Acetaminophen (Paracetamol)

D. Nicholas Bateman

Contents Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Pregnant Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Neonatal Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Patients with Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Grading System for Levels of Evidence Supporting

Modulators of Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Recommendations in Critical Care Toxicology,
2nd Edition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Clinical Presentation and Life–Threatening
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Chronic Acetaminophen Overdose . . . . . . . . . . . . . . . . . . . 8
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Acute Single Oral Ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Multiple Ingestions and Therapeutic Error . . . . . . . . . . . 13
Intravenous Acetaminophen Overdose . . . . . . . . . . . . . . . 13
Prognostic Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Psychiatric Assessment Before Orthotopic Liver
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Coagulopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Sepsis and Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

D.N. Bateman
Pharmacology, Toxicology and Therapeutics, The
University of Edinburgh-College of Medicine and
Veterinary Science, Edinburgh, UK
e-mail: drnickbateman@gmail.com

# Springer International Publishing AG 2016 1

J. Brent et al. (eds.), Critical Care Toxicology,
DOI 10.1007/978-3-319-20790-2_108-2
2 D.N. Bateman
Overview
Acetaminophen (paracetamol) was first discovered
in Germany in 1887. It was initially rejected in favor
of the structurally related phenacetin, as it was con-
sidered too toxic. It was only when restudied in the
late 1940s that it was recognized as safer than
alternative agents [1]. It was first marketed as an
antipyretic and analgesic in the USA, as Tylenol,
and UK, as Panadol, in the 1950s [2].
Toxicity from acetaminophen overdose was ini-
tially recognized in 1966, about 10 years after mar-
keting, when the first cases were reported in
Scotland [3, 4]. At that time there were no effective
therapies, and morbidity and mortality from acet-
aminophen overdose climbed steadily as overdoses
increased (Fig. 1) [5]. In the 1970s there were a
significant number of cases in the Royal Infirmary
poisons unit in Edinburgh, and Laurie Prescott and
colleagues did important work, allowing rapid pro-
gress in knowledge. Initial studies showed the rela-
tionship of plasma concentration of acetaminophen
to risk of toxicity (II-3) [6]. Animal studies had
suggested both the mechanism of action of acet-
aminophen and potential antidotes. Studies were
then done in the UK and North America evaluating
three of these, cysteamine, methionine, and
acetylcysteine. By the end of that decade the evi-
dence was clear from UK data that acetylcysteine
(N-acetylcysteine, NAC) was the antidote of choice
(II-3) [7], but for many years there were differences
in the approach to giving this antidote, as intrave-
nous formulations were at that time not licensed for
use in the USA [8, 9]. Despite an available antidote,
which halted the increase in mortality, deaths did
not subsequently decline. As a result, in the UK,
changes were introduced in 1998 to the pack sizes
available for over-the-counter sale (maximum 16 g
in a pharmacy, 8 g in a general store sale), in an
attempt to reduce mortality [10]. The magnitude of
change in mortality and morbidity this has caused
remains a topic of debate [11].
Because acetaminophen is available without
prescription, “over-the-counter,” worldwide it is
commonly used in overdose, but the precise num-
ber of deaths caused is uncertain. In the UK, for
example, at least 150 deaths per annum may be
attributed to ingestion of acetaminophen with and
without ethanol, and an almost equal number of
deaths involve ingestion of acetaminophen as part
of an overdose [5]. Acetaminophen remains the
most common cause of acute liver failure as seen
in hospitals in the USA and UK, and is important
in many other countries [12, 13]. Among over-
dose patients, there are a number of patients who
suffer from toxicity due to taking supratherapeutic
doses. This is in part due to the confusion in
labeling of acetaminophen-containing medica-
tions, the availability of different types of prod-
ucts containing acetaminophen, a lack of
understanding in the community of what products
contain acetaminophen [14], and the narrow ther-
apeutic index of this compound. It may also be
that factors such as acute starvation are as impor-
tant in man as they are in animal models of acet-
aminophen toxicity. Repeat ingestion of
supratherapeutic doses appears to result in a
greater risk of liver damage than the same dose
as a single ingestion [15].
Although antidote therapy is effective if given
soon after ingestion of an overdose, it is clear that its
efficacy declines over time and in patients who take
multiple therapeutic doses in excess it is often too
late for acetylcysteine to be effective (II-2)
[16]. Although other approaches to therapy have
been studied in animal models these are yet to be
put into the clinic. In patients with severe liver injury
liver transplantation may be effective. Present issues
in clinical toxicology of acetaminophen include the
use of safer, potentially shorter and simpler antidote
regimens, better predictive tests for indicating which
patients are at risk, and which therefore allow better
risk stratification than the present nomograms that
have been in use for 40 years.
The introduction of modified release prepara-
tions of acetaminophen has resulted in a problem
in overdose management, since these make risk
assessment more difficult, as the nomograms may
not be applicable due to delays in acetaminophen
absorption [17]. In addition over the past few
years intravenous acetaminophen has become
more widely used, particularly postoperatively,
and sadly cases of toxicity have been associated
with supratherapeutic use by this route [18].
Acetaminophen (Paracetamol) 3

a ICD-8 ICD-9 ICD-10

NAC Pack size Co-proxamol

800 restriction

700

600
Number of deaths

500 All Deaths

Para+/−Dextro
400
Para alone/+ EtOH
300

200

100

0
1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009

b ICD-8 ICD-9 ICD-10

NAC Pack size Co-proxamol

15 restriction
14
Deaths per million population

13
12
All Deaths
11
10 Para+/−Dextro
9
Para alone/+ EtOH
8
7
6
5
4
3
2
1
0
1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009

Fig. 1 Deaths from acetaminophen poisoning in England
1969–2011, (a) total numbers; (b) per million population).
Down arrows indicate potential influences on mortality:
introduction of acetylcysteine as an antidote in 1975;
reduction in pack sizes available for sale over-the counter
in 1998; and withdrawal of propoxyphene containing acet-
aminophen codrug (coproxamol) over 2 years 2005–2007
(Data from Bateman 2014 Clin Tox 52 821–23, with kind
permission of Prof R J Flanagan)

