1

Second Meeting of the Subcommittee of the Expert Committee on the

Selection and Use of Essential Medicines
Geneva, 29 September to 3 October 2008
REVIEW OF N-ACETYLCYSTEINE FOR THE TREATMENT OF
ACETAMINOPHEN (PARACETAMOL) TOXICITY IN PEDIATRICS
D. Adam Algren, M.D.
Assistant Professor of Emergency Medicine and Pediatrics
Divisions of Emergency Medicine and Pediatric Pharmacology & Medical Toxicology
University of Missouri !ansas "ity
Attending Physician, Truman Medical "enter, !ansas "ity, M#
Attending Medical Toxicologist, "hildren$s Mercy %os&itals and "linics, !ansas "ity, M#
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E(E"UT)*E +UMMA,-
Acetamino&hen .&aracetamol/ toxicity is a common cause of drug0induced
he&atotoxicity in children and adults. 10acetylcysteine .1A"/ has 2een used for several
decades and has &roven to 2e the antidote of choice in treating acetamino&hen0induced
he&atotoxicity. There is significant clinical evidence to su&&ort that oral and intravenous
1A" are e3ually efficacious in the &revention of he&atotoxicity. An im&ortant factor in
assessing the efficacy of 1A" is the timing of thera&y initiation in relation to the ingestion.
Patients that ingest an acute overdose and have 1A" thera&y initiated 4ithin 5 hours do 4ell
and have less than a 167 incidence of he&atotoxicity and generally do not develo& liver
failure or die. Those &atients that chronically ingest excessive doses of acetamino&hen over
many hours and8or have 1A" thera&y initiated more than 5 hours after an acute overdose
have an a&&roximately 50967 incidence of he&atotoxicity. Unli:e clinical scenarios in 4hich
1A" thera&y is initiated early, &atients that have administration delayed are at ris: of
develo&ing fulminant he&atic failure and death.
#ral administration is the &referred route for 1A" thera&y unless contraindications
exist .e.g as&iration, &ersistent vomiting/. The usual recommended loading dose is 1;6
mg8:g follo4ed in ; hours 2y a maintenance dose of <6 mg8:g orally given every ; hours.
This dosing is commonly recommended to 2e continued for <' hours= ho4ever more recent
clinical ex&erience su&&orts tailoring the duration of thera&y to the &atient$s clinical
condition. )ntravenous 1A" is recommended in situations in 4hich the &atient is not a2le to
tolerate oral administration of 1A" or has fulminant he&atic failure. The most commonly
used )* &rotocol is to administer 196 mg8:g )* over 1 hour, follo4ed 2y 96 mg8:g over ;
hours, then 166 mg8:g over 1> hours. A modified intravenous dosing formulation for
&ediatric &atients .4eighing less than ;6 :g/ is recommended to &revent excessive fluid
administration.
The antidotal efficacy of 1A" is determined 2y great extent to the time that treatment
is initiated after an overdose of acetamino&hen. 1A" thera&y should 2e initiated 4ithin 5
hours of an acute ingestion and other4ise as soon as &ossi2le. ?hile many &rotocols have
defined lengths of treatment, it is generally recommended that 1A" 2e administered until the
serum acetamino&hen concentration is undetecta2le .@16 mcg8ml/ and the &atient is clinically
4ell 4ith normal liver function tests. )n cases of he&atotoxicity, 1A" should 2e continued
untilA 1/ the serum liver transaminases fall to less than 1666 )U8B, 2iliru2in and coagulation
studies are normal, and the &atient is clinically 4ell= '/ the &atient receives a liver trans&lant=
or C/ the &atient dies.
Doth oral and intravenous 1A" are 4ell tolerated. 1ausea and vomiting are common
4ith oral administration. )ntravenous use has 2een associated 4ith the develo&ment of
ana&hylactoid reactions. Eenerally these reactions are characteriFed 2y the develo&ment of a
mild rash or urticaria. They ty&ically res&ond to antihistamines and often the infusion is a2le
to 2e com&leted. Bife0threatening ana&hylactoid reactions and deaths have 2een re&orted, 2ut
are uncommon.
C
P,#P#+AB
The ?orld %ealth #rganiFation Model Bist of Essential Medicines and Model
Gormulary of '66> lists acetylcysteine .1A"/ as an antidote for use in the treatment of
acetamino&hen .&aracetamol/ overdose.
1,'
)t is &ro&osed that acetylcysteine 2e considered
the antidote of choice in the treatment of acetamino&hen toxicity. Acetylcysteine is 4idely
availa2le and can 2e administered 2y 2oth oral and intravenous .)*/ routes. Doth oral and )*
use of 1A" in this setting have &roven to 2e safe and effective.
)1T,#DU"T)#1
Acetamino&hen .Paracetamol/ is used 4orld4ide for its analgesic and anti&yretic
&ro&erties. )t is 4idely availa2le and &resent in many &rescri&tion and non0&rescri&tion
medications. Unfortunately, ho4ever, acetamino&hen toxicity remains the most common
cause of drug0induced he&atic failure. ,e&eated su&rathera&eutic misuse, non0intentional
misuse, and intentional ingestion may all result in he&atic toxicity.
The mechanism of acetamino&hen toxicity has 2een 4ell studied. Gollo4ing
ingestion a maHority .IJ67/ of acetamino&hen undergoes &hase )) meta2olism .via
glucuronidation and sulfation/ to &roduce non0toxic meta2olites. A small fraction .@90167/
of acetamino&hen is meta2oliFed 2y "-P;96 isoforms .&redominately "-P'E1/ to 10acetyl0
&02enFo3uinoneimine .1APK)/, a toxic meta2olite. Under normal conditions 1APK) is
detoxified through conHugation 4ith glutathione. ?ith acetamino&hen toxicity, cellular
glutathione is de&leted resulting in the availa2ility of 1APK) to 2ind to cellular
macromoleclues, the conse3uences of 4hich are he&atocellular inHury and cell death. %e&atic
toxicity is generally thought to occur 4hen glutathione stores are de&leted to less than C67 of
normal.
