Therapeutic Misadventures with Acetaminophen

I first heard the title expression “Therapeutic Misadventure” from one of my mentors, Jim Heubi (J Pediatr 1998; 132: 22-27), though he did not coin the term.  As a personal aside, Jim interviewed me prior to my pediatric residency and helped convince me to train in Cincinnati.

Some have said the phrase is a ‘nice medical term for a mistake.’  A more precise definition: “therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease” (from the following link: Therapeutic misadventure).

The latest data on therapeutic misadventures with acetaminophen has emerged in a recent report: Pediatrics 2013; 131; e740-e746.

This observational cohort study analyzed a group of 666 children from 22 sites who were enrolled in the Pediatric Acute Liver Failure (PALF) study.  The children were subdivided based on acetaminophen (N-acetyl-p-aminophenol [APAP]) exposure: 85 with single toxic dose exposure (SE), 83 with chronic exposure (CE) ≥ 2 doses, and 498 with no exposure.

Among the CE group, 22% were assigned a final diagnosis of APAP toxicity; the majority in the CE group had 3 to 7 days of exposure to APAP.  The median dose was 31 mg/kg/day. Only 31 CE patients had serum APAP levels performed; in this group, a similar proportion to SE patients had elevated APAP levels ≥10 mg/L (68% in CE and 66% in SE).   Besides APAP toxicity, final diagnosis included indeterminate in 31 (37%), autoimmune (7%), metabolic (5%), infection (8%), and other (21%).

Among the SE group, 82 (96.5%) had APAP overdose as final diagnosis and 3 (3.5%) as indeterminate.

Among the NE group, 234 (47%) had a final diagnosis of indeterminate; other diagnosis in the remaining: infection 51 (10.2%), metabolic 72 (14.5%), autoimmune 34 (6.8 %), and other 107 (21.5%)

Clinical outcomes: 21 days after enrollment, 68% of CE patients were alive without liver transplantation; this compared with 92% of SE patients and 48% of NE patients.  In both the CE and NE patients, there was a high percentage of patients with indeterminate etiology.  Indeterminate ALF is associated with increased risk of liver transplantation and death.

Conclusions from the authors: a low serum bilirubin and high ALT should raise suspicion for CE to APAP.  CE patients outcomes were not as favorable as SE patients.  Better communication between physicians and families about the risk of prolonged use of APAP is needed.

Related blog links:

N-acetylcysteine for Acute Liver Failure

A study which took 8 years to complete (2001-2009) and involved more than 20 pediatric liver transplant centers has shown that N-acetylcysteine (NAC) is NOT effective for nonacetaminophen acute liver failure in the pediatric population (Hepatology 2013; 57: 1542-49).

Eligible patients were drawn from a registry of pediatric acute liver failure (PALF) patients.  Among 607 who were enrolled in the registry, 271 were eligible for the NAC trial and 184 of these patients (families) agreed to participate.  The most common reasons for patients to be ineligible for the study included acetaminophen toxicity, previous NAC treatment, sepsis, and “reason unknown.”

The design of the study was doubly masked with patients stratified by age and hepatic encephalopathy.  Patients either received intravenous NAC (150 mg/kg/d) or D5W for up to 7 consecutive days.

Key findings:

  • No significant difference in 1-year survival: 73% of NAC patients and 82% of placebo patients
  • NAC patients had lower 1-year liver transplant free survival (p = 0.03): 35% in NAC group compared to 53% of placebo patients.

The study did have several limitations.  Despite the lengthy enrollment period, the absolute number of patients was only 92 in each group.  In addition, there were differences in the diagnoses in both groups and the ages of the groups, though these were unlikely to change the results.  With regard to diagnoses, both groups had ~60% with an indeterminate reason for PALF.  However, the NAC group had an increased number with metabolic diseases (14% compared with 5% in placebo group); the most common metabolic disease was Wilson’s disease (7 in NAC group and 3 in placebo group).  The NAC group had a median age of 3.7 years compared with 4.5 years for the placebo group.

Another limitation was in testing for acetaminophen-cysteine adducts (A-CA) which can be used as a marker of acetaminophen exposure.  This was performed retrospectively in 84 of the participants.  A-CA was positive in 9 (six from placebo and three from treatment arm).  Again, this was unlikely to change the results as there were no statistical differences in clinical features of those who were tested for A-CA compared with those who were not.

