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History

14-year-old Thai girl CC : Ingested more than 20 tablets of paracetamol 3 hr ago PI : 3 hr PTA, patient took approximately 20 tablets of paracetamol after she argued with her boyfriend. 30 min PTA, She developed nausea and vomiting with clear fluid, then her mother took her to Siriraj hospital. 30 min PTA, She developed nausea and vomiting with clear fluid, then her mother took her to Siriraj hospital.

PH : No underlying disease History of suicidal attempt by softly cut her wrist few months ago History of suicidal attempt by softly cut her wrist few months ago Personal history : No smoking, no alcoholic drinking, no drug addiction, cheerful, sensitive, tantrum Drug history : no other drugs used, no history of drug allergy Family history :  Father is a noodle vendor, alcohol drinker and smoker.  Mother is a healthy seamstress, does not smoke and drink.  12 years old healthy brother Development : normal development, fair school performance (GPA 2.9)

Physical examination

V/S : T 36.4, P 100/min, RR 24/min, BP 120/80 mmHg, Ht 158 cm (P50-75), Wt 58 Kg (>P97) GA : 14 years old Thai girl on NG tube, good consciousness, no pallor, no jaundice, no dyspnea, no dry lips, capillary refill < 2 sec, no diaphoresis HEENT: no icteric sclera

RS : normal breath sounds, no adventitious sounds CVS : normal S1,S2, no murmur Abd : soft, no tenderness, liver not palpable & not tender, liver span 9 cm, normal bowel sound

GU: no CVA tenderness NS: E4V5M6, good consciousness Pupils 4 mm BRTL on both sides CN – grossly intact Motor – normal tone, motor power grade 5/5 all extremities Sensory – no impairment DTR 2+ all

Problem lists 1. Overdose paracetamol ingestion (180 mg/kg) 3 hr prior to presentation 2. Nausea and vomiting for 30 min 3.Probable suicidal attempt

Diagnosis Acute paracetamol overdose

Investigation

Management

Paracetamol Poisoning Acute paracetamol overdose Ingestion of 7.5 grams (150 mg/kg) or more of paracetamol within 4 hours in one dose Chronic paracetamol overdose Ingestion of 4 grams or more of paracetamol per 24 hours

Pharmacokinetic  Therapeutic dose is 10 to 15 mg/kg/dose in children given every 4-6 hours  Maximum recommended dose is 80 mg/kg/day in children  Acetaminophen is rapidly and completely absorbed from GI tract  Toxicity is likely occur with single ingestion greater than mg/kg in children Michael J Burns,Scott L Firedman,Anne M Larson. Pathophysiology and Diagnosis of acetaminophen(Paracetamol) intoxication : Uptodate ver14.2

Pharmacokinetic  Therapeutic serum concentrations range from mcg/ml  Serum concentration peak between ½ to 1 hour after an oral therapeutic dose and 4 hours following overdose ingestion  Elimination half-life range from 2-4 hours but greater in patient with hepatotoxicity Michael J Burns,Scott L Firedman,Anne M Larson. Pathophysiology and Diagnosis of acetaminophen(Paracetamol) intoxication : Uptodate ver14.2

Metabolism  90% of acetaminophen is metabolized in liver to sulfate and glucuronide conjugates which are excreted in urine  5% of acetaminophen is excreted unchanged in urine

 In children, sulfation is the primary pathway until the age of years, whereas glucuronidation predominates in adolescents and adults  Hepatotoxicity is the result of formation of the reactive and toxic metabolite NAPQI by the cytochrome P450 (CYP) system Metabolism

Metabolism  NAPQI covalently binds covalently with hepatocytes molecule, causing oxidative injury and hepatocellular centrilobular necrosis and the release of cytokines from damaged hepatocytes may initiate a secondary inflammatory response, extended the zone of hepatic injury  Glutathione can bind NAPQI and lead to excretion of nontoxic cysteine and mercaptate compound

Metabolism

Modified from: Mitchell JR, Thorgeirsson SS, Potter WZ, et al: Acetaminophen-induced hepatic injury: Protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974; 16:678–684.

