Published online February 16, 2007
PEDIATRICS Vol. 119 No. 3 March 2007, pp. e778-e782 (doi:10.1542/peds.2006-0029)
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EXPERIENCE & REASON

Sinus Bradycardia After Intravenous Pulse Methylprednisolone

Jonathan D. Akikusa, MBBSa,b, Brian M. Feldman, MDa,b,c, Gil J. Gross, MDb,d, Earl D. Silverman, MDa,b,e and Rayfel Schneider, MBBcha,b

a Divisions of Rheumatology
d Cardiology, Hospital For Sick Children, Toronto, Ontario, Canada
b Departments of Pediatrics
c Health Policy Management and Evaluation and Population Health Sciences
e Immunology, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

High-dose intravenous pulse methylprednisolone is an important therapeutic modality for many autoimmune conditions in both children and adults. Adverse effects of this therapy include hypertension, hyperglycemia, and, in children, behavioral changes. Cardiac rhythm disturbances, both tachyarrhythmias and bradyarrhythmias, have been reported in adults but much less commonly in children. Here we report our experience over a 6-month period with 5 children with rheumatic diseases who developed sinus bradycardia during consecutive daily therapy with intravenous pulse methylprednisolone. Reductions in resting heart rate of between 35% and 50% of baseline were observed in each case. All patients were asymptomatic, and all recovered spontaneously over a variable period of time after cessation of pulse therapy. Sinus bradycardia after repeated administration of high-dose pulse methylprednisolone in children may be more common than previously appreciated.

Key Words: bradycardia • steroids • pulse methylprednisolone

Abbreviations: bpm, beats per minute • ECG, electrocardiogram • QTc, rate-corrected QT interval

High-dose intravenous pulse corticosteroid therapy first came into clinical use >30 years ago in the treatment of acute rejection of renal grafts.1 Since then, the range of diseases for which it is used has expanded to include many immune-mediated inflammatory conditions.2–6 Given the extremely high doses of corticosteroids used, the safety of this therapy has been of particular interest.7,8 Of note have been cardiac adverse effects, with >30 cases of cardiac events reported in adults over the last 23 years. These events have included both tachyarrhythmias and bradyarrhythmias, cardiac failure, and myocardial infarction, in some cases resulting in death.9–15 Cardiac events in children have been reported less frequently.16–21 Over a 6-month period at our institution, 5 children with acute rheumatic diseases treated as inpatients with pulse corticosteroid therapy developed prolonged sinus bradycardia. All were undergoing continuous cardiac monitoring before, during, and after their infusions. None received pharmacologic therapy for their bradycardia. Here we present 2 illustrative case histories and a summary of all 5 patients and briefly review the literature on cardiac arrhythmias complicating pulse steroid therapy to heighten awareness of this adverse effect in children.

CASE REPORTS

Case 1.
A previously well 12-year-old boy was prescribed a 3-day course of high-dose pulse methylprednisolone therapy (1.0 g daily) for the treatment of Wegener granulomatosis. Ten hours after the second dose, ~35 hours after the first, in the early hours of the morning, the patient developed persistent resting bradycardia with a heart rate of 35 beats per minute (bpm) (previous resting heart rate: 95 bpm; Fig 1A). His blood pressure was normal, and when roused from sleep his heart rate increased transiently into the normal range. An electrocardiogram (ECG) revealed a sinus bradycardia with prolongation of the rate-corrected QT interval (QTc) (0.58 seconds [reference: <0.44 seconds]). Serum electrolyte and creatinine levels were within reference range. No specific therapy was given; however, the planned third dose of methylprednisolone was omitted, and high-dose oral corticosteroids were commenced instead. His resting bradycardia resolved over 5 days. A follow-up ECG was normal.


Figure 1
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  		FIGURE 1 Heart rate (black line) and mean blood pressure (gray line) over time of cases 1 (A) and 2 (B), plotted as 15-point moving averages. Vertical lines indicate the timing of intravenous pulse steroid infusions, and horizontal dashed lines indicate the age-specific 5th and 95th centiles for heart rate.

 
Case 2.
A previously well 6-year-old boy was prescribed a 3-day course of high-dose pulse methylprednisolone therapy (750 mg daily) for the initial treatment of juvenile dermatomyositis. Ten hours after receiving his third pulse, ~50 hours after the first dose, in the early hours of the morning, the patient developed persistent resting bradycardia with a heart rate of 45 bpm (previous resting heart rate: 93 bpm; Fig 1B). He was asymptomatic. An ECG performed at the time revealed sinus bradycardia with a normal QTc. Serum electrolyte and creatinine levels were within reference range. No specific therapy was given, and the bradycardia resolved over 8 days.

Table 1 outlines the significant features of the 2 described cases and those of the 3 other children who developed bradycardia during pulse methylprednisolone therapy at our institution. All had an adequate nutritional state. All were treated using the same protocol (30 mg/kg methylprednisolone to a maximum of 1000 mg diluted in 100 mL normal saline or 5% dextrose/0.2% normal saline infused over 30–60 minutes) and all had continuous monitoring of vital signs before, during, and after the infusions. Each patient had had >1 dose at the time of onset of the bradycardia, which occurred at a median of 50 hours after the first infusion. Recorded heart rates at the nadir of bradycardia in each patient were below the 5th percentile for age. In all the cases, bradycardia was most prominent at rest or during sleep. Although heart rates increased when the patients were roused through the day, they were usually at the lower limit of normal for age and decreased again as they fell asleep. One child had a blood pressure above the 99th centile for age at the time his bradycardia was noted. Blood pressure in the other 4 patients was normal. Electrocardiography revealed sinus bradycardia in all the cases. One patient was found to have a prolonged QTc. Four children had electrolyte levels checked at the time the bradycardia was first noted; one had a low serum calcium level, and another had borderline-low serum potassium and magnesium levels. In both cases, bradycardia persisted despite correction of the observed abnormalities. The bradycardia was asymptomatic in all patients and resolved without specific drug therapy over 3 to 10 days.


