Jourmd of Hepatology 1997; 26 (Suppl.
I): 41-46
Prhlted ht Demnark • All rights reserved
Mtmksgaard. Copenhagen
Paracetamol-induced acute liver failure: prevention and management
John G. O'Grady
hsstitute o f Liver Studies. King ~" College Hospital. London. UK
p ARACETAMOLis one of the most widely used anal-
gesics. Approximately 30 million packs containing
paracetamol are sold annually in the UK (l). The popu-
larity of paracetamol has been based on its reputation
for low toxicity particularly when compared with its
main alternative, aspirin. The latter has been associated
with the development of Reye's syndrome in children
and gastric irritation in adults. The toxicity profile of
paracetamol has largely been identified in association
with overdosages, although recently attention has been
focused on enhanced toxicity in patients subject to en-
zyme induction, e.g. epileptics and chronic alcohol con-
sumers (2-5). The hepatotoxicity is not directly due to
paracetamol, but is caused by an unstable metabolite,
N-acetyl-p-benzoquinoneimine (NAPQI), which is in-
activated by glutathione (6). NAPQI accumulates when
glutathione is depleted, leading to lipid peroxidation
and cell damage and N-acetylcysteine and methionine
act as substrates for the repletion of glutathione stores
(6). Additional mechanisms that have been proposed for
the hepatotoxicity implicate neutrophiis or macro-
phages and these may be abrogated by the anti-oxidant
effect of N-acetylcysteine (3,7).
Estimates of the number of paracetamol overdoses
in the UK range up to 70000 per year (1). The esti-
mated number of deaths following paracetamol over-
dose range between 150 and 500 per year in the UK,
with no evidence that this number is decreasing (8,9).
A similar number of patients survive after prolonged
and expensive hospitalisation or even after salvage by
liver transplantation.
Prevention strategies
The dose-dependent nature of the hepatotoxicity of
paracetamol, and the parasuicidal rather than suicidal
intent in the majority of cases, suggest that a consider-
Correspondence: Dr John G. O'Grady, MD, Institute of
Liver Studies, King's College Hospital, Denmark Hill,
London SE5 9PJ, UK. Tel: 0171-346 3255.
Fax: 0171-346 3 ! 67. e-mail: e.withrington@kcl.ac.uk.
Copyright © European Association
for the Study of the Liter 1997
Journal of Hepatology
ISSN 0169-5185
ISBN 87-16-15656-0
able proportion could be prevented. The marketing of
paracetamol in the UK as an inexpensive preparation
of up to 50 g in a bottle means that it is widely avail-
able when parasuicidal gestures are contemplated. The
UK government is currently consulting on a proposal
to restrict the sale of paracetamol to quantities of 6 g
in general outlets and 15 g in pharmacies (1). An
analysis of 560 patients with severe paracetamol hepa-
totoxicity showed that only 8% had taken less than 12
g and of these only 27% died or required liver trans-
plantation (8). The addition of methionine, an alterna-
tive antidote to N-acetylcysteine, to paracetamol tab-
lets is an alternative mechanism to reduce the toxicity
of paracetamol in an overdose situation.
Hepatotoxicity of paracetamol taken with thera-
peutic intent may result from excessive dosing through
lack of realization of the maximal recommended dose
(despite explicit labelling) or lack of awareness of the
presence of paracetamol in a considerable number of
multiple drug combinations. Chronic alcohol con-
sumers and patients with enzyme induction secondary
to antiepileptic therapy are also at risk of hepatotoxic-
ity from paracetamol taken with therapeutic intent (2-
5). In one series of 67 patients with liver damage attri-
buted to therapeutic usage, 64% were considered to be
alcohol abusers (4). Educational initiatives to promote
awareness of these issues are necessary if the explicit
advice on drug packaging and infor~nation sheets is to
be effective.
Management of overdose
N-Acetylcysteine is an effective antidote to paracet-
amol toxicity when given up to 24 h after the overdose
(10). The decision to give N-acetylcysteine is deter-
mined by the blood concentration of paracetamol cor-
rected for the interval after the overdose. N-Acetylcys-
teine is recommended when the level is above a line
that joins 1.32 mmol/1 (200 mg/l) at 4 h and 0.19 mmol/
l (30 rag/l) at 15 h (8). This treatment chart has recently
been modified to reflect the lower threshold for treating
patients prone to enzyme induction (chronic alcohol
41
J. G. O'Grady
consumers, epileptics on therapy) or malnourished pa-
tients. This recommends treatment when the paracet-
amol level is above a line that joins 0.66 mmol/l (100
mg/l) at 4 h and 0.1 mmol/1 (15 mg/l) at 15 h. Patients
presenting more than 15 h after paracetamol ingestion
should be commenced on N-acetylcysteine immedi-
ately and the treatment should be discontinued only
when the investigations reveal no evidence of liver
damage.
