Download Case report: paracetamol poisoning in a 2-year

Hong Kong Journal of Emergency Medicine
Case report: paracetamol poisoning in a 2-year-old child − from international
overview to the role of the Hong Kong Poison Information Centre
JYS Sia
and YC Chan
We report a 2-year-old girl suffering from acute liver failure as a result of paracetamol poisoning. The child
successfully recovered after intensive care. We performed literature search for the past decade and found that
the pathophysiological response in the child was different from that of the adult. Despite paracetamol
poisoning being one of the most common poisonings in the world, there is still no consensus in the treatment
protocol. Hence the role of the Hong Kong Poison Information Centre is briefly discussed. (Hong Kong j.
emerg.med. 2006;13:225-231)
Keywords: Acetaminophen, liver failure, N-acetylcysteine, poisoning
Case
A 2-year-old girl presented to our department for one
minute of generalised tonic-clonic convulsion on 20
November 2002. She enjoyed good past health since
birth. Before the convulsion, she suffered from upper
respiratory tract infection for two days and received
medications prescribed by a private practitioner. The
labels of the prescription were hand-written, namely
Amoxil (amoxycillin), domperidone, Xylyxanthramic
Correspondence to:
Sia Yin Shan, Jacky, MBBS, MRCSEd
Ruttonjee Hospital, Accident & Emergency Department, 266
Queen’s Road East, Wanchai, Hong Kong
Email: [email protected]
Hong Kong Poison Information Centre, Hong Kong
Chan Yiu Cheung, FRCSEd, FHKCEM, FHKAM(Emergency Medicine)
acid, Hydroxyacetamide and others but illegible. The
dosages were not labelled. Worse still, Xylysanthramic
acid and Hydroxyacetamide are not registered
pharmaceuticals in Hong Kong. In the middle of the
night, her mother noticed a decrease in conscious level
of her child. Further history did not reveal any
concurrent use of herbal medication. There was neither
travel nor trauma history.
Her condition at arrival was fair. The blood pressure
was 109/51 mmHg and the pulse rate was 180 beats
per minute. The tympanic temperature was 38.9°C
and the pulse oximeter showed 98% saturation on
room air. The child was sleepy and weak. The pupils
were 1 mm in diameter and not reactive to light.
The cardiovascular, respiratory and abdominal
examinations were unremarkable. The neck was soft
and Babinski response was negative bilaterally. The
226
Hong Kong j. emerg. med. „ Vol. 13(4) „ Oct 2006
bedside blood sugar level was 1.8 mmol/L. Intravenous
dextrose was given in the form of D10 but her clinical
response was poor and she remained sleepy after
30 ml of D10. The X-ray chest was normal. The clinical
diagnosis was hypoglycaemia and convulsion.
Subsequently, the patient was transferred to the
paediatric unit in Queen Mary Hospital.
and liver enzymes started to decrease after the NAC
(Figures 1 & 2). She was able to respond on day 3
after admission and was discharged on day 10 after
the intensive management.
After admission, her condition deteriorated with
respiratory failure that required intubation and
mechanical ventilation. She was then transferred to
the intensive care unit for further management. Blood
tests including complete blood picture, renal function,
liver function, prothrombin time, activated partial
thromboplastin time, blood culture, and blood gas
analysis, were performed. Metabolic workup including
organic acid, carnitine, lactate, pyruvate, and
amino acid profile were also performed. The results
revealed aspartate transaminase >3,000 U/L, alanine
transaminase >2,254 U/L, international normalised
ratio >3.0. Urgent viral study excluded the possibility
of hepatitis B, hepatitis C, human immunodeficiency
virus (HIV) antibody and acute cytomegalovirus
infection. Computerised tomography of the brain
was normal but lumbar puncture was withheld
due to the deranged coagulation profile. Urgent
electroencephalogram revealed generalised slowing.
