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Canadian Journal of Anesthesia 51:829-833 (2004)
© Canadian Anesthesiologists' Society, 2004
Cardiothoracic Anesthesia, Respiration and Airway

Decreased heart rate and blood pressure in a recent cardiac transplant patient after spinal anesthesia

[Baisse de la fréquence cardiaque et de la tension artérielle après rachianesthésie chez un patient qui a récemment reçu une greffe cardiaque]

René Allard, MD, Roupen Hatzakorzian, MDCM FRCPC, Alain Deschamps, MD PhD FRCPC and Steven B. Backman, MDCM PhD FRCPC

From the Department of Anaesthesia, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

Address correspondence to: Dr. Steven B. Backman, Department of Anaesthesia, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada. Phone: 514-842-1231, ext. 34883; E-mail: steven.backman{at}muhc.mcgill.ca


   Abstract
TOP
 Abstract
Introduction
 Case report
 Discussion
 References
 
Purpose: To describe the cardiovascular effects of neuraxial blockade in a heart transplant patient.

Clinical features: A 69-yr-old 70-kg male underwent orthotopic heart transplant (bicaval anastomosis technique) for ischemic cardiomyopathy. Five months after transplantation, the patient underwent a transurethral bladder tumour resection under spinal anesthesia. Two millilitres of bupivacaine 0.75% (15 mg) were injected intrathecally at L3–4 and the patient remained seated for approximately 20 sec prior to assuming the lithotomy position. Subsequently, both blood pressure (BP) and heart rate (HR) diminished gradually (BP and HR immediately pre-spinal: 113 mmHg (mean arterial pressure) and 92 beats·min–1, respectively; nadir BP and HR: 94 mmHg (16.8% decrease) 30 min postspinal and 73 beats·min–1 (20.7% decrease) 40 min postspinal, respectively). HR and mean BP were highly correlated (r = 0.9410, P < 0.0001, R2 = 0.8854). The dermatome level of neuraxial anesthesia, determined by sensitivity to pin prick, was T8 (five minutes) and T6 (ten minutes) postinjection of spinal anesthetic. Control patients (n = 10) undergoing elective urological procedures with identical anesthesia management demonstrated very similar cardiovascular responses.

Conclusions: Although cardiac transplant patients may tolerate neuraxial anesthesia admirably, a fall in HR may ensue which theoretically could have important physiological consequences. It is argued that the change in HR in the transplanted patient was mediated by mechanisms intrinsic to the transplanted heart and/or by reduced catecholamine secretion from the adrenal medulla. It is emphasized that HR changes observed in cardiac transplant patients do not necessarily imply reinnervation of the transplanted organ.


   Introduction
TOP
 Abstract
 Introduction
Case report
 Discussion
 References
 
HARVESTING of the donor heart for transplant results in complete extrinsic cardiac denervation. In spite of considerable clinical experience with this procedure, reinnervation of the transplanted heart remains controversial.1 Although there is a substantial body of literature that denies reinnervation,2–8 there is emerging evidence to suggest that, to some extent, this may occur. Afferent reinnervation is supported by reports of angina accompanied by objective evidence of cardiac ischemia.9,10 Evidence for sympathetic reinnervation derives from the emergence of a low-frequency heart rate (HR) variability in some transplants,11–13 and the appearance of appropriate, albeit diminished, reflex changes in HR.11,14–16 In addition, experiments suggest catecholamine uptake, storage or release from presumed cardiac sympathetic postganglionic neurons in the transplanted heart.15,17–19 Evidence for parasympathetic reinnervation derives from reports of a high-frequency variability in HR in a small number of transplants,20,21 and the demonstration of atropine-sensitive reflex changes in HR.22 In addition, there are a few reports describing vasovagal syncopal-like episodes in cardiac transplant patients.23–25 The issue of reinnervation may be additionally complicated by the surgical technique. When recipient right and left atrial cuffs are joined to the corresponding donor atria, the remnant recipient right atrium remains innervated and may diminish the potential for reinnervation of the donor heart. With the bicaval anastomosis technique, the recipient’s heart is totally excised and there is no innervated recipient atrial tissue to potentially interfere with the process of reinnervation.26

