I:

PresentationsofAcutePhenytoinOverdose

LARRYB. MELLICK,MD,* J. ALAN MORGAN,DO,tGARYA. MELLICK,DO:!:

A 15-year-oldboyingested19.6g (15g verifiable)phenytoinsodiumapproximatelyfourhoursbeforeemergencydepartmentpresentation.ThepatientsurvivedthesuicideaUemptwithonlysupportivecare,despitetheingestionof 392mg/kganda peakserumlevelof 100.8 g/mL.A widespectrumof physicalfind-ingsconsistentwith acutemassiveingestionof phenytoinwasnoted.Thiscasereportanda reviewof casesreportedin theEnglishliteratureofacutesingleanticonvulsantingestionfurtherdelineatetheclinicalpresentationof acutephenytoinoverdose.(AmJ EmergMed1989;7:61-67.@ 1989byW.B.SaundersCompany.)

Phenytoin has been used as an anticonvulsant sinceits therapeutic benefit was first reported in the late1930s.1-3Subsequently, the therapeutic usefulness ofthis medication has been well established.

Following the introduction of phenytoin, reports ofvarious adverse effects and descriptions of gradual andacute intoxications began to appear in the literature.For gradual intoxication, clinical presentation andother adverse effects have been well described. How-ever, the presentation following acute oral overdoseand intoxication seems less well delineated. There-fore, in this report the signs and symptoms of acutephenytoin ingestion and intoxication are specificallyreviewed. This presentation was accomplished bymeans of a review of the English literature and ourown report of a case of massive ingestion.

CASEREPORT

On November 15, 1985 a 15-year-old white boy with ahistory of absence seizures presented to the emergency de-partment (ED) of Brooke Army Medical Center (San Anto-

From the 'Emergency Medicine Service, Tripier Army MedicalCenter, Tripier AMC, HI; the tDepartment of Emergency Medi-cine, USA MEDDAC, Fort Hood, TX; and the :j:Department ofNeurology, University of Cincinnati Medical Center, Cincinnati.

Manuscript received June 16, 1986; revision accepted February26,1988.

The opinions and assertions contained herein are those of theauthors and should not be construed as official or representingthe views of the Department of Defense or the Department of theArmy.

Address reprint requests to Dr Larry B. Mellick: 1888 Walnut HillPark Dr, Columbus, OH 43232.

Key Words: Phenytoin, anticonvulsant overdose.

@1989 by W.B. Saunders Company.

0735-6757/89/0701-0015$5.00/0

nio, TX) after acutelyingestinga largenumberofphenytoincapsulesover a two-hour period. When awakening the boyfor school his parents found him lying on the bedroom floorin a pool of pink vomitus and surrounded by several emptyDilantin (Parke-Davis, Morris Plains, NJ) bottles. Historyelicitedfromthe familyrevealeda past diagnosisof border-line schizophrenia and multiple suicide threats over the pastweek.

On presentation the patient demonstrated the followingvital signs: BP, 108/80;pulse, 68/min; shallow respirations,24/min;and temperature, 99.4°P. General physical examina-tion demonstrated a thin and seemingly mute adolescent boywith intermittent body movements best characterized aschoreoathetoid. Physical contact with the patient resulted inmarked increases in these movements and occasionalopisthotonic posturing. The patient would open his eyes tocommand but did not or could not communicate throughspeech. The pupils were midposition and reactive to light,and the patient appeared unable to fixate his eyes. Exami-nationof the pharynxwitha tonguebladeresultedin parox-ysms of retching, opisthotonic posturing, and vomiting.Chest examination demonstrated shallow movements of thethorax. The lungs were clear to auscultation. Examination ofthe heart demonstrated a normal rhythm and no murmurs.The extremities demonstrated brisk, lII-IV/IV, symmetricaldeeptendonreflexes,a three-beatankleclonus,andupwardgoing toes. The presence of ataxia or tremor could not bedetermined because of the dominant choreoathetoid andopisthotonic presentation.

