Iranian Journal of Pharmaceutical Sciences Winter 2010: 6(1): 13-18ijps.sums.ac.ir

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Original Article

Intravenous Methylprednisolone, a Possible Cause of the Atrial Fibrillation

Afsaneh Vazina,*, Gholamreza Rouzitalaba, Mohammad Firoozifarb, Farid Zandb

aDepartment of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences,Shiraz, Iran

bAnesthesiology and Critical Care Department, Faculty of Medicine, Shiraz University ofMedical Sciences, Shiraz, Iran

AbstractWe are presenting a case illustrating atrial fibrillation (AF) following the use of

methylprednisolone in a patient with pelvic and femur fracture. A 48- year- old manwith no significant past medical history, was admitted to the emergency departmentafter injury in a car accident. He suffered a multiple bone fracture with chiefcomplaints of pain and shortness of breath. He was transferred to the ICU. To preventfat embolism syndrome, he was treated with methylprednisolone 500 mg every 6h. About 4 h after the second dose, his normal sinus rhythm changed to a sinustachycardia and then to AF. The methylprednisolone therapy was discontinued. Afterabout 8 h of methylprednisolone discontinuation, the patient's normal sinus rhythmreturned. Corticosteroids have been utilized for prevention and treatment of fatembolism syndrome, although there is uncertainty about their effectiveness. Cardiacdysrhythmias have been reported following the use of methylprednisolone. Onepossible mechanism of methylprednisolone induced AF is the direct effect on cellmembrane, resulting in potassium efflux, which in turn, may initiate cardiacdysrhythmias. Previous methylprednisolone-associated AF case reports suggest ahigher chance of AF occurrence with higher dose of methylprednisolone. Corticos-teroids should be used with caution, especially when high doses are indicated andin patients with high risk for arrhythmias.

Keywords: Arrhythmia; Atrial fibrillation; Fat embolism; Methylprednisolone. Received: May 11, 2009; Accepted: October 27, 2009

1. IntroductionFat embolism syndrome (FES) was first

recognized and clinically described in thenineteenth century by Zenker (1862), Czerny

(1875), and Scriba (1880). The syndrome hasbeen associated with traumatic and non-traumatic disorders which contributes to thedevelopment of acute respiratory distresssyndrome [1]. FES rarely occurs due to thenonorthopedic causes [2].

Fat embolism is the release/formation of fatglobules into the circulation and is usually

*Corresponding authors: A. Vazin, Assistant Professor of PharmacyPractice, Shiraz University of Medical Sciences, School ofPharmacy, Shiraz, IranTel: (+98)711-2424128, Fax: (+98)711-2424126E-mail: Vazeena@sums.ac.ir

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lodged in respiratory venous capillary bedsthat may cause FES, which is associated witha series of respiratory symptoms, hypoxiaand even death. The formation andconsequences of fat emboli is highlyunpredictable and it seems to have highmorbidity and mortality (10-20%) rate,especially in elderly and in patients withmultiple underlying medical problems [3].

The treatment of manifestations of FES ismainly supportive care. Different modalitiessuch as early fracture fixation and generalICU management have been proposed fortreatment and prevention of fat embolism [4-6]. The role of corticosteroids is controversialin reducing morbidity and complications.While one study by Lindeque, et al. hassupported the use of methylprednisolone inpatients with FES after long bone fractures,another report by Richards does notrecommend routine use of corticosteroids toprevent fat embolism [1, 3-5].

Despite several case reports of cardiacarrhythmias in association with methylpred-nisolone [8-11], serious cardiovascular sideeffects are very rare and high dose methyl-prednisolone pulse therapy is generally

considered safe [7]. In our institution, methyl-prednisolone is routinely used in patientswith long bone fractures for prevention offat emboli.

Several cases of atrial fibrillation havebeen reported with IV methylprednisolonepulse therapy, however, none have beenutilizing this medication for treatment orprevention of FES. This report is trying todiscuss the use of methylprednisolone inpatients with, or at high risk for, fat emboli andreports a possible sequel, AF, with its use.

