1. Toxic Alcohols and ASA Heather Patterson PGY-3 Jan 17, 2007

2. Objectives Review of: –Toxicokinetics –Basic Pathophysiology –Clinical Features –Managment

3. Case 1: 18M Drinking with friends –Brought to ED because he was having ++N/V and abdo pain and seemed overly intoxicated –Thought it was strange because he really hadn’t had that much to drink –Mixed their own drinks. But didn’t have enough booze for “good” drinks. So they added a little of this, a little of that – just to help out a bit.

4. Investigations Usual toxic w/u Labs –Lytes, including Ca –Anion and osmolar gaps –Urine for crystals

5. Case Osmolar gap: 12 Anion gap: 14 What is your DDx for anion + osmolar gap? –Methanol –Ethylene glycol –Propylene glycol –Alcoholic or starvation ketoacidosis –DKA –Acteonitrile

6. Case With toxic alcohol ingestions: –What causes an osmolar gap? –What causes an anion gap?

7. Case Who is the sickest? –Patient A: wide osmolar gap, minimal AG –Patient B: smaller osmolar gap, high AG

8. Ddx of Osmolar Gap P Proteins A Alcohols ( EtOH, methanol, ethylene glycol, isopropanol, propylene glycol, diethylene glycol, triethylene glycol ) S Sugars ( mannitol, glycerol, sorbital ) C Contrast dyes A Acidosis ( ketoacidosis, lactic acidosis ) L Lipids A Acetone Osmolar Gap DDx

9. Osmolar Gap Osmolality –Solute/kg of solvent L ab measures Osmolarity –Solute/liter of solution –You calculate!

10. Osmolarity Formulas Other formulas……. Osmolality

11. Osmolarity Formulas Calgary –1.86Na + BUN + glucose + 9 –1.86: 93% is in Na+, Cl- (ionized form) and the remainder is in the NaCl (nonionized form) –+9 factor: Accounts for other osmotially active molecules ie K, Ca, proteins –Thought to be the best formula: Dorwat Clin Chemistry 1975. Osmolality Formulas

12. Case 1 Intoxicated male Na 140, BUN 5, Gluc 5, EtOH 75 Osmolality = 385 Does he have a gap? How does EtOH effect osmolar gaps? Case

13. Ethanol and the Osmolar Gap Increase in osmolar gap with rising EtOH in a non 1:1 relationship Many different EtOH conversion factors have been developed… –Geller 1986: 1.20 –Galvan 1992: 1.14 –Synder 1992:1.20 –Hoffman 1993:1.09 –Pappas 1985:1.12 –Britten 1972:1.74 –Glasser 1973: 1.1 EtOH and Osmolar Gap

14. Purssell. Ann Emerg Med 2001: 38: 653- 659. –Derived a formula to account for the relationship between ethanol and osmolar gap –Prospectively validated –Best formula = EtOH (mmol/L) X 1.25 EtOH and Osmolar Gap

15. 35 yo male Took a swig of a mug that had antifreeze Na 140BUN 5 Gluc 5HCO3 24 EtOH 25 Osmolality 321 Osmolarity = 321 No anion gap What is a normal osmolar gap? Case

16. Case 2: osmolar gap = 0 Can osmolar gaps be used to rule out toxic alcohol ingestions? Is there a “cutoff” where toxic alcohols should be routinely measured? Osmolar Gap

17. Normal Osmolar Gap: Hoffman. J Toxicol Clin Toxicol. 1993 2Na + BUN + Gluc + EtOH -8 -2 +4 +10 -14

18. When should we measure toxic alcohols? Calgary (1.86Na + BUN + Gluc + EtOH +9) –Osmolar gap > 10: measure methanol and ethylene glycol Edmonton (2Na + BUN + Gluc + EtOH) –Osmolar gap > 2: measure ethylene glycol –Osmolar gap > 5: measure methanol Osmolar Gap

19. Can these cut offs r/o a significant toxic alcohol ingestion? Baseline -14 Osm gap 0 Methanol level of 14!!! -140

20. Additional problems/questions: –What is the normal distribution for the formula that we use in Calgary for osmolarity? –What is the true effect of EtOH? –What is a significant toxic alcohol level? Nobody really knows! Evidence for when to dialyze based on case series and case reports. Are you willing to miss a methanol level of 5, 10, or 15 mmol/L? Osmolar Gap

