American Journal of Therapeutics 23, e1091–e1093 (2016)
A Literature Review Revisiting Phenytoin-Induced Sinus Arrest Shireen Parsai, BSc,1 Imad Hariri, MD,2 Mohammad Taleb, MD,3 and Youngsook Yoon, MD3*
Classically, phenytoin (PTN) infusion for the treatment of status epilepticus has been proven to be associated with cardiovascular toxicity, including dysrhythmias, hypotension, and cardiovascular collapse. Subsequently, fosphenytoin (FOS) was introduced on the market in 1997 with claims of having less cardiac toxicity. However, since then, many accounts of cardiac events have been reported undermining these claims. FOS gained popularity due to its water solubility, which allows 3 times faster infusion in comparison with PTN with less venous irritation and local toxicity. FOS is the phosphate ester prodrug of PTN and is rapidly converted to PTN independent of the dose and rate of administration. Intravenous FOS and PTN are bioequivalent. Adverse cardiac effects of both intravenous FOS and PTN have been correlated to the rate of infusion, concentration of the agent, known risk factors, or preexisting hypersensitivity, and most cases have been identified after infusing a loading dose of these medications. This case report is unique, in that, the patient developed sinus arrest while concurrently receiving oral PTN and intravenous FOS. Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting. Keywords: phenytoin, fosphenytoin, sinus pause, sinus arrest, adverse effect, Dilantin, bradydysrhythmia, telemetry, cardiopulmonary
CASE PRESENTATION T.M., a 25-year-old African American man with a medical history of generalized tonic–clonic seizure disorder, bipolar, schizoaffective disorder, and mental retardation with developmental delay presented to the emergency department (ED) for acute onset of altered mental status and visual hallucinations.1–3
1
College of Medicine and Life Sciences, The University of Toledo, Toledo, OH; 2Department of Medicine, The University of Toledo, Toledo, OH; 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Toledo, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Pulmonary and Critical Care Medicine, Department of Medicine, 3000 Arlington Ave., Mail Stop 1186, Toledo, OH 43614. E-mail: [email protected]
The patient was transferred to the ED after his cousin called 911 reporting that T.M. was not “acting right.” He arrived to the ED within 1 hour of the onset of symptoms and continuously stated “I was drugged” in addition to saying “things look scary” and “it feels like I’m dreaming.” The patient’s family members reported that, earlier that day, he was drinking alcohol, smoking marijuana, and consuming prescription medications including hydromorphone tablets, after which he was found to be exhibiting odd behavior and hallucinating. He had no history of exhibiting similar behavior in the past. The patient had been using the following prescription medications: methylphenidate, lamotrigine 25 mg orally daily, levetiracetam 750 mg orally twice daily, and seroquel 300 mg orally at bedtime. Social history was notable for occasional alcohol use, former cigarette use, and illicit drug use including marijuana and various other controlled drugs.
1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e1092
Parsai et al
Table 1. Medication administration report. Medication FOS sodium, 126 mL; solution IV 5 1290 mg PE PTN sodium extended 100 mg oral tablet
Day 1
Day 2
Day 3
—
—
Start 16:14, infused over 240 min
—
21:51, 1 tablet
Initial vital signs were blood pressure 140/73 mm Hg, pulse 107 bpm, respirations 18 per minute, and temperature 97.9°F. The patient was alert and oriented to self but disoriented to time, place, and situation. He exhibited marked anxiety and active visual hallucinations. His physical examination was otherwise unremarkable. Initial laboratory data were remarkable for white blood count 13.5/mm3, hemoglobin 16.9 g/dL, potassium 3.1 mEq/L, blood urea nitrogen 12, and creatinine 1.06 mg/dL. Initial ethanol level was 0.114%, and salicylic acid was less than 3 mg/L. Ten-panel toxicology screen was negative. Initial imaging consisted of a computed tomography of the brain, which demonstrated no evidence of an acute intracranial process. Chest x-ray was also obtained revealing no definitive acute disease. Electrocardiogram revealed a normal sinus rhythm without any acute abnormalities. In the ED, naloxone was administered, after which the patient became arousable. A working diagnosis of drug overdose secondary to polysubstance abuse was made. The patient was started on intravenous fluid hydration and naloxone infusion and subsequently admitted to the medical intensive care unit for further management.