Toxicology screen showed that the paracetamol level
was 556 µmol/L at 8-hour. N-acetylcysteine (NAC)
was initiated, starting with 1,800 mg in 200 ml
dextrose over 1 hour, then 630 mg in 150 ml dextrose
over 4 hours, then 1,200 mg in 250 ml dextrose over
16 hours and finally 1,200 mg in 250 ml dextrose over
24 hours. Besides, urine toxicology tests revealed the
presence of benzodiazepine, mefenamic acid,
chlorpheniramine, methadone, normethadone and
ephedrine. As a result, the medications prescribed by
the private practitioner were sent for qualitative and
quantitative analysis and was compatible with the urine
results. Hence the patient suffered from liver failure
due to paracetamol overdose complicated by
hypoglycaemia and seizure. Narcotics, anticholinergics
and anti-inflammatory drugs might contribute to the
clinical presentation of the patient. The child remained
sleepy, with episodic hypoglycaemia requiring repeated
infusion of dextrose solution. The paracetamol level
Paracetamol poisoning is one of the most common drug
poisonings in the world. In the United Kingdom,
nearly 50% of drug poisoning was due to it. 1 The
mortality was about 100 to 200 victims per year. 2-4
Reviewing the database in the Toxic Exposure
Sur veillance System ( TESS) of the American
Association of Poison Control Centers in 2004, 19,590
cases were under the age of six. 4 The reasons for its
highest occurrence are multi-factorial. Firstly, the
public believes it is a safe medication. Secondly, it is
easily available in the market. Unintentional misuse is
the third main reason for paediatric poisoning due to
the lack of safety container at home. Finally, dosing
error can occur due to mistakes of parents, physicians
and even pharmacists.5
Discussion
Figure 1. Decreasing trend of paracetamol level after the
initiation of N-acetylcysteine.
Figure 2. Response of liver enzymes after the initiation of
N-acetylcysteine.
Sia et al./Paracetamol poisoning in a 2-year-old child
The pathophysiological mechanism of paracetamol
poisoning is well known. Normally the acetaminophen
is mainly metabolised to non-toxic metabolites that
are renally excreted. However, in overdose situation,
the non-toxic metabolic pathways are saturated and
more paracetamol will go through metabolism by the
c y t o c h r o m e P 4 5 0 p a t h w a y, r e s u l t i n g i n t h e
accumulation of the toxic metabolite N-acetyl-pbenzoquinoneimine (NAPQI). The NAPQI is
detoxified by glutathione until the store is depleted.
The NAPQI will then bind to cellular proteins causing
damage and cell death.
The 4-stage clinical manifestation is also well
documented although it may be non-specific in
paediatric patients. During the first few hours, the
patient may present with non-specific symptoms such
as vomiting alone. Then the second stage follows
during which the patient remains asymptomatic. After
two to three days, in the third stage, the patient may
deteriorate rapidly with symptoms of acute hepatitis
and liver failure. Then finally the symptoms resolved
in about 7 to 10 days' time. However, death can result
if hepatic failure occurs.
227
Investigations should include complete blood picture,
renal function, liver function, coagulation profile and
toxicology screening. These are helpful to predict the
risk of hepatocellular damage as shown in Table 1. 1,6
In research, scientists found that inflammatory
cytokines are elevated in paracetamol poisoning. James
et al conducted a study to evaluate the relationship
between these cytokines and hepatocellular toxicity.
Tumour necrosis factors, interleukin (IL) -alpha, IL-beta,
IL-6, IL-8 and IL-10 were measured in adults and
children (total 35 patients) who suffered from
poisoning. The result showed that only IL-8 >20 ng/ml
was associated with peak prothrombin time value,
which is one of the predictors in hepatocellular damage.
Nevertheless, the authors concluded that further study
would be needed before its clinical usage could be
developed.7
Measurement of acetaminophen-protein adducts is
another area of scientific breakthrough in studying the
risk of hepatocellular toxicity.8 It is highly specific for
paracetamol induced hepatic injury since it is a
biomarker in the centrilobular region of the liver of
laboratory animals. It will be present in subjects whose
Table 1. Factors predicting risk of hepatotoxicity
Sens %
Spec %
LR+
(1) Clinical finding at presentation
(a) Probable toxicity by nomogram
88
72
3.14
(b) Time to treatment >10 hours
88
72
3.14
(c) Emesis at presentation
67
38
1.08
6.25
(2) Laboratory finding
(a) PT >14 seconds within 24 hours
75
88
(b) AST or ALT >100 iu/L within 24 hours
50
100
(c) PT >14 seconds within 48 hours
88
84
(d) AST or ALT >100 iu/L within 48 hours
81
100
(a) 24 hours: increase in PT, AST, ALT
81
88
6.75
(b) 48 hours: increase in PT, AST, ALT
100
88
8.33
100
72
3.57
>1000
5.50
>1000
(3) Combination
(4) Probable toxicity by nomogram or AST or ALT >100 iu/L within 24 hours
Sens: sensitivity; Spec: specificity; LR+: positive likelihood ratio = sensitivity/(1-specificity); PT: prothrombin time; AST: aspartate transaminase
ALT: alanine transaminase
Hong Kong j. emerg. med. „ Vol. 13(4) „ Oct 2006
228
liver transaminase level is greater than 6,000 iu/L. Its
clinical usefulness is inconclusive in human.