C
"hildren may 2e less susce&ti2le to acetamino&hen toxicity
;,9
conse3uent to a
develo&mentally associated increase in sulfation a2ility.
>
"ertain factors can &lace &atients at higher ris: of acetamino&hen toxicity. Diseases, such as
alcoholism, malnutrition, %)* and cancer are associated 4ith glutathione deficiency. This
could result in a decreased a2ility to detoxify 1APK). "oncurrent use of drugs or ethanol
that induce "-P'E1 and &otentially, other "-P;96 enFymes involved in 1APK) &roduction
.eg. "-P1A', "-PCA;/ could result in an increase in the amount of acetamino&hen that is
meta2oliFed to 1APK). "hronic ethanol use has 2een associated 4ith an increased ris: of
acetamino&hen he&atotoxicity.
)n the first ; to > hours follo4ing an acetamino&hen ingestion, &atients may 2e
asym&tomatic or may have mild sym&toms such as nausea or vomiting. A latent &eriod may
then ensue in 4hich the &atient a&&ears clinically 4ell. %o4ever, 4ith the develo&ment of
1APK) and de&letion of he&atic glutathione stores to a critical level, he&atotoxicity ensures.
Most &atients 4ill develo& elevations of the A+T and ABT 4ithin '; hours of an ingestion,
and almost all 4ith have elevations at C> hours.
<
#ccasionally, there is a delay in rise of the
transaminases. Eenerally, maximal he&atotoxicity occurs at <'0J> hours. Progression to
he&atic failure is characteriFed 2y develo&ment of ence&halo&athy, coma, cere2ral edema,
coagulo&athy, gastrointestinal 2leeding, and se&sis. Most deaths from he&atic failure occur
4ithin the first 4ee: follo4ing an acetamino&hen overdose. Patients that recover do 4ell and
do not develo& chronic liver dysfunction.
;
Gollo4ing an acute acetamino&hen ingestion, current recommendations are to o2tain a
serum acetamino&hen level ; hours follo4ing the ingestion. This level can then 2e &lotted on
the ,ummac:0Matthe4 nomogram to determine the &atient$s ris: of he&atotoxicity. There is
limited evidence that follo4ing an ingestion of acetamino&hen elixir that a serum level
o2tained t4o hours &ost0ingestion can determine children at ris: for he&atotoxicity.
5
#2taining a serum acetamino&hen level &rior to com&lete a2sor&tion of an ingested dose
limits the &redictive a2ility of the nomogram. Ginally, the rate of decline for a serum
acetamino&hen level follo4ing overdose can not 2e &redicted using the ,ummac:0Matthe4
nomogram.
An alternative a&&roach to la2oratory testing is 4arranted in cases of chronic
acetamino&hen ingestion or re&eated su&rathera&eutic dosing. A chronic ingestion is
generally defined as occurring over more than ;05 hours. )n such cases an acetamino&hen
level should 2e o2tained along 4ith liver function and coagulation &rofiles. )f the
acetamino&hen level is I16mcg8ml or the A+T or ABT are I96 )U8B, then 1A" thera&y is
recommended.
J,16
This a&&roach has 2een evaluated in a &ros&ective case series of ';J
&atients. 1o &atient that 4as 2elo4 the recommended la2oratory &arameters su2se3uently
develo&ed he&atotoxicity.
J
An acute acetamino&hen ingestion of L196 mg8:g is &otentially toxic. +everal studies
have revie4ed the incidence of he&atotoxicity in &atients 4ho &resent 4ithin the M&ossi2leN
he&atotoxicity range 4hen &lotted on the ,ummac:0Matthe4 nomogram. Drand4ene et al.
retros&ectively identified 'C &atients .19 4ere @15 years old/ that had acetamino&hen serum
levels in the M&ossi2lyN toxic range that did not develo& he&atotoxicity 4hen 1A" 4as
4ithheld.
11
+ome evidence suggests that the threshold dose of 196 mg8:g is too conservative
and that u& to '66 mg8:g may 2e ingested 4ithout develo&ment of toxicity .es&ecially in
children/. "aravati assessed the ris: of children having a toxic .&ossi2le and &ro2a2le/
acetamino&hen level according to the ,ummac:0Matthe4 nomogram follo4ing an acute,
unintentional ingestion. A total of 1,619 &atients .mean age '5 O 1' months/ 4ere identified
that ingested a mean APAP dose of '1C O 1;5 mg8:g. +ix &atients 4ere identified 4ith
&otentially or &ro2a2ly toxic acetamino&hen ingestions. )n three cases, the amount ingested
4as I'66 mg8:g, and in the remaining three the amount ingested 4as undetermined.
1'
+u2se3uently, Mohler and colleagues &ros&ectively assessed for he&atotoxicity in &ediatric
&atients that ingested u& to '66 mg8:g of acetamino&hen. They identified 1,6CJ &atients that
met the inclusion criteria. Gollo4 u& data 4as not availa2le for '6 of these &atients. #f the
remaining 1,61J &atients all 4ere asym&tomatic and 4ithout evidence of he&atotoxicity at <'
hour follo4 u&.
1C
+everal decades of ex&erience have &roven that 1A" is the treatment of choice for
acetamino&hen &oisoning. Prior to the introduction of 1A", B0methionine 4as used as a
treatment for he&atotoxicity, ho4ever 1A" has su2se3uently &roven to 2e more
efficacious
1;,19
and easier to administer given the availa2ility of commercial dosing forms.
1A" has several mechanisms of action that are 2eneficial in the treatment of acetamino&hen
&oisoning 4hich include serving as a glutathione re&lacement and a free radical scavenger,
2inding 1APK) directly and increasing microcirculatory oxygenation.
1>
Efficacy of 1A" and &rognosis are associated 4ith the ty&e of acetamino&hen
ingestion .acute vs chronic/ and the time from ingestion to the initiation of 1A" treatment.
Those &atients that &resent early follo4ing a single, acute ingestion or those &atients that
have normal liver functions tests on admission are &ro2a2ly at lo4er ris: and do 4ell 4ith
1A" thera&y. The definition of APAP0induced he&atotoxicity most commonly re&orted in
9
clinical studies is an A+T and8or ABT I1666 )U8B, or other evidence of he&atic failure. Any
reference to he&atotoxicity in this re&ort is 2ased on this definition.
