- Email: [email protected]
Bradycardia in the Early Postoperative Period of Liver Transplantation in Children
Bradycardia in the Early Postoperative Period of Liver Transplantation in Children G.A. Costa, U. Tannuri, and A.F. Delgado ABSTRACT The aim of this investigation was to describe the occurrence of bradycardia during the early postoperative period of liver transplantation in children. We retrospectively analyzed a cohort of 79 children with end-stage liver diseases who underwent liver transplantation. All children experienced ⱖ1 episode of a cardiac rate below the 2nd percentile of a 1-hour minimum duration, which was considered to be bradycardia. Patients ⬍24 months were compared with older ones. The overall incidence of bradycardia was 37% (n ⫽ 31), including 25 patients who displayed bradycardia until postoperative day 3. In all cases, the electrocardiogram was normal, showing sinus rhythm. A comparison of the groups demonstrated an increased incidence of bradycardia among patients ⬍24 months of age (P ⫽ .03). In all patients, there were no hemodynamic consequences; the cardiac rate returned to normal uneventfully. The explanations for bradycardia could not be applied to these patients because none of them had any volume change or electrolyte disturbances; liver function tests were not seriously altered. The mechanisms of this postoperative complications are unclear. ARDIAC arrhythmias are common events after surgical procedures particularly in patients with previous heart disease.1 Among the arrhythmias, bradycardias are rare; they may be related to sinus node dysfunction: sinus bradycardia, sinus pause, sinoatrial atrial node blockade, and sinus arrest. During surgery these disturbances may be due to increased vagal tonus, as a consequence of epidural anesthesia, layngoscopy, or the surgical procedure itself. In addition, postoperative stress predisposes to arrhythmias. Bradycardia may occur as a consequence of many factors: release of catecholamines, tracheal aspiration, increased intracranial pressure, hypoxemia, hypoglycemia, acidosis, electrolyte disturbances and drug therapies, namely digoxin, beta-blockers, and amiodarone.2 The physiologic consequences of arrhythmias depend on its duration, the ventricular response and the baseline cardiac function. In cases of transient bradycardia and no hemodynamic instability, therapeutic intervention is unnecessary. However, in cases of sustained bradycardia with signs of tissue hypoperfusion, drugs like atropine and betaagonists may be indicated.1 In adult patients, bradycardia may be defined as a cardiac rate ⬍60 beats per minute.3 In the pediatric population, the number has not been well established, although guidelines have been proposed based on Holter monitoring studies
C
performed in normal children.3 However, it is important to bear in mind that these conclusions may not be applicable to children in the early postoperative period when they experience fever or pain which predispose to tachycardia. If the patient is bradycardic and hypotensive peripheral tissue hypoperfusion might ensue. We sought to describe the occurrence of bradycardia in the early postoperative period after liver transplantation in children. PATIENTS AND METHODS The Ethical Committee of our institution approved the study protocol. We retrospectively analyzed a cohort of 93 children with end-stage liver diseases who underwent either deceased or living donor liver transplantation from January 2004 to July 2007. The definition of bradycardia in Table 1 included all children presenting ⱖ1 episode of a cardiac rate below the 2nd percentile with a minimum of 1 hour of duration.4 The usual immunosuppressive protocol include intraoperative administration of methylprednisolone, followed by postoperative From the Department of Pediatric Surgery, University of São Paulo Medical School, São Paulo, Brazil. Address reprint requests to Uenis Tannuri, PhD, Department of Pediatric Surgery, University of São Paulo, Av. Dr. Arnaldo 455, 4 andar, sala 4109, São Paulo, Brazil.
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.01.064
© 2010 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
1774
Transplantation Proceedings, 42, 1774 –1776 (2010)
EARLY POSTOPERATIVE BRADY CARDIA
1775
Table 1. Cardiac Rate by Age Age
Percentile 2nd (beats per minute)
⬍1 d 1–2 d 3–6 d 1–3 wk 1–2 m 3–5 m 6–11 m 1–2 y 3–4 y 5–7 y 8–11 y 12–15 y
93 91 91 107 121 106 109 89 73 65 62 60
oral administration of tacrolimus (to achieve blood levels of 6 – 8 ng/mL) and prednisone (2 mg/kg daily for the first 5 days after the transplantation tapered to an average maintenance dose of 0.3 mg/kg daily over the following week). We did not employ basiliximab, a chimeric anti–interleukin (IL) 2-R monoclonal antibody, or thymoglobulin induction treatment. Postoperative pain control included the administration of dipirone or tramadol but not phentanyl. Patients ⬍24 months were compared with older ones. Values were expressed as percentages with the chi-square test for statistical comparisons. The level of significance was P ⱕ .05.
