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 Table of Contents  
BRIEF REPORT
Year : 2015  |  Volume : 1  |  Issue : 1  |  Page : 23-26

Late onset bradycardia: An unusual Side-Effect of high dose dexamethasone pulse therapy in patients of pemphigus vulgaris: A case series of five patients


1 Department of Dermatology, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur, Maharashtra, India
2 Department of Medicine, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur, Maharashtra, India

Date of Web Publication1-Dec-2015

Correspondence Address:
Shuken Dashore
Department of Dermatology, NKP Salve Institute of Medical Sciences and Lata Mangeshkar Hospital, Nagpur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/WKMP-0110.170754

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  Abstract 

Introduction: High-dose corticosteroids are used for various autoimmune and inflammatory diseases. When supra-pharmacologic doses of corticosteroids are used intravenously for the treatment of immunobullous diseases such as pemphigus, it is likely to be associated with side effects such as electrolyte disturbances, hypertension, and psychosis. Case Reports: In these case series, we report five patients receiving high-dose of dexamethasone with or without cyclophosphamide pulse, developing an unusual form of late onset bradycardia. Details of these patients developing bradycardia after dexamethasone pulse therapy are presented here. In all of these cases, bradycardia can be attributed to high-dose intravenous dexamethasone therapy. Bradyarrhythmias and sinus bradycardia may occur as an adverse effect of pulse therapy. Conclusion: Late onset of bradycardia is usually delayed in comparison to steroid infusion and frequently not apparent even after the 3rd day. Bradycardia may be associated with dizziness and may lead to fall and unnecessary trauma. Dermatologists should be aware of this complication, and timely referral to physician is essential.

Keywords: Bradycardia, pemphigus, pulse therapy


How to cite this article:
Dashore S, Pande S, Borkar M, Pande A. Late onset bradycardia: An unusual Side-Effect of high dose dexamethasone pulse therapy in patients of pemphigus vulgaris: A case series of five patients. Indian J Drugs Dermatol 2015;1:23-6

How to cite this URL:
Dashore S, Pande S, Borkar M, Pande A. Late onset bradycardia: An unusual Side-Effect of high dose dexamethasone pulse therapy in patients of pemphigus vulgaris: A case series of five patients. Indian J Drugs Dermatol [serial online] 2015 [cited 2024 Mar 29];1:23-6. Available from: https://www.ijdd.in/text.asp?2015/1/1/23/170754




  Introduction Top


Corticosteroids have been used in various immune-mediated and inflammatory diseases. High-dose intravenous corticosteroid pulse therapy was first used 30 years ago for the treatment of acute rejection in renal transplantation.[1] Its first dermatologic use was for the treatment of pyoderma gangrenosum.[2] Since then, its use has expanded to multitude of indications, most importantly pemphigus vulgaris. Due to the suprapharmacologic doses of corticosteroids used in pulse therapy, it is associated with multitude of side effects. Multiple cardiac adverse effects may be seen, for example, tachyarrhythmias,[3] bradyarrhythmias,[4] cardiac failure,[5] and myocardial infarction.[5] Sudden cardiac death has also been reported.[5] The case series takes into account 35 patients of pemphigus vulgaris who received high-dose dexamethasone pulse therapy (injection dexamethasone 100 mg intravenously in 500 ml normal saline given over 3 h with injection cyclophosphamide [some cases] 500 mg intravenously) over a period of 6 months.


  Case Reports Top


Case 1

A 34-year-old female patient came with a history of erosions over chest and back since 1 month. She was diagnosed as a case of pemphigus vulgaris on biopsy and was started on dexamethasone cyclophosphamide pulse (DCP) therapy (injection dexamethasone 100 mg intravenously in 500 ml normal saline over 3 h on three consecutive days + injection. cyclophosphamide 500 mg on the 2nd day). Prepulse investigations and electrocardiogram (ECG) were within normal limits. Mean prepulse heart rate was 88 beats/min (bpm). The patient was asymptomatic and had no other complaints suggestive of any cardiac illness. Three days of dexamethasone infusion were uneventful. Approximately, 18 h after the third dose or on the 4th day, patient developed persistent resting bradycardia with heart rate of 44 bpm (previous heart rate being 88 bpm). The patient suffered slight dizziness on walking. ECG revealed sinus bradycardia with no other abnormalities. Lowest saturation percent of oxygen (SpO2) was 90% and patient was started on continuous cardiac and SpO2 monitoring and was resolved with O2 supplementation through mask. Serum electrolytes including serum sodium, potassium, calcium, magnesium, and creatinine were within normal limits. Two-dimensional echocardiography study showed normal cardiac function other than bradycardia. On physician's advice, cyclophosphamide was stopped, but the omission of cyclophosphamide in therapy did not resolve the bradycardia. No specific therapy was given and bradycardia resolved after 7 days. The patient received four more cycles of dexamethasone pulse therapy without cyclophosphamide, but the bradycardia recurred with each cycle; however, the intensity and duration decreased with each pulse. Bradycardia resolved after the fourth cycle and did not recur after that.