Multi&le series in adults and children have demonstrated that &atients 4ho have ta:en
multi&le ingestions of acetamino&hen and8or have a delayed &resentation and treatment are at
higher ris: for severe he&atotoxicity.
1<01J
Thus, it is recommended that caution 2e exercised
4hen administering IJ6 mg8:g8day of acetamino&hen to a Msic:N child .vomiting, diarrhea,
&oor oral inta:e/ younger than ' years of age, es&ecially 4hen acetamino&hen is re3uired for
more than 1 day.
'6
Eenerally s&ea:ing, data su&&orting the dosing regimens and efficacy of
1A" in treating an acute ingestion of acetamino&hen can not 2e extra&olated to the
treatment of chronic acetamino&hen ingestion and8or cases of &rotracted su&rathera&eutic
administration of the drug.
?hile 1A" is generally acce&ted across the develo&ed 4orld as the &refera2le
antidote, its 2roader acce&tance must 2e &redicated u&on information 4hich demonstrates not
only its thera&eutic su&eriority to other treatments 2ut also, clear and current evidence that
su&&orts its glo2al ado&tion as the antidote of choice for this condition. This re&ort 4ill
revie4 and summariFe the availa2le evidence regardingA
a/ The efficacy of oral and )* 1A" for the treatment of acetamino&hen toxicity.
2/ The safety of oral and )* 1A" for the treatment of acetamino&hen toxicity.
c/ +ide effect &rofile of oral and )* 1A".
d/ Duration of treatment and follo4 u& la2oratory testing in those receiving 1A" thera&y.
e/ Gormulations and recommended dosage.
B)TE,ATU,E ,E*)E?
The studies for this revie4 4ere identified 2y &erforming a search of the Pu2Med and
Medline data2ases using the search termsA Macetamino&henN and M&oisoningN,
Macetamino&henN and MtoxicityN, and Macetamino&henN and MacetylcysteineN. The dates
included 1J>>0'66<. The "ochrane Data2ase for +ystematic ,evie4s 4as also searched and
a relevant data for revie4 4ere identified.
'1
The 2i2liogra&hies of selected articles 4ere also
revie4ed to identify any studies not found 2y the original literature search.
"U,,E1T B)+T)1E #G A"ET-B"-+TE)1E
The ?%# Model list for '66> currently lists only the intravenous formulation of
acetylcysteine .'66 mg8ml, 16 ml am&oule/. Gor 2oth adults and children the recommended
dose is 196mg8:g )* over 19 minutes follo4ed 2y 96 mg8:g over ; hours then 166 mg8:g
over 1> hours. Administration and &re&aration is determined 2y the age of the &atient. )n the
those I1' years old, the recommended total volume .1A" and )* fluid/ for the 2olus, ; hour
infusion, and 1> hours infusion are '66 ml, 966 ml, and 1 liter, res&ectively. )n children @1'
years of age .2ut over '6 :g/ the recommended volumes are 166 ml, '96 ml, and 966ml,
res&ectively. )n those children under '6 :g it is recommended to administer Cml8:g, <ml8:g,
and 1;ml8:g, res&ectively. )t is noted that hy&ersensitivity reactions may 2e managed 2y
decreasing the infusion rate or discontinuing the infusion. Use of medications, such as
inhaled 2eta agonists or antihistamines, may also 2e necessary.
>
EGG)"A"-
The use of 1A" for the treatment of acetamino&hen &oisoning originated in England
in the 1J<6$s. +u2se3uently, multi&le studies have &roven 1A" to 2e efficacious in the
treatment of acetamino&hen &oisoning. Early animal studies demonstrated the a2ility of
1A" to attenuate or &revent he&atotoxicity.
''
#ne randomiFed trial evaluated efficacy of
1A" in the treatment of &atients 4ith acetamino&hen0induced fulminant he&atic failure.
'C
After several early 1A" trials sho4ed &romising results, su2se3uent human investigations
have consisted mostly of o2servational studies due to ethical concerns of 4ithholding a
&otential lifesaving treatment. Thus, there are no randomiFed controlled trials that evaluate
1A" thera&y for &revention of acetamino&hen0induced he&atotoxicity. Bi:e4ise, no
randomiFed efficacy trials have 2een conducted in children. Many of the trials evaluate
efficacy 2ased on the outcomes of historical control &atients.
)n the only randomiFed trial re&orted in the literature, &atients 4ith acetamino&hen0
induced fulminant he&atic failure 4ere assigned to receive )* 1A" treatment versus standard
su&&ortive8intensive care. The mean age of the treatment &atients 4as CC yr .range 1<0>6/.
The treatment and control grou& had similar 2aseline characteristics and severity of illness.
1A" treatment 4as associated 4ith ;57 .1'8'9 &atients/ survival com&ared to '67 .98'9
&atients/ survival in the control grou& .&P6.6C</. Patients treated 4ith 1A" had a lo4er
incidence of cere2ral edema .;67 vs. >57 &P6.6;</.
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+everal early case series also examined the utility of 1A". #ne series re&orted the
use of )* 1A" in 19 &atients.
';
#ne &atient 4as 1> years old= the remaining 1; &atients 4ere
all adults. T4elve &atients 4ere treated 4ithin 16 hours of their ingestion. The remaining
&atients had 1A" initiated at a mean of 19.1 hours .16.'0'C.9 hours/ follo4ing ingestion.
Those &atients treated 4ithin 16 hours did 4ell= one &atient develo&ed he&atotoxicity. 1o
&atients develo&ed ence&halo&athy or he&atic failure. The C &atients treated after 16 hours all
develo&ed he&atotoxicity, ho4ever all recovered 4ithout se3uelae.
';
Prescott, et al. later re&orted their ex&erience 4ith the use of )* 1A" for the
&revention and treatment of acetamino&hen he&atotoxicity in 166 &atients.
