidered as an alternative to surveillance EMB.


lass III:

. The routine clinical use of electrocardiographic param-eters for acute heart allograft rejection monitoring is notrecommended.

Level of Evidence: C.. The use of echocardiography as an alternative to EMB

for rejection monitoring is not recommended.Level of Evidence: C.

. The routine clinical use of MRI for acute allograft rejec-tion monitoring is not recommended.

Level of Evidence: C.. The use of brain natriuretic peptide (BNP), troponin I or

T, or C-reactive protein (CRP) levels for acute heartallograft rejection monitoring is not recommended.

Level of Evidence: C.. The use of systemic inflammatory markers for acute

heart allograft rejection monitoring is not recommended.Level of Evidence: C.

. Routine use of non-invasive testing modalities (ECG,imaging, or biomarkers) is not recommended as the pri-mary method for acute heart allograft rejection surveil-lance in older children and adolescents.


opic 2: Monitoring of Immunosuppressive Drug
evels

Rs(C

1

C

1

2

3

4

5

6


ecommendations for the Monitoring of Immunosuppres-ive Drug Levels136–149:See Table 7)lass I:

. The use of the microemulsion formulation of CYA isrecommended because it is associated with more favor-able pharmacokinetic features compared with the oil-

Table 7 Drugs That Affect the Levels of Tacrolimus,Cyclosporine, Sirolimus, and Everolimus

Decrease immunosuppressionlevels

Increase immunosuppressionlevels

Anti-epileptics Anti-microbialsCarbamazepine ClarithromycinFosphenytoin ErythromycinPhenobarbital Metronidazole and tinidazolePhenytoin Quinupristin/dalfopristin

LevofloxacinAnti-microbials Anti-fungalsCaspofungin ClotrimazoleNafcillin ItraconazoleRifabutin KetoconazoleRifampin FluconazoleRifapentine Posaconazole

VoriconazoleAnti-retroviral Therapy Anti-retroviral therapyEfavirenz Protease inhibitors (general)Etravirine AmprenavirNevirapine Atazanavir

DarunavirFosamprenavirIndinavirNelfinavirRitonavirSaquinavirTipranavir

Others CardiovascularAntacids containing

magnesium, calcium, oraluminum (tacrolimus only)

Amiodarone

Deferasirox DiltiazemModafinil VerapamilSt. John’s wortThalidomideTiclopidineTroglitazone

NutraceuticalsBitter orangeGrapefruit juiceOthersRilonaceptTheophyllineCimetidineFluvoxamineGlipizideGlyburideImatinibNefazodone

based compound.


lass IIa:

. At present, 2-hour post-dose (C2) levels should not re-place 12-hour trough (C0) concentrations for routinemonitoring of CYA exposure in most patients, but maybe useful in selected patients in whom a better charac-terization of the pharmacokinetic profile of CYA is de-sired.

Level of Evidence: B.. Measurement of 12-hour trough CYA concentration is

the recommended form of therapeutic drug monitoringfor routine clinical use. The target levels are dependenton the method used (high-performance liquid chroma-tography [HPLC] vs enzyme multiplied immunoassaytechnique [EMIT] vs cloned enzyme donor immunoas-say method [CEDIA]), concomitant immunosuppres-sion, toxicity risks, and time after HT. In general, whenused in conjunction with azathioprine (AZA) or a my-cophenolic acid (MPA) preparation, the average CYAtrough concentration target using the Abbot TDX assay(or equivalent) is 325 ng/ml (range, 275–375 ng/ml) forthe 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.. At present, CYA trough concentration targets when

CYA is used in combination with proliferation signalinhibitor (PSI; mammalian target of rapamycin [mTOR]inhibitors) agents have not been adequately determined.

Level of Evidence: C.. Measurement of 12-hour trough concentration for twice-

daily TAC and a 24-hour trough concentration for once-daily TAC is the recommended drug monitoring methodfor routine clinical use. The therapeutic range of TAClevels varies depending on concomitant drugs, toxicityconcerns, and time after HT. In general, when used inconjunction with AZA or a MPA preparation, TACtrough concentration targets range between 10 and 15ng/ml during the early post-operative period (Days0–60), between 8 and 12 ng/ml for the next 3 to 6months, and between 5 and 10 ng/ml in stable patients 6months after HT.

Level of Evidence: C.. At this time, target therapeutic TAC trough concentra-

tions when TAC is used in combination with PSI (mTORinhibitors) agents have not been adequately determined.

Level of Evidence: C.. Therapeutic drug monitoring for PSIs using trough con-

centration levels is recommended for sirolimus (SRL)and everolimus (EVL). Levels should be measured atleast 5 days after adjustment of the dose, when a newsteady state is achieved. When used in combination withCYA, the optimal trough target level for EVL is between3 and 8 ng/ml. The corresponding optimal trough levelfor SRL is 4 to 12 ng/ml.


7

8

C

1

2

3

4

5

6

C

1

2

TR

RR(C

1


. In pediatric HT recipients, TAC and CYA should bemonitored using C0 levels when twice-daily dosing isused. Target levels are comparable to those in adults, butslightly lower targets may be used in low-risk patientssuch as non-sensitized infant HT recipients.

Level of Evidence: C.. There are insufficient data to support routine monitoring

of MPA levels in pediatric recipients. However, inter-mittent monitoring is reasonable when there is ongoingrejection, doubts about adequacy of dosing (eg, infantsand young children), and to assess medical compliance.


lass IIb:

. At this time replacement of twice-daily TAC with once-daily TAC dosing cannot be recommended in HT recip-ients. Should a patient require the once-daily formula-tion, appropriate monitoring should be used to ensuremaintenance of appropriate levels and preserved heartallograft function.

Level of Evidence: C.. In patients with a therapeutic 12-hour trough concentra-

tion for twice daily TAC but evidence of potential drug-related toxicity or reduced efficacy (rejection), a 3-hourpost-dose level (C3) may help to adjust TAC doses.

Level of Evidence: C.. In selected situations (rejection, infection, renal failure,

malnutrition, and certain ethnic populations) where it issuspected that altered MMF exposure contributes toheart allograft dysfunction, measurement of trough MPAlevels may be used to guide drug dosing. In such cases,a MPA level of � 1.5 mg/liter is considered to besub-therapeutic.

Table 8 Significant Differences in Primary End Points betwee

Author (year) Study N Follow-up

Kobashigawa163 (1998) MMF vs AZA 650 3 years

Reichart209 (1998) TAC vs CYA 82 1 yearTaylor153 (1999) TAC vs CYA 85 1 yearEisen157 (2003) EVL vs AZA 634 1 year

Keogh156 (2004) SRL vs AZA 136 2 years

Grimm154 (2006) TAC vs CYA 314 1.5 year

Kobashigawa158 (2006) TAC/MMF vsTAC/SRL vsCYA/MMF

343 1 year

Baran159 (2007) TAC/MMF vs TAC 58 1 yearLehmkuhl160 (2008) EVL/rd-CYA vs

MMFsd-CYA176 1 year

CAV, cardiac allograft vasculopathy; CYA, cyclosporine; EVL, everolimmycophenolate mofetil; MMFsd, mycophenolate mofetil/standard exposu

aTreated-patient population (see text).bReanalysis of MMF IVUS data.209


. Dose adjustments and frequency of therapy with poly-clonal antibodies (eg, anti-thymocyte globulin) used asinduction therapy can be monitored with daily measure-ment of CD3 or CD2 counts with the goal of maintainingthe CD2 or CD3 count between 25 and 50 cells/mm3 orabsolute total lymphocyte counts � 100 to 200 cells/mm3.

Level of Evidence: C.. In pediatric HT recipients CYA C2 monitoring may be

performed instead of C0 in centers with extensive expe-rience with this form of monitoring.

Level of Evidence: C.. As in adults, routine monitoring of SRL and EVL at C0

is recommended also in children.Level of Evidence: C.

lass III:

. Routine therapeutic drug monitoring of MPA levels toadjust MMF doses cannot be recommended at this time.

Level of Evidence: C.. Measuring CD 25 saturation to adjust the dose of anti-

interleukin-2 receptor antibodies remains experimentaland its routine clinical use cannot be recommended.


opic 3: Principles of Immunosuppression andecommended Regimens

ecommendations on the Principles of Immunosuppressiveegimens in Heart Transplant Recipients150–210:See Table 8, Table 9A, Table 9B, and Table 10)lass I:

. Maintenance therapy should include a CNI in all pedi-

y Groups from Major Clinical Trials

al Rejection CAV by IVUS

higherivala

MMF � less rejection NS; MMF � less CAVat 1 yearb

NSNSEVL groups � less rejection EVL groups � less

CAVSRL groups � less rejection

at 6 monthsSRL groups � less

CAVTAC � less rejection at 6

months. . .

NS; TAC groups � lowerany-treated rejection

. . .

NS NSNS . . .

/rd, everolimus/reduced exposure; IVUS, intravascular ultrasound; MMF,not statistically significant; SRL, sirolimus; TAC, tacrolimus.

n Stud

Surviv

MMF �surv

NSNSNS

NS

NS

NS

NSNS

us; EVLre; NS,

atric HT recipients.

2

3

C

1

2

3

4

5

6

7


Level of Evidence: C.. In adults, the use of statins beginning 1 to 2 weeks after

HT is recommended regardless of cholesterol levels.Owing to pharmacologic interactions with CNI and riskfor toxicity, initial statin doses should be lower thanthose recommended for hyperlipidemia.

Level of Evidence: A.. Creatinine kinase levels should be monitored in all chil-

dren receiving statins.Level of Evidence: C.

lass IIa:

. Calcineurin inhibitor-based therapy remains the standardin immunosuppressive protocols used after HT.

Level of Evidence: B.. MMF, EVL, or SRL as tolerated, should be included in

contemporary immunosuppressive regimens becausetherapies including these drugs have been shown to re-duce onset and progression of cardiac allograft vascu-lopathy (CAV) as assessed by intravascular ultrasound(IVUS).

Table 9 (A) Significant Differences in Adverse Events From th

First author (year) Study No. Renal fu

Kobashigawa163 (1998) MMF vs AZA 650

Reichart209 (1998) TAC vs CYA 82 NSTaylor153 (1999) TAC vs CYA 85 NS

Eisen157 (2003) EVL vs AZA 634 EVL grouworsefuncti

Keogh156 (2004) SRL vs AZA 136 SRL grouworsefuncti

Grimm154 (2006) TAC vs CYA 314 NS

Kobashigawa158 (2006) TAC/MMF vs TAC/SRLvs CYA/MMF

343 TAC/MMbest rfuncti

Baran159 (2007) TAC/MMF vs TAC 58 NS

Lehmkuhl160 (2008) EVL/rd-CYA vsMMFsd-CYA

176 NS

See Table 8 for abbreviations.


. Immunosuppressive induction with polyclonal antibodypreparations may be beneficial in patients at high risk ofrenal dysfunction when used with the intent to delay oravoid the use of a CNI.

