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Keywords:

  • phenytoin;
  • intravenous;
  • telemetry;
  • electrocardiography;
  • arrhythmia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Guidelines recommend the use of cardiac telemetry when phenytoin is administered intravenously. Clinical areas where telemetry is available may not always be the most suitable place to monitor and treat these sick patients. We sought to clarify the evidence regarding the need for cardiac telemetry during intravenous infusion of phenytoin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

In 1938, oral phenytoin (diphenylhydantoin) was introduced as an anticonvulsant, and the first case of bradycardia associated with its use was described the following year.[1] Intravenous (IV) phenytoin became available in 1958 for the treatment of status epilepticus, and in 1967, it was advocated for cardiac arrhythmias, especially arrhythmias because of excess digitalis. In that year, the first cardiac death associated with IV phenytoin was reported: ‘A patient suffered cardiac arrest after rapid IV injection of diphenylhydantoin …’. Authors state that ‘slow infusion and careful monitoring of both the electrocardiogram (ECG) and blood pressure (BP) are mandatory when diphenylhydantoin is employed intravenously as an anti-arrhythmic agent’.[2]

It is a Class 1B anti-arrhythmic drug and was used for this indication in the 1960s and 70s. Its use in this setting has been associated with pro-arrhythmia predominantly causing bradyarrhythmia[3, 4] and ventricular arrhythmias.[5, 6]

Concerns over rhythm disturbances associated with IV phenytoin use are reflected in recommendations and guidelines in several drug information references: The 2012 Australian Product Information states that ‘continuous monitoring of the ECG and BP is essential’. This recommendation is included in the phenytoin monograph of the Australian Injectable Drugs Handbook (2011). While, the Australian Therapeutic Guidelines 2011 and the Australian Medicines Handbook 2012 recommend monitoring of ECG and BP during IV administration and state that phenytoin should be slowed or stopped if arrhythmias occur.

However, the risk and frequency of rhythm disturbances associated with IV phenytoin are not outlined in these drug references. Furthermore, IV phenytoin is no longer utilised as an anti-arrhythmic drug, and these historical reports may not be applicable to current indications for the drug or modern drug administration protocols. Finally, given IV phenytoin is used for seizure treatment or prophylaxis, moving sick patients to an area with telemetry may result in them being in a location that is not the most appropriate for their overall care. We sought to clarify the evidence behind the guideline recommendations of continuous ECG monitoring during administration of IV phenytoin.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

A literature review of IV phenytoin and cardiac rhythm disturbance was undertaken. Databases searched were: MEDLINE (1948 to March 2012), EMBASE (1980 to March 2012), PUBMED (1946 to March 2012), EBM Reviews (March 2012) and Drugdex (April 2012). The search was limited to English language and humans. The search strategy employed the following terms: phenytoin, diphenylhydantoin, diphenylhydantoinate, hydantoins, dilantin; and arrhythmia, cardiac arrhythmia, tachycardia, ventricular fibrillation, heart arrest, cardiac arrest, asystole, bradycardia, heart block, heart rhythm, death, electrocardiograph, ECG, EKG, cardiotoxicity; or brain diseases. References and citations of retrieved papers were examined to identify any additional appropriate papers.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

IV phenytoin and reported mortality

There have been 14 reports of death during or immediately following IV phenytoin administration[2, 3, 5-14] (Table 1). All are historical, published between 1966 and 1988. The majority (9/14) occurred in the first 2 years following its indication for treatment of cardiac arrhythmias. Death occurred in seven males and six females, and sex was not stated in one report. The mean age at the time of the fatal event was 69 years (range 44–85 years). In these patients, IV phenytoin was used for treatment of cardiac arrhythmias in 11 and was used for the treatment of seizures in only three patients. All patients had significant comorbidities, and at least nine patients were treated with digoxin or were digoxin toxic. Documentation of other cardiac drugs was incomplete. In at least 10 patients, the rate of phenytoin IV injection was rapid. The probable cause of death was cardiac in 11 cases and respiratory in 3 cases.

Table 1. Summary of deaths thought attributable to IV phenytoin
Age/sexDiagnosis/treatmentsDose and effectsAuthors commentsContributing factorsReference
  1. AV, atrioventricular; CHF, congestive heart failure; Conc, concentration; CNS, central nervous system; F, female; IV, intravenous; K, potassium plasma concentration; M, male; MI, myocardial infarction; PAT, paroxysmal atrial tachycardia; SR, sinus rhythm; VF, ventricular fibrillation; VPC, ventricular premature contraction; VT, ventricular tachycardia.

