Acute PaYacetamol

Poisoning: TWo Case

Studies and a Review
Ker J, VeCnAleret)MMed(lnt)(Pret)
Summary
ErasmusRfE, mecre
Tbis article presents a reuietu on MPraxMed(Pret)MD(Pret)

parctcetlmol as a tberapeutic agent but

alsc.tas a potentictl toxin, based on two S Afr Fam Pract
patient stuclies. Tbepatbophysiologt,
1995;16:102-6.
cliagnostic approach and management o.f
paracetamol poisoning is discussed.

Curricuhun Vitae
Introduction
. f u t t t t ' si r ' t ' ts' t I r t l i t t l t t f I l t c { ' t t i t ' t r s it . ) 't . t f
I' r't'lt t r"it t t | ] t.l | | | | {/ I i f lL't/ tt i I l.t t t :lt I J(.'lt{t KEYWORDS
i t t l ( ) - l t r t t t l . l l . l l t ' z l( l t r l t i r t l ( ) 1 5 . i l t Paracetamol (Acetaminophen) is
widely used as an analgesic Poisoning;
i t , . , l tIIL t t , . l i i I t i t t 'tir , \r t l t l t t t i t t I t r t t , t t l sl;l i ' * I and
{}I ll('sl)i tr t I () t']:'.1lt't I i t-i t t t' t i f I I I | | "r t'tt'()L'! {t antipyretic and is readily available Acetaminophen;
[ ! r t s l t i t t r l | | 9 t i o , 1 ( ) , $ . ) . i !. / . t c r tf l r t r t l t l f
without prescription. It was first used Physicians,Family;
I t ; l t t l L l t i l i h i l l ' l l t t s l t i l t t Il 1 t ) . \ ' J - l l l l j l
in medicine by von Mering in 1893, but
. l i i l t t t ' si t ' ( t t t i t i l t )! ) t ' ! ti t l ( . 'l l t r r ( l i t e t I ( ) 3 . i - Diagnosis.
I t),\t)) tltt t'i ttq tt,l.titlt I i tuL' Ltt,ii,rr.srlAr.) it only gained popularity after 1949
l ; L tt ' l i i t t t t ' i L ' t ' lt t t ' t , t ' t t l . l l t , t l t t t t s t t . after being recognised as the major
{ , ' t r r r t ' ; t I l . yl t t ! s l ' t ' i t t r -i I t t r I | ) l t . \ ' " s i t ; i r t!trtt
active metabolite of both acetanilid
ll.tc I )t'ltrtt l ntt,u! ttl .llttlitirir,. lirlrr lrslJ-t'
r ; J 'l ' rt . ' f ; t t ' i tttt ; t i l I l l : 1 ' t ' n t t t t ' t ' t l! l t l s l . t i ! t t l . and phenacetin.'
tt t t tl t/ r'i,.qi.cfr'r"{.,r/ {;it f iltur:t tl,]lisl sirrr,'r,
/ t ) ( ) i . 1 1 i . s; ' r i l t ' r ' r , s / s( t i t , ; " - l - s l l t t t t t i . After oral ingestion paracetamol is
lr'i'$ritirirr;t' ..lJt1.r( /., litt t t(l ittrt t I *t.i I lt."tff't
! ' . r t t I L t t ' t .' .f t t t ; t t ' si - st t t t t t ' itt ' t l t t i t ( l l l . ) L ' \ , ' rapidly and almost completely
l . r r u ' tt'! ! " t tt l t l l l J , ' r ' , , . absorbed from the gastro-intestinal
tract and 85 - 95 o/ois metabolised
Departnrentof InternalFledicine
primarily by the liver and excreted in
F*rultyof Meclicine,
LJiriversity
of Pretoria
the urine as a non toxic substance,
l i t ; l t l t . 1 '1 r ' r i t . ' r l t t t s( l 1 t ( r l i fi ( ( l t t ' i / l . t t i The remaining 5 - 15 % is metabolized
ll t lt'lrlt .l)t,;li llri' { nii,r'rl*l.l' uf l:}r'r,/ril.rrr
through Cytochrome P-450 to a toxic
i;t lt)--+. I lt' t'rtrttftIi'tal l]ti, .ll 1';'lt.r',lk'r/
t t f [ : l ] t i u t l l r t s r / o r ' l r ; r l / l l i r 5 1 . q ' l i lri u r r i l l ' intermediate which is detoxified by
.l/t'i/it i;,,r'. 1iri/tt'l'ft'rlrl-;r-r ('r/ glutathione present in the liver cell.
l i r t i r t ' t ' t ' t t! I i t i ; i i t l : f t i i . r r r :i . r - 7 r r " r t l r / ir'ilr
'. During an overdose glutathione is
. { r r i r l ' .l l i r l , r r l i r r / f i t ' t : :t I t : r t ' r t t l t t ' t ' t rll! t {
. l r ' i / r / t . . , t i .tl.'t f i : t t t t Ii i . f l ' t ' t ! t! i L ' t ' .P r i t t t t t ' . 1 ' exhausted and then hepatic cell
t , r ; & ' , r : l r 1 l i t . , ;i t l / ( ' 1 1 ' . { /l .t !t , i N t t t ' t t t l t i l t i t ' necrosis with subsequent liver failure
l ; , , . ' , 1 t t - i r t!i l' t. r ' r ' , , 1 rt t' l l l . t t '( i l ' { t i ! t l I L r . , develops. Paracetamol remains the
t J r f r l r , 1 ' { ' / r 1 { ' rtrtif ! l . t t ' l , r i l r t g t 'o f " t i . t t ,( i l } .
commonest cause of fulminent
l : : ' . ,t . r . ! . r . i 1 r q ' i r y ll1' ;,t i f t , . s s t , : i t t l . ' t t t t ti ! _ l '
i / i ' r / t .t ; ; i ' t r I I i t ( [ ; t i t i ' r : s i l . ir' t f ' f i t t ' l o r i t t hepatic failure in the United Kingdom,
i t s t t l I t J ; I i r , r r l l r , r i /t ' ! t t s l t t ! t t l . accounting for 60 - 650/oof all cases.'z
Paracetamol is the most commonly
Eep;rrtmentnf F;rnrily
Meclicine
Frcuity*f f{edicjne,Universityof Pretarla. reported potentially toxic pharma-
PO Box *67" PRETORIA000| ceutical ingestion in both adults and