Level of Evidence: B.. In pediatric HT recipients, routine use of induction ther-

apy with a polyclonal preparation is indicated whencomplete CS avoidance is planned after HT.

Level of Evidence: C.. Routine use of statins is recommended for all pediatric

patients with evidence of hyperlipidemia, CAV, or afterretransplantation.

Level of Evidence: C.. TAC is the preferred CNI for pediatric HT recipients

considered at high immunologic risk (eg, sensitizedrecipients with evidence of donor-specific antibody[DSA]).

Level of Evidence: C.. CS avoidance, early CS weaning, or very low dose main-

tenance CS therapy are all acceptable therapeutic ap-proaches.

r Clinical Trials

InfectionsCholesterol &triglycerides Hypertension

MMF � moreanyopportunisticinfection

NS CYA � more hypertensionNS CYA �

higherchol & tri

CYA � more hypertension

EVL groups �lower viral/CMV but morebacterialinfections

EVL groups� higherchol & tri

NS

SRL groups �lower CMV butmorepneumonia

NS for chol;SRLgroups �highertrig

NS

NS CYA �higherchol & tri

CYA � more hypertension

TAC/SRL �lower viral butmore fungalinfections

NS for chol;TAC/MMF� lowertrig

NS

TAC/MMF �morehospitalizedinfections

. . . . . .

EVL � Less CMVinfections

. . . . . .

e Majo

nction

ps �renalon

ps �renalon

F �enalon


8

9

C

1

2

3

4

5

6

7

8


. If used, CS weaning should be attempted if there aresignificant CS side effects and no recent rejection epi-sodes (eg, within 6 months).

Level of Evidence: C.. Pediatric recipients with pre-formed alloantibodies and a

positive donor-specific cross-match should receive in-duction therapy, and TAC-based “triple therapy” withCSs and either MMF or an mTOR inhibitor.


lass IIb:

. The results of clinical trials suggest that TAC-basedregimens may be associated with lower rejection ratesbut not with superior survival after HT than CYA-based regimens.


Table 9 (B) Significant Differences in Adverse Events From th

First author (year) Study N Hematologi

Kobashigawa163 (1998) MMF vs AZA 650 AZA � mor

Reichart209 (1998) TAC vs CYA 82 . . .

Taylor153 (1999) TAC vs CYA 85 NSEisen157 (2003) EVL vs AZA 634 NSKeogh156 (2004) SRL vs AZA 136 SRL groups

& thromb

Grimm154 (2006) TAC vs CYA 314 TAC � more

Kobashigawa158 (2006) TAC/MMF vs TAC/SRLvs CYA/MMF

343 NS

Baran159 (2007) TAC/MMF vs TAC 58 NSLehmkuhl160 (2008) EVL/rd-CYA vs

MMFsd-CYA176 MMF � mor

See Table 8 for abbreviations.

Table 10 Recommendation for Statin Doses in HeartTransplant Patients201,202,210,387–393

Drug Dose Risks

Pravastatin 20–40 mg394 Myositis (lower)Simvastatin 5–20 mg395 Myositis (higher)

� 20 mg not recommendedAtorvastatin 10–20 mg387 Myositis (higher)Fluvastatin 40–80 mg389 Myositis (lower)Lovastatin 20 mg390 Myositis (higher)Rosuvastatin 5–20 mg388 Myositis

. The adverse events of immunosuppressive drugs observedin randomized clinical trials underscore the need for indi-vidualization of immunosuppression according to the char-acteristics and risks of the individual HT recipient.

Level of Evidence: C.. Most children should receive adjunctive therapy with an

anti-metabolite or a PSI.Level of Evidence: C.

. If a child is intolerant of adjunctive therapy, the decisionwhether or not to replace it with another agent should bemade after review of the patient’s rejection history andimmunologic risk. TAC monotherapy is acceptable inpatients with a benign rejection history.

Level of Evidence: C.. For children diagnosed with CAV, the addition of an

mTOR inhibitor should be strongly considered.Level of Evidence: C.

. Routine use of immunosuppressive induction in all pa-tients has not been shown to be superior to immunosup-pressive regimens that do not use such therapy.

Level of Evidence: B.. Immunosuppressive induction with anti-thymocyte glob-

ulin (ATG) may be beneficial in patients at high risk foracute rejection.

Level of Evidence: C.. Routine use of statins is recommended for adolescents

and selected younger children with at an increased risk ofrejection or CAV.

r Clinical Trials

GI Disorders Other

penia MMF � more diarrhea andesophagitis

NS for hyperglycemiatreatment

. . . NS for glucoseintolerance

. . . . . .NS NS for wound infection

re anemiaenia

AZA � more nausea; SRLgroups � more diarrhea

AZA � more arrhythmiaand atrial fibrillation;SRL groups � moremouth ulcers &abnormal healing

ia CYA � more cholelithiasis TAC � more diabetesmellitus & tremor;CYA � more gumhyperplasia &hirsutism

. . . TAC/SRL � moreinsulin therapy &impaired woundhealing; NS fordiabetes mellitus

. . . NS for malignancyopenia . . . . . .

e Majo

c

e leuko

� moocytop

anem

e leuk


T

RC(C

1

2

3

4

5

6

7

8

9

1

1

RAC

1

2

3

4

5

C

1

2


opic 4: Treatment of Acute Cellular Rejection

ecommendations for Treatment of Symptomatic Acuteellular Rejection205–207,211–217:See Table 11)lass I:

. An EMB should be performed as early as possible ifthere is suspicion of symptomatic acute heart allograftrejection.

Level of Evidence: C.. The HT recipient with symptomatic acute cellular rejec-

tion should be hospitalized. Patients with hemodynamiccompromise should be treated in the ICU.

Level of Evidence: C.. High-dose IV CS should be first-line therapy for symp-

tomatic acute cellular rejection irrespective of ISHLTEMB grade (1R, 2R or 3R).

Level of Evidence: C.. Cytolytic immunosuppressive therapy with anti-thymo-

cyte antibodies should be administered in addition to IVCS if hemodynamic compromise is present, and espe-cially if there is no clinical improvement within 12 to 24hours of IV CS administration.

Level of Evidence: C.. IV inotropes and vasopressors should be used as nec-

essary to maintain adequate CO and systemic bloodpressure until recovery of heart allograft function oc-curs.

Level of Evidence: C.. Anti-microbial prophylaxis against opportunistic in-

fections should be administered when high-dose CSand/or cytolytic therapy are used for the treatment ofrejection.

Level of Evidence: C.. Appropriate adjustments of maintenance immunosup-

pressive therapy should be made to decrease the risk

Table 11 Suggested Dosing of Medications Used forTreatment of Acute Cellular Rejection

Medication Dose Duration

CorticosteroidsMethylprednisolone

(high-dose)250–1000 mg/day IV 3 daysa

Prednisone 1–3 mg/kg/day PO 3–5 daysa

Polyclonal anti-thymocyteantibody

Thymoglobulinb 0.75–1.5 mg/kg/day 5–14 daysATGAMb 10 mg/kg/day 5–14 daysATG-Freseniusb 3 mg/kg/day 5–14 days

Monoclonal antibody 5 mg/day 5–14 daysMuromonoab-

CD3 (OKT3)b

ATG, anti-thymocyte gamma-globulin-fresenius; ATGAM, anti-thy-mocyte gamma-globulin; IV, intravenous; PO, oral (per os).

aCorticosteroid taper can be considered.bPremedicate with CS, anti-histamine and anti-pyretic.

of recurrent rejection. These can include ascertain-

ment of compliance with current therapy, increase inthe dose of current immunosuppressive agent(s), ad-dition of new agent(s), or conversion to differentagent(s).

Level of Evidence: C.. Follow-up EMB should be done 1 to 2 weeks after

initiation of therapy for acute cellular rejection.Level of Evidence: C.

. Serial echocardiograms should be used to monitorchanges in heart allograft function in response to anti-rejection therapy.

Level of Evidence: C.0. In a patient with low-grade acute cellular rejection and

hemodynamic compromise, the possibility of AMRshould also be entertained (see AMR section).

Level of Evidence: C.1. Interleukin-2 receptor blockers should not be used to

reverse acute cellular rejection.Level of Evidence: C.

ecommendations for the Treatment of Asymptomaticcute Cellular Rejection:205–207,211–217

lass I:

. Severe acute cellular rejection (ISHLT 3R) diagnosedby surveillance EMB should be treated even in theabsence of symptoms or evidence of heart allograftdysfunction.

Level of Evidence: C.. High dose IV CS should be given for asymptomatic

severe (ISHLT 3R) acute cellular rejection.Level of Evidence: C.

. Asymptomatic moderate acute cellular rejection (ISHLT2R) can be treated with either IV or oral CS.

Level of Evidence: C.. Adjustment of maintenance immunosuppressive therapy

should be done in patients with asymptomatic moderate(ISHLT 2R) or severe (ISHLT 3R) acute cellular rejec-tion. This can include an increase of the dose of currentmedications, addition of an agent, or conversion to adifferent maintenance regimen.

Level of Evidence: C.. Anti-microbial prophylaxis against opportunistic infec-

tions should be administered when high-dose CSs and/orcytolytic therapy are used for treatment of rejection..


lass IIa:

. The performance of a follow-up EMB should be consid-ered 2 to 4 weeks after initiation of therapy for asymp-tomatic moderate or severe acute cellular rejection.

Level of Evidence: C.. Cytolytic immunosuppressive therapy can be considered

if there is no histologic resolution of rejection on thefollow-up EMB.


3

C

1

RAC

1

2

3

C

1

2

TM

RtC

1

1

C

1

Rj(C

1

2


. Asymptomatic mild cellular rejection (ISHLT 1R) doesnot require treatment in the vast majority of cases.


lass IIb:

. Asymptomatic moderate cellular rejection (ISHLT2R), especially if occurring later than 12 months afterHT, may not require treatment. Close surveillance(clinical, echocardiographic, and follow-up EMB) isstrongly suggested if no treatment is administered inthis setting.


ecommendations for Treatment of Recurrent or Resistantcute Cellular Rejection:218,219

lass I:

. For recurrent or CS-resistant acute cellular rejection,cytolytic immunosuppressive therapy with anti-thymo-cyte antibodies should be considered.

Level of Evidence: C.. Maintenance immunosuppression should be re-evaluated

in patients with recurrent/resistant HT rejection (seeabove).

Level of Evidence: C.. Frequent surveillance of heart allograft function (eg, by

echocardiography) is recommended in patients with re-current/resistant rejection, even if persistently asymp-tomatic.


lass IIb:

. Additional approaches that can be considered for recur-rent or resistant acute cellular rejection include metho-trexate pulse therapy, photopheresis, and total lymphoidirradiation.

Level of Evidence: B.. Evaluation of EMB specimens for concomitant anti-

body-mediated rejection (AMR; see the Recommen-dations for Treatment of Antibody-Mediated Rejec-tion) and determination of the presence of anti-HLAantibodies in the HT recipient’s serum is also sug-gested.

