1. No category

Treatment
of Diphenhydramine
CardiacToxicity
withPhenytoin:
lmplicationof Treatment
of
Type1aAntiarrhythmicToxicity
MichaelB. Gutman,
MD, PhD,FRCPC,
FACEP
Department
of
Traumatology
and
Emergency
Medicine,
University
of Connecticut,
Hartford.
CT,USA
RobertNoseworthy,
MD,FRCPC
Department
of Emergency
Medicine,
Royal
Columbian
Hospital,
NewWest
Minister,
BC,Canada
Roy Pursell,MD,
FRCPC,FACEP
Department
ofSurgery,
Division
of Emergency
Medicine,
andBritish
Poison
Columbia
Center,
University
of British
Vancouver,
BC,
Columbia,
Canada
forCorrespondence:
Address
Michael
Gutman,
MD,PhD,
FRCPC,
FACEP
Department
of Emergency
Medicine
St.Francis
Hospital
andMedicalCenter
114Woodland
Street
Hartford,
CT06105USA
Tel:+(860)
714-4017
Fax:+(860)
714-8046
E-mail:
mgut
@comcast.net
Abstract
Case Report: A 30 year old female ingesteda lar-ueanlount of diphenhydramine.
S h o rtl y a fte r. she exhi bi tedsei zureacti vi ty and w i de-conrpl extachyca r dia.
Seizur e
and or ot r acheal
a c ti v i ty w a s successful l ytreatedw i th i ntravenousbenzodi azepi nes
i n t u b a t i o nW
. i d e - c o m p l e xt a c h y c a r d i ai n i t i a l l y r e s o l v e du ' i t h i n t r a v e n o u s o d i u m
b i c a r b o n a t eb u t l a t e r r e c u r r e dd e s p i t ea l k a l i n i z a t i o nt o a p H o f 7 . 5 2 a n d a r t e r i a l
pCO,28 mmHg. The wide complextachycardiaresolvedshortlyafier the intravenous
infusionof phenytoin750 mg.
Drug screeningfor tricyclic overdoseas well as other common toxic ingestantswas
n e g a ti v e .
Conclusion:Phenytoinrnay havehad therapeuticvaluein this caseof cardiactoxicity
from diphenhydramine
that was refractoryto alkalinizationwith sodiumbicarbonate.
lntroduction
Diphenhydramine
ingestionresultingin toxicity has beenreportedvery commonly( l).
of diphenhydramine
is similarto
Thereis someevidenceto suggest
that the cardiotoxicity
(TCA) toxicity.in thatit hastype la antiarrhythmic
(2).
properties
tricyclicanti-depressant
We will presenta casein which the usualmodalitiesfbr type la antiamhythmic
toxicity
were unsuccessful
in treatinga diphenhydramine
cardiotoxicitybut phenytoinwas.We
w i l l th e n re vi ew the l i teratureand di scussthe use of phenytoi ni n treat ingt ype la
antiarrhythmic
toxicity.
CaseStudy
The patient.a 30 year old Koreanf'erlale.awoke her boyfriendlyin-ebesideher with
noisy laboredbreathing.Her eyeswere open but she was not respondingto touch or
v o i c e . S h e had l ast been seen aw ake and w el l one hour before. The pat ient had
(diphenhydramine)
one month before.The patient
atternptedsuicidewith Sominex,,,,
had no othermedicalproblemsand asidefrom Sominex,u,
was on no medication.
On e h o u r a nd fi fteen rni nutesafter l ast bei ng seen w el l the pati entbe ganhaving
generalizedseizureslastingat leastthirty five minutes.Paramedics
treatedthe patient
pre-hospital
with Valium,",20 mg IV, midazolam5 mg IV and endotracheal
intubation.
They alsoadministered100ml of D50W IV, eventhougha chemstrip,.showednormal
fingerstickglucoserange,thiamin50 mg and Narcan0.8 mg IV.
Initially when the paramedicsarrivedand were beginningto treat the seizure.a sinus
ta c h y c a rd i aat a rate of 120 w as noted on the cardi acmoni tor.The syst olicblood
pressurewas 120 mmHg. As the seizureprogressedthe QRS complex was noted to
w i d e n . An onl i ne order w as gi ven to admi ni sterN aH C O3 88 meq. IV. The Q RS
narrowedshortly thereafter.
The paramedicsarrived with the patientto the emergencydepartment(ED) 45 minutes
afterthe first patientcontactat the scene.At that time, in the ED, the oxygensaturation
w a s I O O % .g l u c o m e t esr h o w e ds e r u mg l u c o s ea t l l m m o l / l ( 1 9 8 m g / d l ) ;p u l s e
130/minwide complex;blood pressurell0/70: ventilated@ l6lmin. Her temperature
w a s 3 8 .8 " C .The pati ent' sw ei ght w as approxi matel y50 K g. H er neck was supple.
