1. Aspirin & Paracetamol (Acetaminophen) Poisoning Kent R. Olson, M.D. California Poison Control System University of California, San Francisco

2. Case Study: u A 76 year old woman was brought by her family because of increasing confusion and agitation, and difficulty breathing. u Exam: restless, irritable elderly woman. Temp: 38.2 CResp: 26 HR: 102BP: 110/76

3. u Laboratory: Na: 144K: 3.2 Cl: 110HCO3: 16 BUN: 10 mmolglucose: 5 mmol/L u Arterial blood gases: pH: 7.48pCO2: 14pO2: 98 u Salicylate: 68 mg/dL (5 mmol/L) Case, continued: Anion gap: 18 mmol/L Anion gap: 18 mmol/L

4. Acute vs. Chronic Salicylism: u Acute Overdose: –younger age –child: accidental –adult: suicidal –no underlying illness –ASA levels high –mortality rate lower u Chronic Intoxication: –older age –accidental overmedication –underlying disease –serum ASA variable –mortality >25%

5. Mechanisms of Salicylate Toxicity: u Respiratory center stimulation: –tachypnea, respiratory alkalosis –compensatory loss of bicarbonate in urine u Uncoupling of oxidative phosphorylation: –generation of excess heat –lactic acidosis u Cellular metabolic dysfunction –metabolic acidosis

6. Clinical Findings in Salicylism: u MILD to MODERATE –tinnitus, nausea, vomiting –tachypnea with respiratory alkalosis –metabolic acidosis –irritability, lethargy –low-grade fever –dehydration u SEVERE POISONING –hyperpnea - resp. distress –hyperpyrexia –severe acidosis –coagulopathy (PT elev.) –coma, convulsions –pulmonary edema/ARDS –cardiovascular collapse

7. Estimation of Severity of Salicylism: u History: –acute ingestion of > 200 mg/kg –chronic use of > 4 gm/day u Clinical indicators: –mental status –metabolic acidosis & respiratory alkalosis u Serum salicylate level

8. Salicylate Levels: u May help predict severity after single acute OD –6 hr serum level > 100 mg/dL (7 mmoL) serious u Pitfalls in use of “Done” Nomogram: –massive ingestion: tablet mass & delayed peak –chronic intoxication –altered serum pH may contribute to toxicity

9. Salicylate is a Weak Acid ( pK a 3.5 ): TISSUES (pH 6.8) BLOOD (pH 7.4) URINE (pH variable) HA H + + A - HA HA AcidosisAlkalosis

10. Treatment of Salicylate Poisoning: u Gastrointestinal decontamination –for acute OD –activated charcoal (goal is 10:1 AC:ASA ratio) –lavage for massive recent ingestion u Supportive measures: –ABCs plus dextrose if low blood glucose –volume replacement with IV fluids –external cooling

11. Enhanced Elimination of Salicylate: u Urine alkalinization: –1 liter dextrose in 0.25 NS + 100 mEq NaHCO 3 –add KCl 20 mEq/L once urine flow established –run at 150-200 mL/hr (2-3 cc/kg) –monitor urine pH (goal 7-8) u Repeated dose activated charcoal –assures adequate gut decontamination –may enhance elimination by “gut dialysis”

12. Indications for Hemodialysis: u Serum salicylate levels: –acute OD: >100-120 mg/dL (7-8 mmoL) –chronic: 60-80 mg/dL if elderly, altered CNS u Severe acidosis u Renal failure u Coma, convulsions u Progressive deterioration

13. Case Study: u A 17 year old young man took a bottle of aspirin and several glasses of whiskey after failing his exams. He is drunk and depressed. u BP 120/80HR 105 Resp 14Temp 37 C u Glucose 5 mmoL (90 mg/dL) EtOH 30 mmoL (140 mg/dL) Anion gap 12 mmoL

14. Case, continued: u Serum salicylate: not detectable u He is treated with intravenous fluids, given a psychiatric referral, and sent home with his parents. u 3 days later he returns with jaundice and lethargy. WHAT IS YOUR DIAGNOSIS?

15. Paracetamol Poisoning u Common analgesic –frequently considered “aspirin” by lay persons –often found in combination products u Diagnosis easily missed –often overlooked in history –no characteristic early symptoms or signs –only reliable Dx: STAT SERUM LEVEL

16. u Normal metabolism - 3 routes: –glucuronidation –sulfation –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: NontoxicmetabolitesNontoxicmetabolites

17. Paracetamol Toxicity: u Overdose: –sulfation and glucuronidation saturated –increased production of p-450 metabolite glutathione eventually depletedglutathione eventually depleted reactive intermediate injures cellsreactive intermediate injures cells u Higher-risk groups: enhanced p-450 activity –chronic alcoholics –chronic use of anticonvulsants, INH

18. Clinical Manifestations of Toxicity: u Early: non-specific –anorexia, vomiting u 24-48 hrs: –onset of liver injury AST, ALT may exceed 10,000 IUAST, ALT may exceed 10,000 IU –prothrombin time (PT) often elevated early uncertain prognostic valueuncertain prognostic value –renal injury may also occur

19. Paracetamol Toxicity, continued: u 2-5 days: –liver & kidney injury resolve in most patients –some patients may develop fulminant liver failure progressive rise in PT, bilirubinprogressive rise in PT, bilirubin metabolic acidosis, hypoglycemiametabolic acidosis, hypoglycemia encephalopathyencephalopathy DEATHDEATH

20. Prediction of Paracetamol Toxicity: u History: –acute ingestion of 150-200 mg/kg or 7-8 gm –chronic use of 4-6 gm/day in high-risk group u Clinical evaluation: –serum paracetamol level is only reliable predictor –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

22. APAP (mg/L) Poss. Toxic Prob. Toxic hrs Serum APAP level Note: co-ingestion of Nyquil plus up to 44 g Tylenol ER Ref: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510 Tylenol “Extended Relief” Case:

23. Pitfalls with Nomogram: u Chronic intoxication u Delayed or erratic absorption –massive or mixed ingestion –Extended-Relief Tylenol (new USA product) u High-risk groups –reduce nomogram line by 50%?

24. Treatment of APAP Poisoning: u Gut decontamination –activated charcoal +/- lavage –avoid ipecac-induced emesis u Antidote: N-acetylcysteine (NAC) –provides 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 benefit prolonged administration for liver failureprolonged administration for liver failure

25. N-acetylcysteine Prophylaxis: u ORAL (USA) –Dose: 140 mg/kg PO...followed by140 mg/kg PO...followed by 70 mg/kg q 4 hrs70 mg/kg q 4 hrs –Duration - controversial: standard: 72 hrsstandard: 72 hrs some centers: 24-36 hrssome centers: 24-36 hrs u INTRAVENOUS –Dose: 150 mg/kg IV over 15 min...followed by150 mg/kg IV over 15 min...followed by 50 mg/kg over 4 hrs...followed by50 mg/kg over 4 hrs...followed by 100 mg/kg over 16 hrs100 mg/kg over 16 hrs –Total duration 20 hrs 4Initiate NAC within 8-10 hours, if possible 4Extended treatment may be needed for liver failure 4Initiate NAC within 8-10 hours, if possible 4Extended treatment may be needed for liver failure