57FComplex AV rhythm with multifocal VPCs because of digitalis or hypoxia, or both

Phenytoin 250 mg over 1–3 min

∼2 h later – died of acute respiratory insufficiency

Death not attributable to phenytoin

Rapid administration

Respiratory death

? Digoxin present

Conn[3]
??Terminally ill, complete AV dissociation, idioventricular rhythm

Phenytoin 350 mg over 30–120 sec

60 sec after phenytoin infusion -cardiac arrest

‘Mortality …traced directly to improper use of phenytoin’

Phenytoin inappropriate indication

Rapid administration

Rosen et al. [7]
85F

Sepsis, hypoxia, semiconscious, CHF

Suspected digitalis intoxication

Phenytoin 150 mg over 3 min – fatal VF – resuscitation failed‘underlying sepsis and hypoxia may have been a contributing factor’

Rapid administration

Digoxin toxicity

Gellerman and Martinez[5]
82MMoribund, supraventricular tachycardia, digoxin

Phenytoin 250 mg over 2.5 min

[RIGHTWARDS ARROW] AV nodal rhythm [RIGHTWARDS ARROW] cardiac arrest; resuscitation, but died within 3 h

‘ventricular standstill, the apparent direct result of rapidly administered IV diphenylhydantoin’

Rapid administration

Digoxin present

Goldschlager and Karliner[2]
67MDyspnoea, CHF, digitalis, K 5.6, VT

Phenytoin 250 mg over 1 min

[RIGHTWARDS ARROW] hypotension, apnoea, resuscitation failed

‘speed of injection is of paramount importance’

that is, not too fast

Rapid administration

Possible digoxin toxicity

Karliner[8]
75FSepsis, CHF, digitalis intoxication, PAT

Phenytoin 100 mg IV

PAT [RIGHTWARDS ARROW] SR

[RIGHTWARDS ARROW] asystole, resuscitation failed

‘impossible to attribute the episode of asystole directly to dilantin in such a critically ill patient’

? Rate of administration

? Manual injection

? Digoxin toxicity

Keeran[9]
67F

Acute pulmonary oedema, acute ischaemia, Hypotension

Atrial flutter, regular digoxin, additional 0.4 mg lanatoside C IV

Phenytoin 250 mg over 2 min [RIGHTWARDS ARROW] SR, then idioventricular rhythm, cardiac arrest; resuscitation failed‘Caution in dose and rapidity of IV administration of diphenylhydantoin’

Rapid administration

Digitalis present

Unger and Sklaroff[10]
70M

Acute pulmonary oedema

digoxin, atrial flutter

Phenytoin 250 mg over 3 min [RIGHTWARDS ARROW]

AV block, asystole

As above

Rapid administration

Digoxin present

Unger and Sklaroff[10]
67MMultiple MIs, CHF, chronic phenytoin 300 mg/d for neuralgia, digitalis intoxicationPhenytoin 250 mg over 5 min resulted in opisthotonic posture, apnoea requiring ventilation, then complete AV block, asystole‘a CNS toxic condition …from IV diphenylhydantoin’CNS toxicity because of phenytoin, digoxin toxicityRussell and Bousvaros[6]
76F

CHF

Persistent bigeminy, suspected digoxin toxicity

Phenytoin 250 mg over 3 min – complete heart block [RIGHTWARDS ARROW] asystole, resuscitation failed‘advanced age, severe CHF and digitalis toxicity may be important predisposing factors’

? Digoxin toxicity

Rapid administration

Voigt[11]
60M

Ruptured brain abscess, meningitis

Epilepsia partialis continua seizure

Phenytoin 500 mg injected directly – rate < 100 mg/min

2 min later [RIGHTWARDS ARROW] apnoea/respiratory arrest and death

Post-mortem findings – ruptured brain abscess

Respiratory arrest

? Erratic concentration

? Admin rate

Wallis et al.[12]
76FHistory of tuberculosis (isoniazid), CHF, hypoxia, suspected digitalis intoxicationPhenytoin 100 mg over 3 min – nodal rhythm [RIGHTWARDS ARROW] asystole, resuscitation failed‘In elderly patients with digitalis toxicity hypoxia, and intraventricular conduction defects, IV phenytoin may be dangerous’Digoxin toxicityZoneraich et al.[13]
68M

Biventricular heart failure, pulmonary hypertension, generalised seizures

Digoxin

Phenytoin 880 mg infused manually over 25 min [RIGHTWARDS ARROW] sinus bradycardia and hypotension, asystole.