'9
The mean age of
their cases 4as CC years .range 1C05'/. #nly one of >' &atients treated 4ithin 16 hours of
ingestion develo&ed he&atotoxicity. )n those &atients that 4ere treated 4ith 1A" 2et4een
160'; hours .mean 19 hours/ of ingestion he&atotoxicity occurred in 9C7. There 4ere no
deaths in those treated 4ithin 16 hours, and t4o deaths related to he&atic failure in those
&atients treated after 16 hours. The incidence of he&atotoxicity in their historical controls
4as 9'0957 .C deaths/.
'9
,umac: and colleagues revie4ed the use of oral 1A" in t4o o2servational studies.
'>
#f those &atients confirmed to have toxic acetamino&hen levels t4o 4ere less than age 9, <5
&atients 4ere 2et4een the ages of 1' and '1, and the remainder of the &atients .'6/ 4ere
adults. 1o cases of he&atotoxicity develo&ed in those that had 1A" initiated 4ithin 16 hours
.;J &atients/. %o4ever, there 4as a ;97 incidence of he&atotoxicity in those that had a delay
to initiation of 1A" thera&y I16 hours.
'>
The t4o children that 4ere younger than 9 years
old did not develo& he&atotoxicity. )n this study, the time of 1A" initiation relative to the
acetamino&hen overdose and s&ecific &ediatric data 4ere not other4ise re&orted. A follo4
u& study 2y the same investigators assessed the use of oral 1A" in >>' &atients.
'<
T4enty
three &atients 4ere younger than age 1C= &atient ages 4ere not further s&ecified. Patients .all
ages included/ treated 4ith oral 1A" 4ithin 16 hours of ingestion had a <7 incidence of
<
he&atotoxicity. %e&atotoxicity increased to 'J7 and >'7 in those treated 2et4een 1601>
hours and I'; hours, res&ectively.
'<
1o s&ecific adverse effects related to 1A"
administration 4ere re&orted.
The largest study to evaluate the efficacy of 1A" 4as a national multi0center study
that re&orted data collected from 1J<>01J59.
'5
A total of ',6'C &atients had toxic
acetamino&hen concentrations 2ased on the nomogram. A maHority .<57/ of the &atients
4ere 2et4een 16 and C6 years of age. #nly C7 of &atients 4ere younger than five years old.
+&ecific data regarding the &ediatric &atients 4as not re&orted further. Those &atients treated
4ithin 5016 hours of ingestion had a >057 incidence of he&atotoxicity com&ared to '>0C;7
in those treated 160'; hours after ingestion. %e&atotoxicity 4as noted in ;17 of &atients that
had 1A" initiated 2et4een 1> and '; hours. There 4ere 16 acetamino&hen0related he&atic
failure deaths in &atients that 4ere treated 4ith 1A" 4ithin '; hours. There 4ere no deaths
in those treated 4ithin 5016 hours and only one death of a &atient treated 4ithin 1> hours .this
&atient had significantly elevated liver transaminases at the time of 1A" initiation suggesting
that there have 2een an error in the history of the time of ingestion.
'5
Unli:e &ervious studies
that cast dou2t on the efficacy of delayed 1A" thera&y, this trial 4as a2le to sho4 efficacy
.com&ared to historical controls/ u& to '; hours follo4ing ingestion.
An o2servational trial 4as conducted to assess efficacy of a ;5 hour )* 1A" &rotocol
.com&ared to the &reviously studied '6 hour &rotocol/ in 1<J &atients &resenting 4ithin ';
hours of an acute APAP overdose.
'J
The mean .O+D/ age of the su2Hects 4as '1 O J years.
A maHority .997/ 4ere 2et4een 16 and '6 years old. +ix &atients 4ere younger than 9 years
old. %e&atotoxicity 4as o2served in <8J< .<7/ of &atients treated 4ithin 16 hours. )f 1A"
thera&y 4as initiated greater than 16 hours follo4ing the ingestion the incidence of
he&atotoxicity increased to ;6819> .'>7/.
'J
T4o acetamino&hen0related deaths 4ere
re&orted in those treated 4ith 1A" 4ithin '; hours. Doth of these su2Hects had elevated
transaminases on &resentation and had a delay in initiation of 1A" thera&y .1C.9 hours and
'' hours/.
Dur:hart, et al. conducted an investigation to assess the utility of cimetidine in
addition to normal antidotal thera&y in those 4ith acetamino&hen toxicity.
C6
Although the
&rimary &ur&ose of this study 4as not to evaluate 1A", all &atients 4ere treated 4ith 1A".
Thus, it &rovided data that can 2e com&ared to historical controls. The mean age of the 16<
study su2Hects 4as 'C years .range 1'0<6/. Gorty seven &atients 4ere under 15 years of age.
The mean time of initiation of 1A" 4as 1;.9 hours after ingestion. +u2Hects treated 4ithin
1> hours .1'8<; &atients/ of ingestion had a 1>7 incidence of he&atotoxicity com&ared to
C97 .118C1 &atients/ in those treated after 1> hours. There 4ere no cases of he&atic failure or
death.
C6
The use of late 1A" administration in &atients 4ith acetamino&hen0induced
fulminant he&atic failure also a&&ears to 2e 2eneficial.
C1
The ;C study su2Hects 4ere
com&ared to 9< control &atients. Mean .O+D/ age of the study and control grou&s 4ere '5.>
O 16.< and CC.; O 1C.9 years, res&ectively. Pediatric data 4ere not s&ecifically re&orted.
Although not s&ecifically stated, it is &resumed that the 1A" 4as administered )* as this 4as
the most &o&ular route of administration in the country 4here this study 4as conducted
.England/. Median delay to hos&ital &resentation 4as a&&roximately 1>.9 hours in 2oth
grou&s. T4o &atients 4ere treated 4ithin 16 hours. 1either &atient develo&ed
he&atotoxicity. )n those treated after 16 hours, '18;1 .917/ develo&ed he&atic failure and 19
died. The control grou& &rogressed to he&atic failure in <97 of cases and CC died.
C1
5
Additional case series also su&&ort late administration of 1A".
