Hydrocortisone-induced symptomatic sinus bradycardia

Abstract

Steroids are commonly prescribed medications that have a wide range of adverse effects. Bradycardia is one of the rare but significant side effects of steroid use, and only a few cases have been reported with bradycardia as a side effect. In this report, we present a case of a woman in her early 50s who developed severe symptomatic sinus bradycardia following high-dose administration of intravenous hydrocortisone, initiated for acute exacerbation of Crohn’s disease. Her symptoms entirely resolved after discontinuation of the steroid. This case highlights the importance of obtaining baseline ECG and cardiac monitoring in patients treated with pulsed high-dose steroids.

Background

Corticosteroids are used to treat various autoimmune and acute inflammatory conditions. More specifically, hydrocortisone is used in short-term high doses for remission induction in patients with moderate-to-severe flares of Crohn’s disease.¹

Although steroid therapy’s more common side effects are hyperglycaemia, electrolyte abnormalities, hypertension, osteoporosis and gastritis, physicians need to be aware of the cardiovascular side effects of short-term steroids. Researchers have described changes in blood pressure, heart rate, cardiac dysrhythmias and even death in patients receiving short-term intravenous steroids.^{2 3}

Very few studies have reviewed the causal relationship between sinus bradycardia and hydrocortisone. In this case report, we describe an episode of symptomatic sinus bradycardia occurring after 48 hours of high-dose hydrocortisone therapy in a woman in her early 50s admitted with an acute flare of Crohn’s disease.

Case presentation

A woman in her early 50s with a background of recurrent admission for Crohn’s disease was admitted to the hospital with sudden onset severe colicky abdominal pain associated with nausea and bilious vomiting.

On physical examination, she was afebrile with a temperature of 37.0 °C, mildly dehydrated, not dyspnoeic or tachypnoeic, with a respiratory rate of 18 per minute. Her blood pressure was 116/64 mm Hg, and her pulse rate was 65 beats per minute. Her abdomen was mildly distended, soft and tender in the right iliac fossa, with no guarding or enlarged organs. Examination of the cardiorespiratory and neurological system was unremarkable.

She was diagnosed with small bowel obstruction secondary to an acute flare of Crohn’s disease. The baseline investigations were within normal limits, and we commenced treatment with intravenous fluids, analgesia, anti-emetics and high-dose hydrocortisone, and her symptoms subsided following treatment.

However, 48 hours after admission, she developed palpitations and became clammy. She was assessed and found to be bradycardic with a pulse rate of 28 beats per minute and blood pressure of 110/62 mm Hg. There was no associated chest pain, loss of consciousness or shortness of breath. Interestingly, the patient linked her symptoms to the steroid administration and declined an evening dose in an attempt to increase her heart rate.

We commenced telemetry, repeated her investigations, reviewed medications and discontinued the hydrocortisone. Without further intervention, her symptoms resolved, and her pulse rate gradually returned to her baseline over 48 hours.

Investigations

Preliminary baseline investigations on admission were within normal limits and negative for COVID-19 PCR. CT scan of the abdomen showed active multifocal Crohn’s disease within the terminal ileum with significant stricturing, inflammation and skip lesions.

Repeat investigations done at the onset of bradycardia can be summarised in table 1. We checked the cardiac enzymes, thyroid function and electrolytes, and they were within normal limits. ECG showed sinus bradycardia with a heart rate of 31 beats per minute, PR interval 168 milliseconds, QRS duration 96 milliseconds, QTc 410 milliseconds and there was no evidence of coronary ischaemia as seen in figure 1. Echocardiography was done and showed normal left ventricular ejection fraction with no regional wall motion abnormality.

Table 1.

Table showing result of investigations done at the onset of bradycardia

Investigations	Result	Normal range
Haemoglobin	124 g/L	115–165 g/L
White blood cell count	4.6×109/ L	4.0–11.0×109/ L
Neutrophil	3.8×109/ L	1.7–7.5×109/ L
Platelet	379×109/ L	150–400×109/ L
Thyroid-stimulating hormone	0.78 mU/L	0.35–5.50 mU/L
Free T4	13.1 pmol/L	7.0–17.0 pmol/L
Potassium	4.0 mmol/L	3.5–5.3 mmol/L
Magnesium	0.78 mmol/L	0.7–1.0 mmol/L
Corrected calcium	2.37 mmol/L	2.20–2.60 mmol/L
Urea	3.5 mmol/L	2.5–7.8 mmol/L
Creatinine	52 umol/L	46–92 umol/L
eGfr	>90 mL/min/1.73 m2	>90 mL/min/1.73 m2
Troponin	2 ng/L	<12 ng/L
CRP	7 mg/L	<5 mg/L

Figure 1.

ECG showing sinus bradycardia at the onset of symptoms.

Differential diagnosis

Sinus bradycardia is frequently encountered in clinical practice, ranging from being an incidental finding in otherwise healthy adults to a presentation of multiple disease processes such as myocardial infarction, myocarditis, hypothermia, hypoxia, hormonal disorders, electrolyte derangements, raised intracranial pressures, drugs, infections, toxins or due to intrinsic conduction disorders.

These were ruled out after a normal systemic examination and further investigations. Her inflammatory markers, serum potassium, calcium, troponin I and thyroid function tests checked at the onset of symptoms were all within normal limits. She had a normal echocardiogram and was not on any rate-limiting medication, such as beta-blockers or digoxin.

Every day, the telemetry recordings were analysed, and no atrioventricular conduction delay or other conduction anomalies were found.

