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HistoryHistory

14-14-yearyear-- old Thai girl old Thai girl

CC CC : Ingested more than 20 tablets of : Ingested more than 20 tablets of paracetamol 3 hr agoparacetamol 3 hr ago

PI PI : 3 hr PTA, patient took : 3 hr PTA, patient took approximately 20 tablets of paracetamol approximately 20 tablets of paracetamol after she argued with her boyfriend.after she argued with her boyfriend.

30 min PTA, She developed nausea 30 min PTA, She developed nausea and vomiting with clear fluid, then her and vomiting with clear fluid, then her mother took her to Siriraj hospital.mother took her to Siriraj hospital.

PH PH : No underlying disease: No underlying disease

History of suicidal attempt by softly cut her wrist few months agoHistory of suicidal attempt by softly cut her wrist few months ago

Personal historyPersonal history : No smoking, no alcoholic drinking, no drug : No smoking, no alcoholic drinking, no drug addiction, cheerful, sensitive, tantrumaddiction, cheerful, sensitive, tantrum

Drug historyDrug history : no other drugs used, no history of drug allergy: no other drugs used, no history of drug allergy

Family historyFamily history : : Father is a noodle vendor, alcohol drinker and smoker. Father is a noodle vendor, alcohol drinker and smoker. Mother is a healthy seamstress, does not smoke and drink. Mother is a healthy seamstress, does not smoke and drink. 12 years old healthy brother12 years old healthy brother

DevelopmentDevelopment : normal development, fair school performance (GPA : normal development, fair school performance (GPA 2.9)2.9)

Physical Physical examinationexamination

V/S V/S : T 36.4, P 100/min, RR 24/min, BP : T 36.4, P 100/min, RR 24/min, BP 120/80 120/80 mmHg, Ht 158 cm (P50-75), Wt 58 mmHg, Ht 158 cm (P50-75), Wt 58 Kg (>P97)Kg (>P97)

GA GA : 14 years old Thai girl on NG tube, good : 14 years old Thai girl on NG tube, good consciousness, no pallor, no jaundice, no consciousness, no pallor, no jaundice, no dyspnea, no dry lips, capillary refill < 2 dyspnea, no dry lips, capillary refill < 2

sec, sec, no diaphoresisno diaphoresis

HEENTHEENT : no icteric sclera: no icteric sclera

RSRS : normal breath sounds, no : normal breath sounds, no adventitious adventitious soundssounds

CVSCVS : normal S1,S2, no murmur: normal S1,S2, no murmur

AbdAbd : soft, no tenderness, liver not : soft, no tenderness, liver not palpable & palpable & not tender, liver span 9 not tender, liver span 9 cm, normal bowel cm, normal bowel sound sound

GUGU : no CVA tenderness: no CVA tenderness

NSNS : E4V5M6, good consciousness: E4V5M6, good consciousnessPupils 4 mm BRTL on both sidesPupils 4 mm BRTL on both sidesCN – grossly intactCN – grossly intactMotor – normal tone, motor power Motor – normal tone, motor power

grade grade 5/5 all extremities 5/5 all extremitiesSensory – no impairmentSensory – no impairmentDTR 2+ allDTR 2+ all

Problem listsProblem lists

1.1. Overdose paracetamol ingestion Overdose paracetamol ingestion

(180 mg/kg) (180 mg/kg) 3 hr prior to presentation3 hr prior to presentation

2. 2. Nausea and vomiting for 30 minNausea and vomiting for 30 min

3.3. Probable suicidal attemptProbable suicidal attempt

DiagnosisDiagnosis

Acute paracetamol overdoseAcute paracetamol overdose

InvestigationInvestigation

3.7 3.8

ManagementManagement

Paracetamol Paracetamol PoisoningPoisoning

Acute paracetamol overdoseAcute paracetamol overdose

Ingestion of 7.5 grams (150 Ingestion of 7.5 grams (150 mg/kg) or more of paracetamol mg/kg) or more of paracetamol within 4 hours in one dosewithin 4 hours in one dose