2. Case presentationA 48 year-old male was brought to the

emergency department after an injury in acar accident with the chief complaint ofshortness of breath and pelvic pain and wasadmitted to the ICU. The patient was intubateddue to bilateral pneumothorax, which wasthe result of chest injury. Mechanicalventilation was initiated and a chest tube wasinserted. He had no relevant past medicalhistory for any disease. He had never smokedand had no other risk factors forcardiovascular disease. Initially, his cardiacmonitor showed normal sinus rhythm.

Figure 1. The electrocardiogram indicating atrial fibrillation in a patient receiving high dose of methylprednisolone.

Atrial fibrillation by methylprednisolon

On admission to the ICU, he was afebrile,with pulse rate 95 beats/min., respiratory rate24 breaths/min. and blood pressure(BP)115/70 mmHg. Arterial blood gas showedPaO2 92.6 mmHg, PaCO2 35.6 mmHg, HCO3

-

24.8 mEq/ml, O2 saturation 97.7% and pH

7.46. Laboratory tests were done on admissionto ICU, Hgb 10.6gm/dl; white cell count 8500cells/L; platelet 158000 cells/L; Na+ 138meq/L; K+: 4.1 meq/L; BUN 22 mg/dl; Cr 0.9mg/dl. X rays showed pelvic, mid and distalport right femur fractures. Traction splint wasapplied.

His medications on admission to the ICUwere as follows: Enoxaparin 60 mg sub-coetaneous everyday, ranitidine 50 mg IVevery 8 h, cefazolin 1 g IV every 6 h,gentamycin 60 mg IV every 8 h.

On second day of admission, to prevent theoccurrence of FES, methylprednisolone wasinitiated at 500 mg, administered IV over 2 hand repeated every 6 h. About 4 h after thesecond dose, his normal sinus rhythm changedto a sinus tachycardia and then to AF (Figure1). His vital signs prior to the AF episodewere stable: Respiratory rate 16 beats/min.,BP 125/75 mmHg, Temp 37.2 °C. Serumelectrolytes and atrial blood gases at the timeof AF revealed: K+ 3.7 mEq/L, Mg++ 2.69mEq/L, Ca++ 8.6 mEq/L, PaO2 80.4 mmHg,

PaCO2 39.4 mmHg, HCO3- 27.1 mEq/ml, O2

saturation 93.6% and pH 7.45.The methylprednisolone therapy was

discontinued and to control his heart rate,verapamil 5 mg was administeredintravenously. After about 8 h of methylpred-nisolone discontinuation, the patient's normalsinus rhythm returned (Figure 2).

3. DiscussionCorticosteroids have been used to prevent

or treat fat embolism syndrome, althoughthere is uncertainty about their effectiveness.The proposed mechanism by which corticos-teroids exert their therapeutic effects intreatment of FES is stabilization ofmembranes, inhibition of complementmediated leukocyte aggregation and limit-ation of rising the level of free fatty acids.Among corticosteroids, methylprednisoloneis the preferred agent for prevention ortreatment of FES [11].

Our case was a middle-aged man whodeveloped AF after second dose of methyl-prednisolone. Other concurrent drugtreatments were continued after the resolutionof observed arrhythmia (enoxaparin,ranitidine, cefazolin, gentamycin).Furthermore, lack of evidence to suggest thatthose drug therapies can cause AF suggeststhat there is very low possibility that thesedrugs caused AF in our patient. His previousECG had shown normal heart rhythm and

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Table1. Characteristics of patients experiencing atrial fibrillation associated with methylprednisolone therapy.Onset of atrial Previous

Author Age Gender Dose Infusion fibrillation after Disease cardiovascular(years) time methylprednisolone disease

initiationUeda et al., 12 F 1 g IV 2 h After 24 h Systemic lupus No1988 daily erytheomatosusUeda et al., 16 M 1 g IV 4 h After 24 h Idiopathic No1988 daily nephrotic syndromeAslam et al., 37 F 40 mg Not At day 3 Systemic lupus Yes2001 every stated erytheomatosus

