Aspirin & Paracetamol Aspirin & Paracetamol (Acetaminophen) Poisoning(Acetaminophen) Poisoning

Aspirin & Paracetamol Aspirin & Paracetamol (Acetaminophen) Poisoning(Acetaminophen) Poisoning

Kent R. Olson, M.D.Kent R. Olson, M.D.

California Poison Control SystemCalifornia Poison Control System

University of California, San FranciscoUniversity of California, San Francisco

Case Study:Case Study:Case Study:Case Study:

A 76 year old woman was brought by her A 76 year old woman was brought by her family because of increasing confusion and family because of increasing confusion and agitation, and difficulty breathing.agitation, and difficulty breathing.

Exam: restless, irritable elderly woman.Exam: restless, irritable elderly woman.Temp: 38.2 CTemp: 38.2 C Resp: 26Resp: 26HR: 102HR: 102 BP: 110/76 BP: 110/76

Laboratory:Laboratory:Na: 144Na: 144 K: 3.2K: 3.2Cl: 110Cl: 110 HCO3: 16HCO3: 16BUN: 10 mmolBUN: 10 mmol glucose: 5 mmol/Lglucose: 5 mmol/L

Arterial blood gases:Arterial blood gases:pH: 7.48pH: 7.48 pCO2: 14pCO2: 14 pO2: 98pO2: 98

Salicylate:Salicylate:68 mg/dL (5 mmol/L)68 mg/dL (5 mmol/L)

Case, continued:Case, continued:Case, continued:Case, continued:

Anion gap:Anion gap:18 mmol/L18 mmol/L

Anion gap:Anion gap:18 mmol/L18 mmol/L

Acute vs. Chronic Salicylism:Acute vs. Chronic Salicylism:Acute vs. Chronic Salicylism:Acute vs. Chronic Salicylism:

Acute Overdose:Acute Overdose:

– younger ageyounger age– child: accidentalchild: accidental– adult: suicidaladult: suicidal– no underlying illnessno underlying illness– ASA levels highASA levels high– mortality rate lowermortality rate lower

Chronic Intoxication:Chronic Intoxication:

– older ageolder age– accidental accidental

overmedicationovermedication– underlying diseaseunderlying disease– serum ASA variableserum ASA variable– mortality >25%mortality >25%

Mechanisms of Salicylate Toxicity:Mechanisms of Salicylate Toxicity:Mechanisms of Salicylate Toxicity:Mechanisms of Salicylate Toxicity:

Respiratory center stimulation:Respiratory center stimulation:– tachypnea, respiratory alkalosistachypnea, respiratory alkalosis– compensatory loss of bicarbonate in urinecompensatory loss of bicarbonate in urine

Uncoupling of oxidative phosphorylation:Uncoupling of oxidative phosphorylation:– generation of excess heat generation of excess heat – lactic acidosislactic acidosis

Cellular metabolic dysfunctionCellular metabolic dysfunction– metabolic acidosismetabolic acidosis

Clinical Findings in Salicylism:Clinical Findings in Salicylism:Clinical Findings in Salicylism:Clinical Findings in Salicylism:

MILD to MODERATEMILD to MODERATE

– tinnitus, nausea, vomitingtinnitus, nausea, vomiting– tachypnea with tachypnea with

respiratory alkalosisrespiratory alkalosis– metabolic acidosismetabolic acidosis– irritability, lethargyirritability, lethargy– low-grade feverlow-grade fever– dehydrationdehydration

SEVERE POISONINGSEVERE POISONING

– hyperpnea - resp. hyperpnea - resp. distressdistress

– hyperpyrexiahyperpyrexia– severe acidosissevere acidosis– coagulopathy (PT elev.)coagulopathy (PT elev.)– coma, convulsionscoma, convulsions– pulmonary edema/ARDSpulmonary edema/ARDS– cardiovascular collapsecardiovascular collapse

Estimation of Severity of Salicylism:Estimation of Severity of Salicylism:Estimation of Severity of Salicylism:Estimation of Severity of Salicylism:

History:History:– acute ingestion of > 200 mg/kgacute ingestion of > 200 mg/kg– chronic use of > 4 gm/daychronic use of > 4 gm/day

Clinical indicators:Clinical indicators:– mental statusmental status– metabolic acidosis & respiratory alkalosismetabolic acidosis & respiratory alkalosis

Serum salicylate levelSerum salicylate level

Salicylate Levels:Salicylate Levels:Salicylate Levels:Salicylate Levels:

May help predict severity after single acute ODMay help predict severity after single acute OD– 6 hr serum level > 100 mg/dL (7 mmoL) serious6 hr serum level > 100 mg/dL (7 mmoL) serious

Pitfalls in use of “Done” Nomogram:Pitfalls in use of “Done” Nomogram:– massive ingestion: tablet mass & delayed peakmassive ingestion: tablet mass & delayed peak– chronic intoxication chronic intoxication – altered serum pH may contribute to toxicityaltered serum pH may contribute to toxicity