s A F A r r r r L py R A c r r c E 1 ' A Z F E B R U A R1y9 9 5
 children, resulting in over 100,000 Siagnosfic Approach Fi:r';r{:r,r1 l ::t::;i: r:' :! rr
;rr'11ry1

calls to United States poison centres (:'itlf iiili{,1f tr{rlr 1 Ci!L}5t} {.!j

in 1991,"and despite the availability of Early recognition and treatment is

a specific antidote, fatalities still
occur. It was found that acute
paracetamol poisoning is common in
Cape Town.'
The purpose of this article is to
'et) discuss the clinical presentation .of
paracetamol poisoning using two
patient studies, and to review modern
concepts in the management.
a t l ! : . ! r i l! . , x i! i t r . i : : : : : , : i : , : : i : ; : : '
essential. A history of ingestion is
essential, but the most reliable
nlethod of diagnosis is a determina-
tion of plasma paracetamol concen-
tration." Determination of a paraceta-
mol plasma concentration should be
done routinely in those cases with an
unreliable history, because poisoned
patients frequently have no clinical
abnormalities until manv hours after a

Patient Studies I
itanr,nr
The first patient is a 17-year old
Day 1 Day 2 Day 3 Day 5 Normal
female who was admitted to the
values
medical ward with a history that she
Total Bilirubin 19 10,5 I 4€! u mol&
had taken 45 paracetamol tablets
Conjugated
(22,5 gram) a few hours previously.
Bilirubin <5 0-4u moVL_
The results of blood tests performed
Alkaline
over the next few days are presented
Phogphatlqpe 1L_0_100 98 26-78rU/L
in Table I. This demonstrated high
levels of liver enzymes,indicating
G/qr n"7
ll 80 9-34rU/L
A_L_T 2180 4868L3s4 1,169 rc.37NlL
Iiver cell necrosis. The prothrombin
activity as well as bilirubin remained
AST 3 590 3 440 329 71 ILAoIUiL
normal. She made an uneventful
LDH _1. ": 2_39 156 6-o:?QQ
I@
4{bumin _38 39-59grI'
recovery.
Prothrombin
aclivity 140 o/o I00 o/o
The second patient is a 20-year old
female who developed jaundice three
days after she had ingested 35
paracetamol tablets (17,5 gram). The
paracetamol overdose. Early identifi-
results of the blood tests performed
cation of unrecognised poisoning and
on this patient during her stay in
treatment with the specific antidote
hospital is presented in Table II. This
patient demonstrates extremely high will prevent morbidity and possible
modality. Due to the common formu-
levels of liver enzymes with the ALT :.i: fr*,f;1iij 'D:rt-i:r i- :i
lation of paracetamol with opioids,
more than eighteen thousand units.
the possibility of paracetamol toxicity i*:.'.:-ii t i::: t,l',;:::: :: ::.:.:- :i :.:
Her prothrombin activity dropped to
should also be considered in every
37 0/oof normal. A consultation with
'ii"!'L:i
I1)11iii"ril L:"il;l rn +;:

case of suspected opioid ingestion.

the liver unit was requested with the if 6i;:l ;,ifltl;:Il lr i::i

possibility in mind that she might

When a reliable history is available,
need aggressive treatment which
patients with ingestions less than 150
might include consideration for liver
mg/kg in children, or 7,5 gram in
transplantation. She made a complete
adults clo not require further
recovery and was discharged 7 days
evaluation for toxicity, provided they
after admission.
do not have chronic liver disease.