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T4enty su2Hects .mean age
C> years, range 150<> years/ 4ere treated a median of 19.9 .range 1'0';/ hours follo4ing
ingestion. Again, the route of 1A" administration 4as not s&ecified, 2ut is &resumed to have
2een )*. %e&atotoxicity develo&ed in C67 of those treated 2et4een 1' and 19 hours of
ingestion and ;67 of su2Hects treated 2et4een 19 and '; hours. Those 4ith delays in time to
treatment had higher &ea:s in their liver transaminases and coagulation &arameters. 1o
su2Hects develo&ed he&atic failure and no deaths occurred.
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Perry and +hannon evaluated the efficacy of oral versus intravenous .)*/ 1A" in
&ediatric &atients.
CC
)ntravenous 1A" thera&y 4as administered to children that &resented
4ithin '; hours of an acute overdose. These &atients .'J cases/ 4ere com&ared to control
&atients .'9 cases/ treated 4ith oral 1A". The mean age of the treatment and control grou&s
4as 2oth 19 years. T4o &atients 4ere younger than 9. The incidence of he&atotoxicity 4as
com&ara2le 2et4een )* .57/ and oral .>.J7/ 1A".
CC
The )* 1A" treatment grou& had a
higher incidence of coagulo&athy .57 vs. 67/= ho4ever, there 4ere no e&isodes of clinically
significant 2leeding. )t 4as not re&orted if the &atients 4ho develo&ed coagulo&athy had
other evidence of he&atotoxicity. A2normal coagulation &arameters have 2een su2se3uently
re&orted 2y others and it is thought that )* 1A" can interfere 4ith the la2oratory testing for
coagulo&athy.
C;
Data from this study su&&orts a conclusion that )* and oral 1A" are of
com&ara2le efficacy in children.
Duc:ley and colleagues revie4ed their ex&erience 4ith the use of )* 1A" in the
treatment of '69 &atients.
C9
Median age of the &atients 4as '; years .range 605J/. #f 1>'
&atients 4ith &otentially toxic serum acetamino&hen levels, 1C< .597/ 4ere treated 4ith
1A". The remaining &atients that 4ere treated &resented I'; hours follo4ing ingestion or
had a non0toxic acetamino&hen level. The incidence of he&atotoxicity in those &atients 4ith
toxic APAP concentrations 4as 57, com&ared to '67 in those 4ith a delayed &resentation or
un:no4n time of ingestion.
C9
T4o &atients, 2oth of 4hom &resented I'; hours follo4ing
ingestion, died from he&atic failure. Data s&ecific to children 4as not further re&orted in
their results. Bi:e other studies, a delay in initiation of 1A" 4as associated 4ith a higher
incidence of he&atotoxicity.
-i& and Dart 2riefly summariFed their ex&erience 4ith the use of the recently
a&&roved )* 1A" formulation. They included CC &atients ranging in age from 1C0;5. T4o
children 4ere included .ages 1C and 1;/. All &atients had &otentially toxic serum
acetamino&hen concentrations 2ased on the nomogram. All 4ere treated 4ith a '6 hour )*
1A" &rotocol that 4as 2egun 4ithin ;05 hours of ingestion. There 4ere no cases of
he&atotoxicity or death re&orted.
C>
Most recently, ?hyte et al. revie4ed their 1> year
ex&erience 4ith the use of )* 1A" in a cohort of CJJ &atients.
C<
Most &atients 4ere 2et4een
1> and ;6 years old and the youngest 4as ; years old. Pediatric s&ecific data 4ere not
re&orted further in their results. Patients treated 4ithin 5 hours .nP>;/ had a lo4er incidence
.C7 vs '97/ of he&atotoxicity com&ared to those that 4ere treated later than 5 hours .nPC'.
There 4ere five deaths of 4hich t4o 4ere Hudged to have resulted from APAP0induced
he&atic failure.
C<
Bastly, the effect of gastrointestinal decontamination on &reventing acetamino&hen
toxicity can not 2e ignored 4hen examining the literature evaluating the efficacy of 1A".
Most of studies assessing efficacy of 1A" have occurred in &atients that have received
various forms of gastrointestinal decontamination &erformed at different time intervals from
ingestion. Eastrointestinal decontamination is certainly a &otential confounder in evaluating
J
the existing literature on the efficacy of 1A". A detailed discussion of gastrointestinal
decontamination is 2eyond the sco&e of this revie4= ho4ever the reader is referred to several
recent evidence 2ased guidelines.
C50;1
There is concern a2out concomitant administration of
oral 1A" and activated charcoal. )t is generally recommended that oral 1A" and activated
charcoal administration 2e se&arated 2y one hour if feasi2le. +ome have recommended
increasing the dose of 1A" 4hen co0administered 4ith activated charcoal.
;'
%o4ever, there
is a volunteer study as 4ell as o2servational evidence that demonstrate co0administration of
1A" and activated charcoal is safe and does not decrease the efficacy of 1A" or result in
&oorer clinical outcomes.
;C,;;
,ecent evidence suggests that administration of activated
charcoal is associated 4ith a decreased incidence of he&atotoxicity in those individuals that
have 1A" thera&y initiated 4ithin '; hours.
;9,;>
AD*E,+E EGGE"T+8+AGET-
#ral administration of 1A" is usually 4ell tolerated. The most common side effects
are nausea, vomiting, and a2dominal &ain.
;<
The distasteful odor of 1A" .eg. a:in to rotten
eggs/ may contri2ute to intolerance and vomiting of the administered dose. "oncomitant use
of antiemetics can hel& decrease 1A"0associated nausea and vomiting. +erious adverse
effects related to oral 1A" use are rare. There is one re&ort in the literature of a &atient that
develo&ed an ana&hylactoid reaction .tongue s4elling and rash/ after administration of the 5
th
dose of 1A" in a treatment regimen.
;5
The &atient 4as treated 4ith methyl&rednisolone and
di&henhydramine and 4as a2le to com&lete all 1< doses of 1A". )t is not re&orted if any
other medications 4ere administered that could have 2een res&onsi2le for this &atients
sym&toms. There are t4o other re&orts &u2lished in a2stract form of rash associated 4ith
oral 1A" thera&y.
