AKSHAT JAIN

14 year old came in with the c/o Lethargy feeling “cold”/ “weak”, Chest pain and Vomiting

On questioning revealed that she had taken almost 40 to 70 , 500 mg tablets of tylenol at home after she failed the school

exam this afternoon.

Ingestion 3-4 hrs. PTA approx.

THE CASE

PE: VS Temp- 95.5F, B.P- 109/57,P-88,R-18.

Thin and pale and drowsy and dizzy female HEENT: Dry Mucosa , Sig Pallor , neck supple

Chest: CTA Cvs: Normal , S1,S2 , No murmur

Abd: soft, non tender Neuro: Drowsy but arousable, otherwise intact

EXAM

CBC – 7.17<11.5/36.3>295 , N-69 ,L-22.2BMP- 136/3.9/102/18 13/0.7 153/9.0

LFT- 17/16/80/0.45/0.15/7.9/4.1ACETAMINOPHEN LEVELS – P

SALICYLATES- <1.7PT-18.5 (9.5-11.4)PTT-31.2 (28-37)

INR- 1.76 (0.8-1.14)

LABS

ACETAMINOPHEN LEVELS

4-5 HRS – 239.6

CRITICAL LABS

ACETAMINOPHEN TOXICITY

119,785 acetaminophen exposures

One-half of these exposures were from ACM

46 percent of the exposures were intentional.

Thirty percent of the exposures occurred among children younger than six years

ACM was involved in 259 deaths

EPIDIMEOLOGICAL PEARLS

• When adult acetaminophen formulations are administered to children

• Through misreading (or unclear) instruction guidelines for liquid preparations

(e.g. substituting the infant drop formulation [100 mg/mL] for the less concentrated elixir or syrup [32 to 33 mg/mL])

• Through "intentional" overdose, when parents perceive that effective therapy has not been achieved

• Children who are at increased risk for hepatotoxicity with CYP2E1 enzyme-inducing drugs LIKE carbamazepine,

phenobarbital, rifampin, and INH

• Through mixing acetaminophen with other prescription or nonprescription preparations containing acetaminophen

POSSIBLITY OF INAPPROPARIATE DOSING

• The minimal toxic dose for a single ingestion is 150 mg/kg for a child or 7.5 to 10 g for an adult .

• Toxicity is likely to occur with single ingestions greater than 250 mg/kg or ingestions of greater than 12 g in a 24-hour period .

• Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity.

In chronic ingestions (eg, multiple supra-therapeutic doses), the minimum toxic threshold for children appears to be 150 to 175

mg/kg over two to four days.

WHAT’S THE TOXIC DOSE ? – OUR PT HAD TAKEN 750

MG/KG

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract.

Peak serum concentrations ½ -2 hours after a therapeutic oral dose

Within 4 hrs. following overdose of immediate-release preparation

>4hrs following overdose of Extended release prep.

Half Life 2-4hrs for all standard preparations.

APPLIED PHARMACOLOGY

METABOLISM AND ELIMINATION

TIMELINE

Ingestion of 200 mg/kg or 10 grams, whichever is LESS, acutely or over 24 hours

Ingestion of an unknown amount of ACM

Ingestion of ACM with intent for self harm

Known exposure to ACM with signs of toxicity (eg, vomiting, right upper quadrant pain, altered mental status)

Repeated supra-therapeutic ingestion ACM150 mg/kg or 6 grams, whichever is LESS, per 24 hour period over 48 hours .In children less than six years of age,100 mg/kg or more per 24 hour period

for the preceding 72 hours or longer

Children with conditions that predispose to ACM toxicity (eg, fasting, liver disease): 100 mg/kg or 4 grams, whichever is LESS, per day

WHEN TO REFER TO ED

Includes other causes of hepatic failure:

Viral hepatitis (hepatitis A, hepatitis B, hepatitis C, Epstein Barr virus, cytomegalovirus, varicella)

Inborn errors of metabolism (eg, Wilson's disease, alpha-1 antitrypsin deficiency, fatty acid oxidation abnormalities)

Drug- or toxin-induced hepatitis

Reye's syndrome

Ischemic hepatitis ("shock liver")

DIFFERENTIAL

Vatican Deemed Toddler's Near-Death Experience a MiracleBenedicta McCarthy, Now 25, Accidentally Ingested 19 Times

Lethal Dose of Acetaminophen and Survived

Hepatic injury can be prevented in nearly all patients treated with NAC within 8 hours of an acute ingestion, regardless of

the magnitude of the acetaminophen overdose.

Early treatment is important, as deaths are highly unlikely in patients treated prior to 16 hours following an acute

overdose.

Intravenous NAC may be of benefit when rendered as late as 36 to 80 hours in patients presenting with fulminant hepatic

failure, coagulapathy, and encephalopathy.

TIME-SENSITIVE TREATMENT ISSUES

 Following acute overdose, children younger than five years appear to be less susceptible to hepatotoxicity than older

children and adults .Because

-Increased metabolism via sulfation-Regeneration of Glutathione

-Increased propensity to vomit after ingestion

HEPATOTOXICITY

MANAGEMENT

MANAGEMENT OF CHRONIC TOXICITY

Loading dose: 150 mg/kg in 3 mL per kg of diluent given IV over 60 minutes.

