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Incompatibility between intravenous amiodarone and heparin in an infant
International Journal of Cardiology 145 (2010) e70 – e73 www.elsevier.com/locate/ijcard
Letter to the Editor
Incompatibility between intravenous amiodarone and heparin in an infant Gabriele Bronzetti a,⁎, Cinzia D’Angelo a , Elisabetta Mariucci a , Fernando Maria Picchio a , Giuseppe Boriani b b
a Pediatric Cardiology and Adult Congenital Unit, University of Bologna, Italy Institute of Cardiology, University of Bologna, Azienda Ospedaliera S.Orsola-Malpighi, Bologna, Italy
Received 12 October 2008; accepted 14 December 2008 Available online 3 February 2009
Abstract Amiodarone is an effective antiarrhythmic agent and represents the drug of choice in the treatment of severe arrhythmias, especially in the setting of ventricular dysfunction. Amiodarone has the potential for interaction with many cardiac and non-cardiac drugs. Nonetheless few incompatibilities have been reported. We report the incompatibility between amiodarone and heparin administrated in the same vein in a case of a one month old baby with atrial flutter. This topic needs more attention, due to the frequent co-administration of these two drugs in tachyarrhytmias with high thromboembolic risk. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Intravenous amiodarone; Heparin; Incompatibility; Atrial flutter
1. Introduction
2. Case report
Amiodarone is a powerful antiarrhythmic drug, available for oral and intravenous administration, and is used in the treatment and prevention of both ventricular and supraventricular arrhythmias in adults and children [1,2]. Many of these patients have underlying conditions requiring anticoagulation for the prevention of thromboembolism. Given that amiodarone and its metabolites are inhibitors of the hepatic metabolism of many drugs, potentially harmful drug interactions may result from coadministration. Incompatibilities with other drugs leading to inactivation are less known but equally important. In the present report we provide an example of the interplay between amiodarone and heparin.
A one month-old baby girl, from twin pregnancy at 38 weeks of gestation with birth weight of 2.870 kg and a normal APGAR score, called the parents' attention because of poor feeding. There was no history of flu or other viral illnesses. She was brought to the hospital and clinical examination after admission demonstrated that the patient was alert and responsive; the weight was 3.870 kg, the oxygen saturation was 98% on room air, blood pressure 72/ 50 mm Hg, heart rate 220 beats/min, respiratory rate 70 breaths/min. A pansystolic murmur and gallop were audible on auscultation. A standard electrocardiogram demonstrated an atrial flutter (AFl) with 2:1 conduction (atrial rate 500 beats/min; ventricular rate 250 beats/min) (Fig. 1). Echocardiography showed a moderate biventricular dilation, severely impaired left ventricular function (ejection fraction 15%), biatrial enlargement with “smoke effect”, flattening of the interventricular septum (D-shaped left ventricle), and severe mitral and tricuspid regurgitation. The echo picture was
⁎ Corresponding author. Institute of Cardiology of Bologna, S. Orsola Hospital, Via, Massarenti 9, 40138 Bologna, Italy. Tel.: +39 51 349858; fax: +39 51 344859. E-mail address: [email protected] (G. Bronzetti). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.12.158
Fig. 1. Atrial flutter recorded by a normal 12-lead elettrocardiogram (ECG) at admission to our institute.
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G. Bronzetti et al. / International Journal of Cardiology 145 (2009) e70–e73
Fig. 2. (A) Atrial flutter cycle length slowed dramatically until sinus rhythm. (B) Sinus rhythm with frequent atrial ectopic beats. (C) Stable sinus rhythm three hours after amiodarone infusion.
