1. Knut Erik Hovda, MD, PhD The Norwegian Center for NBC Medicine Department of Acute Medicine Oslo University Hospital, Ullevaal Oslo, Norway Methanol poisoning outbreaks – Rapid diagnosis and management APAMT 2011 Penang, Malaysia

2. Overview Background –Methanol and its metabolism –The methanol challenge –Goal and room for improvement –Obstacles –A possible solution: The formate analysis Results/discussion Conclusion

3. Methanol and metabolism Adjusted from Hovda KE. PhD thesis 2005.

5. The methanol challenge High morbidity and mortality, even with small doses (minimum lethal dose estimated 1g/kg 1 ) Specific and efficient treatment exists, but suffers from often late diagnosis and initiation of treatment Probably the most frequently reported toxicant in outbreaks, these are often in the developing world 1 Roe O. Crit Rev Toxicol 1982; 10(4): 275-286

6. Goal and room for improvement Strategy for mass poisonings: –The general medical rule applies: Optimal treatment for as many as possible How: –Early diagnosis –Effective treatment –Cost-beneficial treatment

7. Diagnostics….(I) 1.Patient history 2.Clinical features 1.Hyperventilation 2.Pseudopapillitis* 3.Symtoms may vary (visual disturbances, GI- symptoms, chest pain, dyspnoea) *hyperemia of the papilla without dioptric difference

8. Diagnostics….(I) 1.Patient history 2.Clinical features 1.Hyperventilation 2.Pseudopapillitis* 3.Symtoms may vary (visual disturbances, GI- symptoms, chest pain, dyspnoea) *hyperemia of the papilla without dioptric difference

9. Diagnostics….(I) 1.Patient history 2.Clinical features 1.Hyperventilation 2.Pseudopapillitis* 3.Symtoms may vary (visual disturbances, GI- symptoms, chest pain, dyspnoea) *hyperemia of the papilla without dioptric difference

10. Pseudopapillitis Before After Methanol exposure From Ingemansson SO. PhD thesis Stockholm 1983

11. Diagnostics….(I) 1.Patient history 2.Clinical features 1.Hyperventilation 2.Pseudopapillitis* 3.Symtoms may vary (visual disturbances, GI- symptoms, chest pain, dyspnoea) *hyperemia of the papilla without dioptric difference

12. Diagnostics….(II) 3.Analytical features: a.Arterial blood gas (ABG) b.Osmolal gap (OG) (to be used together with the anion gap (AG)) c.Specific serum analyses of the toxic alcohol (gold standard. Time consuming and less available) d.S-formate analysis* (very simple, cheap and fast. High specificity and sensitivity. At present less available) * Hovda KE et al. J Anal Toxicol 2005; 29(6): 586-588

13. Diagnostics….(II) 3.Analytical features: a.Arterial blood gas (ABG) b.Osmolal gap (OG) (to be used together with the anion gap (AG)) c.Specific serum analyses of the toxic alcohol (gold standard. Time consuming and less available) d.S-formate analysis* (very simple, cheap and fast. High specificity and sensitivity. At present less available) * Hovda KE et al. J Anal Toxicol 2005; 29(6): 586-588

14. BUFFERS (Hb, proteins) ACIDOSIS Formate¯ H + Formic acid Methanol ↑ OG Antidote

15. CO ₂ HCO ₃ ¯ Hypervent H₂OH₂O BUFFERS (Hb, proteins) ACIDOSIS Formate¯ H + Formic acid Methanol ↑ OG Antidote

16. ↑ AG Cl¯ HCO ₃¯ Prot¯ CO ₂ HCO ₃ ¯ Hypervent H₂OH₂O BUFFERS (Hb, proteins) ACIDOSIS Formate¯ H + Formic acid Methanol ↑ OG Antidote

17. Three stages of methanol poisoning Hovda KE et al. Int Care Med 2004 ; 30(9): 1842-6

18. Diagnostics….(II) 3.Analytical features: a.Arterial blood gas (ABG) b.Osmolal gap (OG) (to be used together with the anion gap (AG)) c.Specific serum analyses of the toxic alcohol (gold standard. Time consuming and less available) d.S-formate analysis* (very simple, cheap and fast. High specificity and sensitivity. At present less available) * Hovda KE et al. J Anal Toxicol 2005; 29(6): 586-588

19. Diagnostics….(II) 3.Analytical features: a.Arterial blood gas (ABG) b.Osmolal gap (OG) (to be used together with the anion gap (AG)) c.Specific serum analyses of the toxic alcohol (gold standard. Time consuming and less available) d.S-formate analysis* (very simple, cheap and fast. High specificity and sensitivity. At present less available) * Hovda KE et al. J Anal Toxicol 2005; 29(6): 586-588