Salicylate is a Weak Acid (Salicylate is a Weak Acid (pKpKaa 3.5 3.5):):Salicylate is a Weak Acid (Salicylate is a Weak Acid (pKpKaa 3.5 3.5):):

TISSUESTISSUES(pH 6.8)(pH 6.8)

BLOODBLOOD(pH 7.4)(pH 7.4)

URINEURINE(pH variable)(pH variable)

HAHA

HH++ + A + A--

HAHA

HH++ ++ AA--

HAHA

HH+ + ++ AA--

Acidosis Alkalosis

Treatment of Salicylate Poisoning:Treatment of Salicylate Poisoning:Treatment of Salicylate Poisoning:Treatment of Salicylate Poisoning:

Gastrointestinal decontaminationGastrointestinal decontamination– for acute ODfor acute OD– activated charcoal (goal is 10:1 AC:ASA ratio)activated charcoal (goal is 10:1 AC:ASA ratio)– lavage for massive recent ingestionlavage for massive recent ingestion

Supportive measures:Supportive measures:– ABCs plus dextrose if low blood glucoseABCs plus dextrose if low blood glucose– volume replacement with IV fluidsvolume replacement with IV fluids– external coolingexternal cooling

Enhanced Elimination of Salicylate:Enhanced Elimination of Salicylate:Enhanced Elimination of Salicylate:Enhanced Elimination of Salicylate:

Urine alkalinization:Urine alkalinization:– 1 liter dextrose in 0.25 NS + 100 mEq NaHCO1 liter dextrose in 0.25 NS + 100 mEq NaHCO33

– add KCl 20 mEq/L once urine flow establishedadd KCl 20 mEq/L once urine flow established– run at 150-200 mL/hr (2-3 cc/kg)run at 150-200 mL/hr (2-3 cc/kg)– monitor urine pH (goal 7-8)monitor urine pH (goal 7-8)

Repeated dose activated charcoalRepeated dose activated charcoal– assures adequate gut decontaminationassures adequate gut decontamination– may enhance elimination by “gut dialysis”may enhance elimination by “gut dialysis”

Indications for Hemodialysis:Indications for Hemodialysis:Indications for Hemodialysis:Indications for Hemodialysis:

Serum salicylate levels:Serum salicylate levels:– acute OD: >100-120 mg/dL (7-8 mmoL)acute OD: >100-120 mg/dL (7-8 mmoL)– chronic: 60-80 mg/dL if elderly, altered CNSchronic: 60-80 mg/dL if elderly, altered CNS

Severe acidosisSevere acidosis Renal failureRenal failure Coma, convulsionsComa, convulsions Progressive deteriorationProgressive deterioration

Case Study:Case Study:Case Study:Case Study:

A 17 year old young man took a bottle of A 17 year old young man took a bottle of aspirin and several glasses of whiskey after aspirin and several glasses of whiskey after failing his exams. He is drunk and depressed.failing his exams. He is drunk and depressed.

BP 120/80BP 120/80 HR 105HR 105Resp 14Resp 14 Temp 37 CTemp 37 C

Glucose 5 mmoL (90 mg/dL)Glucose 5 mmoL (90 mg/dL)EtOH 30 mmoL (140 mg/dL)EtOH 30 mmoL (140 mg/dL)Anion gap 12 mmoL Anion gap 12 mmoL

Case, continued:Case, continued:Case, continued:Case, continued:

Serum salicylate: Serum salicylate: not detectablenot detectable

He is treated with intravenous fluids, given a He is treated with intravenous fluids, given a psychiatric referral, and sent home with his psychiatric referral, and sent home with his parents.parents.

3 days later he returns with jaundice and 3 days later he returns with jaundice and lethargy.lethargy.

WHAT IS YOUR DIAGNOSIS?WHAT IS YOUR DIAGNOSIS?

Paracetamol PoisoningParacetamol PoisoningParacetamol PoisoningParacetamol Poisoning

Common analgesicCommon analgesic– frequently considered “aspirin” by lay personsfrequently considered “aspirin” by lay persons– often found in combination productsoften found in combination products

Diagnosis easily missedDiagnosis easily missed– often overlooked in historyoften overlooked in history– no characteristic early symptoms or signsno characteristic early symptoms or signs– only reliable Dx: only reliable Dx: STAT SERUM LEVELSTAT SERUM LEVEL

Normal metabolism - 3 routes:Normal metabolism - 3 routes:

– glucuronidationglucuronidation

– sulfationsulfation

– mixed function oxidase (p-450 system)mixed function oxidase (p-450 system)• creates a highly reactive intermediate metabolitecreates a highly reactive intermediate metabolite• normally rapidly scavenged by intracellular glutathionenormally rapidly scavenged by intracellular glutathione

Mechanism of Paracetamol Toxicity:Mechanism of Paracetamol Toxicity:Mechanism of Paracetamol Toxicity:Mechanism of Paracetamol Toxicity:

NontoxicNontoxicmetabolitesmetabolites

NontoxicNontoxicmetabolitesmetabolites

Paracetamol Toxicity:Paracetamol Toxicity:Paracetamol Toxicity:Paracetamol Toxicity:

