Anesthetic considerations after heart transplantation

INTRODUCTION — In the United States, the number of heart transplants has increased during the past several years, with more than 3000 performed in 2018 [1,2]. While the majority are performed in adult recipients, approximately 600 to 700 occur in patients <18 years old. Due to the high rate of survival and increased life expectancy, adult and pediatric patients with heart transplants are likely to present for an elective or emergency noncardiac surgical procedure post-transplantation.

Heart transplant recipients present unique anesthetic challenges that include altered autonomic physiology and response to medications due to denervation of the donor heart, side effects of chronically administered immunosuppressive medications, and medical comorbidities. This topic will discuss anesthetic and perioperative management for heart transplant recipients who subsequently undergo a noncardiac surgical procedure. A separate topic addresses anesthetic management for heart transplantation surgery. (See "Anesthesia for heart transplantation".)

PREANESTHETIC ASSESSMENT

General concerns for heart transplant recipients — In adult patients, the one-year survival rate after heart transplantation is about 90 percent and the five-year rate is about 70 percent; however, only about 20 percent survive ≥20 years [3]. In pediatric patients, the one-year survival rate is approximately 80 to 90 percent and the five-year survival rate is 70 to 80 percent [4]. Some pediatric transplant recipients are in their 20s after heart transplantation and are in relatively good health. Such patients may eventually need a noncardiac surgical procedure. Several small studies have reported that 15 to 47 percent of heart transplant recipients subsequently undergo one or more noncardiac surgical procedures [5-7]. One retrospective study that included 207 post-transplantation patients noted that 35 percent subsequently underwent noncardiac surgery, and that urological procedures were the most commonly performed cases [8].

Both adult and pediatric cardiac transplant patients have complex medical considerations that require detailed assessment before planned noncardiac surgery. As noted below, specific concerns typically differ for patients in the early post-transplant period (first 6 to 12 months) compared with the later period (after 12 months). Preoperative assessment is accomplished in conjunction with the patient's heart transplant management team. Consultation is particularly important if a surgical procedure is necessary in the first 6 to 12 months after transplantation.

Early post-transplantation period (6 to 12 months) — During the first 6 to 12 months after transplantation, elective surgical procedures are deferred. During this period, patients have a greater risk of complications including:

●Acute rejection – Acute graft dysfunction secondary to rejection and ischemic injury often manifests as right ventricular dysfunction. During the preoperative assessment, tests of graft function are reviewed, including electrocardiograms, echocardiograms, angiograms, surveillance biomarkers such as B-type natriuretic peptide, endomyocardial biopsy results, and/or gene expression profiling. (See "Heart transplantation in adults: Graft dysfunction".)

●Immunosuppression-related complications – Immunosuppressive medications are generally targeted at a higher therapeutic level during the first three to six months after cardiac transplantation, typically necessitating adrenal suppression prophylaxis (see 'Adrenal suppression prophylaxis' below). Notably, immunosuppression-related complications such as renal dysfunction from calcineurin inhibitors, steroid-induced diabetes, steroid-induced myopathy, leukopenia, and infection are more likely during this early post-transplantation period. Ideally, the patient should be on a stable immunosuppressive regimen prior to scheduling elective surgery. (See "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy".)

●Infection – Immunosuppressive therapy increases infection risk. When feasible, surgery is deferred until any active infection has been treated. (See "Infection in the solid organ transplant recipient".)

●Exacerbation of comorbidities

•Renal dysfunction – Preoperative renal insufficiency is often present as chronic renal hypoperfusion is common due to pre-transplantation heart failure. Other risk factors include post-transplantation nephrotoxic immunosuppressive regimes and repeated exposure to contrast media during cardiac catheterization procedures. The baseline creatinine level and glomerular filtration rate are noted, as well as urinalysis and spot urine albumin/creatinine ratio.

•Liver dysfunction – Congestive hepatopathy is often present due to pre-transplantation heart failure, with variable improvement post-transplantation due to improved cardiac output. In particular, liver disease after a previous Fontan procedure followed by heart transplantation may be severe with congestive hepatopathy and fibrosis or cirrhosis (see "Management of complications in patients with Fontan circulation", section on 'Liver disease'). Also, patients with arrhythmias may be taking hepatotoxic medications such as amiodarone. The standard model for end-stage liver disease (MELD) scores are useful in determining severity of liver disease prior to noncardiac surgery in adult patients. (See "Model for End-stage Liver Disease (MELD)".)