Initial treatment in the ED consisted of airway protectionby nasotracheal intubation in preparation for gastric lavagewith a large-bore tube. Gastric lavage with a total of 4 Lnormal saline was performed. Subsequently, 300 mL mag-nesium citrate with 60 g charcoal was administered throughthe lavagetube. Due to the remote possibilityof a mixedoverdose and the patient's hypoventilation, 3.2 mgnaloxonehydrochloride (Narcan; Endo Pharmaceuticals, Inc, PuertoRico) was administered intravenously (IV).

Laboratory data in the ED demonstrated an initial arterialblood gas of pH, 7.406; PC02, 46.8; P02, 90.3; and HC03,29.4. Serum electrolytes were as follows: sodium, 139;chlo-ride, 101; potassium, 4.0; C02' 27; BUN, II; Cr, 0.1. TheDilantin level was 45 f.Lg/mLon arrival to the ED. The WBCcount was 3.3, hemoglobin was 17.2, and hematocrit was50.7.The chest x-ray demonstrated appropriate nasotrachealtube placement and no evidence of pulmonary aspiration.ECG findings were appropriate for age and demonstrated noconduction or rhythm abnormalities. The patient was admit-ted to the pediatric intensive care unit (ICU) for continuedtherapy and monitoring.

HospitalCourseAfter admission to the pediatric ICU at Brooke Army

Medical Center, the patient required only supportive care.

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Aggressive cathartic and charcoal therapy was continuedthroughout 'hospitalization. The patient's clinical presenta-tion and associated phenytoin levels are presented below.

The initial phenytoin level obtained in the ED was 45fJ..g/mL.Peaking of the anticonvulsant level at 100.8fJ..g/mLoccurred in the afternoon of the second day. Throughout thefirst three days of hospitalization the patient's condition var-ied between combativeness, agitation, and responsivenessonly to pain. During periods of severe agitation, diazepamwas intermittently required to calm the patient. The phenyt-oin level obtained in the early morning of the third day was87.0 fJ..g/mL.By the fourth day of admission he became lesscombative and was responsive to verbal stimuli. Serum lev-els on day 4 were 65.4 fJ..g/mLat 10AMand 55.0 fJ..g/mL12hours later. On day 5, the patient was oriented, eating, andambulatory, despite being markedly ataxic. Serum levelsmeasured 12hours apart were 42.6 fJ..g/mLand 42.4 fJ..g/mL.At that time he related that he had ingested 196pills at 2 AMon the day of admission. Nystagmus, both horizontal andvertical, persisted until day 7 (serum level, 26.4 fJ..g/mL).After eight days of hospitalization the patient was trans-ferred to a residential psychiatric facility.

Serious potential consequences of overdose did not occurin this case. Our patient demonstrated no hypotension orcardiac arrhythmia as a consequence of the massive phenyt-oin ingestion.4 A febrile response did occur on the secondday of hospitalization. Because the intubated patient hadother potential sources of temperature elevation (ie, at-electasis) that were not specifically investigated by physi-cians in the ICU, we cannot attribute this finding to phenyt-oin intoxication. Nevertheless, fevers have been describedin cases of acute phenytoin intoxications.5.6

Laboratory documentation of the patient's condition dem-onstrated several abnormalities. These included mild liverfunction and marked creatine kinase (CK) abnormalities(probably caused by agitation and associated muscletrauma). The highest levels, documented on November 18,were as follows: CK, 6,267 U/L; LDH, 2247U/L; total bil-irubin, 1.4 mg/dL; unconjugated bilirubin, 0.9 mg/dL;SGOT, 171.These abnormalities resolved gradually over theremaininghospitalization. Several ECGs obtained during thecourse of hospitalization demonstrated no abnormalities inrhythm or conduction.