RESULTS
Complete data were available for 79 of the 93 patients who underwent liver transplantation. Eighty-four liver transplants were performed in these patients: re-transplant (n ⫽ 5), deceased donor (54), and living related donor (n ⫽ 30) cases. Fifteen patients died (19%) and the mean intensive care unit stay was 10 days (median, 7). Mean patient age and weight were 50 months (median, 36) and 17 kg (median, 12), respectively. Biliary atresia was the main cause of liver disease leading to transplantation (n ⫽ 45; 56.9%), followed by fulminant hepatic failure (n ⫽ 14; 17.7%), and other causes (n ⫽ 20; 25.3%). No patient displayed any form of cardiac disease before transplantation. The overall incidence of bradycardia was 37% (n ⫽ 31) with 25 patients continuing with this until finding postoperative day 3. In all cases, the electrocardiogram was normal, showing sinus rhythm (Fig 1). No electrolyte abnormality (hypokalemia, hypomagnesemia, or hypocalcemia) was detected during the bradycardiac episodes. The incidences of bradycardia in the 2 groups of patients are
Fig 2. Incidence of bradycardia in the 2 groups of patients. Note the increased incidence in the group of patients ⬍24 months of age (P ⫽ .03).
shown in Figure 2. Group comparisons demonstrated an increased incidence of bradycardia among patients younger than 24 months of age (P ⫽ .03). There were no hemodynamic consequences among all the patients who presented with bradycardia; the cardiac rate returned to normal uneventfully. One patient died due to sepsis. DISCUSSION
The importance of this communication is based on the concern when a pediatric patient presents with persistent bradycardia in the early postoperative period, especially among patients ⬍2 years of age. In fact, we verified that this age group is at greater risk for this problem. Interestingly, we could not be demonstrate that bradycardia caused physiologic consequences or a relationship to mortality. Our patients underwent a thorough preoperative cardiac functional evaluation; none presented cardiac disease before liver transplantation. One possible cause of bradycardia may be narcotic administration in the intensive care unit. Nevertheless, other patients in our unit received the same pain control protocol but did not present bradycardia as did transplant patients. This observation led us to perform this retrospective search. There are only 2 reports about bradycardia related to liver transplantation. In a review of 50 liver transplanted children, Molin et al5 reported a 74% occurrence of bradycardia among 37 children which was attributed to a side effect of cyclosporine. It is important note that our scheme of immunosuppression did not include cyclosporine. In another retrospective review of 46 pediatric patients, the
Fig 1. EKG of a patient demonstrating bradycardia (paper speed 25 mm/sec; cardiac rate ⫽ 50 beats/min).
1776
majority of patients displayed a fall in heart rate during caval clamping. No patient showed a rise in heart rate, as would have been expected in adult subjects. The possible causes were variations in preload, changes in temperature and arterial CO2 as well as accumulation of anesthetics owing to the altered metabolism in the anhepatic phase.6 These explanations may not be applicable to our patients, because none of them showed any volemic change and liver tests were not seriously altered, compatible with benign postoperative periods. Patients who undergo liver transplantation often are treated with diuretics preoperatively to control ascites, which may result in low magnesium and potassium levels. In addition, patients receive insulin and glucose during the graft reperfusion phase, seeking to lessen the impact of hyperkalemia, which may lower the serum potassium level as well. Postoperatively, patients often became alkalotic as they metabolize citrate to bicarbonate, which also reduces potassium levels. Also, rapid infusion of blood products may result in hypomagnesemia or hypocalcemia secondary to the liver’s inability to clear citrate. None of these abnormalities were present in our patients. Similar to other series, biliary atresia was the main cause of liver disease leading to liver transplantation (56.9%), followed by fulminant hepatic failure. In this retrospective review, we showed an increased incidence of bradycardia among patients ⬍2 years.7 Possibly, changes in drug metab-
COSTA, TANNURI, AND DELGADO