While the evidence for limited cardiac reinnervation is intriguing, a careful review of this subject concluded that functional reinnervation of the transplanted heart rarely, if ever, occurs.1 Accordingly, it is anticipated that changes in HR, normally produced by altered cardiac autonomic tone, are absent in this unique type of patient and a relatively stable HR is expected. In this report we describe the coincidental fall in HR and blood pressure (BP) of a cardiac transplant patient following spinal anesthesia for a urological procedure. These hemodynamic changes are compared with those of patients with a normally innervated heart undergoing similar surgery with the same anesthetic technique. This report is unique in that, as far as we are aware, hemodynamic changes in a cardiac transplant patient following neuraxial anesthesia have heretofore not been described.


   Case report
TOP
 Abstract
 Introduction
 Case report
Discussion
 References
 
A 69-yr-old 70-kg white man underwent orthotopic heart transplant (bicaval anastomosis technique) for ischemic cardiomyopathy. Co-morbid conditions included diabetes, hypertension, manic depression, diverticulitis, hiatus hernia, and remote history of alcoholism and smoking. Five months following transplantation, the patient underwent a transurethral bladder tumour resection. Laboratory investigation indicated elevated blood urea nitrogen (12.9 mMol·L–1) and creatinine 133 (mMol·L–1) and anemia (hematocrit 0.25). A 12-lead electrocardiogram (ECG) demonstrated a normal sinus rhythm at 77 beats·min–1 and a right bundle branch block. Recent endomyocardial biopsy indicated no evidence for rejection. The patient’s medications were tolbutamide 500 mg BID, atorvastatin 30 mg QD, ramipril 2.5 mg QD, fosamax 80 mg QWK, clonazepam 0.5 mg TID, fluoxetine 40 mg QD, omeprazole 20 mg QD, cyclosporine 25 mg BID, prednisone 7.5 mg QD, amlodipine 5 mg QD, sirolimus 1 mg QD, calcium 500 mg BID, and magnesium 100 mg QD.

Following insertion of an iv catheter (18 gauge) in an upper extremity (normal saline infused at 100 mL·hr–1), midazolam 1.0 mg was administered for sedation. A 27-gauge Whitacre spinal needle was subsequently inserted into the intrathecal space at the L3–4 interspace under sterile conditions with the patient in the seated position. Two millilitres of bupivacaine 0.75% (15 mg) were injected, and the patient remained seated for approximately 20 sec prior to assuming the lithotomy position. Monitoring consisted of non-invasive BP recording, ECG (leads II and V), and pulse oximetry. The patient breathed a mixture of room air and oxygen delivered via nasal prongs (2 L·min–1). Following injection of spinal anesthetic, both BP and HR gradually diminished (Figure 1Go; BP and HR immediately pre-spinal: 113 mmHg (mean arterial pressure) and 92 beats·min–1, respectively; nadir BP and HR: 94 mmHg (16.8% decrease) 30 min postspinal and 73 beats·min–1 (20.7% decrease) 40 min postspinal, respectively). HR and mean BP were highly correlated (r = 0.9410, P < 0.0001, R2 = 0.8854). The dermatome level of neuraxial anesthesia, determined by sensitivity to pin prick, was T8 (five minutes) and T6 (ten minutes) postinjection of spinal anesthetic.



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  		FIGURE 1 Spinal block produces coincident fall in systemic arterial pressure and heart rate in a cardiac transplant patient. Arrow denotes time of intrathecal administration of bupivacaine.

 
In a subsequent series of ten patients undergoing elective urological procedures [transurethral bladder tumour resection (n = 6); transurethral laser prostatectomy (n = 4)], HR and BP changes were recorded for comparison. These patients received identical sedation (midazolam 1.0 mg iv) spinal neuraxial anesthesia, intraoperative positioning (lithotomy) and fluid management, and inotropic or vasopressor drugs were not administered. Following injection of spinal anesthetic, BP and HR gradually diminished during the subsequent 60 min period (Figure 2Go; BP and HR immediately pre-spinal: 103.2 ± 16.0 mmHg (mean arterial pressure; mean ± SD) and 82.4 ± 16.4 beats·min–1, respectively; nadir BP and HR: 77.8 ± 17.1 mmHg (26.1 ± 10.8% decrease) 30 min postspinal and 62.3 ± 14.7 beats·min–1 (22.7 ± 9.6% decrease) 54 min postspinal, respectively). HR and mean BP were highly correlated (r = 0.8523, P < 0.0001, R2 = 0.7265). The median dermatome level of neuraxial anesthesia, determined by sensitivity to pin prick, was T8 (range: T4–T10, five minutes) and T6 (range: T2–T8, ten minutes) postinjection of spinal anesthetic.



