Early and Late Outcomes in patients after heart transplant
The objectives of this lecture are as follows:
1) To learn predictors of mortality and other adverse outcomes in patients presenting for heart
transplant
2) To discuss the early and long-term outcomes and complications in the patient after heart
transplantation.
3) To review anesthetic concerns when these patients present for non-cardiac surgery following
heart transplantation
Pre-transplant donor and recipient risk factors associated with increased mortality post-transplant
 Older donor age
 Increased recipient weight and body mass index
 Higher rates of recipient diabetes mellitus and recipient nicotine use history
 Longer allograft ischemic time
 Higher proportion of recipients with panel-reactive antibody (PRA) > 10%
 Congenital heart disease
 Pre-transplant LVAD use
 Requirement of post-operative short term extracorporeal mechanical circulatory support
 Recipient on ventilator at time of transplant
 Recipient history of dialysis
 Female > Male
 Infection within 2 weeks of transplant treated with antibiotics
 Transplant volume at institution decreasing
 Compatible but non-identical ABO
 Prior transfusions
 Ischemic cardiomyopathy > non-ischemic cardiomyopathy
 Increasing pre-transplant serum creatinine, bilirubin and increasing pulmonary vascular
resistance
 Increasing recipient age
 As patient survival progresses to 5 years, drug-treated rejection prior to first hospital
discharge and rejection between discharge and first year become significantly associated
with increasing mortality.
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Intra and post-operative vasoplegia
 5-15% incidence
 Associated with longer ischemic times, donor recipient weight mismatch, platelet
transfusion, VAD, TAH and acidosis
 Results in delayed extubation, more ECMO, more IABP use, increased incidence of open
chest, prolonged ICU stay, increased morbidity and mortality
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Early graft failure
 Primary cause of 30 day mortality post OHT
 Occurs in 10% of patients with a 56% or greater mortality
 Multifactorial pathophysiology
 Possible link with redo operation, increased blood products, long ischemic time.
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Only modifiable risk factor is optimal D/R matching
Reasons for improved early outcomes
 Improved organ transplantation
 Better tolerated immunosuppression and new agents
 Careful patient selection
 Multidisciplinary transplant centers with improved follow up
Better early outcomes = more late allograft failure, coronary artery disease is the major cause of
allograft loss after the first year post-transplant.
Coronary artery disease post OHT (TCAD)
 32% of patients at 5 years, 53% 10 years
 TCAD is characterized by an aggressive form of diffuse arterial narrowing
 Chronic allograft rejection usually presents as accelerated CAD
 Asymptomatic secondary to denervation of the heart should have periodic coronary
angiography.
 Diffuse nature makes PCI mostly palliative
 Statins helpful in preventing incidence and progression of the disease
Rejection
 Most likely to occur in the first 3-6 months
 Symptoms: fatigue, premature ventricular contractions, heart failure, myocardial
infarction
 Graded 0-4, 4 being the worst
 Three types: hyper-acute, acute vascular, and acute cellular
 Most common is acute cellular rejection
 Factors associated with acute cellular rejection: Younger, female, non O blood type,
donor specific mismatch, HLA mismatch, CMV +, and OKT3 sensitization
 Acute vascular rejection has greater mortality than acute cellular and associated with a 10
fold increase in TCAD
 Endomyocardial biopsy is the gold standard for diagnosis of rejection
Immunosuppression
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Consequences of immunosuppression: malignancy, infection, steroid induced
osteoporosis
Current agents are fairly non specific because they inhibit lymphocyte subsets rather than
act directly at donor specific allo-antigens
Blunting of T lymphocyte is extremely important post transplant because they initiate
antigen recognition and moderate allograft rejection
B lymphocyte activation- humoral component is also important
Calcineurin inhibitors key for improved survival of OHT. Tacrolimus use has overtaken
cyclosporine in recent years.
