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Preanesthetic evaluation of the patient with end-stage heart failure
Accepted Manuscript Pre-Anesthesia Evaluation of the Patient with End-Stage Heart Failure Michele Sumler, MD, Ratna Vadlamudi
PII:
S1521-6896(17)30037-X
DOI:
10.1016/j.bpa.2017.06.001
Reference:
YBEAN 944
To appear in:
Best Practice & Research Clinical Anaesthesiology
Received Date: 9 April 2017 Revised Date:
10 May 2017
Accepted Date: 16 June 2017
Please cite this article as: Sumler M, Vadlamudi R, Pre-Anesthesia Evaluation of the Patient with End-Stage Heart Failure, Best Practice & Research Clinical Anaesthesiology (2017), doi: 10.1016/ j.bpa.2017.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pre-Anesthesia Evaluation of the Patient with End-Stage Heart Failure
Michele Sumler, MD
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[email protected] Emory University Department of Anesthesiology, Division of Cardiothoracic Anesthesiology 404-778-3940 (F)
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404-778-5793 (W)
Ratna Vadlamudi
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[email protected]
Emory University Department of Anesthesiology, Division of Cardiothoracic Anesthesiology 404-778-3940 (F)
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404-778-5793 (W)
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Keywords
End stage heart failure
Mechanical circulatory support (MCS) implantation
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Pre-anesthetic evaluation
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Orthotopic heart transplantation (OHT)
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Abstract
Heart failure currently affects > 5 million patients in the United States [1]. Advanced heart failure is associated with high mortality and poor quality of life. It is estimated that between 5% and 10% of all patients with heart failure (HF) have an advanced form of the disease [1]. Orthotopic heart transplantation (OHT) is an accepted therapy for stage D heart failure [3]
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(Figure 1).
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Stage D HF
Medical management Hospitalization with specialized interventions
Orthotopic heart transplantation Mechanical circulatory support Palliative care
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Unfortunately, the number of patients with the disease exceeds the number of available organs. This makes appropriate patient selection vital to the field of transplantation. Anesthetic evaluation of the patient presenting for orthotopic heart transplantation (OHT)
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or mechanical circulatory support (MCS) implantation is a vital component of the patient’s perioperative course. Patients often have had extensive diagnostic testing and assessment prior to being listed for OHT or considered for MCS implantation. Due to the often urgent nature of these
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procedures, the cardiac anesthesiologist must conduct a focused review of the relevant
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information and perform a focused patient interview and physical exam.
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Introduction to Heart Failure
Heart failure has significant public health impact, is associated with decreased quality of life, substantial resource utilization, and decreased life expectancy [2]. HF is classified according
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to symptoms and anatomic considerations (see tables 1 and 2). Table 1. American College of Cardiology Foundation/American Heart Association (ACCF/AHA) stages of heart failure [2]:
At risk for HF but without symptoms or structural heart disease
B
Structural heart disease without signs or symptoms of HF
C
Structural heart disease with prior or current HF symptoms
D
Refractory HF requiring specialized interventions
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A
Table 2. New York Heart Association (NYHA) Classification [2]:
III
IV
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II
No limitations to physical activity
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I
Slight limitations to physical activity
Marked limitations to physical activity
HF symptoms at rest
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Stage D heart failure is defined as advanced progression of disease despite maximal therapies.
Surgical therapy
• Diuretics • Afterload reduction • β-blockers • Anti-arrhythmics
• Coronary revascularization • Structural heart interventions • MCS implantation
• Cardiac resynchronization therapy
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Indications for heart transplantation
Device therapy
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Medical therapy
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Table 3. Types of therapies for end stage heart failure:
The American College of Cardiology (ACC) /American Heart Association (AHA)
•
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guidelines include the following indications for cardiac transplantation [1]: Refractory cardiogenic shock requiring intra-aortic balloon pump (IABP) counterpulsation or left ventricular assist device (LVAD) Cardiogenic shock requiring continuous intravenous inotropic therapy
•
Peak VO2 (VO2max) less than 10 mL/kg per min
•
New York Heart Association (NYHA) class of III or IV despite maximized
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•
medical and resynchronization therapy
•
Recurrent life-threatening left ventricular arrhythmias despite an implantable cardiac defibrillator, antiarrhythmic therapy, or catheter-based ablation
•
End-stage congenital heart failure with no evidence of pulmonary hypertension
•
Refractory angina without potential medical or surgical therapeutic options
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The European Society of Cardiology also describes a series of features that should be met before patients are considered for heart transplantation [4]: •
Severe symptoms, with dyspnea at rest or with minimal exertion (NYHA class
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III or IV) Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
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Objective evidence of severe cardiac dysfunction (at least one of the following): –
Left ventricular ejection fraction less than 30%
–
Pseudonormal or restrictive mitral inflow pattern on Doppler
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•
echocardiography –
High left and/or right ventricular filling pressure severely impaired functional capacity demonstrated by one of the following: inability to exercise
6-minute walk test distance less than 300 m (or less in women or patients
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–
who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min;
One or more hospitalizations for HF in the past 6 months.
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•
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Contraindications to Heart Transplantation
Contraindications to transplantation have evolved since the advent of heart
transplantation, with many centers expanding criteria for acceptance [1]. Conventional contraindications to transplantation are listed below [1]: Absolute contraindications: •
Systemic illness with a life expectancy < 2 years despite OHT: –
Active or recent solid organ or blood malignancy within 5 years
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–
AIDS with frequent opportunistic infections
–
Systemic lupus erythematosis, sarcoidosis, or amyloidosis that has multisystem involvement and is still active
Irreversible renal or hepatic dysfunction in patients considered for only OHT
•
Significant obstructive pulmonary disease (FEV1 < 1 L/min)
•
Fixed pulmonary hypertension:
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•
Pulmonary artery systolic pressure > 60 mmHg
–
Mean transpulmonary gradient > 15 mmHg
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Pulmonary vascular resistance > 6 Wood units
Relative contraindications:
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–
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Age > 72
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Any active infection (with exception of device related infection in VAD recipients)
Active peptic ulcer disease
•
Severe diabetes mellitus with end-organ damage (neuropathy, nephropathy, or
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•
retinopathy)
Severe peripheral vascular or cerebrovascular disease:
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•
–
Peripheral vascular disease not amenable to surgical or percutaneous
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therapy
•
–
Symptomatic carotid stenosis
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Ankle brachial index < 0.7
–
Uncorrected abdominal aortic aneurysm > 6 cm
Morbid obesity (body mass index > 35 kg/m2) or cachexia (body mass index < 18 kg/m2)
•
Creatinine > 2.5 mg/dL or creatinine clearance < 25 mL/min
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Bilirubin > 2.5 mg/dL, serum transaminases > 3x, INR > 1.5 off warfarin
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Severe pulmonary dysfunction with FEV1 < 40% normal
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Recent pulmonary infarction within 6 to 8 weeks
•
Difficult to control hypertension
•
Irreversible neurologic or neuromuscular disorder
•
Active mental illness or psychosocial instability
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Drug, tobacco, or alcohol abuse within 6 months
•
Heparin induced thrombocytopenia within 100 days
Systems Based Assessment
Neurologic
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•
Patients with end stage heart failure may have neurologic complications of a chronic low
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cardiac output state, manifested by encephalopathy or overt cerebrovascular accident (CVA). If encephalopathy is severe, patients may presents for surgery intubated, preventing a thorough preanesthetic evaluation.