METHODS

A search of the English literature since 1966for allreferences to phenytoin was accomplished throughMedline services. Earlier and unlisted references wereobtained by diligent and progressive review of all titleslisted in each report obtained. Subsequently, all casereports of acute single-drug (phenytoin) ingestions(Table 1) were reviewed for all described signs andsymptoms. These reported signs and symptoms weretallied and are presented below (Table 2). For the pur-poses of this investigation, an ingestion and intoxica-tion was considered acute if it occurred within a 24-hour period. Gradual intoxication occurring duringtherapeutic dose manipulations and acute mixed inges-

62

TABLE1. AcutePhenytoin Ingestions From theEnglish Literature

" Fatal ingestions reported.t Two patients shared 4 g phenytoin.

tions that included phenytoin were excluded from thisreview.

DISCUSSION

The signs and symptoms associated with acute phe-nytoin intoxication were extracted from 27 casereports.6-25Significant variability existed between re-ports in completeness of described physical examina-tions. Therefore, our tally partially reflects those phys-ical findings and symptoms considered pertinent toeach author's presentation. Nevertheless, we feel thatthis information collection is unique and reflects thepresentation of intoxication after acute ingestion oflarge amounts of phenytoin (Table 3).

The observed signs and reported symptoms follow-ing acute phenytoin ingestion and overdose are depen-dent on several factors. These factors include the timefrom ingestion to ED presentation, the serum levels ofthe drug, and yet undefined patient factors that allowapparent tolerance in some individuals.

Following massive ingestion, serum levels of phe-nytoin are effected by altered pharmacokinetics. Inacute intoxication the phenytoin metabolizing en-zymes are saturated. With saturation drug metabolismswitches from first-order to zero-order pharmacoki-

Year Amount (g) Age Reference

1940 4.5 25 yr 71941 2.9 19 yr 81948 25 18 yr 91950 0.6 4.5 yr 101951" - 16 yr 111956 8.26 20 yr 121957 0.88 2.15 yr 131957 1.17 3 yr 131957" 3.2 3.25 yr 141958 - 2 yr 151966" 2 4.5 yr 161966 0.8 20 mo 61966 t 2 yr 171966 t 3 yr 171968 - 3 yr 181968 - 3 yr 181968 2.8 2.5 yr 191972 1-2 4 yr 201973 4.5 2 yr 211973 3.0 4 yr 211973 1.12 3 yr 211975" - 37 yr 221975" - 18 yr 221976 2.5-4 16 yr 231976 3 46 yr 231979 1.5 6 yr 241982 1.5-2.0 2 yr 25

TABLE2. Signs and Symptoms of 27 Acute PhenytoinIngestions and Intoxications6-25

Sign/Symptom

AtaxiaResponse to painful stimuliLethargyHorizontal nystagmusComaAgitation/combativenessSluggish pupil/normal sizeHyperreflexiaSomnolent/stuporousVomitingDifficulty, eye fixationBabinski reflexConfusion/disorientationHyporeflexiaWidebae/staggering gaitDeathVertical nystagmusAbdominal/cremasteric reflexesPupils normalSeizureNauseaDiplopiaHallucinations

Vertigo/dizzinessSlurred speechDysarthriaTremorAnkle clonus

Irregular respirationsAbsent corneal reflexesOpisthotonic posturingBlurred vision

DiaphoresisHeadacheEuphoriaIntention tremorHypotensionMiotic pupilsShallow respirationsWeaknessLoss of oculovestibular reflexesApneaTongue fasciculationsHypotoniaPhotophobia

netics and the drug is metabolized at a fixed rate.26-28With gradual intoxications, attempts have been madeto correlate serum levels and specific signs andsymptoms.29-31Because the literature reflects the factthat serum level quantitation is only recently available,this review makes no attempt to correlate serum levelsand observed signs and symptoms.

