Does Oxybutynin Hydrochloride Cause Arrhythmia in Children with Bladder Dysfunction?

Abstract

Aim: Pediatric surgeons frequently encounter children presenting with voiding dysfunction symptoms, including urgency, frequency, and incontinence. Antimuscarinic agents (Oxybutynin) are the main drugs used to treat patients with overactive bladder (OAB) syndrome, defined as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Increased QT dispersion is known to be the cause of ventricular arrhythmia in various systemic diseases and leads to increased mortality and morbidity. Method: This study represents a subset of a complete data set, considering only those children aged admitted to the Pediatric Surgery and Pediatric Nephrology Clinics during the period January 2011 to July 2012. Result: In this study, we have determined that the QT interval changes significantly depending on the use of oxybutynin. The QT changes increased cardiac arrhythmia in children. Conclusion: For this reason, children using such drugs should be closely monitored for cardiac arrhythmia.

Does Oxybutynin Hydrochloride Cause Arrhythmia in Children with Bladder Dysfunction? DOI: 10.5455/medarh.2013.67.202-204

Med Arh. 2013 Jun; 67(3): 202-204Received: February 28th 2013 | Accepted: April 25th 2013

CONFLICT OF INTEREST: NONE DECLARED

ORIGINAL PAPER

Does Oxybutynin Hydrochloride Cause Arrhythmia in Children with Bladder Dysfunction?

Ilhan Ciftci1, Derya Arslan2, Harun Peru3, Derya Cimen2, Bulent Oran2, Metin Gunduz4

Department of Pediatric Surgery, University of Selcuk, Selcuklu Medical Faculty, Konya, Turkey1

Department of Pediatric Cardiology, University of Selcuk, Selcuklu Medical Faculty, Konya, Turkey2

Department of Pediatric Nephrology, University of Selcuk, Selcuklu Medical Faculty, Konya, Turkey3

Department of Pediatric Surgery, Konya Training and Research Hospital, Konya, Turkey4

Aim: Pediatric surgeons frequently encounter children presenting with voiding dysfunction symptoms, including urgency, frequency, and incontinence. Antimuscarinic agents (Oxybutynin) are the main drugs used to treat patients with overactive bladder (OAB)

syndrome, dened as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia. Increased QT dispersion is known to be the cause of ventricular arrhythmia in various systemic diseases and leads to increased mortality and morbidity. Method:

This study represents a subset of a complete data set, considering only those children aged admitted to the Pediatric Surgery and Pediatric Nephrology Clinics during the period January 2011 to July 2012. Result: In this study, we have determined that the QT interval changes signicantly depending on the use of oxybutynin. The QT changes increased cardiac arrhythmia in children.

Conclusion: For this reason, children using such drugs should be closely monitored for cardiac arrhythmia. Key words: cholinergic antagonists; oxybutynin; urinary incontinence; overactive bladder; children; QT interval.

Corresponding author: Ilhan Ciftci, MD. Selcuk Universitesi Selcuklu Tip Fakultesi, Cocuk Cerrahisi A. D. Konya, Turkey. Tel: [phone]. Fax: [phone]. E-mail: [email protected]

1. INTRODUCTION

Pediatric surgeons frequently encounter children presenting with voiding dysfunction symptoms, including urgency, frequency, and incontinence. This clinical occurrence often suggests overactive bladder and, thus, failed bladder lling. Antimuscarinic agents are the main drugs used to treat patients with overactive bladder (OAB) syndrome, dened as urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia (1). Anticholinergic agents such as oxybutynin chloride have been eective for overactive bladder (2). The treatment of OAB with antimuscarinics is not curative, and since OAB is a chronic disease, treatment may be life-

long. There is a concern that antimuscarinics used for the treatment of OAB can cause increases in HR that may be harmful. Another concern is whether or not these drugs have a potential risk of producing QT interval changes (3, 4). Antimuscarinic-induced increases in HR may put these patients at increased risk. However, increases in HR have, as a rule, not been reported as a major adverse eect in OAB studies of antimuscarinics, and use of these drugs did not seem to increase the risks of ventricular arrhythmias and sudden death in older patients, according to a retrospective database study (5).