Dehydration due to vomiting, and in a minority of
cases to vasodilatation, is common and intravenous
fluids should be commenced. The initial assessment of
the severity of the overdose will include arterial pH (a
metabolic acidosis more than 24 h after the overdose
carries prognostic significance), prothrombin time
(best indicator of liver damage), serum creatinine (best
indicator of renal damage), haemoglobin (bleeding
from gastric erosions may bccur early), platelet count
(severe thrombocytopenia occurs early in a number of
patients) and serum amylase (screen for pancreatitis).
The development of a metabolic acidosis, a severe or
progressive coagulopathy, encephalopathy of any grade
or renal failure indicates that the patient should be
transferred tO a specialist centre without delay.
Medical management of established liver failure
Encephalopathy
The management options for encephalopathy are
limited and restriction of dietary protein, lactulose and
bowel decontamination are ineffective in the face of the
rapidly progressive encephalopathy characteristic of
paracetamol-induced liver failure. Grade 3-4 encepha-
lopathy usually develops by the fourth day after the
overdose and mechanical ventilation is indicated at this
time.
Cerebral oedema and hypoxic neurological
complications
The reported incidence of these complications in pa-
tients developing grade 4 encephalopathy following
paracetamol ranges up to 77% (11). The risk was
shown to be decreased from 68% to 40% by the admin-
istration of N-acetylcysteine at a mean of 56 h (range
36-80 h) after the overdose (12). The neurological com-
plications represent a spectrum of changes within the
brain arid neurological death can occur as a conse-
quence of classical brain-stem herniation or hypoxic
brain damage (13). The optimal management is based
on the accurate assessment of the following par-
ameters - intracranial pressure, cerebral perfusion
pressure, cerebral blood flow, cerebral oxygen meta-
bolic rate and extraction and seizure activity (13).
Mannitol remains the mainstay of treatment of
42
surges in intracranial pressure that may compromise
brain-stem function. A rapid bolus of 0.3-1.0 g/kg is
recommended to achieve the maximal diuretic effect,
and in anuric patients a diuresis is simulated by ultra-
filtrating three times the administered volume over the
subsequent 30 min (13,14). This process is repeated as
determined by the pattern of clinical relapses unless
the serum osmolarity exceeds 320 mOsm. Sodium thio-
pentone was shown transiently to control cerebral oed-
ema that had become unresponsive to mannitol but
without any ultimate benefit in survival rates (15). Its
role is limited by loss of efficacy and haemodynamic
instability following its administration. Chronic hyper-
ventilation was reported not to be of benefit, but acute
hyperventilation (preferably using low-tidal volumes to
prevent increases in intrathoracic pressure reducing ve-
nous return from the head) combined with hyperoxy-
genation of arterial blood may control surges in intra-
cranial pressure that are unresponsive to other modalit-
ies (13,14,16).
In the later stages of the neurological complications,
the emphasis of management changes to the preser-
vation of cerebral perfusion pressure, augmentative
oxygen delivery and manipulation of the neuronal
microcirculation to promote cerebral oxygen extraction
(13). The patient is now nursed with the trunk at a 0-
10° to the horizontal (17). Cerebral perfusion pressure
should be maintained greater than 50 mmHg with the
appropriate use of inotropes. Occult seizure activity
may contribute to neurological instability in patients
with grade 4 encephalopathy and will require treat-
ment with phenytoin or diazepam if detected (18).
hfection
The studies of infection in acute liver failure from
King's College Hospital have been dominated by pa-
tients with paracetamol-induced disease. In a study
where 78% of the patients had paracetamol hepatotox-
icity, bacterial and fungal infection was documented in
82nYoand 34%, respectively, of patients with grade 3-4
encephalopathy (19). Paracetamol-induced liver failure
accounted for 70% of the 104 cases in the controlled
trials of the prophylactic use of the SPEAR regimen
(1.5 gm IV cefuroxime every 8 h, colistin 100 mg NG
every 6 h, tobramycin 80 mg NG every 6 h, amphote-
ricin B 500 mg NG every 6 h, topical antimicrobials to
oropharynx and anterior nares), which showed that in
patients with at least grade 2 encephalopathy the inci-
dence of culture-positive bacterial infection was re-
duced from 61.3% to 32.1% when the regimen was in-
itiated before there was clinical suspicion of infection
(20). An analysis of the findings of this study suggested
that the reduction in the incidence of bacterial infec-

tion was due to the parenteral antibiotic rather than
the non-absorbable component of the regimen (20). A
subsequent study in which paracetamol cases ac-
counted for 80'7o of the 108 patients, showed that a
broader parenteral antibiotic regimen (ceftazidime 1 g
IV every 8 h, flucloxacillin 500 mg IV every 6 h) when
used prophylactically reduced the incidence of con-
firmed bacterial infection in the cohort who became
encephalopathic to 26% (21). However, this early and
aggressive antibiotic therapy was associated with the
emergence of bacteria showing resistance to multiple
antibiotics in 9'7o of the encephalopathic patients (21).