SA FAMILY PRACTICE 103 F E B R U A Rl eYe s

When the paracetamol plasma potential seriousness of the A 2il year old needed
concentration is above 150 pg/ml at 4 intoxication. Nausea, vomiting, aggressive treatmer!t
hours or above 15 pg/ml after 15 anorexia and abdominal pain occur
after inE*stirrg S$
hours, liver functions should be during the initial 24 hours and may
performed. The aspartate amino- persist for a week or more. Clinical paracetamol tfiblet{i -

transferase (AST) is used as a
sensitive marker of liver injury and is
of prognostic value. If AST indicates
hepatocellular injury, then serial
determinations of AST, alanine
aminotransferase (AIT), prothrombin
time (PT), bilirubin, electrolytes and
glucose are warranted.n
indications of hepatic damage become even liver transplantaiion
manifest within 2 to 4 days of
wGs cons!dered:
ingestion of toxic doses. Severe liver
damage (with levels of aspartate
aminotransferase activity in excess of
1000 IU per liter of plasma) occurs in
90o/oof patients with plasma concen-
trations of acetaminophen greater

Pathophysiology and ClinicaN

Features

In adults, hepatotoxicity may occur

after ingestion of a single dose of 10
to 15 gram (200 to 250 mg/kg)
paracetamol and a dose of 25 gram or Conjugated
more is potentially fatal.' When high Bilirubin 43.6 25.6 53.1 o-au-llq!I,
doses of paracetamol are ingested, it Alkaline
1-_::-:_'::-

undergoes N-hydroxylation to form N- Phqqphq@e - 132 26-78rU/L

acefizl-para-benzoquinoneimine (\IAPQD, G/GT 300 9-34rU/L
a highly reactive intermediate metabo- 4I,! _ - rLe45 9,340 ? ?p5 8j]0_
IU.&
lite which reacts with sulphydryl .{sT_ _ _,1'-0-,995
_lgs5-_Eq u-??ryni
groups in proteins and glutathione. LDH 190 60-200ru/L
When hepatic glutathione is depleted ru i[-..-- - - -W n9-Esil-
after the ingestion of large quantities Prothrombin
of paracetamol, reaction with hepatic activity 37 o/o l0A o/o
proteins is increased and hepatic
necrosis is the result.

There are other conditions which are than 300 pg/ml at 4 hours, or 45 pg/ml
associated with depletion of hepatic at 15 hours after ingestion ofthe drug.
glutathione. These conditions cause Minimal hepatic damage can be
the liver to have an increased anticipated when the drug Determinethe piasma
susceptibility to the toxic effects of concentration is less than 120 pg/ml at
paracetanrcl
paracetamol. These patients are 4 hours, or 30 pg/ml at 12 hours after
ingestion. c()fl$e{"}trati(}r!
rguti;xelv
therefore high-risk patients and may
develop toxic effects at a lower dose The clinical course of paracetamol
of ingestion. Chronic alcohol abuse, poisoning can be divided into 4
malnutrition, patients on anticonvul- stages.''
sants and rifampicin all constitute this Stage I: 0,5 to 24 hours after ingestion,
high risk group. is characterisedby anorexia, nausea,
vomiting, malaise, pallor and
Sympton-rsof acute poisoning during diaphoresis.
the first 2 days do not reflect the