Antimuscarinic drugs especially oxybutynin used for bladder dysfunction in children. Information about

the cardiac side eects of these drugs in children is not available in the literature. Our goal in doing this work is to determine the eects on QT dispersion caused by the use of antimuscarinic drugs in children.

2. PATIENTS AND METHODS

This study represents a subset of a complete data set, considering only those children aged admitted to the Pediatric Surgery and Pediatric Nephrology Clinics during the period January 2012 to July 2011. Boys and girls aged 515 years were eligible for inclusion in the study if they had urinary urgency and frequency (8 micturitions on average per 24 h), and/or urge incontinence (incontinence episodes in the daytime at least once a week). Children presenting with overactive bladder, persistent incontinence, and a partial UDS response to an optimal dose of a well-tolerated, extended-release anticholinergic were invited to enter a prospective, open-label protocol. This study was approved by our institutional ethics board. A group of 3 female and 17 male patients was prospectively enrolled and followed a minimum of 1 month after beginning anticholinergic treatment. A total of 20 patients with nonneurogenic overactive bladder were included in this study using well-dened criteria, including intensive medical and behavioral therapy that failed to cure

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Does Oxybutynin Hydrochloride Cause Arrhythmia in Children with Bladder Dysfunction?

urgency and incontinence symptoms, absent correctable neurological anomalies. We observed these patients for QT dispersion, age, gender, heart rate, and body weight.

Before study inclusion, a complete questionnaire, physical examination, urinalysis, abdominal ultrasound, ECG, and echocardiograph were done. As part of the systematic follow-up, every month, patients were re-evaluated with a detailed questionnaire, physical examination, urinalysis, and ECG.

Patients were excluded if they had cardiovascular, hepatic, renal, gastrointestinal, or haematological disease, psychiatric disorder, or diabetes insipidus. Patients were also excluded if they had known anatomical abnormalities of the urinary tract, episodes of bacteriuria within 4 weeks before the study start, any condition that was a contra indication for anticholinergic therapy, treatment with other drugs having effects on the lower urinary tract, a residual urine volume (measured by ultrasonography) of>5 mL at repeated investigations (at the pre-trial screening), a history of clinically signicant hypersensitivity or severe allergy, or a history of severe adverse drug reaction or intolerance to anticholinergic drugs.

Electrodes were inserted in anatomical positions according to routine procedure and ECG strips were recorded for 10 seconds with a standard device. 12-lead electrocardiograms (ECG) of all the patients were obtained at amplitude of 20mm/mV and a velocity of 50mm/s. The patients were subjected to manual ECG analysis by three cardiologists who were blinded to the study. QT intervals were manually measured in all possible leads. The QT interval was dened as the interval from the onset of the QRS complex to the end of the T wave, which was dened as its return to the T-P baseline. The measurements were carried out with a precision of 0.01 mm (0.4 ms). If the U wave was present, the QT interval was measured to the nadir of the curve between the T and U waves (6) (Figure 1).

The QT intervals were corrected us

ing Bazetts formula to compensate for its known dependence on heart rate: QTc = QT / RR. Measurements of QT and RR intervals were carried out in 3

consecutive cardiac cycles in all leads, and average values were obtained [7]. QT dispersion was determined as the dierence between the maximal and minimal corrected QT interval in different leads.

The mean standard deviation was observed. The paired t-test was used for repeated measurements. All statistical analyses involved SPSS for Windows version 15.0 (SPSS, Chicago, IL, USA); p values <0.05 were accepted as statistically signicant.