Table 12 Examples of Therapies for Antibody-Mediated Rejec

Therapeutic modality Dose

Plasmapheresis 1–2 plasma exchanges

IV Ig 100–1,000 mg/kg

Rituximab 375 mg/m2

IV Ig, intravenous immunoglobulin.Based on Grauhan O et al,221 Leech SH et al,226 Michaels PJ et al,228 M


opic 5: Treatment of Hyperacute and Antibody-ediated Rejection

ecommendations for the Treatment of Hyperacute Rejec-ion:25,220

lass I:

. Treatment for hyperacute rejection should be initiated assoon as the diagnosis is made, preferably when the HTrecipient is still in the operating room. Treatments thatshould be considered include (1) high-dose IV CS; (2)plasmapheresis; (3) IV immunoglobulin; (4) cytolyticimmunosuppressive therapy; (5) IV CNI (CYA, TAC)and metabolic cycle inhibitors (MMF); (6) IV inotropesand vasopressors; and (7) MCS.


. Intraoperative myocardial EMB should be obtained toconfirm the diagnosis of hyperacute heart allograft rejec-tion.


lass IIb:

. Urgent retransplantation may be considered if the abovemeasures do not result in restoration of acceptable heartallograft function, but repeat HT in the setting of hyper-acute rejection is associated with high mortality.


ecommendations for Treatment of Antibody Mediated Re-ection85,221–229:See Table 12)lass IIa:

. The following treatments can be used to disrupt theimmune-mediated injury of the heart allograft in AMR:(1) high-dose IV CS and (2) cytolytic immunosuppres-sive therapy.

Level of Evidence: C.. The following treatments may be used to remove circu-

lating anti-HLA antibodies or decrease their reactivity:(1) plasmapheresis; (2) immune apheresis (immunoad-

Frequency Duration

Daily 3–5 daysEvery other day 1–2 weeks3 times per week 1–4 weeksOnce weekly 2–4 weeks1–3 times per week, often given

after each plasmapheresis1–4 weeks

Once weekly 1–4 weeks

et al,229 Kaczmarek I et al,222 Takemoto SK et al,85 and Bierl C et al.396

tion

iller LW

sorption); and (3) IV Ig.

3

4

5

6

7

C

1

2

T

RtC

1

C

1

2

3

4

5

C

1

TT

C

MRGGJ

T

RpC

1

2

C

1


Level of Evidence: C.. The following treatments are used to maintain adequate

cardiac output and systemic blood pressure: (1) IV ino-tropes and vasopressors and (2) MCS.

Level of Evidence: C.. When AMR is suspected, EMB examination should be

expanded to include immunohistochemistry stains forcomplement split products and possibly antibody.

Level of Evidence: C.. Recipient serum should be screened for presence, quan-

tity, and specificity of anti-donor (HLA) antibodies.Level of Evidence: C.

. Follow-up EMB should be performed 1 to 4 weeks afterinitiation of therapy and include immunohistochemistryexamination.

Level of Evidence: C.. Adjustment of maintenance immunosuppressive therapy

may be considered. This can include increase in the doseof current immunosuppressive agent(s), addition of newagent(s), or conversion to different agent(s).


lass IIb:

. Systemic anti-coagulation may decrease intravascularthrombosis in the heart allograft.

Level of Evidence: C.. Emergent retransplantation may be considered if the

above measures do not restore acceptable heart allograftfunction, but outcomes in this situation are unfavorable.


opic 6: Management of Late Acute Rejection

ecommendation for the Management of Late Acute Rejec-ion:230,231

lass I:

. Maintenance immunosuppression and the intensity ofclinical follow-up should be reevaluated after symptom-atic or asymptomatic late acute heart allograft rejection.


lass IIa:

. After the first year, EMB surveillance (eg, every 4–6months) for an extended period of time is recommendedin patients at higher risk for late acute rejection, toreduce the risk of rejection with hemodynamic compro-mise, and to reduce the risk of death in African-Ameri-can recipients.

Level of Evidence: C.. Repeated education on the critical importance of adher-

ence to treatment, and early reporting of symptoms con-tribute to the prevention and early recognition of lateacute rejection.

Level of Evidence: C.. Patients at low risk for late rejection do not appear to

significantly benefit from indefinite EMB surveillance.The usefulness of long-term routine EMB should be
evaluated against the risks and the costs of the procedure.
Repeated EMB increase the probability of damage to theTV apparatus and collection of non-diagnostic material.

Level of Evidence: C.. In pediatric HT recipients, CAV should be considered in

the differential diagnosis of late symptomatic or asymp-tomatic rejection when heart allograft dysfunction ispresent. Coronary angiography (and possibly IVUS)should be considered in these patients.

Level of Evidence: C.. In pediatric HT recipients, late rejection has negative

prognostic implications and may be associated with anincreased risk for subsequent development of CAV; con-sequently, a follow-up coronary angiography may berecommended.


lass IIb:

. In pediatric HT recipients, withholding treatment forasymptomatic mild-moderate late heart allograft rejec-tion is reasonable but requires close follow-up.


ask Force 3: Long-term Care of Heartransplant Recipients

hair: Sharon Hunt, MD; Co-Chair: Michael BurchContributing Writers: Geetha Bhat, MD; Charles Canter,

D; Richard Chinnock, MD; Marisa Crespo-Leiro, MD;eynolds Delgado, MD; Fabienne Dobbels, PhD; Kathleenrady, PhD; Walter Kao, MD; Jaqueline Lamour, MD;areth Parry, MD; Jignesh Patel, MD; Daniela Pini, MD;

effrey Towbin, MD; Gene Wolfel, MD

opic 1: Minimization of Immunosuppression

ecommendations for the Minimization of Immunosup-ression:159,162,188,232–242

lass I:

. CS withdrawal can be successfully achieved 3 to 6months after HT in many low-risk patients (those with-out circulating anti-HLA antibodies, non-multiparouswomen, those without a history of rejection, and olderHT recipients).

Level of Evidence: B.. Lower levels of CNI in HT recipients should be sought

when CNI are used in conjunction with MMF (comparedwith AZA) because with this combination lower levelsare safe and associated with lower rejection rates as wellas improved renal function.


lass IIa:

. A PSI may be substituted for CNI later than 6 monthsafter HT to reduce CNI-related nephrotoxicity and CAVin low-risk recipients.


C

1

2

3

4

C

1

2

TA

RpC

1

2

3

C

1

T

RC(C

1

2

3

4

5


lass IIb:

. CNI monotherapy with early CS withdrawal may beconsidered in highly selected individuals. This strategyhas been associated with acceptable short-term outcomesin HT recipients.

Level of Evidence: B.. In pediatric HT recipients, minimization of immunosup-

pression by CS withdrawal is common practice and ap-pears safe, with the majority of children being free of CSby 5 years after HT.

Level of Evidence: C.. Due to variable pharmacokinetics in children, strategies

for minimization of immunosuppression in the pediatricpopulation may require a greater reliance on drug levelsmonitoring than in adults.

Level of Evidence: C.. The use of PSI may be considered in pediatric HT re-

cipients to reduce CAV and nephrotoxicity, but insuffi-cient data are available on the effects of PSI in children.


lass III:

. In HT recipients, substitution of PSI for MMF for the specificpurpose of lowering CNI exposure to reduce CNI-relatednephrotoxicity is not recommended due to the interaction be-tween CNI and PSI, which enhances CNI nephrotoxicity.

Level of Evidence: C.. Substitution of a PSI for MMF earlier than 3 months

after HT is not recommended due to a higher risk ofrejection as well as delayed wound healing.


opic 2: Management of Neurologic Complicationsfter Heart Transplantation

ecommendations for the Management of Neurologic Com-lications After Heart Transplantation:243–246

lass I:

. Management of HT recipients with seizures should in-clude reduction of CNI doses (taking into considerationthe risk of inadequate immunosuppression) and correc-tion of hypomagnesemia, if present.

Level of Evidence: C.. The occurrence of encephalopathy late after HT should

prompt neurologic consultation and imaging to identifypossible underlying etiologies.

Table 13 Basic Criteria for the Interpretation of Intravascula

Normal

Baseline study (4–6 weeks after hearttransplantation)

0.25–0.50 mm intimal

Study 1 year after heart transplantation No change in intimal t


. Posterior reversible leukoencephalopathy (PRES) inHT recipients should be managed with a reduction ofCNI doses or substitution with an alternative CNI.


lass IIb:

. Heart transplant recipients who continue to experienceseizures after a reduction in the CNI dose may benefitfrom CNI withdrawal and substitution with a PSI (SRL,EVL).


opic 3: Cardiac Allograft Vasculopathy

ecommendations for the Diagnosis and Management ofardiac Allograft Vasculopathy155–157,164,247–267

See Table 13)lass I:

. Primary prevention of CAV in HT recipients shouldinclude strict control of cardiovascular risk factors (hy-pertension, diabetes, hyperlipidemia, smoking, and obe-sity) as well as strategies for the prevention of CMVinfection.

Level of Evidence: C.. In HT recipients, statin therapy has been shown to reduce

CAV and improve long-term outcomes regardless oflipid levels and should be considered for all HT recipi-ents (adult and pediatric).

Level of Evidence: A.. Annual or biannual coronary angiography should be con-

sidered to assess the development of CAV. Patients freeof CAV at 3 to 5 years after HT, especially those withrenal insufficiency, may undergo less frequent invasiveevaluation.

Level of Evidence: C.. Follow-up coronary angiography is recommended at

6 months after a percutaneous coronary interven-tion because of high restenosis rates in HT reci-pients.

Level of Evidence: C.. Selective coronary angiography is the investigation of

choice for the diagnosis of CAV in pediatric HT recip-ients. It should be performed at yearly or biannual inter-vals.

sound Measurements After Heart Transplantation

Abnormal

ess Any intimal lesion � 0.5 mm suggests donor disease247

ss An increase in intimal thickness � 0.5 mm from baselinesuggests accelerated CAV associated with adverseoutcomes249

r Ultra

thickn

hickne


C

1

2

3

4

5

6

7

8

9

1

C

1

2

T

RHC

1

2

3

4

C

1

TT

RTC

1

2

3


lass IIa:

. A baseline coronary angiogram at 4 to 6 weeks after HTmay be considered to exclude donor coronary arterydisease.

Level of Evidence: C.. IVUS in conjunction with coronary angiography with a

baseline study at 4 to 6 weeks and at 1 year after HT isan option to exclude donor coronary artery disease, todetect rapidly progressive CAV, and provide prognosticinformation.

Level of Evidence: B.. In HT recipients with established CAV, the substitution

of MMF or AZA with a PSI can be considered.Level of Evidence: B.

. A PSI can been used in pediatric HT recipients whodevelop CAV, but the effect of PSI on the progression ofCAV in children is unknown.

Level of Evidence: C.. IVUS can be safely used in older pediatric HT recipients

to assess CAV.Level of Evidence: C.

. Evaluation of coronary flow reserve in conjunction withcoronary angiography may be useful for the detection ofsmall-vessel coronary disease, which is a manifestationof CAV.

