Sinus Node Dysfunction Associated with Lithium Therapy in a Child

Abstract

Lithium salts have been used extensively in both adults and children during the last 30 years, for the treatment of a variety of psychiatric conditions, including bipolar disorder. The cardiac side effects of lithium in adult patients have been well described. However, to the best of our knowledge, there are no reports of lithium-induced cardiac side effects in pediatric patients. We describe the case of a 9-year-old boy who developed cardiac toxicity while receiving long-term lithium therapy. (Tex Heart Inst J 2002;29:200–2)

Lithium salts were introduced for psychiatric application about 50 years ago to treat mania. Their use for this purpose was delayed in the United States until 1970 ¹ due, in part, to lithium's uncontrolled use as a salt substitute and instances of resultant toxicity in individuals with cardiac disease. Convincing evidence for both the safety and the efficacy of lithium salts has subsequently been established, leading to its extensive use in adult and pediatric patients for the treatment of mania and major depression associated with bipolar illness, and for the prevention of recurrent episodes of manic-depressive illness. ¹

The cardiac side effects of lithium have been well described at a wide range of plasma concentrations. ² These side effects range from asymptomatic electrocardiographic (ECG) changes to arrhythmias. In recent years, several cases of toxicity have been reported in adults. ^3–8 However, we found no reports in the world medical literature concerning the adverse effects of lithium on cardiac conduction in a pediatric patient. We describe the case of a 9-year-old boy who developed sinus node dysfunction as a result of treatment with lithium.

Case Report

In February 2001, an obese (53 kg, >95th percentile), 9-year-old boy presented at a local emergency room with a history of fever, cough, ataxia, and altered mental status. He had previously been diagnosed with bipolar disorder, for which he had been hospitalized numerous times. During the past year, his medications had included a combination of lithium (1200 mg/day, 3 times per day) and clozapine (250 mg/day, twice per day). Whereas his lithium dosage remained constant, his clozapine dosage had been increased 3 months before this admission. The boy had no history of symptoms related to the cardiovascular system. Because he lived with foster parents, no biological family history was available.

At presentation, the patient's initial evaluation included a complete blood count, electrolytes, arterial blood gas, cerebrospinal fluid analysis, chest radiography, computed tomographic (CT) scan of the head, all of which were normal, and blood cultures and urine toxic screen, the results of which were subsequently negative. Due to his deteriorating clinical condition, he was transferred to the Pediatric Intensive Care Unit (PICU) at our institution, where additional test results included a lithium level of 1 mEq/L (therapeutic range, 0.8–1.2 mEq/L), a normal ECG (Fig. 1), and a nasopharyngeal swab that was positive for influenza A.

Fig. 1 Admission electrocardiogram shows sinus rhythm with normal amplitudes and intervals.

After treatment for his influenza symptoms, including rehydration, the patient improved clinically and was transferred to the pediatric psychiatric ward for adjustment of his psychiatric medications. Three days later, he was transferred back to the medical ward for treatment of moderate dehydration secondary to vomiting and decreased oral intake. He was noted to have concomitant asymptomatic sinus bradycardia with a baseline heart rate of 50 beats/min. This abnormal heart rate response to dehydration was identified, and the cardiology service was consulted.

At that time, an ECG showed sinus bradycardia with a junctional escape rhythm of 40 beats/min (Fig. 2). A 24-hour Holter monitor revealed sinus bradycardia with a junctional escape rhythm, and decreased heart rate variability that ranged from 40 to 60 beats/min. Due to the bradycardia, we tested the serum lithium level again and found it to be in the toxic range (1.29 mEq/L). Therefore, the lithium was stopped. Thyroid function tests also were obtained to rule out hypothyroidism, which is a well-described adverse effect of lithium therapy; the results were within normal limits.

Fig. 2 Electrocardiogram shows sinus bradycardia with junctional escape rhythm at a rate of 40 beats/min.

As treatment continued, the patient was monitored by telemetry for cardiac arrhythmias and given intravenous fluids for rehydration. Three days later, his serum lithium had subsided to an acceptable therapeutic level of 0.95 mEq/L, and his baseline heart rate and its variability gradually returned to normal. An exercise stress test was performed to eliminate the possibility of any intrinsic or residual sinus node dysfunction. During the exercise stress test, his sinus node had an appropriate response with a rate of 152 beats/min; however, the test was terminated due to lack of cooperation by the patient. A 24-hour Holter monitor was repeated, the results of which showed sinus rhythm throughout and normal heart rate variability (range, 60–120 beats/min).

Discussion

Lithium salts are highly water soluble and are well absorbed by the gastrointestinal tract. Complete absorption occurs in about 8 hours, with peak concentrations occurring 2 to 4 hours after an oral dose. Lithium is initially distributed in the extracellular fluid and then accumulates gradually in various tissues. Approximately 95% of a single dose of lithium is eliminated in the urine; with repeated administration, the excretion increases until a steady state is reached after 5 to 7 days. ^1,3 Lithium toxicity in patients undergoing long-term therapy is caused by an inability to adequately excrete the lithium salts, which can occur secondary to renal disease or sodium deficiency (for instance, dehydration secondary to vomiting or diarrhea), when the lithium ion is selectively reabsorbed in the renal tubules. ³

Lithium's cardiac side effects, ranging from benign to severe, have been described at both therapeutic and toxic serum levels in adult patients. ^2–9 Asymptomatic electrocardiographic changes are commonly seen—specifically, changes in the T wave, characterized by flattening, isoelectricity, or inversion. These changes have a reported incidence varying from 20% to 30% up to 100% and resemble the abnormalities seen in cases of hypokalemia with the presence of U waves. ² Other conduction defects and rhythm disturbances have also been reported, ^2–9 including sinus node dysfunction, atrial flutter, atrioventricular block, right bundle branch block, left anterior hemiblock, ventricular tachycardia, ventricular fibrillation, and QT segment prolongation. Lithium also has been reported to cause interstitial myocarditis. ⁷

To our knowledge, we describe the 1st known case of a pediatric patient who developed sinus node dysfunction during lithium therapy. His serum lithium level at the time of sinus node dysfunction was only slightly above the upper limit of the therapeutic range. This finding is consistent with reports in adults with regard to lithium effects on the cardiac conduction system, where no clear-cut relationship exists between serum levels and the severity of manifestations. In fact, many of the cardiac effects of lithium have occurred in patients whose levels were within the therapeutic range. ³

In our patient, the discontinuation of lithium therapy and subsequent rehydration resulted in the recovery of normal function of the sinoatrial node. The normal results of the patient's ECG, Holter monitor, and exercise stress test after his serum lithium levels returned to the therapeutic range confirmed the relationship between the lithium toxicity and the sinus node dysfunction.

On the basis of a report in the literature ⁹ describing irreversible sinus node dysfunction induced by resumption of lithium therapy in an adult patient with a similar history, we recommended that lithium therapy not be resumed in our patient.

In summary, this case report shows that lithium toxicity can occur in pediatric patients, even without modifications in dosage, when intercurrent illnesses cause retention of lithium salts. Therefore, pediatric patients with suspected lithium toxicity should be monitored for cardiac side effects, and discontinuation of lithium should be considered if such effects are observed.