Cardiac monitored

‘Rapid manual infusion of IV phenytoin has little or no place in modern medicine.’

Infusion conc 17.5 mg/mL

Rapid IV push

Peak phenytoin levels

Higher infusion conc

? Digoxin

York and Coleridge[14]
44M

Cirrhosis of liver

Repetitive seizures

Phenytoin 500 mg infused manually over 14 min.

15 min later [RIGHTWARDS ARROW] hypotension, apnoea [RIGHTWARDS ARROW] 2o AV block, asystole.

Cardiac monitored

As above

Rapid IV push

Peak phenytoin levels

Higher infusion conc

York and Coleridge[14]

IV phenytoin for seizure control and other non-cardiac indications – effect on heart rhythm

Given that the use of IV phenytoin as a treatment for arrhythmias is largely confined to the history books, we examined the published literature on the frequency of adverse cardiac events in patients who received IV phenytoin for a non-cardiac indication. Twenty-six studies reporting adverse effects were identified.[12, 15-39] They were published between 1958 and 2011 (Table 2), comprising a study population of 2254 patients aged from 6 days to 94 years. Twenty-one adverse cardiac rate or rhythm events were reported – 0.9% incidence. There were no life-threatening arrhythmias reported: atrial fibrillation in one patient, bradycardia in nine, tachycardia in two, increased PR interval in one, unspecified change in heart rate in four, ventricular premature contractions in two, dropped beats in one and junctional bradycardia in one patient. No ventricular tachyarrhythmia or significant atrioventricular (AV) block were reported. Authors considered that 12 adverse cardiac events were related to high concentrations or rapid rate of administration[20, 21, 36] and seven adverse events occurred where phenytoin was injected manually.[16, 18] In summary, there has been a very low incidence of adverse cardiac events reported in the literature, with no life-threatening events identified in any series examining the use of IV phenytoin for a non-cardiac indication.

Table 2. Adverse cardiac rhythm effects in studies of IV PHT used for non-cardiac indications

Patients

Reason for PHT use

IV PHT dose (D), rate (R) and concentration (C)

Adverse events

Cardiac rhythm

Comments/conclusionReference
  1. AE, adverse effect; AF, atrial fibrillation; BP, blood pressure; bpm, beats per minute; Conc, concentration; CV, cardiovascular; ECG, electrocardiogram; ED, emergency department; HR, heart rate; IV, intravenous; NS, normal saline; PHT, phenytoin; QRS, QRS complex; RCT, randomised, controlled trial; SA, sinoatrial; —, no comments or conclusions.

Case reports

11 patients

Age: 6 days to 11 years

Continuous convulsions

D: 25–500 mg

R: IV slowly

C: 250 mg/5 mL

‘No side effects or toxic manifestations were noted’‘IV phenytoin is a safe, speedy, and effect method of controlling continuous convulsions in children’McWilliam[15]

33 patients

Age: 28–79 years

Acute seizure disorders

D: 1000 mg IV

R: ≤100 mg/min

Injected into tubing of NS or dextrose

Death (see Table 1)

‘Adverse cardiopulmonary effects were encountered when phenytoin was infused too rapidly.’

Recommend rate: ≤50 mg/min

Wallis et al.[12]
15 young healthy volunteers

D: 250 mg IV

R: 30–42 mg bolus every minute

4 – sudden marked sinus bradycardia

Bradycardia occurred about 20 sec after the third aliquot (bolus)

Resolved with atropine

Barron[16]

33 patients

Age: 21–82 years

Seizure treatment or prophylaxis

D: 10–17 mg/kg

R: <93 mg/min

ECG monitoring in 29 patients

‘no cardiac irregularities’Safe, effective means of …stopping seizure activityWilder et al.[17]

52 patients

159 doses to 139 patients

Age: 17–94 years

Seizures

Diazepam then

D: 650–2000 mg

R: 50 mg/min

C: 5–12 mg/mL

Cardiac rhythm monitored

1 – AF

1 – Sinus tachycardia

1 – Increased PR-interval

3 deaths within 24 h of infusion, not attributed to PHT

Direct manual injection into tubing

No infusion pump

Concentrated solution

Cranford et al.[18]
6 patients

D: 15 mg/kg

R: 30–50 mg/min

C: 6.5–11.5 mg/mL

ECG monitoring

No cardiotoxicitySalem et al.[19]