;J,96
)ntravenous use of 1A" is associated 4ith a higher incidence of adverse reactions.
1ausea and vomiting are the most common adverse effects re&orted.
C<,;<
The most serious
adverse effects are ana&hylactoid reactions. Most commonly these reactions are
characteriFed 2y the develo&ment of rash, urticaria, and &ruritis. %o4ever, more serious and
&otentially fatal reactions can occur and manifest 4ith 2ronchos&asm and hy&otension.
Patients 4ith asthma a&&ear to 2e at higher ris: for develo&ing serious ana&hylactoid
reactions.
9109;
1umerous case re&orts and case series have examined the incidence of
ana&hylactoid reactions and other adverse effects associated 4ith )* 1A". The incidence of
ana&hylactoid reactions varied from 60;57.
'C0'9, 'J, C10CC, C9, C<, ;<, 91, 99095
The 4ide varia2ility in
the incidence of adverse effects re&orted is li:ely multifactorial .definition, &ros&ective vs
retros&ective data collection, etc/. +erious or life threatening reactions a&&ear to 2e
uncommon .@97 incidence/. Many ana&hylactoid reactions a&&ear to 2e related to the ra&id
initial infusion over 19 minutes.
C9, 99, 95
Thus, it is generally recommended that an initial )*
dose of 1A" 2e infused over >6 minutes. !err, et al. &ros&ectively evaluated the
relationshi& 2et4een )* 1A" infusion rate and incidence of adverse effects. They
randomiFed 16J &atients to receive the 19 minute infusion and <1 &atients to receive a >6
minute infusion. ?hile the incidence of adverse effects 4as similar 2et4een the grou&s
.;97 vs C57/, there 4as a trend to4ard fe4er adverse effects in the >6 minute grou&.
9J
Management of ana&hylactoid reactions ty&ically involves discontinuing the infusion and
&roviding sym&tomatic treatment such as administration of antihistamines, corticosteroids
and rarely .ie., 4hen hy&otension is &resent/ e&ine&hrine. )n most instances, the infusion can
2e restarted at a slo4er infusion rate and 2e com&leted 4ithout further &ro2lems.
>6
16
)* 1A" administration has also 2een re&orted to result in hy&onatremia .4ith
resultant seiFures/ as a result of administration of large volumes of hy&otonic fluid.
>1
This is
most li:ely to occur in small children 2ecause early )* 1A" &rotocols did not adHust the
volume of )* fluid to account for &atient 4eight. More recently, ho4ever, the manufacturer
has u&dated its guidelines for the use of 1A" in children 4eighing less than ;6 :g to &revent
excessive fluid administration. Ginally, &u2lished information &ertaining to overdose of )*
1A" is scant. )n a single case re&ort, a massive )* 1A" dose .',;96 mg8:g/ in a C6 month
old &atient resulted in status e&ilec&ticus, intracranial hy&ertension, and death.
>'
)nformation
contained in the re&ort could not differentiate a direct effect of 1A" vs. fluid and electrolyte
com&lications of treatment as 2eing associated 4ith the demise of the &atient.
DU,AT)#1 #G T,EATME1T8G#BB#? UP BAD#,AT#,- TE+T)1E
The duration of a course of 1A" treatment should consider not only the APAP dose
.and time course/ 2ut also, a given &atient$s clinical and la2oratory findings. )n those &atients
4ith evidence of he&atotoxicity .A+T or ABT I1666 )U8B/, 1A" treatment should 2e
continued until one of the follo4ing occursA 1/ The &atient has a dro& in A+T and ABT 2elo4
1666 )U8B and other la2oratory studies .2iliru2in and coagulation &arameters/ and clinical
status confirm the &atient$s toxicity is resolving, '/ the &atient receives a liver trans&lant, or
C/ the &atient dies from fulminant he&atic failure.
The duration of treatment in those 4ithout clinical or la2oratory evidence of
he&atotoxicity is increasingly de2ated. The original oral 1A" &rotocol a&&roved 2y the Good
and Drug Administration called for the administration of oral 1A" for <' hours .1< doses/.
This is in contrast to the recently a&&roved )* 1A" that s&ecifies a '6 hour treatment
&rotocol. The continued administration of oral 1A" for <' hours in an asym&tomatic &atient
4ith normal la2oratory studies after C> hours of treatment is &ro2a2ly un4arranted.
)dentifying &atients at minimal ris: for su2se3uent develo&ment of he&atotoxicity is critical
to determining 4ho re3uires 1A" treatment. Qames, et al. 4ere a2le to determine in a
retros&ective revie4 of cases that &atients 4ith normal BGT$s at ;5 hours or normal BGT$s at
'; hours 4ith an acetamino&hen serum level under the M&ro2a2leN toxicity line on the
,ummac:0Matthe4 nomogram follo4ing an acute ingestion 4ere at lo4 ris: for the
develo&ment of he&atotoxicity.
>C
Patient0tailored 1A" thera&y 4ould allo4 individualiFation of treatment and early
discontinuation of 1A" at a time 4hen the &atient 4as determined to not 2e at further ris: for
toxicity. +everal investigators have examined outcomes in &atients treated 4ith shortened
courses of oral 1A". ?oo, et al. re&orted their ex&erience 4ith shortened course oral 1A"
thera&y in the treatment of acute acetamino&hen overdoses.
>;
They identified <9 &atients
4ith &ossi2le he&atotoxicity .2ased on the ,ummac:0Matthe4 nomogram/ that had 1A"
started 4ithin '; hours of their ingestion. The duration of thera&y ranged from less than ';
hours to >; hours. The mean and median duration of thera&y 4as C1 hours. #verall, >
&atients develo&ed la2oratory evidence of he&atotoxicity .A+T or ABT I1666 )U8B/.
>;
This
4as more common .;8> &atients/ in those that had 1A" initiated I16 hours follo4ing their
ingestion. 1o &atient re3uired liver trans&lantation and no deaths occurred. The incidence of
he&atotoxicity in this study is com&ara2le to other studies evaluating oral 1A" thera&y.