In some ways, the results are surprising due to prospective studies in adults showing benefit of NAC in ALF and a previous retrospective uncontrolled pediatric study suggesting efficacy in PALF.  Ultimately, this study proves again that pediatric patients are not “small adults” and highlights the need for prospective pediatric drug trials.

Bottom-Line:

NAC works for acetaminophen-induced ALF but is not helpful for other causes of PALF.

Related blog links:

Advice on drug-induced liver injury (DILI)

Practical information and advice on continuing or stopping drugs with associated hepatoxicity is available from a recent commentary (Gastroenterol Hepatol 2012; 8: 333-36).

Most drugs with a “bump” in aminotransferases do not need to be stopped.  Many drugs induce an “adaptive response” in which elevated LFTs will spontaneously resolve; this is most common in the first 12 weeks of drug usage.  This type of response must be distinguished from an immune reaction/hypersensitivity response which is much more likely to progress.  A hypersensitivity response could include rash, fever, and eosinophilia.

Recommended STOP RULES:

  • Drugs that cause symptomatic hepatitis: abdominal pain, jaundice, loss of appetite.
  • ALT values that exceed 8 times the ULN
  • ALT values >3 times the ULN and Bilirubin >2 times the ULN

Other caveats:

  • If the ALT value is >3 times the ULN but not associated with symptoms or rise in bilirubin, the drug can likely be continued with periodic monitoring.
  • ALT values >5 times the ULN require more intensive monitoring.
  • Hy’s law (named for Hyman Zimmerman): AST or ALT > 3 ULN AND   bili > 3 ULN indicate serious hepatotoxicity with >10% mortality rate.
  • Statins have similar rates of hepatotoxicity as the general population
  • Acetaminophen accounts for 40-50% of the 2000-2500 U.S. cases per year of acute liver failure (ALF).  Of the remaining cases of ALF, about 12% (250-300) are due to other cases of DILI.  Isoniazid is the 2nd most common cause of ALF due to DILI with about 50 cases.
  • Potential risk factors for DILI include alcohol usage, obesity, adult age group, and female gender.

Additional blog entries and references:

When death is on the line

Pediatric pharmaceutical poisoning

  • -J Pediatr 2011; 158: 802. Developing liver toxicity with valproic acid (VPA) is a contraindication to OLTx (even in the absence of documented mitochondrial dz). Rx with carnitine and d/c VPA. 82% of 17 children died w/in 1 yr of OLTx. POLG1 mutations are associated with Alpers syndrome. (Ann Neurol 2004; 55: 706.)
  • -NEJM 2009; 360: 1575. propylthiouracil assoc c liver failure in ~1 in 2000
  • -JPGN 2008; 47: 395-405. Drug-related hepatotoxicity and acute liver failure.
  • -NEJM 2003; 349: 474. (review)
  • PDF] What Do We Mean by Looking?  FDA powerpoint with related information

When death is on the line

“Never go against a Sicilian when death is on the line“! –from The Princess Bride

With acetaminophen-induced hepatic failure, King’s College Hospital (KCH) Criteria have been helpful for predicting death.  While the Sequential Organ Failure Assessment (SOFA) was not designed by a Sicilian (to the best of my knowledge), it is more sensitive at predicting death than KCH Criteria (Liver Transplantation 2012; 18: 405-412, & editorial 384-86) .

SOFA measures organ dysfunction by evaluating each of the following on a 0-4 scale: respiratory, hepatic, coagulation, cardiovascular, neurologic, and renal.

In the cited study, 125 consecutive adult patients (mean age 38 years) with acetaminophen-induced acute liver failure were evaluated.  KCH criteria had highest specificity (83%) and lowest sensitivity (47%).  The SOFA score had the best discriminative ability.  A SOFA score >7 during the first 96 hours predicted death or transplantation with a 95% sensitivity and 70.5% specificity.  Other specific predictors of poor outcome included higher lactate levels, worsened coagulation parameters, and need for mechanical ventilation.  In this cohort, 67 (54%) survived with medical management, 35 (28%) died and 23 (18%) received a liver transplant.

While sensitivity and specificity will vary based on pretest probability/specific population, what is clear is that relying on KCH criteria alone would be unwise.

