Management of specific poisons: Organophosphates and carbamate Alcohol

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Management of specific poisonsOrganophosphates
and carbamateAlcohol

• Dr. Manisha Desai

University College of Medical Sciences GTB
Hospital, Delhi
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History

• 1854 -Synthesis of OP compound (TEPP)- by
  Phillipe de Clermont. Not used actively then.
• 1930- Gerhard Schrader,German synthesised
  parathion.His priority shifted to nerve gas
  agents used during World War 2
• Early 1900 Carbamates were developed in Africa
  from calabar bean. Physostigmine, used to treat
  glaucoma
• 50 years later, neostigmine, was synthesized and
  used for the treatment of myasthenia gravis
• In 1960s and 1970s, carbamates were synthesized
  for pesticidal use.

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• CMs are preferred for pesticide use over OPs
  because the former are safer reversible
  inhibitors of AChE unlike OP.
• In 1984, an estimated 4 lakh people were exposed
  to a toxic methyl isocyanate gas (used in the
  production of CM pesticides) that leaked from the
  Union Carbide plant in Bhopal, India.
• Annual incidence of acute insecticide poisoning -
  3 million (approx.) worldwide.

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CHOLINERGIC POISONING

• Cholinergic (anticholinesterase) agents are used
  in
• clinical medicine (neostigmine, physostigmine)
• as insecticide
• as weapon of mass destruction(tabun,sarin,soman)
• Most anticholinersterase poisoning occurs during
  the
• agricultural use (accidental dermal
  contamination)
• home use of aerosol insecticide
• accidental and suicidal ingestion

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• ORGANOPHOSPHORUS POISONING

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STRUCTURE

• OP insecticides are anticholinesterase agents
  esters, amides or thiol derivatives of phosphoric
  acid.
• The R1 and R2 moieties are alkyl or aryl group
  and linked by oxygen and sulphur atom to
  phosphorus
  
• R1 O or S
• P
• R2 RL

PO - phosphate, oxon PS -
Phosphorothioate R1, R2 alkyl or aryl grp (
two methyl or two ethyl grp) RL leaving group
least stable, displaced on phosphorylation of
AChE. Specific to individual OP
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• Phosphorothioates,PS
  Phosphates,PO
• (Diazinon, Parathion)
  (Dichlorvos)
• -Require biological activation -
  Biologically active early
  
• delayed symptom onset
  symptom onset
• -Stored extensively in fat,
• prolonged intoxication,
• clinical relapse after
• apparent recovery.

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• Dimethyl OP (dichlorvas, malathion,
  dimethoate)
• Diethyl OP (chlorpyrifos,diazinon,parathion)
• Dimethyl phosphorylated AChE
• - faster rate of spontaneous re activation
• - may recover without oxime therapy

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How does AChE act?

• The entire process takes about 150 microseconds
• True AChE nervous tissue, surface of RBCs.
• ButyrylChE/PseudoChE- serum, liver.

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What do OP do?
Alkyl phosphorylation of Serine-OH group at the
esteric site of enzyme.
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• Forms an irreversible covalent phosphate linkage
• Extent of inhibition of AChE depends on the rate
  constant for the
• reaction and the time that the enzyme is
  exposed to the drug

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Further fate of the enzyme

• REACTIVATION spontaneous hydrolysis of the
  enzyme- OP complex may take many hrs.
• -accelerated by oximes.
• -with Carbamate poisoning, enzyme activity
  resumes in 24hrs
• AGEING - strengthening the phosphorus-enzyme
  bond by breakage of one of the oxygen phosphorus
  bond of the inhibitor
• - Once ageing has occurred ,the complex is
  difficult to split even with oximes
• - Enzyme resynthesis is the only mean to
  restore function

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Pharmacokinetics

• Effectively absorbed by all routes
• Dermal / conjunctival
• Inhalational during spraying
• Gastrointestinal Ingestion

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..Pharmacokinetics (contd.)

• Phase 1 reactions
• ?
• - Oxidative desulfuration, dearylation
• ?
• Reactive oxon metabolite (PS ? PO
  (oxons))
• Ex Parathion ? Paraoxon (1000 fold
  increase in potency)
• All Ops must be in oxon formation (PO) to
  inhibit AChE
• - Hydrolysis by paraoxanases, esterases
• Phase 2 reactions
• Conjugation metabolites are water soluble
  and readily excreted

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..Pharmacokinetics (contd.)