Level of Evidence: C.. Treadmill or dobutamine stress echocardiography and

myocardial perfusion imaging may all be useful for thedetection of CAV in HT recipients unable to undergoinvasive evaluation. Non-invasive testing for CAV istechnically possible in children.

Level of Evidence: B.. Percutaneous coronary intervention with drug-eluting

stents is recommended in both adults and children withCAV and offers short-term palliation for appropriatediscrete lesions.

Level of Evidence: C.. Surgical revascularization in HT recipients with CAV is

an option in highly selected patients who have lesionsamenable to surgical revascularization.

Level of Evidence: C.0. Cardiac retransplantation may be considered in patients

with severe CAV and absence of contraindications forrepeat HT.


lass IIb:

. Ultrafast computed tomography (CT) for the detection ofcoronary calcium has been used mostly as an investiga-tional tool for assessing CAV in HT recipients, but isbeing superseded by advances in CT angiography.

Level of Evidence: C.. CT coronary angiography shows promise in the evalua-

tion of CAV in HT recipients, although higher restingheart rates in these patients limit the technical quality ofthis study.


opic 4: Malignancy After Heart Transplantation

ecommendations on the Approach to Malignancy Aftereart Transplantation:268–271

lass I:

. Recommendations regarding screening for breast, colon,and prostate cancer in the general population should alsobe followed in HT recipients.

Level of Evidence: C.. It is recommended that HT recipients have close skin

cancer surveillance, including education on preventivemeasures and yearly dermatologic examinations.

Level of Evidence: C.. Initial evaluation and a therapeutic plan for post-trans-

plant lymphoproliferative disorder (PTLD) in HT recip-ients should be done at the transplant center by physi-cians familiar with transplant-associated malignancies.

Level of Evidence: C.. There is no evidence to support a reduction in immuno-

suppression in patients with solid tumors unrelated to thelymphoid system. Maintenance immunosuppressionshould be continued unless there are specific reasons toreduce certain drugs, such as reduction of bone marrow-suppressive agents if leucopenia occurs.


lass IIa:

. Chronic immunosuppression should be minimized in HTrecipients as possible, particularly in patients at high riskfor malignancy.


opic 5: Chronic Kidney Disease After Heartransplantation

ecommendations on Chronic Kidney Disease After Heartransplantation:70,242–244,272–282

lass I:

. Estimation of glomerular filtration rate (GFR) with themodified diet in renal disease (MDRD) equation, urinal-ysis, and spot urine albumin/creatinine ratio should beobtained at least yearly after HT. Measurement of sCr forestimation of GFR should be obtained more often inpatients with GFR � 60 ml/min/1.73 m2, and/or fastGFR decline in the past (� 4 ml/min/1.73 m2 per year).

Level of Evidence: C.. Although in children there is no consensus on the opti-

mal method to estimate GFR, this measurement shouldbe done and a urinalysis obtained at least yearly inpediatric HT recipients.

Level of Evidence: C.. Heart transplant recipients with an estimated GFR � 30

ml/min/1.73 m2, proteinuria � 500 mg/day (or urinealbumin/creatinine ratio � 500 mg/g), or rapidly declin-ing GFR (� 4 ml/min/1.73 m2 per year), should be
referred to a nephrologist for management of metabolic

4

5

6

7

8

9

1

C

1

TH

RHC

1

2

3

4

5

6

7

8

C

1

TI

Rc(C

1


abnormalities and other complications of renal insuffi-ciency and consideration of renal transplantation.

Level of Evidence: C.. In all HT recipients (adult and pediatric) with chronic

kidney disease (CKD), CNI exposure should be loweredto the minimum level required for effective immunosup-pression. In patients taking AZA, this may be achievedby conversion of AZA to MMF.

Level of Evidence: B.. Owing to the potential for precipitating rejection, CNI-

free regimens should be used with caution in HT recip-ients with significant renal insufficiency that persistsdespite CNI reduction.

Level of Evidence: C.. In pediatric HT recipients, CS minimization or with-

drawal should be attempted to avoid hypertension andsubsequent CKD, as long as there is no clinical rejection.There are no strong data in adult HT recipients.

Level of Evidence: B.. Interventions that have been proven to slow the progres-

sion of CKD in the general population should be con-sidered in all HT recipients. These include strict glucoseand blood pressure control and use of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin re-ceptor blocker (ARB). The American Diabetes Associa-tion (ADA) or the International Diabetes FederationGuidelines should be used to manage diabetes. Bloodpressure should be treated according to the Joint NationalCommittee VII or the European Society of Cardiology2007 Guidelines.

Level of Evidence: C.. In pediatric HT recipients, diabetes is rare. In contrast,

hypertension is common, and adequate blood pressurecontrol with a CCB or ACEI is warranted to avoid CKD.

Level of Evidence: C.. Hemoglobin (Hgb) levels should be measured at least

annually in all HT patients with CKD. If anemia (Hgb �13.5 g/dl in adult men; � 12 g/dl in adult women) isdetected, iron status should be addressed and erythropoi-esis-stimulating agents should be used to maintain Hgblevels between 11 and 13 g/dl.

Level of Evidence: C.0. Kidney transplantation should be considered the treat-

ment of choice for all HT recipients (adult and pediat-ric) with end-stage renal disease who are appropriatecandidates. Living donation should be considered.


lass IIa:

. CCBs should be considered the anti-hypertensive drug ofchoice when optimal blood pressure control cannot beachieved with ACEI/ARB or when these drugs are con-traindicated in HT recipients.


opic 6: Management of Diabetes Mellitus After
eart Transplantation
ecommendations for the Management of Diabetes AfterT:283–288

lass I:

. Prevention, early detection, and appropriate therapy fordiabetes should be considered as an important compo-nent of patient care after HT.

Level of Evidence: C.. Patients should be periodically screened for diabetes

after HT by measuring fasting plasma glucose levelsor with an oral glucose tolerance test (more sensitivescreening test for pre-diabetic state) and HgbA1C de-termination, as appropriate. The frequency of screen-ing will depend on risk factors and immunosuppres-sive therapy.

Level of Evidence: C.. Therapies for short-term peri-operative and long-term

chronic glycemic control in HT recipients should bebased on ADA recommendations.

Level of Evidence: C.. Heart transplant recipients with diabetes should be coun-

seled regarding weight control, diet and nutrition, andexercise.

Level of Evidence: C.. Pre-HT risk factors should be assessed, and diabetogenic

immunosuppressive medications should be minimizedwhenever possible in HT recipients.

Level of Evidence: C.. CS-sparing regimens and decreased CNI doses should be

used as appropriate to prevent diabetes in HT recipients.Level of Evidence: C.

. Associated cardiovascular risk factors (in addition todiabetes), such as hyperlipidemia and hypertension,should be managed aggressively in HT recipients. An-nual measurements of lipids levels should be performedaccording to ADA recommendations.

Level of Evidence: C.. Annual screening should be performed for diabetic com-

plications (ophthalmology, podiatry, peripheral vasculardisease, etc) in HT recipients with diabetes.


lass IIa:

. An endocrinology consultation may be considered whena pre-diabetic state or diabetes is diagnosed in a HTrecipient.


opic 7: Other Complications of Chronicmmunosuppression

ecommendations on the Management of Various Compli-ations of Chronic Immunosuppression289–333:See Table 14)lass I:

. Recommendations for addressing other complicationsof immunosuppression include regular screening for
adverse events, minimizing drug doses, drug substitu-

T

RtC

1


tion, and drug withdrawal (as previously discussed),as well as initiating targeted therapies for a specificcomplication. For example, anti-hyperuricemic ther-apy and concurrent risk reduction may be used toprevent recurrent attacks of gout, whereas acquiredcataracts require surgical intervention. It is importantto assess for contraindications and drug interactionswhen medically treating complications of immunosup-pression.

Table 14 Complications of Immunosuppressive Drugs

Drug Toxicities

Calcineurin inhibitors: cyclosporineand tacrolimus

Cardiovascular: hypertenNeurologic: headache, tr

syndrome ParkinsonismHematologic: Anemia, leDermatologic: fibrovascuGastrointestinal: nausea,

malakoplakia, eosinopveno-occlusive disease

Endocrine/metabolic: hyphyperlipemia311

Renal: renal dysfunctionInfection311

Mammalian target of rapamycininhibitors

Cardiovascular: edema, hNeurologic: Headache, pHematologic: Anemia, th

thromboses298,311,319,3

Respiratory: Dyspnea, pualveolar hemorrhage29

Endocrine and metabolicDermatologic: Acneiform

healing complicationsMusculoskeletal: extremi

impaired wound healinGastrointestinal: Diarrhea

hepatotoxicity311,325,3

Genitourinary: urinary traMycophenolate mofetil Infection (eg, herpes sim

Gastrointestinal (eg, naudistension and pain, e

Metabolism and nutritionCardiovascular (eg, hypeHematologic (eg, leukopNervous system (eg, heaRespiratory (eg, dyspneaRenal (eg, increased BUDermatologic (eg, rash)3

Corticosteroids (CS) Gastrointestinal (eg, pepNeuromuscular and skele

myopathy)311,330–333

Central nervous system (Dermatologic (eg, bruisinEndocrine and metabolic

growth suppression inunresponsiveness in ti

Ocular complications (eg

BOOP, bronchiolitis obliterans with organizing pneumonia; BUN, blo


opic 8: Hypertension After Heart Transplantation

ecommendations on the Management of Hypertension Af-er Heart Transplantation:334–339

lass I:

. Because anti-hypertensive therapy in HT recipients hasbenefits similar to those in the general population, hy-pertension after HT should be treated to achieve the same

dema311

insomnia, hearing loss posterior reversible encephalopathytral and peripheral neuropathy, seizures303–311

ia, thrombotic microangiopathy, eosinophilia294,311,312

yps alopecia,295,313 hirsutism, gingival hyperplasia296

ea, steatohepatitis, cholestatic jaundice, colonicastroenterocolitis, villous atrophy/food allergies, hepatic,311,314–317

phatemia, hypomagnesemia, hyperglycemia, hyperkalemia,

opathy311

nsion311

ive multifocal encephalopathy, optic neuropathy311,318

cytopenia, thrombotic microangiopathy, venous

ry toxicity, interstitial pneumonitis, c, alveolar proteinosis,1,321,322

rtriglyceridemia, hypercholesterolemia311

dermatitis, ulcerating rash: perforating collagenosis, woundcence, leukocytoclastic vasculitis301,323

hedema (bilateral and unilateral); lingual angioedema;24

ea, vomiting, gastroduodenal ulcer disease;

ection, infertility (oligospermia)302,311,327

irus and cytomegalovirus)291,328,329

nstipation, diarrhea, vomiting, dyspepsia, abdominalgitis)291,328,329

, hyperglycemia, hypercholesterolemia, gout)291,311

n, peripheral edema)291,311

hrombocytopenia)291,311,328

tremor)291,311

ratory tract infection, cough)291

or creatinine)311

er, esophagitis, pancreatitis)311

, osteoporosis, pathologic fractures, muscle mass loss, CS

otional instability, headache)311

n fragile skin, impaired wound healing)311

ements (eg, diabetes mellitus, hyperlipidemia, fluid retention,en, adrenal suppression, adrenocortical and pituitaryf stress, and menstrual irregularities)311

oma, cataracts)311

nitrogen.

sion, eemor,, cen

ukopenlar poldiarrh

hilic g294,297

ophos

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yperterogressrombo20

lmona9,300,31

: Hypefacial

: dehisty lympg289,3

, naus26

ct infplex v

sea, cosophaal (egrtensioenia, tdache,, respiN and/11

tic ulctal (eg

eg, emg, thiderangchildrmes o, glauc

od urea

goals recommended for the general population.