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An assessment of the patient’s baseline neurologic function should be obtained, focusing on mental status, gross motor and sensory function. Note should be made of any significant
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deficits so that any alterations from baseline can be assessed post surgically. Severe, symptomatic cerebrovascular disease, defined as prior transient ischemic attack (TIA) or CVA may be a contraindication to transplantation [5, 6]. Patients with history of TIA or CVA are also at an increased risk for further cerebrovascular events and have higher long term rates of death [6]. However, prior TIA or CVA does not appear to increase the rate of death after OHT [6, 7]. Depression is known to have a higher incidence in heart failure patients, with some metaanalyses indicating a prevalence of up to 40% [8]. Depression is also an independent predictor of
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mortality and patients are frequently managed with anti-depressant therapy. The anesthesiologist should be aware of what pharmacologic therapy the patient is on, as this may have implications for the intraoperative and postoperative management. Specifically, many anti-depressant
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therapies will impair the uptake of serotonin and may predispose patients to serotonin syndrome; particularly if they are treated for vasoplegic syndrome with methylene blue [9].
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Cardiovascular
Patients presenting for OHT or MCS implantation have severe, end stage heart failure
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that has failed medical management. Non-ischemic cardiomyopathy, ischemic cardiomyopathy, valvular cardiomyopathy, congenital heart disease, and need for redo-transplantation are the commonest indications [5].
These patients are often managed on continuous inotrope and vasopressor infusions, intravenous diuretics, and in severe cases, mechanical assist devices such as IABP
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counterpulsation, percutaneous temporary ventricular assist devices or implanted ventricular assist devices, which were placed as a bridge to transplantation (BTT). Their medication regimen is complex and involves diuretics, afterload reducers, vasodilators, anti-arrhythmics, and
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anticoagulants. Patients also frequently have cardiovascular implantable electronic device (CIED). Continuous inotrope infusions are usually administered via a peripherally inserted central
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catheter (PICC) or via standard central venous lines (CVL). Many patients are deemed too critical to be managed at home and are hospitalized long-term until a suitable donor heart becomes available. This may predispose them to an increased infection risk due to the presence of the indwelling lines described above or other chronic catheters and drains associated with the management of critically ill patients.
Diagnostic testing
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All patients presenting for OHT or MCS implantation will have had echocardiographic assessment of cardiac function as well as angiography to assess for coronary anatomy and pulmonary hypertension. Attention should be paid to the level of pulmonary hypertension that is
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present and if it is reversible with vasodilator or other medical therapies. There are 3 main classes of pulmonary vasodilating agents: prostacyclins, endothelin receptor antagonists, and
phosphodiesterase-5 inhibitors. Irreversible significant pulmonary hypertension, defined as
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incidence of donor heart right ventricular failure [4, 5].
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pulmonary vascular resistance > 6 Wood units is a contraindication for OHT, due to increased
Vascular access
As stated above, patients may have long standing PICC or CVL in situ for administration of continuous inotropic infusions. Determining the length of time a line has been in place as well as reviewing the patient’s vascular anatomy will help plan for vascular access for the procedure.
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Patients with long standing inotropic dependence may have stenosis of central veins.
CIED management
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CIEDs will be removed at the end of an OHT. To prevent oversensing, ICD therapy is disabled during OHT and MCS implantation with availability for external defibrillation. Changes
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in pacemaker settings are made and rely on how dependent the patient is on pacing [10].
Medication management
Complex medication regimens are the norm for these patients. The anesthesiologist
should pay particular attention to anticoagulant medications. Patients are often on chronic vitamin-K antagonists or newer, non vitamin-K oral anticoagulants. It is important to note when the last dose was administered and formulate a plan for managing continued anticoagulant effect. Vitamin K can be given for reversal of warfarin. Non vitamin-K oral anticoagulants will have less
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anticoagulant effect 12-24 hours after the last dose, especially if renal clearance is normal. However, due to the urgent nature of OHT, patients present for surgery with evidence of active anticoagulant effect. No guidelines exist for reversal of these newer oral anticoagulants, but a
be indicated in reversing these agents [11].
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Pulmonary
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specific reversal agent does exist for dabigatran. Prothrombin complex concentrates (PCCs) may
Patients with significant intrinsic lung disease are not candidates for OHT but may be
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candidates for MCS as destination therapy. Attention should be paid to diagnostic data, such as pulmonary function tests. Decompensated patients may have significant pulmonary edema and may be intubated prior to presenting for surgery. Appropriate plans should be made as pulmonary compliance will be decreased and intraoperative ventilation and oxygenation may be impaired. Patients with known or suspected obstructive sleep apnea (OSA) should be managed very
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cautiously prior to surgery. If sedation is planned to obtain invasive access, consideration should be given to utilizing continuous positive airway pressure (CPAP) or bi-level positive airway
Renal
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pressure (BiPAP) support.
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Renal dysfunction is one of the most common comorbidities in patients with heart failure [12]. Patients may have renal disease related to heart failure or due to other risk factors for chronic kidney disease (CKD), such as diabetes or chronic hypertension. Renal dysfunction is an independent predictor of mortality and rehospitalization in patients with heart failure and the prevalence of CKD approaches 30% in patients with heart failure [12, 13]. The presence of concomitant heart failure and renal dysfunction has been termed as “cardiorenal syndrome” [12]. This complex syndrome is due to congestion, chronic low cardiac output state, inflammation, chronic anemia and neurohormonal activation [12].