There were no signsof heador neck trauma.There was good air entry bilaterally.The
heart soundswere normal with good peripheralpulses.The abdomenwas soft and no
lsraeliJournalof EmergencyMedicineVol 3, No. 3, September2003
Phenytoin for Diphenhydramine
Toxicity
m a s s e sw e r e f e l t . T h e p u p i l s w e r e 4 m m a n d
non-reactive.Fundi were normal. Her eyes were
lr ll ,
closedand she was flexing all four limbs to pain.
There were no gag or cornealreflexesand no doll's
r l
eye movement.No skin lesionswereobserved.
Ir rl il ,
(figure l) showeda
A 12 lead electrocardiogram
wide complex tachycardiawhich was interpretedat
the time, and later confirmedby two cardiologists.
as likely beinga ventriculartachycardia(VT).
W i thi n l 5 mi nutesof arri val to the E D NaHCO T
l l r
one ampule (50 ml. 88 meq) and two ampulesin
, ll.ltli i11r1,,,i
f.i,i;,,.-.;{. I L D5W @ 250 cc/h was administered.She also
receivedactivatedcharcoal,50 g by nasogastric
Fipure l. This is a l2 lead ECG of the putient discussetlirt this renort Drittr to tube.
triutment with nhent'toin. It illusirute.s'tlte run.t ol' rt'ide cotrrDle.\'tu<'lt't'<'urtliu
(arrou's). The alsterisksindicote likelv lit.siottbetns. This ECG vits inlerni'eted
bt' A r t e r i a l b l o o d g a s e s( A B G ) f i v e m i n u t e sa f t e r
'
tvvoc'arcliologi.r/.s
cl.rlikeh representiig'run.sof' Ventriculur Tu<'hyt'urtliu.
admi ni strati onof N aH C OTw er€ pH 7.52l'pCO 2
28 mmHg;0.234 mmHg; and -HCOr23meq/L. A
chest
x-ray was normal.
,i t i1.1
i 11'
A half hour after arrival to the ED. initial blood
work-up showed sodium (Na) 139 meq/L;
Potassium(K) 2.6 meq/L; Chloride (CI
100meq/L and serumglucosel5.l meq/L.
A l cohol , acetyl sal i cyl i caci d and acetam inophen
levels were not detected.A tricyclic antidepressant
screeningwas negative.Urine toxicology screening
was not done.
Thirty five minutesafter arriving in the ED, runs of
VT continued.Over the next 45 minutes,despite
l i d o c a i n e ,a 3 m g / K g I V b o l u s . f o l l o w e d b y
4 mg/min infusion and anotherampuleof NaHCOT
Ficure 2. This i.r a I2 teud ECG of the same Dutienl
inlusion lluu
l,lluston
hutl sIoJrD(u.
stoppetl. There
I nere ure
ure n(,
nlitIOnRer
long,er nins ol v
bei ng admi ni stered,runs of V T conti nu ed.KC I
tliar the QT inteiial is .still ahnonnullt long.
40 meq [V was administeredand a repeatABG
showedpH 7.53; pCO:26mmHg; O:188 mmHg; -HCO,22meqil- and K 3.4 meqlL.
In order to treat the VT, phenytoin750mg IV was administeredover 30 minutes,the
infusion beginningtwo hours after arrival in the ED. No further VT was observedonce
the infusion had stopped.
Procainamide,amiodaroneand bretylium were not consideredfor treatmentbecause
the ECG had a prolongedQT interval suggestiveof type Ia antiarrhythmictoxicity and
thesedrugsare contraindicatedin this circumstance.
A CT scanof the headwas normal.
One hour after the phenytoininfusion beganthe BP was notedto be only 87/51 mmHg.
Following IV NS 500 ml bolus,the BP was 92178mmHg with a sinustachycardiaof
100 beats/min.(Figure2). A repeatdoseof activatedcharcoal50 g was given and the
patientwas transferredto the intensivecare unit.
She was extubatedlater that day. She admitted to taking more than twenty 50mg
capletsof Sominex,,.Eventuallyshe was transferredto psychiatrywith no known long
term neurologicor cardiacsequelae.
,
.-'l
Discussion
Diphenhydramine
is an Hl antagonist.It's toxic actionswith exceptionto its cardiac
effects,are primarily due to its anticholinergicproperties(3). Toxicity is common (4).
(4).
Anticholinergicpoisoningusuallypredominates
Tachyarrhythmias,bradyarrhythmias,ventriculartachycardia.ventricular fibrillation,
bundle branchblocks, hypotensionand completecardiovascularcollapsehave been
2003'ltnugo ,3 ll)rl ,3 i'l9lnTilNlgt) r)Nlurn nDil tn)
5
Phenytoin for Diphenhydramine Toxicity
observedfollowing large diphenhydramineingestion(5). In most reportedfatal or life
threatening
cases.the cardiactoxicity presentsfollowing seizureactivity(3,4,6).
