Case Report
 
Cardiac arrest after intravenous infusion of fosphenytoin
Kanae Inoue1, Tetsuya Yumoto2, Hiromichi Naito3, Atsunori Nakao4
1Clinical Resident, Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Okayama, Japan
2Assistant Professor, Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Okayama, Japan
3Associate Professor, Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Okayama, Japan
4Professor, Department of Emergency and Critical Care Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, Japan

Article ID: Z01201801CR10879KI
doi:10.5348/ijcri-201810-CR-10879

Corresponding Author:
Atsunori Nakao,
MD, PhD, Department of Emergency and Critical Care Medicine,
Okayama University Graduate School of Medicine,
Dentistry, and Pharmaceutical Sciences,
2-5-1 Shikata-cho, Kita-ku,
Okayama-shi, Okayama,
Japan, 700-8558

Access full text article on other devices

  Access PDF of article on other devices

[Abstract HTML]   [Full Text HTML]   [Full Text PDF]   [Print This Article]
[Similar article in Pumed] [Similar article in Google Scholar]


How to cite this article
Inoue K, Yumoto T, Naito H, Nakao A. Cardiac arrest after intravenous infusion of fosphenytoin. Int J Case Rep Images 2018;9(1):60–62.


ABSTRACT

Introduction: Fosphenytoin, a water-soluble phenytoin prodrug, is given intravenously to administer phenytoin possibly more safely than intravenous administration of phenytoin.
Case Report: A 71-year-old female was admitted to our hospital’s emergency department with head trauma. She had a history of seizures that were incompletely controlled with carbamazepine. She suffered a tonic-clonic epileptic seizure in the intensive care unit and fosphenytoin was intravenously administered. After approximately three minutes of the intravenous drip-infusion, she developed sudden bradycardia followed by cardiac arrest. The patient required cardiopulmonary resuscitation and intratracheal intubation for five minutes before becoming hemodynamically stable. Mechanisms of electrocardiogram alteration by fosphenytoin were discussed.
Conclusion: Clinicians should be more aware of the association of fosphenytoin with adverse cardiac events. Baseline electrogram should be obtained for all patients receiving fosphenytoin to identify underlying cardiac problems.

Keywords: Adverse effect, Cardiac arrest, Fosphenytoin


INTRODUCTION

Phenytoin, used to treat status epilepticus, is associated with cardiovascular toxicity including arrhythmia and hypotension. Recently, the phenytoin prodrug fosphenytoin was introduced. Fosphenytoin is generally considered more water-soluble and can be efficiently administered intravenously to deliver phenytoin [1]. Intravenously administered fosphenytoin offers several benefits over intravenously administered phenytoin, including a faster infusion rate, decreased pain and irritation at the infusion site, and fewer cardiovascular complications [2][3]. However, the intravenous administration of fosphenytoin may also induce adverse cardiovascular events in some patients [4][5][6]. Here, we investigated the clinical characteristics of patients who experienced hypotension following an intravenous infusion of a fosphenytoin loading dose. This report may help physicians more aware of fosphenytoin critical adverse effects in the emergency unit or intensive care unit (ICU).


CASE REPORT

A 71-year-old female was admitted to our hospital’s emergency department with head trauma. The patient’s height and weight were 145 cm and 41.3 kg, respectively. She had no prior history of drug allergies or cardiopulmonary problems. Her initial vital signs were as follows: blood pressure 138/74 mmHg, heart rate 96/min, respiratory rate 18 breaths per minute, and body temperature 36.4°C. Laboratory data were unremarkable except for a serum potassium level of 3.5 mEq/L, calcium level of 7.6 mg/dL, albumin level of 2.6 g/dL, and creatinine level of 0.83 mg/dL. Chest X-ray was unremarkable without cardiomegaly or pneumonia. Computed tomography demonstrated multiple low density area in the brain indicating old cerebral infarction, but no evidence of acute intracranial hemorrhage. The patient was given intravenous fluid hydration with lactate Ringer solution (150 mL/h) and was subsequently admitted to the ICU for further management.

Since the patient had developed a cerebral infarction five years before, she had a history of seizures that were incompletely controlled with carbamazepine 800 mg/day. At day-2 in the ICU, she suddenly presented clonic convulsions and required intravenous fosphenytoin injection (1500 mg phenytoin equivalent unit at 150 PE/min via an infusion pump). Approximately, three minutes into the administration of the intravenous drip-infusion, she developed sudden bradycardia followed by cardiac arrest (Figure 1). The patient required cardiopulmonary resuscitation for five minutes before becoming hemodynamically stable and undergoing intratracheal intubation. Plasma phenytoin concentration measured after resuscitation was 24.2 µg/mL. After the patient was extubated the following day, her clinical course was uneventful with oral sodium valproate administration (800 mg/day).


Cursor on image to zoom/Click text to open image
Figure 1: Electrocardiogram approximately three minutes after the administration of the intravenous drip-infusion of fosphenytoin demonstrated sudden bradycardia followed by cardiac arrest.