24 patients

Age: 18–63 years

Major motor seizures

Baseline PHT level 0–7.1 mg/L

D: 10 mg/kg

R: 33 mg/min

IV piggy-back

C: 5–12 mg/mL

ECG monitoring

1 patient – bradycardia and hypotension

4 patients – change in HR >20/min or [DOWNWARDS ARROW] systolic BP >20 mmHg – all recovered

Author: ‘Incidence of cardiovascular side effects may be related to rate of administration or to the concentration of phenytoin sodium employed’Boike et al.[20]

200 consecutive patients in hospital ED

Age: 16–86 years

Seizures

D; 500–1500 mg (mean: 887 mg)

R: variable mean 29 mg/min

Piggy-back giving varying rate and conc

HR monitoring

ECG, if change in vital signs

72 complications in 51 patients

7 CV events in 6 patients

Hypotension-bradycardia – 3 cases

Arrhythmia – 4 episodes

2 patients – PVCs

1 patient on 2 occasions – dropped beats because of SA node arrest or SA node exit block – no symptoms

Author: ‘All seven cardiovascular complications were related to high drug concentrations administered at a rapid rate.’

‘Important factors in these cardiac cases were: administration rate >40 mg/min; high infusion concentration ≥6.6 mg/mL; a ≥800 mg phenytoin dose’

Earnest et al.[21]

28 neurosurgery patients received 93 PHT infusions

Age: 21–76 years

D: 300 mg every 6 h for 4 doses

R: 3–20 mg/min

(mean 10 mg/min)

In NS or lactated ringers solution

ECG monitoring

Small decrease in HR: 86 ± 17 bpm versus 84 ± 14 bpm (statistically, but not clinically, significant).

No arrhythmias

No bradycardia

No hypotension

‘1800 phenytoin infusions administered to >400 patients (for neurosurgical seizure prophylaxis) – no reported cases of arrhythmias.’

‘many ward patients receiving phenytoin without problems’ at doses of ≤1000 mg

Gannaway et al.[22]

RCT

281 patients

PHT 140

Age: mean 47 years

Post-craniotomy seizure prophylaxis

D: 250 mg bd IVNo cardiac AEs reportedNorth et al.[23]

RCT

41 patients

PHT 25

Age: mean 9.4 years

Post-traumatic seizure prophylaxis

D: 11 mg/kg IV

R: 25 mg/min

Using constant rate infusion pump

No cardiac AEs reportedYoung et al.[24]

38 patients

Age: 18–72 years

Seizures

D: 18 mg/kg

using a constant infusion pump

R: 20–40 mg/min

C: 10 mg/mL

Constant ECG monitoring

Toxic PHT levels immediately postinfusion in 22 patients and 4-h postinfusion in 16 patients. No rhythm disturbances.

No ECG changes.

‘IV phenytoin can be administered rapidly and safely using a constant infusion of the drug.’

Carducci et al.[25]

26 patients

Eclampsia seizure prophylaxis

D: 750–1250 mg

R: 50–125 mg/min

C: 1 mg/mL

Continuous ECG monitoring

‘No ECG abnormalities’Slater et al.[26]

37 patients

17–72 years

Seizures

D: 225–1300 mg

R: 40 mg/min

C: 4.5–13.5 mg/mL

Pulse, if irregular, then ECG

‘No clinically important changes in HR’Dela-Cruz et al.[27]

RCT

PHT 189 patients

Post-craniotomy seizure prophylaxis

D: 15 mg/kg

R: over 15–20 min

C: ?undiluted

HR monitored

‘No arrhythmia’Lee et al.[28]

RCT

PHT 28 patients

Alcohol withdrawal seizures

D: 15 mg/kg (max. 1000 mg)

R: ≤37 mg/min

C: ≤3.7 mg/mL

Cardiac monitoring

No cardiac AEsChance[29]

Prospective

42 patients

Age: 20–87 years

Acute onset seizures

Group 1:

≤50 years without atherosclerotic heart disease

26 patients

Age: mean 32 years

Group 2:

>50 years or with atherosclerotic heart disease

16 patients

Age: mean 60 years

D: 15 mg/kg as piggy-back infusion with NS

Group 1 R: 50 mg/min

Group 2 R: 25 mg/min

C: 10 mg/mL

Protocol not modified in patients taking PHT. IV given as a ‘piggy-back’ infusion.