In 1992Clark and Vance (2) reporteda diphenhydramineintentionaloverdoseresulting
seizureactivity.and then ventriculartachycardia
in progressiveloss of consciousness,
with a normal blood pressure.Presuminginitially that the TCA overdosewas the cause
they alkalinized(pH>7.45)the patientwith an IV NaHCO,
of the clinical presentation,
an abolition of the VT. No TCA ingestionwas found
infusion
observed
bolus and
and
o n s e ru m a nal ysi sor hi story. A s a resul t the authorsi ntroducedthe concept of
toxicity being causedby a quinidinelike or type la antiarrhythmic
diphenhydramine
" membranest abilizer "
to x i c i ty s i m i l ar to TC A poi soni ng.D i phenhydrami nei s a
becauseof its fast Na' channelblockade properties.resulting in intrinsic pacemaker
( 2) .
A V node bl ockadeand re-entrantventri cul artachydi srrh yt hm ias
s u p p re s s i on,
"antagonizing"Na. channel
cardiotoxicityby
NaHCO, may combatdiphenhydramine
blockadeeither by the provision of hypertonicsaline and/or an alkaline environment
(2,8,9).Thus it seemsthat diphenhydramine
is similarto other type la antiarrhythmic
properties
and the ability of NaHCO.to treatits
in
its
electrophysiologic
toxicitiesboth
cardiotoxicity.But what if NaHCOTdoesn'twork?
In the early 80's, phenytoinwas advocatedas the antiarrhythmicof choice for digoxin
and TCA overdose(10,1l,l2). Sincethen,Digibind "'has becomeprimarytherapyfor
seriousdigoxin overdose.Many authoritiesdo not recommendphenytoin in TCA
overdose(13) and thus, by inferencefor, all other type la antiarrhythmictoxicities.
T h i s re c o mmendati oni s basedon tw o ani mal studi es.These studi esinvolved an
i n tra v e n o u sami tri ptyl i nei nfusi on model i n dogs (14) and rabbi ts(15) . I n t he dog
study, one group was given phenytoin l9mg/Kg and the control group, none. The
numberof episodesof VT per animal and the durationof VT was significantlygreater
in the phenytoingroup. The plasmalevels of amitriptyline were not comparedin the
phenytoin versusthe control group. But the authorsdid report that there were higher
p l a s m al e vel s of ami tri ptyl i nei n the group w i th V T. The authorsconc ludedt hat :
l. phenytoincausesincreasedVT in TCA overdose,2. thereare no clear indicationsfor
"negative effects" on
phenytoin in TCA toxicity and 3. phenytoin may have similar
other type la antianhythmictoxicities.In the Rabbit study, phenytoinprophylaxisdid
"rescue" (authorsused quotes)
not preventdeath from amitriptylineinfusion and a
phenytoininfusion reversedonly two of twelve animals' cardiacarrhythmias.These
"rescue"doesn'tdelayor treatcardiac
authorsconcludedthat phenytoinprophylaxisor
a rrh y th mi aor preventdeath.H ow ever, the observati ondescri bedabo ve could be
interpreteddifferentlyand might lead to differentconclusionsas describedbelow.
There is poor clinical applicabilityof a constanttoxic infusion rnodelcomparedto real
life scenariosinvolving usually single large ingestions.In the dog study the authors
notedthat phenytoinresultedin more TCA being requiredbeforeVT was elicited.It is
possiblethat the increasedincidenceof VT and mortality was causedby a greaterlevel
of amitriptyline in the group with phenytoin.Furthermore,the blood pressurewas not
controlledin either study. In the rabbit study,the authorsadmit that the blood pressure
"substantially"lower
was not monitoredand in the dog study the phenytoingroup had
BPs than the control group. It is possiblethat the hypotensionin the phenytoingroup
resultedin myocardialhypoperfusionand thus increasedventricularirritability. These
interpretationssuggestthat thesetwo animal studiesshould be viewed with caution as
being the basisfor prohibitionof phenytoinin TCA or any other type I a toxicity.
There is some evidencefrom other studiesthat phenytoin has therapeuticeffects in
TCA and type la antiarrhythmictoxicities.Hagermanet al, l98l (16) describeda case
s e ri e si n v ol vi ng l 0 pati entsw i th TC A overdoseresul ti ng i n varyi ng degr eesof
conductionblock and QRS widening that had a reversalof cardiotoxicityafter 5 to 7
mg/Kg phenytoinIV.
Maxwell et al, 1994, reportedtwo casesof neonatesgiven bupivacainefor spinal
anesthesiaresulting in VT refractory to alkalinization and usual ACLS protocol,
including lidocaineand bretylium, which convertedto sinus rhythm soon after the
lsraeliJournalof EmergencyMedicineVol 3, No. 3, September2003
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