2

3

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apid

sAospiotmia

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1

2

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8

9

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Level of Evidence: C.. Lifestyle modifications, including weight loss, low-so-

dium diet, and exercise are appropriate adjuncts to facil-itate control of blood pressure in HT recipients.

Level of Evidence: C.. Drug choice for treatment of hypertension in HT recip-

ients is empiric and depends on blood pressure re-sponses. CCBs are most widely used, but ACEI andARB may be preferred in diabetic recipients, and a2-drug regimen can include both CCB and ACEI/ARB.

Level of Evidence: C.. Modification of risk factors such as diabetes and hyper-

lipidemia are appropriate as adjunctive treatment forhypertension in HT recipients.

Level of Evidence: C.. Appropriate adjustment of immunosuppressive therapy,

especially CS weaning, may be helpful in managementof hypertension in HT recipients.


lass IIa:

. Hypertension is common in both adults and childrenafter HT and can be assessed with ambulatory bloodpressure monitoring.


opic 9: Prophylaxis for Corticosteroid-Inducedone Disease

aps in Evidence:Bisphosphonates continue to suppress bone reabsorption

fter discontinuation of therapy. It is not known, however, ifre-operative administration of these drugs can prevent thencreased bone loss that develops after HT with the intro-uction of CS.

Gaps in Evidence340:The predictive role of bone mass density (BMD) mea-

urement for fracture risk is unproven in HT recipients.lthough several studies have described a beneficial effectf bisphosphonates and vitamin D analogues on bone den-ity in adult HT recipients, none of these studies has beenowered to detect a decrease in fracture rate. In addition,mportant issues that remain unresolved include which is theptimal bisphosphonate, the route and duration of adminis-ration, and whether therapy should be continuous or inter-ittent. More research is also needed to define appropriate

ndications for bisphosphonate therapy and the optimalgent, dose, and duration of use in pediatric patients.

The potential role in the HT population of the recombi-ant human parathyroid hormone (teriparatide), a boneorming agent, and strontium ranelate, the first agent totimulate bone formation while decreasing reabsorption,eserves investigation.

ecommendations for the Prophylaxis of Corticosteroid-nduced Bone Disease After Heart Transplantation:341–351

lass I:

. All adult HT candidates should be screened for pre-existing bone disease, preferably at the time of place-ment on the waiting list. In adults, baseline BMD shouldbe obtained with a dual energy x-ray absorptiometry(DEXA) scan of the lumbar spine and femoral neck.

Level of Evidence: C.. The presence of low BMD or vertebral fractures should

prompt evaluation and treatment of correctable second-ary causes of osteoporosis, because significant improve-ment in BMD can be attained during the waiting periodfor HT. Bisphosphonates should be considered the treat-ment of choice.

Level of Evidence: C.. All HT candidates and recipients should have the rec-

ommended daily allowance for calcium (1,000–1,500mg, depending on age and menopausal status) and vita-min D (400–1,000 IU, or as necessary to maintain serum25-hydroxyvitamin D levels above 30 ng/ml � 75 nmol/L).

Level of Evidence: C.. After HT, regular weight-bearing and muscle-strength-

ening exercises should be encouraged to reduce the riskof falls and fractures and to increase bone density.

Level of Evidence: B.. In pediatric HT recipients, it is important to monitor

growth and pubertal development and be alert to thedevelopment of signs and symptoms of bone disease.

Level of Evidence: C.. Reduction or withdrawal of CS in pediatric HT recipi-

ents should be considered in the absence of precedingrejection with close monitoring for clinical rejection.

Level of Evidence: B.. After HT, children should be encouraged to increase

physical activity; daily intake of calcium with vitamin Dthrough diet or supplements should meet recommenda-tions for age.

Level of Evidence: C.. All adult HT recipients should begin anti-resorptive ther-

apy with bisphosphonates immediately after HT andcontinue it at least throughout the first post-operativeyear.

Level of Evidence: B.. Bisphosphonates can be used to treat bone loss in long-

term HT recipients and should be used in addition tocalcium and vitamin D.

Level of Evidence: C.0. In pediatric HT recipients who have not reached bone

maturity, bisphosphonates should be restricted to pa-tients with reduction in bone mass density associatedwith low-trauma fractures or vertebral compression.


lass IIa:

. It is reasonable to perform spine radiographs in all adultHT candidates to detect existing fractures.

Level of Evidence: C.. After the first post-HT year, if glucocorticoids have been

discontinued and BMD is relatively normal (T score �

3

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RtC

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1.5), it is reasonable to stop bisphosphonates, whilemaintaining a high degree of vigilance for osteoporosis.

Level of Evidence: C.. Proximal femur and lumbar spine BMD should be as-

sessed by DEXA scanning in all adult patients 1 yearafter HT. Thereafter, annual reassessments are wise inpatients receiving CS and/or bisphosphonate therapy.However, it should be kept in mind that increases inBMD with bisphosphonates account for a small fractionof their efficacy in preventing bone fractures. It is rea-sonable to repeat BMD measurement in 2 years in pa-tients with osteopenia and in 3 years in patients withnormal bone density. Any clinical suggestion of fractureshould prompt bone radiographs.


lass IIb:

. Active metabolites of vitamin D (calcidiol, alfacalcidol,and calcitriol) should not be regarded as the first-linetreatment for bone loss after HT. If they are used, fre-quent monitoring of urine and serum calcium levels isrequired, because hypercalcemia and hypercalciuria arecommon and may develop anytime during treatment.


lass III:

. Calcitonin should not be used to prevent early bone lossafter HT.


opic 10: Reproductive Health After Heartransplantation

ecommendations on Pregnancy After Heart Transplanta-ion:352–354

lass I:

. A multidisciplinary team, involving specialists in mater-nal and fetal medicine, cardiology and transplant medi-cine, anesthesia, neonatology, psychology, genetics, andsocial services, is important in the care of pregnant HTrecipients.

Level of Evidence: C.. The management plan for pregnant HT recipients should

be individualized according to the status of the motherand the allograft she received and is best achieved at theprimary transplant institution in collaboration with localor referring physicians.

Level of Evidence: C.. Individual factors in a HT recipient who wishes to be-

come pregnant should be considered, including the riskof acute rejection and infection, review of concomitanttherapy that is potentially toxic or teratogenic, and re-view of the adequacy of graft function. After carefulconsideration of these individual factors, patients shouldbe counseled on the risks of pregnancy and pregnancydiscouraged if graft dysfunction and significant CAV areexpected to preclude a successful outcome.


. Pregnancy in a HT recipient should generally not beattempted sooner than 1 year after HT.

Level of Evidence: C.. In a HT recipient who wishes to become pregnant, base-

line tests should be obtained to determine the patient’scardiac status and should include an ECG and echocar-diogram (and coronary angiography if not performedwithin the previous 6 months) with the option of right-heart catheterization and EMB, if clinically indicated.

Level of Evidence: C.. Baseline assessment of renal and liver function should be

obtained in a pregnant HT recipient and frequent moni-toring of blood pressure, urine cultures, and surveillancefor pre-eclampsia and gestational diabetes should bedone.

Level of Evidence: C.. CNIs and CS should be continued in a pregnant HT

recipient, but MMF (class D) should be discontinued.Level of Evidence: C.

. Blood levels of CNI should be monitored closely duringpregnancy due to large fluctuations in levels during thepregnancy-related changes in plasma and interstitial vol-ume and hepatic and renal blood flow.

Level of Evidence: C.. Frequent surveillance for rejection is imperative in a

pregnant HT recipient, although surveillance EMB doneunder fluoroscopy should be avoided. An EMB underechocardiographic guidance or fluoroscopy with leadedpatient draping can be performed if necessary.


lass IIb:

. The use of AZA (also class D), as a substitute for MMF,is somewhat controversial, and avoidance of both agentsin a pregnant HT recipient should be decided on the basisof the balance of maternal and fetal risk.


lass III:

. It is uncertain whether the potential risks of drug expo-sure for the infant outweigh the benefits of breastfeeding,which is therefore not recommended for HT recipients.


ecommendations for Contraception After Heart Transplan-ation:355,356

lass I:

. Before combination hormonal contraception is pre-scribed, a HT recipient should be screened for risk fac-tors for a hypercoagulable state (a strong family or per-sonal history of thromboembolic events).

Level of Evidence: C.. Combined hormonal contraception inhibits the CYP-450

3A4 pathway, and immunosuppressant drug blood levelsshould be monitored carefully when starting this therapyin HT recipients.


3

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1

C

1

2

RmC

1

2

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4

RtC

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TA

RAC

1

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C

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TH

Rg(


. Barrier methods provide inadequate pregnancy protec-tion and should be used as an adjunct to other methods inHT recipients. They should be recommended for allsexually active adolescents for sexually transmitted in-fection (STI) prevention.


lass IIb:

. Intrauterine devices (IUD) have been generally not rec-ommended in HT recipients and, in particular, in nullip-arous patients because of the increased risk of IUDexpulsion in nulliparous women and because of concernsregarding increased risk of pelvic inflammatory infectionand infertility.


lass III:

. Depo-medroxyprogesterone acetate has been associatedwith decreased bone density and, therefore, is not rou-tinely recommended for HT recipients.

Level of Evidence: C.. Hormonal contraception should not be prescribed in HT

recipients who have significant hypertension, knownCAV, estrogen-sensitive cancers, or active liver disease.


ecommendations for the Management of Sexually Trans-itted Infections357:

lass I:

. Clinicians should obtain a confidential sexual historyfrom adolescent HT recipients and may consider routinereferral to an adolescent medicine specialist who willprovide thorough and confidential reproductive healthcare.

Level of Evidence: C.. Sexually active adolescents and adult HT recipients with

multiple partners should be advised to undergo screeningfor STI, including a complete anogenital examination toscreen for anogenital warts, molluscum, herpes simplexvirus (HSV), or other lesions at an appropriate clinic atregular intervals.

Level of Evidence: C.. A complaint of genitourinary symptoms or disclosure of

high-risk behavior should trigger a full evaluation forSTI in HT recipients. Genitourinary symptoms may alsobe an indication for empiric anti-microbial therapy whileawaiting results of STI screening.

Level of Evidence: C.. The quadrivalent human papillomavirus (HPV) vaccine

may prevent persistent HPV infection, cervical and vul-vovaginal cancer precursor lesions, and genital wartssecondary to HPV types 6, 11, 16, and 18. Womenshould receive all 3 doses before HT. There is no con-traindication to administering the vaccine to women afterHT, although no studies have confirmed immunogenicityor efficacy in this population.