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Chronic or acute heart failure
Cardiovascular risk factors
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Chronic kidney disease
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Figure 2
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Cardiorenal syndrome
Estimated glomerular filtration rate (eGFR) should be evaluated. Decreased creatinine
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clearance, defined as eGFR < 30 mL/min, is a relative contraindication to OHT alone and may require combined OHT and renal transplantation [5]. Renal biopsy is common in these patients to
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differentiate between intrinsic renal disease, which may require combined OHT and renal transplantation, and renal disease secondary to chronic HF. This decision regarding combined transplantation is made prior to the patient presenting for surgery.
Gastrointestinal and Hepatic
Patients with end stage heart failure often have concomitant liver disease. This can range from mild liver injury to severe cardiac cirrhosis. Chronically elevated right-sided pressures lead
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to hepatic congestion, which is manifested as elevated transaminases and can progress to hepatomegaly with ascites [14]. Hypoperfusion and chronic medication effect are also implicated
Table 4. Type of hepatic injury in end stage heart failure: Result
Cholestatic
Elevated bilirubin and alkaline phosphatase
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Type of injury
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in liver disease in HF patients [15].
Hepatocellular Elevated transaminases (alanine aminotransferase [ALT] and aspartate
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aminotransferase [AST]
Milder liver injury can reverse with OHT or MCS implantation but patients with severe liver disease are contraindicated for surgery due to high morbidity and mortality [14]. Acute cardiogenic liver injury, also known as ischemic hepatitis, is described as critical hypoperfusion
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coupled with venous congestion [15]. Select patients may be candidates for combined OHT and liver transplantation, which is pre-determined as in the case of combined OHT and renal transplantation. Similar to patients with combined cardiac and renal disease, liver biopsy may be
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Hematologic
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performed to aid in determining appropriate transplant listing.
Hematologic derangements can range from anemia due to cardiorenal syndrome and
volume overload to thrombocytopenia due to liver disease [12, 14]. Even significant anemia and thrombocytopenia is managed conservatively in the pre-surgery period, to minimize exposure of patients to potential antigens and reduce the chances of antibody formation. Sensitized patients, with high panel reactive antibody levels, may be contraindicated to OHT as the pool of available organs will be limited and post transplant outcomes are worse [16].
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Endocrine
Diabetes mellitus (DM) is frequent in prevalence in patients with HF, up to 40% [17]. Cardiovascular disease is the leading cause of death in patients with DM, with up to 75% of
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diabetics dying of cardiovascular disease [17]. Achieving glycemic control is a mainstay of HF management in ambulatory and hospitalized patients. Assessment of the glycosylated hemoglobin (HbA1C) will inform as to the patient’s glycemic control in the prior 3 months [17].
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Alterations in normal thyroid function are clearly linked to cardiovascular disease [18].
Thyroid hormone receptors are present in myocardial and vascular endothelial cells and thyroid
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hormones directly affect the heart, exerting inotropic and chronotropic effects [18]. Even subclinical hypo- or hyperthyroidism can have deleterious effects on cardiac function [18]. Medications commonly used in managing severe HF are implicated in derangements from normal thyroid function, particularly amiodarone and dopamine [18]. It is known that T3 levels are decreased in the immediate post-operative period after coronary artery bypass graft (CABG)
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surgery and small studies have shown decreased mortality in CABG patients treated with T3 [18]. Pre-operative assessment of thyroid function, particularly in patients chronically on medical therapy known to interfere with normal thyroid parameters, should be performed. Some centers
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advocate for the use of T3 in the in the post-operative period for OHT patients.
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Infectious Disease
Pre-surgery infectious complications are increasing due to the use of in-dwelling
catheters for continuous inotropic and vasopressor support and increase in rate of patients with MCS presenting for OHT [20]. If patients are on current antimicrobial therapy, that regimen should be continued in the pre-surgical period. Patients with chronic viral diseases, such as human immunodeficiency virus (HIV) or hepatitis B or C viruses, are eligible for OHT, if their disease is well-managed and without evidence of significant complications. In the case of HIV, for example, compliance with anti-
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retroviral therapy with stable and adequate CD4 cell counts is mandatory for consideration for OHT [5]. In patients with chronic hepatitis B or C infections, liver biopsy is performed to rule out severe liver disease [5]. Presence of cirrhosis, hepatocellular carcinoma or portal hypertension is
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contraindications to OHT [5].
Laboratory data
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After completing a review of the above organ systems and determining the severity of
any comorbid conditions, attention should turn to review of the patient’s most recent laboratory
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values. These values will vary in detail, dependent on the patient’s acuity. Hospitalized, inotropeand vasopressor-dependent patients may have mixed venous oxygen saturation, in addition to frequent arterial blood gases if the patient is intubated and mechanically ventilated. Chronic hyponatremia due to volume overload is common. Other abnormalities are usually related to specific organ system dysfunction; elevated creatinine in cardiorenal or medical renal disease, for
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example.
Table 5. Below is a summary of common laboratory value derangements: Etiology
Anemia
Chronic volume overload
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Abnormal laboratory value
Iron deficiency
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Chronic kidney disease
Elevated creatinine
Sodium derangements
Chronic kidney disease Medication effect Cardiorenal syndrome Hyponatremia: Chronic volume overload, diuretic use Hypernatremia: Free water loss, poor water intake
Potassium derangements
Hypokalemia: diuretic use
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Hyperkalemia: chronic kidney disease, medication effect Hyperglycemia
Diabetes mellitus, insulin resistance
Low albumin
Chronic kidney disease, chronic liver disease, poor nutritional
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status Transaminitis
Liver congestion or cirrhosis, medication effect
Abnormal thyroid function
Medication effect
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tests Medication effect, liver disease
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Elevated INR
Imaging studies
At a minimum, patients presenting for OHT or MCS implantation will have had transthoracic echocardiography, left and right heart catheterization, and chest radiography
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performed. Review of this data is important for development of an anesthetic plan. Other imaging will be obtained dependent on specific comorbidities; carotid ultrasound in patients with known
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or suspected cerebrovascular disease, for example.
Focused Physical Exam and Interview
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Once relevant information has been obtained and reviewed, the cardiac anesthesiologist
should perform a focused interview and physical exam. NPO status should be determined; due to the urgent nature of OHTs, strict fasting may not be possible and the anesthesiologist should be prepared for a potential full stomach patient. A thorough airway examination should be performed and concerns for possible difficult airway noted. If a difficult airway is anticipated, plans should be made according to the American Society of Anesthesiologists (ASA) difficult
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airway algorithm [19] or other regional medical society recommendations for the management of the difficult airway. The remainder of the exam should focus on assessing the severity of the patient’s heart
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failure: signs such as jugular venous distension, dyspnea, orthopnea, peripheral edema are all evidence of significant volume overload that may limit the patient’s position during induction and venous access placement.
