knut erik hovda, md, phd the norwegian center for nbc medicine department of acute medicine oslo...

Knut Erik Hovda, MD, PhDThe Norwegian Center for NBC Medicine

Department of Acute MedicineOslo University Hospital, Ullevaal

Oslo, Norway

Methanol poisoning outbreaks – Rapid diagnosis and management

APAMT 2011 Penang, Malaysia

Overview

• Background – Methanol and its metabolism– The methanol challenge– Goal and room for improvement– Obstacles– A possible solution: The formate analysis

• Results/discussion• Conclusion

Methanol and metabolism

Adjusted from Hovda KE. PhD thesis 2005.

The methanol challenge

• High morbidity and mortality, even with small doses (minimum lethal dose estimated 1g/kg1)

• 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

1Roe O. Crit Rev Toxicol 1982; 10(4): 275-286

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

Diagnostics….(I)

1. Patient history2. Clinical features

1. Hyperventilation2. Pseudopapillitis*3. Symtoms may vary (visual disturbances, GI-

symptoms, chest pain, dyspnoea)

*hyperemia of the papilla without dioptric difference

Diagnostics….(I)

1. Patient history2. Clinical features

1. Hyperventilation2. Pseudopapillitis*3. Symtoms may vary (visual disturbances, GI-

symptoms, chest pain, dyspnoea)

*hyperemia of the papilla without dioptric difference

Diagnostics….(I)

1. Patient history2. Clinical features

1. Hyperventilation2. Pseudopapillitis*3. Symtoms may vary (visual disturbances, GI-

symptoms, chest pain, dyspnoea)

*hyperemia of the papilla without dioptric difference

Pseudopapillitis

Before After

Methanol exposureFrom Ingemansson SO. PhD thesis Stockholm 1983

Diagnostics….(I)

1. Patient history2. Clinical features

1. Hyperventilation2. Pseudopapillitis*3. Symtoms may vary (visual disturbances, GI-

symptoms, chest pain, dyspnoea)

*hyperemia of the papilla without dioptric difference

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

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

BUFFERS (Hb, proteins)

ACIDOSIS

Formate¯

H + Formic acid

Methanol

↑ OG

Antidote

CO₂

HCO₃¯

Hypervent

H₂O

BUFFERS (Hb, proteins)

ACIDOSIS

Formate¯

H +Formic acid

Methanol

↑ OG

Antidote

↑ AG

CO₂

HCO₃¯

Hypervent

H₂O

BUFFERS (Hb, proteins)

ACIDOSIS

Formate¯

H +Formic acid

Methanol

↑ OG

Antidote

Three stages of methanol poisoning

Hovda KE et al. Int Care Med 2004; 30(9): 1842-6

0

10

20

30

40

50

60

70

80

Res

ult o

f ana

lyze

s (m

mol

/L

or m

Osm

/kgH

2O)

Anion gap

Osmolal gap

S-methanol

S-formate

AG

OG

AG

OG

AG

OG

EARLY INTERMEDIATE LATE

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

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

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! 1Sejersted OM et al. Tidsskr Nor Laegeforen 1981: 699-7062Hovda KE et al. J Intern Med 2005; 258(2): 181-903Bennett JL et al Medicine(Baltimore)1953;32:431-463 4Paasma R et al. Clin Toxicol 2007; 45:152-1585Swartz RD et al Medicine(Baltimore)1981;60: 373-382

Diffuse symptoms

Often lacking

Septic? Other MA?

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.

Possible solution (I)The formate analysis

• Background:– Formate – the toxic metabolite of

methanolNo formate produced = no symptoms from

methanol poisoning: Patients admitted with a metabolic

acidosis without increased S-formate = metabolic acidosis NOT because of metOH poisoning!

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 3rd world) and lack of necessary reagents

HCOOH + NAD+ ↔ CO2 + NADH + H+

enzyme: Formate dehydrogenase (FDH)

NADH: absorbance of 340 nM:

Possible solution (III)Formate analysis - principles

FDH

FDH

Hovda KE. PhD thesis 2005.

1Schaller 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.

Simplified algorithmPatient with

suspected metOH poisoning

Metabolic acidosis

No metabolic acidosis

S-formate ↑ 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

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

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

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?)

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

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

Thank you for your kind attention!

k.e.hovda@medisin.uio.no