20. Obstacles (I) 1.Symptoms mimicking other diagnoses: Typical symptoms: –Dyspnoea (15-41%) 1-4 –GI symptoms (18-67%) 1-5 –Visual disturbances (33-55%) 1,2,4,5  Hyperventilation! 1 Sejersted OM et al. Tidsskr Nor Laegeforen 1981: 699-706 2 Hovda KE et al. J Intern Med 2005; 258(2): 181-90 3 Bennett JL et al Medicine(Baltimore)1953;32:431-463 4 Paasma R et al. Clin Toxicol 2007; 45:152-158 5 Swartz RD et al Medicine(Baltimore)1981;60: 373-382 Diffuse symptoms Often lacking Septic? Other MA?

21. Obstacles (II) 2.Resources (economical and knowledge) and lack of equipment Methanol analysis involves GC-MS and is not available most places. Time consuming. Osmolality analysis is hardly ever available outside the developed world. Excellent substitute if available, but unspecific.

22. Possible solution (I) The formate analysis Background: –Formate – the toxic metabolite of methanol No formate produced = no symptoms from methanol poisoning:  Patients admitted with a metabolic acidosis without increased S-formate = metabolic acidosis NOT because of metOH poisoning!

23. Possible solution (II) Pro et contra +Advantage: +Cheap +Simple (used on very frequently found analyzers. Kit.) +Fast (<30 min) +Kits can be stored in central places (Can be stored for decades) -Limitation: -Lack of knowledge -Lack of necessary apparatus (generally available most places, also in many parts of the 3 rd world) and lack of necessary reagents

24. HCOOH + NAD + ↔ CO 2 + NADH + H + enzyme: Formate dehydrogenase (FDH) NADH: absorbance of 340 nM: Possible solution (III) Formate analysis - principles FDH Hovda KE. PhD thesis 2005. 1 Schaller KH, Triebig GT. Formate Determination with Formate Dehydrogenase. In: Bergmeyer HU, editor. Methods of enzymatic analysis. 3rd ed. Weinheim, Germany: Verlag Chemie; 1984. p. 668-72.

26. Simplified algorithm Patient with suspected metOH poisoning Metabolic acidosis No metabolic acidosis S-formate ↑S-formate - S-formate ↑ Methanol poisoning Metabolic acidosis of other origin New S-formate after 4-6 hrs if still suspicious or metabolic acidosis Early, no metabolism yet or no methanol poisoning

27. The formate analysis – a prospective study 15 methanol poisoned patients*: –15/15 ↑ S-methanol (13-450 mg/dL / 4-141 mmol/L) –10/15 symptoms –14/15 ↑ S-formate (2-148 mg/dL / 0.4-32 mmol/L)  S-formate detected in 4/5 before symptoms started Very sensitive (1.3 mmol/L or 4 mg/dL) and specific** Upper reference range 0.4 mmol/L or 2 mg/dL** * Hovda KE et al. J Anal Toxicol 2005; 29(6): 586-588 **Urdal P. Clin Chem 1984; 30: 911-913

28. Suggestion for a formate kit Content: –1 vial of formate dehydrogenase –1 vial of NAD + –1 vial with positive control –1 direction for use 1 kit can be used for 10, 50 or even 100 patients within a few days. Very low costs NAD FDH

29. Economical aspects Estimated prize; –Formate dehydrogenase (FDH) represents approximately 70% of the costs of the method (the rest is mainly NAD-costs) –Cost of 250U of FDH; Euro 256 (USD 325) Need for FDH pr analysis; 1.6-1.8U –Total cost/analysis; Euro 2-3? (USD 2.5-4?)

30. Result/discussion Developing countries: Earlier diagnosis and hence better treatment where it is mostly needed Developed countries: Simplified diagnosis (and hence treatment?), especially during mass outbreaks: Fast, secure and efficient approach. Cost-beneficial Great value of the method in the clinical setting with a metabolic acidosis of unknown origin

31. Conclusion The formate analysis legitimate its existence in the diagnostic setting because: –It is fast and cheap, has a high sensitivity and specificity –Used on metabolic acidosis of unknown origin it enhances a simple diagnostic approach –Otherwise undiagnosed patients can get their correct diagnosis and treatment established –Interesting both where resources are scarce and in western countries for fast diagnosis and positive cost-benefit

32. Thank you for your kind attention! k.e.hovda@medisin.uio.no