Cardiac monitoring

Group 1: no arrhythmia

Group 2: 1 patient – hypotension and junctional bradycardia – hypotension resolved with fluid, bradycardia resolved spontaneously within 4 h

Author: In patients with atherosclerotic CV disease, IV PHT rates should not exceed 25 mg/min.

PHT conc 10 mg/mL

No mention of concomitant drug therapy.

Patient was 87 years and weighed 45 kg ?albumin levels. Plasma PHT level 30 (N: 10–20 mg/L)

Donovan and Cline[30]

43 patients

Seizures

D: 16 mg/kg

R: 25–40 mg/min

Continuous ECG monitoring

No arrhythmia, PR interval or QRS interval prolongationAuthor: For patients older than 50 years and those with atherosclerotic CV disease, limiting rate to 25 mg/min and reducing conc. ameliorate side-effectsSchmidt et al.[31]

Retrospective

164 patients

224 presentations

Age: 12–83 years

Seizure

D: 50–1000 mg

R: 15–50 mg/min

C: 3.3-3.7 mg/mL

No abnormal rhythms

Abnormal neurological signs 9%

Hypotension 4.9%

Hypotension was associated with presence of abnormal neurological signs at presentation but no association with other demographic, clinical or dosing dataBinder et al.[32]

20 patients

Age: mean 47 years

Cerebral neoplasms

Postoperative seizure prophylaxis

D: 10 mg/kg or 15 mg/kg

R: ≤50 mg/min

HR and BP continuously monitored

No CV disturbances observedLevati et al.[33]

RCT

PHT 208 patients

Post-traumatic seizure prophylaxis

D: 20 mg/kgNo cardiac AEs reportedHaltiner et al.[34]

RCT

PHT 100 patients

Post-craniotomy seizure prophylaxis

D: 18 mg/kg

R: ≤50 mg/min

Continuous ECG and BP monitoring

No arrhythmiasDe Santis et al.[35]

Prospective study

22 children

Age: 0.5–14 years

100 doses of IV PHT

D: 18–20 mg/kg loading or 3–6 mg/kg/for maintenance doses

Continuous ECG monitoring

AE 6 patients (27%)

1 – tachycardia

Tachycardia resolved with discontinuation of PHT infusion.

Author: Excessive rates of infusion (of either PHT or the subsequent saline ‘flush’) potentially explained tachycardia and other AEs.

Seven doses exceeded minimum recommended infusion rate. Forty-eight doses ‘flushed’ more rapidly than recommended.

Appleton and Gill[36]

Consecutive patients

PHT 90 patients

Age: mean 58 years

Therapeutic reason

D: 15 mg/kg

R: over 4 h

C: <7.5 mg/mL

HR and BP before and after IV PHT

No rhythm disturbancesMartinelli and Muhlebach[37]

Retrospective

653 patients

Age:16-97y

Traumatic brain injury seizure prophylaxis

D: 17 mg/kg

R: over 30–60 min

Cardiac monitoring

Rhythm disturbance: One patient – bradycardia recorded during IV PHTDebenham et al.[38]

Retrospective

27 children

34 loading doses

Acute generalised tonic-clonic seizure

D: 14.9–19.7 mg/kgNo reported toxicityHawcutt et al.[39]

Case reports and adverse drug reaction reports

These studies of IV phenytoin revealed a relatively small number of patients experiencing adverse cardiac rhythm effects, so other sources were reviewed, namely case reports in the world literature and adverse drug reaction reports to the Office of Medicines Safety Monitoring, Australian Therapeutic Goods Administration (TGA).

There were four published case reports of cardiac rhythm disturbances associated with IV phenytoin use for seizures (Table 3). One patient developed complete AV block with standard doses.[41] Two cases, one resulting in sinus arrest and the other in asystole occurred when excessive doses were inadvertently administered,[42, 43] and a preterm infant developed persistent bradycardia with toxic phenytoin plasma concentrations.[40] All patients recovered. These case reports suggest that adverse cardiac rhythm events may be associated with peak phenytoin concentrations.