Case 2

A 67-year-old female patient with pemphigus vulgaris was started on dexamethasone pulse therapy (injection dexamethasone 50 mg IV in 500 ml normal saline). On the 3rd day, patient had a fall due to dizziness in early morning hours. During resuscitation, the patient was noted to have a bradycardia of 44 bpm (prepulse heart rate 92 bpm). She regained consciousness immediately. Serum electrolytes (sodium, potassium, calcium, and magnesium) and creatinine were within normal limits and ECG showed sinus bradycardia. The patient was asymptomatic after that with no functional deficit and bradycardia resolved after 3 days.

Case 3

A 45-year-old female patient was diagnosed as a case of pemphigus vulgaris and was started on dexamethasone DCP therapy (Inj dexamethasone 50 mg intravenously in 500 ml normal saline over 3 h on 3 consecutive days + injection cyclophosphamide 500 mg on the 2nd day). The first 2 days of pulse therapy infusion were uneventful. On the 3rd day, patient was found to have bradycardia of 40 bpm in the early morning hours on routine monitoring. The heart rate rose to 58 bpm on standing up. Serum electrolytes (sodium, potassium, calcium, and magnesium) and creatinine were within normal limits and ECG showed sinus bradycardia. Early morning serum cortisol was sent which was found to be low, 3.2 μg/dl (5–25 μg/dl). The patient was asymptomatic. The third infusion was omitted and the patient was kept under monitoring. Her bradycardia resolved spontaneously after 3 days and did not recur in the further pulses.

Case 4

A 42-year-old female patient with pemphigus vulgaris was started on dexamethasone pulse therapy (injection dexamethasone 50 mg intravenously in 500 ml normal saline). The first cycle was uneventful. During the second cycle, patient developed bradycardia with resting heart rate of 56 bpm on the 4th day (after completing 3 days of infusion). The patient was asymptomatic and her serum electrolytes and creatinine were within normal limits. ECG showed sinus bradycardia. Early morning serum cortisol was sent for the patient and was found to be normal, i.e., 7.8 μg/dl (5-25 μg/dl). The patient's symptoms resolved after 5 days and this bradycardia was recurrent over next two cycles.

Case 5

A 52-year-old female patient, a case of pemphigus vulgaris receiving dexamethasone DCP therapy (injection dexamethasone 100 mg IV in 500 ml normal saline + injection cyclophosphamide 500 mg), came for the third cycle of pulse therapy. After three uneventful days of pulse therapy, patient developed bradycardia on the 4th day. The patient was asymptomatic and serum electrolytes and creatinine were normal. Her bradycardia resolved after 4 days and did not recur then onward.

None of the patients had a preexisting cardiac condition. All the patients were treated with either DCP therapy or plain dexamethasone pulse therapy (injection dexamethasone 100 mg in 500 ml normal saline over 3 h at 45–50 drops/min with injection dexamethasone 100 mg + injection cyclophosphamide 500 mg in 500 ml 5% dextrose over 3 h on the 2nd day). Some patients received lower dose of 50 mg dexamethasone as weight adjusted dose (<45 kg). All the patients had continuous cardiac monitoring before, during, and after the infusion with normal pretreatment ECGs. Bradycardia occurred after a mean of 64 h (42–80 h) after the first infusion. Heart rate was lowest in the morning and increased slightly on waking up from sleep and on standing. Blood pressure was normal in all the patients and usually remained on the lower side. Serum creatinine and serum electrolytes were within normal limits. Bradycardia was symptomatic only in two patients and resolved spontaneously within 3–8 days. Three out of five patients developed bradycardia on their first cycle of pulse therapy, one patient developed it in the second, and one patient during the third cycle. Three patients developed recurrent bradycardia after every pulse for a few pulses, although the intensity and chronicity of bradycardia decreased after each pulse and finally disappeared. [Table 1] summarizes the characteristics of these five cases that developed bradycardia after pulse therapy. Graph 1 denotes temporal co-relation of change in heart rate and blood pressure.
Table 1: Characteristics of the Five Cases of Pemphigus Vulgaris that Developed Bradycardia after Dexamethasone and Cyclophosphamide Pulse Therapy

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  Discussion Top


High-dose intravenous corticosteroid pulse therapy has been used for several decades for the treatment of autoimmune disorders. Arrhythmias have been reported to occur from 1% to 82% of patients receiving therapy.[6] Sinus tachycardia is the most common described arrhythmia with pulse therapy followed by sinus bradycardia, atrial fibrillation, and ventricular tachycardia.[7] One study reported sinus bradycardia in 41.9% patients that underwent methylprednisolone pulse, which was diagnosed by Holter monitoring. Only one study showed association of bradycardia with dexamethasone (33% cases).[7] The late onset of arrhythmias make it difficult to identify steroid as a cause. The mean time for the development of bradycardia from the initiation of pulse therapy in our study was 64 h (42–80 h).

