Conference Lectures

ANAESTHESIA FOR HEART TRANSPLANTATION

 

The first human cardiac transplant was done by Christian Barnard in 1966. By the early 1980s, cardiac transplantation gained widespread acceptance as a realistic option for patients with end-stage heart failure and cardiomyopathy.   Heart transplantation experienced explosive growth in the mid-to-late 1980s, but the annual number of heart transplants worldwide reached a plateau by the early 1990s at approximately 3500 per year. The factor limiting continued growth has been a shortage of suitable donors.

Adult patients on the heart transplant waiting list are assigned a status of 1A, 1B, or 2 as follows: (i)status 1A patients require mechanical circulatory support, mechanical ventilation, high-dose or multiple inotropes, with continuous monitoring of left ventricular filling pressure,(ii) status 1B patients require mechanical circulatory support beyond 30 days or inotropic support without continuous monitoring of left ventricular filling pressure, (iii) all other patients are classified as status2.

Indications  For Adult Cardiac Transplantation Idiopathic dilated cardiomyopathy Ischemic cardiomyopathy Viral cardiomyopathy Systemic diseases e.g.- amyloidosis Complex congenital heart disease

The 1-year survival rate after heart transplantation is reported to be 79%, with a subsequent mortality rate of approximately 4%/year. One-year survival rate after repeat heart transplantation more than 6 months after the original procedure is slightly lower (63%) but substantially worse if performed within 6 months of the original grafting (39%).

 

 

Risk Factors for mortality in cardiac transplantation
Recipient Factors	Medical Center Factors	Donor Factors
prior transplantation poor human leukocyte antigen matching ventilator dependence age race	volume of heart transplants performed ischemic time	Race Sex age

Cause of death after Cardiac transplantation
Early deaths	Intermediate-Term Deaths	Late death
graft failure	acute rejection infection	allograft vasculopathy lymphoproliferative disease malignancy chronic rejection

Recipient Selection
Potential candidates for heart transplantation are subjected to a multidisciplinary evaluation including a complete history and physical examination, electrocardiography, chest radiography, cardiac catheterization, pulmonary function tests, hematology, blood biochemistry( renal and hepatic function), and viral serology. Ambulatory electrocardiography, echocardiography, and nuclear gated scans are performed if necessary. The goals of this evaluation are to confirm a diagnosis of end-stage heart disease that is not amenable to other treatment options and that will likely lead to death within 1 to 2 years, as well as to exclude extracardiac organ dysfunction that could lead to death soon after heart transplantation. Patients typically have New York Heart Association Class IV symptoms and a left ventricular ejection fraction less than 20%.

Contraindications for heart transplantation Physiologic age of <60 years Pulmonary hypertension with the a fixed PVR (PVR > 500dynes) transpulmonary gradient > 15 mm Hg Active infection Recent pulmonary thromboembolism

Donor Selection and Graft Harvest

Requirement for Donor selection Brain death Age <35 years ABO compatibility Normal echocardiography  No CAD (coronary angiography, if needed) Absence of  (i) sepsis (ii) Prolonged cardiac arrest (iii) Severe chest trauma (iv) High inotropic requirement  Size compatibility within 20%

After identification of brain-death, the accepting transplant center is alerted which must further evaluate the suitability of the allograft. Most brain-dead donors are hemodynamically unstable due to the following reasons (i) hypovolemia (secondary to diuretics or diabetes insipidus), (ii) myocardial injury (possibly a result of “catecholamine storm” during periods of increased intracranial pressure),(iii) inadequate sympathetic tone because of brainstem infarction, (iv) abnormalities of neuroendocrine function such as low T3 and T4 levels.