Level of Evidence: C. C

ecommendations for the Management of Erectile Dysfunc-ion After Heart Transplantation358:lass I:

. Possible iatrogenic causes of erectile dysfunction (ED)should be identified in HT recipients, and alternativemedications should be used where possible.

Level of Evidence: C.. In HT recipients with ED, use of phosphodiesterase

inhibitors can be considered. Concomitant nitrate ther-apy is contraindicated similarly to the general popula-tion.

Level of Evidence: C.. In HT recipients with ED, consider referral to an ED

specialist for possible intra-cavernous injections of pros-taglandin E1 if phosphodiesterase inhibitors are ineffec-tive or contraindicated.


opic 11: Exercise and Physical Rehabilitationfter Heart Transplantation

ecommendations for Exercise and Physical Rehabilitationfter Heart Transplantation:359–368

lass I:

. The routine use of cardiac rehabilitation with perfor-mance of aerobic exercise training is recommended afterHT. The short-term benefits of this approach includeimprovement in exercise capacity and possible modifi-cation of cardiovascular risk factors such as obesity,hypertension, and glucose intolerance. There is currentlyno information on potential long-term benefits.

Level of Evidence: B.. Resistance exercise is also strongly encouraged in HT

recipients to restore BMD and prevent the adverse ef-fects of CS and CNI therapy on skeletal muscle. Resis-tance exercise should be additive to other therapies forbone mineral loss and muscle atrophy.


lass IIa:

. Exercise should be encouraged after pediatric HT, al-though no data on the long-term benefits exist. Exercisehas been shown to produce short-term improvements infunctional capacity and perhaps to decrease obesity-re-lated morbidity. Specific exercise programs should betailored to the specific needs and co-morbidities of theindividual HT recipient.


opic 12: Management of Intercurrent Surgery ineart Transplant Recipients

ecommendations on the Management of Intercurrent Sur-ery in Heart Transplant Recipients369:See Table 15)
lass I:

1

2

3

4

5

6

TOT

RpC

1

2

3

4

5

6


. HT recipients requiring intercurrent surgical proceduresshould have a full pre-operative assessment in collabo-ration with the transplant team, particularly in prepara-tion for major procedures requiring general or regionalanesthesia.

Level of Evidence: C.. For many surgical procedures, prophylactic anti-biotic

administration is now the norm. Protocols may needmodification in HT recipients. Aminoglycoside anti-bi-otics and erythromycin are best avoided because of therisk of worsening renal dysfunction when used in com-bination with CYA or TAC.

Level of Evidence: C.. When needed, blood products used in HT recipients

should be leukocyte poor. ABO-incompatible infant HTrecipients require specialized blood products and mustbe discussed with the transplant center.

Level of Evidence: C.. Anesthesia can be safely induced provided that there is

clear understanding that the HT is denervated. The rest-ing heart rate is usually higher in HT recipients. Al-though most allografts have a resting heart rate of ap-proximately 90 beats/min, some have resting sinus ratesas high as 130 beats/min, which do not require treatment.It must be remembered that a relative, symptomatic,bradycardia that requires treatment will not respond toatropine. Isoproterenol infusion and pacing are the usualmodes of management of HT bradyarrhythmias. Al-though uncommon, the likeliest sustained atrial arrhyth-mia is atrial flutter. Likewise, the denervated heart issuper-sensitive to adenosine, and the use of standarddoses to treat atrial tachyarrhythmias may result in pro-longed asystole. Amiodarone is recommended as thedrug of choice for atrial tachyarrhythmias in HT recipi-ents.

Level of Evidence: C.. Care with fluid balance is important because decreased

intravascular volume will exacerbate renal dysfunction,and fluid excess may not be well tolerated by HT recip-ients. For major surgery, CVP monitoring may be nec-essary.

Table 15 Conversion of Oral to Intravenous Doses ofImmunosuppressive Drugs

Cyclosporine One-third of oral daily doseeither as a continuousinfusion over 24 hours,or divided into two 6-hourly infusions twicedaily

Tacrolimus One-fifth of the oral dailydose as a continuousinfusion over 24 hours

Mycophenolatemofetil

Same as oral dose

Azathioprine Same as oral dose


. Immunosuppression should not be discontinued or omit-ted without discussion with the HT team. However, itmay be prudent to omit the dose of CNI on the morningof surgery to avoid potentiating the detrimental effect ofdehydration on renal function. Thereafter, immunosup-pression should be continued as normal. If medicationscannot be given orally CYA should be given IV (often asa 6-hour infusion every 12 hours or as a continuousinfusion over 24 hours) at a third of the daily oral dose;TAC can be given IV at a dose one-fifth of the total dailyoral dose over 24 hours; AZA should be given IV oncedaily at the same dose as that taken orally; MMF can begiven IV at the same dose taken orally.


opic 13: Return to Work or School andccupational Restrictions After Heartransplantation

ecommendations on Return to Work or School and Occu-ational Restrictions After Heart Transplantation:370–372

lass IIa:

. Health care providers should know that return to workfor HT recipients is possible, and not passively supportthe sick role of patients.

Level of Evidence: C.. Return to work should be discussed before HT as the

goal of post-operative rehabilitation, and not as an ex-ception.

Level of Evidence: C.. Patients should be encouraged to maintain their jobs as

long as possible before HT because this facilitates returnto work after HT.

Level of Evidence: C.. Short-term and long-term goals for returning to work

should be discussed as part of the discharge planningafter HT.

Level of Evidence: C.. An employment specialist (eg, a social worker) should

be appointed who can set up a proactive employmentatmosphere and facilitate the return to work process afterHT.

Level of Evidence: C.. This employment specialist should (1) perform a formal

assessment of the patient’s educational backgrounds,skills, beliefs, functional and physical limitations, andformer work experiences; (2) formulate a career planwith the patient that may help the patient to enter orrejoin the work force or acquire further vocational train-ing; (3) have knowledge of the job market and collabo-rate with the HT team in learning which physical limi-tations of the patient must be taken into account; (4)educate future employers about HT and share insightsabout an individual patient’s abilities and restrictions inview of post-operative rehabilitation.


TH

RHC

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4


opic 14: Return to Operating a Vehicle Aftereart Transplantation

ecommendations for the Operation of a Vehicle Aftereart Transplantationlass I

. Assessment and discussion of the ability to drive a motorvehicle should be included in the early follow-up of HTrecipients.

Level of Evidence: C.. Gate stability, tremor, and other neurologic abnormali-

ties should be assessed before HT recipients obtain per-mission to drive.

Level of Evidence: C.. If symptomatic bradycardia is present after HT, the im-

plantation of a permanent pacemaker should be consid-ered before driving is permissible.

Level of Evidence: C.. The absence of severe hypoglycemic events should be

ascertained before HT recipients are permitted todrive.

Level of Evidence: C.. Occupational driving requires that HT recipients meet

their country’s requirements for occupational driving.Level of Evidence: C.

. A high level of scrutiny is required for HT recipientsrequesting to pilot an aircraft due to the risk of suddendeath associated with CAV.


opic 15: Cardiac Retransplantation

ecommendations for Cardiac Retransplantation:373–375

lass I:

. Retransplantation is indicated in children with at leastmoderate systolic heart allograft dysfunction and/or se-vere diastolic dysfunction and at least moderate CAV.


lass IIa:

. It is reasonable to consider listing for retransplantationthose adult HT recipients who develop severe CAV notamenable to medical or surgical therapy and symptomsof heart failure or ischemia.

Level of Evidence: C.. It is reasonable to consider listing for retransplantation

those HT recipients with heart allograft dysfunction andsymptomatic heart failure occurring in the absence ofacute rejection.

Level of Evidence: C.. It is reasonable to consider retransplantation in children

with normal heart allograft function and severe CAV.Level of Evidence: B.

lass IIb:

. Patients with severe CAV not amenable to medical orsurgical therapy with asymptomatic moderate to severeLV dysfunction may be considered for retransplantation.


lass III:

. Adult and pediatric HT recipients with heart allograftfailure due to acute rejection or occurring less than 6months after the first HT and complicated by hemody-namic compromise are inappropriate candidates for re-transplantation.


opic 16: Endocarditis Prophylaxis After Heartransplantation

ecommendations on Endocarditis Prophylaxis in Heartransplant Recipients:lass IIa:

. There are insufficient data to support specific recommen-dations for endocarditis prophylaxis in HT recipients.However, these patients are at risk of acquired valvulardysfunction, and the outcome of endocarditis is so poorin HT recipients that the use of anti-biotic prophylaxisfor dental procedures is considered reasonable in patientswith valvulopathies.


opic 17: Frequency of Routine Tests and Clinicisits in Heart Transplant Recipients

ecommendation on the Frequency of Routine Tests andlinic Visits in Heart Transplant Recipients376:lass IIa:

. Lifelong follow-up by the transplant center is recom-mended for HT recipients due to (1) the possibility of acuteand/or chronic rejection; (2) the chronic use, toxicity, anddrug interactions of immunosuppressants and the associatedrisks for infection and malignancy; and (3) comorbiditiesrequiring specialized monitoring and management.

Level of Evidence: C.. Follow-up for HT recipients should be provided by a

multidisciplinary team, including surgeons, cardiolo-gists, nurses, psychologists, social workers, dieticians,and physiotherapists, among many others. Patients andcaregivers should recognize that HT requires a life-longcommitment to medical care.

Level of Evidence: C.. The frequency of follow-up visits for HT recipients will

depend on the time since HT and the post-operativeclinical course.

Level of Evidence: C.. In case of an uneventful recovery, follow-up visits are best

scheduled every 7 to 10 days during the first month afterHT, then every 14 days during the second month, monthlyduring the first year, and every 3 to 6 months thereafter.


5

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BBBBS


. The frequency of follow-up should be increased if com-plications occur, particularly in patients with challengingmedical or psychosocial conditions.

Level of Evidence: C.. Ancillary services, including home care nursing, cardiac

rehabilitation, psychologic support, nutritional planning,or patient support groups may also be used as resourcesin the follow-up of HT recipients, with the understandingthat providers of community health care services mustcommunicate with the clinicians at the transplant centerto ensure that the care delivered complies with the HTcenter’s standards.

Level of Evidence: C.. Local health professionals should inform the transplant

center in the case of the following events: (1) hospital-ization for any reason; (2) change in medication, includ-ing the addition of any anti-biotic, anti-fungal, or anti-viral therapy for confirmed or presumed infection; (3)hypotension or unexplained drop in systolic blood pres-sure � 20 mm Hg from baseline; (4) increase in restingheart rate � 10 beats/min over baseline; (5) fever �101°F (38°C) or any unexplained fever � 100.5° F for �48 hours (38°C); (6) � 2-pound weight gain in 1 week(ie, 900 g or more); (7) unexplained weight loss of � 5pounds (ie, 2.3 kg); (8) elective surgery; (9) increasedshortness of breath; (10) pneumonia or any respiratoryinfection; (11) syncope; (12) chest pain other than mus-culoskeletal symptoms; (13) decline � 10% in forcedexpiratory volume in 1 second; (14) abdominal pain;(15) nausea, vomiting or diarrhea; (16) cerebral vascularevent, seizure, or mental status changes.


lass I:

. In addition to routine outpatient follow-up visits, HTrecipients should have more prolonged visits every 1 to2 years for more detailed clinical assessment.