The most common problem nowadays is the absence
of treatment consensus in the world − a question that
has remained for decades irking scientists. Is there any
difference when we give antidote to the child as we do
to the adult? If yes, what is the difference? Should we
use the Rumack-Matthew nomogram? What should
be the value of serum paracetamol level before we
initiate NAC?
Anatomical and physiological differences
It could be disputed that the ratio of liver weight to
body weight is relatively larger in a child when
compared to that of an adult. This is shown in Table 2.
Bond found that the relatively larger liver weight offers
protection due to greater glutathione storage. Indeed
the toxicity is the interaction of drug, total glutathione
store, glutathione synthetic ability and the individual's
percentage of cytochrome oxidative metabolism.
According to Bond's data, the toxic level of paracetamol
should be expressed as milligrams of ingestion per
kilogram of liver weight rather than body weight. This
implies that a child has to ingest a larger quantity of
paracetamol before toxicity occurs, 9 but then what
should be the dosage?
Anderson et al retrospectively collected data of 1,000
children aged 1 to 5 presenting to the emergency
department with accidental paracetamol ingestion from
January 1995 to June 1997.10 He compared the timeconcentration relationship of the drug level in children
with the database in adult. He showed that clearance
of drug was a non-linear function of weight while in
Table 2. Relationship between age and liver weight.
Age in year
Average weight of liver per
kilogram of body weight (g/kg)
3
35.8 - 41.0
6
31.7 - 34.3
9
30.0 - 32.0
12
23.8 - 27.0
15
24.0 - 24.4
18
24.8 - 26.6
contrast dose was an expression of linear function of
weight. By using sophisticated statistical analysis
(PharSight Trial Designer), they calculated the
simulation dose in paediatric patients as 300 mg/kg
before toxic effect occurs as compared to the 150 mg/
kg in adult patients. The possible toxicity should be at
a level of 225 mg/L at 2-hour interval rather than the
traditional 150 mg/L in adult. They suggested those
who ingested more than 250 mg/kg should have serum
paracetamol checked. The 2-hour interval was used
because children got faster metabolism and had shorter
elimination half-lives. However this guideline is invalid
when the child is older than 12 years old as the
metabolism will be similar to the adult.
Could the scientific calculation be extrapolated
to clinical practice?
Bond collected database from the American Association
of Poison Control Centers and reviewed the data
retrospectively.9 All of them ingested less than 200 mg/
kg of paracetamol. He found that 3 out of 866 children
aged from 1 to 6 years were reported to have probable
risk of liver damage according to the nomogram but
none of them suffered. Mohler et al enrolled 1,039
patients who ingested less than 200 mg/kg of
paracetamol. About 93% of the patients ingested less
than 150 mg/kg while 7% of the patients ingested 150
to 200 mg/kg of paracetamol. They reviewed the data
and found that none of them developed hepatocellular
damage. They suggested those who ingested less than
200 mg/kg unintentionally could be observed at home.
This could reduce hospital cost and parental anxiety.11
However Caravati and his colleagues challenged the
validity of Mohler's paper since only a small proportion
of the patients were within the probable risk dosage
i.e. 150 to 200 mg/kg. Worse still, Mohler's team did
not propose their protocol for their own management
despite they recommended others to follow their
guideline. Caravati criticised this would only give a
false sense of safety to the patient, parents and doctors.12
Alander et al studied paracetamol poisoning from
another point of view. He retrospectively reviewed the
databases from two regional children's hospitals from
January 1988 to December 1997. 1 A total of 322
patients were included and their age ranged from 1 to
Sia et al./Paracetamol poisoning in a 2-year-old child
17. The reason for ingestion was categorised as
intentional and unintentional. The range of dose
reported was from 4 mg/kg to 8,333 mg/kg. The
median dose was about 172 mg/kg in the intentional
group and 150 mg/kg in the unintentional group. No
hepatocellular damage was found under the age of 9.
However, Isbister challenged the validity of Alander's
study that failure to categorise the age properly was
the most paramount confounding variable.13
Caravati conducted a prospective study investigating
the relationship between dose ingestion and patient
outcome in the Utah Poison Control Center.14 A total
of 1,015 patients aged from 1 to 72 months old were
recorded. The mean dose was 213±148 mg/kg.