21. So how do we use this most effectively? –Osmolar gaps are NOT 100% reliable to exclude treatable toxic alcohol ingestions –Low suspicion ------ check osmolar gap –High suspicion ------ low threshold to check toxic alcohol levels regardless of osmolar gap Remember: osmolar gaps are irrelevant when the patient has an AGMA from toxic metabolites Osmolar Gap

22. Methanol What products contain methanol? –Paint remover, varnish, washer fluid, antifreeze, carborator fluid, glass cleaner, gasoline substitute, canned heating products, wood spirits/alcohol What is a toxic dose: –Blindness: 4ml of 40% –Lethal: 15ml of 40% Peak levels and half life? –30-90 min –T ½ = 14-20 h for small ingestions –T ½ = 24-30h for large ingestions

23. Methanol Metabolism

24. Methanol Why is the half life longer with higher doses of methanol? Clue – what is first order kinetics vs zero order kinetics?

25. Basic Pathophysiology Formic acid: –High affinity for iron –Indirectly inhibits cytochrome oxidase enzymes –Leads to ATP depletion, anaerobic metabolism, lactic acidosis Ocular injury: –Myelin damage  axonal disruption –Acidosis  increased diffusion of formic acid into neurons  increased acidosis etc etc

26. Basic Pathophysiology Basal Ganglia: –Uncertain why the affinity for the basal ganglia – especially the putamen –Hemorrhage, necrosis, cysts

27. Methanol: clinical features Onset: –May be delayed 18+ hours especially if coingested with EtOH Vitals: –CVS normal unless preterminal (hypotension, dysrhythmias) –Tachypnea – Kussmauls is uncommon

28. Methanol: clinical features Cardinal Presentation: GI + Ocular + CNS GI: –N/V/ abdo pain, pancreatitis with increased amylase –Due to mucosal irritation Ocular (50%): –Most common: “Snow field: or dense central scotoma –Diplopia, blurred vision, photophobia, fixed dilated pupils, retinal edema/hyperemia –LOOK AT THE RETINA Changes occur 18-48h

29. Methanol: clinical features CNS –This is a spectrum –Headache, dizziness/vertigo, ataxia, confusion, sz, coma –May be difficult to assess if they have coingestants or are significantly altered

30. Case You send a urine sample from your intoxicated teenager. Lab report: –Many octahedral crystals –Urine fluoresces under wood’s lamp If the urine didn’t fluoresce can you r/o EG toxicity?

31. EG: Pathophysiology

32. Multiple toxic metabolites – oxalate is the most toxic Mechanism for tissue toxicity not fully understood. Tissues targeted: –CNS –Kidney –Lung –Muscle including cardiac –Retinal

33. EG: Clinical Stage 1: Acute neurological (1-12h) –Inebriated, ataxic –Hallucinations, sz, coma, death –Fundi N Occular abnormalities not seen in pure ingestion

34. EG: Clinical Stage 2: Cardiopulmonary (12-24h) –Tachy, mild HTN, tachypnea –Arrhythmias secondary to ↓ Ca –ARDS, CV collapse, Cardiomegaly

35. EG: Clinical Stage 3: Nephrotoxicity (24-72h) –Urine crystals Ca oxalate 50% Dihydrate or monohydrate –Hematuria, proteinuria –Flank/CVA tenderness –ATN –Oliguric or anuric ARF

36. EG: Clinical Stage 4: Delayed Neuro Sequelae (6-12days) –CN palsies VII, VIII common –Multiple possible neurological findings focal and cognitive deficits

37. Mangement: Approach The 5 A’s –ABCs and supportive care –Alkalinize –Alcoholize –Accelerate Elimination – Dialysis –Adjuncts Goals: –Correct acidosis –Block alcohol dehydrogenase –Remove parent alcohol

38. Mangement: Decontamination Is charcoal indicated with toxic alcohol ingestion? CHILE: –Caustics –Hydrocarboms –Iron –Lead, Li –Ethanol/methanol/ethylene glycol