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  		TABLE 1 Summary of the Clinical Features and Investigations of the 5 Patients

 

DISCUSSION

High-dose intravenous pulse methylprednisolone has become an important therapeutic modality for clinicians treating diseases in which rapid control of immune-mediated processes is required. Arrhythmias have been reported to occur in anywhere from 1% to 82% of patients receiving such therapy.7,8,13,21 Those most commonly described are sinus bradycardia, atrial fibrillation/flutter, and ventricular tachycardia.10–13,22,23 The majority of reports have been in adults; however, arrhythmias have occurred in pediatric patients.16–21 Although most frequently reported in association with intravenous methylprednisolone at a dose of 30 mg/kg (maximum of 1.0 g), arrhythmias may also occur at lower doses20,24,25 and with administration by the intramuscular or even oral route.19,22 They have been reported after both single and consecutive daily doses, and their onset may occur as early as during administration of the methylprednisolone to as late as several days afterward.23,26–28 The late development of arrhythmias may make it difficult to identify methylprednisolone as the cause if the association is not appreciated. The mean time to development of bradycardia from initiation of therapy in our cases was 44 hours (range: 24–60 hours).

Symptoms resulting from arrhythmias in reported cases have ranged from none to palpitations, loss of consciousness, and cardiac arrest.11,13,19,20,22,23 Interventions have varied from simple observation to administration of chronotropic or antiarrhythmic agents11,28,29 to temporary cardiac pacing.19 The reported duration of arrhythmias has varied from hours to days. All our patients were asymptomatic and continued to have bradycardia for at least 72 hours after it was first noted.

The mechanisms underlying the development of arrhythmias in association with high-dose steroids are unknown. In animal studies, high-dose methylprednisolone has significant effects on cardiovascular physiology that may be mediated both by direct action on the myocardial cell membrane and via alterations in cardiovascular sensitivity to catecholamines.30,31 In humans, intravenous methylprednisolone alters the stimulation threshold of myocardial cells and, when given in pulse doses, alters serum potassium and the urinary excretion of both potassium and sodium; these changes might conceivably alter electrolyte shifts across myocardial cell membranes.13,32,33 Although 2 of our patients had abnormal electrolyte levels at the time their arrhythmias were detected, correction of the abnormalities did not have any immediate effect on their bradycardia. Alternatively, it is possible that pulse methylprednisolone–induced changes in sodium and water physiology result in expansion of plasma volume, triggering a reflex bradycardia by activation of low-pressure baroreceptors.34 Because this was a retrospective study, we were unable to explore this possibility further in our patients. Other proposed mechanisms for development of arrhythmias in association with high-dose steroid therapy include reaction to excipients in the steroid preparations or the presence of a "predisposed" myocardium.16 One of our patients was found to have a prolonged QTc at the time of his bradycardia. Whether this represents an effect of pulse methylprednisolone (which has not previously been reported), an underlying electrophysiological defect, or a combination of both is unclear. Carriers of certain long QT syndrome gene mutations or polymorphisms may manifest a prolonged QTc only when exposed to a predisposing factor(s).35 Hypertension is a recognized adverse effect of pulse methylprednisolone,8 and baroreceptor-mediated reflex heart rate reduction is a potential explanation for bradycardia in this setting. All but 1 of our patients were normotensive at the time of their bradycardia, a finding similar to that of a previous report that indicated a lack of consistent change in blood pressure in adult patients with steroid-induced bradycardia.28 Finally, it is possible that the activity of the underlying inflammatory diseases in our patients, with associated hyperdynamic circulation, contributed to the baseline heart rate seen in our patients and that reduction in inflammation as a result of treatment was responsible for the observed decrease in heart rate. Although this may be true to some extent, a sustained heart rate below the 5th percentile in this situation would not be expected. Furthermore, in each case the observed bradycardia was observed to resolve after the cessation of pulse methylprednisolone, which makes it likely to have been a "real" effect and not simply a reduction in inflammatory response. It is likely that arrhythmias after pulse methylprednisolone therapy have a multifactorial origin. Our current practice when an arrhythmia is noted during pulse methylprednisolone therapy is to obtain an ECG, check serum sodium, potassium, calcium, magnesium, and albumin levels, and correct any electrolyte abnormalities identified. Inpatients have continuous cardiac monitoring.

CONCLUSIONS

Bradyarrhythmias, particularly sinus bradycardia, may occur as an adverse effect of intravenous methylprednisolone pulse therapy administered on consecutive days in children. Reductions in heart rate are usually delayed in relation to the steroid infusion and frequently not apparent until the second or third day of therapy. Although their duration may be prolonged, typically continuing for several days after the cessation of pulse methylprednisolone therapy, symptoms are rare. Spontaneous resolution can be expected.

FOOTNOTES

Accepted Sep 15, 2006.

Address correspondence to Rayfel Schneider, MBBch, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail: rayfel.schneider{at}sickkids.ca

The authors have indicated they have no financial relationships relevant to this article to disclose.

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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