Liver function studies are reviewed during the preoperative assessment. These include the prothrombin time and international normalized ratio to assess potential liver-related coagulopathy, as well as bilirubin, aspartate aminotransferase, and alanine transaminase.

•Other common acute or chronic comorbidities. (See "Heart transplantation in adults: Prognosis", section on 'Medical conditions after cardiac transplantation that may affect outcome'.)

-Steroid-induced diabetes mellitus.

-Hypertension requiring treatment with antihypertensive therapy (typically angiotensin-converting enzyme inhibitors or angiotensin receptor blockers).

-Pulmonary diseases (eg, restrictive lung disease, reactive airway disease, recurrent pneumonias). A history of prolonged ventilatory support suggests underlying pulmonary dysfunction and risk for postoperative respiratory failure. The chest radiograph and any pulmonary function testing results are reviewed during the preanesthetic assessment.

-Congenital anomalies in patients who have congenital heart disease (CHD). Examples include airway abnormalities, hypotonia, and pectus excavatum.

Late post-transplantation period (>12 months) — After approximately one year post-transplantation, risk of acute rejection has diminished, and the immunosuppressive regimen has usually stabilized. Primary concerns during this period include:

●Allograft vasculopathy – Allograft vasculopathy is a fibrous concentric intimal hyperplasia that extends for the length of the coronary arteries and is the predominant risk for graft dysfunction and chronic rejection in the late post-transplantation period. Right ventricular dysfunction, tricuspid regurgitation due to right ventricular dilation, and/or biventricular diastolic and systolic dysfunction may be noted on echocardiography. Patients with allograft vasculopathy are at risk for myocardial ischemia, intravascular volume overload, or arrhythmias during noncardiac procedures. As in the early post-transplantation period, cardiac studies are reviewed, including echocardiograms, angiograms, and the results of right heart catheterization and endomyocardial biopsy. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy" and "Heart transplantation in adults: Graft dysfunction".)

●Stability of the current immunosuppressive regimen – Typically, the immunosuppression regimen is stabilized in the first 6 months. Immunosuppression-related complications are less likely after the first 6 to 12 month period. (See "Heart transplantation in adults: Induction and maintenance of immunosuppressive therapy".)

●Risk of malignancy including post-transplant lymphoproliferative disease – Due to high-dose immunosuppression, malignancies are common in both children and adults after heart transplantation. Since these malignancies may involve the airway, careful examination for symptoms or signs of airway obstruction or potential difficulty with airway management is necessary. Details are discussed separately. (See "Approach to the difficult airway in adults for emergency medicine and critical care", section on 'Identifying the anatomically difficult airway' and "Management of the difficult airway for pediatric anesthesia", section on 'Prediction of the pediatric difficult airway'.)

●Overall level of activity and exercise tolerance – These serve as indirect measures of cardiopulmonary function. In pediatric patients, normal growth and puberty progression is similar to age-matched non-transplant recipients in the absence of high-dose steroid therapy.

ANESTHETIC MANAGEMENT AFTER PREVIOUS HEART TRANSPLANTATION

Special considerations after heart transplantation — There are several distinct changes in pharmacology and hemodynamic physiology after cardiac transplantation.

Hemodynamic effects of denervation of the heart — Cardiac autonomic denervation occurs due to explantation of the native heart during transplantation. This results in loss of autonomic nervous system innervation for both the parasympathetic and sympathetic responses. Visceral innervation is also lost. The following effects are evident:

●The graft heart usually has a higher resting heart rate (HR) at 90 to 130 beats per minute compared with a native heart due to lack of parasympathetic innervation, although HR may vary depending on the age of the graft.

●Valsalva maneuvers and carotid massage are not effective.

●Baroreceptor reflexes (eg, during tracheal intubation) are lost.

●The Starling effect is retained such that the denervated heart responds to increases in preload with an increase in stroke volume and cardiac output.

●During episodes of myocardial ischemia, classic chest pain may not be experienced due to absent visceral innervation.

●The denervated heart is extremely dependent on adequate intravascular volume and preload. Although a compensatory reflex sympathetic tachycardic response cannot be mounted due to autonomic denervation, the Starling effect remains intact such that the heart will respond to increases in preload with increases in stroke volume and cardiac output. Administration of a direct-acting vasopressor agent is also effective to treat hypotension.