s A F A M T L yp R A c r r c E 1 0 4 F E B R U A R1y9 9 5
Stage II: 24to 48 hours after ingestion,
entails the resolution of stage I and the
development of right upper quadrant
abdominal pain and tenderness,
elevated serum bilirubin, prothrombin
time and hepatic enzymes, and
oliguria.
Stage III: 72-96 hours after ingestion, is
characterised by peak liver function
abnormalities while anorexia, nausea,
vomiting, malaise may reappear.
During stage IV: 4 days to 2 weeks
after ingestion, resolution of hepatic
dysfunction usually takes place.
Fatalities generally occur between 3
and 5 days after overdose but have
been reported at other times3 and
hepatic regeneration becomes
complete in survivors. The rate of
recovery varies but is complete by 5 to
7 days, although recovery can be
longer in severely poisoned patients.
Management
According to Sommers? all patients
suspected of paracetamol poisoning
should be admitted to hospital for
observation. Gastric lavage and
activated charcoal are only of benefit
if given within 4 hours of ingestion of
an overdose of paracetamol. If a
mixed ingestion of paracetamol and
another drug is suspected, then
charcoal should be used as indicated
regardless of the time delay and
without regard to the specific
treatment of paracetamol toxicity.
N-acetylcysteine (NAC) is the current
treatment of choice for paracetamol
overdose. NAC supplies additional
glutathione to enhance glutathione
supply.' NAC may have other actions
that ameliorate organ damage after
injury has occurred.
The efficacy of acetylcysteine as an Poisoned patients often
antidote for paracetamol has been show no clinical
defined, but the optimal time of dosing
abnormalitiesuntil many
is still under debate. The ideal time to
start acetylcysteine treatment is hours after the overdose.
within B hours of ingestion of
paracetamol.o
Neither intravenous nor oral NAC has
been shown to be the superior route
of administration, because each
dosing protocol is very effective when
treatment is initiated within 10 hours
of ingestion.'' The dosage schedule
for oral treatment is 140 mg/kg,
followed by 70 mg/kg every 4 hours
for 17 doses (total of 18 doses
equaling 1330 mg/kg in 68 hours), and
for intravenous treatment 150 mg/kg
IV as a bolus over 15 minutes, then 50
mgikg over 4 hours, then 100 mg/kg
over 16 hours (total of 300 mg/kg in 20
hours).
Tfeatment with acetylcysteine up to 24
hours after the overdose is both safe
and beneficial." All patients with
evidence of severe toxicity should be "All patients suspected
given acetylcysteine regardless of the
of paracetamol
duration after which they present.'z
poisoninEshouldbe
The use of acetylcysteine up to 72
hours postoverdose significantly admitted to hospital for
decreasesboth the progression of observation"
hepatic encephalopathy and
mortality.'1
Cimetidine has been considered as an
adjunctive agent due to its ability to
inhibit cytochrome P-450. Cimetidine
may have an additional protective
effect when used with acetylcysteine
in paracetamol overdose.r2'"r
The improvements in intensive care
and the advent of orthotopic liver
transplantation have allowed the
rescue of a previously untreatable
small group of patients with this
poisoning.2''*
s A F A M T L yp R A c r r c E 1 0 5 F E B R U A R1y9 9 5
Rofarences 8. Lauterburg BH, Corcoran GB, Mitchell JR. Start ncetylcysteine
Mechanism of action of N-acetylcysteine in
lreatment I hours after
1. Gilman AG, Goodman LS, Rall TW, Murad the protection against the hepatotoxicity of
F. (Eds). The pharmacological basis of acetaminophen in rats in vivo. J CIin taking paracetamol-

therapeutics. 7th Ed. New York: Macmillan Invest 1983;71

:980-91. safe and beneficial
Publishing Company, 1985:692-5. 9. Smilkstein MJ, Knapp GL, Kulig KW,
2. Makin AJ, Wendon J, Williams R. Rumack BH. Efficacy of oral N-
Management of severe cases of acetylcysteine in the treatment of
paracetamol overdosage BR J Hosp Med acetaminophen overdose. N Engl J Med
1994;52:210-13. 1988;319: 1557-62.
3. Litovitz TL, Holm KC, Bailey KM, et al. 10. Smilkstein MJ, Bronstein AC, Linden C, et
1991 Annual Report of AAPCC National al. Acetaminophen overdose: a 48-hour
Collection System. Am J Emerg Med intravenous N-acetylcysteine treatment
1992;10:452-505. protocol. Ann Emerg Med 1991;20:1058-63.
MonteagudoFSE, Folb PI. Paracetamol 11. Harrison PM, Keays R, Broy GP, Alexander
poisoningat Groote SchuurHospital. A 5 GJM, Williams R. Improved outcome of
year experience. S Afr Med J 1987;72:773- paracetamol - induced fulminant hepatic
o. failure by late administration of
Anker AL, Smilkstein MJ. Acetaminophen. acetylcysteine. Lancet 1990; 335: 1572-3.
Conceptsand controversies. Emerg Med 12. Speeg KV. Potential use of cimetidine for
(2):335-47
Clin North Amer 1994;12 . treatment of acetaminophen overdose.
Linden CH, Rumack BH. Acetaminophen Pharmacotherapy 1987; 7: 125S-33S.
o v e r d o s e .E m e r g M e d C l i n N o r t h A m 13. Rolbanol GC, Marcuord SP. Cimetidine in
1984(2);103-19. the treatment of Acetaminophen overdose.
SommersDe K. Die behandelingvan akute J CIin Gastroenterol 1991; 13:79-82.
vergiftiging. 3de uitgawe. Durban: 14. O'Grady JG, Wendon J, Tan KC. et al: Liver
Butterworths. 1992:34-9. transplantation after paracetamol
overdose. BrMedJ 1991; 303:221-3.

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