2 (COX-2) enzymes with a reduction in prosta-

Clinical Pharmacology
Although acetaminophen has been used exten-
sively for more than 50 years, its precise mecha-
nism of action therapeutically remains unclear.
While it has been shown to inhibit both cyclo-
oxygenase 1 (COX-1) and cyclo-oxygenase
glandin (PG) production [19, 20], its pharmaco-
logical effect appears to be primarily mediated via
inhibition of COX-2 and prostaglandin E2 syn-
thesis (PGE2) [21, 22]. In vivo, acetaminophen
has similar effects to selective COX-2 inhibitors,
with only mild COX-1 effects [23]. Animal stud-
ies have suggested that acetaminophen inhibits
4 D.N. Bateman
COX-3, a variant of COX-1 [23, 24]. COX-3
encodes proteins with different amino acid
sequences to COX-1 and COX-2, and so it is
unlikely that it plays a significant role in
PG-mediated pain and fever. Furthermore, the
low level of expression of COX-3 in humans
suggests that it may be of little clinical
relevance [25].
Despite similarities with classic nonsteroidal
anti-inflammatory drugs (NSAIDs), however,
the anti-inflammatory effect of acetaminophen
is weak [24]. This may be related to peroxide
concentration, as acetaminophen-induced COX
inhibition is less active at sites of inflammation
where peroxide concentration is high, but more
active centrally at sites of low peroxide concen-
tration, probably in the brain [19, 26]. Animal
models suggest additional analgesic effects may
be mediated via serotonergic [27], opioid [28], or
cannabinoid systems [29]. Animal studies using
COX-2 knockout mice have also demonstrated
that COX-2 is responsible for the febrile
response [30], suggesting that the antipyretic
mechanism of acetaminophen may be mediated
via COX-2 inhibition. In overdose none of these
pharmacological effects are likely to be impor-
tant in the majority of patients, although
increased kaliuresis with resultant hypokalaemia
suggests an effect on renal function associated
with the effects of acetaminophen on renal
prostaglandins [31].
The kinetics and metabolism of acetaminophen
at therapeutic doses are well understood. Gastric
emptying is the rate-limiting step in absorption,
and, as acetaminophen is absorbed rapidly from
the small intestine, speed of absorption of acet-
aminophen has been used as a measure of gastric
motility. Absorption is usually complete by
60–90 min after a therapeutic dose. Liquid prepa-
rations may be completely absorbed within
20 min [32]. With ingestion of excessive doses
of standard-release preparations, absorption may
be delayed but is almost invariably complete
within 4 h. Coingested drugs that delay gastric
emptying may delay absorption of acetamino-
phen. Thus a peak serum acetaminophen
concentration occurring later than 4 h after over-
dose is rare but has been noted, for example, after
coingestion of drugs that impair gastric motility,
such as the opioid propoxyphene [33] and anti-
cholinergic diphenhydramine [34]. A major con-
cern for clinical toxicologists has been the
introduction by pharmaceutical companies of
modified release acetaminophen preparations. As
these are associated with peak
plasma concentrations delayed more than 4 h
after overdose they interfere with the use of the
standard nomogram approach to assessing acet-
aminophen dose, and hence risk of toxicity
[35–37].
In therapeutic dose acetaminophen elimination
follows first-order kinetics. It has a half-life of
2–4 h, which is prolonged in patients with acute
acetaminophen-induced liver damage. At thera-
peutic doses protein binding is 15–20 %, and the
volume of distribution is approximately 0.9 L/kg
[32]. It is obviously more difficult to study these
aspects in patients with overdose, as the dose
actually absorbed is often uncertain. With the
onset of liver injury the elimination of acetamin-
ophen is delayed [6, 38]. More than 90 % of
acetaminophen is conjugated in the liver by a
combination of sulfation and glucuronidation;
approximately 4–7 % is excreted unchanged in
urine. The remainder (about 4 % at therapeutic
doses) is metabolized by the cytochrome P-450
mixed-function oxidase system [39], primarily by
CYP2E1 with a smaller contribution by CYP1A2,
to a toxic metabolite N-acetyl-p-benzoqui-
noneimine (NAPQI).
Pharmacokinetics of Acetaminophen at
Therapeutic Dose
Volume of distribution: 0.9 L/kg
Protein binding: 15–20 %
Mechanisms of clearance (at therapeutic
dose): hepatic >90 %, renal 4–7 %
Toxic metabolite: N-acetyl-p-
benzoquinoneimine
Methods to enhance clearance: dialysis
(may be appropriate to consider in massive
overdose but is normally used in patients ther-
apeutically for management of renal failure)
Acetaminophen (Paracetamol) 5

Acetaminophen Quantity
HN−C−CH3 HN−C−CH3 HN−C−CH3

Glucuronide OH Sulfate
Cytochrome Activity
P450
Store
Reactive N-acetyl-Benzoquinone imine NAPQI
Glutathione Metabolite Macromolecules

O O
HN C CH3 HN C CH3
NAC
Glutathione Macromolecules
Cell Death
OH OH

Mercapturic NAC ??
Acid

Fig. 2 Metabolism of acetaminophen showing main metabolites, mechanism of toxicity, and primary site of action of
acetylcysteine (“?? NAC” indicates unknown mechanism of benefit in liver failure prophylaxis, see text)

