Somebody Like BLUE… -- Two Cases of Poisoning

1. Somebody Like BLUE…-- Two Cases of Poisoning By Chan Yuen Sze, Christina Resident of PMH ICU

2. Case 1 • M/22 • Mild mental retardation, education up to F.5 in special school • Lives alone. Poor social and family support. • NKDA, smoker and drinker • History of suicidal attempt by ingestion of insecticide • History of substance abuse and panadol poisoning • Defaulted FU from Psychi

3. Worked as security guard in Park Island • Admitted PMH 18-7-08 for ingestion of ~ 200ml of“purple blue fluid” in the security kiosk at ~ 00:30 am after being scolded by his supervisor during work • Attended to AED on 18-7-08 at ~ 02:00 am

4. In AED • Presented with semi-consciousness and drooling of saliva in AED • BP 115/52, P 107 regular • Temp 37.5C • Hstix 5.1 • SpO2 100% on RA, RR 16/min • PEARL 3mm, GCS E4V4M6. Sleepy but arousable • Buccal mucosa normal, no burn marks • No vomiting • Chest clear, no SOB • CXR clear, no pulmonary edema • No gastric lavage / activated charcoal given in AED

5. 1st set of blood result on 18-7-08 at 03:00 am • Electrolyte and L/RFT normal • VBG: pH 7.43, pCO2 4.63, pO2 6.18, HCO3 22.4, BE -2.0, SaO2 83.8% • Ethanol level < 2 mmol/L Paracetamol < 66 umol/L Salicylate < 0.30 mmol/L

6. What are you going to check at this moment? • What is your differential diagnosis?

7. Blood result on 18-7-08 at 12:56 • Repeat VBG: pH 7.30, HCO3 21.8, BE -4.7, pCO2 6.07, pO2 5.03

8. Blood result on 18-7-08 at 20:00 • Repeat ABG: pH 7.34, HCO3 18.1, BE -7.6, pCO2 4.53, pO2 16.38 • Anion gap = Na – Cl – HCO3 = 136 – 108 – 18.1 = 9.9 mmol/L (normal 10 +/- 4)

9. Measured Plasma osmolality 324 mmol/kg (N = 270-290 mmol/kg) on 18-7-08 at 03:00 am • Repeat Measured Plasma Osmolality = 331 mmol/kg on 18-7-08 at 20:00 • Calculated Plasma osmolality = 2x[Na] + [glucose] + [urea[ = 2 x 136 + 5.6 + 2.7 = 272 + 5.6 + 2.7 = 280.3 mmol/kg • Osmolar Gap = Measured P osm – Calculated P osm = 331 – 280.3 = 50.7 (normal 10-15)

10. What is the causes of elevated osmolar gap?

11. The Osmolar Gap is another important diagnostic tool for differentiating the causes of metabolic acidosis. Plasma osmolarity = 2 x [Na] + [glucose] + [urea](all in mmol/L) The normal osmolar gap is  10-15 mmol/L H20 • The osmolar gap is increased in the presence of low molecular weight substances that are not included in the formula for calculating plasma osmolarity • Common substances that increase the osmolar gap are: ethanol, ethylene glycol, methanol, acetone, isopropyl ethanol and propylene glycol. • In a patient suspected of poisoning, a high osmolar gap (particularly if ≥ 25) with an otherwise unexplained high anion gap metabolic acidosis is suggestive of either methanol or ethylene glycol intoxication. • Elevated osmolar gap is relatively nonspecific Also commonly seen in alcoholic and diabetic ketoacidosis, lactic acidosis and in chronic renal failure.

12. High osmolar gap metabolic acidosis • So, what do you think the bottle of “purple blue liquid” is???

13. Blood Methanol level > 30 mmol/L • Transferred to ICU for further management

14. Methanol Poisoning

15. Toxic alcohol refer to: Methanol, Ethylene glycol, Isopropanol • Uses of Methanol: Gasoline antifreeze 100% solution Windshield washer fluid – up to 30% Denaturants in paint and varnish removers – small % Fuels – about 4% • Properties: High volatility Low freezing point

16. Almost all cases of acute methanol toxicity result from ingestion, as a result of: • Ethanol substitutes • Ethanol additives • Accidental ingestions of household products • Contamination of products meant for ingestion • Suicidal attempts • Rarely, cases of poisoning have followed inhalation or dermal absorption.