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The anesthesiologist should also inquire as to the patient’s current medication regimen
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and any missed doses, which may lead to worsening hemodynamics.
Sedation
Pre-surgery sedation should be used cautiously in patients presenting for OHT or MCS implantation. These patients may have tenuous cardio-pulmonary reserve and even modest sedation may cause significant hemodynamic and respiratory compromise. This is also important
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in the event the transplant is cancelled due to donor organ issues as sedation may preclude discharging a patient back to their previous care setting.
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Management of Immunosuppressants
Immunosuppression options for patients undergoing transplantation have evolved over
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the years. As a result of these advancements, 1-year survival after cardiac transplantation approaches 90%, with 50% of patients surviving >11 years [1]. Table 6. Triple drug therapy is the mainstay for immunosuppression in OHT [20]: Calcineurin inhibitors
Cyclosporine or tacrolimus
Steroids
Prednisone
Anti-metabolites
Mycophenolate mofetil
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Calcineurin inhibitors function to block T cell activation. Steroids decrease inflammation and prevent the proliferation of T cells, B cells and antigen presenting cells. Mycophenolate mofetil also blocks the proliferation of T and B cells [20]. Calcineurin inhibitors in particular are
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known nephrotoxins, leading to decreased glomerular filtration rate. To help mitigate this effect, monoclonal or polyclonal antibodies against T cells are used as induction immunosuppression therapy. These agents are antithymocyte polyclonal antibody (ATG) or interleukin 2 receptor
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monoclonal antibody (basiliximab) [20].
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Conclusion
Orthotopic heart transplantation remains the gold standard for patients with advanced heart failure. These patients can represent a challenge due to multisystem involvement, which results because of the effects of heart failure. A thorough evaluation should be performed including a review of organ systems, medications, lab values and physical examination.
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Although advancements have been made in the field of heart transplantation, the biggest challenge remains that the number of patients in need of transplants far outweighs donor heart availability. Mechanical circulatory support (MCS) devices have facilitated the treatment of this
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patient population. Continued development of current therapies is needed in the treatment of
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advanced heart failure.
Practice Points •
Every organ system in patients undergoing heart transplantation should be carefully assessed on the day of surgery
•
Sedation should be used cautiously
•
Close attention should be paid to the immunosuppression regimen in patients undergoing heart transplantation
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•
Management of the patient’s coagulation status should be formulated and discussed with the surgical team
•
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Research Agenda
The demand for hearts drastically outnumbers the current supply; studies into how to
expand the donor pool would be beneficial to the field of heart transplantation and would
•
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ultimately save lives
Although there have been major advancements in immunosuppressive therapy, continued
are needed •
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research into limiting the side effects of these drugs and improving overall graft survival
Continued improvement in the treatment of heart failure is still needed as this would ultimately decrease the number of patients requiring heart transplants
•
Research in the area of stem cells may be helpful in restoring damaged cardiac cells and
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improving overall heart function
Continued research and development in the area of mechanical circulatory support
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devices will also be helpful in decreasing the recipient pool
Conflict of interest:
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None.
References:
1. Mancini D, Lietz K. Selection of cardiac transplantation candidates in 2010. Circulation 2010; 122 (2): 173-83. 2. Mazurek JA, Jessup M. Understanding heart failure. Heart Failure Clin 2017; 13: 1-19.
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3. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused Update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on practice
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guidelines: Developed in collaboration with the international society for heart and lung transplantation. Circulation 2009; 119: 1977-2016.
4. McMurray JJ, Adamopoulos S, Anker SD, et al. European Society of Cardiology
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Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The
task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the
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European Society of Cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803-69. 5. Mehra MR, Canter CE, Hannan MM et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016; 35 (1): 1-23.
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6. Patlolla V, Mogulla V, DeNofrio D et al. Outcomes in patients with symptomatic cerebrovascular disease undergoing heart transplantation. JACC 2011; 58 (10): 1036-41. 7. Taylor DO, Stehlik J, Edwards LB et al. Registry of the International Society for Heart
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and Lung Transplantation: Twenty-sixth Official Adult Heart Transplant Report-2009. J Heart Lung Transplant 2009; 28: 1007-22.
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8. Angermann CE, Gelbrich G, Störk S et al. Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: The MOOD-HF randomized clinical trial. JAMA 2016; 315 (24): 2683-93.
9. Wolvetang T, Janse R, H MT. Serotonin syndrome after methylene blue administration during cardiac surgery: A case report and review. J Cardiothorac Vasc Anesth 2016; 30 (4): 1042-45.
10. Crossley GH, Poole JE, Rozner MA et al. The Heart Rhythm Society (HRS)/American Society of Anesthesiologists (ASA) Expert Consensus Statement on perioperative
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management of patients with implantable defibrillators, pacemakers and arrhythmia monitors: Facilities and patient management. Heart Rhythm 2011; 8 (7): 1114-54. 11. Aronis KN, Hylek EM. Who, when, and how to reverse non-vitamin K oral
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anticoagulants. J Thromb Thrombolysis 2016; 41: 253-72. 12. Carubelli V, Lombardi C, Gorga E et al. Cardiorenal interactions. Heart Failure Clin 2016; 12: 335-47.
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13. Cleland JGF, Carubelli V, Castiello T et al. Renal dysfunction in acute and chronic heart failure: Prevalence, incidence and prognosis. Heart Failure Rev 2012; 17: 133-49.
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14. Pendyal A, Gelow JM. Cardiohepatic interactions: Implications for management in advanced heart failure. Heart Failure Clin 2016; 12: 349-61.
15. Samsky MD, Patel CB, DeWald TA et al. Cardiohepatic interactions in heart failure: An overview and clinical implications. JACC 2013; 61: 2397-405. 16. Al-Mohaissen MA, Virani SA. Allosensitization in heart transplantation: An overview.
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Can J Cardiol 2014; 30: 161-72.
17. Mancini GBJ, Cheng AY, Connelly K et al. Diabetes for cardiologists: Practical issues in diagnosis and management. Can J Cardiol 2017; 33: 366-77.
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18. Jabbar A, Pingitore A, Pearce SHS et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 2017; 14: 39-55.
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19. Practice Guidelines for Management of the Difficult Airway: An updated report by the American Society of Anesthesiologists Task Force on management of the difficult airway. Anesthesiology 2013; 118 (2): 251-70.