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  		FIGURE 2 Spinal block produces coincident decrease in systemic arterial pressure and heart rate in patients with normally innervated hearts (n = 10; mean ± SD). Cardiovascular response following neuraxial block is essentially similar to that seen in the cardiac transplant patient (Figure 1Go). Arrow denotes time of intrathecal administration of bupivacaine.

 

   Discussion
TOP
 Abstract
 Introduction
 Case report
 Discussion
References
 
We report the coincident fall in HR and BP in a cardiac transplant recipient following spinal anesthesia. These changes were similar to those observed in patients with normally innervated hearts. Such changes in HR are of particular interest when considered in the context of the controversy regarding reinnervation of the transplanted organ.1 As the patient had undergone transplantation only five months previously, and, as reinnervation of the transplanted heart (when demonstrable) is not evident before one year after transplantation,14,18,19,26 the response is unlikely to have been mediated by reflex activation of the sinoatrial (SA) node directly via the central nervous system. Because the patient underwent transplantation using the bicaval anastomosis technique, changes in donor HR could not have been mediated by altered rate of contraction of remnant innervated atrial tissue.27–29 Possibly, the hypotension produced by spinal block resulted in cardiac ischemia with decreased perfusion of the SA node of the donor heart. Such a mechanism has been suggested to account for a lethal bradyarrhythmia30 and for bradycardia following protamine-induced hypotension31 in transplanted patients. Bradyarrhythmias in the post-transplant period appear to be highly correlated to disruption of the SA node blood supply in the transplanted heart.32 However, in the present study, as HR and BP both fell gradually without signs of ischemia (ECG unchanged), and the decreases in systemic arterial pressure were modest, such an explanation does not seem plausible. Another possibility is activation of an intrinsic stretch-related mechanism in the transplanted heart. For example, increases in right atrial pressure in the denervated mammalian heart can evoke an increase in HR and, when the pressure is decreased, the pattern is reversed.33 Such a mechanism may account for the small amplitude, high-frequency variability in HR observed in transplants.34 HR in the transplanted heart may also be influenced by catecholamines secreted from the adrenal gland, and such a mechanism appears to mediate, in part, the exercise-induced increase in HR in this type of patient.35 It is anticipated that a T6 dermatome-level block, as produced by the neuraxial anesthetic, would significantly diminish sympathetic drive to the adrenal glands36,37 and thus effect the reduction in HR observed in the transplanted patient. Such a mechanism could also contribute to the decrease in HR observed in the patients with normally innervated hearts, although these decreases may have been somewhat dampened by an intact baroreceptor reflex. Additionally, with these patients, it is conceivable that the fall in HR may have resulted from blockade of sympathetic cardioac-celeratory fibres located in mid-thoracic segments.38

Regardless of the etiology underlying the cardiac response described in this report, it may be relevant that, preoperatively, the transplanted patient demonstrated a relatively low HR (77 beats·min–1) and right bundle branch block suggesting dysfunction of the sinus node and conducting pathway. Consideration should be given to the possibility that such dysfunction may have contributed to the cardiovascular response described in this report. Of note, a relatively low incidence of sinus node dysfunction is reported with patients who have undergone transplantation using the bicaval anastomosis technique.39,40 Of course, the effects of perioperative medications on the cardiac responses are unknown.