Treatment

The cardiology team liaised with the primary general surgical team, gastroenterology and hospital pharmacy. Her medications which included enoxaparin sodium, hydrocortisone, metronidazole, paracetamol and protein dietary supplements were reviewed, and the hydrocortisone was stopped. Atropine was not given as her symptoms resolved at rest, and her blood pressure was stable. We advised that a non-steroid agent be used in the medical management of her Crohn’s disease.

Outcome and follow-up

The patient’s heart rate slowly improved after the withdrawal of hydrocortisone and returned to baseline after 48 hours. An ECG was repeated, which showed sinus rhythm with a heart rate of 84 beats per minute, PR interval 157 milliseconds, QRS duration 84 milliseconds, and QTc 421 milliseconds as seen in figure 2. She subsequently had exploratory laparotomy and ileal resection as definitive management for her Crohn’s disease.

Figure 2.

ECG showing heart rate of 84 beats per minute.

A 24-hour Holter was recorded at follow-up, which showed sinus rhythm, heart rate spread of 51–119 beats per minute with a mean heart rate of 74 beats per minute. No symptoms were reported in the patient diary.

Discussion

The first report of corticosteroid-induced bradycardia was made in 1986. A few hypotheses were put up to account for its occurrence, but the precise process is still unknown. According to one theory, corticosteroids’ abrupt changes to the physiology of water and electrolytes in humans cause the plasma volume to increase, activating the low-pressure baroreceptors and causing bradycardia.

The altered sensitivity of the sinoatrial node to catecholamines by steroids, is another mechanism of bradycardia.^{4 5} Corticosteroid-induced bradycardia is also thought to be due to transient injury to the myocardium.⁶ However, this was excluded in our case as the patient had a normal echocardiogram.

A literature review revealed that steroid-induced bradycardia is likely underdiagnosed because most patients are asymptomatic,^{2 7 8} in contrast to our case where the patient experienced symptoms. Although the bradycardia resolves spontaneously after discontinuation of the medication, it is also crucial to rule out other, more prevalent causes of bradycardia, such as hypothyroidism, electrolyte imbalance and the use of drugs including beta-blockers, calcium channel blockers and digitalis. Our patient’s thyroid function was normal, and she did not use any rate-limiting medication.^{5 9}

There have been reports of bradycardia associated with prednisolone, methylprednisolone and dexamethasone. However, to our knowledge, there is only one reported incidence of bradycardia due to high-dose hydrocortisone. The patient received intravenous hydrocortisone 200 mg three times per day (total of 600 mg per day) for treatment of lupus nephritis compared with our patient who received 100 mg four times per day (total of 400 mg per day) for the treatment of Crohn’s disease.⁵

Bradycardia was observed to occur from as early as after the first steroid dose,⁵ to approximately after 7 days of steroid therapy.⁴ However, in this case, she developed bradycardia on the third day, which was consistent with findings by Hallberg et al.¹⁰

The Naranjo scale in table 2, is an adverse drug reaction probability scale developed in 1991 to help standardise the assessment of causality of an adverse drug event. Total scores range from −4 to +13; a score of ≥9 is considered a definite adverse reaction, probable adverse reaction if 5–8, possible if 1–4 and doubtful if ≤0. In our case, the calculated score was 8, which suggests a probable adverse reaction.^{6 8 11}

Table 2.

Naranjo adverse drug reaction probability scale

Questions	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	+1
Did the adverse event appear after the suspected drug was administered?	+2	–1	0	+2
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?	+1	0	0	+1
Did the adverse event reappear when the drug was readministered?	+2	–1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	–1	+2	0	+2
Did the reaction occur when the placebo was given?	–1	+1	0	0
Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	+1
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total score				8

CRP, C-reactive protein; eGFR, estimated glomerular filtration rate.

Patient’s perspective.

After about 48 hours of admission, I started to feel strange, “my face and chest often became flushed, my heart felt fluttery and I felt a strange pressure in my chest”. I noticed this feeling felt more intense following hydrocortisone administration.

My husband visited me later that evening, and we went for a stroll outside the ward. I started to feel faint, sweaty and my legs started to feel “jelly-like”. He gave me his fitbit, and we found my heart rate was 38 beats per minute.

In the hospital, I started keeping track of my heart rate, which was consistently very low. I became more anxious after learning that it dropped to 27 beats per minute while I slept.

I asked the nursing staff if it was possible that the steroids I was taking were to blame for my low heart rate, and they tried to convince me that this was not the case. I went online and saw that, in extremely rare circumstances, steroids could result in bradycardia. Since I had never taken steroids before, I quickly surmised that they were to blame for my low heart rate.

I chose to decline the next steroid dose to get my heart rate back to normal, but it remained low. Although I was merely afraid and attempting to determine why my heart rate was so low, it appeared as though I was being non-compliant with treatment.

The cardiologist came to see me the next day, checked my heart and repeated my blood tests. I discussed the possibility of the steroids causing my low heart rate, and he heard my concerns, investigated it and stopped my steroids. My heart rate slowly returned to normal after 48 hours.

I hope sharing my experience will help increase awareness of bradycardia as a rare side effect of hydrocortisone.

Learning points.

• Bradycardia is a rare but reversible side effect of high-dose steroid administration.

• This case emphasises the importance of reviewing medications when assessing the acutely unwell patient.

• Clinicians should obtain a baseline ECG and cardiac monitoring in patients treated with pulsed high-dose steroids.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).