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PII:
S1521-6896(17)30037-X
DOI:
10.1016/j.bpa.2017.06.001
Reference:
YBEAN 944
To appear in:
Best Practice & Research Clinical Anaesthesiology
Received Date: 9 April 2017 Revised Date:
10 May 2017
Accepted Date: 16 June 2017
Please cite this article as: Sumler M, Vadlamudi R, Pre-Anesthesia Evaluation of the Patient with End-Stage Heart Failure, Best Practice & Research Clinical Anaesthesiology (2017), doi: 10.1016/ j.bpa.2017.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Pre-Anesthesia Evaluation of the Patient with End-Stage Heart Failure
Michele Sumler, MD
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[email protected] Emory University Department of Anesthesiology, Division of Cardiothoracic Anesthesiology 404-778-3940 (F)
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404-778-5793 (W)
Ratna Vadlamudi
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[email protected]
Emory University Department of Anesthesiology, Division of Cardiothoracic Anesthesiology 404-778-3940 (F)
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404-778-5793 (W)
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Keywords
End stage heart failure
Mechanical circulatory support (MCS) implantation
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Pre-anesthetic evaluation
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Orthotopic heart transplantation (OHT)
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Abstract
Heart failure currently affects > 5 million patients in the United States [1]. Advanced heart failure is associated with high mortality and poor quality of life. It is estimated that between 5% and 10% of all patients with heart failure (HF) have an advanced form of the disease [1]. Orthotopic heart transplantation (OHT) is an accepted therapy for stage D heart failure [3]
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(Figure 1).
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Stage D HF
Medical management Hospitalization with specialized interventions
Orthotopic heart transplantation Mechanical circulatory support Palliative care
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Unfortunately, the number of patients with the disease exceeds the number of available organs. This makes appropriate patient selection vital to the field of transplantation. Anesthetic evaluation of the patient presenting for orthotopic heart transplantation (OHT)
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or mechanical circulatory support (MCS) implantation is a vital component of the patient’s perioperative course. Patients often have had extensive diagnostic testing and assessment prior to being listed for OHT or considered for MCS implantation. Due to the often urgent nature of these
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procedures, the cardiac anesthesiologist must conduct a focused review of the relevant
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information and perform a focused patient interview and physical exam.
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Introduction to Heart Failure
Heart failure has significant public health impact, is associated with decreased quality of life, substantial resource utilization, and decreased life expectancy [2]. HF is classified according
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to symptoms and anatomic considerations (see tables 1 and 2). Table 1. American College of Cardiology Foundation/American Heart Association (ACCF/AHA) stages of heart failure [2]:
At risk for HF but without symptoms or structural heart disease
B
Structural heart disease without signs or symptoms of HF
C
Structural heart disease with prior or current HF symptoms
D
Refractory HF requiring specialized interventions
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A
Table 2. New York Heart Association (NYHA) Classification [2]:
III
IV
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II
No limitations to physical activity
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I
Slight limitations to physical activity
Marked limitations to physical activity
HF symptoms at rest
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Stage D heart failure is defined as advanced progression of disease despite maximal therapies.
Surgical therapy
• Diuretics • Afterload reduction • β-blockers • Anti-arrhythmics
• Coronary revascularization • Structural heart interventions • MCS implantation
• Cardiac resynchronization therapy
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Indications for heart transplantation
Device therapy
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Medical therapy
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Table 3. Types of therapies for end stage heart failure:
The American College of Cardiology (ACC) /American Heart Association (AHA)
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guidelines include the following indications for cardiac transplantation [1]: Refractory cardiogenic shock requiring intra-aortic balloon pump (IABP) counterpulsation or left ventricular assist device (LVAD) Cardiogenic shock requiring continuous intravenous inotropic therapy
•
Peak VO2 (VO2max) less than 10 mL/kg per min
•
New York Heart Association (NYHA) class of III or IV despite maximized
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medical and resynchronization therapy
•
Recurrent life-threatening left ventricular arrhythmias despite an implantable cardiac defibrillator, antiarrhythmic therapy, or catheter-based ablation
•
End-stage congenital heart failure with no evidence of pulmonary hypertension
•
Refractory angina without potential medical or surgical therapeutic options
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The European Society of Cardiology also describes a series of features that should be met before patients are considered for heart transplantation [4]: •
Severe symptoms, with dyspnea at rest or with minimal exertion (NYHA class
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III or IV) Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
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Objective evidence of severe cardiac dysfunction (at least one of the following): –
Left ventricular ejection fraction less than 30%
–
Pseudonormal or restrictive mitral inflow pattern on Doppler
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•
echocardiography –
High left and/or right ventricular filling pressure severely impaired functional capacity demonstrated by one of the following: inability to exercise
6-minute walk test distance less than 300 m (or less in women or patients
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–
who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min;
One or more hospitalizations for HF in the past 6 months.
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Contraindications to Heart Transplantation
Contraindications to transplantation have evolved since the advent of heart
transplantation, with many centers expanding criteria for acceptance [1]. Conventional contraindications to transplantation are listed below [1]: Absolute contraindications: •
Systemic illness with a life expectancy < 2 years despite OHT: –
Active or recent solid organ or blood malignancy within 5 years
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–
AIDS with frequent opportunistic infections
–
Systemic lupus erythematosis, sarcoidosis, or amyloidosis that has multisystem involvement and is still active
Irreversible renal or hepatic dysfunction in patients considered for only OHT
•
Significant obstructive pulmonary disease (FEV1 < 1 L/min)
•
Fixed pulmonary hypertension:
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Pulmonary artery systolic pressure > 60 mmHg
–
Mean transpulmonary gradient > 15 mmHg
–
Pulmonary vascular resistance > 6 Wood units
Relative contraindications:
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–
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Age > 72
•
Any active infection (with exception of device related infection in VAD recipients)
Active peptic ulcer disease
•
Severe diabetes mellitus with end-organ damage (neuropathy, nephropathy, or
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•
retinopathy)
Severe peripheral vascular or cerebrovascular disease:
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–
Peripheral vascular disease not amenable to surgical or percutaneous
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therapy
•
–
Symptomatic carotid stenosis
–
Ankle brachial index < 0.7
–
Uncorrected abdominal aortic aneurysm > 6 cm
Morbid obesity (body mass index > 35 kg/m2) or cachexia (body mass index < 18 kg/m2)
•
Creatinine > 2.5 mg/dL or creatinine clearance < 25 mL/min
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Bilirubin > 2.5 mg/dL, serum transaminases > 3x, INR > 1.5 off warfarin
•
Severe pulmonary dysfunction with FEV1 < 40% normal
•
Recent pulmonary infarction within 6 to 8 weeks
•
Difficult to control hypertension
•
Irreversible neurologic or neuromuscular disorder
•
Active mental illness or psychosocial instability
•
Drug, tobacco, or alcohol abuse within 6 months
•
Heparin induced thrombocytopenia within 100 days
Systems Based Assessment
Neurologic
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•
Patients with end stage heart failure may have neurologic complications of a chronic low
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cardiac output state, manifested by encephalopathy or overt cerebrovascular accident (CVA). If encephalopathy is severe, patients may presents for surgery intubated, preventing a thorough preanesthetic evaluation.