3. RESULTS

The study included a total of 3 girls and 17 boys who had persistent urgency and incontinence after a minimum of 1 month of therapy with an optimal dose of a well-tolerated, extended-release oxybutynin hydrochloride treatment. The mean patient age was 9 years (range5 to 15) (Table 1). There wasa predominance of boy patients 17 (85%) among the admissions; girl patients accounted for 3 admissions, a rate of 15%. Theage and body weight of thepatients caused no statistically signicant dierence.

All electrocardiogramsand urinary analyses werenormal. No urinary upper tract deterioration wasnoted on subsequent ultra-sounds. Tolerability wasassessed by documentingagent therapy experienceusing a questionnaire administered by a pediatricsurgeon. The patients andparents were asked to report any adverse event as soon as it occurred to prevent recollection bias.

A comparison of the QT wave variability parameters of both analyses demonstrated that there was a significant dierence between the QT max and QT min values (p: 0.05); the QT wave dispersion levels of the patients were higher than in the initial analysis (p: 0.05) (Table 2). The heart rate before and after the administration of oxybutynin showed no statistically signicant dierence (Table 1).

4. DISCUSSION

Oxybutynin has historically been the drug of choice for the treatment of overactive bladder in adults; it has also been widely used in children. All anti-cholinergic drugs can have bothersome adverse eects. Dry mouth is the most common; however, constipation, gastro-oesophageal reux, blurred vision, urinary retention, and adverse cognitive eects can also occur, although these symptoms are generally less bothersome in children (8). Oxybutynin appears to be particularly noxious in children, with reports of CNS eects such as hallucinations, psychosis, and concentration problems (9).

Jones et al. investigated the cardioactive properties of oxybutynin in guinea pigs and rabbit cardiac tissue.

Recordings of membrane currents from whole-cell-congured ventricular myocytes showed action potentials from guinea pig and rabbit papillary muscles. L-type Ca2+ current [I (Ca),L], inward rectier K+ current [I(K1)], and delayed rectier K+ current [I(K)] were unaected by < or = 1 mM oxybutynin and inhibited by higher concentrations. Because the peak therapeutic plasma concentrations of oxybutynin are in the 0.010.1 mM range, the investigators concluded that it was highly unlikely that oxybutynin would have adverse effects on cardiac electrical activity (10).

Std.

Deviation

QT wave dispersionbefore medication 40 132 82,85 26,256

QT wave dispersionafter medication 68 152 103,70 25,159

Age 5 15 9,00 2,791 Body weight 13 54 32,60 10,894 Heart rate beforemedication 57 98 86,90 8,454

Heart rate aftermedication 64 96 84,60 8,432

Table 1. Patients data.

QT wave dispersion before medication

QT wave dispersion after medication

Minimum

Maximum Mean

Mean 82,85 103,70 Std.

Deviation 26,256 25,159

Table 2. QT wave dispersion levels of the patients.

Normal Parameters

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Does Oxybutynin Hydrochloride Cause Arrhythmia in Children with Bladder Dysfunction?

Abrams et al. compared the efficacy, safety, and tolerability of oxybutynin and propiverine in a randomized crossover study. HR and HRV were monitored with ECG recordings on a Holter monitor at baseline and at the end of the treatment period. The patients on regimens of propiverine 20 mg daily and propiverine 15 mg three times a day had a statistically signicant increased HR and decreased HRV. Patients on oxybutynin had a similar HR and HRV compared with those on placebo (11).

QT prolongation is produced by many widely used drugs, such as the antiarrhythmic agents sotalol, amiodarone, quinolone, macrolide antibiotics, and methadone. A larger dierence between the action potential duration in adjacent regions of the ventricular myocardium enables circular reentry activity between areas with delayed repolarisation and those with excitable myocytes (12). QT dispersion indicates ventricular repolarisation time and heterogeneity. Increased QT dispersion is known to be the cause of ventricular arrhythmia in various systemic diseases and leads to increased mortality and morbidity. (13).

Information on the possible QT effects of oxybutynin in patients is scarce, and specic studies seem to be lacking. The drug did not cause changes in the ECGs of elderly patients with urinary incontinence (14).

