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