09:11, 1 tablet; 16:17, 1 tablet
The neurology team was consulted to rule out a possible breakthrough seizure with a postictal state causing his altered mental status. He underwent electroencephalographic monitoring, which was normal during wakefulness and light drowsiness with no epileptiform activity seen. The psychiatry team was also consulted to rule out pseudoseizures and concluded that the patient had both a conversion disorder and mood disorder. Lamotrigine was recommended for antiepileptic properties and moodstabilizing effects. Meanwhile, the neurology team suggested that the patient may have experienced a breakthrough seizure and recommended phenytoin (PTN) loading. Refer to Table 1 for a timeline of FOS infusion and oral PTN as was administered. During administration of FOS, 85.6 phenytoin equivalents (PE) had been infused over 16 minutes when the patient briefly lost consciousness. This correlated with an 11-second sinus arrest detected on telemetry as represented in Figure 1. No vitals were recorded at the time of sinus arrest; however, scheduled vital checks 30 minutes before the event and 1 hour and 30 minutes after the event were at baseline. Electrocardiogram during that time showed normal sinus rhythm with nonspecific ST elevations, likely correlating with
FIGURE 1. Rhythm strip. Heart rate, 47 beats per minute; respiration rate, 11.54 per second. Eleven-second sinus arrest. American Journal of Therapeutics (2016) 23(4)
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Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Revisiting Phenytoin-Induced Sinus Arrest
early repolarization. Cardiac enzymes were trended and were negative. Echocardiogram was obtained, which showed an ejection fraction of 55% with no significant valvular abnormalities and normal diastolic function. The neurology team’s assessment was PTN-induced sinus arrest. The patient was monitored for 48 hours and then discharged home on levetiracetam and lamotrigine for seizure prophylaxis. A 30-day event monitor was recommended by the cardiology team; which was negative for any arrhythmias.
e1093 Table 2. Unbound and bound PTN levels.
3/16 3/17 3/18 3/19 3/20
Free PTN levels, mg/mL
PTN levels, mg/mL
,0.5 ,0.5 — ,0.5 ,0.5
— ,2.5 7.7 — ,2.5
05:43 11:16 05:25 05:45
DISCUSSION
CONCLUSIONS
Adams et al1 identified 29 cardiac events likely related to FOS infusion, 10 of which resulted in cardiac deaths. Sinus arrest occurred in 5 of these cases. In conjunction with the reported cases identified in the literature, this case report provides more evidence that FOS is associated with more cardiac toxicity than previously anticipated. Adams et al recommended an infusion rate below 150 PE/min for high-risk groups. For indications other than status epilepticus, recommendations were made to consider FOS administration through the intramuscular route or oral PTN loading. Our case identifies a patient in which these recommendations were followed, yet adverse cardiac events still occurred. Over 4 hours (240 minutes), 1290 mg PE of FOS were administered at a rate of 5.38 PE/min. Sinus arrest developed after administration of 86.1 PE (16 minutes) in the setting of 3 doses of oral PTN already administered. The patient had received a total of 300 mg in the previous 24 hours with a subtherapeutic free PTN level (Table 2). This is the lowest dose of FOS at which cardiac events have developed in all case reports identified.
Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting. All cases of cardiac events in patients receiving any route of FOS and PTN are encouraged to be reported to further increase our awareness of such reactions.
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REFERENCES 1. Adams BD, Buckley NH, Kim JY, et al. Fosphenytoin may cause hemodynamically unstable bradydysrhythmias. J Emerg Med. 2006;30:75–79. 2. Holliday SM, Benfield P, Plosker GL. Fosphenytoin. Pharmacoeconomic implications of therapy. Pharmacoeconomics. 1998;14:685–690. 3. York RC, Coleridge ST. Cardiopulmonary arrest following intravenous phenytoin loading. Am J Emerg Med. 1988; 6:255–259.