olism and accumulation of narcotics used for postoperative pain control may offer explanations for bradycardia.8 However, our pain control protocol included only dipirone and tramadol, which do not usually produce bradycardia. The mechanisms of bradycardia occurrence in the early postoperative period after liver transplantation in children are unclear. REFERENCES 1. Hollenberg SM, Dellinger RP: Noncardiac surgery: postoperative arrhythmias. Crit Care Med 28:145, 2000 2. Nichols DG, Ungerleider RM, Spevat PJ, et al: Critical Heart Disease in infants and children. 2nd ed. New York: Elsevier, 2006 3. Doniger SJ, Sharieff GQ: Pediatric dysrhythmias. Pediatr Clin North Am 53:85, 2006 4. Taketomo CK, Hodding JH, Kraus DM: Pediatric dosage handbook, 12th ed. Hudson, Ohio: Lexi-comp; 2005 5. Moulin D, Clement de Clety S, Reynaert M, et al: Intensive care for children after orthotopic liver transplantation. Intens Care Med 15(suppl 1):S71, 1989 6. McDonnell N, Ames WA, Potter D: Bradycardia in children less than two years of age during liver transplantation. Transpl Int 11:237, 1998 7. Alonso EM, Besedovsky A, Emerick K, et al: General criteria for pediatric liver transplantation. In: Busuttil RW, Klintmalm GK, eds: Transplantation of the liver, 2nd ed. Philadelphia: Elsevier Saunders, 2005 8. Murat I, Levron JC, Berg A, et al: Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 68:717, 1988
C
performed in normal children.3 However, it is important to bear in mind that these conclusions may not be applicable to children in the early postoperative period when they experience fever or pain which predispose to tachycardia. If the patient is bradycardic and hypotensive peripheral tissue hypoperfusion might ensue. We sought to describe the occurrence of bradycardia in the early postoperative period after liver transplantation in children. PATIENTS AND METHODS The Ethical Committee of our institution approved the study protocol. We retrospectively analyzed a cohort of 93 children with end-stage liver diseases who underwent either deceased or living donor liver transplantation from January 2004 to July 2007. The definition of bradycardia in Table 1 included all children presenting ⱖ1 episode of a cardiac rate below the 2nd percentile with a minimum of 1 hour of duration.4 The usual immunosuppressive protocol include intraoperative administration of methylprednisolone, followed by postoperative From the Department of Pediatric Surgery, University of São Paulo Medical School, São Paulo, Brazil. Address reprint requests to Uenis Tannuri, PhD, Department of Pediatric Surgery, University of São Paulo, Av. Dr. Arnaldo 455, 4 andar, sala 4109, São Paulo, Brazil.
0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.01.064
© 2010 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
1774
Transplantation Proceedings, 42, 1774 –1776 (2010)
EARLY POSTOPERATIVE BRADY CARDIA
1775
Table 1. Cardiac Rate by Age Age
Percentile 2nd (beats per minute)
⬍1 d 1–2 d 3–6 d 1–3 wk 1–2 m 3–5 m 6–11 m 1–2 y 3–4 y 5–7 y 8–11 y 12–15 y
93 91 91 107 121 106 109 89 73 65 62 60
oral administration of tacrolimus (to achieve blood levels of 6 – 8 ng/mL) and prednisone (2 mg/kg daily for the first 5 days after the transplantation tapered to an average maintenance dose of 0.3 mg/kg daily over the following week). We did not employ basiliximab, a chimeric anti–interleukin (IL) 2-R monoclonal antibody, or thymoglobulin induction treatment. Postoperative pain control included the administration of dipirone or tramadol but not phentanyl. Patients ⬍24 months were compared with older ones. Values were expressed as percentages with the chi-square test for statistical comparisons. The level of significance was P ⱕ .05.
RESULTS
Complete data were available for 79 of the 93 patients who underwent liver transplantation. Eighty-four liver transplants were performed in these patients: re-transplant (n ⫽ 5), deceased donor (54), and living related donor (n ⫽ 30) cases. Fifteen patients died (19%) and the mean intensive care unit stay was 10 days (median, 7). Mean patient age and weight were 50 months (median, 36) and 17 kg (median, 12), respectively. Biliary atresia was the main cause of liver disease leading to transplantation (n ⫽ 45; 56.9%), followed by fulminant hepatic failure (n ⫽ 14; 17.7%), and other causes (n ⫽ 20; 25.3%). No patient displayed any form of cardiac disease before transplantation. The overall incidence of bradycardia was 37% (n ⫽ 31) with 25 patients continuing with this until finding postoperative day 3. In all cases, the electrocardiogram was normal, showing sinus rhythm (Fig 1). No electrolyte abnormality (hypokalemia, hypomagnesemia, or hypocalcemia) was detected during the bradycardiac episodes. The incidences of bradycardia in the 2 groups of patients are
Fig 2. Incidence of bradycardia in the 2 groups of patients. Note the increased incidence in the group of patients ⬍24 months of age (P ⫽ .03).