Pharmacologic changes after denervation of the heart — Responses to commonly used vasoactive agents and antiarrhythmic agents are affected by denervation of the transplanted heart:

●Indirectly-acting vasopressor agents that exert their effects via the autonomic nervous system (eg, ephedrine) are ineffective, but direct-acting agents (eg, phenylephrine) remain effective because the intrinsic alpha and beta receptors in the grafted heart are intact.

●Responses to vasodilator agents (eg, nitroglycerin, hydralazine) and to anesthetic agents with vasodilatory effects (eg, propofol) may result in profound hypotension because the compensatory reflex tachycardic response is not present in a transplanted heart. To avoid or minimize hypotension, these agents are administered in small incremental doses or titrated very gradually

●Anticholinergic medications (eg, glycopyrrolate, atropine) will not effectively treat bradycardia, but will retain their effects in noncardiac tissues.

●Direct-acting chronotropic agents (eg, isoproterenol) or techniques (eg, electrical pacing) are effective for treatment of bradyarrhythmias.

●Digoxin (a commonly used antiarrhythmic and inotropic agent) will not have a rate-controlling effect, but will retain its inotropic effect.

●Adenosine, which is a short-acting agent in a native heart, will have a significantly prolonged and profound bradycardic effect on a denervated heart.

Post-transplantation effects of commonly used anesthetic or adjuvant agents include:

●Neuromuscular blocking agents (NMBAs) such as pancuronium and succinylcholine will not exert usual effects on HR, but will retain their extracardiac effects.

●Reversal agents for neuromuscular blockade that are acetylcholinesterase inhibitors such as neostigmine do not cause bradycardia. Nevertheless, rare cases of advanced heart block and asystole have been reported after neostigmine administration to heart transplant recipients [9-13], presumably due to some degree of parasympathetic reinnervation of the transplanted heart after a period of time [14].

The newer reversal agent sugammadex acts via a different mechanism than acetylcholinesterase inhibitors and does not have cholinergic effects. However, it should also be used with caution in heart transplant recipients [15].

Risk of myocardial ischemia — Patients are at risk for myocardial ischemia due to transplant-related coronary artery disease (ie, cardiac allograft vasculopathy). Anesthetic management for patients with cardiac allograft vasculopathy is similar to that for other patients with ischemic heart disease. (See "Anesthesia for noncardiac surgery in patients with ischemic heart disease".)

Airway and ventilation considerations — Oral rather than nasal endotracheal intubation is preferred to minimize infection risk in immunocompromised post-transplantation patients. However, a heightened bleeding risk may still exist, owing to gingival hyperplasia from cyclosporine, increased vascularity of mucosal surfaces due to collaterals in patients with CHD, and any chronically administered anticoagulant medications.

After intubation, hyperventilation is avoided because calcineurin inhibitors (ie, cyclosporin, tacrolimus) administered as part of the immunosuppression regimen may decrease seizure thresholds.

Adrenal suppression prophylaxis — Almost all heart transplant recipients patients have a high likelihood of adrenal suppression due to chronic prednisone administration. Supplemental glucocorticoids are given in accordance with the magnitude of the anticipated stress of the procedure (table 1). Notably, the usual morning oral dose of glucocorticoid is always administered, regardless of whether additional glucocorticoid will be given just prior to the procedure. (See "The management of the surgical patient taking glucocorticoids", section on 'Perioperative glucocorticoids'.)

Surgical infection prophylaxis — Antibiotic prophylaxis is administered according to institutional protocols. However, aminoglycosides and erythromycin are avoided due to the risk of renal injury when used with calcineurin inhibitors. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults".)

Monitoring considerations

●Electrocardiogram (ECG) – ECG abnormalities are common including:

•Dual P waves due to the presence of native atrial cuff tissue and the transplanted atrium, which each generate electrical activity.

•Right bundle branch block due to frequent endomyocardial biopsies, which is present in up to 75 percent of transplant recipients.

•Atrial dysrhythmias due to the lack of vagal tone and increased endogenous catecholamine levels.