American Journal of Therapeutics (2016) 23(4)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A Literature Review Revisiting Phenytoin-Induced Sinus Arrest Shireen Parsai, BSc,1 Imad Hariri, MD,2 Mohammad Taleb, MD,3 and Youngsook Yoon, MD3*
Classically, phenytoin (PTN) infusion for the treatment of status epilepticus has been proven to be associated with cardiovascular toxicity, including dysrhythmias, hypotension, and cardiovascular collapse. Subsequently, fosphenytoin (FOS) was introduced on the market in 1997 with claims of having less cardiac toxicity. However, since then, many accounts of cardiac events have been reported undermining these claims. FOS gained popularity due to its water solubility, which allows 3 times faster infusion in comparison with PTN with less venous irritation and local toxicity. FOS is the phosphate ester prodrug of PTN and is rapidly converted to PTN independent of the dose and rate of administration. Intravenous FOS and PTN are bioequivalent. Adverse cardiac effects of both intravenous FOS and PTN have been correlated to the rate of infusion, concentration of the agent, known risk factors, or preexisting hypersensitivity, and most cases have been identified after infusing a loading dose of these medications. This case report is unique, in that, the patient developed sinus arrest while concurrently receiving oral PTN and intravenous FOS. Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting. Keywords: phenytoin, fosphenytoin, sinus pause, sinus arrest, adverse effect, Dilantin, bradydysrhythmia, telemetry, cardiopulmonary
CASE PRESENTATION T.M., a 25-year-old African American man with a medical history of generalized tonic–clonic seizure disorder, bipolar, schizoaffective disorder, and mental retardation with developmental delay presented to the emergency department (ED) for acute onset of altered mental status and visual hallucinations.1–3
1
College of Medicine and Life Sciences, The University of Toledo, Toledo, OH; 2Department of Medicine, The University of Toledo, Toledo, OH; 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Toledo, Toledo, OH. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Pulmonary and Critical Care Medicine, Department of Medicine, 3000 Arlington Ave., Mail Stop 1186, Toledo, OH 43614. E-mail: [email protected]
The patient was transferred to the ED after his cousin called 911 reporting that T.M. was not “acting right.” He arrived to the ED within 1 hour of the onset of symptoms and continuously stated “I was drugged” in addition to saying “things look scary” and “it feels like I’m dreaming.” The patient’s family members reported that, earlier that day, he was drinking alcohol, smoking marijuana, and consuming prescription medications including hydromorphone tablets, after which he was found to be exhibiting odd behavior and hallucinating. He had no history of exhibiting similar behavior in the past. The patient had been using the following prescription medications: methylphenidate, lamotrigine 25 mg orally daily, levetiracetam 750 mg orally twice daily, and seroquel 300 mg orally at bedtime. Social history was notable for occasional alcohol use, former cigarette use, and illicit drug use including marijuana and various other controlled drugs.
1075–2765 Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e1092
Parsai et al
Table 1. Medication administration report. Medication FOS sodium, 126 mL; solution IV 5 1290 mg PE PTN sodium extended 100 mg oral tablet
Day 1
Day 2
Day 3
—
—
Start 16:14, infused over 240 min
—
21:51, 1 tablet
Initial vital signs were blood pressure 140/73 mm Hg, pulse 107 bpm, respirations 18 per minute, and temperature 97.9°F. The patient was alert and oriented to self but disoriented to time, place, and situation. He exhibited marked anxiety and active visual hallucinations. His physical examination was otherwise unremarkable. Initial laboratory data were remarkable for white blood count 13.5/mm3, hemoglobin 16.9 g/dL, potassium 3.1 mEq/L, blood urea nitrogen 12, and creatinine 1.06 mg/dL. Initial ethanol level was 0.114%, and salicylic acid was less than 3 mg/L. Ten-panel toxicology screen was negative. Initial imaging consisted of a computed tomography of the brain, which demonstrated no evidence of an acute intracranial process. Chest x-ray was also obtained revealing no definitive acute disease. Electrocardiogram revealed a normal sinus rhythm without any acute abnormalities. In the ED, naloxone was administered, after which the patient became arousable. A working diagnosis of drug overdose secondary to polysubstance abuse was made. The patient was started on intravenous fluid hydration and naloxone infusion and subsequently admitted to the medical intensive care unit for further management.