Second dose: 50 mg/kg in 7 mL per kg of diluent given IV over 4 hours (12.5 mg/kg NAC per hour)

Third dose: 100 mg/kg in 14 mL per kg of diluent given IV over 16 hours (6.25 mg/kg NAC per hour)

Compatibility –IV NAC is compatible with 5 percent dextrose, 0.45 percent

normal saline

SPECIFICS OF NAC THERAPY

Serum AST or ALT, prothrombin (or INR), electrolytes, BUN, creatinine, arterial pH, and lactate should be repeated at the end of intravenous therapy

or every 24 hours during oral therapy.

Patients who have been treated with intravenous NAC will often have a slightly elevated INR (up to 1.3).

MONITORING

Adverse drug events associated with ORAL NAC include nausea and vomiting.

Adverse drug events associated with I.V. NAC include anaphylactoid reaction (e.g., nausea, flushing, vomiting, rash, urticaria, pruritus,

angioedema, dyspnea, wheezing, bronchospasm, tachycardia, and hypotension), anaphylaxis, and

death

TREATMENT ADVERSE EFFECTS

Patients presenting with or progressing to fulminant hepatic failure should be treated with continuous intravenous NAC

and receive a timely referral to a liver unit and assessment of candidacy for orthotopic liver transplantation

FULMINANT LIVER FAILURE

Arterial lactate concentration >3.5 mmol/L after fluid resuscitation OR

Arterial pH <7.3, and lactate >3.0 mmol/L after fluid resuscitation , OR

PT/INR >100 seconds/6.0 seconds AND encephalopathy grade 3 or more AND creatinine

>3.3 mg/dL (300 micromol/L) within 24 hours AND a normal arterial pH.

WHEN TO REFER FROM PICU TO LTC

Marked hepatocellular necrosis is present in a zonal, centrilobular pattern, while the inflammatory infiltrate is

minimal

HISTOPATH ACUTE LIVER INJURY

THE REALITY OF PRESENT TIMES

Mortality rate from ACM overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually

decreases.

Acidemia is the most important single indicator of probable mortality and the need for transplantation.

One study has shown that a factor V level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor VIII

to factor V of less than 30 indicated a good prognosis (100% survival).

Patients adequately managed are expected to fully recover and have a normal life expectancy and quality of life.

Of the patients who progress past clinical stage III, 99% have clinical resolution.

PROGNOSIS

ACETAMINOPHEN LEVELS

4-5 HRS – 239.610 HRS – 110 (BELLVUE)22 HRS - <10 (BELLVUE)

2 DAYS PICU , 2 DAYS PEDS FLOOR , 5 DAYS PSYCHE FLOOR

DISCHARGED HOME YESTERDAY .

NO HEPATOTOXICITY … YAAY !!

FOLLOW UP

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Rivera-Penera, T, Gugig, R, Davis, J, et al. Outcome of acetaminophen overdose in pediatric patients and factors contributing to hepatotoxicity. J Pediatr 1997; 130:300.

Heubi, JE, Barbacci, MB, Zimmerman, HJ. Therapeutic misadventures with acetaminophen: hepatoxicity after multiple doses in children. J Pediatr 1998; 132:22.

Benson, GD. Hepatotoxicity following the therapeutic use of antipyretic analgesics. Am J Med 1983; 75:85.

Watson, WA, Litovitz, TL, Rodgers GC, Jr, et al. 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003; 21:353.

Alander, SW, Dowd, MD, Bratton, SL, Kearns, GL. Pediatric acetaminophen overdose: risk factors associated with hepatocellular injury. Arch Pediatr Adolesc Med 2000; 154:346.

Myers, WC, Otto, TA, Harris, E, et al. Acetaminophen overdose as a suicidal gesture: a survey of adolescents' knowledge of its potential for toxicity. J Am Acad Child Adolesc Psychiatry 1992; 31:686.

Hickson, GB, Altemeier, WA, Martin, ED, Campbell, PW. Parental administration of chemical agents: a cause of apparent life-threatening events. Pediatrics 1989; 83:772.

Hickson, GB, Greene, JW, Ghishan, FK, Craft, LT. Apparent intentional poisoning of an infant with acetaminophen. Am J Dis Child 1983; 137:917.

Gee, P, Ardagh, M. Paediatric exploratory ingestions of paracetamol. N Z Med J 1998; 111:186.

American Academy of Pediatrics. Committee on Drugs.. Acetaminophen toxicity in children. Pediatrics 2001; 108:1020.

Kearns, GL, Leeder, JS, Wasserman, GS. Acetaminophen intoxication during treatment: what you don't know can hurt you. Clin Pediatr (Phila) 2000; 39:133.

Blake, KV, Bailey, D, Zientek, GM, Hendeles, L. Death of a child associated with multiple overdoses of acetaminophen. Clin Pharm 1988; 7:391.

Smith, DW, Isakson, G, Frankel, LR, Kerner JA, Jr. Hepatic failure following ingestion of multiple doses of acetaminophen in a young child. J Pediatr Gastroenterol Nutr 1986; 5:822.

Nadir, A, McFadden, R, Griggs, J, et al. Parental and medical over-administration of acetaminophen causing lethal hepatotoxicity in a 10-year-old. J Okla State Med Assoc 1994; 87:261.

REFERENCES

EMINEM