39. Mangement: Alkalinize Goal: –pH 7.45-7.5 Rationale?: –Normalizing pH ioninzes formic acid/oxalic acid and limits its movement into CNS/eyes –Helpful in those with cardiovascular instability Method? –Bolus: 1-2 mEq/kg –Maintenance: 1.5-2x mainenance

40. Management: Alcoholize When to start an antidote? AACT Consensus statements –Strong suspicion of ingestion and 2 of: Osmole gap > 10, pH < 7.3, or Bicarb < 20, or Urinary oxalate crystals (EG) –Documented ingestion and OG > 10 –Me >6 mmol/L, EG > 3 mmol/L

41. Management: Alcoholize/Antidote What options do you have? EtOH vs Fomepizole? EtOH: –Cheap –Difficult to dose –Metabolic effects –Toxic effects Fomepizole: –Expensive –Easy q12h dosing –No drunk and rowdy pt

42. Management: Alcoholize EtOH infusion (10% solution): –Loading dose: 10cc/kg –Maintenance: 1cc/kg/hr –Goal: 20-30mmol/L –Dosing in alcoholics? –Dosing during dialysis? Often infusion runs for 2-3 days What can you use if no IV EtOH available?

43. Managment: Antidote Fomepizole: –Loading: 15 mg/kg load –Maintenance 10 mg/kg q12hr X4, then 15 mg/kg q12hr –Continue treatment until methanol level is acceptable, pt asymptomatic, and normal pH

44. Managemt: Adjuncts How do the treatment of Methanol and Ethylene glycol differ?

45. Methanol: Adjuncts Folate: –Cofactor in conversion of formic acid to H20 and CO2 –Dose: 50mg IV q4h x 2 days

46. EG: Adjunts Dosing: –Thiamine 100mg IV q6h –Mg 2-4g IV –Pyridoxine 50 IV q6h x 2days

47. EG: Managment What about the hypocalcemia? –MUST be replaced –Calcium chloride (10%) 10 mls –Follow levels and EKG

48. Real Case You are the STARs doc-on call Called from Taber 14month old M found on the floor with small container that used to hold fuel for a model car –80% Methanol 60 mins post suspected ingestion Not curretly showing symptoms/signs of intoxication

49. Real Case 30 minutes later, the child starts looking a bit intoxicated –It is also WAY past his bedtime –Parents say he always “walks like that”

50. Case 52M found on park bench altered LOC Bottle of rubbing alcohol beside him –It is half full

51. Isopropyl Alcohol Not so tasty Found in: –Rubbing alcohol, disinfectants, solvents, hair products, jewelry cleaners, dtergtents, paint thinners, some antifreeze Has 2x the CNS depressant activity of EtOH

52. Toxicokinetics Absorption: –GI –Resp –Dermal Peak levels –30min-3h –T ½ 3-7h Toxic Dose: –1ml/kg of 70% Lethal dose: –2-3ml/kg –(less in kids)

53. Isopropyl: Pathophysiology Ketosis WITHOUT acidosis

54. Isopropyl: Pathophysiology Mechanism of CNS depression not well understood Acetone: –Direct myocardial depressant –Peripheral vasodilatation

55. Isopropyl: Clinical features General: –Intoxicated –Smells like acetone Vitals: –Normal –Sinus tach –Possible – hypotension, ↓ RR

56. Isopropyl: Clinical features GI: –N/V, pain –+/- hematemesis – hemorrhagic gastritis CNS –Altered  confusion  coma –Loss DTR and corneals, +babinski –Nystagmus

57. Isopropyl: Investigations Labs: –Helpful trid: Minimal acidosis + ketonuria (no glucosuria) + osmolar gap –Elevated Isopropyl Alcohol –Others: ARF Hepatic failure Hypoglycemia Hemolysis Rhabdo

58. Isopropyl: Management How would you like to manage this patient? Decontamination? Alkalinization? Alcoholization? Accelerated Elimination?

59. Isopropyl: Management What if the patient has a GCS of 7? What if the patient has a pressure of 78/40?

60. Isopropyl: Management What are the indications for dialysis? –>66mmol/L –Refractory hypotension **** Coma is NOT an indication for dialysis ****

61. Isopropyl: Management Your patient has now been stable for some time. There are no ongoing signs of intoxication, no hypotension or hypoglycemia. Can this patient go home?

