Introduction
Graves’ disease is an autoimmune disorder characterised by the presence of thyroid-stimulating hormone receptor antibodies, which cause hyperthyroidism. The incidence in children before the age of 15 years is 1 to 2.91/100,000 per year. Reference Mooij, Cheetham and Verburg1
High thyroid hormone levels cause increased heart rate through a positive chronotropic effect. Excessive thyroid hormones may cause myocardial damage, in particular triiodothyronine (T3). Increased metabolic rate, total blood volume, and other effects of T3 causes heart failure and thyrotoxic cardiomyopathy. Reference Biondi2 Sinus tachycardia due to hyperthyroidism has been reported at a rate of 28%–73% in adult studies. Reference Go, George and Tahsin3,Reference Osman, Gammage and Sheppard4 Beta-blockers are generally considered the first-line treatment for ventricular rate control in patients with thyrotoxicosis. Reference Kim, Cho and Kim5 However, some patients may remain symptomatic. Ivabradine selectively and specifically inhibits f-channels within the sinoatrial node in a dose-dependent way, prolongs diastolic depolarisation, increases ventricular filling time, slows the sinoatrial node, and ultimately reduces heart rate. Other than sinus node effects, no effects on myocardial contractility or relaxation, ventricular repolarisation, or conduction have been demonstrated. This feature makes ivabradine superior to beta-blockers and calcium channel blockers. Reference Medina, Khan and Spagnola6 Studies have reported that ivabradine is safe to use alone or with beta-blockers in inappropriate sinus tachycardia or sinus tachycardia secondary to hyperthyroidism. Reference Medina, Khan and Spagnola6–Reference Ptaszynski, Kaczmarek and Ruta8 However, there is no data on this subject in the literature for the paediatric age group.
We present a case of sinus tachycardia due to hyperthyroidism that persisted despite maximum doses of beta-blockers and was successfully treated with ivabradine. To our knowledge, this is the first reported use of ivabradine in tachycardia due to hyperthyroidism in childhood.
Case report
A female patient, aged 13 years and 11 months, was admitted to the emergency department for palpitations after the school nurse recorded her heart rate as 147 beats per minute 2 years ago. Prior to admission, the patient reported experiencing hair loss, sweating, and a weight loss of 3–4 kilos. Additionally, thyroid hormone levels were low 1 year ago after a flu infection but were normal at the follow-up visit 15 days later. The patient’s grandmother had a history of thyroid disease and was prescribed thyromazole. During the physical examination, the patient’s weight was recorded as 37 kg, with a height of 153 cm. The heart rate was 145 beats per minute, the blood pressure was 110/70 mmHg, and the thyroid was palpable at grade 1B. Additionally, the patient exhibited tremors and exophthalmos. The electrocardiogram showed no additional features except sinus tachycardia (Figure 1), and the echocardiogram showed no cardiomyopathic changes with a normal ejection fraction.
Emergency department admission electrocardiography.
In the emergency department, Adenosine (0.1 mg/kg) test and Metoprolol (0.1 mg/kg) treatment were administered intravenously for tachycardia. However, tachycardia persisted. Electrocardiogram records during emergency department practice are shared in Figure 2. Laboratory tests revealed hyperthyroidism with thyroid-stimulating hormone levels below 0.003 mU/L, free thyroxine (fT4) levels of 3.15 ng/dL (normal range: 0.7–1.48), and free triiodothyronine (fT3) levels above 20 ng/L. Thyroid ultrasound revealed heterogeneous echogenicity with increased thyroid size and vascularity. The Pediatric Endocrinology department diagnosed Graves’ disease and initiated methimazole as treatment. The patient was prescribed propranolol (40 mg twice a day, 2 mg/kg/day) to be used when experiencing palpitations. During the follow-up, the patient reported experiencing palpitations and subsequently attended the Pediatric Cardiology outpatient clinic. Despite routine propranolol treatment (80 mg/day, 2 mg/kg/day), the patient continued to experience palpitations and high blood pressure. The patient’s thyroid function tests could not be fully controlled, resulting in an increase in the dose of antithyroid medication. Due to ongoing tachycardia complaints, the dose of propranolol was gradually increased to 40 mg four times a day (4 mg/kg/day). No changes were detected in the electrocardiogram during this period. Despite the administration of the maximum dose of antithyroid drugs, euthyroidism could not be maintained, and surgery or radioactive iodine treatment was recommended.
Electrocardiography before, during, and after adenosine administration in the emergency department.