Usually, no intervention is done for bradycardia due to transient nature of the arrhythmia. The mechanisms underlying the development of arrhythmias in association with high-dose steroids are unknown. Animal studies have shown that high-dose corticosteroid therapy might blunt the chronotropic response of catecholamines in the heart, owing to down regulation of alpha-1 and beta-1 receptors which could potentially lead to bradycardia.[8] However, this has not been definitively shown to occur in human subjects. Other studies suggest a transient shift in renal electrolytes (sodium, potassium, and calcium) excretion after intravenous methylprednisolone administration in patients, which can lead to shifts across myocardial cell membranes and differing cardiac dysrhythmias.[9] Though we did not come across any electrolyte disturbances in our patients, other studies have shown that correction of electrolyte imbalances does not correct the bradycardia. Hypertension is a recognized adverse effect of pulse therapy and baroreceptor-mediated reflex heart rate reduction is a potential explanation for bradycardia in this setting. However, all 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.[10] We performed early morning serum cortisol levels in two patients which were found to be lower. This finding may point toward hypothalamo-pituitary-adrenal axis suppression (hypothalamic–pituitary–adrenal axis) as a cause of this bradycardia. The blood pressure also remains on the lower side supporting the finding.[11] Further studies are required to confirm this hypothesis.

Bradyarrhythmias and sinus bradycardia may occur as an adverse effect of pulse therapy. Onset of bradycardia is usually delayed in comparison to steroid infusion and frequently not apparent even after the 3rd day. Bradycardia may be associated with dizziness and may lead to fall and unnecessary trauma. In our case series, we encountered sinus bradycardia in 15% cases receiving pulse therapy over a period of 6 months. This bradycardia is usually recurrent with each pulse and persists even after removal of cyclophosphamide suggesting the role of high-dose of dexamethasone. Bradycardia may not resolve after correcting electrolyte imbalance, if any. Spontaneous resolution of bradycardia may be expected. Probability of developing bradycardia is usually more in the first few pulses. Physiological dose of steroids should be considered to be given for a few days after completing the pulse therapy to reduce the chances of addisonian crisis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Woods JE, Anderson CF, DeWeerd JH, Johnson WJ,Donadio JV Jr, Leary FJ, et al. High-dosage intravenously administered methylprednisolone in renal transplantation. A preliminary report. JAMA 1973;223:896-9.  Back to cited text no. 1
[PUBMED]    
2.
Galun E, Flugelman MY, Rachmilewitz D. Pyoderma gangrenosum complicating ulcerative colitis: Successful treatment with methylprednisolone pulse therapy and dapsone. Am J Gastroenterol 1986;81:988-9.  Back to cited text no. 2
[PUBMED]    
3.
Chikanza C, Fernandes L. Arrhythmia after pulse methylprednisolone therapy. Br J Rheumatol 1991;30:392-3.  Back to cited text no. 3
[PUBMED]    
4.
Sethy PK, Khandpur S, Sharma VK. Randomized open comparative trial of dexamethasone-cyclophosphamide pulse and daily oral cyclophosphamide versus cyclophosphamide pulse and daily oral prednisolone in pemphigus vulgaris. Indian J Dermatol Venereol Leprol 2009;75:476-82.  Back to cited text no. 4
[PUBMED]  Medknow Journal  
5.
Smith RS, Warren DJ. Effects of high-dose intravenous methylprednisolone on circulation in humans. Transplantation 1983;35:349-51.  Back to cited text no. 5
    
6.
Akikusa JD, Feldman BM, Gross GJ, Silverman ED, Schneider R. Sinus bradycardia after intravenous pulse methylprednisolone. Pediatrics 2007;119:e778-82.  Back to cited text no. 6
    
7.
Jain R, Bali H, Sharma VK, Kumar B. Cardiovascular effects of corticosteroid pulse therapy: A prospective controlled study on pemphigus patients. Int J Dermatol 2005;44:285-8.  Back to cited text no. 7
    
8.
Hall ED, Plaster M, Braughler JM. Acute cardiovascular response to a single large intravenous dose of methylprednisolone and its effects on the responses to norepinephrine and isoproterenol. Proc Soc Exp Biol Med 1983;173:338-43.  Back to cited text no. 8
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9.
Svorcík C, Bicíková L. Effect of drugs on the stimulation threshold of the human heart. Cor Vasa 1978;20:184-95.  Back to cited text no. 9
    
10.
Tvede N, Nielsen LP, Andersen V. Bradycardia after high-dose intravenous methylprednisolone therapy. Scand J Rheumatol 1986;15:302-4.  Back to cited text no. 10
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11.
Lee WS, Lum LC, Harun F. Addisonian-like crisis in congenital hypopituitarism and cholestatic jaundice. Med J Malaysia 2003;58:279-81.  Back to cited text no. 11
    



 
 
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