compatible with primary dilated cardiomyopathy complicated by AFl, but primary AFl complicated by tachycardiomyopathy appeared more likely. Oral furosemide was given at the dose of 4 mg every 8 h. At the same time intravenous loading with digoxin was administered (60 mcg in 20 min). The clinical condition deteriorated rapidly and amiodarone was started by a peripheral venous access, due the impossibility to obtain a central venous line (loading dose of 5 mg/kg in 30′ followed by 15 mg/kg/day as infusion). Based upon the echocardiographic findings of hypokinetic left ventricle, atrial enlargement and prothrombotic features (“smoke effect”), sodium heparin (500 IU/Kg/day) was started in the same vein line. Surprisingly, three hours after amiodarone infusion, AFl remained unchanged and the ventricular rate was the same. Then electrical cardioversion was attempted with increasing energy (5, 10, and 15 J, biphasic DC-shock) with no success. The arrhythmia was therefore defined refractory and the baby was transferred to our institute by helicopter. On admission she was manifestly in heart failure, although stable. A central venous catheter was placed in the right femoral vein and amiodarone infusion was moved from the
previous line to the central one at the same dosage, while sodium heparin was continued in the peripheral one. Right after the abovementioned catheters setting the patient promptly improved. Initially AFl cycle length slowed dramatically until a more reasonable heart rate (Fig. 2A). After three hours AFl ceased and sinus rhythm resumed although disturbed by frequent atrial ectopic beats (Fig. 2B–C). Simultaneously left ventricle ejection fraction increased up to 45%. Two days later the echocardiogram was completely normal. Amiodarone was discontinued and flecainide was started at the dose of 7.5 mg three times a day. 3. Discussion Incessant supraventricular tachycardia (SVT) in infants is relatively rare but may lead to tachycardiomyopathy and even death. Among SVT, AFl is a typical fetal arrhythmia which could persist or recur in the first weeks of life. Management of patients with AFl involves 3 objectives: a) rate control in order to have an acceptable cardiac output and to prevent tachycardia-induced cardiomyopathy (tachycardiomyopathy); b) cardioversion to sinus rhythm by drugs,
G. Bronzetti et al. / International Journal of Cardiology 145 (2009) e70–e73
transesophageal overdrive or DC shocks. c) prevention of thromboembolism. Accordingly, antiarrhythmic drugs are often accompanied by anticoagulants; atrial thrombosis may complicate AFl or atrial fibrillation at any age [1]. In this case the poor systolic function suggested amiodarone as a first line therapy. At the same time it was critical to start heparin infusion because of prothrombotic signs on echo. When the baby came to our attention the most surprising fact was that amiodarone at an appropriate dose was not effective, both in terms of rate control and conversion, despite the peripheral line working without leakage, phlebitis or swelling of the arm. Therefore we suspected the incompatibility between amiodarone and heparin as the explanation for the therapeutic failure [3]. The latter phenomenon is reported in the information leaflet but could be scotomized by the belief that sodium heparin is a “friendly” drug, compatible with most drugs. Moreover, amiodarone is well known and dreaded for its side effects and interactions [4] rather than for its incompatibility. We suppose that, in this case, the non-response to amiodarone was just the incompatibility with heparin, as confirmed by the swift clinical and instrumental improvement once the administration of the two drugs was carried out through two different routes of infusion. Special precautions need to be followed in the use of intravenous amiodarone. This drug admixed with 5% dextrose injection to a concentration of 4 mg/mL is incompatible and forms a precipitate with aminophylline, cefamandole nafate, cefazolin sodium, and mezlocillin sodium. Amiodarone also forms a precipitate with sodium bicarbonate at a concentration of 3 mg/mL and with heparin sodium at an unknown concentration [3,5]. When used in high concentrations (N 2 mg/mL), it must be delivered through a central vein because it can cause peripheral phlebitis (in b 3% of patients). However, in critical conditions and for short term, even a peripheral line