The cardiac transplant patient poses unique anesthetic challenges resulting from side effects of immuno-suppressive agents, graft rejection and denervation. They are particularly sensitive to hypovolemia, as cardiac output is so dependent on preload (Frank-Starling mechanism).1,3 This report illustrates that although cardiac transplant patients may tolerate neuraxial anesthesia admirably, a fall in HR may ensue which theoretically could have important physiological consequences. It is suggested that the change in HR described in this report was mediated by mechanisms intrinsic to the transplanted heart and/or by reduced catecholamine secretion from the adrenal medulla. As noted previously,31 changes in HR in cardiac transplant patients should not be interpreted as unequivocal evidence for reinnervation of the transplanted organ.


   Footnotes
 
Accepted for publication January 21, 2004. Revision accepted May 14, 2004.


   References
TOP
 Abstract
 Introduction
 Case report
 Discussion
 References
 
1 Stainback R. Orthotopic cardiac transplantation: a model of the denervated heart. In: Robertson D, Biaggioni I (Eds). Disorders of the Autonomic Nervous System. Luxembourg: Harwood Academic Publishers; 1995: 335–74.

2 Stinson EB, Griepp RB, Schroeder JS, Dong E Jr, Shumway NE. Hemodynamic observations one and two years after cardiac transplantation in man. Circulation 1972; 65: 1183–94.

3 Pope SE, Stinson EB, Daughters GT II, Schroeder JS, Ingels NB Jr, Alderman EL. Exercise response of the denervated heart in long-term cardiac transplant recipients. Am J Cardiol 1980; 46: 213–8.[Medline]

4 Kavanagh T, Yacoub MH, Mertens DJ, Kennedy J, Campbell RB, Sawyer P. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulation 1988; 77: 162–71.[Abstract/Free Full Text]

5 Smith ML, Ellenbogen KA, Eckberg DL, Sheehan HM, Thames MD. Subnormal parasympathetic activity after cardiac transplantation. Am J Cardiol 1990; 66: 1243–6.[Medline]

6 Ehrman J, Keteyian S, Fedel F, Rhoads K, Levine TB, Shepard R. Cardiovascular responses of heart transplant recipients to graded exercise testing. J Appl Physiol 1992; 73: 260–4.[Abstract/Free Full Text]

7 Givertz MM, Hartley LH, Colucci WS. Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation 1997; 96: 232–7.[Abstract/Free Full Text]

8 Raczak G, La Rovere MT, Mortara A, et al. Arterial baroreflex modulation of heart rate in patients early after heart transplantation: lack of parasympathetic reinnervation. J Heart Lung Transplant 1999; 18: 399–406.[Medline]

9 Stark RP, McGinn AL, Wilson RF. Chest pain in cardiac-transplant recipients. Evidence of sensory reinnervation after cardiac transplantation. N Engl J Med 1991; 324: 1791–4.[Medline]

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11 Bernardi L, Valle F, Leuzzi S, et al. Non-respiratory components of heart rate variability in heart transplant recipients: evidence of autonomic reinnervation? Clin Sci 1994; 86: 537–45.[Medline]

12 Lord SW, Clayton RH, Mitchell L, Dark JH, Murray A, McComb JM. Sympathetic reinnervation and heart rate variability after cardiac transplantation. Heart 1997; 77: 532–8.[Abstract/Free Full Text]

13 van de Borne P, Neubauer J, Rahnama M, et al. Differential characteristics of neural circulatory control: early versus late after cardiac transplantation. Circulation 2001; 104: 1809–13.[Abstract/Free Full Text]

14 Rudas L, Pflugfelder PW, Menkis AH, Novick RJ, McKenzie FN, Kostuk WJ. Evolution of heart rate responsiveness after orthotopic cardiac transplantation. Am J Cardiol 1991; 68: 232–6.[Medline]

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16 Bengel FM, Uberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med 2001; 345: 731–8.[Abstract/Free Full Text]

17 Schwaiblmair M, von Scheidt W, Uberfuhr P, et al. Functional significance of cardiac reinnervation in heart transplant recipients. J Heart Lung Transplant 1999; 18: 838–45.[Medline]

18 Schwaiger M, Hutchins GD, Kalff V, et al. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography. J Clin Invest 1991; 87: 1681–90.