09:11, 1 tablet; 16:17, 1 tablet
The neurology team was consulted to rule out a possible breakthrough seizure with a postictal state causing his altered mental status. He underwent electroencephalographic monitoring, which was normal during wakefulness and light drowsiness with no epileptiform activity seen. The psychiatry team was also consulted to rule out pseudoseizures and concluded that the patient had both a conversion disorder and mood disorder. Lamotrigine was recommended for antiepileptic properties and moodstabilizing effects. Meanwhile, the neurology team suggested that the patient may have experienced a breakthrough seizure and recommended phenytoin (PTN) loading. Refer to Table 1 for a timeline of FOS infusion and oral PTN as was administered. During administration of FOS, 85.6 phenytoin equivalents (PE) had been infused over 16 minutes when the patient briefly lost consciousness. This correlated with an 11-second sinus arrest detected on telemetry as represented in Figure 1. No vitals were recorded at the time of sinus arrest; however, scheduled vital checks 30 minutes before the event and 1 hour and 30 minutes after the event were at baseline. Electrocardiogram during that time showed normal sinus rhythm with nonspecific ST elevations, likely correlating with
FIGURE 1. Rhythm strip. Heart rate, 47 beats per minute; respiration rate, 11.54 per second. Eleven-second sinus arrest. American Journal of Therapeutics (2016) 23(4)
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Revisiting Phenytoin-Induced Sinus Arrest
early repolarization. Cardiac enzymes were trended and were negative. Echocardiogram was obtained, which showed an ejection fraction of 55% with no significant valvular abnormalities and normal diastolic function. The neurology team’s assessment was PTN-induced sinus arrest. The patient was monitored for 48 hours and then discharged home on levetiracetam and lamotrigine for seizure prophylaxis. A 30-day event monitor was recommended by the cardiology team; which was negative for any arrhythmias.
e1093 Table 2. Unbound and bound PTN levels.
3/16 3/17 3/18 3/19 3/20
Free PTN levels, mg/mL
PTN levels, mg/mL
,0.5 ,0.5 — ,0.5 ,0.5
— ,2.5 7.7 — ,2.5
05:43 11:16 05:25 05:45
DISCUSSION
CONCLUSIONS
Adams et al1 identified 29 cardiac events likely related to FOS infusion, 10 of which resulted in cardiac deaths. Sinus arrest occurred in 5 of these cases. In conjunction with the reported cases identified in the literature, this case report provides more evidence that FOS is associated with more cardiac toxicity than previously anticipated. Adams et al recommended an infusion rate below 150 PE/min for high-risk groups. For indications other than status epilepticus, recommendations were made to consider FOS administration through the intramuscular route or oral PTN loading. Our case identifies a patient in which these recommendations were followed, yet adverse cardiac events still occurred. Over 4 hours (240 minutes), 1290 mg PE of FOS were administered at a rate of 5.38 PE/min. Sinus arrest developed after administration of 86.1 PE (16 minutes) in the setting of 3 doses of oral PTN already administered. The patient had received a total of 300 mg in the previous 24 hours with a subtherapeutic free PTN level (Table 2). This is the lowest dose of FOS at which cardiac events have developed in all case reports identified.
Clinicians should be more cognizant of the association of FOS and PTN with adverse cardiac events. Baseline electrocardiogram should be obtained on all patients prescribed FOS or PTN to identify underlying cardiac problems that may place the patient in a higher risk category. Telemetry should be performed on all patients receiving PTN in an inpatient setting. All cases of cardiac events in patients receiving any route of FOS and PTN are encouraged to be reported to further increase our awareness of such reactions.
www.americantherapeutics.com
REFERENCES 1. Adams BD, Buckley NH, Kim JY, et al. Fosphenytoin may cause hemodynamically unstable bradydysrhythmias. J Emerg Med. 2006;30:75–79. 2. Holliday SM, Benfield P, Plosker GL. Fosphenytoin. Pharmacoeconomic implications of therapy. Pharmacoeconomics. 1998;14:685–690. 3. York RC, Coleridge ST. Cardiopulmonary arrest following intravenous phenytoin loading. Am J Emerg Med. 1988; 6:255–259.
American Journal of Therapeutics (2016) 23(4)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