Steps in donor heart harvest median sternotomy Heparinization of donor Cannulation of great vessels for CPB Aorta cross-clamped Cardioplegia delivered SVC, IVC transected Heart cooled Aorta, Pulmonary veins, PA transected Heart excised and transported in ice-cold saline  Ex-vivo storage < 6 hrs

 

Orthotopic Heart Transplantation Orthotopic Heart Transplantation (surgical aspects): Median sternotomy (may be a repeat sternotomy !) Heart arrested with cardioplegia Aorta & PA are dissected & divided above the level of their respectively valves Atria are transected at grooves Donor graft implanted, beginning at LA anastomosis Foramen ovale if patent, is closed Followed by RA, PA and Aorta anastomosis Wearing from CPB

Pathophysiology before Transplantation:
The pathophysiology of heart transplant candidates is largely that of end-stage cardiomyopathy and is as follows:

• Systolic dysfunction, characterized by decreased stroke volume and increased end-diastolic volume and diastolic dysfunction, characterized by an increased LVEDP and LAP.
•  As compensatory mechanisms to maintain CO fail, the increased LV pressures lead to increases in pulmonary venous pressures and development of pulmonary vascular congestion and edema.
• Autonomic sympathetic tone is increased in patients with heart failure, leading to generalized vasoconstriction, as well as salt and water retention.
• Vasoconstriction and ventricular dilation combine to substantially increase myocardial wall tension. In due course of time, the high levels of endogenous catecholamines lead to a decrease in the sensitivity of the heart and vasculature to catecholamines agents by a decrease in receptor density (i.e., “down-regulation”) and a decrease in myocardial norepinephrine stores.
•  Invariably most of these patients receive diuretics; hypokalemia and hypomagnesemia secondary to urinary losses are likely, as well as hypovolemia from excessive diuresis is common.
• Vasodilators (such as nitrates, hydralazine, and angiotensin-converting enzyme inhibitors) decrease impedance to LV emptying and improve cardiac function and survival in patients with end-stage heart failure.
• Digoxin is an effective but weak inotrope, and its use is indicated to control ventricular rate in atrial fibrillation..
•  Phosphodiesterase inhibitors such as milrinone, and enoximone are efficacious, but chronic therapy is restricted by concerns about increased mortality in those receiving these agents.
• Inotrope-dependent patients often are treated with intravenous infusions of β-adrenergic agonists such as dopamine or dobutamine.
• Patients who are refractory to medical measures may be supported with intra-aortic balloon counterpulsation, but its use is fraught with significant vascular complications and essentially immobilizes the patient.
• Many patients with low CO are maintained on anticoagulants such as warfarin to prevent pulmonary or systemic embolization, especially if they have atrial fibrillation.

Pathophysiology after Transplantation:
The physiology of patients after heart transplantation is of interest both  to anesthesiologists in cardiac transplant centers and to the anesthesiology community at large because a substantial portion of these patients return for subsequent surgical procedures.

• Denervation: Denervation does not significantly change baseline cardiac function, but it does substantially alter the cardiac response to demands for increased CO. Normally, increases in heart rate can rapidly increase CO, but this mechanism is not available to the transplanted heart. Heart rate increases only gradually with exercise, and this effect is mediated by circulating catecholamines. Increases in CO in response to exercise are instead mostly mediated via an increase in stroke volume. Therefore, maintenance of adequate preload in cardiac transplant recipients is crucial. Denervation has important implications in the choice of pharmacologic agents used after cardiac transplantation. Drugs that act indirectly on the heart via either the sympathetic (ephedrine) or parasympathetic (atropine, pancuronium, edrophonium) nervous systems generally will be ineffective. Drugs with a mixture of direct and indirect effects will exhibit only their direct effects (leading to the absence of the normal increase in refractory period of the atrio-ventricular node with digoxin, tachycardia with norepinephrine infusion, and bradycardia with neostigmine). Thus, agents with direct cardiac effects (such as epinephrine or isoproterenol) are the drugs of choice for altering cardiac physiology after transplantation. However, the chronically high catecholamine levels found in cardiac transplant recipients may blunt the effect of β-adrenergic agents, as opposed to normal responses to β-adrenergic agents.

• Allograft coronary vasculopathy remains the greatest threat to long-term survival after heart transplantation. Allografts are prone to the accelerated development of an unusual form of coronary atherosclerosis that is characterized by circumferential, diffuse involvement of entire coronary arterial segments, as opposed to the conventional form of coronary atherosclerosis with focal plaques often found in eccentric positions in proximal coronary arteries. Therefore, the anesthesiologist should assume that there is a substantial risk for coronary vasculopathy in any heart transplant recipient beyond the first 2 years, regardless of symptoms, the results of noninvasive testing, and even angiography.

