EXPLANATION


The cardiac allograft demonstrates altered physiology due to denervation of the autonomic nervous system. Parasympathetic innervation is lost making the resting heart rate slightly higher than normal. Holter studies have demonstrated higher minimum heart rates, similar maximal heart rates, and decreased heart rate variability in patients after heart transplantation. Because of the loss of the baroreceptor reflex, the transplanted heart does not make rapid compensatory adjustments in heart rate. The transplanted heart has been described as “preload dependent” because it relies on Frank-Starling forces and end-diastolic volume to maintain cardiac output in the absence of the ability to alter the heart rate rapidly. Conversely, the intrinsic properties of the cardiac muscle are preserved.


Adenosine, a drug commonly used to treat supraventricular tachycardia (SVT), is a purine nucleoside that binds to G protein coupled receptors in the heart. In the sinus node, activation of these receptors decreases the rate of spontaneous depolarization by reducing intracellular cyclic AMP levels, leading to a decreased heart rate. In the atrioventricular (AV) node, activation of these receptors results in the inhibition of L-type calcium channels, which in turn decreases conduction velocity and leads to AV block.


The sinus node and AV node of the transplanted heart are hypersensitive to the pharmacologic effects of adenosine as compared to the native, non-transplanted heart. A 1990 study by Ellenbogen et al demonstrated that the sinus node and the AV node in patients who had undergone heart transplantation exhibited an exaggerated response to adenosine administration. Twenty-eight heart transplant patients and nine patients without heart transplantation were administered increasing doses of adenosine during an electrophysiology study. The study demonstrated that the sinus node cycle length was significantly greater and the duration of the chronotropic effect of adenosine was prolonged in the heart transplant patients. Similar results were demonstrated in the AV node.


In a small series of patients undergoing pharmacologic stress testing with adenosine, Toft et al demonstrated that 4% of non-transplanted heart patients developed AV block during the test. Based on this study and others, the administration of adenosine to cardiac transplant recipients is often considered a relative contraindication due to the possibility of prolonged heart block. However, more recent evidence suggests that this caution may have been overstated.


A single-center, prospective study by Flyer et al (2017) investigated the pharmacologic effects of adenosine in stable heart transplant patients who were undergoing cardiac catheterization. Electrophysiological measurements were taken during the administration of increasing doses of adenosine in eighty patients between the ages of six months and 25 years. Adenosine dosing was initiated at 12.5 mcg/kg and increased to 25mcg/kg, 50mcg/kg, 100mcg/kg and 200mcg/kg. Patients over sixty kilograms received 0.8 mg, 1.5 mg, 3 mg, 6 mg, and 12 mg of adenosine incrementally. Dose escalation was stopped when AV block or clinically significant asystole occurred (i.e. sinus pause or AV block greater than twelve seconds). The results indicated that a dose of 12.5 mcg/kg did not cause AV block in any patient. Twelve percent developed AV block after a dose of 25mcg/kg, 31% after 50 mcg/kg, 72% after 100 mcg/kg, and 96% after 200mcg/kg. None of the patients needed rescue pacing after adenosine administration. The mean duration of adenosine effect was 4.3 seconds, and the longest duration was 8.4 seconds. There was no association between the dose of adenosine needed to produce AV block and the time from the heart transplant. The authors concluded that adenosine is safe and efficacious in the stable heart transplant population. They suggested that the initial adenosine dose should be 25 mcg/kg, which is a quarter of the dose recommended in the PALS and ACLS algorithms to treat supraventricular tachycardia. If the desired effect is not achieved, the dose should be increased gradually.


For the patient in the stem, the initial dose of adenosine used to treat supraventricular tachycardia should be decreased. The 2023 International Society of Heart and Lung Transplantation (ISHLT) guideline for the care of heart transplant recipients recommends an initial dose of 25 mcg/kg (or 1.5 mg in patients over 60 kg) in conjunction with a gradual dose increase until the desired clinical response is achieved for administration of the drug adenosine.


REFERENCES


Kleiman Z, Zabala LM. Post orthotopic cardiac transplantation. In: Berenstain LK, Spaeth JP (Eds). Congenital Cardiac Anesthesia: A Case-Based Approach. Cambridge University Press, Cambridge, UK; 2021. 290-298.


Toft J, Mortensen J, Hesse B. Risk of atrioventricular block during adenosine pharmacologic stress testing in heart transplant recipients. Am J Cardiol. 1998;82(5):696-697, A9. doi:10.1016/s0002-9149(98)00392-0


Ellenbogen KA, Thames MD, DiMarco JP, Sheehan H, Lerman BB. Electrophysiological effects of adenosine in the transplanted human heart. Evidence of super sensitivity. Circulation. 1990;81(3):821-828. doi:10.1161/01.cir.81.3.821


Flyer JN, Zuckerman WA, Richmond ME, et al. Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation. Circulation. 2017;135(25):2485-2493. doi:10.1161/CIRCULATIONAHA.117.028087


Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023; 42(5): e1-e141. doi.org/10.1016/j.healun.2022.10.015