ChoreoathetoidMovements

Transient chorea induced after acute IV loading ofphenytoin has been previously described. 32,33Choreoathetoid movements are also described with

MELLICK, MORGAN, AND MELLICK. ACUTE PHENYTOIN OVERDOSE

TABLE3. Signs and Symptoms of Acute Ph~nytoin Overdose

,'CHOREOATHETOID"N

17131210109887766666555554444443333333332222222111

C-choreoathetoid movementsH-hyperactive/hypoactive deep tendon reflexesO-opisthotonic posturingR-respiratory pattern changes

IrregularShallowApnea

E-emesis and nauseaO-obtundation

StuporousSomnolentPain response onlyComa

A-ataxia and gait changesT-tremorH-hallucinations

VisualAuditory

E-extensor response, toesT-thought and speech disturbancesO-ophthalmologic findings

Pupillary light reflex changesNystagmusAbsent corneal, oculovestibular, oculocephalic reflexesDiplopia

I-irritabilityOften fluctuations between agitated and semicomatosestates

D-dizziness/vertigo

gradual phenytoin intoxications.22.34-4oOur case ap-pears to be the first case of acute oral overdose pre-senting with choreoathetoid movements reported.

HyperactiveReflexes

Hyperreflexia was described frequently in the casesreviewed.6,13.17.19,20Our patient demonstrated briskreflexes on presentation to the ED. However, on pre-sentation to the ICU his deep tendon reflexes weredocumented as IIIV. Other reports hinted at simi-lar variability in physical examination. Six patientswere described as having decreased deep tendon re-flexes.9-1l,14.23,24Additionally, ankle clonus was de-scribed in three cases. 6,8,24

OpisthotonicPosture

At initial presentation our patient demonstratedspasms of bowing the body forward, with the head andheels were bent backward. This posturing would occurtransiently following tactile or noxious stimuli.Opisthotonic posturing has previously been describedwith gradual intoxications and with levels as low as 40JJ.g/mL.41,42Similar presentations are described in re-ports of three other cases of acute intoxication.15.19,24

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RespiratoryPatternChanges

Irregular and shallow respirations were described inthree and two patients, respectively. 13,15,19Our patientdemonstrated very shallow respirations and arterialblood gas findings consistent with a mild ventilatorydeficiency. Apnea resulting in a fatal CNS insult wasreportedfollowingan isolatedphenytoinoverdose.16

Emesis

Vomiting was a dominant finding in our patient'spresentation. A gag stimulus considered minimal re-sulted in prolonged retching, Other reports indicatethat vomiting is common following acute phenytoinintoxication.8,9,12-14,16,20Nausea was described in fourcase reports,8-10,12

Obtundation

Mental status changes were frequently reportedin the literature, A spectrum of changes weredescribed, commonly occurring in individual patients.Descriptive terminology included the following: leth-argy6,7,13-15,17,20,2\ responsive only to painfulstimuli 11,13-17,19,21,23-25;comatose7, 11,16,19,23,24,43;andsomnolent or stuporous.l0,17,20,21,23-25Our patientdemonstrated similar changes in level of conscious-ness. Even at the highest documented levels responseto painful stimuliwas described. However, applicationof the Glasgow Coma Scale to the reported patientswould have provided greater descriptive consistencyand clarity. Of special significance for the evaluationof comatose patients was the reported losses of ocu-locephalic, oculovestibular, and corneal reflexes in pa-tients reported by Spector et ae3 and absent cornealreflexes reported by Tenckhoff et al.19Unfortunately,these examinations were not performed or docu-mented in most of the cases reported.

Seizures associated with gradual phenytoin toxicityhave been reported,28,44,45,46Five patients with acuteintoxication had evidence of transient seizureactivity.6,14,15,21,24However, the relationship betweenseizures and phenytoin toxicity in these patients is notclear. One patient had seizures associated with fever;in fact, in this case the phenytoin was administeredacutely and at excessive doses because of the onset ofseizures with a high fever, At admission the patienthad a temperature of 105°F.6Another patient had whatwas thought to be a seizure 48 hours after overdose.This 6-year-old girl with marked opisthotonic postur-ing had a "generalized tonic spasm. ,,24Another childwith uncontrollable seizures while on chronic phenyt-oin administration had seizures 15 to 18 hours afteradmission for a fatal overdose. 14True seizure activity