17. Absorption of methanol following oral administration is rapid • Peak absorption occurs within 30 – 60 mins • Methanol is water-soluble and has a distribution phase analogous to the body water • The mean distribution half-life after ingestion is 8 mins • The rapid absorption and distribution of methanol results in peak concentration within 30 – 60 mins • => That’s why gastric lavage and activated charcoal is not going to help in our case

18. Pathophysiology • Methanol has a relatively low toxicity • The adverse effects are thought to be from the accumulation of formic acid, a metabolite of methanol metabolism

19. Metabolism of Methanol in Liver 10-Formyl Tetrahydrofolate Synthetase Half life 20 hours Half life 1-2 mins

20. Folinic acid Half life 1-2 mins Half life 20 hours Inhibition by Ethanol or Fomepizole

21. Role of Formic acid • Formic acid accumulation αtoxicity of methanol • Formic acid Cytochrome c oxidase Anaerobic metabolism mitochondria Increasing Acidosis Lactate

22. Clinical presentation • Initial symptoms generally occur 12-24 hours after ingestion Interval between Ingestion and Appearance of symptoms Volume of methanol ingested α Competitive inhibition Amount of ethanol concomitantly ingested The minimal lethal dose in adults = 1mg/kg

23. Ocular Toxicity • Ocular toxicity caused by formic acid directly Produces larger amount of undissociated formic acid Acidosis Increase Occular toxicity Greater diffusion Into cells

24. Ocular Toxicity Amount of undissociated formic acid Acidosis diffusion Into cells Ocular toxicity

25. Target optic disc and Retrolaminar section of Optic nerve Undissociated Formic acid Optic disc edema Breakdown of myelin sheaths Optic nerve lesion Cytochrome oxidase Vision loss Halts conduction of Action potential Damages myelin sheaths Depletion of Retinal and Optic Nerve ATP Histotoxic Hypoxia

26. Patients initially present with diminished visual acuity, which can progress to scotomata • Blurred vision, photophobia and “feeling of being in a snow field” were common complaints in over one half of patients • Early signs are hyperemia of the optic disc and reduced pupillary responses to light • Later signs is edema of optic disc with loss of physiological cupping • Most patients recover normal visual function with immediate therapy; however, permanent ocular sequelae occur up to 25-33%, which include diminished pupillary reactions to light, optic atrophy, optic cupping, peripherial constriction of visual fields, central scotoma, reduced visual acuity, loss of color vision and blindness • Blindness is usually permanent; however, some recovery of visual function may occur within several months.

27. Pronounced pale, atrophic optic discs with “Pseudoglaucomatous” thinning of the neuroretinal rim area – optic neuropathy secondary to methanol intoxication

28. Neurotoxicity Disinhibition and ataxia Headache, nausea, vomiting, epigastric pain Obtundation and coma Seizure As a complication of metabolic derangement or damage to the brain parenchyma

29. Failure of Na-K ATPase pump Cytochrome oxidase Formic acid Neurotoxicity Methanol appears to affect the basal ganglia, primarily the putamen.

30. CT scan showing symmetrical areas of low attenuation in the peripheral white matter (small arrows) and symmetrical hypointensities in both lentiform nuclei (bold arrow)

31. T2-weighted (A) and T1-weighted (B) images showed haemorrhagic changes in bilateral putamen and in the cortical white matter lesions Bilateral symmetric necrotic areas in the basal ganglia (putamen; arrow) in the T1 weighted image (hypointense lesions with marginal contrast enhancement) are typical of methanol intoxication

32. Cardiac: Tachycardia, hypertension, cardiac arrhythmias, depressed cardiac contractility leading to shock and heart failure • Resp: Tachypnoea, pulmonary edema, acute respiratory distress, may requiring intubation • GI: Nausea, vomiting, abdominal pain. Haemorrhagic pancreatitis in 2/3 of patients. Elevation of hepatic aminotransferases usually is mild and transient • Kidney: Myoglobinuria is a rare complication of methanol poisoning, but may cause renal dysfunction. A patient with an admission methanol concentration of 400mg/dL developed acute renal failure in association with myoglobinuria. Renal dysfunction peaked on the 8th hospital day and returned to normal within one month.

33. Differential Diagnoses • Other toxic alcohol intoxication: Ethanol intoxication, Ethylene glycol intoxication • Other drug or poisoning: Carbon monoxide poisoning, arsenic, cocaine • Head injury, subdural haematoma • CNS infection: Viral encephalitis, viral meningitis • Other encephalopathy: Uraemic encephalopathy, paraneoplastic encephalopathy, cerebral lupus • Seizures and epilepsy

34. Work-up • Blood test: Metabolic acidosis, high anion gap and osmolar gap, high lactate level • RFT, urine myoglobin • Serum amylase • Serum methanol level – definitive diagnosis. Peak levels are achieved 60-90 mins after ingestion, but the level DO NOT correlate with the level of toxicity, and thus are not a good indicator of prognosis. • CT scan and MRI • Visual evoked potentials (VEP) and electroretinograms (ERG): to document retinal dysfunction and monitor treatment response

35. Management • Gastrointestinal decontamination: Methanol is absorbed rapidly and even if gastrointestinal decontamination techniques were effective, there would be little opportunity to prevent its absorption. • Gastric lavage: without any evidence to support its use • Activated charcoal: discouraged because methanol is not absorbed by activated charcoal