Chronic paracetamol overdoseChronic paracetamol overdose

Ingestion of 4 grams or Ingestion of 4 grams or more of paracetamol per 24 hoursmore of paracetamol per 24 hours

PharmacokineticPharmacokinetic Therapeutic dose is 10 to 15 Therapeutic dose is 10 to 15 mg/kg/dose in children given every 4-6 mg/kg/dose in children given every 4-6 hourshoursMaximum recommended dose is 80 Maximum recommended dose is 80 mg/kg/day in children mg/kg/day in children Acetaminophen is rapidly and Acetaminophen is rapidly and completely absorbed from GI tractcompletely absorbed from GI tractToxicity is likely occur with single Toxicity is likely occur with single ingestion greater than 150-200 mg/kg ingestion greater than 150-200 mg/kg in childrenin children Michael J Burns,Scott L Firedman,Anne M Larson. Pathophysiology and Diagnosis of

acetaminophen(Paracetamol) intoxication : Uptodate ver14.2

PharmacokineticPharmacokineticTherapeutic serum concentrationsTherapeutic serum concentrations range from 10-20 mcg/mlrange from 10-20 mcg/mlSerum concentration peak between ½ Serum concentration peak between ½ to 1 hour after an oral therapeutic dose to 1 hour after an oral therapeutic dose and 4 hours following overdose and 4 hours following overdose ingestioningestionElimination half-life range from 2-4 Elimination half-life range from 2-4 hours but greater in patient with hours but greater in patient with hepatotoxicityhepatotoxicity Michael J Burns,Scott L Firedman,Anne M Larson. Pathophysiology and Diagnosis of

acetaminophen(Paracetamol) intoxication : Uptodate ver14.2

MetabolismMetabolism

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

High risk for hepatotoxicityHigh risk for hepatotoxicityAcute febrile illnessAcute febrile illnessPre-existing liver diseasesPre-existing liver diseasesExcessive cytochrome P450 activity due Excessive cytochrome P450 activity due to induction by other drug use (such as to induction by other drug use (such as ethanol, isoniazid ethanol, isoniazid ((INHINH)), rifampin, , rifampin, phenytoin, phenobarbital, barbiturates, phenytoin, phenobarbital, barbiturates, and carbamazepine)and carbamazepine)Decreased capacity for glucuronidation or Decreased capacity for glucuronidation or sulfationsulfationDepletion of glutathione stores due to Depletion of glutathione stores due to malnutritionmalnutrition (or chronic alcohol ingestion)(or chronic alcohol ingestion)

Anker Anthony , Acetaminophen : Ford:Clinical Toxicology, 1st ed. 2001 ; Ford:Clinical Toxicology, 1st ed. 2001 ; 29

Clinical Clinical presentationpresentation

1Phase 1Phase - 0524: . - 0524: . hourshours

Anorexia, nausea, vomiting, malaise, pallor,diaphoresis

2Phase 2Phase - 2448: - 2448: hours hours

‘‘ Onset of Toxicity Onset of Toxicity’’

Less pronounce phase 1 manifestations, RUQ Less pronounce phase 1 manifestations, RUQ pain, elevation of liver enzymes, bilirubin, IN pain, elevation of liver enzymes, bilirubin, IN

RR

3Phase 3Phase - 7296: - 7296: hourshours ‘‘ Time of Maximal Toxicity Time of Maximal Toxicity’’

Sequelae of hepatic necrosis Sequelae of hepatic necrosis. Hepatic . Hepatic failure,failure, coagulopathy, hepatic encephalopa coagulopathy, hepatic encephalopathythy, , Renal failure Renal failure

4Phase 4Phase 96 96 - hours 2 weeks - hours 2 weeksD eath may occur in patients with

fulminant hepatic failure or multiorgan failure, If the damage reversible, complete If the damage reversible, complete

resolution resolution , ,

Modified from Linden CH, Rumack BH: Acetaminophen overdose. Emerg Med Clin NorthAm 1984; 2:103.