Systemic antifungal therapy may be appropriate in
patients with risk factors for fungal infection, e.g.
those with renal failure, previous or concomitant thio-
pentone therapy or liver transplantation. Systemic
fungal infection (CandMa sps accounts for the vast ma-
jority) is notoriously difficult to diagnose and a high
index of suspicion is required (13). Two valuable senti-
nel markers of fungal infection are a white cell count
20>( 109/1 and an arrest in the recovery of coagulation
activity (13).
Haemodynamic #Tstabilio, and o.~vgen debt
Hypotension occurring despite adequate intravascular
volumes (pulmonary capillary wedge pressure 10-14
mmHg) is treated with vasopressor agents, using
noradrenaline if the cardiac index exceeds 4.5
litres- min-~ • (m2) -t or adrenaline if the cardiac out-
put needs to be boosted above this threshold (22). In a
study in which paracetamol accounted for 67'/0 of the
patients, the initial stabilizing dose to achieve a mean
arterial pressure above 60 mmHg ranged between 0.2-
1.8 ltg'kg-J • min-J of adrenaline and 0.2-2.0
/Lg. k g - I . min-I of noradrenaline (22). Vasopressor
agents may cause or aggravate an oxygen debt and pro-
stacycline infused at a rate of 5 ng-kg-~, min-~ im-
proved when used in conjunction with both adrenaline
and noradrenaline (22). N-acetylcysteine infusion in 12
cases of paracetamol-induced liver failure was as effec-
tive as prostacyclin in improving oxygen metabolism
(23).
Renal failure
Extracorporeal renal support was required in 75% of
cases of paracetamol-induced liver failure that pro-
gressed to grade 3-4 encephalopathy (11). Renal fail-
ure can also be the dominant organ failure after par-
acetamol overdose, occurring in the absence of signifi-
cant liver damage. The renal impairment occurs early
in the clinical course and has the characteristics of
tubular damage without the intermediate functional
hepatorenal dysfunction seen in acute liver failure of
Paracetamol-induced fiver failure
other aetiologies. This suggests that the renal impair-
ment is a direct manifestation of paracetamol toxicity.
Continuous support systems are associated with less
haemodynamic instability and a lower risk of aggravat-
ing latent or established cerebral oedema than inter-
mittent haemodialysis (24). The coagulopathy of acute
liver failure does not negate the need for anticoagu-
lants and paradoxically heparin requirements are in-
creased during haemodialysis (25,26). Prostacyclin in-
fusions in doses of 2-5 ng. kg - j - min -~ proved su-
perior to heparin anticoagulation in continuous sys-
tems with respect to the functional duration of the
filtres and the haemorrhagic complications observed
(27).
Coagulopathy
The most severe derangements of laboratory par-
ameters of coagulation are seen after paracetamol
overdose. Unlike other aetiologies of acute liver failure,
prothrombin times in excess of 100 s may be observed
in the absence of any encephalopathy or significant
bleeding tendency. In other situations, however, the co-
agulopathy is an important instrument when assessing
prognosis and monitoring disease progression. Conse-
quently, repletion of coagulation factors with fresh
frozen plasma is not advised in the absence of clinical
bleeding unless in anticipation of invasive procedures.
Thrombocytopenia may be very severe following a par-
acetamol overdose and is a more important risk factor
for haemorrhage (28).
Indications for transplantation
Criteria have been identified for use within specialist
centres to identify the cohort most in need of liver
transplantation, and the King's College criteria are
shown in Table 1 (29). However, these criteria are im-
perfect in that the segregation of survivors from non-
survivors is not absolute. In the original analysis, the
discriminatory power of a metabolic acidosis with an
arterial pH <7.30 on the second or subsequent day
after a paracetamol overdose was very strong, being
TABLE 1
Selection criteria for liver transplantation following paracetamol
overdose
Criteria Sensitivity Specificity
Arterial pH <7.30* 0.49 0.99
or all three of following:
Grade 3-4 encephalopathy, 0.45 0.94
creatinine >300 itmol/1 and
prothrombin time > 100 s
* Threshold reduced to pH <7.25 in some centres (see text).
43
J. G. O'Grad),
associated with a 95% mortality (29). Changes in sub-
sequent medical practices, especially the more liberal
use of N-acetylcysteine and more aggressive early rehy-
dration, appear to have improved the survival rate in
these patients and consequently the discriminatory
threshold used in practice at King's College has been
reduced to <7.25. However, this alteration has not yet
been validated by a clinical study. In the absence of the
early metabolic acidosis, the combination of advanced
encephalopathy (grade 3-4), renal failure (serum~crea -
tinine >300 pmoi/l) and a severe coagulopathy (pro-
thrombin time >I00 s) are required before a poor out-
come can be predicted with confidence (29).