Overdose:Overdose:– sulfation and glucuronidation saturatedsulfation and glucuronidation saturated– increased production of p-450 metaboliteincreased production of p-450 metabolite

• glutathione eventually depleted glutathione eventually depleted • reactive intermediate injures cellsreactive intermediate injures cells

Higher-risk groups: Higher-risk groups: enhanced p-450 activity enhanced p-450 activity

– chronic alcoholicschronic alcoholics– chronic use of anticonvulsants, INHchronic use of anticonvulsants, INH

Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:

Early: Early: non-specificnon-specific– anorexia, vomitinganorexia, vomiting

24-48 hrs:24-48 hrs:– onset of liver injuryonset of liver injury

• AST, ALT may exceed 10,000 IUAST, ALT may exceed 10,000 IU

– prothrombin time (PT) often elevated earlyprothrombin time (PT) often elevated early• uncertain prognostic valueuncertain prognostic value

– renal injury may also occurrenal injury may also occur

Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:

2-5 days:2-5 days:

– liver & kidney injury resolve in most patientsliver & kidney injury resolve in most patients

– some patients may develop some patients may develop fulminant liver failurefulminant liver failure• progressive rise in PT, bilirubinprogressive rise in PT, bilirubin• metabolic acidosis, hypoglycemiametabolic acidosis, hypoglycemia• encephalopathy encephalopathy • DEATHDEATH

Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:

History:History:– acute ingestion of 150-200 mg/kg or 7-8 gmacute ingestion of 150-200 mg/kg or 7-8 gm– chronic use of 4-6 gm/day in high-risk groupchronic use of 4-6 gm/day in high-risk group

Clinical evaluation:Clinical evaluation:– serum paracetamol level is only reliable predictorserum paracetamol level is only reliable predictor– levels associated with “probable toxicity”:levels associated with “probable toxicity”:

• 200 mg/L at 4 hrs after acute ingestion200 mg/L at 4 hrs after acute ingestion• 100 at 8 hrs100 at 8 hrs• 50 at 12 hrs50 at 12 hrs

1

10

100

1000

0 5 10 15 20 25

APAP(mg/L)

Poss. Toxic

Prob. Toxic

hrs

Serum APAP level

Note: co-ingestion of Nyquil plus up to 44 g Tylenol ERRef: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510

Tylenol “Extended Relief” Case:Tylenol “Extended Relief” Case:Tylenol “Extended Relief” Case:Tylenol “Extended Relief” Case:

Pitfalls with Nomogram:Pitfalls with Nomogram:Pitfalls with Nomogram:Pitfalls with Nomogram:

Chronic intoxicationChronic intoxication

Delayed or erratic absorptionDelayed or erratic absorption– massive or mixed ingestionmassive or mixed ingestion– Extended-Relief Tylenol (new USA product)Extended-Relief Tylenol (new USA product)

High-risk groupsHigh-risk groups– reduce nomogram line by 50%?reduce nomogram line by 50%?

Treatment of APAP Poisoning:Treatment of APAP Poisoning:Treatment of APAP Poisoning:Treatment of APAP Poisoning:

Gut decontaminationGut decontamination– activated charcoal +/- lavageactivated charcoal +/- lavage– avoid ipecac-induced emesisavoid ipecac-induced emesis

Antidote: Antidote: N-acetylcysteine (NAC)N-acetylcysteine (NAC)– provides SH group to bind to toxic intermediateprovides SH group to bind to toxic intermediate

• most effective if started within 8-10 hrs after ingestionmost effective if started within 8-10 hrs after ingestion

– may have nonspecific antioxidant benefitmay have nonspecific antioxidant benefit• prolonged administration for liver failureprolonged administration for liver failure

N-acetylcysteine Prophylaxis: N-acetylcysteine Prophylaxis: N-acetylcysteine Prophylaxis: N-acetylcysteine Prophylaxis:

ORAL ORAL (USA)(USA)

– Dose:Dose:• 140 mg/kg PO140 mg/kg PO

......followed byfollowed by• 70 mg/kg q 4 hrs70 mg/kg q 4 hrs

– Duration - controversial:Duration - controversial:• standard: 72 hrsstandard: 72 hrs• some centers: 24-36 hrssome centers: 24-36 hrs

INTRAVENOUSINTRAVENOUS

– Dose:Dose:• 150 mg/kg IV over 15 min150 mg/kg IV over 15 min

......followed byfollowed by• 50 mg/kg over 4 hrs50 mg/kg over 4 hrs

......followed byfollowed by• 100 mg/kg over 16 hrs100 mg/kg over 16 hrs

– Total duration 20 hrsTotal duration 20 hrs

Initiate NAC within 8-10 hours, if possible Initiate NAC within 8-10 hours, if possible Extended treatment may be needed for liver failureExtended treatment may be needed for liver failure

Initiate NAC within 8-10 hours, if possible Initiate NAC within 8-10 hours, if possible Extended treatment may be needed for liver failureExtended treatment may be needed for liver failure