ManagementManagement

Primary surveyPrimary survey Airway Airway BreathingBreathing CirculationCirculation

AdmitAdmit Consult Pediatric toxicologist and Consult Pediatric toxicologist and

psychiatristpsychiatrist

ER ManagementER Management

Activated charcoal (AC)Activated charcoal (AC) Useful to remove unabsorbed drug Useful to remove unabsorbed drug

up to 4 hour after the ingestionup to 4 hour after the ingestion 1 g/Kg p.o. or feed via NG tube1 g/Kg p.o. or feed via NG tube Not useful in paracetamol syrup Not useful in paracetamol syrup

ingestion (absorb in 30 min)ingestion (absorb in 30 min) Antidote = NAC (Antidote = NAC (N-AcetylcysteineN-Acetylcysteine))

Specific Specific ManagementManagement

Anker Anthony , Acetaminophen : Ford:Clinical Toxicology, 1st ed. 2001 ; Ford:Clinical Toxicology, 1st ed. 2001 ; 29

Antidote = N-AcetylcysteineAntidote = N-Acetylcysteine

(NAC)(NAC)

Mechanism of NACMechanism of NAC NAC increases the synthesis and availabili

ty 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

Anker Anthony , Acetaminophen : Ford:Clinical Toxicology, 1st ed. 2001 ; Ford:Clinical Toxicology, 1st ed. 2001 ; 29

In patients with hepatic failure,

NAC decreases the development of cerebral edema, prevents the progression of hepatic encephalopathy, and improves survival rate.

NACNAC

Anker Anthony , Acetaminophen : Ford:Clinical Toxicology, 1st ed. 2001 ; Ford:Clinical Toxicology, 1st ed. 2001 ; 29

NAC

Mechanism of NACMechanism of NAC

If the time of ingestion is known, If the time of ingestion is known, take serum take serum paracetamol level at 4 hrparacetamol level at 4 hr after ingestion, after ingestion, start NAC within 8 hrstart NAC within 8 hr after ingestion when after ingestion when concentration is above the lower line of concentration is above the lower line of Rumack-Matthew nomogramRumack-Matthew nomogram

If the time of ingestion is uncertain. If the time of ingestion is uncertain. The most The most conservative(earliest) estimate of the time of conservative(earliest) estimate of the time of ingestion should be used to determine the ingestion should be used to determine the likelihood of toxicity. Elikelihood of toxicity. Empirical treatment of mpirical treatment of NAC is NAC is safe and reasonablesafe and reasonable

NACNAC

NACNAC 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 awa ited serum acetaminophen level falls below

the nomogram treatment line.

Oral:Oral: 11stst choice choice Low risk of anaphylactoidLow risk of anaphylactoid S.E. = Vomiting (any dose vomited in 1 S.E. = Vomiting (any dose vomited in 1

h of administration should be repeated)h of administration should be repeated)

Intravenous: Intravenous: Useful in intractable vomiting despite Useful in intractable vomiting despite

NG tube instillation & adequate NG tube instillation & adequate antiemetics therapyantiemetics therapy

Can use in Pregnancy, hepatic failure Can use in Pregnancy, hepatic failure Use only under consultationUse only under consultation S.E. = Urticaria, Anaphylactoid reactionS.E. = Urticaria, Anaphylactoid reaction(rarely death)(rarely death)

NAC therapy : PO vs IVNAC therapy : PO vs IV

RouteRoute LoadingLoading dosedose Maintenance doseMaintenance dose CourseCourse

FDAFDAapproappro

valval

OralOral 140 140 mg/kgmg/kg

70 mg/kg every 4 h 70 mg/kg every 4 h 17 doses17 doses 72 h72 h YesYes

Intra-Intra-venouvenou

ss

150 150 mg/kg mg/kg over over

15 min15 min

50 mg/kg over 4 h 50 mg/kg over 4 h followed by followed by

100mg/kg 100mg/kg over 16 hover 16 h

20 h20 h YesYes

Dose of NAC

Rakel , Conn's Current Therapy 2006, 58th ed. ,2006 Saunders, An Imprint of ElsevierRakel , Conn's Current Therapy 2006, 58th ed. ,2006 Saunders, An Imprint of Elsevier

MonitorMonitor Clinical sign & SymptomClinical sign & Symptom

RUQ pain, Jaundice, Conscious, Urine RUQ pain, Jaundice, Conscious, Urine output, output, Abnormal bleedingAbnormal bleeding

Paracetamol Level Paracetamol Level : at 24 hr after : at 24 hr after

ingestioningestion Liver function testLiver function test : SGOT daily: SGOT daily CoagulogramCoagulogram : PT, INR daily: PT, INR daily

Behrman, Kliegman, Jenson , Acetaminophen Poisoning : Nelson 17ed. ,704 : 2366

When to stop NACWhen 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.