 

Anesthetic Management:
Preoperative Evaluation and Preparation:

• The preoperative period often is marked by severe time constraints because of the impending arrival of the donor heart.
•  quick history should screen for last oral intake, recent anticoagulant use, recent deterioration of ventricular function, or change in pattern of angina;
• A physical examination should evaluate present volume status
•  A laboratory review (if available) and a chest radiograph should detect the presence of renal, hepatic, or pulmonary dysfunction.
•  Placement of invasive monitoring before induction will facilitate rapid and accurate response to hemodynamic events during induction.
•  In addition to standard noninvasive monitoring, an arterial catheter and a PA catheter (with a long sterile sheath to allow partial removal during graft implantation) are placed after judicious use of sedation and local anesthetics.
• Large-bore intravenous access is mandatory, especially if a sternotomy has been previously performed, in which case external defibrillator/pacing patches also may be useful.
•  The overall hemodynamic “picture” should be evaluated and optimized insofar as possible just before induction. If the hemodynamics seem tenuous, then starting or increasing an inotrope infusion may be advisable

Anaesthetic induction:

• Most patients presenting for heart transplantation are not in a fasting state and should be considered to have a “full stomach.” Therefore, the induction technique should aim to rapidly achieve control of the airway to prevent aspiration while avoiding myocardial depression.

• A regimen combining a short-acting hypnotic with minimal myocardial depression (etomidate, 0.3 mg/kg), a moderate dose of narcotic to blunt the tachycardic response to laryngoscopy and intubation (fentanyl, 10 µg/kg), and succinylcholine (1.5 mg/kg) is popular; high-dose narcotic techniques with or without benzodiazepines also have been advocated.
•  Vasodilation should be countered with an α-agonist.
•  Anesthesia is maintained with additional narcotic and sedatives (benzodiazepines)

 

Intraoperative Management

• After induction, the stomach is decompressed with an orogastric tube.
•  A complete TEE examination often will reveal useful information not immediately available from other sources, such as the presence of cardiac thrombi , ventricular volume and contractility, and atherosclerosis of the ascending aorta and aortic arch.
• Cross-matched blood should be immediately available once surgery commences, especially if the patient has had a previous sternotomy; patients not previously exposed to cytomegalovirus should receive blood from donors who are likewise cytomegalovirus negative.
•  Sternotomy and cannulation for CPB are performed.
• The PA catheter should be withdrawn from the right heart before completion of bicaval cannulation.
•  Once CPB is initiated, ventilation is discontinued and the absence of a thrill in the carotid arteries is documented.
• Most patients exhibit an excess of intravascular volume, and administration of a diuretic and/ or the use of hemofiltration via the pump may be beneficial by increasing the hemoglobin concentration.
• A dose of glucocorticoid (methylprednisolone, 500 mg) is administered as the last anastomosis is being completed before release of the aortic cross-clamp to attenuate any hyperacute immune response.
• During the period of reperfusion an infusion of an inotrope is begun for both inotropy and chronotropy.
• TEE is used to monitor whether the cardiac chambers are adequately de-aired before weaning from CPB. ). TEE often will provide additional useful information about right- and left-heart function and volume, and document normal flow dynamics through the anastomoses.
• Weaning from bypass begins after ventilation is resumed and the cannula in the SVC is removed.
• The donor heart should be paced if bradycardia is present despite the inotropic infusion.
• Once the patient is separated from CPB, the PA catheter is advanced into position.
• Patients with increased PVR are at risk for acute RV failure and may benefit from a pulmonary vasodilator such as prostaglandin E1 (0.05 to 0.15 µg/kg/min.
•  Protamine then is given to reverse heparin's effect after satisfactory weaning from CPB.
•  Excessive bleeding and coagulopathy is common after heart transplantation, especially if there has been a prior sternotomy. Treatment is similar to that used for other post-bypass bleeding: meticulous attention to surgical hemostasis, empiric administration of platelets, and subsequent addition of fresh-frozen plasma and cryoprecipitate guided by subsequent coagulation studies.
• After adequate hemostasis is achieved, the chest is closed in standard fashion and the patient transferred to the intensive care unit (ICU).