36. Supportive therapy: aim at initiating airway management, correcting electrolyte disturbances, and providing adequate hydration Bicarbonate administration to correct metabolic acidosis. This may help to decrease the amount of active undissociated formic acid and reverse visual deficits, as the inner membrane of mitochondria is only permeable to the undissociated formic acid. Amount of Undissociated Formic acid Ocular toxicity Diffusion Into cells Acidosis

37. Specific Antidote • Ethanol • Fomepizole Folinic acid Inhibition by Ethanol or Fomepizole

38. Rationale for the Use of Ethanol and Fomepizole • Ethanol has approximately 10 times greater affinity for alcohol dehydrogenase than does methanol. Therefore, ethanol competitively inhibits the metabolism of methanol to its toxic metabolite, formate, by occupying the receptor sites of alcohol dehydrogenase • Fomepizole has been shown to be a potent inhibitor of alcohol dehydrogenase • If administered soon after exposure, ethanol and fomepizole should prevent, or at least reduce, the further formation of toxic metabolites

40. Back to our patient Blood Methanol level > 30 mmol/L 30 mmol/L = 1000 mg/L __________ x 30mmol/L = 882 mg/L[ > 200mg/L ] 34 mmol/L Osmolar gap = 50.7 mOsm/kgH2O[ >10 mOsm/kgH2O] Worst Arterial pH = 7.30[ < 7.30] Worst bicarbonate = 17.7 mmol/L[< 20mmol/L]

41. Back to Our Patient [882 mg/L] [50.7 mOsm/kgH2O] [pH = 7.30] [17.7 mmol/L] [58 mOsm/kgH2O]

42. Ocular toxicity: Our patient has no “snow field” vision, blurring of vision, or constriction of peripherial visual field • Neurotoxicity: GCS 14/15, sleepy but arousable. Improved to GCS 15/15 on arrival to ICU • Cardiotoxicity: No cardiogenic shock, BP 115/52. Tachycardia with pulses 107 bpm. No cardiac arrhythmias • Resp toxicity: No tachypnoea, no pulmonary edema • GI toxicity: No vomiting. Amylase normal, no pancreatitis. LFT normal • Renal toxicity: RFT normal

43. Hong Kong Poison Information Centre • Ethanol loading dose: 0.8g/kg (1ml/kg 100% ethanol) diluted by D5 to a 10% ethanol solution iv over 20-60 mins • Maintenance infusion:1-2ml/kg/hr 10% ethanol solution to maintain an serum ethanol level at around 21.7mmol/L (100mg/dL) • Higher dose of maintenance (2-3.5ml/kg/hr 10% ethanol solution) is required during haemodialysis

44. Ethanol vs Fomepizole • There is no clinical data to confirm the superiority of fomepizole over ethanol. But, fomepizole may be preferred to ethanol • Fomepizole • is easier to administer than ethanol, • has a longer duration of action, • does not cause CNS depression, • does not reinforce dependence or provide satisfaction in patients with history of ethanol abuse, • is less injurious to veins compared to ethanol, • has a lesser risk of developing hypoglycaemia in children comparative to ethanol, • would be preferable in pregnant patient in the first trimester because of concerns regarding the fetal alcohol syndrome in ethanol

45. Ethanol dosing is complex Require a continuous IV infusion or an hourly oral dosing schedule Fomepizole dosing is simple 12-hour dosing schedule Is absorbed rapidly by the oral route, but is usually administered intravenously Loading: 15mg/kg iv Maintenance: 10mg/kg Q12h iv x 4 doses, then 15mg/kg iv Q12h Target serum concentration: in excess of 0.8mg/L Ethanol Fomepizole

46. Ethanol Co-ingestion with drugs that produce CNS depression Co-ingestion with disulfiram, metronidazole, or chlorpropamide  flushing and hypotension Patient with hepatic disease Recent history of gastrointestinal ulcers – avoid oral administration of ethanol Fomepizole Known hypersensitivity reactions to fomepizole Relative Contraindications to the Use of Ethanol and Fomepizole

47. Ethanol Signs and symptoms of ethanol intoxication: sedation, ataxia, slurred speech Hypoglycaemia, particularly in children and malnourished patients Local phlebitis Fomepizole Common: headache (12%), nausea (11%), dizziness (7%) Less common: vomiting, diarrhoea, abdominal pain, tachycardia, hypotension, vertigo, lightheadedness, nystagmus, slurred speech, eosinophilia, skin rash Adverse effects of Ethanol and Fomepizole

48. Enhance Elimination of Formic acid • Folinic Acid • Hemodialysis

49. Folinic Acid Folinic acid Inhibition by Ethanol or Fomepizole

50. Folinic Acid vs Folic Acid • Folinic acid is the reduced form of folic acid • Folinic acid is converted rapidly to the bioactive and storage forms of folate in the body: tetrahydrofolic acid derivatives • Folinic acid is preferred to folic acid since it does not require metabolic reduction