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An assessment of the patient’s baseline neurologic function should be obtained, focusing on mental status, gross motor and sensory function. Note should be made of any significant
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deficits so that any alterations from baseline can be assessed post surgically. Severe, symptomatic cerebrovascular disease, defined as prior transient ischemic attack (TIA) or CVA may be a contraindication to transplantation [5, 6]. Patients with history of TIA or CVA are also at an increased risk for further cerebrovascular events and have higher long term rates of death [6]. However, prior TIA or CVA does not appear to increase the rate of death after OHT [6, 7]. Depression is known to have a higher incidence in heart failure patients, with some metaanalyses indicating a prevalence of up to 40% [8]. Depression is also an independent predictor of
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mortality and patients are frequently managed with anti-depressant therapy. The anesthesiologist should be aware of what pharmacologic therapy the patient is on, as this may have implications for the intraoperative and postoperative management. Specifically, many anti-depressant
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therapies will impair the uptake of serotonin and may predispose patients to serotonin syndrome; particularly if they are treated for vasoplegic syndrome with methylene blue [9].
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Cardiovascular
Patients presenting for OHT or MCS implantation have severe, end stage heart failure
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that has failed medical management. Non-ischemic cardiomyopathy, ischemic cardiomyopathy, valvular cardiomyopathy, congenital heart disease, and need for redo-transplantation are the commonest indications [5].
These patients are often managed on continuous inotrope and vasopressor infusions, intravenous diuretics, and in severe cases, mechanical assist devices such as IABP
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counterpulsation, percutaneous temporary ventricular assist devices or implanted ventricular assist devices, which were placed as a bridge to transplantation (BTT). Their medication regimen is complex and involves diuretics, afterload reducers, vasodilators, anti-arrhythmics, and
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anticoagulants. Patients also frequently have cardiovascular implantable electronic device (CIED). Continuous inotrope infusions are usually administered via a peripherally inserted central
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catheter (PICC) or via standard central venous lines (CVL). Many patients are deemed too critical to be managed at home and are hospitalized long-term until a suitable donor heart becomes available. This may predispose them to an increased infection risk due to the presence of the indwelling lines described above or other chronic catheters and drains associated with the management of critically ill patients.
Diagnostic testing
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All patients presenting for OHT or MCS implantation will have had echocardiographic assessment of cardiac function as well as angiography to assess for coronary anatomy and pulmonary hypertension. Attention should be paid to the level of pulmonary hypertension that is
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present and if it is reversible with vasodilator or other medical therapies. There are 3 main classes of pulmonary vasodilating agents: prostacyclins, endothelin receptor antagonists, and
phosphodiesterase-5 inhibitors. Irreversible significant pulmonary hypertension, defined as
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incidence of donor heart right ventricular failure [4, 5].
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pulmonary vascular resistance > 6 Wood units is a contraindication for OHT, due to increased
Vascular access
As stated above, patients may have long standing PICC or CVL in situ for administration of continuous inotropic infusions. Determining the length of time a line has been in place as well as reviewing the patient’s vascular anatomy will help plan for vascular access for the procedure.
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Patients with long standing inotropic dependence may have stenosis of central veins.
CIED management
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CIEDs will be removed at the end of an OHT. To prevent oversensing, ICD therapy is disabled during OHT and MCS implantation with availability for external defibrillation. Changes
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in pacemaker settings are made and rely on how dependent the patient is on pacing [10].
Medication management
Complex medication regimens are the norm for these patients. The anesthesiologist
should pay particular attention to anticoagulant medications. Patients are often on chronic vitamin-K antagonists or newer, non vitamin-K oral anticoagulants. It is important to note when the last dose was administered and formulate a plan for managing continued anticoagulant effect. Vitamin K can be given for reversal of warfarin. Non vitamin-K oral anticoagulants will have less
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anticoagulant effect 12-24 hours after the last dose, especially if renal clearance is normal. However, due to the urgent nature of OHT, patients present for surgery with evidence of active anticoagulant effect. No guidelines exist for reversal of these newer oral anticoagulants, but a
be indicated in reversing these agents [11].
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Pulmonary
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specific reversal agent does exist for dabigatran. Prothrombin complex concentrates (PCCs) may
Patients with significant intrinsic lung disease are not candidates for OHT but may be
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candidates for MCS as destination therapy. Attention should be paid to diagnostic data, such as pulmonary function tests. Decompensated patients may have significant pulmonary edema and may be intubated prior to presenting for surgery. Appropriate plans should be made as pulmonary compliance will be decreased and intraoperative ventilation and oxygenation may be impaired. Patients with known or suspected obstructive sleep apnea (OSA) should be managed very
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cautiously prior to surgery. If sedation is planned to obtain invasive access, consideration should be given to utilizing continuous positive airway pressure (CPAP) or bi-level positive airway
Renal
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pressure (BiPAP) support.
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Renal dysfunction is one of the most common comorbidities in patients with heart failure [12]. Patients may have renal disease related to heart failure or due to other risk factors for chronic kidney disease (CKD), such as diabetes or chronic hypertension. Renal dysfunction is an independent predictor of mortality and rehospitalization in patients with heart failure and the prevalence of CKD approaches 30% in patients with heart failure [12, 13]. The presence of concomitant heart failure and renal dysfunction has been termed as “cardiorenal syndrome” [12]. This complex syndrome is due to congestion, chronic low cardiac output state, inflammation, chronic anemia and neurohormonal activation [12].
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Chronic or acute heart failure
Cardiovascular risk factors
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Chronic kidney disease
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Figure 2
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Cardiorenal syndrome
Estimated glomerular filtration rate (eGFR) should be evaluated. Decreased creatinine
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clearance, defined as eGFR < 30 mL/min, is a relative contraindication to OHT alone and may require combined OHT and renal transplantation [5]. Renal biopsy is common in these patients to
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differentiate between intrinsic renal disease, which may require combined OHT and renal transplantation, and renal disease secondary to chronic HF. This decision regarding combined transplantation is made prior to the patient presenting for surgery.