Table 3. Case reports of adverse cardiac rhythm effects associated with IV PHT administration for non-cardiac indications
Age/sexHistory/diagnosisPHT/effectsTreatment/outcomeCommentsReference
  1. AV, atrioventricular; BP, blood pressure; Conc, concentration; ECG, electrocardiograph; F, female; HR, heart rate; IV, intravenous; L, left; LV, left ventricular; M, male; OD, overdose; PB, phenobarbitone; PHT, phenytoin; SAH, subarachnoid haemorrhage; SR, sinus rhythm; wt, weight.

2-day-old M (32-week preterm)

Seizures

Wt = 1.895 kg

PB IV and

PHT IV, then oral PHT

Persistent bradycardia, not responsive to atropine

Day 15 progressive increase in HRToxic PHT and phenobarb plasma conc.Wiriyathian et al.[40]
65 F

Metastatic melanoma, craniotomy

ECG: SR with LV hypertrophy, L anterior fascicular block.

Seizure prophylaxis:

PHT IV 200 mg, then 8 h later 50 mg at 10 mg/min

[RIGHTWARDS ARROW] complete AV block, [RIGHTWARDS ARROW] asystole

PHT ceased, 12 sec later [RIGHTWARDS ARROW] 2:1 AV block

6 sec later [RIGHTWARDS ARROW] SR

Author: small PHT doses can lead to complete AV block.

? Vagal response to pain at injection site

Randazzo et al.[41]

49 F

OD

SAH & aneurysm

Craniotomy

Seizure prophylaxis

PHT 1500 mg IV over ∼5 min

[RIGHTWARDS ARROW]sinus arrest

18 h later: PHT conc. 36 mg/L. Patient recoveredExcess dose (1500 mg instead of 300 mg), too rapidBerry et al.[42]

25 F

OD

Generalised status epilepticus. Seizures incompletely controlled with carbamazepine 800 mg/day. PHT givenPHT 1500 mg IV at 150 mg/min after 9 min, HR 34, BP 45/0, then asystole

15 min cardiopulmonary resuscitation – patient survived

Confusion between fosphenytoin, and PHT dose and rate

Excess dose, too rapid

Carbamazepine may cause bradycardia also.

DeToledo et al.[43]

Spontaneous case reports to the Office of Medicines Safety Monitoring, TGA, from 1 January 1960 to April 2010 were identified by the following search terms: phenytoin, exploding arrhythmia, bradyarrhythmias, cardiac arrest, tachyarrhythmia and ventricular arrhythmia (Table 4). There was a total of seven spontaneous reports of suspected adverse cardiac reactions to IV phenytoin. In five of these reports, IV phenytoin was the only suspected drug. Of these, only three were rated as certain to have a casual relationship, and they include two cases of cardiac arrest, where the patients recovered, and one case of bradycardia. Reports of suspected adverse cardiac events associated with IV phenytoin over the past 50 years in Australia are rare.

Table 4. Phenytoin – Australian reports of defined adverse cardiac events, including death
 Phenytoin IVPhenytoin IVPhenytoin IVPhenytoin IV
TotalPossibleProbableCertain
  1. Phenytoin IV is the only suspected drug. IV, intravenous; —, no reports.

Number of reports7 (5)4 (2)0 (0)3 (3)
Death – cardiac arrest2 (0)2 (0)
Death – allergic1 (1)1 (1)
Cardiac arrest – recovered2 (2)2 (2)
Bradycardia2 (2)1 (1)1 (1)

Phenytoin overdose

Phenytoin adverse effects are more likely to manifest in cases of phenytoin overdose, as phenytoin has saturable metabolism and therefore very high phenytoin plasma concentrations in overdose. Twenty-seven cases of acute phenytoin intoxication (where phenytoin was the only drug ingested) were published from 1940 to 1982, resulting in only one reported death because of cardiac adverse effects – ventricular arrhythmia – which was probably due to treatment for phenytoin overdose with large doses of amphetamine, caffeine and nikethamide.[44]

Four studies examined the need for ECG monitoring following phenytoin overdose.[45-48] Their authors conclude that phenytoin plasma concentrations >40 mg/L (therapeutic range 10–20 mg/L) do not appear to cause cardiovascular mortality, and routine admission to a telemetry bed in uncomplicated oral phenytoin overdose is not warranted.[45, 47, 48]