detoxifies this metabolite [39, 42, 44–47]. Mito-

Pathophysiology
The basis of acetaminophen toxicity is its meta-
bolic pathway and the availability of natural glu-
tathione (Fig. 2). Acetaminophen is an example
of a substance that undergoes hepatic metabolism
to a toxic metabolite (other examples include
carbon tetrachloride, methanol, and ethylene gly-
col). The metabolizing enzymes are distributed
throughout the body, but the majority of these are
found in the liver, with the highest concentration
in the centrilobular region (zone 3), which is
composed of hepatic acinar cells. A secondary
area of increased concentration is in the kidneys.
Neither acetaminophen nor its conjugated metab-
olites are harmful. However, the metabolite gen-
erated by CYP2E1 is potentially toxic
[40–42]. This metabolite, N-acetyl-p-benzoqui-
noneimine (NAPQI), is very short lived. It binds
to the hepatic cell membrane and injures the lipid
bilayer, if not neutralized by an antioxidant [43],
and glutathione is the primary antioxidant natu-
rally present in the liver that conjugates and
chondrial injury is a component of hepatic injury,
and agents that prevent mitochondrial injury
reduce liver injury from acetaminophen in
animals [48].
At therapeutic doses, acetaminophen is an
extraordinarily safe drug with minimal adverse
effects. However, in an animal model of acetamin-
ophen overdose, NAPQI begins to bind to hepa-
tocytes and causes arylation, cellular injury, and
possibly death when hepatic glutathione stores
have been depleted to less than 70 % of normal
values [44].
Similar reactions are believed to occur in man.
Serious liver damage after a single 75 mg/kg body
weight dose of acetaminophen is rare, even in
patients at increased risk. In patients without risk
factors, a dose less than 150 mg/kg body weight is
unlikely to cause serious liver damage [16]. Chil-
dren younger than 6 years appear to be more
resistant to acetaminophen toxicity than adoles-
cents and adults on a weight basis. This may be
because the liver is a proprtionally larger organ in
6 D.N. Bateman
children than adults. Several large studies of
young children have demonstrated that in this
age-group, a single ingestion of 200 mg/kg or
less is highly unlikely to result in significant tox-
icity (II-3) [49–52].
Chronic supratherapeutic dosing of acetamin-
ophen may also result in toxicity. The manufac-
turers’ recommended daily amount is 4 g/day or
less for adults and 75 mg/kg/day or less for chil-
dren. Toxicity has been reported with ingestion of
more than these recommended doses for a day or
longer [53–55]. Retrospective case series in chil-
dren have reported therapeutic doses (20–25 mg/
kg/day) being associated with hepatotoxicity [56,
57], but the accuracy of these dose estimates is
uncertain.
Whether chronic acetaminophen dosing at nor-
mal theapeutic doses causes liver damage is a
subject which has been raised by studies
suggesting small increases in ALT with chronic
dosing in normal populations [58]. The clinical
relevance of a small increase in ALT is likely very
low, and others have suggested little evidence of
any toxicity from such dosing [59].
Modulators of Toxicity
Toxicity results when the amount of NAPQI pro-
duced from acetaminophen metabolism over-
whelms the capacity for glutathione-mediated
detoxification. Theoretically, any compound that
induces CYP2E1 could increase the amount of
NAPQI produced and thus increase the likelihood
of toxicity. Inducers of CYP2E1 include ethanol,
rifampicin, isoniazid, and carbamazepine (II-3)
[60]. Clinical series suggest that patients who
chronically ingest drugs that induce CYP2E1, or
smoke tobacco, may have poorer outcomes than
the general population after acetaminophen over-
dose (II-3) [61–64]. In addition coingestion of
opiates seems to be associated with increased
toxic effect in acetaminophen overdose
[65]. Patients with depleted glutathione stores
from malnutrition, such as chronic alcoholics,
may also be at increased risk (II-3) [15]. There is
some evidence that coexisting conditions, in par-
ticular myopathies, may increase toxicity risk in
overdose (II-3) [66]. Acute starvation also seems
to increase risk of hepatotoxicity, as in patients
with acute dental pain. In contrast, concomitant
ethanol and acetaminophen ingestion may
decrease the effects of acetaminophen overdose
because of inhibition and competition for
CYP2E1 activity [67]. Phenytoin, which is not a
CYP2E1 inducer, does not appear to increase the
risk of acetaminophen-induced hepatotoxicity
and, in fact, may offer hepatoprotection by
increasing glucuronidation [68].
Age is also a modulator of toxicity. Young
children appear to be more resistant to the toxic
effects of acute acetaminophen overdose. Addi-
tionally, the incidence of hepatotoxicity is much
lower than that observed in the general population
[69]. The corollary to this is the increased risk of
hepatotoxicity in the elderly (II-3) [15, 70, 71].
Clinical Presentation
and Life–Threatening Complications
The clinical manifestations of acetaminophen tox-
icity can vary significantly, depending on the
dose, time of presentation, and whether the toxic-
ity results from acute or chronic ingestion.
Patients who undergo medical evaluation within
several hours after an acute ingestion may be
asymptomatic or have only minor symptoms.
Nausea, vomiting, and occasionally lethargy
may occur early (typically within several hours
of ingestion) in moderate to severe acetamino-
phen poisoning. In our experience, these symp-
toms usually decrease within 12–18 h and may
possibly reflect direct effects of the parent com-
pound (because resolution occurs with declining
acetaminophen levels). Metabolic acidosis is a
feature of evolving liver failure, but it and even
coma have been reported within 4–6 h of a mas-
sive overdose, although coma is extremely rare,
and should alert the physician to alternative diag-
noses or coingestions such as opioids or benzodi-
azepines [72–74]. It is important to exclude
hypoglycemia caused by acetaminophen-induced
liver injury. Patients who first come to medical
attention after the onset of signs of liver injury –
generally at least 24 h after acute ingestion – may
Acetaminophen (Paracetamol)
initially present with abdominal pain, encephalop-
athy, coagulopathy, and renal failure.
Hepatocytes are the primary target after an
acetaminophen overdose. Given NAPQI’s ultra-
short half-life, its initial toxicity is limited to cells
that synthesise it. Most of the life-threatening
complications of acetaminophen poisoning are a
direct result of acute liver injury and the systemic
complications of liver failure. The role of inflam-
matory response is also important in the patho-
genesis of liver damage, as inhibition of this
process in laboratory animals results in less toxic-
ity [75]. The clinical course most commonly
observed with acute acetaminophen hepatotoxic-
ity is hyperacute liver failure, which has been
defined as the development of encephalopathy
within 7 days of the onset of jaundice (although
rarely in very severe acetaminophen poisoning
cases death may occur before jaundice is appar-
ent) [76–78]. Liver failure is the result of NAPQI-
induced hepatocellular injury. The early histo-
pathologic finding after acetaminophen overdose
is centrilobular hepatic necrosis (zone 3) with
periportal sparing [79, 80]. The centrilobular
region is chiefly composed of zone 3 hepatic aci-
nar cells, the site of highest metabolic activity.
Hepatic necrosis results in the release of a wide
range of substances into serum and severe meta-
bolic derangements (e.g., acidosis, hypoglycemia,
and hyperammonemia) from the loss of function-
ing liver.
It is also now clear that there is a consequent
molecular signaling and response with necrosis,
apoptosis, and an inflammatory response caused
by an influx of inflammatory cytokines [81,
82]. In animal models drugs that affect this inflam-
matory response reduce hepatotoxicity.
Coagulopathy and renal failure usually accom-
pany liver failure, although the extent of different
organ involvement may vary. Sepsis (both bacte-
rial and fungal), cardiovascular collapse, and ter-
minal ventricular dysrhythmias may also develop
in patients with ALF. The injured liver has an
ability to regenerate, and ALF is thus potentially
reversible if the patient can be supported through
the acute phase of poisoning, particularly in the
case of acetaminophen poisoning, because hepatic
regeneration occurs from cells situated in the
7
Table 1 Clinical characteristics of encephalopathy
Grade I Slowed thought processes, slurred speech,
untidy appearance, slight tremor
Grade II Increased drowsiness, inappropriate
behavior, easily elicited tremor
Grade III Hypersomnolent, incoherent speech,
marked confusion
Grade IV Coma, no response to painful stimuli
periportal regions (zone 1), which tend to be unaf-
fected by all but the most massive of acetamino-
phen overdoses.
Hepatic encephalopathy is the hallmark of
ALF and develops in severe cases of
acetaminophen-induced hepatotoxicity. In a series
of 171 patients, grade II (Table 1) encephalopathy
was noted at a median of 72 (range 38–120) h after
an acute acetaminophen overdose. Grade IV
encephalopathy was noted within 89 (range
51–141) h following an overdose occurring
12 (range 3–96) h after grade II encephalopathy
[83]. Patients with grade III encephalopathy are at
significant risk for cerebral edema. Death is most
likely to occur 72–96 h after an overdose,
although it may be delayed for up to 10–14 days.
Death occurs most frequently as a complication of
cerebral edema or sepsis. Patients who survive do
not have permanent liver damage.
Renal failure in the setting of acetaminophen
poisoning may be due to a direct renal effect of
NAPQI, prerenally mediated acute tubular necro-