High risk for hepatotoxicity  Acute febrile illness  Pre-existing liver diseases  Excessive cytochrome P450 activity due to induction by other drug use (such as ethanol, isoniazid (INH), rifampin, phenytoin, phenobarbital, barbiturates, and carbamazepine)  Decreased capacity for glucuronidation or sulfation  Depletion of glutathione stores due to malnutrition (or chronic alcohol ingestion) Ford:Clinical Toxicology, 1st ed ; Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1st ed ; 29

Clinical presentation  Phase 1: hours Anorexia, nausea, vomiting, malaise, pallor, diaphoresis  Phase 2: hours ‘Onset of Toxicity’ Less pronounce phase 1 manifestations, RUQ pain, elevation of liver enzymes, bilirubin, INR

 Phase 3: hours ‘Time of Maximal Toxicity’ Sequelae of hepatic necrosis. Hepatic failure, coagulopathy, hepatic encephalopathy, Renal failure Sequelae of hepatic necrosis. Hepatic failure, coagulopathy, hepatic encephalopathy, Renal failure  Phase 4: 96 hours - 2 weeks If the damage reversible, complete resolution, Death may occur in patients with fulminant hepatic failure or multiorgan failure, If the damage reversible, complete resolution, Modified from Linden CH, Rumack BH: Acetaminophen overdose. Emerg Med Clin North Am 1984; 2:103.

Management

 Primary survey Airway Airway Breathing Breathing Circulation Circulation  Admit  Consult Pediatric toxicologist and psychiatrist ER Management

 Activated charcoal (AC) Useful to remove unabsorbed drug up to 4 hour after the ingestion Useful to remove unabsorbed drug up to 4 hour after the ingestion 1 g/Kg p.o. or feed via NG tube 1 g/Kg p.o. or feed via NG tube Not useful in paracetamol syrup ingestion (absorb in 30 min) Not useful in paracetamol syrup ingestion (absorb in 30 min)  Antidote = NAC (N-Acetylcysteine) Specific Management Ford:Clinical Toxicology, 1st ed ; Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1st ed ; 29

Antidote = N-Acetylcysteine (NAC)

Mechanism of NAC   NAC increases the synthesis and availability of glutathione. (NAC is converted to cysteine, which is then converted to glutathione within hepatocytes)   NAC increases the fraction of the initial sulfation product of acetaminophen and reducing the amount of NAPQI Ford:Clinical Toxicology, 1st ed ; Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1st ed ; 29

  In patients with hepatic failure, NAC decreases the development of cerebral edema, prevents the progression of hepatic encephalopathy, and improves survival rate. NAC Ford:Clinical Toxicology, 1st ed ; Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1st ed ; 29

NAC Mechanism of NAC

 If the time of ingestion is known, take serum paracetamol level at 4 hr after ingestion, start NAC within 8 hr after ingestion when concentration is above the lower line of Rumack-Matthew nomogram  If the time of ingestion is uncertain. The most conservative(earliest) estimate of the time of ingestion should be used to determine the likelihood of toxicity. Empirical treatment of NAC is safe and reasonable NAC

NAC   The first doses should be administered empirically when diagnostic acetaminophen levels cannot be obtained within this 8-hour window.   NAC therapy can be discontinued if the awaited serum acetaminophen level falls below the nomogram treatment line.

 Oral: 1 st choice 1 st choice Low risk of anaphylactoid Low risk of anaphylactoid S.E. = Vomiting (any dose vomited in 1 h of administration should be repeated) S.E. = Vomiting (any dose vomited in 1 h of administration should be repeated)  Intravenous: Useful in intractable vomiting despite NG tube instillation & adequate antiemetics therapy Useful in intractable vomiting despite NG tube instillation & adequate antiemetics therapy Can use in Pregnancy, hepatic failure Can use in Pregnancy, hepatic failure Use only under consultation Use only under consultation S.E. = Urticaria, Anaphylactoid reaction S.E. = Urticaria, Anaphylactoid reaction (rarely death) NAC therapy : PO vs IV

RouteLoading dose dose Maintenance dose CourseFDA appro val Oral 140 mg/kg 70 mg/kg every 4 h 17 doses 72 h Yes Intra-venous 150 mg/kg over 15 min 50 mg/kg over 4 h followed by 100mg/kg over 16 h 20 h Yes Dose of NAC  Rakel, Conn's Current Therapy 2006, 58th ed.,2006 Saunders, An Imprint of Elsevier