Anker Anthony , Acetaminophen : Ford:Clinical Toxicology, 1st ed. 2001 ; Ford:Clinical Toxicology, 1st ed. 2001 ; 29

Treatment Treatment (in this patient)(in this patient) - Primary survey was done- Primary survey was done

- Activated charcoal 56 mg at ER- Activated charcoal 56 mg at ER

- NPO and retain NG tube- NPO and retain NG tube

- NAC (150 mg/kg) 6,300 mg + 5%D/W 200 - NAC (150 mg/kg) 6,300 mg + 5%D/W 200 ml IV drip in 1 hrml IV drip in 1 hr

then NAC (50 mg/kg) 2,100 mg + 5%D/W then NAC (50 mg/kg) 2,100 mg + 5%D/W 200 ml IV drip in 4 hr200 ml IV drip in 4 hr

then NAC (100 mg/kg) 4,200 mg + 5%D/W then NAC (100 mg/kg) 4,200 mg + 5%D/W 200 ml IV drip in 16 hr200 ml IV drip in 16 hr

- Consult pediatric psychiatry- Consult pediatric psychiatry

ProgressionProgressionDay 1Day 1 no N/V, no abdominal pain, no malaise, no no N/V, no abdominal pain, no malaise, no

jaundicejaundice

No depressive symptoms No depressive symptoms V/S BP 120/80 mmHg, P 80/minV/S BP 120/80 mmHg, P 80/min Abd : soft, not tender, no hepatospenomegaly, Abd : soft, not tender, no hepatospenomegaly,

active bowel sound active bowel sound Paracetmol level at 24 hr after ingestion = 1.9 Paracetmol level at 24 hr after ingestion = 1.9 LFT : normalLFT : normal I/O = 1492 cc / 810 cc(0.6 cc/kg/hr)I/O = 1492 cc / 810 cc(0.6 cc/kg/hr) Urine pregnancy test = negativeUrine pregnancy test = negative

Day 2Day 2 active ,no N/V , no jaundice ,no abnormal active ,no N/V , no jaundice ,no abnormal

bleedingbleeding V/S : stable , no RUQ pain, V/S : stable , no RUQ pain, no hepatosplenomegalyno hepatosplenomegaly LFT : normalLFT : normal I/O = 2950 cc / 2280 cc( 1.6 cc/kg/hr)I/O = 2950 cc / 2280 cc( 1.6 cc/kg/hr)

Day 3Day 3 Alert, good consciousness, no Alert, good consciousness, no

jaundice ,jaundice ,

no abnormal bleedingno abnormal bleeding I/O = 2500 cc / 2300 cc(1.6 cc/kg/hr)I/O = 2500 cc / 2300 cc(1.6 cc/kg/hr) Plan D/C Plan D/C

Psychiatric Psychiatric assessmentassessment

Dx : Anxiety disorder, NOSDx : Anxiety disorder, NOS

Depression, NOSDepression, NOS HM : fluoxetine (20 mg) sig ½ tab HM : fluoxetine (20 mg) sig ½ tab

oral OD 1 week then 1 tab OD 1 wkoral OD 1 week then 1 tab OD 1 wk

ReferenceReference

Anker Anthony , Acetaminophen : Ford:Clinical Ford:Clinical Toxicology, 1Toxicology, 1stst ed. 2001 ; ed. 2001 ; 29

Rakel , Rakel , Conn's Current Therapy 2006, 58th Conn's Current Therapy 2006, 58th eded. ,2006 Saunders, An Imprint of Elsevier . ,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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