sis, and/or hepatorenal syndrome. Because
CYP2E1 is present in renal tubules, NAPQI is
generated in the kidney. Renal injury manifested
by hematuria, proteinuria, and modest elevations
in blood urea nitrogen and creatinine have been
reported in as many as 8.9 % of patients [84]. It
typically develops within the first 24–48 h but is
easily missed as the process takes a few days to
peak. The injury is normally transient but may
progress to anuric renal failure and require dialy-
sis [84, 85]. Oliguric renal failure necessitating
dialysis has been reported to occur in 1 % of
patients [86]. Renal failure associated with liver
failure is typically delayed 48–72 and is a feature
of severe outcome (II-3) [15, 85]. Clinically
8 D.N. Bateman
significant nephrotoxicity in the absence of hepa-
totoxicity has been reported but is rare [87–89].
Other clinical manifestations associated with
acetaminophen toxicity include pancreatitis and
cardiotoxicity. Pancreatic inflammation, defined
as serum lipase three times the upper limit of the
normal laboratory value, may be found in 30 % or
more of patients with acetaminophen hepatotox-
icity [90]. However, clinical pancreatitis is rare
[85]. Cardiotoxicity, manifested by nonspecific
electrocardiographic changes and alterations con-
sistent with pericarditis, is also rare [85, 91]. The
mechanisms responsible for these less common
findings are unclear but in some cases may have
been due to other undetected coingestants, such as
propoxyphene causing cardiac effects [92].
Chronic Acetaminophen Overdose
The manufacturers’ recommended maximum
daily doses of acetaminophen are 4 g of acetamin-
ophen in adults and 75 mg/kg in children. Inges-
tion of larger supratherapeutic quantities may
result in hepatotoxicity. This is most common in
the context of acute pain syndromes, as in dental
pain, where toxic risk may be increased by acute
starvation. In young children, although hepatotox-
icity has been reported after as little as 150 mg/kg/
day, the general experience is that due to a pro-
portionally increased hepatic mass in children
toxicity is less likely than in adults [56, 93,
94]. Medication error is an important potential
risk in children [95], but Munchausen’s-by-
proxy must also be considered.
Chronic acetaminophen excess is usually a
therapeutic misadventure. Common scenarios
include those involving patients who increase
their daily intake because they believe that it is
safe, patients who use combination products such
as acetaminophen and codeine along with acet-
aminophen, or caretakers who substitute adult for
pediatric suppositories in a young child. The inci-
dence of hepatotoxicity after chronic excess has
not been extensively studied. Certain populations
may be at risk, including patients who are fasting
or who have ingested alcohol in the preceding
5 days [55]. Numerous cases of hepatotoxicity
have been reported in alcoholics after chronic
acetaminophen excess, although the apparent fre-
quency may be due in part to ascertainment bias
[54]. A randomized, double-blind, placebo-con-
trolled trial of 201 long-term alcoholic patients,
failed to show liver injury by conventional blood
tests when recommended doses of acetaminophen
were not exceeded [96].
The clinical presentation of chronic acetamin-
ophen toxicity is variable. Many patients initially
come to medical attention during routine medica-
tion review and are taking excess for reasons such
as acute or chronic pain disorders. These patients
generally have no symptoms directly related to
excessive acetaminophen use. Rarely cases may
present as altered mental status from incipient
ALF, but these usually seem to have had an
acute recent increase in dose. This raises a possi-
bility of adaption to regular excess acetamnophen
dose, and most experienced clinicians will have
come across patients who routinely take addi-
tional acetaminophen above recommended limits
without apparent harm.
Diagnosis
Patients normally present in one of three
scenarios:
(i) With a history of a single overdose as part of
an act of self-harm
(ii) With a history of multiple ingestions as an
act of self-harm
(iii) As a result of therapeutic excess, as in the
case of an acute pain syndrome treated with a
cocktail of remedies, or confusion over the
content and quantities of acetaminophen in
different cold remedies
Occasionally therapeutic misadventure may
occur in hospital environments, as with excess
IV acetaminophen, or from regular excess oral
dosing in underweight, nutritionally challenged
patients.
Patients are often asymptomatic but with
chronic therapeutic or repeat deliberate ingestion
may present with right upper quadrant abdominal
Acetaminophen (Paracetamol)
tenderness, vomiting, or jaundice. De novo pre-
sentation with hepatic encephalopathy is
extremely rare.
Laboratory Evaluation
Determination of risk in acetaminophen overdose
is dependent on the time from the ingestion.
Within the first few hours the acetaminophen
blood concentration is currently the best predictor
of outcome (II-2). A number of nomograms were
produced in the 1970s based on a series of patients
in Edinburgh who were not treated for their over-
dose. These lines start from the plasma concentra-
tion taken at least 4 h after ingestion in an attempt
to avoid any misinterpretation due to measuring
acetaminophen during the absorption phase. All
have a half-life of 4 h, even though this is longer
than that seen in normal therapeutic doses. The
lines derive from graphs drawn by hand and eye
that divide patients with and without hepatotoxic-
ity as defined by a rise in ALT over 1000 IU/L. No
deaths occurred in 54 patients in this series of
70 in those with a plasma concentration below a
line commencing at 300 mg/L acetaminophen 4 h
after ingestion, with the proportion of patients
who developed an ALT over 1000 IU/L increasing
from 23 % at 100 mg/L to 60 % at 200 mg/L
[97]. Prescott used these data to develop a nomo-
gram for the UK with a 4 h concentration of
200 mg/L (200 μg/mL; 1323 μmol/L) to deter-
mine treatment at a time when antidotes were
being developed (II-3) [7]. Rumack and Matthew
also published a similar nomogram that was
reduced by the FDA to 150 mg/L for clinical use
(150 μg/mL; 992 μmol/L) [8, 98]. Subsequently in
the 1990s in the UK a risk assessment approach
was adopted in patients with concentrations
between lines drawn from 100 to 200 mg/L
(662 and 1323 μmol/L) at 4 h (III) [99]. This
assessment included determining whether patients
were alcoholic, taking enzyme-inducing drugs, or
were malnourished. Patients with these features
were treated at the 100 mg/L nomogram line. In
Australia a decision was made to move from the
200 mg/L nomogram to the 150 mg nomogram in
2008 [100].
9
In the UK in 2012 policy was changed by the
UK regulator, the MHRA, in view of the death of
a young woman who had not been thought to be
high risk. All patients in the UK are currently
treated using the 100 mg/L nomogram [101].
Whichever nomogram is being used it is
important to have an accurately timed acetamino-
phen concentration and be aware of the units
being used to report. Confusion can arise when
different laboratories use mass and molar units; in
the UK there has been standardization to mass
units (mg/L) to avoid confusion, and potential
failure to treat [102] (Fig. 3).
It is generally accepted that the accuracy of the
nomogram for prediction becomes less reliable
beyond 15 h, since the original dataset used had
very few patients who presented late. Furthermore
since the elimination of acetaminophen is reduced
by liver injury [6] it would in theory be possible to
use estimates of the half-life of the drug based on
two or more times blood samples to establish
whether injury to the liver had occurred. This is
rarely used in practice but may be useful in man-
aging individual patients, for example, those who
wish to self-discharge against medical advice, or
refuse antidote therapy.
A potential confounder is the accuracy of acet-
aminophen measurement at concentrations below
10 mg/L (66 μmol/L). Some laboratories have
even higher cutoffs for reporting undetectable
concentrations, and this may cause problems in
interpretation of results in patients presenting late
after their overdose. Some countries have also
licensed modified release products of acetamino-
phen, and the nomograms are not likely to be
accurate in this situation [17].
Other blood tests should be routinely measured
at presentation, since these will be necessary to
interpret progress in patients who are determined
to require treatment with antidote. These include a
measurement of renal function, normally creati-
nine, liver function tests, in particular transami-
nase activity, and prothrombin time, often
measured as INR. Admission tests may be predic-
tive of outcome [15, 103]. Other tests have been
suggested to be abnormal in more severe poison-
ing, including urinary phosphate, urinary potas-
sium, and plasma lipase. These have not been
10
Fig. 3 Acetaminophen treatment nomograms. Treatment
is recommended if the plasma acetaminophen concentra-
tion is above the solid (150 mg/L at 4 h) line in North
adopted in routine practice. Some patients will
have compensated or uncompensated metabolic
acidosis shortly after ingesting a significant over-
dose [104]. This acidosis has been associated with
increased lactate formation and has been postu-
lated to occur as a consequence of impaired mito-
chondrial respiration at the level of ubiquinone by
acetaminophen or NAPQI [105, 106]. This early-
onset acidosis tends to resolve spontaneously
within hours [104]. In patients whose clinical
condition continues to deteriorate, however, aci-
dosis often recurs and is highly predictive of
lethality once ALF has developed.
ALT is a sensitive marker of liver injury, and
traditionally an ALT of >1000 IU/L has been