19 Wilson RF, Christensen BV, Olivari MT, Simon A, White CW, Laxson DD. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans. Circulation 1991; 83: 1210–20.[Abstract/Free Full Text]

20 Fallen EL, Kamath MV, Ghista DN, Fitchett D. Spectral analysis of heart rate variability following human heart transplantation: evidence for functional reinnervation. J Auton Nerv Syst 1988; 23: 199–206.[Medline]

21 Ramaekers D, Ector H, Vanhaecke J, van Cleemput J, van de Werf F. Heart rate variability after cardiac transplantation in humans. Pacing Clin Electrophysiol 1996; 19(12 Pt 1): 2112–9.[Medline]

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23 Scherrer U, Vissing S, Morgan BJ, Hanson P, Victor RG. Vasovagal syncope after infusion of a vasodilator in a heart-transplant recipient. N Engl J Med 1990; 322: 602–4.[Medline]

24 Rudas L, Pflugfelder PW, Kostuk WJ. Vasodepressor syncope in a cardiac transplant recipient: a case of vagal reinnervation? Can J Cardiol 1992; 8: 403–5.[Medline]

25 Giannattasio C, Grassi G, Mancia G. Vasovagal syncope with bradycardia during lower body negative pressure in a heart transplant recipient. Blood Press 1993; 2: 309–11.[Medline]

26 Bernardi L, Valenti C, Wdowczyck-Szulc J, et al. Influence of type of surgery on the occurrence of parasympathetic reinnervation after cardiac transplantation. Circulation 1998; 97: 1368–74.[Abstract/Free Full Text]

27 Mason JW, Harrison DC. Electrophysiology and electropharmacology of the transplanted human heart. In: Narula OS (Ed). Cardiac Arrhythmias: Electrophysiology, Diagnosis and Management. Baltimore: Williams and Wilkins Company; 1979: 66–81.

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29 Birnie D, Green MS, Veinot JP, Tang AS, Davies RA. Interatrial conduction of atrial tachycardia in heart transplant recipients: potential pathophysiology. J Heart Lung Transplant 2000; 19: 1007–10.[Medline]

30 Grinstead WC, Smart FW, Pratt CM, et al. Sudden death caused by bradycardia and asystole in a heart transplant patient with coronary arteriopathy. J Heart Lung Transplant 1991; 10: 931–6.[Medline]

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32 DiBiase A, Tse TM, Schnittger I, Wexler L, Stinson EB, Valantine HA. Frequency and mechanism of bradycardia in cardiac transplant recipients and need for pacemakers. Am J Cardiol 1991; 67: 1385–9.[Medline]

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34 Bernardi L, Salvucci F, Suardi R, et al. Evidence for an intrinsic mechanism regulating heart rate variability in the transplanted and the intact heart during submaximal dynamic exercise? Cardiovasc Res 1990; 24: 969–81.[Free Full Text]

35 Bexton RS, Milne JR, Cory-Pearce R, English TA, Camm AJ. Effect of beta blockade on exercise response after cardiac transplantation. Br Heart J 1983; 49: 584–8.[Abstract/Free Full Text]

36 Strack AM, Sawyer WB, Platt KB, Loewy AD. CNS cell groups regulating the sympathetic outflow to adrenal gland as revealed by transneuronal cell body labeling with pseudorabies virus. Brain Res 1989; 491: 274–96.[Medline]

37 Backman SB, Sequeira-Martinho H, Henry JL. Adrenal versus nonadrenal sympathetic preganglionic neurones in the lower thoracic intermediolateral nucleus of the cat: physiological properties. Can J Physiol Pharmacol 1990; 68: 1447–56.[Medline]

38 Backman SB, Stein RD, Polosa C. Organization of the sympathetic innervation of the forelimb resistance vessels in the cat. Anesth Analg 1999; 88: 320–5.[Abstract/Free Full Text]

39 Rothman SA, Jeevanandam V, Combs WG, et al. Eliminating bradyarrhythmias after orthotopic heart transplanation. Circulation 1996; 94(Suppl II): II-278–82.

40 Herre JM, Barnhart GR, Llano A. Cardiac pacemakers in the transplanted heart: short term with the biatrial anastomosis and unnecessary with the bicaval anastomosis. Curr Opin Cardiol 2000; 15: 115–20.[Medline]





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