DISCUSSION

As fosphenytoin has basically the same pharmacological properties as phenytoin, fosphenytoin adverse effects are like those of phenytoin and can be directly explained by an increase in phenytoin concentrations in the blood. These side effects include cardiac arrhythmias, hypotension, dizziness, ataxia, nystagmus, and local dermatological reactions. Purple glove syndrome, an unusual complication of intravenous phenytoin use, normally presents with edema, pain, and injection site discoloration spreading to the distal limb. The syndrome likely occurs with fosphenytoin, but possibly less frequently than with intravenous phenytoin [7][8]. Fosphenytoin may cause hyperphosphatemia in patients with end-stage renal failure [5]. After intravenous injection, the half-life of conversion of fosphenytoin to phenytoin is 15 minutes. Once released, phenytoin has a long plasma half-life of approximately 12–28.9 hours [1][2]. Theoretically, fosphenytoin can alter an electrocardiogram via phenytoin’s direct effects on cardiac conduction and phosphate calcium binding, which could indirectly change cardiac conduction resulting from hypocalcemia. Our patient’s serum calcium, sodium, potassium, and magnesium levels were normal.

Adams et al. [4] found 29 cardiac events related to fosphenytoin infusion, of which 10 resulted in cardiac deaths. Some reports show that manual intravenous push presents a greater possibility of inadvertent overdose during a short time frame, as well as more local symptoms. For indications besides status epilepticus, consideration of intramuscular administration or oral parenteral nutrition loading of fosphenytoin were recommended.

To avoid cardiac complication, an infusion rate below 150 PE/min is recommended. In addition, administration of fosphenytoin through intramuscular route or oral route may be recommended. Blood concentration above 20 µg/mL can be harmful and induce cardiac events [4][6].

In our patient, an apparently appropriate dose of intravenous phenytoin was initiated via infusion pump, and she was monitored appropriately and given supplemental oxygen. This case shows a patient for whom these recommendations were followed, yet adverse cardiac events still occurred. Baseline electrogram should be obtained for all patients prescribed fosphenytoin to uncover underlying cardiac problems. Many institutions restrict the use of fosphenytoin to emergencies, since fosphenytoin costs more than intravenous phenytoin [9].


CONCLUSION

Clinicians should be aware of the association of fosphenytoin with adverse cardiac events. For patients with known cardiac disease or abnormal preinfusion electrocardiography, emergency physicians should reduce the drug concentration and rate of administration.


REFERENCES
  1. Boucher BA. Fosphenytoin: A novel phenytoin prodrug. Pharmacotherapy 1996 Sep–Oct;16(5):777–91.   [Pubmed]    Back to citation no. 1
  2. Fischer JH, Patel TV, Fischer PA. Fosphenytoin: Clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet 2003;42(1):33–58.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Boucher BA, Feler CA, Dean JC, et al. The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients. Pharmacotherapy 1996 Jul–Aug;16(4):638–45.   [Pubmed]    Back to citation no. 3
  4. Adams BD, Buckley NH, Kim JY, Tipps LB. Fosphenytoin may cause hemodynamically unstable bradydysrhythmias. J Emerg Med 2006 Jan;30(1):75–9.   [CrossRef]   [Pubmed]    Back to citation no. 4
  5. McBryde KD, Wilcox J, Kher KK. Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient. Pediatr Nephrol 2005 Aug;20(8):1182–5.   [CrossRef]   [Pubmed]    Back to citation no. 5
  6. Parsai S, Hariri I, Taleb M, Yoon Y. A literature review revisiting phenytoin-induced sinus arrest. Am J Ther 2016 Jul–Aug;23(4):e1091–3.   [CrossRef]   [Pubmed]    Back to citation no. 6
  7. Okogbaa JI, Onor IO, Arije OA, Harris MB, Lillis RA. Phenytoin-induced purple glove syndrome: A case report and review of the literature. Hosp Pharm 2015 May;50(5):391–5.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Chokshi R, Openshaw J, Mehta NN, Mohler E 3rd. Purple glove syndrome following intravenous phenytoin administration. Vasc Med 2007 Feb;12(1):29–31.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. DeToledo JC, Ramsay RE. Fosphenytoin and phenytoin in patients with status epilepticus: Improved tolerability versus increased costs. Drug Saf 2000 Jun;22(6):459–66.   [CrossRef]   [Pubmed]    Back to citation no. 9

[Abstract HTML]   [Full Text HTML]   [Full Text PDF]

Acknowledgements
We thank Christine Heiner for editing the manuscript.

Author Contributions
Kanae Inoue – Substantial contributions to conception and design, Acquisition of data, and interpretation of data, Drafting the article, Revising it critically for important intellectual content,, Final approval of the version to be published
Tetsuya Yumoto – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content,, Final approval of the version to be published
Hiromichi Naito – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content,, Final approval of the version to be published
Atsunori Nakao – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of Submission
The corresponding author is the guarantor of submission.
Source of Support
None
Conflict of Interest
Authors declare no conflict of interest.
Copyright
© 2018 Kanae Inoue et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.