regarded as an index of “severe” hepatotoxicity
in acetaminophen poisoning [107]. This definition
was based on the requirement at that time to dilute
samples with ALT above this activity to determine
the result accurately. It is in reality poorly corre-
lated with outcome, and ALT measurement is not
part of the standard criteria now used to determine
prognosis. However it remains a useful cutoff
D.N. Bateman
America and Australia. In the UK and Ireland the dotted-
dashed line (100 mg/L at 4 h) is used to determine therapy
with acetylcysteine
point to use in clinical decisions regarding the
severity of illness. Rate of rise of ALT is more
important than its actual value, as rate of rise is
better linked to extent of acute liver injury.
Prothrombin time (usually measured as INR) is
one of the best readily available markers of func-
tional hepatic damage, since unlike ALT, which
provides information on cell injury, PT provides
information about hepatic synthetic function. A
rise in INR indicates a decrease in hepatic synthe-
sis of vitamin K–dependent clotting factors (fac-
tors II, VII, IX, X). A rising PT in the setting of
falling transaminase levels is an ominous finding.
Serum transaminase concentrations will generally
fall in both a patient who recovers from hepatic
injury and one who develops ALF and massive
hepatic necrosis. PT, however, will not usually
improve if a patient has progressive liver injury,
and it generally continues to rise in cases of ALF,
especially in the absence of clotting factor
replacement. The finding of a slightly elevated
PT within hours after an acute overdose is com-
mon and usually the result of direct reversible
Acetaminophen (Paracetamol)
inhibition by acetaminophen of vitamin
K–dependent clotting factor synthesis and not a
marker of hepatic injury (II-2) [108].
In patients who have taken a single overdose
and have acetaminophen concentrations below
the nomogram limits, risk of serious hepatic dam-
age is low; they can normally be discharged. Care
should be taken, however, in patients who have
recently consumed more than one ingestion
(within a 24 h period) of acetaminophen, and in
those coingesting drugs that may alter gastrointes-
tinal motility and delay gastric emptying such as
opioids or antihistamines [109]. It is wiser in these
patients, and indeed a sensible precaution in all
patients, to take account of the history of dose
ingested, and where there is disparity between
this and blood results clinicians should be cau-
tious in their decision regarding early discharge,
and double-check timings of ingestion and sam-
ples (III). Kinetic studies suggest a correlation
between dose and concentration across a wide
dose range [110], and historic case series indicate
that history correlates with measured plasma acet-
aminophen concentration (II-3) [111, 112].
The product of acetaminophen and ALT has
been suggested as a tool to better identify those
patients at increased risk of serious liver injury
[113]. Novel biomarkers are now being evaluated
that appear to give earlier indications of liver
injury than present laboratory tests; a lead candi-
date is the microRNA miR 122. Other biomarkers,
of apoptosis and cell necrosis, may also have a
future role (Fig. 4) [82].
Differential Diagnosis
Although acetaminophen is currently the primary
cause of ALF, a number of other toxic and
nontoxic etiologies must also be considered.
Toxic causes include intrinsic, dose-related
hepatotoxins such as carbon tetrachloride, chloro-
form, cyclopeptides from fungi (α-amanitin), cop-
per sulfate, yellow phosphorus, and various herbal
products. Botanicals that have been implicated as
intrinsic hepatotoxins include pennyroyal oil from
Mentha pulegium, chaparral, germander, Jin Bu
Huan, and pyrrolizidine alkaloids from
11
Heliotropium, Senecio (tansy ragwort),
Crotalaria, and Symphytum (comfrey) species.
ALF may also result from idiosyncratic adverse
drug reactions from, for example, phenytoin,
valproic acid, isoniazid, halothane, or nonsteroi-
dal anti-inflammatory agents. Idiosyncratic hepa-
totoxicity is not dose related and may occur after
therapeutic dosing. Liver failure from methylene-
dioxymethamphetamine (MDMA) has also been
described and may occur in association with
severe MDMA-induced heatstroke, or be due to
contaminants in the tablets [114]. Other causes of
fulminant liver failure include viral hepatitis, sep-
sis, hypovolemic shock, cardiogenic shock, heat-
stroke, and Reye’s syndrome [115]. Serology,
clinical history, and occasionally histopathology
help differentiate these entities.
The time course and the clinical and biochem-
ical characteristics of shock liver may appear
remarkably similar to acetaminophen-induced
hepatic failure. Shock liver generally results
from hemorrhage, hypovolemia, and the resultant
hypotension secondary to trauma and operative
procedures. Differentiating between shock and
acetaminophen as the primary hepatic insult may
prove challenging, especially in situations in
which hypotension may have occurred and the
patient has been taking therapeutic amounts of
acetaminophen.
In light of the increasing number of reports of
hepatotoxicity associated with chronic
supratherapeutic dosing, acetaminophen should
always be considered in cases that might other-
wise be attributed to cryptogenic ALF. For any
patient admitted to the critical care unit with ALF
of unknown etiology, the earliest available blood
specimen should be retrieved and tested for acet-
aminophen to assess whether it might be an etio-
logic factor. However, depending on the timing of
the last acetaminophen dose, the plasma concen-
tration may be low or nondetectable and cannot
reliably exclude acetaminophen as the cause. Fur-
thermore, in the setting of severe hyperbilir-
ubinemia (25 mg/dL; 1.46 μmol/L), some
conventional acetaminophen assays performed
by enzyme assay (GDS Diagnostics, Elkhart, IN)
may cross-react with the bilirubin and result in a
falsely elevated or false-positive acetaminophen
12
Paracetamol
overdose HMGB1
NHCOCH3
miR-122
Keratin-18
OH fragments
Keratin-18
Paracetamol
Metabolites
Protein adducts
Sensitive and mechanistic diagnosis of acute liver injury
Fig. 4 Schematic diagram illustrating a range of novel
markers that may have utility in prediction of hepatic
toxicity and hepatic recovery in acetaminophen overdose.
Measurement of biomarkers may identify acute liver injury
early (miRNA-122, HMGB1, K18 isoforms) or provide
prognosis of liver injury (Acetyl-HMGB1). In view of the
multicellular and many aspects of acetaminophen-induced
determination. Measurement of plasma levels
acetaminophen-protein adducts may be a useful
adjunct tool to assess recent acetaminophen intake
and may be of use in indicating that acetamino-
phen is a cause of acute liver failure of uncertain
origin [116, 117].
Treatment
Acute Single Oral Ingestion
Decontamination with a single dose of activated
charcoal should be performed if the patient is seen
within 1 h of ingestion (II-2) [118]. It is unknown
if activated charcoal alters the outcome in patients
who have ingested excessive doses of acetamino-
phen. Caution should be exercised in patients who
may have ingested other substances that might
D.N. Bateman
Immune cell
HMGB1
Hepatocyte
Acetyl-HMGB1
ALT
CSF-1
KIM-1
Outcome Prediction
(Recovery / Transplant / Death)
liver injury, the use of this panel-based approach, alongside
current markers, may enable patient stratification for the
treatment and assessment of efficacy of novel therapeutic
intervention strategies (HMGB1 high-mobility group
box-1) (Based on Dear and Antoine. 2014 Expert Rev.
Clin. Pharmacol. Early online, 1–9)
reduce their conscious level while activated char-
coal is being given, as there is a risk of aspiration
in such patients. In the past, there was concern
about activated charcoal and use of the oral anti-
dote NAC, but the amount of acetylcysteine
adsorbed was not considered clinically important.
Use of NAC is mandatory in all those patients
above the nomogram line used in the country of
treatment (II-2). This currently varies between
“150 mg/L line” used in most countries and the
“100 mg/L line” used in UK and Ireland. Use of
this very conservative threshold in the UK has had
major resource implications which have been
questioned [119].
Acetaminophen intoxication by itself does not
typically produce cardiorespiratory compromise
unless the patient is in hepatic failure. Presence
of such features should lead to a consideration of
other causes, particularly coingested drugs. Rare
Acetaminophen (Paracetamol)
instances of patients presenting in coma and
requiring endotracheal intubation shortly after an
overdose have been reported [72]. This procedure
should, however, not interrupt or delay the use of
intravenous NAC. Acetaminophen is removed by
dialysis, but this modality has little role in most
overdoses given the efficacy of NAC as an anti-
dote. In patients with renal failure haemodialysis
will remove acetaminophen, and also NAC, with a
doubling of the dose of NAC recommended [120].
Multiple Ingestions and Therapeutic
Error
Assessing the need to treat patients in this scenario
is more challenging, as there are no agreed criteria
internationally. It is necessary to use a combina-
tion of history of dose ingested and blood tests
taken on admission to determine treatment. As an
example of the approach used in the UK, in
patients who present less than 24 h after the last
ingestion treatment with NAC is generally started
if the history suggests an amount in 24 h greater
than local guidelines. This dose may vary between
75 mg/kg in 24 h and as much as 200 mg/kg in
24 h in different countries. In patients who are not
jaundiced, do not have right upper quadrant
abdominal pain, and have had their last ingestion
of acetaminophen more than 24 h previously it is