●Use of invasive cardiovascular monitoring – Intraoperative invasive hemodynamic monitors (eg, intra-arterial blood pressure, central venous pressure, transesophageal echocardiography, or less frequently, a pulmonary artery catheter) are indicated if significant blood loss or large intravascular volume shifts are anticipated, particularly in post-transplant patients with evidence of cardiac dysfunction. Notably, frequent use of the right internal jugular vein for right heart catheterization and endomyocardial biopsy in post-transplantation patients may result in significant scarring and/or occlusion of this vessel. In general, the decision to use these additional monitors is guided by the same clinical considerations in cardiac transplant patients as would be used in other surgical patients.

Fluid and hemodynamic management — It is critically important to avoid perioperative hypovolemia so that the transplanted heart has a mechanism to augment cardiac output in response to volume losses or vasodilation. Any loss of intravascular volume such as rapid blood loss or large fluid shifts must be immediately treated with volume administration to avoid decreased preload and significant hemodynamic instability. Some centers adjust anti-rejection medications when multiple units of blood products are transfused during the surgical procedure (eg, administration of pulse-dose methylprednisolone during the intraoperative and early postoperative periods) [16].

Severe hypotension can occur due to vasodilation after administration of certain intravenous or inhalation anesthetic agents or a neuraxial anesthetic technique. Administration of direct-acting vasopressors (eg, phenylephrine, norepinephrine, vasopressin) is often necessary to treat hypotension. (See 'Hemodynamic effects of denervation of the heart' above.)

Choice of anesthetic technique

Monitored anesthesia care or peripheral nerve blocks — Monitored anesthesia care with local anesthesia or a regional anesthetic technique, with or without light sedation, are acceptable anesthetic techniques when appropriate for selected planned noncardiac surgical procedures. An advantage of these techniques is absent or minimal hemodynamic consequences in heart transplant recipients.

Neuraxial anesthesia — Epidural or spinal neuraxial anesthetic techniques are also acceptable when appropriate for the planned surgical procedure. However, spinal or epidural blockade may cause severe hypotension in a post-transplant patient due to loss of sympathetic tone in the absence of normal compensatory reflexes that increase HR and preserve cardiac output (see 'Hemodynamic effects of denervation of the heart' above). Thus, a severe decrease in systemic vascular resistance may occur, with marked vasodilation, venous pooling, and decreased venous return to the heart. Pretreatment with infusion of crystalloid or colloid fluid (typically 500 to 1000 mL) at the time of placement of a neuraxial needle or catheter, in conjunction with administration of a direct-acting vasopressor such as phenylephrine, may maintain preload and vascular tone to mitigate or avoid hypotension. (See "Overview of neuraxial anesthesia", section on 'Cardiovascular' and "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Hypotension'.)

General anesthesia — If general anesthesia is selected, the risk of hypotension during induction can be reduced by ensuring that intravascular volume status is adequate before anesthetic induction. Administration of a direct-acting vasopressor agent may also be necessary. (See 'Hemodynamic effects of denervation of the heart' above.)

Also, anesthetics are administered in incremental small bolus doses or are carefully titrated via inhalation or continuous intravenous infusion, particularly those agents with known vasodilatory properties. Examples include intravenous propofol, dexmedetomidine, or the potent volatile inhalation agents sevoflurane or isoflurane. (See 'Hemodynamic effects of denervation of the heart' above.)

For patients with hepatic or renal dysfunction, we select the NMBA cisatracurium because of its organ-independent metabolic profile via Hoffman elimination (see "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Cisatracurium'). General dosing considerations for anesthetic and adjuvant agents in patients with hepatic or renal dysfunction are discussed separately. (See "Anesthesia for the patient with liver disease", section on 'Effects of liver disease on anesthetic drug administration' and "Anesthesia for dialysis patients" and "Anesthesia for dialysis patients", section on 'General anesthesia'.)

EARLY POSTOPERATIVE COMPLICATIONS — Limited data are available regarding outcomes of post-cardiac transplantation patients undergoing noncardiac surgical procedures.

●Infection – Patients are closely monitored for infection in the postoperative period. Bacterial infections such as sternal wound infections, pneumonia, and urinary tract infections are a significant risk even in patients who are not undergoing a surgical procedure, particularly in the early post-transplantation period (see 'Early post-transplantation period (6 to 12 months)' above). One retrospective study that included 116 noncardiac surgical procedures performed after previous heart transplantation noted that infection occurred in 7 percent of these procedures and was the most common postoperative complication [8].