Postoperative Management and Complications:
Management in the ICU after the conclusion of the procedure essentially is a continuation of the anesthetic management after CPB. The electrocardiogram; arterial, central venous, and/or PA pressures; and arterial oxygen saturation are monitored continuously. Cardiac recipients will continue to require β-adrenergic infusions for chronotropy and inotropy for up to 3 to 4 days. Vasodilators may be necessary to control arterial hypertension and decrease impedance to LV ejection. Patients can be weaned from ventilatory support and extubated when the patient is hemodynamically stable, warm, conscious and not bleeding. The immunosuppressive regimen of choice (typically consisting of cyclosporine, azathioprine, and prednisone, or tacrolimus and prednisone) should be started after arrival in the ICU. Invasive monitoring can be withdrawn as the inotropic support is weaned, and mediastinal chest tubes are removed after drainage subsides (usually after 24 hours). Patients usually can be discharged from the ICU after 2 or 3 days.

 

 

Complications:
Early complications after heart transplantation include acute and hyperacute rejection, cardiac failure, systemic and pulmonary hypertension, cardiac arrhythmias, renal failure, and infection.

• Hyperacute rejection is an extremely rare but devastating syndrome mediated by preformed recipient cytotoxic antibodies against donor heart antigens. The donor heart immediately becomes cyanotic from microvascular thrombosis and ultimately ceases to contract. This syndrome is lethal unless the patient can be supported mechanically until a suitable heart is found.
•  Acute rejection is a constant threat in the early postoperative period and may present in many forms (e.g., low CO, arrhythmias). Acute rejection occurs most frequently during the initial 6 months after transplantation, so its presence is monitored by serial endomyocardial biopsies, with additional biopsies to evaluate any acute changes in clinical status. Detection of rejection mandates an aggressive increase in the level of immunosuppression, usually including pulses of glucocorticoid or a change from cyclosporine to tacrolimus.
• Low CO after transplantation may reflect a number of causative factors: hypovolemia, inadequate adrenergic stimulation, myocardial injury during harvesting, acute rejection, tamponade, or sepsis. Therapy should be guided by invasive monitoring, TEE, and endomyocardial biopsy.
• Systemic hypertension may be caused by pain, so adequate analgesia should be obtained before treating blood pressure with a vasodilator.
• Because fixed pulmonary hypertension will have been excluded during the recipient evaluation, pulmonary hypertension after heart transplantation usually will be transient and responsive to vasodilators such as prostaglandin E1, nitrates, or hydralazine after either orthotopic or heterotopic placement.
• Atrial and ventricular tachyarrhythmias are common after heart transplantation; once rejection has been ruled out as a cause, antiarrhythmics are used for conversion or control (except those acting via indirect mechanisms such as digoxin, or those with negative inotropic properties such as β-blockers and calcium channel blockers). Almost all recipients will require either β-adrenergic agonists or pacing to increase heart rate in the immediate perioperative period, but 10% to 25% of recipients also will require permanent pacing.
• Renal function often improves immediately after transplantation, but immunosuppressive such as cyclosporine and tacrolimus may impair renal function.
• Infection is a constant threat to immunosuppressed recipients. Bacterial pneumonia is frequent early in the postoperative period, with opportunistic viral and fungal infections becoming more common after the first several weeks.

Key points in Heart Transplantation •  Frequency of transplantation remains limited by donor supply • Pathophysiology before transplantation is primarily that of end-stage ventricular failure. • Pathophysiology after transplantation reflects the effects of denervation. • Allograft coronary vasculopathy is a frequent long-term complication.

Acknowledgment
The author acknowledge that the text is modified from Kaplan’s Cardiac Anaestheisa, Echo era, 6th edition.