ο»ΏAcetaminophen toxicity
Toxicity is typically divided into stages, but this may not work perfectly in every patient (especially in patients who ingested several doses of acetaminophen over time).
Stage I (0-24 hours) = Incubation
- Asymptomatic or nonspecific symptoms (anorexia, nausea/vomiting, diaphoresis).
- π¨ Other symptoms during this period usually suggest coingestion or massive ingestion.
- Massive ingestion (>32 grams) may present with mental status alteration and lactic acidosis within 12 hours of ingestion. (25873702) These patients should be considered for specific treatment.π
Stage II (24-72 hours) = Latent period
- Stage I symptoms resolve or improve.
- Right upper-quadrant pain can occur.
- Labs:
- AST/ALT elevation occurs.
- Nephrotoxicity may occur.
Stage III (72-96 hours) = Peak liver toxicity
- Systemic symptoms reappear (nausea/vomiting, anorexia, malaise).
- Hepatic failure emerges (encephalopathy, jaundice, coagulopathy, hypoglycemia, lactic acidosis, shock).
- Greatest risk of death during this period (with common causes being cerebral edema, septic shock, or less commonly hemorrhage). (31307590)
- Labs:
- Transaminases peak 3-4 days after ingestion. Patients with peak transaminase levels
- Hepatorenal syndrome can occur.
- INR elevation.
- Lactic acidosis.
Stage IV (4 days-2 weeks) = Resolution
- Patients who don't die make a complete recovery.
patient evaluation
historical elements
- Timing & amount of ingestion.
- Single ingestion vs. multiple/chronic ingestions.
- Formulation (immediate-release vs. sustained-release).
- History of alcoholism or malnutrition?
- History of known liver disease?
pertinent labs
- Electrolytes & glucose level.
- Lactate can be elevated:
- i) Early-onset lactic acidosis following massive ingestion (within 24 hours). π
- ii) Later-onset lactic acidosis due to hepatic failure (>48 hours after ingestion).
- Marked hyperbilirubinemia (>10 mg/dL) may cause a false-positive acetaminophen level, usually in the low range (0-30 ug/ml). (29605069) Bilirubin elevation in this range usually isn't due to acetaminophen, so other causes of liver injury should be considered.
decontamination?
activated charcoal
- Should be considered if patients present shortly following ingestion and are able to protect their airway (
- Likely provides the greatest benefit to patients with massive acetaminophen poisoning.π (25133498) Some guidelines recommend activated charcoal for up to four hours after an ingestion of >30 grams. (34053705)
- For ingestions involving sustained release formulations, activated charcoal might be considered at even later timepoints (especially a massive, sustained-release formulation). (31786822)
who needs treatment?
preamble: why the ICU perspective is different
- There are roughly two patient populations with acetaminophen toxicity seen in the ICU:
- (1) Patients with liver failure due to acetaminophen poisoning.
- (2) Patients with polysubstance intoxication admitted to ICU for supportive care, who also happen to have a positive acetaminophen level.
- Risk of treating with acetylcysteine in the ICU is negligible.
- Benefit of treating with acetylcysteine is potentially large (rarely may be life-saving).
Rumack-Matthew Nomogram
- This predicts the likelihood of hepatic failure based on acetaminophen level following a one-time ingestion.
- Disagreement exists regarding the ideal cutoff used in the nomogram, as shown above. (28489461) To err on the side of caution, it may be safest to use the United Kingdom treatment line.
- Nomogram confounders might cause the nomogram to fail:
- Incorrect history about timing of intoxication.
- Multiple ingestions or chronic acetaminophen use. (31786822)
- Factors that increase the risk of acetaminophen toxicity:
- Chronic alcoholism (not acute alcohol intoxication)
- Malnutrition
- Drugs that increase acetaminophen toxicity (INH, rifampin, phenobarbital, phenytoin, carbamazepine, trimethoprim-sulfamethoxazole, zidovudine)
- Extended-release acetaminophen preparations
- Delayed gastric emptying (e.g. opioids, gastroparesis)
approach
- This is one approach to acetaminophen intoxication. This strategy places a high priority on not missing cases of acetaminophen injury, and a low priority on avoiding treatment with acetylcysteine.
- For best effect, acetylcysteine should be given within 8 hours of ingestion. If known acetaminophen ingestion occurred >8 hours previously, or if there will be a delay in obtaining acetaminophen levels, it may be safest to start acetylcysteine immediately to avoid treatment delay. You can always stop it later on.
acetylcysteine
IV acetylcysteine is preferred over oral regimen
- Two options are available: a 24-hour IV regimen and a 72-hour oral regimen.
- The 72-hour oral regimen is a logistical nightmare:
- Oral acetylcysteine smells like rotten eggs and makes patients vomit.
- Patients will often refuse to continue with the regimen at some point.
- Extremely safe.
- Faster & logistically easier than the oral regimen.
- It rarely can cause an anaphylactoid reaction, with histamine release due to direct action of the medication. However, this isn't a major problem (more on this below).
- This can be calculated here (although many hospitals will have a computerized protocol for this as well).
- 1st infusion = 150 mg/kg over 60 minutes.
- 2nd infusion = 50 mg/kg over 4 hours.
- 3rd infusion = 100 mg/kg over 16 hours.
- Keep repeating the 3rd infusion until acetaminophen levels are
when to stop the acetylcysteine
- Continue acetylcysteine infusion if there is evidence of liver injury (e.g., ALT > 80 U/L and rising) or persistent elevation of acetaminophen (>10 mg/L). (22998987)
- Treatment failures have been reported if acetylcysteine was stopped prematurely.