Gastrointestinal and Hepatic
Patients with end stage heart failure often have concomitant liver disease. This can range from mild liver injury to severe cardiac cirrhosis. Chronically elevated right-sided pressures lead
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to hepatic congestion, which is manifested as elevated transaminases and can progress to hepatomegaly with ascites [14]. Hypoperfusion and chronic medication effect are also implicated
Table 4. Type of hepatic injury in end stage heart failure: Result
Cholestatic
Elevated bilirubin and alkaline phosphatase
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Type of injury
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in liver disease in HF patients [15].
Hepatocellular Elevated transaminases (alanine aminotransferase [ALT] and aspartate
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aminotransferase [AST]
Milder liver injury can reverse with OHT or MCS implantation but patients with severe liver disease are contraindicated for surgery due to high morbidity and mortality [14]. Acute cardiogenic liver injury, also known as ischemic hepatitis, is described as critical hypoperfusion
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coupled with venous congestion [15]. Select patients may be candidates for combined OHT and liver transplantation, which is pre-determined as in the case of combined OHT and renal transplantation. Similar to patients with combined cardiac and renal disease, liver biopsy may be
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Hematologic
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performed to aid in determining appropriate transplant listing.
Hematologic derangements can range from anemia due to cardiorenal syndrome and
volume overload to thrombocytopenia due to liver disease [12, 14]. Even significant anemia and thrombocytopenia is managed conservatively in the pre-surgery period, to minimize exposure of patients to potential antigens and reduce the chances of antibody formation. Sensitized patients, with high panel reactive antibody levels, may be contraindicated to OHT as the pool of available organs will be limited and post transplant outcomes are worse [16].
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Endocrine
Diabetes mellitus (DM) is frequent in prevalence in patients with HF, up to 40% [17]. Cardiovascular disease is the leading cause of death in patients with DM, with up to 75% of
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diabetics dying of cardiovascular disease [17]. Achieving glycemic control is a mainstay of HF management in ambulatory and hospitalized patients. Assessment of the glycosylated hemoglobin (HbA1C) will inform as to the patient’s glycemic control in the prior 3 months [17].
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Alterations in normal thyroid function are clearly linked to cardiovascular disease [18].
Thyroid hormone receptors are present in myocardial and vascular endothelial cells and thyroid
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hormones directly affect the heart, exerting inotropic and chronotropic effects [18]. Even subclinical hypo- or hyperthyroidism can have deleterious effects on cardiac function [18]. Medications commonly used in managing severe HF are implicated in derangements from normal thyroid function, particularly amiodarone and dopamine [18]. It is known that T3 levels are decreased in the immediate post-operative period after coronary artery bypass graft (CABG)
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surgery and small studies have shown decreased mortality in CABG patients treated with T3 [18]. Pre-operative assessment of thyroid function, particularly in patients chronically on medical therapy known to interfere with normal thyroid parameters, should be performed. Some centers
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advocate for the use of T3 in the in the post-operative period for OHT patients.
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Infectious Disease
Pre-surgery infectious complications are increasing due to the use of in-dwelling
catheters for continuous inotropic and vasopressor support and increase in rate of patients with MCS presenting for OHT [20]. If patients are on current antimicrobial therapy, that regimen should be continued in the pre-surgical period. Patients with chronic viral diseases, such as human immunodeficiency virus (HIV) or hepatitis B or C viruses, are eligible for OHT, if their disease is well-managed and without evidence of significant complications. In the case of HIV, for example, compliance with anti-
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retroviral therapy with stable and adequate CD4 cell counts is mandatory for consideration for OHT [5]. In patients with chronic hepatitis B or C infections, liver biopsy is performed to rule out severe liver disease [5]. Presence of cirrhosis, hepatocellular carcinoma or portal hypertension is
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contraindications to OHT [5].
Laboratory data
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After completing a review of the above organ systems and determining the severity of
any comorbid conditions, attention should turn to review of the patient’s most recent laboratory
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values. These values will vary in detail, dependent on the patient’s acuity. Hospitalized, inotropeand vasopressor-dependent patients may have mixed venous oxygen saturation, in addition to frequent arterial blood gases if the patient is intubated and mechanically ventilated. Chronic hyponatremia due to volume overload is common. Other abnormalities are usually related to specific organ system dysfunction; elevated creatinine in cardiorenal or medical renal disease, for
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example.
Table 5. Below is a summary of common laboratory value derangements: Etiology
Anemia
Chronic volume overload
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Abnormal laboratory value
Iron deficiency
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Chronic kidney disease
Elevated creatinine
Sodium derangements
Chronic kidney disease Medication effect Cardiorenal syndrome Hyponatremia: Chronic volume overload, diuretic use Hypernatremia: Free water loss, poor water intake
Potassium derangements
Hypokalemia: diuretic use
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Hyperkalemia: chronic kidney disease, medication effect Hyperglycemia
Diabetes mellitus, insulin resistance
Low albumin
Chronic kidney disease, chronic liver disease, poor nutritional
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status Transaminitis
Liver congestion or cirrhosis, medication effect
Abnormal thyroid function
Medication effect
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tests Medication effect, liver disease
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Elevated INR
Imaging studies
At a minimum, patients presenting for OHT or MCS implantation will have had transthoracic echocardiography, left and right heart catheterization, and chest radiography
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performed. Review of this data is important for development of an anesthetic plan. Other imaging will be obtained dependent on specific comorbidities; carotid ultrasound in patients with known
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or suspected cerebrovascular disease, for example.
Focused Physical Exam and Interview
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Once relevant information has been obtained and reviewed, the cardiac anesthesiologist
should perform a focused interview and physical exam. NPO status should be determined; due to the urgent nature of OHTs, strict fasting may not be possible and the anesthesiologist should be prepared for a potential full stomach patient. A thorough airway examination should be performed and concerns for possible difficult airway noted. If a difficult airway is anticipated, plans should be made according to the American Society of Anesthesiologists (ASA) difficult
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airway algorithm [19] or other regional medical society recommendations for the management of the difficult airway. The remainder of the exam should focus on assessing the severity of the patient’s heart
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failure: signs such as jugular venous distension, dyspnea, orthopnea, peripheral edema are all evidence of significant volume overload that may limit the patient’s position during induction and venous access placement.
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The anesthesiologist should also inquire as to the patient’s current medication regimen
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and any missed doses, which may lead to worsening hemodynamics.