Effects of drug vehicle

Because of phenytoin's poor solubility, phenytoin injection contains 40% propylene glycol. In animals, rapid administration of propylene glycol may cause bradycardia, and large doses may cause asystole. The likely mechanism is through stimulation of the cardiomotor vagus and transient inhibition of sympathetic activity.[49, 50] Slow administration results in minimal cardiac changes.[49] If propylene glycol in phenytoin injection is responsible for cardiac rhythm effects, then propylene glycol-free IV fosphenytoin (a phenytoin prodrug) should not cause adverse cardiac effects. Two studies compared emergency treatment with IV fosphenytoin and IV phenytoin. Fosphenytoin was administered more rapidly than IV phenytoin and produced higher unbound phenytoin plasma concentrations. Fosphenytoin was associated with tachycardia, and more systemic adverse effects compared with phenytoin, suggesting that the vehicle is not the issue.[51, 52]

Effect of infusion rate on adverse events

The rate of administration was classified as rapid, possibly rapid or erratic in 12/14 deaths associated with IV phenytoin.[2, 3, 5, 7-12, 14] Furthermore, authors of six studies, involving 460 patients, concluded that adverse cardiac rhythm effects were related to the rate of phenytoin infusion.[12, 18, 20, 21, 30, 36] The need for slow administration at a maximum rate of 50 mg/min to avoid adverse rhythm events has been recommended since 1968.[12] Earnest et al. found that the incidence of systemic complications was 27.8% with infusion rates of ≥50 mg/min, compared with 14.6% at slower infusion rates, and he recommended an infusion rate of ≤40 mg/min.[21] In a study using telemetry, no arrhythmias were associated with an infusion rate of 20–40 mg/min.[25] Furthermore, it has been suggested that in patients with cardiovascular disease, IV phenytoin rates should not exceed 25 mg/min[30] and elderly patients or those with unstable cardiopulmonary function may require much slower infusion rates, in some cases no faster than 5–10 mg/min.[53]

Comparison of cardiac rhythm abnormalities with IV phenytoin and other anticonvulsant medications

The incidence of adverse cardiac rhythm disturbances were reviewed in eight studies comparing IV phenytoin and other IV anticonvulsants published from 1988 to 2012[54-61] (Table 5). Six anticonvulsants, either alone or in combination, were administered to 1231 patients: phenytoin alone, 470 patients; phenytoin and diazepam, 149; phenytoin and valproic acid, 31; phenobarbitone, 142; lorazepam, 136; valproic acid alone, 222; and levetiracetam, 81 patients. Continuous ECG monitoring occurred during anticonvulsant infusion in only one study,[55] while an ECG was performed, wherever required, every 5 min in another study.[58] A further five studies measured pulse or heart rate but did not include ECG monitoring as part of the study methodology.[54, 56, 57, 59, 60] As adverse cardiac rhythm events may be associated with rapid infusion of some anticonvulsants, the maximum infusion rate was tabled and exceeded the recommended rate in only one study,[59] where patients weighing greater than 55 kg received phenytoin at greater than 50 mg/min. The incidence of cardiac rhythm abnormalities associated with IV anticonvulsant administration within each of the eight studies was similar between anticonvulsant therapies.

Table 5. Studies of intravenous PHT compared with other intravenous anticonvulsants

Study type

Indication for anticonvulsant

CV monitoringDrugnMaximum infusion rateCardiac rhythm disturbances (%)Reference
  1. † Maximum rate >50 mg/min for patient >55 kg body weight. BP, blood pressure; CV, cardiovascular; Diaz, diazepam; ECG, electrocardiogram; HR, heart rate; LEV, levetiracetam; Loraz, lorazepam; PB, phenobarbitone; PHT, phenytoin; Post-op, post-craniotomy; prn, when required; RCT, randomised, controlled trial; RT, randomised, non-blinded trial; SE, status epilepticus; VPA, valproic acid; —, not documented.

RCT

Generalised convulsive SE

BP, HR

every 5 min initially

PHT12750 mg/min5.5Treiman et al.[54]
Diaz + PHT1315 and 50 mg/min3.1
PB124100 mg/min4.8
Loraz1362 mg/min7.4