• Toxicity depends upon
• Activation step requirement (PS or PO)
• Fat solubility
• Magnitude of exposure(dose)
• Route (onset inhalation gt ingestion gt dermal)
• Suicidal attempt (large amount ingestion likely)
• Presence of solvent like xylene/emulsifier
  (enhances
• absorption)

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Exposure

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CASE REPORT

• A 28yr old female presented to ER in an
  unconscious state with frothing around mouth, and
  involuntary limb movements.Her clothes had
  particles of vomitus. A quick history from
  relatives revealed that patient was found
  unconscious and unresponsive at home with a half
  empty bottle beside

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• Examination
• vitals PR-66/min, regular
• BP-104/60 mm Hg
• RR- 20/min
• SpO2 94 room air
• CVS- S1, S2 normal
• RS B/L crepitations
• CNS GCS E1V1M5
• Pupils bilaterally constricted
• Fasciculations in limbs
• B/L plantars - mute

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PATHOPHYSIOLOGY

• The acute toxicity of anticholinesterase agents
• ?
• Irreversible inhibition of enzyme
  acetylcholinesterase
• ?
• Accumulation of acetylcholine at
• CNS and
• PNS
• - muscarinic sites in PNS,
• - nicotinic sites at sympathetic,
  parasympathetic ganglia and
• - nicotinic sites at NMJ

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INITIAL CHOLINERGIC PHASE - SIGNS SYMPTOMS
MUSCARINIC NICOTINIC CNS
CVS Bradycardia, Hypotension SYMP GANGLIA Tachycardia Hypertension Anxiety, ataxia, restlessness, tremors, insomnia
LUNGS ? secretions Bronchoconstriction SKELETAL MUSCLE Fasciculations, cramps, weakness, paralysis, resp arrest Convulsions , coma, absent reflexes
EYES Miosis ? lacrimation Blurred vision Mydriasis
GIT ? salivation Vomitting Diarrhea
SWEAT GLANDS ? sweating
BLADDER ? urination
DUMBELS Diarrhea,
Diaphoresis Urination Miosis
Bronchorrhea Bronchospasm Bradycardia
Emesis Lacrimation Salivation
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• Miosis, a typical muscarinic sign is not always
  present as mydriasis may occur due to concomitant
  overriding nicotinic stimulation and use of
  atropine
• Other findings-
• Hyperamylasemia with or without clinical
  pancreatitis
• ECG abnormalities- AV block, ST segment elevation
  and arrhythmias

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DIAGNOSIS

• History and high degree of suspicion (awareness
  of diversity of presentation is the first step)
• Examination typical clinical features
• Lab investigations
• Cholinesterase assays
• Nonspecific test like
• - Leukocyte count
• -Blood sugar levels
• - urinary nitrophenols

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RBC AChE

• Present on surface of RBCs.

USES DISADVANTAGES
Mirrors neuronal synapse AChE Rate of regeneration is slower than Butyryl ChE
Good marker of severity of poisoning, Hence less useful marker of recovery
Monitoring of levels may reveal possibilities of when to stop oxime therapy. (Research wrt this is on) Requires temperature control
Technically difficult to perform
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Butyryl/Pseudo choline esterase

• Present in liver and serum

USES DISADVANTAGES
Affected in OP poisoning. Also depressed in alcoholism, cirrhosis, hepatitis, malnutrition. Hence not specific to OP.
recovery indicated by 7 increase in levels each day once OP is eliminated. Some OP depresses it more than RBC AChE. Does not give true idea about neuronal AChE(unlike RBC AChE) and severity of poisoning
Hence, daily assays can be used to assess extent of elimination Only indicates exposure to OP or carbamate at best
More useful marker of recovery Individual variation in normal complement of plasma cholinesterase
Easier to perform test Requires temperature control
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..Cholinestersae assays (cont)

• To summarize, as a marker erythrocyte
  cholinesterase is invariably more specific than
  plasma cholinesterase. However, some OP, depress
  plasma cholinesterase to greater extent.
• Drawback of AChE assays
• Interactions continue to occur between OP,
  AChE and oximes if the blood sample is left at
  room temp even for a few mins.
• Recommended- freshly drawn blood diluted with
  cold saline (at 4 deg C) and place in freezer at
  -20 deg C within 5 mins.