Sedation
Pre-surgery sedation should be used cautiously in patients presenting for OHT or MCS implantation. These patients may have tenuous cardio-pulmonary reserve and even modest sedation may cause significant hemodynamic and respiratory compromise. This is also important
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in the event the transplant is cancelled due to donor organ issues as sedation may preclude discharging a patient back to their previous care setting.
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Management of Immunosuppressants
Immunosuppression options for patients undergoing transplantation have evolved over
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the years. As a result of these advancements, 1-year survival after cardiac transplantation approaches 90%, with 50% of patients surviving >11 years [1]. Table 6. Triple drug therapy is the mainstay for immunosuppression in OHT [20]: Calcineurin inhibitors
Cyclosporine or tacrolimus
Steroids
Prednisone
Anti-metabolites
Mycophenolate mofetil
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Calcineurin inhibitors function to block T cell activation. Steroids decrease inflammation and prevent the proliferation of T cells, B cells and antigen presenting cells. Mycophenolate mofetil also blocks the proliferation of T and B cells [20]. Calcineurin inhibitors in particular are
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known nephrotoxins, leading to decreased glomerular filtration rate. To help mitigate this effect, monoclonal or polyclonal antibodies against T cells are used as induction immunosuppression therapy. These agents are antithymocyte polyclonal antibody (ATG) or interleukin 2 receptor
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monoclonal antibody (basiliximab) [20].
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Conclusion
Orthotopic heart transplantation remains the gold standard for patients with advanced heart failure. These patients can represent a challenge due to multisystem involvement, which results because of the effects of heart failure. A thorough evaluation should be performed including a review of organ systems, medications, lab values and physical examination.
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Although advancements have been made in the field of heart transplantation, the biggest challenge remains that the number of patients in need of transplants far outweighs donor heart availability. Mechanical circulatory support (MCS) devices have facilitated the treatment of this
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patient population. Continued development of current therapies is needed in the treatment of
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advanced heart failure.
Practice Points •
Every organ system in patients undergoing heart transplantation should be carefully assessed on the day of surgery
•
Sedation should be used cautiously
•
Close attention should be paid to the immunosuppression regimen in patients undergoing heart transplantation
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•
Management of the patient’s coagulation status should be formulated and discussed with the surgical team
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Research Agenda
The demand for hearts drastically outnumbers the current supply; studies into how to
expand the donor pool would be beneficial to the field of heart transplantation and would
•
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ultimately save lives
Although there have been major advancements in immunosuppressive therapy, continued
are needed •
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research into limiting the side effects of these drugs and improving overall graft survival
Continued improvement in the treatment of heart failure is still needed as this would ultimately decrease the number of patients requiring heart transplants
•
Research in the area of stem cells may be helpful in restoring damaged cardiac cells and
•
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improving overall heart function
Continued research and development in the area of mechanical circulatory support
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devices will also be helpful in decreasing the recipient pool
Conflict of interest:
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None.
References:
1. Mancini D, Lietz K. Selection of cardiac transplantation candidates in 2010. Circulation 2010; 122 (2): 173-83. 2. Mazurek JA, Jessup M. Understanding heart failure. Heart Failure Clin 2017; 13: 1-19.
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3. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused Update: ACCF/AHA guidelines for the diagnosis and management of heart failure in adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on practice
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guidelines: Developed in collaboration with the international society for heart and lung transplantation. Circulation 2009; 119: 1977-2016.
4. McMurray JJ, Adamopoulos S, Anker SD, et al. European Society of Cardiology
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Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The
task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the
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European Society of Cardiology. Developed in collaboration with the heart failure association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803-69. 5. Mehra MR, Canter CE, Hannan MM et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016; 35 (1): 1-23.
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6. Patlolla V, Mogulla V, DeNofrio D et al. Outcomes in patients with symptomatic cerebrovascular disease undergoing heart transplantation. JACC 2011; 58 (10): 1036-41. 7. Taylor DO, Stehlik J, Edwards LB et al. Registry of the International Society for Heart
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and Lung Transplantation: Twenty-sixth Official Adult Heart Transplant Report-2009. J Heart Lung Transplant 2009; 28: 1007-22.
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8. Angermann CE, Gelbrich G, Störk S et al. Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: The MOOD-HF randomized clinical trial. JAMA 2016; 315 (24): 2683-93.
9. Wolvetang T, Janse R, H MT. Serotonin syndrome after methylene blue administration during cardiac surgery: A case report and review. J Cardiothorac Vasc Anesth 2016; 30 (4): 1042-45.
10. Crossley GH, Poole JE, Rozner MA et al. The Heart Rhythm Society (HRS)/American Society of Anesthesiologists (ASA) Expert Consensus Statement on perioperative
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management of patients with implantable defibrillators, pacemakers and arrhythmia monitors: Facilities and patient management. Heart Rhythm 2011; 8 (7): 1114-54. 11. Aronis KN, Hylek EM. Who, when, and how to reverse non-vitamin K oral
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anticoagulants. J Thromb Thrombolysis 2016; 41: 253-72. 12. Carubelli V, Lombardi C, Gorga E et al. Cardiorenal interactions. Heart Failure Clin 2016; 12: 335-47.
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13. Cleland JGF, Carubelli V, Castiello T et al. Renal dysfunction in acute and chronic heart failure: Prevalence, incidence and prognosis. Heart Failure Rev 2012; 17: 133-49.
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14. Pendyal A, Gelow JM. Cardiohepatic interactions: Implications for management in advanced heart failure. Heart Failure Clin 2016; 12: 349-61.
15. Samsky MD, Patel CB, DeWald TA et al. Cardiohepatic interactions in heart failure: An overview and clinical implications. JACC 2013; 61: 2397-405. 16. Al-Mohaissen MA, Virani SA. Allosensitization in heart transplantation: An overview.
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Can J Cardiol 2014; 30: 161-72.
17. Mancini GBJ, Cheng AY, Connelly K et al. Diabetes for cardiologists: Practical issues in diagnosis and management. Can J Cardiol 2017; 33: 366-77.
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18. Jabbar A, Pingitore A, Pearce SHS et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 2017; 14: 39-55.
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19. Practice Guidelines for Management of the Difficult Airway: An updated report by the American Society of Anesthesiologists Task Force on management of the difficult airway. Anesthesiology 2013; 118 (2): 251-70.
20. Ramakrishna H, Rehfeldt KH, Pajaro OE. Anesthetic pharmacology and perioperative considerations for heart transplantation. Curr Clin Pharmacol 2015; 10 (1): 3-21.