RT

SE

ECG monitoringDiaz + PHT18

2 and

40 mg/min

0Shaner et al.[55]
PB18100 mg/min5.6

RCT

Post-op seizure prophylaxis

Vital signs in recoveryPHT500Beenen et al.[56]
VPA500

Randomised

Convulsive SE

Pulse, BPPHT1450 mg/min0Misra et al.[57]
VPA23over 15 min0
PHT + VPA31 0

Randomised

Benzodiazepine resistant SE

Pulse, BP

ECG every 5 min prn

PHT5050 mg/min0Agarwal et al.[58]
VPA5040 mg/min0

Consecutive

SE or repetitive seizures

Pulse, BP

every 4 h

PHT25over 20 min4Gilad et al.[59]
VPA49over 20 min0

Randomised

Motor focal seizures

Pulse, BP

every 15 min

PHT500Rai et al.[60]
VPA500

Retrospective

Post-op seizure prophylaxis

PHT154over 1 h0Kern et al.[61]
LEV810

Available evidence indicates that IV phenytoin is not associated with increased risk of cardiac rhythm abnormalities compared with conventional IV anticonvulsants: phenobarbitone, diazepam and lorazepam; or with newer IV anticonvulsants: valproic acid and levetiracetam.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Status epilepticus is associated with significant morbidity and mortality,[62] and should be managed in a high dependency (HD) or intensive care unit (ICU) setting.[63] Cardiac telemetry may well form part of the monitoring process for these patients. However, IV phenytoin is also given for recurrent seizures or seizure activity not requiring HD or ICU admission, and current guidelines state cardiac telemetry should be performed.

Guidelines recommending cardiac telemetry are largely based on historical concerns. Despite extensive use over the last 50 years, only 14 reported deaths have occurred with IV phenytoin use. Most were reported in the 1960s and occurred in patients treated with IV phenytoin for arrhythmias mainly associated with digoxin toxicity. They were also a sick population with multiple comorbid conditions. Given that phenytoin is no longer used as an anti-arrhythmic drug, perhaps these reports should not form the basis of guidelines for its use as an anticonvulsant. Indeed, studies with phenytoin overdose do not support significant cardiac rhythm problems with phenytoin.

It is clear from the literature that rapid phenytoin infusion rates resulting in peak plasma phenytoin and propylene glycol concentrations are an important factor contributing to rhythm disturbances. Historically, most adverse cardiac effects were associated with rapid IV administration or manual (erratic) bolus or infusion. In modern practice, IV phenytoin is delivered through a metered infusion device largely removing these concerns.[31]

The perceived need for cardiac telemetry has been ubiquitous in guidelines for phenytoin usage and has triumphed over the available scientific data. A Consensus Guideline published in the Archives of Internal Medicine recommended continuous monitoring of cardiac rate, rhythm and BP, and observation during phenytoin IV administration despite finding low incidences of cardiac adverse events in the modern era. They identified similar risk factors for toxicity and stated that ‘intravenous phenytoin should be avoided in patients with cardiovascular disease or when symptoms of chronic or acute debilitating illness, emanciation, hyponatraemia, peripheral vascular disease, haemodynamic instability, or sepsis are present’ and recommended a phenytoin infusion rate of 30–40 mg/min in healthy adults and 10–20 mg/min in adults with concomitant cardiovascular disease.[64]

Their recommendations are based on the same case reports of arrhythmias we identified in this paper. The difference in interpretation lies in our belief that adverse cardiac rhythm events may be accounted for by either patients' concomitant disease and/or drug therapy, such as digoxin, or phenytoin infusion concentration or rate. The need for cautious phenytoin infusion rates is consistent with our findings, but the need for continuous cardiac monitoring is not.

Our interpretation is supported by the Cochrane Database Systematic Review in 2005 of ‘Anticonvulsant Therapy for Status Epilepticus’ that found no significant difference in the incidence of cardiovascular adverse effects between anticonvulsant treatments for status epilepticus.[65, 66] There are few reports of adverse events with IV phenytoin with modern usage, although we accept that there is potential underreporting of adverse events.[67] Furthermore, recent studies comparing IV phenytoin with newer IV anticonvulsants have not shown a difference in the incidence of adverse cardiac rhythm events.[56-61] Despite this, IV phenytoin has been singled out as requiring telemetry.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

The available evidence does not support a requirement for cardiac telemetry when IV phenytoin is prescribed. It is our concern that mandating transfer from a neurological or general ward to an area where telemetry is available may not always be the most appropriate option, potentially placing the patient in a clinical area with little or no expertise in managing their acute medical problem. As such, we propose that this requirement is removed from guidelines and drug administration protocols. It is important to ensure that patients are treated in the most appropriate clinical area and not have patient location determined by a perceived need for cardiac telemetry.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References