reasonable to withhold NAC therapy until blood
results are available, since the efficacy of the NAC
falls with time. Treatment is then based on pres-
ence of acetaminophen in blood, or of evidence of
liver injury using ALT and INR (prothrombin
time). Decisions on stopping treatment will
depend on the results of blood tests; if these sug-
gest potential toxicity they should be repeated at
the end of an appropriate time interval of NAC
therapy, usually a full 21 h course of antidote.
Intravenous Acetaminophen Overdose
There is much less experience of use of NAC in
IV acetaminophen overdose, but this has become
more often as this route has become more widely
used. The usual nomograms cannot be applied in
13
the situation of IV dosing, as the dose is given
rapidly and the nomogram 4 h interval of assess-
ment may not be correct. These patients may be
subject to therapeutic errors, but also may be
suffering acute starvation [18, 121]. There is
uncertainty as to whether the much higher acet-
aminophen concentrations that result immediately
following IV dosing have toxic significance as
more toxic metabolites could be formed if conju-
gation pathways are overwhelmed. In addition
many patients receiving IV acetaminophen have
been fasted preoperatively, or are in intensive care
units and not receiving full nutrition. Similar con-
cerns may apply to those in intensive care with
muscular dystrophies who are ventilated and
receive acetaminophen (oral or IV) therapy for
muscular dystrophies [66]. For these reasons
some authors have suggested a lower dose thresh-
old for intervention with NAC [18].
Acetylcysteine (N-acetylcysteine)
NAC is a highly effective antidote when adminis-
tered soon after an acetaminophen overdose. It
was selected from a range of potential glutathione
donors in the 1970s. It acts as a glutathione sub-
stitute in addition to enhancing glutathione syn-
thesis and increasing the amount of
acetaminophen that undergoes sulfation (see
Fig. 2) [45]. Its efficacy is primarily a function
of time elapsed since the overdose. NAC is most
effective when administered within the first 8 h
after an acetaminophen overdose, and its effec-
tiveness decreases incrementally every hour
thereafter (II-2) [8, 97].
Indications for ICU Admission
in Acetaminophen Poisoning
Significant acidosis
Any grade of encephalopathy
Coagulopathy requiring treatment
Significant renal failure
Different approaches to using NAC were devel-
oped in the UK and USA. In the 1970s an intrave-
nous formulation of NAC was licensed in the UK
for management of airways disease, and this was
therefore used to administer the drug in
14
acetaminophen overdose [7]. In the USA an oral
formulation had to be used. The UK regimen devel-
oped by Prescott and colleagues in Edinburgh was a
20.25 h IV protocol, delivering 300 mg/kg of NAC
over the duration of treatment, with 150 mg/kg
given in the first 15 min, 50 mg per kilogram over
4 h, and 100 mg/kg over 20 h. The regimen used in
North America was 140 mg/kg initially followed by
70 mg/kg every 4 h for 17 doses [8]. Case series
using longer intravenous [122, 123] and shorter oral
regimens have also been reported. The standard
North American IV regimens subsequently devel-
oped use a 21 h protocol, with the first infusion,
similar in dose to the original Prescott regimen,
being given over 1 h (Table 2). Recently in the
UK regulatory decision has been made to also
move to the 1 h initial IV dose [101]. In view of
the relatively low lipid solubility of acetaminophen
and the relationship between NAC dose and
adverse event risk some authorities advise using a
maximum weight of 110 kg in obese patients and
pregnancy when calculating NAC dose [124]. A
recent study in comparing patients with weights
above and below 100 kg did not show an excess
of ADRs in the heavier patients [125], although
detected rates of ADRs were very much lower
than seen in prospective studies, throwing some
doubt on the validity of these findings.
The Danish approach to acetaminophen poi-
soning has been very different to anywhere else
worldwide. They have historically treated all
patients with paracetamol excess [126]. This is
not a cost-effective approach, and risks excess
NAC anaphylactoid effects in patients with low
acetaminophen concentrations [127].
NAC is effective if given early after acetamin-
ophen ingestion but is recognized to lose efficacy
the longer the interval between acetaminophen
dose and treatment (II-2) [8]. No parallel study
has been done comparing oral and IVantidote use,
but comparing historical groups there is no strong
evidence of the major difference in the efficacy of
different regimens (II-2) [128]. There is a theoret-
ical risk, based on calculations of the potential
hepatic production of NAPQI in acetaminophen
overdose, that the dose of NAC in the current IV
regimen is less than would be required to provide
full antidote efficacy in very large overdoses of
D.N. Bateman
Table 2 Acetylcysteine regimens
Regimen Loading dose Followed by Total dose
21 h IV 150 mg/kg 50 mg/kg over 300 mg/kg
over 1 h 4h
100 mg/kg over
16 h
72 h PO 140 mg/kg 70 mg/kg every 1330 mg/
4 h for 17 doses kg
acetaminophen (e.g., 4 h acetaminophen concen-
trations >600 mg/L) (III) [9]. Some toxicologists
advise a doubling of NAC in such patients; how-
ever, this practice is controversial since the meta-
bolic interaction between antidote and
acetaminophen reactive metabolites at these con-
centrations is unknown. Potential confounders
include substrate inhibition within the liver and
saturation of the capacity to generate glutathione
from NAC.
Adverse effects to NAC have been recognized
since the antidote was first used. Major adverse
effects seen are nausea and vomiting and anaphy-
lactoid reactions. Death has been reported, but this
is most likely due to overdosage with IV NAC due
to miscalculation and confusion in the dosage
form in the 1980s. Rates of adverse reactions are
variously reported and are likely to depend on the
methods used to ascertain them [129]. Prospective
close monitoring results in far higher estimates
than retrospective analysis [130]. Nausea and
vomiting requiring treatment with antiemetics
seems to occur between 20 % and 30 % of patients
[127]. Symptoms of nausea are far more frequent,
reaching 70 % in prospective studies
(I) [131]. The incidence of nausea and vomiting
does not seem related to the quantity of acetamin-
ophen ingested. In contrast, anaphylactoid reac-
tions are inversely related to the plasma
concentration of acetaminophen (II-3) [132,
133]. Thus, recent changes in the UK to treat
patients with lower plasma concentrations of acet-
aminophen have resulted in increasing risk of
adverse effects from the antidote [133]. Anaphy-
lactoid reactions seem due to histamine release
[130] and can be treated successfully using anti-
histamines, with the addition of beta-receptor ago-
nists when bronchospasm is present. As the
mechanism is not immunological there is no
Acetaminophen (Paracetamol)
necessity to use corticosteroids in managing this
reaction. In severe cases adrenaline may be
required, and in patients with hypotension addi-
tional fluid should be given intravenously. Nausea
and vomiting should be treated with a standard
antiemetic, although it would seem prudent to
avoid ondansetron in view of the signal of toxicity
when used in acetaminophen overdose [131].
A recent clinical trial studied the effect of a
shorter, 12 h, IV protocol delivering 100 mg/kg
NAC over 2 h and 200 mg/kg over 10 h. This
study was primarily to examine effects on adverse
reactions to NAC and was not powered to assess
relative efficacy against the 20.25 h regimen used
as control; however, it suggested no lack of infe-
riority of the shorter regimen [131]. Further work
using this protocol is needed before it can be used
widely in clinical practice; nevertheless, it sug-
gests potentially even shorter treatment may be
possible in selected patients. This is perhaps not
surprising bearing in mind the short half-life of
acetaminophen at therapeutic dose [32].
Most patients who are treated worldwide will
now receive a standard 21-h intravenous protocol
of NAC. The oral regimen should only be consid-
ered in those in whom IV access is impossible or
in situations where IV therapy is unavailable.
Methionine [107], an alternative oral antidote,
seems of less efficacy based on historic studies,
but is still used in some countries.
Blood samples need to be taken at the end of
the treatment period to ensure that the patient is fit
to discharge. Mandatory tests include measure-
ment of transaminase (usually ALT), serum creat-
inine, and prothrombin time. Many clinicians will
also wish for a repeat acetaminophen concentra-
tion to ensure that the drug has been eliminated. In
the USA for patients who have taken a large
overdose, or who have a prolonged half-life,
such measurement of acetaminophen concentra-
tions prior to discontinuing therapy is essential,
and the standard of care, to ensure that NAC is not
stopped while significant levels of acetaminophen
are still circulating.
Interpretation of blood tests post treatment is
relatively straightforward. The rate of rise in trans-
aminase is related to the severity of toxicity, and
therefore very small perturbations in
15
measurements are normally insignificant clini-
cally [134]. Many clinicians will use a doubling
in ALT to determine whether hepatotoxicity is
likely. Acetylcysteine interferes with the measure-
ment of INR [108, 135], and thus a small rise (e.g.,
to less than 1.4) with a normal ALT can usually be
ignored. Acetylcysteine continuation should be
considered in those with a rising ALT, or other
features suggesting impending liver failure. Hep-
atotoxicity in acetaminophen poisoning was tra-
ditionally defined as an ALT over 1000 IU/L
