Paracetamol Flashcards
Discuss risk assessment for acute paracetamol overdose
-Life threatening hepatotoxicity is uncommon and fatalities are rare
-The threshold dose for paracetamol induced hepatic injury in adults is extremely variable but usually considered to be >10 G or 200mg/kg
- THe risk of heaptic injury following a single acute ingestion without NAC is prediceted by plotting a serum paracetamol level taken 4-15 hours later on the Prescott or Rumack Matthew nomogram.
The probability of hepatotoxicity (defined as peak AST or ALT >1000 IU/L) is
– 1-2% if 4 hours level is <200mg.k
-30% if 4 hour level is 200-300
–90% if >300 g/L
The risk of hepatic injury with NAC therapy is determined primarily by time from overdose to commencement of NAC
- Survival is 100% where NAC is commenced within 8 hours of ingestion (small % of patients develop minor elevation of hepatic transaminases)
- Benefit is reduced where NAC is commenced 8-24 hours
- Benefit is not estabilised if NAC is commenced > 24 hours following ingestion except in fulminant hepatic failure where IV NAC decreases cerebral oedema inotrope requirement and moratility
Where time of ingestion not nknownor is staggered dosing more difficult.
Patients who present >8 hours after overdose with eleaveted hepatic transaminases are assumed to ahve early paracetamol induced hepatotoxicity
- the patient who present > 24 hours following an overdose and has normal hepatic transaminases and no paracetamol level has little risk
-For Massive ingestions >500mg/kg standard NAC administration protocols may be insufficient to prevent hepatotoxicity
Discuss risk assessment for acute paracetamol overdose in children
There are no reports of death following single acute non intentioanl paracetamol exposure in children under 8 years of age.
Ingestion of <200mg/kg as a single dose or over a period of 8 hours does not warrant
- decontamination
- referral to hospital
- serum paracetaol levels
- liver function test
- antidote treatment or follow-up
Discuss TM and TK of paracetamol
TM: Elevated production of NAPQI following paracetmaol leads to depletion of hepatic glutathione stores. Once glutathione levels reach a critical threshold NAPQI starts to bind to toher proteins causing hepatoctye injury. The hallmark of paracetamol induced hepatic injury is centrilobular necrosis
TK
Paracetamol is well absorbed from the small intestine follwoing oral admin. Peak levels usually occur within 1-2 hours for a standard tablet of capsule preparation and within 30 minutes for liquir preparations.
The VD is 0.9L/Kg. 90% of paracetamol undergoes hepatic glucuronidation or sulfation. These conjugates are excreted in urine. Most of the remainder is oxidised by the Cyp450 system to form NAPQI a potentially toxic intermediate Under normal circumstances NAPQI is immediatly bound by intracellulr glutathione and eliminated in the urine as mercapturic adducts
Discuss clinical phases of acute paracetamol overdose
Phase 1 <24 hours
-Patients are frequently asymptomatic but have nausea and vomting
Phase 2 1-3 days
- RUQ tenderness
- Hepatic transaminases rise rapidly to a peak at 48-72 hours and may reach 15000-20000.
- Hepatotoxicity is defined as an ALT or AST >1000IU/L/ In survivors the ALT/AST rapidly decline to normal
- PT and INR are at their most abnormal within hours of peak AST/ALT
- hyperbilirubinaemia also occurs and renal function may be impaired
Phase 3 (3-4days)
- In very severe causes hepatotoxicity progresses to fluminant hepatic failure with coaguloapthy, jaundice encephalopathy and MOF
- Death may occur in this phase. Non survivors demonstrate
- HAGMA with lacteamia despit resuscitation,
- Renal failure
- worsening coagulopathy
- encephaloapthy
Phase 4 (4 days - 2 weeks) - Recovery phase during which hepatic structure and fucntion return to normal
Discuss IX in paracetamol OD
Serum paracetamol
- If time of ingestion is known a timed paracetamol level is taken at 4 or more hours to establish risk of hepatottoxicity and need for treatment
- if NAC is commenced wihtin 8 hours of a single acute ingestion the first serum paracetamol is the only level needed
- Following massive (>500mg/kg) the paracetmol level is repeated toward the end of the NAC infusion. A detectable paracetamol concentration is an indication to continue NAC
LFTs
-If NAC ic commenced later than 8 horus baseline and serial transaminase levels are also taken to detect and monitor heaptic injury - levels are not linked to ourcome
Coags
-elevation of INR is an important marker of hepatic injury
Platelets, renal fucntion and gas
*Although commonly done and clincally useful extrapolation of the treatment line from 15-24 hours has not been formally validated
Discuss management of acute paracetamol OD
RESUS
ACBD
D: oral activated charcoal is not life saving