Many centers use peri-operative anti-lymphocyte antibody or anti-thymocyte globulin
Steroids (prednisone) still used in 71% of OHT
Most common combination of drugs is Tacrolimus and MMF with/or without prednisone
Azathioprine
 Converted into 6-Mercaptopurine
 Inhibits early step in de novo purine synthesis
o Several steps of salvage pathway as well
 Ultimately inhibits DNA synthesis
 Impact most felt on actively dividing lymphocytes
 SE: Pancytopenia, GI upset/Diarrhea, Skin Cancers
Mycophenolate Mofetil (Cellcept)(MMF)
 Hydrolyzed to Mycphenolic Acid
 Inhibits de novo (ONLY) guanine synthesis
 Activated Lymphocytes rely solely on this pathway
 Other cell lines not as affected
 Studies have shown decreased mortality compared to Azathioprine
 Superior to Imuran in prevention of B-Cell Activation (Antibody Mediated
Rejection)
 SE: Leukopenia, GI Upset/Diarrhea, Skin Ca
Cyclosporine (CSA, Gengraf, Neoral, Sandimmune)
 Blocks IL-2 Transcription
 Major SE: Nephrotoxicity, HTN, Neurotoxicity, Hyperlipidemia
 Other SE: Hirsutism, Gingival Hyperplasia, Liver Dysfunction
 Pharmacokinetics and pharmacodynamics are complex
 Frequent serum level monitoring required
 Neoral better bioavailability than Sandimmune
Tacrolimus (Prograff, FK-506)
 Discovered in 1984
 Macrolide Antibiotic
 Product of Stretpomyces tsurubanensis fermentation
 Improved SE profile from CSA (HTN, Renal Dysfunction, Hirsuitism, Gingival
Hyperplasia)
 ? Less Acute Rejection Episodes
 Hyperlipidemia and DM worse
mTOR Kinase Inhibitors
 Sirolimus (Rapamune), Everolimus (Afinitor)
 Isolated from Streptomyces hygroscopicus
 Discovered initially as an antifungal agent
 Some studies showing protection against and reversal of transplant vasculopathy
 SE: Poor Wound Healing, Hypertriglyceridemia, Renal Dysfunction, Fluid
Retention, Leukopenia, ?Increased Rejection if used without CI.
Induction Agents
 OKT3, Thymoglobulin, Simulect, Campath
 Used in ~ 50% of Heart Transplants
 Decreased need for CI’s Perioperatively
 Decreased Acute Rejection Early on
 Increased success with early steroid withdrawal
 Increased risk for PTLD
 Typically used in “High Risk” pts (AA, Renal Dysfunction, Elevated PRAs, ReTx)
Around 3300 heart transplants are performed per year, the patients are living longer with 50%
living more than 10 years post transplant.
Increased survival has lead to an increase in non-cardiac procedures in OHT patients from 15% in
1990 to 34%.
These patients are at higher risk for post-operative morbidity and mortality for most procedures
and thus it is beneficial for anesthesiologists to be able to optimize these patients for non-cardiac
surgery and be able to safely take care of them in the operating theater.
Main issues for the anesthesiologist
 Understand the physiological and pharmacological interactions in a denervated heart
 Know the side effects of immunosuppression
 Understand risk of infection and potential for rejection
Preoperative assessment
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Focus on graft function and possibility of rejection. A recent echocardiogram and
myocardial biopsy will give provide this information.
Assess patient activity level and general well being
Rejection should be ruled out for elective surgery, acute or chronic rejection leads to
increased morbidity and mortality.
EKG, assess for silent coronary artery disease. Dysrhythmias are also common, 50% of
patients, secondary to lack of vagal tone, possibly rejection or circulating catecholamines
Rule out infection, chest x-ray for sure (Lung is most common source), patient may not
have typical symptoms secondary to immunosuppression, physician must have a high
index of suspicion
Reducing or missing immunosuppression doses can lead to increased risk of rejection, do
not stop without discussion with transplant team
75% of cardiac patients have hypertension, thus assessment of adequacy of control
should be part of the pre-op workup
Assess end organ function, liver, kidney and bone marrow function are major side effects
of immunosuppressive drugs (See drugs above)
Tacrolimus and Cyclosporine are followed by drug levels, assess when last drawn
Intraoperative Management
 The heart is denervated so compensatory responses to physiologic changes are delayed
 Address antibiotic prophylaxis and duration.
 Loss of vagal tone leads to higher than normal resting heart rate
 Intact Frank-Starling curve and preload dependence for ventricular output
 No compensatory increase in heart rate with hypovolemia or hypotension, stroke volume
will be increased by an increase in circulating catecholamines
 Vagolytic drugs will be ineffective
 Reduced myocardial response to exercise occurs 2-6 years post transplant
 Denervated heart responds normally to glucagon, norepinephrine, epinephrine and
propranolol
 Caution if using spinal anesthesia because of delayed response to hypotension
 There is the possibility of prolonged neuromuscular blockade with cyclosporine and
azathioprine, exercise caution with dosing.
 Tacrolimus and Cyclosporine lower the seizure threshold, avoid hyperventilation
References
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lung transplantation: Twenty-sixth official adult heart transplant report- 2009. The
Journal of Heart and Lung Transplantation 2009; 28:1007-22.
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outcomes associated with vasoplegia in recipients of orthotopic heart transplantation in
the contemporary era. The Journal of Heart and Lung Transplantation 2012; 31(3): 282287.
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