Seventy-eight percent of their patients received
decontamination if they ingested greater than 140 mg/
kg. Statistical analysis showed that no hepatotoxicity
was noted if patients ingested 100-200 mg/kg. None
of the patients developed potentially toxic
concentrations in the 140 to 200 mg/kg dose range
even without gastro-intestinal (GI) decontamination.
They recommended for those who ingested within this
range should have prompt GI decontamination
preferably within one hour and could be safely
discharged home. Any dosage greater than 200 mg/kg
should have serum concentration checked. Their
decontamination guideline is compatible with the
recent statement by the American Academy of Clinical
Toxicology and the European Association of Poisons
Centers and Clinical Toxicologists. GI decontamination
and activated charcoal are not required after one hour
of ingestion.15 On the contrary, the American Academy
of Pediatrics held a different opinion in which they
thought activated charcoal could be given even within
6 to 8 hours after the acute ingestion. 16
But then what should be the dosage of NAC to
initiate?
Indeed, treatment is variable all over the world. The
intravenous route is used in Canada and UK while the
oral route is the practice in the US.17 Wallace and his
team published the only evidence-based flowchart in
2002 and was accepted by the Royal College of
Paediatrics and Child Health as a Good Practice
Consensus Statement (Figure 3). The dose is 150 mg/kg
229
in 3 ml/kg of 5% dextrose over 15 minutes, followed by
50 mg/kg in 7 ml/kg 5% dextrose over 4 hours followed
by 100 mg/kg in 14 ml/kg 5% dextrose over 16 hours.
For continuation of NAC as adjuvant therapy for
hepatic failure, it should be given at 150 mg/kg per
24 hours.18
Summary
This article raises several important points. First of all,
a child is not a miniature of adult. We should be aware
of the precipitating factors (Table 3) and non-specific
toxicological manifestations in this population.
Se c o n d l y, t h e re i s s t i l l n o c o n s e n s u s o n t h e
management of paracetamol poisoning in the world
despite it is the most common poisoning. A standard
dosing regimen or treatment protocol for common
toxicological problems is absolutely indicated in our
locality. Thirdly, the identification of prescription in
private practices is important. It was well illustrated in
our case since the hand-written prescription was illegible
and we had no idea what exactly Xylyxanthramic acid
and Hydroxyacetamide contained.
The Hong Kong Poison Information Centre (HKPIC),
established in 2005, is the pioneer in toxicology
management in Hong Kong. Currently it provides
consultation service to health care professionals
regarding poison information and poisoned patient
management. It is worthwhile developing our own
protocols for emergency management of common
poisonings such as paracetamol in adult and paediatric
patients. The report published by Litovitz and his coworkers showed that the number of poisoning deaths
reported to the medical examiner alone was 7 times
more than that to the regional poison center. 19
Protocols, management plans and expert advice could
be faxed to the medical officer asking for consultation.
Whether we should set up a compulsory reporting
system is debatable, but a simple notification sheet,
similar to the notification of infectious diseases
developed by the Department of Health, should be
highly advocated. The corollary is the accumulation
of our updated database for analysis in future and
continuous quality improvement could be conducted.
230
Hong Kong j. emerg. med. „ Vol. 13(4) „ Oct 2006
Figure 3. Flow chart to guide management in paracetamol poisoning. (Reproduced with permission from the BMJ Publishing
Group. In: Wallace CI, Dargan PI, Jones AL. Paracetamol overdose: an evidence based flowchart to guide management. Emerg Med
J 2002;19(3):202-5. The reference numbers quoted in the chart correspond to references cited in that article only.)
Sia et al./Paracetamol poisoning in a 2-year-old child
Table 3. Precipitating factors in paracetamol poisoning
Risk factors16
Childhood obesity
Chronic liver problem
Chronic medical illness
Concomitant viral infection
Diabetes mellitus
Malnutrition
Prolonged fasting
Repetitive small doses
Co-ingestion of anti-histamine
Enzyme inducers
(1) Human: isoniazid, rifampicin, phenobarbital,
carbamazepine, ethanol
(2) Animal: dexamethasone, doxorubicin, prolonged fasting
231
Reasons
Depletion of glutathione store
Slower metabolism
Non-specific clinical manifestation causing delay in medical
consultation
Slow down gastric emptying
Induction of cytochrome P450
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