●Exacerbation of renal or hepatic dysfunction - Patients are susceptible to exacerbation of chronic renal or hepatic insufficiency during and after additional surgical procedures performed after heart transplantation.

SUMMARY AND RECOMMENDATIONS

●Special concerns after heart transplantation – Both adult and pediatric cardiac transplant patients have altered autonomic physiology and response to medications due to denervation of the donor heart, as well as side effects of chronically administered immunosuppressive medications, and complex medical comorbidities that require detailed assessment before planned noncardiac surgery. Preoperative assessment is accomplished in conjunction with the patient's heart transplant management team. (See 'General concerns for heart transplant recipients' above.)

●Concerns in the first 6 to 12 months – During the first 6 to 12 months after transplantation, elective surgical procedures are deferred because patients have a greater risk of complications including (see 'Early post-transplantation period (6 to 12 months)' above):

•Acute graft dysfunction due to rejection

•Immunosuppression-related complications

•Infection

•Exacerbation of comorbidities

-Renal dysfunction

-Liver dysfunction

-Other common acute or chronic comorbidities (eg, steroid-induced diabetes mellitus, hypertension, pulmonary diseases, congenital anomalies)

●Concerns after 12 months – After approximately one year following heart transplantation, primary concerns differ and include (see 'Late post-transplantation period (>12 months)' above):

•Allograft vasculopathy with myocardial ischemia

•Stability of the current immunosuppressive regimen

•Overall level of activity and exercise tolerance as indirect measures of cardiopulmonary function

●Pharmacologic alterations – Cardiac autonomic denervation occurs during transplantation, resulting in loss of autonomic nervous system innervation for both the parasympathetic and sympathetic responses, as well as loss of visceral innervation. Thus, only direct-acting vasoconstrictor agents (eg, phenylephrine, vasopressin) or chronotropic agents (eg, isoproterenol) are effective, while indirect-acting agents (eg, ephedrine) and anticholinergic agents (eg, atropine) are not effective. Also, hypotensive responses to vasodilator agents (eg, nitroglycerin, hydralazine) may result in profound hypotension. (See 'Pharmacologic changes after denervation of the heart' above.)

●Hemodynamic considerations – It is critically important to avoid perioperative hypovolemia so that the transplanted heart has a mechanism to augment cardiac output (CO) in response to volume losses or vasodilation. Losses of intravascular volume such as rapid blood loss or large fluid shifts are immediately treated with volume administration. Also, severe hypotension can occur due to vasodilation after administration of certain intravenous or inhalation anesthetic agents or a neuraxial anesthetic technique. Administration of direct-acting vasopressors (eg, phenylephrine, norepinephrine, vasopressin) is often necessary to treat hypotension. (See 'Hemodynamic effects of denervation of the heart' above and 'Fluid and hemodynamic management' above.)

●Monitoring considerations – We typically use intraoperative invasive hemodynamic monitors (eg, intra-arterial blood pressure, central venous pressure, transesophageal echocardiography, or less frequently, a pulmonary artery catheter) if significant blood loss, large intravascular volume shifts are anticipated, particularly when cardiac dysfunction exists. (See 'Monitoring considerations' above.)

●Choice of anesthetic technique

•Monitored anesthesia care with local or regional anesthesia – Monitored anesthesia care or regional anesthetic techniques such as peripheral nerve block(s) with or without light sedation are acceptable techniques when appropriate for selected planned noncardiac surgical procedures, having the advantage of absent or minimal hemodynamic consequences in heart transplant recipients. (See 'Monitored anesthesia care or peripheral nerve blocks' above.)

•Neuraxial anesthesia – Neuraxial (ie, spinal or epidural) anesthesia may result in severe hypotension from decreases in systemic vascular resistance, venous pooling, and decreased venous return to the heart due to sympathetic blockade in the absence of a compensatory tachycardic response and ability to preserve CO. (See 'Neuraxial anesthesia' above.)

●General anesthesia – If general anesthesia is selected, we reduce the risk of hypotension during induction by ensuring that intravascular volume status is adequate and administering a direct-acting vasopressor agent if necessary. Also, anesthetics are administered in incremental small bolus doses or are carefully titrated via inhalation or continuous intravenous infusion, particularly those agents with known vasodilatory properties. (See 'General anesthesia' above.)