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may be safely employed [3,5]. Especially in children, in case of paucity of veins and need of contemporary use of amiodarone and heparin, the latter could be administered subcutaneously [2,6]. In conclusion, although the adverse effects of amiodarone and its interaction with important drugs like warfarin, digoxin, phenytoin and others are well-known, little emphasis is given to its incompatibilities. This aspect is significant because this kind of incompatibility may impair the effectiveness of one of the most important drugs in the treatment of tachyarrhythmias. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [7]. References [1] Roden DM. Antiarrhythmic drugs. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. Goodman's and Gilman's: The pharmacological basis of therapeutics. Tenth edition. Philadelphia: McGrawHill; 2001. p. 933–70. [2] Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of intravenous amiodarone in infants and children. Am J Cardiol 1994;74:573–7. [3] Goldschlager N, Epstein AE, Naccarelli GV, et al. Practice guidelines sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone. Heart Rhythm Sep 2007;4(9):1250–9. [4] Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007 Sep 19;298(11):1312–22 Review. [5] Naccarelli GV, Jalal S. Intravenous amiodarone. Another option in the acute management of sustained ventricular tachyarrhythmias. Circulation Dec 1 1995;92(11):3154–5. [6] Albisetti M, Andrew M. Low molecular weight heparin in children. Eur J Pediatr 2002;161(2):71–7. [7] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
Letter to the Editor
Incompatibility between intravenous amiodarone and heparin in an infant Gabriele Bronzetti a,⁎, Cinzia D’Angelo a , Elisabetta Mariucci a , Fernando Maria Picchio a , Giuseppe Boriani b b
a Pediatric Cardiology and Adult Congenital Unit, University of Bologna, Italy Institute of Cardiology, University of Bologna, Azienda Ospedaliera S.Orsola-Malpighi, Bologna, Italy
Received 12 October 2008; accepted 14 December 2008 Available online 3 February 2009
Abstract Amiodarone is an effective antiarrhythmic agent and represents the drug of choice in the treatment of severe arrhythmias, especially in the setting of ventricular dysfunction. Amiodarone has the potential for interaction with many cardiac and non-cardiac drugs. Nonetheless few incompatibilities have been reported. We report the incompatibility between amiodarone and heparin administrated in the same vein in a case of a one month old baby with atrial flutter. This topic needs more attention, due to the frequent co-administration of these two drugs in tachyarrhytmias with high thromboembolic risk. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Intravenous amiodarone; Heparin; Incompatibility; Atrial flutter
1. Introduction
2. Case report
Amiodarone is a powerful antiarrhythmic drug, available for oral and intravenous administration, and is used in the treatment and prevention of both ventricular and supraventricular arrhythmias in adults and children [1,2]. Many of these patients have underlying conditions requiring anticoagulation for the prevention of thromboembolism. Given that amiodarone and its metabolites are inhibitors of the hepatic metabolism of many drugs, potentially harmful drug interactions may result from coadministration. Incompatibilities with other drugs leading to inactivation are less known but equally important. In the present report we provide an example of the interplay between amiodarone and heparin.
A one month-old baby girl, from twin pregnancy at 38 weeks of gestation with birth weight of 2.870 kg and a normal APGAR score, called the parents' attention because of poor feeding. There was no history of flu or other viral illnesses. She was brought to the hospital and clinical examination after admission demonstrated that the patient was alert and responsive; the weight was 3.870 kg, the oxygen saturation was 98% on room air, blood pressure 72/ 50 mm Hg, heart rate 220 beats/min, respiratory rate 70 breaths/min. A pansystolic murmur and gallop were audible on auscultation. A standard electrocardiogram demonstrated an atrial flutter (AFl) with 2:1 conduction (atrial rate 500 beats/min; ventricular rate 250 beats/min) (Fig. 1). Echocardiography showed a moderate biventricular dilation, severely impaired left ventricular function (ejection fraction 15%), biatrial enlargement with “smoke effect”, flattening of the interventricular septum (D-shaped left ventricle), and severe mitral and tricuspid regurgitation. The echo picture was
⁎ Corresponding author. Institute of Cardiology of Bologna, S. Orsola Hospital, Via, Massarenti 9, 40138 Bologna, Italy. Tel.: +39 51 349858; fax: +39 51 344859. E-mail address: [email protected] (G. Bronzetti). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.12.158
Fig. 1. Atrial flutter recorded by a normal 12-lead elettrocardiogram (ECG) at admission to our institute.
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G. Bronzetti et al. / International Journal of Cardiology 145 (2009) e70–e73
Fig. 2. (A) Atrial flutter cycle length slowed dramatically until sinus rhythm. (B) Sinus rhythm with frequent atrial ectopic beats. (C) Stable sinus rhythm three hours after amiodarone infusion.