62. Isopropyl: Management Key things to remember: –ABCs! –Evaluate for hypoglycemia –Watch for GI bleeding –Dialysis when indicated

63. Thanks Rob and Ingrid!

65. Case 55F Brought in by EMS Called by neighbours who saw her confused and acting bizarrely. PMHx –DM2 –HTN –GERD Meds: –Adalat –Gluconorm –Pantoloc

66. Case Vitals: –38.0 –HR 90s –RR 16 –BP 130/80 –95% RA –CS 9.5 Physical exam: –CVS N –Chest clear –Abdo soft –GCS 13, no focal findings EKG: –Sinus tach

67. Case Video here…

68. Case What some of the key features of this presentation? –Clue: breathing and LOC Based on this, what would you like to do next?

69. Case

70. ASA Common drug – multiple preparations Highest mortality rate of OTC analgesics in OD (~0.5%) Most fatalities for single drug OD in Ontario in ’83-’84

72. ASA GI absorption –Speed of absorption: Liquids > plain ASA > EC or SR preps Pylorospasm with large ingestions Concretions due poor solubility in gastric secretions Ionic form binds albumin and other proteins

73. ASA: Toxicokinetics Plasma levels: –Detectible at 30 min –Peak levels 2-4 hours

74. ASA: Toxicokinetics Toxicity: –<150mg/kg = non toxic –150-300mg/kg = mild to mod toxicity –300-500mg/kg = severe toxicity –>500mg/kg = lethal

75. ASA Elimination: –Therapeutic doses – first order kinetics –Toxic doses – zero order kinetics Hepatic mechanism overwhelmed Excretion is renal Half life: –Increases with toxic levels to 15-30h

76. ASA – Pharmacokinetics HA  H + + A - Weak organic acid – 99.99% ionized at pH 7.4 –pKa low therefore most of ASA is in ionic form at physiological pH Only non-ionized form can cross membranes

77. ASA – Clinical features Correlation of symptoms with increasing ASA levels Symptoms do NOT allow you to r/o significant toxicity What is the usual progression of symptoms? (ie what systems are affected in which order) GI  Metabolic  CNS  Renal and Respiratory

78. S + S of Salicylate Toxicity Renal / Respiratory failure Coma, Seizures CNS (confusion, irritability, delirium, visual hallucinations, lethargy) Metabolic Acidosis Dehydration / Electrolyte Abnormalities Hyperventilation / Resp alkalosis Nausea + Vomiting Fever, Diaphoresis Tinnitus, Hearing Changes Asymptomatic SALICYLATE CONCSALICYLATE CONC ASA – Clinical features

79. ASA – Clinical features: GI Gastritis –local effects Vomiting –Stimulation of cerebral chemoreceptors –Decreased gastric motility –Pylorospasm

81. ASA – Clinical features: Metabolic How does ASA affect oxidative phosphorylation? What are the effects on cellular metabolism?

82. ASA – Clinical features: Metabolic ASA uncouples oxidative phosphorylation and prevents production of ATP Increased anaerobic metabolism Catabolic state –Lipolysis –Proteolysis –Glycogenolysis and gluconeogenesis

84. ASA – Clinical features: Metabolic Tinnitis: –Occurs before hearing loss –Due to metabolic changes in the endolymph Pyrexia: –Due to uncoupling of oxidative phosphorylation

86. ASA – Clinical features: Metabolic Hypokalemia: –Due to GI losses –Direct increase in renal excretion –Cellular shift with bicarb Alterations in glucose homeostasis: –Hyperglycemia early –Hypoglycemia late –Paradoxical CNS hypoglycemia Cerebral glycolysis

87. ASA – Clinical features: Metabolic What is the common progression of the acid-base disturbances in the course of ASA toxicity? –Respiratory alkalosis –Resp alkalosis, met acidosis –Resp alkalosis but pCO2 increasing, met acidosis

88. ASA – Clinical features: Metabolic What are the 4 mechanisms for metabolic acidosis in ASA toxicity? –Lactic Acid –FFA –Amino Acids –Salicylic Acid, acetosalicylic acid