Among the more serious concerns related to the antimuscarinics used in the treatment of OAB are the risk of adverse cardiac effects, particularly increases in HR, QT interval prolongation, and the induction of polymorphic ventricular tachycardia (torsade de pointes). However, the potential of

the dierent agents to increase HR or to prolong the QT interval has not been extensively explored (15).

The aforementioned studies were performed in adults. Cardiac side effects in adults have been revealed. There is no study addressing the cardiac side eects and the eects on the QT of the use of oxybutynin in children. In our study, we determined that the QT interval changes signicantly depending on the use of oxybutynin. The QT changes increased cardiac arrhythmia in children. For this reason, children using such drugs should be closely monitored for cardiac arrhythmia.

REFERENCES

1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003; 61: 37-49.

2. Yucel S, Akkaya E, Guntekin E, Kukul E, Danisman A, Akman S, et al. Should we switch over to tolterodine in every child with non-neurogenic daytime urinary incontinence in whom oxybutynin failed? Urology. 2005; 65: 369.

3. Palatini P, Julius S. Elevated heart rate: a major risk factor for cardiovascular disease. Clin Exp Hypertens. 2004; 26: 637-644.

4. Lanza GA, Fox K, Crea F. Heart rate: a risk factor for cardiac diseases and outcomes? Pathophysiology of cardiac diseases and the potential role of heart rate slowing. Adv Cardiol. 2006; 43: 1-16.

5. Wang PS, Levin R, Zhao SZ, Avorn J. Uri-nary antispasmodic use and the risks of ventricular arrhythmia and sudden death in older patients. J Am Geriatr Soc. 2002; 50: 117-124.

6. Dogan Y, Soylu A, Eren GA, Poturoglu S, Dolapcioglu C, Sonmez K, et al. Evaluation of QT and P wave dispersion and

mean platelet volume among inamma-tory bowel disease patients. Int J Med Sci. 2011; 8(7): 540-546.7. Guntekin U, Gunes Y, Tuncer M, Gumrukcuoglu HA, Kaya Y. The eect of altitude on P-wave and QT duration and dispersion. Pacing Clin Electrophysiol. 2008 Jul; 31(7): 889-892.

8. Todorova A, Vonderheid-Guth B, Dimpfel W. Eects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol. 2001; 41: 636-644.

9. Hjlms K, Hellstrm AL, Mogren K, Lckgren G, Stenberg A. The overactive bladder in children: a potential future indication for tolterodine. BJU Int. 2001 Apr; 87(6): 569-574.

10. Jones SE, Kasamaki Y, Shuba LM, Ogura T, McCullough JR, McDonald TF. Analysis of the electrophysiologic eects of short-term oxybutynin on guinea pig and rabbit ventricular cells. J Cardiovasc Pharmacol. 2000; 35: 334-340.

11. Abrams P, Cardozo L, Chapple C, Serdarevic D, Hargreaves K, Khullar V. 1032 Study Group. Comparison of the efcacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome. Int J Urol. 2006; 13: 692-698.

12. Correll CU, Lops JD, Figen V, Malhotra AK, Kane JM, Manu P. QT interval duration and dispersion in children and adolescents treated with ziprasidone. J Clin Psychiatry. 2011 Jun; 72(6): 854-860.

13. Polat TB, Saz EU, Nursoy MA. Eects of salbutamol given by metered-dose inhaler on dispersion of ventricular repolarization. Anadolu Kardiyol Derg. 2011 May; 11(3): 232-236. doi: 10.5152/ akd.2011.063.

14. Hussain RM, Hartigan-Go K, Thomas SH, Ford GA. Eect of oxybutynin on the QTc interval in elderly patients with uri-nary incontinence. Br J Clin Pharmacol. 1996; 41: 73-75.

15. Andersson KE, Campeau L, Olshansky B. Cardiac eects of muscarinic receptor antagonists used for voiding dysfunction. Br J Clin Pharmacol. 2011 Aug; 72(2): 186-196.

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