EM/ANAES/CC POSTING
CASE STUDY/ASSIGNMENT-2
1) What happens to the overdosed paracetamol in the
body?
Following an overdose of paracetamol that is ingested into the body, it is
rapidly absorbed from the gastrointestinal tract, and peak serum concentrations
are usually achieved within 2 hours. Delayed absorption can occur especially
after overdose of paracetamol combined with opioid or antimuscarinic
medications, as well as those with altered-release kinetics such as extended-
release preparations.
In overdose, normal pathways for paracetamol metabolism are saturated and a
larger proportion is oxidised by the CYP450 system to a reactive metabolite,
N-acetyl-p-benzoquioneimine (NAPQI).
NAPQI is detoxified by hepatic glutathione to a nontoxic compound that can
be renally eliminated. However, when hepatic stores of glutathione decrease to
<30% of normal in the setting of overdose, NAPQI binds to hepatic
macromolecules, resulting in a centrilobular hepatic necrosis.
Observed hepatocyte damage typically progresses with cell lysis on the second
day after an acute toxic exposure, releasing hepatic enzymes (such as
transaminases) and NAPQI-hepatic protein adducts into the circulation where
they are detectable in the serum. This corresponds generally to the
development of overt clinical toxicity.
2)What are the signs and symptoms of paracetamol
poisoning?
The clinical presentation of paracetamol poisoning can be roughly divided into
four stages. During the first 24 hours after exposure (stage 1), patients may be
asymptomatic or have minimal and nonspecific clinical effects of toxicity,
such as anorexia, nausea, vomiting, and malaise. By days 2 to 3 (stage 2),
findings seen in stage 1 often improve, but clinical signs of hepatotoxicity
(including right upper quadrant pain and tenderness) may occur and serum
transaminases may be elevated. Even without treatment, most patients with
mild to moderate hepatotoxicity recover without sequelae. However, by days 3
to 4 (stage 3), some patients will progress to fulminant hepatic failure.
Characteristic stage 3 findings include metabolic acidosis, coagulopathy, renal
failure, encephalopathy, and recurrent GI symptoms. Patients who survive the
complications of fulminant hepatic failure begin to recover over the next 2
weeks (stage 4), with complete resolution of hepatic dysfunction in survivors
after 1 to 3 months.
Paracetamol may also cause acute, extrahepatic toxic effects, presumably
because of the presence of CYP450 or similar enzymes (e.g., prostaglandin H
synthase) in other organs. In rare cases, isolated renal injury, cardiac toxicity,
and pancreatitis may occur. Ingestion of massive doses of paracetamol (e.g.,
>500 milligrams/kg or peak plasma paracetamol concentration >750
micrograms/mL or >5000 micromole/L) can cause early-onset metabolic
acidosis with an elevated lactate and altered sensorium even in the absence of
either liver failure or hypotension. Likely mechanisms for this finding include
depletion of liver glutathione stores resulting in generation of 5-oxoproline
and metabolite-induced inhibition of mitochondrial respiration.
3)What is the management of paracetamol poisoning?
Treatment guidelines for oral paracetamol poisoning are based on the time to
presentation to the ED after ingestion: <4 hours, between 4 hours and 24
hours, and unknown time or >24 hours before presentation. The risk of
hepatotoxicity increases with the lag time between ingestion and initiation of
acetylcysteine therapy.
The optimal outcome with acetylcysteine therapy is achieved when it is
administered within 8 hours after ingestion, so the optimal “decision-time
window” for treatment is between the 4-hour acetaminophen concentration
measurement and 8-hour goal to initiate acetylcysteine.
No further acetaminophen serum measurements are necessary once the need
for acetylcysteine therapy has been determined until the completion of the
course of therapy. All patients requiring acetylcysteine therapy should be
admitted until the completion of the therapy
For patients who present to the ED within 4 hours and are likely to have a
significant paracetamol overdose, treatment begins with GI decontamination
(usually activated charcoal) while awaiting the 4-hour postingestion
paracetamol concentration.
If the clinical laboratory can report the paracetamol concentration within the
8-hour postingestion window, wait for the serum paracetamol concentration
and plot the result on the nomogram to determine whether acetylcysteine
therapy is necessary.
If the paracetamol concentration will not be available by 8 hours after
ingestion, empirically initiate acetylcysteine therapy, by either route, without
waiting for the result. Subsequently, when the paracetamol concentration is
determined, the need for acetylcysteine therapy can be determined with the use
of the nomogram.
For patients who present >4 hours but <24 hours following paracetamol
ingestion, determine the serum paracetamol concentration as soon as possible.
GI decontamination may be performed, particularly for suspected co-
ingestants, but it may have limited effectiveness because of the delay in
presentation.
If the laboratory can determine the paracetamol concentration within 8 hours
after ingestion, await the paracetamol concentration and plot the result on the
nomogram to determine if acetylcysteine therapy is necessary. Otherwise,
empirically administer acetylcysteine.
For patients in whom the time of paracetamol ingestion remains unknown or is
>24 hours or for those with suggestive clinical findings of paracetamol
poisoning, a serum paracetamol concentration and serum transaminase,
bilirubin, and prothrombin time tests should be determined. Initiate
acetylcysteine therapy as soon as possible while awaiting laboratory results.
In this scenario, a detectable paracetamol concentration (>10 micrograms/mL
or >66 micromole/L) suggests that the patient may be at risk for developing
hepatotoxicity. Similarly, elevated serum transaminases suggest the possibility
of ongoing hepatic toxicity.
Therefore, continued acetylcysteine therapy is indicated if the paracetamol
concentration is measurable or if the serum transaminases are elevated. If
serum paracetamol concentration is <10 micrograms/mL (<66 micromole/L)
and the serum transaminases are not elevated, the acetylcysteine can be
discontinued.
Recheck serum paracetamol and transaminase levels at the completion of
acetylcysteine therapy with continuation of acetylcysteine infusion at the rate
of 6.25 milligrams/kg per hour. If serum paracetamol concentration is not
detectable or is <10 micrograms/mL (66 micromole/L) and transaminase
concentrations are normal, the acetylcysteine therapy can be discontinued.
If either the serum paracetamol concentration or liver function tests are
elevated, the acetylcysteine should be continued until the serum paracetamol
concentration is undetectable and the patient has demonstrated clearly
downtrending transaminases (at least two values) and there are no signs of
synthetic liver dysfunction.
Patients who are not at risk for developing paracetamol-induced hepatotoxicity
should be observed in the ED for 4 to 6 hours to exclude potentially toxic co-
ingestants before disposition.
Psychiatric evaluation should be considered for patients with intentional
paracetamol overdoses. Cases of paracetamol ingestion or toxicity should be
reported to the regional poison control center for both data collection purposes
and assistance with management.