64

verified by EEG studies occurred in a two-year-oldboy withno previoushistoryof seizures.15 Duringtheprevious day this patient had experienced hypotensionfollowing dialysis, which was treated with levartere-nol. Later in the hospitalization he was reported to behyponatremic. Another patient with no previous his-tory of seizures was described by his mother as havingquick, generalized jerking movements just before hispresentation for admission. No other evidence or ver-ificationof a possibleseizureevent was available.21

Ataxia

This finding was most frequently documented.Ataxia occurred in 17of the reported acute phenytoinintoxications.6,8-10,12,13,16-21,23This finding is com-monly reported in cases of gradual intoxication. In an-other six cases a wide-base or staggering gait wasdescribed.8,10,12,13,20,24

Tremor

"Tremor" was described in three cases.8,10,24An-other two patients demonstrated intention tremor.9,12

Hallucinations

Auditory or visual hallucinations were reported infour cases. 10,12,13,18

ExtensorToe Responses

The presence of a Babinski reflex was reported rel-atively frequently. 9,13,19,24Our patient demonstratedan extensor toe response at the time of presentation tothe ED. Babinski reflexes have also been reportedwith gradual intoxication.42

Thoughtand Speech Disturbances

A euphoric state was described in three of 27patients8,9,12;while confusion or disorientation wasdocumented in reports of six cases. S,10,13,18Speech ab-normalities, such as slurred speechS-l0,12 anddysarthria,8,12,23were not infrequent findings.

OphthalmologicDisturbances

Information useful in the differential evaluation ofcomatose patients is that pupil size was most com-monly normal and that light reflexes were eithersluggish,6,7,12,13,18,19,21,23 absent,14 or nor-maI.7,10,13,19,21Miotic pupils were described in two ofthe 27 patients.ll,16 Interestingly, both of the patientswith miotic pupils died. A third death14was reportedin a patient described as having absent pupillary re-flexes. We might speculate that miosis either resulted

from an unknown mixed ingestion or was a conse-quence of therapeutic interventions in these patients.The other and less clear alternative is that miosis oc-curs at more toxic serum levels of phenytoin.

Diplopia was reported in four patients,8,9,12,19whereas difficulty with eye fixation was reported inSiX.8,12,23,24As mentioned previously, opthalmoplegiahas been described with acute oral and IV intoxica-tions.Z3 Blurred vision was also reported.8,10,12

Descriptions of nystagmus are common in reports ofchronic intoxication.43,47,48This finding was also com-mon in cases of acute intoxication. Horizontal and ver-tical nystagmus was present in our patient. Horizontalnystagmus occurred in ten patients,8,IZ,13,ZO,ZI,Z3andvertical nystagmus was documented in five.6,9,IZ,19Asin our patient, bidirectional nystagmus was often seenin the same patient.6,9,IZ,19

Irritability

Irritability, agitation, or combativeness was de-scribed in nine patients.lO,IZ,13,15,16,ZO,ZI,Z3On arrival atthe ED our patient demonstrated marked agitation inresponse to minimalexternal stimuli. Simple touchingalone would result in choreoathetoid movements andopisthotonic posturing. Additionally, his hospitalcourse was characterized by intermittent agitation re-quiring the use of restraints. At other times the patientwas responsive only to painful stimuli. Diazepam wasused intermittently by physicians in the ICU duringperiods of extreme agitation; we are unable to delin-eate its exact role in the patient's clinical presentation.Nevertheless, other reports (of cases in which diaze-pam was not used) implied similar fluctuations be-tween agitated and depressed mental states.

Dizziness

Dizziness or vertigo was reported in four cases.7-9,18Our patient also complained of dizziness.