Despite the administration of the maximum tolerated dose of beta-blocker (during the 50-day period, 4 mg/kg/day) and the maximum dose of antithyroid therapy (30 mg methimazole daily), the patient’s tachycardia persisted. Subsequently, following the acquisition of the requisite consent from the patient’s parent, a modification was made to the medical treatment plan, which was changed to ivabradine 2.5 mg twice daily (0.1 mg/kg/day). Prior to starting ivabradine, an electrocardiogram showed sinus tachycardia (120 bpm) and a QTc of 444 msec (Figure 3), while echocardiographic imaging was normal. Ivabradine was initiated at 2.5 mg twice daily on the first day, with the dose being increased to 3.75 mg twice daily (0.2 mg/kg/day). The patient’s heart rate decreased from 100/min to 79/min. After increasing the ivabradine dosage to 3.75 mg twice daily (0.2 mg/kg/day), the patient’s QTc was measured as 459 msec on the first day. The following day, the QTc value decreased to 400 msec (Table 1, Figure 3). The patient’s heart rate decreased below 100 beats per minute within 24 hours of treatment (Figure 4). During this period, the recommendation was to utilize propranolol treatment when necessary. The patient reported a daily intake of one or two tablets of propranolol.
Electrocardiography before and during Ivabradine use.
Change in heart rate with treatment.
Corrected QT interval changes on electrocardiogram
Qtc = corrected QT interval.
Discussion
Our patient is the first paediatric case in the literature who presented with sinus tachycardia due to hyperthyroidism, whose complaints persisted despite maximum dose beta-blocker treatment and in whom Ivabradine was used.
Beta-blockers are considered the first-line treatment for tachycardia in patients with thyrotoxicosis. In a study conducted on patients with inappropriate sinus tachycardia, it was reported that beta-blocker treatment was beneficial in terms of increasing physical functions, even if the patients did not complain of palpitations. Reference Tagami, Yambe and Tanaka9 But some patients do not respond to pharmacological therapy or may have non-tolerable side effects or have contraindications. Our patient also has tachycardia despite maximum dose of propranolol.
In their study with rats, Kim and colleagues showed that hyperthyroidism causes increase in heart rate, decrease in contractile function, myocyte hypertrophy, and fibrosis in the ventricle, and increase in cardiac remodelling. It was shown that heart rate decreased and contractile function improved in rats given ivabradine. However, it was observed that myocyte hypertrophy and fibrosis did not improve. Reference Kim, Cho and Kim5 This result emphasises the importance of effective treatment without delay in terms of cardiac functions in patients with hyperthyroidism.
Ptaszynski et al published an adult case series, highlighting that ivabradine can be used as second-line therapy in combination with maximum dose beta-blocker therapy or as monotherapy when beta-blockers are contraindicated or ineffective. Reference Ptaszynski, Kaczmarek and Ruta8 In the case report of a 65-year-old woman with tachycardia-induced cardiomyopathy due to thyrotoxicosis, the patient was successfully treated with the combination of ivabradine and carbimazole, and her cardiac functions increased and her arrhythmia improved. Reference Alam and Zaman10 Based on this literature data, we managed sinus tachycardia effectively by using Ivabradine to treat our patient.
In their publication by Donne et al. with 28 children, it was reported that the use of ivabradine was safe and effective, but studies with a larger number of patients were required. They found that there was no QTc prolongation or other electrocardiogram changes. Reference Donne, Roses-Noguer and Till11 The side effects of ivabradine are bradycardia (4% to 10%), hypertension (9%), atrial fibrillation (8%), and heart block, sinoatrial arrest, and phosphene (3%). Reference Nawarskas, Bowman and Anderson12 In practical use, the frequency of side effects is reported to be low and usually does not require discontinuation of the drug. There were no side effects in our patient. In our patient, QTc was at the upper limit after the first dose, but it returned to normal afterwards.
We describe the first paediatric case of persistent sinus tachycardia secondary to hyperthyroidism refractory to maximal doses of propranolol. Our case emphasises that the use of ivabradine is promising and can be considered in cases where tachycardia cannot be controlled despite beta-blockers in children with hyperthyroidism.
Conclusion
In conclusion, in patients with tachycardia, hyperthyroidism should not be missed. The importance of detecting hyperthyroidism in these patients when they first present cannot be overstated. If diagnosis is delayed, heart failure, arrhythmias, and thyrotoxic cardiomyopathy may develop. We think that ivabradine may be a first-line treatment as an alternative to beta-blockers in sinus tachycardia secondary to hyperthyroidism, as it has a low incidence of side effects and is effective at an appropriate dose. Future large prospective trials are needed to examine the efficacy and safety of ivabradine or combined therapy with beta-blockers in the treatment of hyperthyroidism-related tachycardia.
Acknowledgements
We would like to thank the entire paediatric team at Başkent University Ankara Hospital for the exceptional care given to our patient.
Financial support
The authors have no relevant financial or non-financial interests to disclose.
Competing interests
The authors have no conflicts of interest to declare that are relevant to the content of this article.
Ethical standard
The participant and her mother have consented to the submission of the case report to the journal.