Monitor  Clinical sign & Symptom RUQ pain, Jaundice, Conscious, Urine output, Abnormal bleeding  Paracetamol Level : at 24 hr after ingestion ingestion  Liver function test : SGOT daily  Coagulogram : PT, INR daily Behrman, Kliegman, Jenson, Acetaminophen Poisoning : Nelson 17ed.,704 : 2366

When to stop NAC   Acetaminophen level is nondetectable and the absence of evidence of liver injury at 24 hours is documented   Patients with evidence of liver injury are treated for the full 72-hour course. Ford:Clinical Toxicology, 1st ed ; Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1st ed ; 29

Prolonged course of NAC therapy  If the AST > 1,000 u/L or INR > 2 or hepatic encephalopathy develops, intravenous NAC should be given.  Endpoint: AST < 1,000 and AST < 1,000 and INR < 2 and INR < 2 and Hepatic encephalopathy resolve Hepatic encephalopathy resolve

Treatment (in this patient) - Primary survey was done - Activated charcoal 56 mg at ER - NPO and retain NG tube - NAC (150 mg/kg) 6,300 mg + 5%D/W 200 ml IV drip in 1 hr then NAC (50 mg/kg) 2,100 mg + 5%D/W 200 ml IV drip in 4 hr then NAC (50 mg/kg) 2,100 mg + 5%D/W 200 ml IV drip in 4 hr then NAC (100 mg/kg) 4,200 mg + 5%D/W 200 ml IV drip in 16 hr then NAC (100 mg/kg) 4,200 mg + 5%D/W 200 ml IV drip in 16 hr - Consult pediatric psychiatry

Progression Day 1  no N/V, no abdominal pain, no malaise, no jaundice No depressive symptoms  V/S BP 120/80 mmHg, P 80/min  Abd : soft, not tender, no hepatospenomegaly, active bowel sound  Paracetmol level at 24 hr after ingestion = 1.9  LFT : normal  I/O = 1492 cc / 810 cc(0.6 cc/kg/hr)  Urine pregnancy test = negative

Day 2  active,no N/V, no jaundice,no abnormal bleeding  V/S : stable, no RUQ pain,  no hepatosplenomegaly  LFT : normal  I/O = 2950 cc / 2280 cc( 1.6 cc/kg/hr)

Day 3  Alert, good consciousness, no jaundice, no abnormal bleeding  I/O = 2500 cc / 2300 cc(1.6 cc/kg/hr)  Plan D/C

Psychiatric assessment  Dx : Anxiety disorder, NOS Depression, NOS Depression, NOS  HM : fluoxetine (20 mg) sig ½ tab oral OD 1 week then 1 tab OD 1 wk

Psychiatric management indications in admitting patient indications in admitting patient the patient insist to repeat to commit suicide the patient insist to repeat to commit suicide patient who is aggressive, incooperative, fluctuation in mood,drunk or a drugs addict patient who is aggressive, incooperative, fluctuation in mood,drunk or a drugs addict underlying psychiatrics problem underlying psychiatrics problem reside with unsafe family reside with unsafe family indications in discharging patient indications in discharging patient calm and able to control his moodcalm and able to control his mood admit to commit suicidal attempt and agree to seek help should the suicidal urge arisesadmit to commit suicidal attempt and agree to seek help should the suicidal urge arises educate parents how to how to safe keep drugs and fetal weaponseducate parents how to how to safe keep drugs and fetal weapons familial understanding and psychological supportfamilial understanding and psychological support follow up and consults pediatric psychiatristfollow up and consults pediatric psychiatrist

Reference  Ford:Clinical Toxicology, 1 st ed ;  Anker Anthony, Acetaminophen : Ford:Clinical Toxicology, 1 st ed ; 29  Rakel, Conn's Current Therapy 2006, 58th ed.,2006 Saunders, An Imprint of Elsevier   Behrman, Kliegman, Jenson, Acetaminophen Poisoning : Nelson 17ed.,704 : 2366   Michael J Burns,Scott L Firedman,Anne M Larson. Pathophysiology and Diagnosis of acetaminophen(Paracetamol) intoxication : Uptodate ver14.2

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