- Continue at the same rate, equal to the rate of the third IV dose in the protocol (100 mg/kg infused over 16 hours β repeatedly).
- (1) Acetaminophen level is
- (2) Transaminases are either down-trending or stable.
- For patients with hepatic failure, acetylcysteine should be continued until the liver is making a robust recovery (e.g., transaminases are definitively falling and the INR is <2).
- Note that small fluctuations in ALT (e.g., +/- 20 U/L or +/- 10%) are common and don't necessarily indicate the need for ongoing acetylcysteine, especially if the ALT level is low. (31786822)
anaphylactoid reactions from IV acetylcysteine
- Rapid administration of acetylcysteine can cause an anaphylactoid reaction. This involves histamine release due to a direct action of the medication (not an IgE-mediated allergic reaction).
- Anaphylactoid reactions are uncommon (especially if the initial dose is infused more slowly, over 60 minutes). When they do occur, they are usually mild (involving the skin only). They invariably occur within six hours of initiation of acetylcysteine, most often within the first two hours. (29423816)
- Treatment may be as follows:
- Only symptom is flushing: continue acetylcysteine, carefully monitor patient.
- Urticaria: IV diphenhydramine 1 mg/kg, consider steroid, continue acetylcysteine.
- Angioedema: IV diphenhydramine 1 mg/kg, steroid, hold acetylcysteine for one hour.
- Respiratory symptoms or hypotension: IV diphenhydramine 1 mg/kg, steroid, hold acetylcysteine for one hour, epinephrine (intramuscular bolus or infusion).
pregnancy
- Acetaminophen poses a risk of hepatic failure to both mother and fetus.
- Acetylcysteine is safe and beneficial in pregnancy.
- IV acetylcysteine may be especially preferable because it achieves higher serum drug levels and avoids vomiting (of course, IV acetylcysteine is generally the treatment of choice regardless of pregnancy status). If IV acetylcysteine is unavailable, then oral acetylcysteine may be used.
- In a prospective observational study of pregnant women, delayed treatment with acetylcysteine was associated with increased risk of miscarriage and fetal death. (2748061)
massive acetaminophen poisoning
definition?
- One clinical definition of massive poisoning may be defined as patients with any of the following:
- (a) Acetaminophen levels above the β300-lineβ (red line above).
- (b) Known ingestion of >30 grams or >500 mg/kg (whichever is lower). (30777470; 31786822)
clinical presentation of massive acetaminophen poisoning
management of massive poisoning: overview
- (1) Charcoal may be useful in these patients (if patients present within
- (2) High-dose acetylcysteine is the cornerstone of management (more below).
- (3) Hemodialysis may also be indicated (more below).
high-dose acetylcysteine
- Rationale for using high-dose acetylcysteine:
- (1) Evidence shows that standard doses of acetylcysteine can be inadequate in the context of massive poisoning. From a basic science standpoint, acetylcysteine neutralizes NAPQI in a 1:1 molar ratio, so the dose of acetylcysteine should be scaled up in proportion to the amount of acetaminophen.
- (2) If dialysis is used, this will remove acetylcysteine, thereby aggravating the mismatch between acetylcysteine dose vs. NAPQI levels. Intermittent hemodialysis may remove up to 50% of acetylcysteine. (25133498)
- Case reports describe toxicity (including hemolysis and cerebral edema) following dosing errors resulting in excessive administration of acetylcysteine (e.g. 5-fold increase in the first dose, or 10-fold increase in the maintenance doses). (25767408, 21970774)
- Toxicity from acetylcysteine is therefore clearly possible. Case reports describe toxicity in the context of egregious dosing errors. Whether toxicity might occur at somewhat lower doses is unknown.
- The first and second dose of acetylcysteine are kept the same, but the infusion rate of the third dose is increased in proportion to the severity of intoxication.
- Intoxications over the 600 line (purple line below): third dose of 25 mg/kg/hr (quadruple the standard dose).
- Intoxications over the 450 line (green line below): third dose of 18.75 mg/kg/hr (triple the standard dose).
- Intoxications over the 300 line (red line below): third dose of 12.5 mg/kg/hr (double the standard dose).
hemodialysis
- Dialysis can remove both acetaminophen and toxic metabolites (NAPQI). This may be beneficial in massive poisoning, where acetylcysteine won't necessarily work.
- Indications for dialysis based on the EXTRIP guidelines are shown below (note that βECTRβ = dialysis). (25133498) π
- Dialysis is not an alternative to acetylcysteine. In fact, patients who are dialyzed require higher doses of acetylcysteine (e.g., double the dose in patients undergoing intermittent hemodialysis). (34053705)
management of hepatic failure
acetylcysteine infusion
- Acetylcysteine still provides benefit, even if delayed until after hepatic failure has occurred.
- A RCT demonstrated 28% mortality benefit among patients with established hepatic failure. (1954453)
- β οΈ Don't allow the acetylcysteine infusion to stop until the liver is clearly improving and the acetaminophen level is zero.
consider transfer to liver transplant center
- Patients with acute hepatic failure can be candidates for transplantation, even if recently suicidal.
- Patients with severe liver injury (e.g. encephalopathy, pH
management of renal failure
renal failure in acetaminophen toxicity
- This occurs in 10-25% of patients, and >50% of patients with acute hepatic failure. (29605069)
- Potential mechanisms?
- i) Direct effect of toxic metabolites
- ii) Can occurs as a result of hepatorenal syndrome
treatment