Patient0tailored 1A" treatment 4as also evaluated in a series of '< &atients, '1 of 4hom
received 1A" for less than <' hours.
>9
1one of the &atients treated 4ith a shortened course
of 1A" develo&ed he&atotoxicity. Most recently, use of a shortened course of 1A" 4as
evaluated in '69 &atients.
>>
1o &atient in this series develo&ed he&atotoxicity. Thus, there is
11
increasing evidence to su&&ort shortening the duration of oral 1A" thera&y to C> hours in
cases in 4hich the &atient is asym&tomatic 4ith normal liver function tests at C> hours.
><
Dased on an assessment of the recent literature, &atients that are receiving 1A"
thera&y should receive at least daily la2oratory studies including the follo4ingA serum APAP
level .until less than 16 mcg8ml/, serum chemistries .including creatinine/, liver function tests
.eg., ABT, A+T, total and direct 2iliru2in/, and coagulation studies .eg., )1,, &rothrom2in
time/.
G#,MUBAT)#1 A1D ,E"#MME1DED D#+AEE
1A" is availa2le as a solution for oral administration. Additionally, there is a sterile,
&yrogen0free commercially availa2le solution for intravenous administration. "linical
ex&erience and the availa2le literature also &rovide su&&ort for the administration of the oral
form of 1A" after &assing it through a 6.'' micron steriliFing filter .4hich does not remove
all &yrogens/. ?hen the oral formulation of 1A" is &re&ared for intravenous administration,
it should 2e used 4ithin >6 hours. ?hen used 4ithin this timeframe there is less than 167
decom&osition and the &re&ared solutions remain free of 2acterial gro4th.
>5
Administration
of oral 1A" solution intravenously is less costly than using the commercially availa2le
sterile solution.
#ral 1A" is initiated 4ith a loading dose of 1;6 mg8:g follo4ed 2y <6 mg8:g every ;
hours. The most commonly cited &rotocol recommends continued administration for <'
hours= ho4ever duration of thera&y should 2e individualiFed to each &atient as descri2ed
a2ove. )f vomiting occurs 4ithin 1 hour of administration the dose should 2e re&eated.
)ntravenous 1A" should 2e used 4hen contraindications to oral thera&y exist .e.g.
ris: of as&iration, &ersistent vomiting/ or in cases of fulminant he&atic failure. )n adults the
dose is 196 mg8:g administered over >6 minutes, follo4ed 2y 96mg8:g over ; hours, then
166 mg8:g over 1> hours. )n children 4eighing less than C6:g the final concentration of the
)* solution re3uires modification .to a final concentration of ;6mg8ml/ so that an excessive
amount of fluid is not re3uired. The manufacturer of )* 1A" recommends it 2e
administered 4ith dextrose 97, 2ut it is also com&ati2le 4ith R normal saline. The
manufacturer has a recommended dosing schedule for &atients less than ;6 :g .Ta2le/.
>J
Ta2le. Dosing of )* 1A" in Patients ?eighing less than ;6 :g.
Dody ?eight B#AD)1E Dose
196 mg8:g over >6 minutes
+E"#1D Dose
96 mg8:g over ; hours
T%),D Dose
166 mg8:g over 1> hours
.:g/ .l2/ 1A"
.mB/
97
Dextrose
.mB/
1A"
.mB/
97
Dextrose
.mB/
1A"
.mB/
97
Dextrose
.mB/
C6 >> ''.9 166 <.9 '96 19 966
'9 99 15.<9 166 >.'9 '96 1'.9 966
'6 ;; 19 >6 9 1;6 16 '56
19 CC 11.'9 ;9 C.<9 169 <.9 '16
16 '' <.9 C6 '.9 <6 9 1;6
1'
+UMMA,-
1A" should 2e considered the antidote of choice for the &revention and treatment of
acetamino&hen0induced he&atotoxicity. Doth oral and )* 1A" are acce&ta2le and a&&ear to
2e e3ually efficacious. #ral 1A" should 2e considered the &referred treatment unless the
&atient is at ris: of as&irating, has &ersistent vomiting, or develo&s he&atic failure. Doth oral
and )* 1A" are generally 4ell tolerated. )* 1A" is associated 4ith ana&hylactoid
reactions, most of 4hich are mild and easily treated. Bife0threatening reactions a&&ear to 2e
uncommon. )ntravenous 1A" is 4ell tolerated in children, ho4ever in those 4eighing less
than ;6 :g it is recommended that the concentration8formulation 2e modified to &revent
excessive fluid administration. ,ecent evidence su&&orts tailoring the duration of thera&y
de&ending on the &atient$s clinical status and la2oratory data.
,EGE,E1"E+
1. ?%# Model Bist of Essential Medicines. ?orld %ealth #rganiFation. 19
th
edition .March
'66</. Availa2le atA htt&A88444.4ho.int8 m edicines8&u2lication s 8E MB19.&df. Accessed
1ovem2er C6, '66<.
'. ?%# Model Gormulary. ?orld %ealth #rganiFation. Edition '66>. Availa2le atA
htt&A88 m ednetC.4ho.int8 E MBi28ModelBist84 m f'66>.&df. Accessed 1ovem2er C6, '66<.
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)nduced %e&atic 1ecrosis. ). ,ole of Drug Meta2olism. Q Pharmacol Ex& Ther.
1J<C=15<A15901J;.
;. Peterson ,E, ,umac: D%. Age as a *aria2le in Acetamino&hen #verdose. Arch )nt
Med. 1J51=1;1ACJ60JC.
9. ,umac: D%. Acetamino&hen #verdose in -oung "hildren. Treatment and Effects of
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>. Alam +1, ,o2erts ,Q, Gischer BQ. Age0related Differences in +alicylamide and
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1C
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Acta Paediatr. '66>=J9A11>90<1.
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1>
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of Adverse Events After #ral 10Acetylcysteine Administered 2y the )ntravenous ,oute to
Patients 4ith +us&ected Acetamino&hen PoisoningT Ann Emerg Med. '66C=;'A<;1096.