[107]. This cutoff is rather arbitrary, and many
patients will recover without liver unit care at
this concentration. Acetylcysteine can be
discontinued when ALT starts to improve and
INR begins to recover. Extensive clinical experi-
ence by the author in several thousand cases has
shown that it is not necessary to treat until normal
values have returned. Jaundice is a late feature in
acetaminophen-induced liver failure, and mea-
surement of bilirubin is of most value in the man-
agement of acute liver failure.
Interpretation of serum creatinine is also
affected by the use of acetylcysteine since it
impairs the synthesis of creatinine. Rising creati-
nine above 10 % of baseline should therefore be
regarded as potentially indicating onset of renal
impairment. In this circumstance it is prudent to
recheck the blood test since patients with renal
damage may not show the full clinical syndrome
of renal failure until 3–5 days after acetaminophen
overdose.
In patients who go on to develop liver injury it
is important to continue to administer NAC, as
there is evidence that this is protective in hepatic
coma (II-2) [136, 137]. Monitoring progress
requires regular measurement of liver and renal
function and clotting tests. As liver injury
develops synthesis of clotting factors is impaired,
and those with the shortest half-life (factors V and
VII) disappear most rapidly. Measurement of the
concentrations of individual clotting factors may
therefore be considered in patients with incipient
hepatic failure in an attempt to estimate severity.
Patients who develop renal injury and hepatic
injury in combination seem to have a far worse
prognosis, and those who present with renal injury
have a high mortality (II-3) [15]. It is sensible to
16
discuss patients with significant hepatic damage,
for example, rapidly rising ALT, clotting distur-
bance and renal injury, with a liver unit as some
patients may go on to require hepatic transplanta-
tion. The King’s College criteria are widely used
as an assessment tool in this situation.
Liver Transplantation and Management
of Fulminant Hepatic Failure
In patients in whom ALF develops from acetamin-
ophen toxicity, the most pressing question is
whether orthotopic liver transplantation (OLT) is
necessary for their survival. Patients need to be
discussed early with a local liver unit, and transfer
of the patient will be determined by local criteria. In
patients with severe coagulopathy, renal failure,
acidosis, hypoglycaemia, and encephalopathy
care in a liver unit is mandatory. Most hepatologists
will consider rate of disease progression, patient
age, and laboratory markers. Thus a prothrombin
time that is greater in seconds than the hours after
overdose is used in the UK as a marker of poor
prognosis. In patients with overdose there may also
be psychological aspects to consider in relation to
managing patients post transplant that may influ-
ence decision to transplant.
To date there is little evidence that artificial
liver devices have a benefit in this clinical situa-
tion. Transplantation is therefore a key treatment
methodology in severe cases. To make an
informed recommendation with regard to OLT it
is necessary to consider the natural history of
patients who do not undergo transplantation, as
well as the utility of prognostic indicators. Most
patients in whom ALF develops from acetamino-
phen toxicity survive and fully recover without
transplantation. The King’s College group
reported their experience in 1255 patients with
ALF and 908 with acute liver injury (ALI) from
acetaminophen toxicity treated at their center
between 1973 and 2008 [71]. Those with ALF
were older, more likely to be female, and to have
renal injury at admission to the liver unit. The
majority survived without OLT, and only
147 were transplanted, survival from which
improved significantly over the 35 y period of
the study to the order of 80 % [71]. The presence
of overt encephalopathy was strongly associated
D.N. Bateman
with poorer outcome. The capacity for liver recov-
ery is better in acetaminophen poisoning than
other causes of acute liver failure [138].
The search for highly sensitive and specific
prognostic factors continues. Reliable indicators
are critically important because patients may have
sudden clinical deterioration and die before trans-
plantation can take place. The window of oppor-
tunity for successful transplantation is often less
than 24 h. In contrast, transplantation should be
avoided in patients expected to survive because
liver function recovers completely and transplan-
tation unnecessarily dooms the patient to a life-
time of immunosuppressive therapy.
Auxiliary transplantation is a techique in which
a partial liver graft is placed while the patient’s
liver recovers, and which can then be allowed to
reject or be removed. It seems attractive in theory
but is technically demanding and experience is
limited in acetaminophen overdose [138].
Prognostic Indicators
Several groups have studied prognostic indicators
to develop criteria for transplantation. The most
widely published transplant criteria were derived
at the King’s College Hospital liver unit in London
(Table 3). According to these criteria, patients
should be considered for liver transplantation if
their arterial pH is less than 7.3 at 24 h or later
after acetaminophen ingestion despite fluid resus-
citation and treatment with sodium bicarbonate or
if they have a combination of grade III or IV
encephalopathy, serum creatinine level higher
than 3.4 mg/dL (300 μmol/L), and INR longer
than 6.5 [138]. These criteria were originally
derived from 310 acetaminophen-poisoned
patients studied between 1973 and 1985 [139].
They were later validated by the same investigators
Table 3 Original King’s College Criteria for
Transplantation
PH < 7.25 24 h after overdose despite fluid resuscitation
and sodium bicarbonate
Concurrent presence of grade III-IV encephalopathy,
creatinine >3.4 mg/dL (300 μmol/L), and INR more
than 6.5
Acetaminophen (Paracetamol)
in a group of 120 patients treated between 1990 and
1994. The positive predictive value of these criteria
for a fatal outcome is 88 %, and the negative
predictive value is 65 % [140]. An alternative
scoring system is the MELD score suggested as
an improvement, and more recently the Acute
Liver Failure Group Index has been used. The
latter includes coma grade, laboratory results
(INR, bilirubin, and phosphorus) and an apoptosis
marker (M30) and is reported as an improvement
on the Kings College Hospital criteria [141]. Pre-
sent UK criteria for emergency transplantation in
acetaminophen poisoning are
1. pH < 7.25 despite fluid resuscitation
2. Severe coagulopathy (INR > 6.5) and renal
failure (anuria or serum creatinine
>300 μmol/L) and grade 3–4 encephalopathy
3. Serum lactate >3.5 on admission or >3.0 after
fluid resuscitation
4. Any two criteria from category 2 combined
with clinical deterioration in the absence of
sepsis [141]
O’Grady has also suggested some criteria
when transplantation is contraindicated, and
these include compromised brainstem function,
invasive fungal infection, rapid increasing need
for inotropes, and severe pancreatitis [141]. Long-
term quality of life is impaired in those receiving
transplants, further emphasizing the need to care-
fully assess the use of this therapy in
acetaminophen-induced liver failure [142].
Psychiatric Assessment Before
Orthotopic Liver Transplantation
Psychiatric assessment for transplant feasibility is
an essential aspect of the transplantation evalua-
tion [143]. OLT is a major operative procedure,
and its ultimate success is in part dependent on the
transplant recipient’s compliance with post-
transplant care, including the need for lifelong
immunosuppressive therapy. Although a suicide
attempt or a history of ethanol or substance abuse
by itself does not preclude transplant suitability,
skilled assessment by a psychiatrist who has a
17
close working relationship with the transplant
team is essential to determine the likelihood of
long-term post-transplant compliance. Ongoing
substance abuse is a probable contraindication to
this procedure. The long-term medical and psy-
chiatric outcomes in those with hepatic transplan-
tation for acetaminophen overdose seem similar to
other groups [144].
Medical Management
Aggressive medical management is warranted for
patients with ALF in an attempt to stabilize the
patient and prevent further deterioration. Medical
issues that arise include treatment of
coagulopathy, renal failure, encephalopathy, cere-
bral edema, sepsis, cardiovascular collapse, met-
abolic derangements, and respiratory failure.
Coagulopathy
Coagulopathy will develop in many patients as
demonstrated by an increased PT and INR. How-
ever, given the use of PT/INR as an indicator for
the need for liver transplantation, many recom-
mend that vitamin K and factor replacement with
fresh frozen plasma be withheld unless the patient
has frank bleeding or requires an invasive proce-
dure such as an arterial line, central line, or inser-
tion of an intracranial pressure monitor. The
efficacy of vitamin K therapy in patients with
acetaminophen-induced hepatic synthetic dys-
function is of uncertain value, and as the primary
problem is failure to synthesize clotting factors
this is not unexpected. Active hemorrhage, most
often upper gastrointestinal bleeding, necessitates
treatment with fresh frozen plasma and red blood
cell transfusion as needed. The use of H2-blockers
may reduce the risk of such bleeding.
Renal Failure
Renal failure occurs in more than 75 % of cases of
ALF from acetaminophen overdose and is an
indicator of adverse outcomes [15]. Decreased
urine output may be the sign of acute renal failure,
hepatorenal syndrome, and/or undertreated
18
hypovolemia. Fluid resuscitation in these cases
may inadvertently lead to fluid overload and pul-