Additional references:

  • -J Pediatr 2011; 159: 813.  Study of ALF in young infants.  38% were indeterminate, ~14% NH, 12% herpes.  n=148. 60% survived w/o OLT, 24% died, 16% OLT
  • -Hepatology 2010; 53: 567.  18% of indeterminate ALF may be due to acetaminophen toxicity.
  • The King’s College Criteria identify two groups of patients that have a poor prognosis with acetaminophen induced liver failure (http://en.wikipedia.org/wiki/King’s_College_Criteria)
  • -J Pediatr 2009; 155:801.  Diagnostic evaluation in ALF  –wide variation.  Often not tested for AIH, wilson’s, HAV, HBV
  • -NEJM 2009; 361: 2105.  Changes in FDA labeling of analgesics.  ~30,000 hospitalizations /yr due to acetaminophen overdose in U.S.  –1/2 inadvertent overdose.  Maximum dose -650mg.
  • -Hepatology 2007; 46: 966.  AASLD public policy.  It is leading cause of acute liver failure in U.S –50% of cases with 30% mortality rate.  500 deaths annually.  10% of cases may occur in those receiving the proper doses. In single year, acetaminophen causes more deaths than all the years of statins.
  • -JAMA 2006; 296: 87-93.  Prospective study of daily 4gm acetaminophen in healthy volunteers.  (stayed at research facility).  ALT >3 ULN in 38%.  Resolved over 6 days.
  • -Liver Transplantation 2006; 12: 682.
    -Hepatology 2005; 42: 1364-72.  74 pts died & 23 needed Tx during  6 yr period at 22 tertiary care centers.  48% of cases were unintentional overdoses.
  • -J Pediatr 2002; 140: 522.  Predictors of outcome p acetaminophen ingestion.

Pediatric pharmaceutical poisoning

Overdosing and taking a bad mix of medications is not just a problem in adults.  This remains a big problem in pediatrics (J Pediatr 2012; 160: 190-192, 265-70).  The study and accompanying editorial discuss the ongoing impact of pediatric pharmaceutical poisoning and what can be done to improve the situation.  This study involved 453,559 children (<5yrs) who had ingestion of a single product (55% prescription, 45% OTC).  Child self-exposure was responsible for 95%.  Between 2001-2008, these exposures led to 248,023 health care visits, 41,847 admissions, and 18,191 significant injuries.  This data likely underestimates the full extent as the data was collected ‘passively’ by the National Poison Data System (from the U.S. Poison Control Centers).

Although the number of ingestions has been increasing, the number of deaths declined marginally from 2001-2004 to 2005-2008, mainly due to a decline in pediatric acetaminophen deaths.  The authors conclude the problem is getting worse, not better.

What can be done to decrease this burden?

1. Packaging.  Since the poison prevention packaging act was passed in 1970, it has been recognized that the child-resistant closure (CRC) is not sufficient.  The main problem has been that once the vial is open, the entire contents of the vial are available for ingestion.

Options: insertion of needleless syringe for liquid medicines, requiring pressure to be applied to bottle to express medicine & blister packs (inside CRC container) for pills.

2. Targeting interventions for the highest risk medications.  Opioids, cardiovascular agents, and sedatives.

3. Healthy People 2020.  A collaborative approach to this problem is underway.

In our patient populations, we need to remember that the medications we prescribe may be inadvertently ingested by our patients (overdose) or by their siblings.  A word of precaution may save a life.

Additional references:

  • -Pediatrics 2011; 127: e1597-9. Preventing medication overdoses in young children.
  • -Ann Emerg Med 2009; 47: 348-54. Unrecognized toll of opioid abuse on young children.
  • -NEJM 2009; 361: 2105. Changes in FDA labeling of analgesics. ~30,000 hospitalizations  each year due to acetaminophen overdose in U.S. –1/2 inadvertent overdose.
  • -Hepatology 2007; 46: 966. AASLD public policy re: acetaminophen. It is leading cause of acute liver failure in U.S.  500 deaths annually. 10% of cases may occur in those receiving the proper doses.
  • -JAMA 2006; 296: 87-93. Prospective study of daily 4gm acetaminophen in healthy volunteers. (stayed at research facility). ALT >3 ULN in 38%. Resolved over 6 days.
  • http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId+27