Transplantation and other surgical procedures
The UK figures indicate that although paracetamol ac-
counts for 56--57% of patients with acute liver failure,
only 7-9% of patients with paracetamol-induced dis-
ease underwent liver transplantation (30-32). In the
US only 4% of all emergency transplantation for acute
liver failure was for paracetamol-induced disease (33).
The overall survival rates following transplantation
were 67-70%, which are similar to the survival rates
seen for other aetiologies of acute liver failure (32,33).
Of the patients listed for transplantation, 41-57% died
or developed contraindications to transplantation be-
fore an organ became available (8,30,32). This pro-
portion is higher than for other aetiologies of acute
liver failure and illustrates the narrow window period
available for transplantation•
The deselection of patients from the transplant wait-
ing list .when the clinical condition deteriorates to the
extent that proceeding to transplantation is futile, is
difficult but necessary if a valuable resource is not to
be wasted. No definite role has yet been confirmed for
intracranial pressure monitoring (18,34) or cerebral
oxygen consumption (35) in deciding the difficult ques-
tion of when irreversible brain damage has occurred•
Deselecting patients with cerebral perfusion pressures
<40 mmHg for 2 or more hours has been advocated
and has resulted in a reduced incidence of failure of
neurological recovery after transplantation (36,37).
However, two studies have documented survival both
with and wit.hout transplantation in such patients
(34,37): Accelerating inotrope requirements, uncon-
trolled sepsis and severe respiratory failure are other
imprecise contraindications to transplantation (38).
The improvement in haemodynamic and neurologi-
cal stabilization observed after hepatectomy led to the
development of a two-staged procedure whereby hepa-
tectomy precedes liver transplantation by a variable
period of time (39,40)• It is an act of desperation in the
hope that a liver graft will become available and, be-
44
cause of the rapid deterioration typical of paracetamol
cases, it is most often considered in this setting. The
longest anhepatic time in an ultimate survivor was 21
h and 45 min in a series of cases that predominantly
• involved patients with liver graft failure rather than
acute liver failure (40). The risk of sepsis, especially
fungal infection, increased as the duration between the
two procedures was prolonged, and was the major
cause of death (40). In our experience this technique is
best reserved for situations where the patient is un-
stable but there is the likely availability of an organ
within 12-18 h (41).
Auxiliary liver transplantation has been pioneered
for patients with the potential to recover morpholog-
ically normal liver• In theory, it combines the advan-
tages of transplantation with the ability to withdraw
immunosuppression when regeneration has been dem-
onstrated in the native liver• The surgical techniques
allow either heterotopic or orthotopic placement of the
graft using the right or left lobe. Current opinion fa-
vors the orthotopic approach as it preserves anatomic
relationships, maintains autoregulation of portal ve-
nous blood flow and is associated with better venous
out-flow from the graft (42). The optimal indications
for auxiliary transplantation are as yet unclear. The
neurological and haemodynamic benefits derived from
the devascularisation or removal of the diseased liver
are completely or partially lost with this approach, and
in unstable patients standard orthotopic transplan-
tation may give better survival rates• On the other
hand, the excellent potential for liver regeneration to a
normal architecture in paracetamol cases and the con-
siderable grey-area in the ability to assess prognosis
early in these cases, make auxiliary transplantation an
attractive option in these patients•
Extracorporeal systems
Charcoal haemoperfusion was the most extensively as-
sessed of the extracorporeal systems to reduce circu-
lating toxins in acute liver failure. Paracetamol-induced
acute liver failure accounted for 62% of the 137 patients
entered into the controlled trials that showed no benefit
with respect to survival with charcoal haemoperfusion
(l 1). Current interest in extracorporeal systems revolves
around two bioartificial liver devices, one of which in-
corporates a charcoal column (43-45). The hybrid bi-
oartificial liver (BAL) intermittently exposes separated
plasma to a cartridge containing porcine hepatocytes at-
tached to collagen-coated microcarriers after the
plasma has been passed through a charcoal column de-
signed to remove substances toxic to the hepatocytes
(44). The extracorporeal liver assist device (ELAD) con-
tinuously exposes whole blood to cartridges containing

approximately 200 g of well differentiated human
hepatoblastoma cells that retain contact inhibition (43).
Pilot studies demonstrated some neurological improve-
ment and modest biochemical changes but no direct im-
pact on survival was observed (43--45). The only con-
trolled study, to which paracetamol-induced disease
contributed 71% of the subjects, failed to demonstrate a
definite role for E L A D either as a salvage procedure or
as a bridge to transplantation (45). However, these and
newer refined systems warrant further assessment in
larger, properly constructed trials.
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