monary edema. Hemodialysis may be warranted,
although the criteria for initiation are not well
established [120]. Venovenous hemofiltration is
an alternative therapy and regularly used to sup-
port renal and metabolic complications. Low-dose
dopamine (2–4 μg/kg/h) may improve renal per-
fusion and function. Nephrotoxic drugs should be
avoided, and dosing of medications undergoing
significant clearance by the kidney should be
adjusted for renal insufficiency.
Encephalopathy
Because the most common cause of death in
patients with ALF is intracranial hypertension,
with resultant brain herniation, the onset of
hepatic encephalopathy is an ominous finding.
Blood ammonia concentrations are usually ele-
vated, but the degree of ammonia elevation corre-
lates poorly with the extent of encephalopathy.
Computed tomography of the head should be
performed if the patient’s mental status deterio-
rates suddenly to evaluate for evidence of intra-
cranial hemorrhage or cerebral edema.
Sepsis and Shock
Patients with ALF who survive the first 4–5 days
after an acute overdose remain at risk for compli-
cations of systemic inflammatory response syn-
drome (SIRS), sepsis, and hemodynamic collapse.
SIRS is associated with worsening encephalopa-
thy and a poorer prognosis. Susceptibility to
infection, both bacterial and fungal, appears to
be as common in ALF secondary to acetamino-
phen overdose as in other etiologies [145,
146]. Infections are thought to be the direct
cause of death in around 20 % of patients with
ALF. The most common sites of infection are the
respiratory tract, urinary tract, and blood. Bacter-
emia may be a direct result of seeding from a
catheter or from decreased integrity of gastroin-
testinal mucosa. Endotoxemia, macrophage acti-
vation, and cytokine and tumor necrosis factor
D.N. Bateman
release may all occur and lead to a clinical condi-
tion resembling septic shock. Because the only
early sign of infection may be worsening enceph-
alopathy or renal dysfunction, a high index of
suspicion for infection, including daily cultures
of blood, urine, and other fluids, has been
recommended. The administration of broad-
spectrum antibiotics is warranted if there is evi-
dence of fever or other signs of infection. Anti-
fungal agents may also need to be given to
patients who do not respond rapidly to antibiotics.
The use of prophylactic antibiotics and antifun-
gals in these patients remains controversial.
Hemodynamic collapse and sudden death may
also occur in patients with ALF secondary to
acetaminophen overdose. Measurement of central
venous pressure may prove useful to optimize
fluid management. Continuous cardiac monitor-
ing is essential. Norepinephrine or epinephrine
infusions may be used to keep mean arterial pres-
sure above 60 mmHg.
Hypoglycemia
Hypoglycemia from impaired gluconeogenesis
and decreased hepatic glycogen stores is one of
the most significant metabolic derangements in
patients with ALF. Hypoglycemia develops in
more than 40 % of these patients, and therefore
frequent glucose monitoring is critical. Patients
with hypoglycemia may require 10 % dextrose
infusions. The delivery of more concentrated glu-
cose solutions through a central line may be nec-
essary in patients with refractory hypoglycemia.
Metabolic acidosis should be aggressively
corrected with sodium bicarbonate infusion.
Hypophosphatemia is also common and should
be corrected.
Sedation
Careful consideration must be given to which
agents should be used for sedation in patients
with ALF. No controlled studies have been
conducted that address this issue. If drugs are
used, an agent that does not have active
Acetaminophen (Paracetamol)
metabolites may be preferable. Offset of drug
effect may be prolonged.
Criteria for ICU Discharge in Acetaminophen
Poisoning
Resolution of major metabolic abnormalities
Improving coagulopathy
Resolving encephalopathy
Special Populations
Pregnant Patients
Acetaminophen is the preferred analgesic/antipy-
retic during pregnancy because it is safe at thera-
peutic doses and there is no evidence that it is
teratogenic [147]. However, while there is poten-
tial for fetal toxicity after a maternal overdose the
major determinant of fetal outcome is the health of
the mother. A Scandinavian study suggested an
excess of spontaneous abortion in those with a
range of acute overdoses in pregnancy and
3 months before conception (13 acetaminophen).
Spontaneous abortion was 10 % more frequent,
but there was no excess in malformations. Acet-
aminophen freely crosses the placenta, and the
fetal liver is capable of elaborating detectable
amounts of NAPQI by about 14 weeks’ gestation
[148]. NAC also crosses the placenta; after a
maternal overdose it was found in the cord blood
of delivered infants (n = 4) at concentrations
equivalent to those in maternal blood [149]. Acet-
aminophen overdose in pregnancy has been
reported to result in fetal morbidity and mortality;
treatment delay is significantly correlated with
fetal loss [148, 150]. Pregnant women who have
ingested a potentially toxic amount of acetamino-
phen should receive treatment as per nonpregnant
patients. It seems prudent to use the patient’s
actual weight when determining the dose of
NAC (to a maximum of 110 kg). Other interven-
tions such as emergency cesarean section are not
usually warranted. However, cesarean section
may be contemplated for near-term infants if the
mother has substantial acetaminophen-induced
hepatic necrosis. Liver transplantation has been
19
reported successfully in pregnancy in the second
trimester, though with fetal loss in this case [151].
Neonatal Patients
Neonates have been safely and effectively treated
with IV NAC. Data from a 55-day-old infant born
at 29 weeks of gestation indicate slower metabo-
lism in preterm infants in keeping with kinetic pre-
dictions [152]. Care must be taken to not give
excessive free water, which can result in
hyponatremia, and specific regimens for managing
infants are published: for example, using 3 ml/kg/h
of 50 mg/ml NAC for 1 h followed by 2 ml/kg/h of
6.25 mg/ml NAC for 4 h and then 1 ml/kg/h NAC
of 6.25 mg/ml for 16 h, normally given in either
5 % glucose or 0.9 % sodium chloride [101, 124].
Patients with Myopathies
There are data suggesting that children with
myopathies are at greater risk of liver damage
from acetaminophen. Both children in this report
were in intensive care, one post operatively and
the other having a chest infection. The reason for
the toxicity is unclear; starvation is an obvious
risk factor, and both children were under 60 kg
in weight (40 and 55 kg) [66]. Particular care is
needed in use and dose of acetaminophen to avoid
toxicity in such patients.
Key Points in Acetaminophen Poisoning
1. IV NAC is a highly effective antidote
when given shortly after an acute overdose
and is the treatment of choice.
2. Decision to treat should be based on a
nomogram assessing concentration of
acetaminophen taken at least 4 h after a
single ingestion.
3. In patients presenting more than 8–10 h
after a single ingestion history of ingested
dose should be used to assess need for
therapy with NAC.
(continued)
20
4. In those taking multiple overdoses, or
therapeutic excess, the decision to treat is
based on history of dose ingested, usually
in the last 24 h, on blood results or on
presence of symptoms suggestive of liver
injury.
5. History of dose ingested correlates well
with the plasma concentration of acet-
aminophen in most patients. If in doubt
(e.g., the timing or amount of ingestion)
err on the side of prompt treatment with
NAC, and revise treatment once blood
tests are available.
6. Oral NAC may be used in patients in
whom IV therapy is not possible, but
care needs to be taken in preventing
vomiting.
7. Time to treatment is a key determinant in
patient outcome, and delay should be
avoided, particularly more than 10 h after
acetaminophen ingestion.
8. Most patients with significant hepatotox-
icity (AST >1000 IU/L) and
coagulopathy after acetaminophen over-
dose survive without liver transplantation.
9. Presence of acute renal injury at presenta-
tion is a marker of poor prognosis.
10. It is essential to check blood results after a
course of NAC, and only discharge
patients if these are within acceptable
limits.
11. Further doses of NAC are indicated in
those with abnormal liver function.
12. Patients who survive an acetaminophen
overdose have no residual liver damage.
13. Unless clinically indicated, fresh frozen
plasma and vitamin K should not be
given if the patient has an elevated PT
because the PT is an important prognostic
indicator.
14. NAC can decrease morbidity and mortal-
ity when administered to patients with ful-
minant hepatic failure after an acute
acetaminophen overdose.
15. Selective use of liver transplantation as a
treatment modality for patients with ful-
minant hepatic failure from
D.N. Bateman
acetaminophen toxicity, especially in the
presence of acidemia, may prove
beneficial.
Grading System for Levels of Evidence
Supporting Recommendations
in Critical Care Toxicology, 2nd Edition
I. Evidence obtained from at least one properly
randomized controlled trial.
II-1. Evidence obtained from well-designed con-
trolled trials without randomization.
II-2. Evidence obtained from well-designed
cohort or case-control analytic studies, pref-
erably from more than one center or research
group.
II-3. Evidence obtained from multiple time series
with or without the intervention. Dramatic
results in uncontrolled experiments (such as
the results of the introduction of penicillin
treatment in the 1940s) could also be
regarded as this type of evidence.
III. Opinions of respected authorities, based on
clinical experience, descriptive studies and
case reports, or reports of expert committees.
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