89. ABG analysis

90. ASA – Clinical features: Metabolic The ABG…. Let’s work through our patient’s ABG –1. Acidemia vs Alkalemia –2. Metabolic or respiratory –3. Anion gap –4. “Rule of 15” –5. Delta gap –6. Osmolar gap

91. ASA – Clinical features: Metabolic 7.34/15/62/8 Na 140 K 3.8 Cl 114 1. Acidemia vs Alkalemia 2. Metabolic or respiratory 3. Anion gap 4. “Rule of 15” 5. Delta gap 6. Osmolar gap

92. Rule of 15 Creates a new set point for the pCO 2 –pCO 2 appropriate = normal compensation –pCO 2 too low = superimposed primary resp alkalosis –pCO 2 too high = superimposed primary resp acidosis Note: as HCO 3 falls below 10 you need to use the formula HCO 3 x 1.5 + 8 = expected pCO 2 Thanks Marc

93. ASA – Clinical features: Metabolic Respiratory compensation for Metabolic d/o CompensationPaCO 2 : HCO 3 - Metabolic Acidosis1:1 Metabolic Alkalosis1: 0.75 Thanks Marc

94. ASA – Clinical features: Metabolic CompensationPaCO 2 : HCO 3 - Acute Resp Acidosis10:1 Acute Resp Alkalosis10:2 Chronic Resp Acidosis10:3 Chronic Resp Alkalosis10:4 Metabolic compensation for Respiratory d/o

95. Back to the case… How would you decontaminate the patient? –AC/MDAC –+/- WBI for EC/SR tabs

96. Case: What are the indications for bicarb? –ASA level >2.5 –Suspected/known ingestion, symptomatic and levels pending

97. Case: You have asked the nurses to get some bicarb. How do you administer it? How does it work?

98. Ion trapping HA H + + A - HA A - + H + Blood Urine HA H + + A - HA A - + H + Blood: lower pH Urine: higher pH Fig. 2a: Unionized molecules diffuse across renal tubular membranes from blood to renal filtrate but ionized ones cannot cross from one compartment into the other. Fig. 2b: When urine is alkalinized, weak acids like salicylates will dissociate into ions, become “trapped” and excreted in the urine. Unionized parent molecules then diffuse down their concentration gradient from blood into the urine. pKa=3.5 pH=8

99. Case: You have started your bicarb infusion –Urine pH is NOT reaching the target –What may inhibit the ability to alkalinize the urine? K Hypovolemia When would you stop the bicarb? –Level <2.5 and declining –Asymptomatic –AG corrected

100. Case: She is now on 100% NRB and sats are 83% Her pCO2 is 30 (from 15) and pO2 is 50 What do you think is going on?

101. ASA – Clinical features: Resp Pulmonary edema: –Mechanism is unknown –Non-cardiogenic Risk factors –>30y –Smoker –Chronic toxicity –Met acidosis –ASA >2.9

102. Case: What would you like to do now? Do you have any concerns about intubating this patient? What drugs would you use?

103. Case: As you are setting up to intubate your patient, she has a generalized seizure. What drugs would you like to use in this situation? After 2 doses of benzos she is still seizing. The nurses ask if you would like to load her with dilantin?

104. Case: Does this patient need dialysis? –Neurotoxicity Altered mental status, sz, cerebral edema –Pulmonary edema –Renal insufficiency that interferes with administration of bicarb –Fluid overload that interferes with administration of bicarb –ASA >7 –Clinical deterioration despite aggressive care

105. Summary of ASA management ABCDEs AC/MDAC or WBI with SR preps Bolus NaHCO3 Bicarb infusion + 40 Meq KCl at 2-3x maintenance Replace K +/- dialysis Monitor: –Urine pH q1h for pH 8 –K+ q2h –Glucose

106. Case: 65M feeling unwell with viral infection for 1 week. Comes in with nausea and vomiting and his hearing hasn’t been right Hasn’t changed or added any new meds No other symptoms Doesn’t like acetominophen or ibuprofen and so has been taking “extra” ASA every day.

107. Case: How would you like to manage this patient?