Level of Evidence: B.. The purpose of the follow-up visits is to monitor for

rejection and screen for adverse events, and may includethe following: (1) a complete physical examination; (2)review of the medication and changes to the medicationbased on the results of the examinations; (3) blood work;(4) echocardiogram; (5) coronary angiography and IVUS(every 1 to 2 years); (6) EMB according to the typicalschedule outlined in the chart below; (7) additional ed-ucation and/or interaction with members of the multidis-ciplinary team. An example of a typical biopsy schedulefor the first year could be:

iopsy 1, 2, 3, 4, and 5: Weeklyiopsy 6, 7, and 8: Every 14 daysiopsy 9 and 10: Every 3 weeksiopsy 11, 12, and 13: Every 4 weeksubsequent biopsies duringthe 1st year after HT: Every 5 to 6 weeks

This recommendation is addressed in more detail in Taskorce 2.


. In pediatric practice, far fewer biopsies are performeddue to the need for general anesthesia in small childrenand the difficulties with venous access and bioptomemanipulation in small hearts and vessels. There is noconsensus on the frequency of biopsy in children. Somecenters do no EMB at all, but instead use detailed echo-cardiographic assessment. Besides scheduled clinic ap-pointments, the patients should be encouraged to contactthe transplant center with questions, concerns, or unex-pected symptoms.


opic 18: Psychologic Issues Particularly Relatedo Adherence to Medical Therapy in Heartransplant Recipients

ecommendations on Psychologic Issues After Heart Trans-lantation:377–383

lass IIa:

. Adherence with the prescribed regimen should be rou-tinely assessed at every HT outpatient clinic visit.

Level of Evidence: C.. Because there is currently no gold standard for adherence

assessment in HT recipients, it is recommended to com-bine methods to increase accuracy of assessment (eg, acombination of self-report or parent report in case ofchildren, drug levels assessment, and clinical judgment).

Level of Evidence: C.. Attention should be given not only to adherence to the

immunosuppressive regimen but also to all other healthrecommendations appropriate for HT recipients.

Level of Evidence: C.. Barriers to adherence should be discussed in an open,

non-threatening way during visits with HT recipients.Level of Evidence: C.

. Tailored interventions, in close collaboration with theHT recipient and his or her family, should be consideredand their efficacy explored. Strategies that seem mosteffective include offering education repeatedly, reducingthe complexity of the medication regimen, providingfeedback on a patient’s behavior, and combining strate-gies.

Level of Evidence: C.. Strategies to enhance maturity and independence may be

particularly helpful in the adolescent HT recipients.Level of Evidence: C.

. Because adherence to medical recommendations is acomplex issue, health care teams would benefit fromtraining in measuring adherence, discussing its barriers,and implementing adherence-enhancing interventionsfor HT recipients.

Level of Evidence: C.. Each HT center should closely collaborate with a spe-

cialized nurse or psychologist who can screen and mon-

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C

1

2

3

TT

RTC

1

2

3

AA


itor all HT recipients at risk for non-adherence. Investingin specialized staff may result in better transplant out-comes in the long-term, although further studies testingthe efficacy of adherence-enhancing interventions arewarranted.

Level of Evidence: C.. Depressive symptoms should be regularly evaluated dur-

ing follow-up of HT recipients. This can best be done byuser-friendly, validated screening instruments. All pa-tients with elevated scores should be referred to special-ized treatment.

Level of Evidence: C.0. Each HT team should include a psychologist who is

qualified to detect and treat depression. Multidisci-plinary treatment teams are better prepared to addresspsychosocial risk factors for poor outcomes after HT.


lass I:

. Serotonin reuptake inhibitors, particularly citalopram,and new-generation anti-depressants (mirtazapine) maybe the best choice for HT recipients because they have nosignificant impact on blood pressure, heart rate, rhythm,or conduction intervals.

Level of Evidence: B.. Agents that interact with the metabolism of CYA and

TAC via the CYP450 system (eg, fluvoxamine, nefaz-odone) should be avoided because they may alter CNIlevels.

Level of Evidence: B.. Tricyclic anti-depressants (eg, imipramine, desipramine,

amitriptyline, and clomipramine) are associated with car-diovascular toxicity (conduction delay, orthostatic hypo-tension, and anti-cholinergic effects) and may lower sei-zure thresholds, and therefore, their use should berestricted to HT recipients with severe depression refrac-tory to other therapies. Monoamine oxidase inhibitors(MAOIs) should be avoided because of their hypotensiveeffects, interactions with anesthetic and pressor agents,and need for dietary restrictions. Herbal medicines suchas St. John’s wort (Hypericum perforatum) can be harm-ful because it lowers CYA levels.


opic 19: Management of the Transition fromediatric to Adult Care After Heartransplantation

ecommendations on the Management of the Transitionrom Pediatric to Adult Care After Heart Transplantation:84–386

lass I:

. Critical milestones to be achieved by pediatric HT re-cipients before transition to adult care include (1) under-standing of and ability to describe the original cause oftheir organ failure and need for HT (initial education
may have been primarily provided to the parents of the A
HT recipient, and repetition is necessary to ensure un-derstanding of the clinical condition by the HT recipient;(2) awareness of the long and short-term clinical impli-cations of chronic immunosuppression (infection pre-vention, cancer surveillance, academic and vocationalaspirations); (3) comprehension of the impact of HTstatus on sexuality and reproductive health (impact ofpregnancy, effect of medications on fertility, any poten-tial teratogenicity of medications, role of genetic coun-seling and genetic risk of disease recurrence in offspring,and increased susceptibility to sexually transmitted dis-ease); (4) demonstration of a sense of responsibility forself-care (knowledge of medications, ability to obtainprescription refills, adherence to medication and officevisits schedules, ability to independently communicatewith health providers, recognition of symptoms andsigns requiring immediate medical attention, and under-standing of health care coverage and eligibility require-ments).

Level of Evidence: C.. Health care providers should simultaneously prepare the

parents for the transition from pediatric to adult care byencouraging independence and self-responsibility in thechild.

Level of Evidence: C.. Practitioners who care for adults should cultivate part-

nerships with their pediatric colleagues to gain insightinto the care of adolescents and the impact of childhoodchronic disease on development and management ofchildhood causes of end-stage organ failure and congen-ital diseases. Ideal adult site resources also include adedicated transfer liaison nurse coordinator, a socialworker, and a reproductive specialist.


opic 20: Principles of Shared Care After Heartransplantation

ecommendations on Principles of Shared Care After Heartransplantation:lass I:

. The HT team should ensure that other involved physiciansknow telephone numbers and electronic mail addresses ofthe HT team to enable contact at all times and guaranteeprompt responses to referring physicians’ queries.

Level of Evidence: C.. It is helpful for physicians outside the HT team to receive

the patient’s plan for scheduled HT office visits at thetransplant center.

Level of Evidence: C.. Formal procedures should be instituted to regularly in-

form the referring physician of clinical results and med-ical regimens.


BBREVIATIONSAIR � atrium paced, atrium sensed inhibited rate modulation
CC � American College of Cardiology

AAAAAAaAAABBBCCCCCCCCCCCCCCCDmDDEEEEEEEFGHHHHHHHHII

IIITIIILLLMMMMMmMPPPPPPPPPPPRrRsSSSTTTTTVVV

CC

mti


CEI � angiotensin converting enzyme inhibitorCT � activated clotting timeDA � American Diabetes AssociationHA � American Heart AssociationMR � antibody-mediated rejectionP � aerosolized pentamidine

PTT � activated partial thromboplastin timeRB � angiotensin receptor blockerTG � anti-thymocyte globulinZA � azathioprineiV � biventricularMD � bone mass densityNP � brain natriuretic peptideAV � cardiac allograft vasculopathyCB � calcium channel blockerEDIA � cloned enzyme donor immunoassay methodI � cardiac indexKD � chronic kidney diseaseO � cardiac outputPB � cardiopulmonary bypassMV � cytomegalovirusNI � calcineurin inhibitorRP � C-reactive proteinS � corticosteroidT � computed tomographyVP � central venous pressureYA � cyclosporineYP3A � cytochrome P-450 3A4DDR � dual-paced, dual-sensed, dual-response to sensing, rateodulationEXA � dual energy x-ray absorptiometrySA � donor specific antibodyCG � electrocardiogramD � erectile dysfunctionCMO � extracorporeal membrane oxygenationMB � endomyocardial biopsyMIT � enzyme multiplied immunoassay techniqueSC � European Society of CardiologyVL � everolimusFP � fresh frozen plasmaFR � glomerular filtration rategb � hemoglobinIT � heparin-induced thrombocytopeniaLA � human leukocyte antigenPLC � high-performance liquid chromatographyPV � human papillomavirusRS � Heart Rhythm SocietySV � herpes simplex virusT � heart transplant

CU � intensive care unitg � immunoglobulin

Name Commercial Int

Allen S. Anderson XDxDavid A. Baran XDx

AstellasGileadGSKUnited Therape

Geetha Bhat Nothing to dis

gG � immunoglobulin GNR � international normalized unitSHLT � International Society for Heart and Lungransplantation

UD � intrauterine deviceV � intravenousVUS � intravascular ultrasoundV � left ventricleVEF � left ventricular ejection fractionVH � left ventricular hypertrophyAOI � monoamine oxidase inhibitorsCS � mechanical circulatory supportDRD equation � modified diet in renal disease equationMF � mycophenolate mofetilPA � mycophenolic acidTOR � mammalian target of rapamycinVO2 � mixed venous oxygen

AWP � pulmonary artery wedge pressureCC � prothrombin plasma concentratesFA-100 � platelets function assay 100GF � primary graft failureRA � panel reactive antibodiesRES � posterior reversible leukoencephalopathySI � proliferation signal inhibitorTLD � posttransplant lymphoproliferative disorderT � prothrombin timeTT � partial thromboplastin timeVR � pulmonary vascular resistanceAP � right atrial pressure

FVII � recombinant factor 7V � right ventricle

Cr � serum creatinineRL � sirolimusTI � sexually transmitted infectionVT � sustained ventricular tachycardiaAC � tacrolimusEE � transesophageal echocardiogramMP/SMZ � trimethoprim/sulfamethoxazoleTE � transthoracic echocardiogramV � tricuspid valveAD � ventricular assist deviceER � ventricular evoked responsesT � ventricular tachycardia

onflict of Interest Disclosuresontributing Writers and ReviewsEach writing group member and editorial oversight com-

ittee member completed a disclosure form that is main-ained on file at the ISHLT headquarters. The conflict ofnterest disclosures are as follows:

Relationship

Grant research/supportGrant research/supportGrant research/supportSpeakers bureauSpeakers bureauAdvisory board

erest

uticsclose


Name Commercial Interest Relationship

Michael Burch Novartis ConsultantCharles Canter Novartis Consultant

Blue Cross/Blue Shield consultantMichael Carboni Nothing to discloseMichael Chan Nothing to discloseRichard Chinnock Nothing to discloseMaria Rosa Costanzo CHF Solutions Consultant; speaker

St. Jude Speaker; research grantCardiomems Research grantParacor Research grant

Marisa Crespo-Leiro Roche Research grant/speakerNovartis Research grant/speakerWyeth Research grantAstellas Pharma Research grant/speaker

Diego Delgado Astellas Research grantNovartis Research grant

Reynolds Delgado Gilead Speakers bureauEli Lily Speakers bureau

Thomas Dengler Nothing to discloseShashank Desai Nothing to discloseAnne Dipchand Nothing to discloseFabienne Dobbels Astellas Speaker/research grant

BMS Scientific advisor/research grantSpeakers bureau

Novartis Scientific advisor/speakerHoward Eisen Novartis Grant/research support

Novartis Consultant/scientific advisorWyeth Grant/research supportWyeth Scientific medical/advisory

Savitri Fedson Nothing to discloseDavid Feldman Nothing to disclosePatrick Fis her Nothing to discloseMaria Frigerio Novartis Speaker

Genzyme SpeakerLee Goldberg Thoratec Consultant

Novartis Research grantAlere Sci/medical advisory boardMedtronic ConsultantGSK Speakers bureau

Gonzalo Gonzalez-Stawinski Thoratec Honorarium, travel grantKathleen Grady Nothing to discloseJeff Hosenpud Nothing to discloseSharon Hunt Nothing to discloseMaryl Johnson CVS (Caremark) ConsultantWalter Kao Nothing to discloseAnne Keogh Pfizer Research grant

Heartware Research grantNovartis Research grantBayer Research grantBayer Sci/medical advisory boardGSK Research grantGSK Sci/medical advisory boardActelion Research grantActelion Sci/medical advisory boardActelion Speakers bureau

Abdallah Kfoury XDx Scientific medical/advisoryXDx Grant research/supportNovartis Research grant

Daniel Kim Nothing to discloseJon Kobashigawa Novartis Research grants

R


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XDx

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Consultant/scientific advisorHonorarium

Grant research/supportSci/med advisory board

Consultant/scientific advisorDSMB MemberPrincipal investigatorConsultant

Grant/research supportConsultant/scientific advisorGrant/research supportConsultant/scientific advisorGrant research/support

ConsultantConsultantGrant research/supportSpeakerConsultant/scientific advisorSpeaker’s bureauConsultant

Speakers bureauConsultant/scientific advisorSpeaker’s bureauGrant/research supportResearch grantSpeakers bureauGrant/research support

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https://www.researchgate.net/publication/12315668_Utility_of_extracorporeal_membrane_oxygenation_for_early_graft_failure_following_heart_transplantation_in_infancy?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/8491674_The_expanding_role_of_the_transplant_pharmacist_in_the_multidisiplinary_practice_of_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/8433074_Perioperative_haemostatic_agents?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

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https://www.researchgate.net/publication/15629093_Role_of_transcriptional_activation_of_IKBalpha_inmediation_of_immunosuppression_by_glucocorticoids?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/15465755_Bourdage_JS_Hamlin_DM_Comparative_polyclonal_antithymocyte_globulin_and_antilymphocyteantilymphoblast_globulin_anti-CD_antigen_analysis_by_flow_cytometry?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/15291383_A_comprehensive_definition_of_the_major_antibody_specificities_in_polyclonal_rabbit_antithymocyte_globulin?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/14817815_A_prospective_randomized_study_of_prophylactic_OKT3_versus_equine_antithymocyte_globulin_after_heart_transplantation-increased_morbidity_with_OKT3?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/13550308_A_randomized_active-controlled_trial_of_mycophenolate_mofetil_in_heart_transplant_recipients_Mycophenolate_Mofetil_Investigators?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/11753625_Mycophenolic_acid_MPA_levels_in_pediatric_heart_transplant_recipients_receiving_mycophenolate_mofetil?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/11388894_CD3_monitoring_of_antithymocyte_globulin_therapy_in_thoracic_organ_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/10948341_Clopidogrel_and_rhabdomyolysis_after_heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/8446423_Sirolimus_in_De_Novo_Heart_Transplant_Recipients_Reduces_Acute_Rejection_and_Prevents_Coronary_Artery_Disease_at_2_Years_A_Randomized_Clinical_Trial?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy






















https://www.researchgate.net/publication/8403138_Gajarski_RJ_Crowley_DC_Zamberlan_MC_Lake_KD_Lack_of_correlation_between_MMF_dose_and_MPA_level_in_pediatric_and_young_adult_cardiac_transplant_patients_does_the_MPA_level_matter_Am_J_Transplant_4_1495?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/23143527_Aggressive_steroid_weaning_after_cardiac_transplantation_is_possible_without_the_additional_risk_of_significant_rejection?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/239480166_391_Alemtuzumab_Induction_Facilitates_Steroid-Free_Maintenance_Immunosuppresion_in_Human_Cardiac_Transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




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19. Keogh AM, Arnold RH, Macdonald PS, et al. A randomized trial oftacrolimus (FK506) versus total lymphoid irradiation for the controlof repetitive rejection after cardiac transplantation. J Heart Lung
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https://www.researchgate.net/publication/14830626_OKT3_treatment_of_cardiac_allograft_rejection?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/12389444_Role_of_statins_in_the_management_of_dyslipidemias_after_cardiac_transplant_Randomized_controlled_trial_comparing_the_efficacy_and_safety_of_atorvastatin_with_pravastatin?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/11817680_Simvas-tatin_treatment_is_associated_with_improvement_in_coronary_endothelial_function_and_decreased_cytokine_activation_in_patients_after_Heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/257476611_Simvastatin_initiated_early_after_heart_transplantation_8-Year_prospective_experience?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy
























https://www.researchgate.net/publication/8897019_Hedman_M_Neuvonen_P_J_Neuvonen_M_Holmberg_C_Antikainen_M_Pharmacokinetics_and_pharmacodynamics_of_pravastatin_in_pediatric_and_adolescent_cardiac_transplant_recipients_on_a_regimen_of_triple_immunosup?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




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https://www.researchgate.net/publication/14887647_Polyclonal_antithymocyte_serum_Immune_prophylaxis_and_rejection_therapy_in_pediatric_heart_transplantation_patients?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/11034915_Efficacy_and_safety_of_atorvastatin_after_pediatric_heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



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https://www.researchgate.net/publication/11346407_Contrasting_the_Neurologic_Complications_of_Cardiac_Transplantation_in_Adults_and_Children?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



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https://www.researchgate.net/publication/8514204_First_Experience_with_Rapamycin-Based_Immunosuppression_to_Improve_Kidney_Function_After_Heart_Transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy













https://www.researchgate.net/publication/257477457_Reduction_of_cyclosporine_after_introduction_of_mycophenolate_mofetil_improves_chronic_renal_dysfunction_in_heart_transplant_recipients_-_The_IMPROVED_multi-centre_study?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy








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https://www.researchgate.net/publication/21585072_Successful_withdrawal_of_corticosteroids_in_heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



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https://www.researchgate.net/publication/21052293_Cellular_and_molecular_mechanisms_of_cyclosporin_nephrotoxicity?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/8444765_Long-term_renal_function_in_pediatric_liver_and_heart_recipients?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/8444765_Long-term_renal_function_in_pediatric_liver_and_heart_recipients?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy





























https://www.researchgate.net/publication/51406489_Transplant-associated_hyperglycemia?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/51406489_Transplant-associated_hyperglycemia?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/237906294_28_Dose_reduction_of_MMF_due_to_gastrointestinal_intolerance_is_associated_with_increased_rejection_in_heart_transplant_recipients?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




https://www.researchgate.net/publication/21222635_Cyclosporine-induced_chronic_nephropathy_an_obliterative_microvascular_renal_injury_J_Am_Soc_Nephrol_2S45-S52?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy







https://www.researchgate.net/publication/8609505_New-onset_diabetes_after_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/8609505_New-onset_diabetes_after_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/13065289_Renal_failure_in_the_recipients_of_nonrenal_solid_organ_transplants?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/13065289_Renal_failure_in_the_recipients_of_nonrenal_solid_organ_transplants?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy




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https://www.researchgate.net/publication/51310801_Mechanisms_of_bone_loss_after_cardiac_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/51310801_Mechanisms_of_bone_loss_after_cardiac_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



















https://www.researchgate.net/publication/23769245_Increased_Pulse_Wave_Velocity_and_Blood_Pressure_in_Children_Who_Have_Undergone_Cardiac_Transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy






https://www.researchgate.net/publication/23304567_Posterior_reversible_encephalopathy_syndrome_in_an_intensive_care_unit_patient_receiving_tacrolimus?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy






https://www.researchgate.net/publication/23393490_Parkinsonism_During_Cyclosporine_Treatment_in_Liver_Transplantation_An_Unusual_Case_Report?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/10909348_Better_late_than_never_Experience_with_intravenous_pamidronate_treatment_in_patients_with_low_bone_mass_or_fractures_following_cadiac_or_liver_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy
















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https://www.researchgate.net/publication/9886986_Exercise_after_heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/9886986_Exercise_after_heart_transplantation?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/21416727_Social_rehabilitation_and_return_to_work_after_cardiac_transplantation_-_A_multicenter_survey?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/12771369_Return_to_work_after_heart_transplantation_12-year_follow-up?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy
































https://www.researchgate.net/publication/23172493_Cardiac_Retransplantation_in_Adults_An_Evidence-Based_Systematic_Review?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/24255875_Exercise_Training_Improves_Aerobic_Capacity_and_Skeletal_Muscle_Function_in_Heart_Transplant_Recipients?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/24349405_Interventions_to_improve_medication-adherence_after_transplantation_A_systemic_review?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/15258739_Chordal_Tissue_in_Endomyocardial_Biopsies?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/24209340_Anaesthesia_for_noncardiac_surgery_in_the_heart_transplant_recipient?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy






https://www.researchgate.net/publication/13674102_Cellular_adaptations_of_skeletal_muscles_to_cyclosporin?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/13674102_Cellular_adaptations_of_skeletal_muscles_to_cyclosporin?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy

https://www.researchgate.net/publication/21269444_Cardiovascular_response_of_heart_transplant_patient_to_exercise_training?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy



https://www.researchgate.net/publication/14025761_The_challenge_of_endomyocardial_biopsy_interpretation_in_assessing_cardiac_allograft_rejection?el=1_x_8&enrichId=rgreq-340f52e7-20e4-498c-8262-5be343ed468c&enrichSource=Y292ZXJQYWdlOzQ1Mjc0NDk5O0FTOjEzMTk0MzQwMDIxODYyNUAxNDA4NDY5MTY2ODYy









The International Society of Heart and Lung Transplantation Guidelines for the care of heart...

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