95. Bynch ,M, ,o2ertson ,. Ana&hylactoid ,eactions to )ntravenous 10AcetylcysteineA A
Pros&ective "ase "ontrolled +tudy. Accid Emerg 1urs. '66;=1'A16019.
9J. !err G, Da4son A, ?hyte )M, Duc:ley 1, Murray B, Eraudins A, et al. The
Australasian "linical Toxicology )nvestigators "olla2oration ,andomiFed Trial of Different
Boading )nfusion ,ates of 10Acetylcysteine. Ann Emerg Med. '669=;9A;6'05.
>6. Dailey D, McEuigan MA. Management of Anal&hylactoid ,eactions to )ntravenous 10
Acetylcysteine. Ann Emerg Med. 1JJ5=C1A<16019.
>1. +ung B, +imons QA, Dayne:a 1B. Dilution of )ntravenous 10Acetylcysteine as a "ause
of %y&onatremia. Pediatrics. 1J<<=166AC5J0J1.
>'. Dailey D, Dlais ,, Betarte A. +tatus E&ile&ticus After a Massive )ntravenous 10
Acetylcysteine #verdose Beading to )ntracranial %y&ertension and Death. Ann Emerg Med.
'66;=;;A;6106>.
>C. Qames BP, ?ells E, Deard ,%, Garrar %". Predictors of #utcome after Acetamino&hen
Poisoning in "hildren and Adolescents. Q Pediatr. '66'=1;6A9''0'>.
>;. ?oo #G, Mueller PD, #lson !,, Anderson )D, !im +-. +horter Duration of #ral 10
Acetylcysteine Thera&y for Acute Acetamino&hen #verdose. Ann Emerg Med.
'666=C9AC>C0>5.
>9. Tsai "B, "hang ?T, ?eng T), Gang "", ?alson PD. A Patient0tailored 10
Acetylcysteine Protocol for Acute Acetamino&hen )ntoxication. "lin Ther. '669='<ACC>0;1.
1<
>>. Detten DP, "antrell GB, Thomas +", ?illiams +,, "lar: ,G. A Pros&ective Evaluation
of +hortened "ourse #ral 10Acetylcysteine for the Treatment of Acute Acetamino&hen
Poisoning. Ann Emerg Med. '66<=96A'<'0J.
><. !ociancic T, ,eed MD. Acetamino&hen )ntoxication and Bength of TreatmentA %o4
Bong is Bong EnoughT Pharmacothera&y. '66C='CA169'09J.
>5. Dri22en ?%, Porto +M, Qeffords D!. +ta2ility and Micro2iology of )nhalant 10
Acetylcysteine Used as an )ntravenous +olution for the Treatment of Acetamino&hen
Poisoning. Ann Emerg Med. '66C=;'AJ01C.
>J. "um2erland Pharmaceuticals )nc. Prescri2ing )nformation for Acetadote. ,evised
Ge2ruary '66>. Availa2le at htt&A88444.ace tadote.net8P)WAcetadoteW,evisedWMar6>.&df.
Accessed Ge2ruary 16, '665.
15
G#,MUBA,-
UsesA Acetamino&hen .&aracetamol/ overdose8toxicity
As little as 1619 g or 196 mg8:g of acetamino&hen ta:en 4ithin '; hours may cause severe
he&atocellular necrosis. Early features of &oisoning, nausea and vomiting, usually resolve
4ithin '; hours. Persistence sym&toms .vomiting, a2dominal &ain, Haundice/ suggest the
develo&ment of liver inHury 4hich is maximal C; days after ingestion. )n s&ite of a lac: of
significant early sym&toms, &atients 4ho have ta:en an acute overdose .I196 mg8:g/ of
acetamino&hen should 2e transferred to hos&ital urgently.
Administration of activated charcoal should 2e considered if acetamino&hen in excess of
196 mg8:g or 1' g, 4hichever is smaller, is thought to have 2een ingested. )f administered,
activated charcoal should 2e given as soon as &ossi2le .ideally 4ithin 1 hour/ follo4ing the
ingestion. The activated charcoal and 10acetylcycstine .1A"/ dose should 2e se&arated 2y
one hour if feasi2le
1A" is most effective 4ithin 5 hours of overdose after 4hich its effectiveness declines.
%o4ever, delayed administration is still 2eneficial. The need for 1A" thera&y is de&endent
on the ty&e of ingestion .acute vs chronic/. )n the setting of an acute overdose a ;0'; hour
serum APAP level can 2e &lotted on the nomogram to determine the ris: of he&atotoxicity
and the need for 1A" thera&y. )n chronic ingestions li2eral use of 1A" is recommended if
the serum APAP is I 16mcg8ml, the A+T or ABT are a2normal, or if the &atient has clinical
evidence of liver inHury.
DoseOral: Adults and childrenX1;6 mg8:g then <6 mg8:g orally every ; hours.
I!ra"eo#s: Adults0000 initially 196 mg8:g over >6 minutes then 96 mg8:g over ; hours then
166 mg8:g over 1> hours. "hildren under ;6:g000 Mix 96 ml of '671A" 4ith 4ith '66 ml
of 97 dextrose to create a ;6 mg8ml solution. The loading dose is 196 mg8:g .C.<9 ml8:g/
over >6 minutes, then 96 mg8:g .1.'9 ml8:g/ over ; hours, follo4ed 2y 166 mg8:g .'.9ml8:g/
over the remaining 1> hours.
Dexrose 97 is the manufacturer recommended fluid for )* administration ho4ever 1A" is
also com&ati2le 4ith R normal saline.
A$"erse-e%%e&!s: Ana&hylactoid hy&ersensitivity0li:e reactions have 2een re&orted 4ith )*
use. Patients 4ith asthma may 2e at higher ris: to have a serious reaction. Eenerally these
reactions may 2e managed 2y reducing infusion rate or sus&ending infusion until reaction has
resolvedXs&ecialist advice may 2e needed .rash may 2e managed 4ith an antihistamine, for
exam&le di&henydramine or chlor&henamine, and acute asthma managed 4ith a short0acting
2eta
'
agonist .such as al2uterol or sal2utamol/.