shown in Figure 2. Group comparisons demonstrated an increased incidence of bradycardia among patients younger than 24 months of age (P ⫽ .03). There were no hemodynamic consequences among all the patients who presented with bradycardia; the cardiac rate returned to normal uneventfully. One patient died due to sepsis. DISCUSSION
The importance of this communication is based on the concern when a pediatric patient presents with persistent bradycardia in the early postoperative period, especially among patients ⬍2 years of age. In fact, we verified that this age group is at greater risk for this problem. Interestingly, we could not be demonstrate that bradycardia caused physiologic consequences or a relationship to mortality. Our patients underwent a thorough preoperative cardiac functional evaluation; none presented cardiac disease before liver transplantation. One possible cause of bradycardia may be narcotic administration in the intensive care unit. Nevertheless, other patients in our unit received the same pain control protocol but did not present bradycardia as did transplant patients. This observation led us to perform this retrospective search. There are only 2 reports about bradycardia related to liver transplantation. In a review of 50 liver transplanted children, Molin et al5 reported a 74% occurrence of bradycardia among 37 children which was attributed to a side effect of cyclosporine. It is important note that our scheme of immunosuppression did not include cyclosporine. In another retrospective review of 46 pediatric patients, the
Fig 1. EKG of a patient demonstrating bradycardia (paper speed 25 mm/sec; cardiac rate ⫽ 50 beats/min).
1776
majority of patients displayed a fall in heart rate during caval clamping. No patient showed a rise in heart rate, as would have been expected in adult subjects. The possible causes were variations in preload, changes in temperature and arterial CO2 as well as accumulation of anesthetics owing to the altered metabolism in the anhepatic phase.6 These explanations may not be applicable to our patients, because none of them showed any volemic change and liver tests were not seriously altered, compatible with benign postoperative periods. Patients who undergo liver transplantation often are treated with diuretics preoperatively to control ascites, which may result in low magnesium and potassium levels. In addition, patients receive insulin and glucose during the graft reperfusion phase, seeking to lessen the impact of hyperkalemia, which may lower the serum potassium level as well. Postoperatively, patients often became alkalotic as they metabolize citrate to bicarbonate, which also reduces potassium levels. Also, rapid infusion of blood products may result in hypomagnesemia or hypocalcemia secondary to the liver’s inability to clear citrate. None of these abnormalities were present in our patients. Similar to other series, biliary atresia was the main cause of liver disease leading to liver transplantation (56.9%), followed by fulminant hepatic failure. In this retrospective review, we showed an increased incidence of bradycardia among patients ⬍2 years.7 Possibly, changes in drug metab-
COSTA, TANNURI, AND DELGADO
olism and accumulation of narcotics used for postoperative pain control may offer explanations for bradycardia.8 However, our pain control protocol included only dipirone and tramadol, which do not usually produce bradycardia. The mechanisms of bradycardia occurrence in the early postoperative period after liver transplantation in children are unclear. REFERENCES 1. Hollenberg SM, Dellinger RP: Noncardiac surgery: postoperative arrhythmias. Crit Care Med 28:145, 2000 2. Nichols DG, Ungerleider RM, Spevat PJ, et al: Critical Heart Disease in infants and children. 2nd ed. New York: Elsevier, 2006 3. Doniger SJ, Sharieff GQ: Pediatric dysrhythmias. Pediatr Clin North Am 53:85, 2006 4. Taketomo CK, Hodding JH, Kraus DM: Pediatric dosage handbook, 12th ed. Hudson, Ohio: Lexi-comp; 2005 5. Moulin D, Clement de Clety S, Reynaert M, et al: Intensive care for children after orthotopic liver transplantation. Intens Care Med 15(suppl 1):S71, 1989 6. McDonnell N, Ames WA, Potter D: Bradycardia in children less than two years of age during liver transplantation. Transpl Int 11:237, 1998 7. Alonso EM, Besedovsky A, Emerick K, et al: General criteria for pediatric liver transplantation. In: Busuttil RW, Klintmalm GK, eds: Transplantation of the liver, 2nd ed. Philadelphia: Elsevier Saunders, 2005 8. Murat I, Levron JC, Berg A, et al: Effects of fentanyl on baroreceptor reflex control of heart rate in newborn infants. Anesthesiology 68:717, 1988