- it may be offered to the cooperative adult who presents within the firsst hour following overdose in which case it may sufficeintly reduce the 4 hour paracetamol level to such a degree that NAC is not necessary
- It is never justified following acute infestion of paracetamol by small children
E: not clinically useful
A: NAC is indicated in all patient in whom the risk assessment suggest potential for poor otucome and in present who present late with clinical or biochemical eveidence of hepatic injury
- presentation within 8 hours - decision for NAC from nomogram
- Presentation 8-24 hours - NAC is initiatied immediatlely continued or ceased once a paracetamol level is aviable and plotted on the nomogram
- Unknown time - if paracetamol is detectable but the time of ingestion is unknown NAC ic commenced. It may be ceased if hepatic transminases are found to be normal at the end of the 20 hour NAC infusion
- Post 24 hours: NAC is only indicated if paracetamol is detectable or heaptic transaminases are elevated. It is continued until hepatic transaminases are falling and the patient is improving .n
D: In patient in whom NAC is started wihtin 8 hours unless massive OD can be discahrged after their 20 hour NAC infusion - ALT should be taken 2 hours prior to finishing the bag and for those with massive a paracetamol level at this time. NAC should continue at the same rate if paracetamol is greater than 10 or LAT is >50
- Patient in whom NAC is stated after the 8 hour period have hepatic transaminases tested at baseline and at the end of the 20 hour infusion. If abnormal NAC continues at 100mg/kg/16 hours and hepatic transaminases are tested every 12-24 horus until falling. If >1000 serial testing also include INR
- In the uncommon case rising INR and hepatic transaminases indicate fulminate hepatic failure arrangement for transfer to a liver tranplant service must be made
*in massive overdose >50g or 500mg/kg may need to increase NAC dose - double second bags
What are the indication for a acute paracetamol overdose to be transferred to a liver transplant centre
INR >3 at 48 hours or >4.5 at any time
- oliguria or creatine >200
- acidosis with a pH <7.3 after resus
- Systolic hypotension with Bp <80
- Hypoglycaemia
- Severe thrombocytopenia
- encephaopathy of any degree
DIscuss PK of modified release paracetamol and how it changes the investigation
PK: Preparations consist of 665mg of paracetamol of which 69% is slow release and 31% is immediate release. This formulation results in rpolonged absorption phase when comapred to standard formationl. Peak normally occurs at 2-3 hours but may be delayed by up to 20 hours following OD
IX Take a 4 hour post ingestion paraceatmol level if under the normogram repeat again in 4 hours time if either over the line start NAC - this if for patient with history of non toxic ingestion dose
The normogram should not be used for any protentional toxic modified release paracetamol ingestion. Levels are useful to guide further management
ALT and paracetamol should be taken towards the end of the infusion if >50 or 10 respectively should be continued. If rising or peristently elevated may require increased dose of NAC
Discuss repeated supratherapeutic dose paracetamol ingestion + risk assessment
Refers to staggered dosing with therapetic intent of >4g/day in adults or >60mg/kg/day in children. In adults usually used to treated chornic pain in children usually therapeutic error.
Repeated supratherapeutic ingestion is responsible for all paracetamol related deaths under 6 years of age and up to 15% of adults. Decision to treat is base on biochemical and clinical features
Risk asssessment
#Rumack-Matthew and Prescott nomograms are not useful.
#Adults ( and children >6years)are referred for biochemical risk assessment if there is a history of infestion of
1) >10grams or >200mg/kg (whichever is less) over a single 24 hour period
2) >12 grame or 300mg/kg over a 48 hours period
3) a daily therapeutic dose per day for more than 48 hours in patients who also have nausea or vomting or hepatic dysfunction as a baseline
If any of the above measure serum paracetamol and ALT if <50L and paracetamol <20 nil further treatment
otherwise commence NAC
Repeat serum paracetamol and ALT 8 hours after previous concentration –> ALT <50 or static and parecatmol <10 if no continue Nac and repeat every 12 hours until the above is acheived
Discuss management of paracetamol liquid ingestion
In children under 6 years if age where ingestion of more than 200mg/kg of liquid paracetamol is suspected a serum paracetamol concentration should be measured at least 2 hours after the ingestion. If 2-4 hours level is belwo 150 NAC is not required. If the 2 hour level is >150 this should be repeated at the 4 hour level and NAC commenced if more than 150
2 hour level should only be used in a well child under the age of 6 with isolated liquid paracetamol ingestion.