8 hMcLuckie et al., 22 M 1 g IV 2 h At day 3 Multiple sclerosis No1993 dailyMoretti et al., 59 M 1 g IV, 2 h, 7 h after Multiple sclerosis No1999 daily the third dose,

125 mg IM bolus after the ninth dose

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his history was negative for cardiacabnormalities or hyperthyroidism, therebymaking a preexisting cardiac problem lesslikely. Moreover, after 8 h of cessation ofmethylprednisolone the patient sinus rhythmreturned to normal. To further determine andestablish causality a validated nomogram,Naranjo Algorithm, was utilized [12]. Totalscore on the Naranjo Algorithm determinedthe probability of causality to be probable(score: 5).

A literature search of Medline (1966-January 2008) revealed five case reports ofAF associated with methylprednisolone thathad been used for treatment of differentunderlying diseases (Table 1) [7-10]. In thecase reported by Aslam et al., although a

relatively smaller dose of methylprednisolonewas utilized, prior history of cardiovasculardisease could have contributed to occurrenceof AF. In other four cases substantially largerdoses were used and in four cases presence ofan autoimmune disease have been reported(Table 1).

Recently, van der Hoof et al. performed acase controlled study on 385 patients to testthe hypothesis that the use of corticosteroidsincreases the risk of new onset AF [13]. In thatstudy, it was reported that high dose corticos-teroids (7.5mg prednisolone equivalent) isassociated with an increased risk of new onsetAF.

In previous case reports, daily doses ofmethylprednisolone that caused AF varied,

Figure 2. The electrocardiogram after methylprednisolone discontinuation in a patient receiving high dose of methyl-prednisolone.

Atrial fibrillation by methylprednisolon

ranging from 120 mg to 1000 mg and all fivecases reported AF within 72 h after beginningpulse methylprednisolone therapy [7-10].This wide dose range suggests that AF is nota dose related event when high doses areutilized. In our case, high dose methylpred-nisolone (500 mg q6h) was associated withdevelopment of AF within 10 h of initialdose.

Concerning the route of administration,AF occurred in two cases of IV methylpred-nisolone pulse therapy. AF is reported withintramuscular administration of methylpred-nisolone in one case [10]. In Huerta et al.study, an increased risk of AF is reportedwith oral steroids, especially with short-termuse [14]. Therefore, it is probable thatdevelopment of arrhythmia is not dependenton the corticosteroids route of administration.

The reason for corticosteroids induced AFis not clearly understood, however, severalmechanisms have been proposed to explainwhy methylprednisolone has this potentialeffect. One possible mechanism is the directeffect of methylprednisolone on the cellmembrane, which causes potassium efflux[15]. This local effect may influence arrhyth-mogenesis. Fujimoto et al. measured serumpotassium in 20 patients before and duringmethylprednisolone therapy. A small butsignificant increase in urinary potassium hasbeen observed which explains the potassiumefflux theory [16]. Other proposedmechanisms are late potential development,anaphylactic reaction and peripheralvasodilation [16-17]. In our patient, besideshigh dose methylprednisolone, low-normalserum potassium (3.7 mg/dl) might havecontributed to the arrhythmia.

4. ConclusionThe patient described here experienced

AF probably induced by methylprednisoloneas validated by the Naranjo probability scale.Corticosteroids should be used with caution,especially in high dose especially in elderly

patients and patients with previouscardiovascular disease. Before and duringthe administration of high dose methylpred-nisolone, close monitoring of ECG andelectrolyte status of patients even withoutknown cardiovascular disease, isrecommended. The effect of corticosteroids infat embolism syndrome is under debate.Further investigations about methylpred-nisolone indication and its appropriate dosein treatment and prevention of fat embolismsyndrome are necessary.

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