compatible with primary dilated cardiomyopathy complicated by AFl, but primary AFl complicated by tachycardiomyopathy appeared more likely. Oral furosemide was given at the dose of 4 mg every 8 h. At the same time intravenous loading with digoxin was administered (60 mcg in 20 min). The clinical condition deteriorated rapidly and amiodarone was started by a peripheral venous access, due the impossibility to obtain a central venous line (loading dose of 5 mg/kg in 30′ followed by 15 mg/kg/day as infusion). Based upon the echocardiographic findings of hypokinetic left ventricle, atrial enlargement and prothrombotic features (“smoke effect”), sodium heparin (500 IU/Kg/day) was started in the same vein line. Surprisingly, three hours after amiodarone infusion, AFl remained unchanged and the ventricular rate was the same. Then electrical cardioversion was attempted with increasing energy (5, 10, and 15 J, biphasic DC-shock) with no success. The arrhythmia was therefore defined refractory and the baby was transferred to our institute by helicopter. On admission she was manifestly in heart failure, although stable. A central venous catheter was placed in the right femoral vein and amiodarone infusion was moved from the
previous line to the central one at the same dosage, while sodium heparin was continued in the peripheral one. Right after the abovementioned catheters setting the patient promptly improved. Initially AFl cycle length slowed dramatically until a more reasonable heart rate (Fig. 2A). After three hours AFl ceased and sinus rhythm resumed although disturbed by frequent atrial ectopic beats (Fig. 2B–C). Simultaneously left ventricle ejection fraction increased up to 45%. Two days later the echocardiogram was completely normal. Amiodarone was discontinued and flecainide was started at the dose of 7.5 mg three times a day. 3. Discussion Incessant supraventricular tachycardia (SVT) in infants is relatively rare but may lead to tachycardiomyopathy and even death. Among SVT, AFl is a typical fetal arrhythmia which could persist or recur in the first weeks of life. Management of patients with AFl involves 3 objectives: a) rate control in order to have an acceptable cardiac output and to prevent tachycardia-induced cardiomyopathy (tachycardiomyopathy); b) cardioversion to sinus rhythm by drugs,
G. Bronzetti et al. / International Journal of Cardiology 145 (2009) e70–e73
transesophageal overdrive or DC shocks. c) prevention of thromboembolism. Accordingly, antiarrhythmic drugs are often accompanied by anticoagulants; atrial thrombosis may complicate AFl or atrial fibrillation at any age [1]. In this case the poor systolic function suggested amiodarone as a first line therapy. At the same time it was critical to start heparin infusion because of prothrombotic signs on echo. When the baby came to our attention the most surprising fact was that amiodarone at an appropriate dose was not effective, both in terms of rate control and conversion, despite the peripheral line working without leakage, phlebitis or swelling of the arm. Therefore we suspected the incompatibility between amiodarone and heparin as the explanation for the therapeutic failure [3]. The latter phenomenon is reported in the information leaflet but could be scotomized by the belief that sodium heparin is a “friendly” drug, compatible with most drugs. Moreover, amiodarone is well known and dreaded for its side effects and interactions [4] rather than for its incompatibility. We suppose that, in this case, the non-response to amiodarone was just the incompatibility with heparin, as confirmed by the swift clinical and instrumental improvement once the administration of the two drugs was carried out through two different routes of infusion. Special precautions need to be followed in the use of intravenous amiodarone. This drug admixed with 5% dextrose injection to a concentration of 4 mg/mL is incompatible and forms a precipitate with aminophylline, cefamandole nafate, cefazolin sodium, and mezlocillin sodium. Amiodarone also forms a precipitate with sodium bicarbonate at a concentration of 3 mg/mL and with heparin sodium at an unknown concentration [3,5]. When used in high concentrations (N 2 mg/mL), it must be delivered through a central vein because it can cause peripheral phlebitis (in b 3% of patients). However, in critical conditions and for short term, even a peripheral line
e73
may be safely employed [3,5]. Especially in children, in case of paucity of veins and need of contemporary use of amiodarone and heparin, the latter could be administered subcutaneously [2,6]. In conclusion, although the adverse effects of amiodarone and its interaction with important drugs like warfarin, digoxin, phenytoin and others are well-known, little emphasis is given to its incompatibilities. This aspect is significant because this kind of incompatibility may impair the effectiveness of one of the most important drugs in the treatment of tachyarrhythmias. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [7]. References [1] Roden DM. Antiarrhythmic drugs. In: Hardman JG, Limbird LE, Goodman Gilman A, editors. Goodman's and Gilman's: The pharmacological basis of therapeutics. Tenth edition. Philadelphia: McGrawHill; 2001. p. 933–70. [2] Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of intravenous amiodarone in infants and children. Am J Cardiol 1994;74:573–7. [3] Goldschlager N, Epstein AE, Naccarelli GV, et al. Practice guidelines sub-committee, North American Society of Pacing and Electrophysiology (HRS). A practical guide for clinicians who treat patients with amiodarone. Heart Rhythm Sep 2007;4(9):1250–9. [4] Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007 Sep 19;298(11):1312–22 Review. [5] Naccarelli GV, Jalal S. Intravenous amiodarone. Another option in the acute management of sustained ventricular tachyarrhythmias. Circulation Dec 1 1995;92(11):3154–5. [6] Albisetti M, Andrew M. Low molecular weight heparin in children. Eur J Pediatr 2002;161(2):71–7. [7] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.