Death

Our patient survived following a massive ingestion;however, deaths are reported in the literature.ll,14,16,ZZA review of these cases suggests that therapeutic in-terventions or limited capabilities for monitoring andsupport of metabolic and respiratory complicationsmay have had a role in the outcome. Large doses ofamphetamine (2.88g), caffeine (72g), and nikethamide(144 g) were administered in one patient who devel-oped cardiac irritability and ventricular arrhythmia be-fore death. II In the second case (patient aged 3 years,4 months), reported in 1956, a total 375 mg caffeinewas administered early in the hospitalization. This pa-tient died quietly 34 hours after ingestion of 3.2 g phe-nytoin (220mg/kg).The report does not describe mon-

MELLICK, MORGAN, AND MELLICK. ACUTE PHENYTOIN OVERDOSE

itoring or documentation of metabolic or respiratorystatus. Supportive measures included IV fluid, gammaglobulin, and antibiotic administration. Documenta-tion of the mechanism of death, as well as descriptionsof attempted resuscitative interventions, are absentfrom the report. 14The third death, reported in 1966,occurred in a 4.5-year-old girl who ingested 2 g phe-nytoin. After 48 hours an episode of apnea occurredand the patient was intubated. Subsequently, she wastransferred to a university hospital where her pupilswere noted to be fixed and dilated. Because of "irre-versible brain damage," the respirator was eventuallystopped and the patient died.16

Other deaths following phenytoin overdoses havebeen described more recently. Coutselinis et al verybriefly report two adults (aged 37 and 18 years) onchronic therapy who were found dead and had post-mortem blood levels of 45 and 48 ,...g/mL.zzThe Na-tional Capital Poison Center has also reported deathsfollowing acute ingestions of phenytoin.49-51Impor-tantly, all three of these ingestions were associatedwith other chemical substances or drugs. The 1983re-port describes an adult who ingested phenytoin, phe-nobarbital, and carbamazepine.49 The adult death re-ported in the 1984report also involved phenobarbitaland carbamazepine.50 In the 1985 summary a 3-year-old boy died following the ingestion of six ormore phenytoin capsules. However, the patient's tox-icology screen also demonstrated benzyl alcohol. As-sociated metabolic derangements were also signifi-cant. Laboratory findings included sodium, 125mEq/L; potassium, 2.9 mEq/L; arterial pH, 7.3; and PCOz,30 mmHg. Diabetes insipidus developed 24 hourspostingestion.51 Nevertheless, 6,826 nonfatal expo-sures to phenytoin were reported over 4 years.49-52

Our patient survived with only supportive care fol-lowing the reported ingestion of 196 phenytoin cap-sules (100mg each). This dosage could not be verifiedbeyond the 150capsules definitely known to be in thepatient's possession. If the patient's account is accu-rate, the amount ingested was 392 mg/kg. However,the amount of phenytoin vomited shortly after inges-tion and following presentation to the ED is unknown.If emesis had not lowered the total phenytoin load andthe patient had not been discovered so soon after in-gesting the drug, a different presentation and outcomemight have occurred. However, survival has been re-ported after a mixed acute ingestion including 21 gphenytoin5 and after a pure ingestion of 25g.9Our casereport supports phenytoin's reputation for relativelymild toxicity and successful therapeutic outcomes de-spite large oral ingestions.

CONCLUSION

In order to better delineate the many signs andsymptoms that develop following ingestion of large

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AMERICAN JOURNAL OF EMERGENCY MEDICINE. Volume 7, Number 2. March 1989

amounts of phenytoin a review of the literature wasperformed. Our review demonstrated that the mostcommon signs and symptoms are ataxia, nystagmus,hyperreflexia, vomiting, Babinski reflexes, disorienta-tion, normal pupillary size with sluggish light reflexes,and central signs of both combativeness and markedmental status depression. Additionally, we describedthe presence of choreoathetoid movements and veri-fied previous reports of opisthotonic posturing in casesof acute phenytoin ingestion and intoxication. We alsohighlighted the previously reported losses of oculo-cephalic, oculovestibular, and corneal reflexes follow-ing acute intoxications. In addition, we questionedwhether phenytoin toxicity had any role in causing oraggravatingseizure activity. Finally, we described oneof the largest acute phenytoin ingestions, with subse-quent survival, reported to date. Our information sup-ports phenytoin's reputation for minimal mortality orlong-term morbidity.

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