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TREATMENT OF OP POISONING

• First aid
• -remove patient from the scene of exposure
  
• -remove contaminated clothing
• - skin, eyes washed thoroughly
• - assess breathing, circulation
• - place patient in left lateral position with
  head lower than feet to reduce risk of aspiration
• Airway management supplemental O2 to keep Pa
  O2 gt 75 mm Hg
• - Tracheal intubation and mechanical
  ventilation (suxamethonium is discourged -
  prolonged block)
• - Regular suctioning

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• -gastric decontamination - controversial,
• 
  - these agents are emetogenic
• 
  - OP are dissolved in hydrocarbon
• 
  solvent that result in significant
• 
  pneumonitis when aspirated
• - Nasogastric aspiration if patient presents
  within 1hr of ingestion.
• - Oral activated charcoal usually recommended
  as some OP binds activated charcoal

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Assessment of severity of OP poisoning
GRADES CNS Secretions Fasciculations Hypotension
0 Awake, alert - - - Only history
1 Awake, alert -
2 Drowsy (SBP lt90)
3 Drowsy/ Comatose Inc FiO2
4 Comatose PaO2 lt 60 on FiO2 gt40, PaCo2 gt45 Mechanical ventilation reqd Abnormal CXR
ICU admission if grade 2 Brent, Wallace,
Burkhart, et al. Organophosphorus and carbamate
insecticides, Methanol poisoning. Critical care
Toxicology.Diagnosis and management of the
critically poisoned patient. Philadelphia,
Elsevier Mosby, 2005 pp 937-947.
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TREATMENT OF OP POISONING

• Atropine
• Oximes ANTIDOTES
• Diazepam

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Atropine in OP poisoning

• Atropine is competitive antagonist of Ach at
  muscarinic receptor
• Has no effect on muscle weakness and paralysis
• No effect on AChE reactivation
• ROLE
• Control of pulmonary secretion and bronchorrhoea
• Control seizures and CNS manifestation of
  poisoning

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..Atropine (cont)

• DOSE
• - Adult - 1-3mg iv (0.05mg/kg) bolus 3
  mins.
• -Children 0.015-0.05mg/kg iv bolus
• ?
• repeated or doubled every 5-10 mins until
  HRgt80 per min/clear chest/symptoms improve
• ?
• atropine infusion started (10-20 of total
  initial dose every hour )

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• Atropine nebulisation in bronchorrhea.
• Dose - 1 amp diluted with 2 ml NS.
• 1 atropine nasal drops have recently been
  developed esp for war conditions (when nerve
  gases are used) because i.v. cannulation might be
  difficult in mass casualties and i.m inj takes
  time to act
• Ref Internet

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• - Inadequate atropine - cholinergic features
  will reappear.
• - Excess atropine- agitation,
  hyperthermia,ileus , urinary retention develops
• (Atropine
  toxicity)
• 
  ?
• stop infusion restart infusion after 30-60
  mins (70-80 initial rate)
• Duration of maintenance atropine- usually 24-48
  hrs (longer in severe cases), gradually withdrawn
  over 3-5 days

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Target end points for atropine therapy

• Clear chest on auscultation with no wheeze
• Heart rategt 80/min
• Pupils no longer pin point (does not imply that
  pupils must be dilated)
• Dry axilla
• Systolic BP gt 80 mm Hg
• Dilated pupils is not a reliable sign of initial
  atropinisation or end point for atropine therapy

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Glycopyrrolate

• Equally effective with fewer side effects
• Does not cross CNS
• ROLE
• Adjunct, when secretions are copious
• In atropine toxicity
• Dose
• 7.5 mg in 200 ml NS titrated infusion or
• 0.2 mg im stat repeated 6 hrly

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Diazepam

• ROLE
• - Reduces anxiety and restlessness
• - Reduces muscle fasciculation
• - Arrests seizures
• - Reduces morbidity and mortality
• - Beneficial role even in absence of seizure
• Dose-
• Adult- 5-10 mg iv 3 mins, repeated every
  10-15 mins (max 30mg in adults)
• Children - 0.2-0.3mg/kg iv 3 mins

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OXIMES IN OP POISONING
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Mechanism of action
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..oximes (cont)

• Monopyridinium oxime- pralidoxime
• Bispyridinium oxime- obidoxime, trimedoxime
• Rote of administration- intravenous, oral and
  intramuscular
• Appropriate plasma level of 20-40mg/L for
  pralidoxime 4mg/L for obidoxime

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..oximes (cont)

• DOSE
• WHO guideline recommends-
• Pralidoxime in 30mg/kg iv 10-20 min ?
  8mg/kg/hr infusion
• Obidoxime 250mg iv ? 0.4mg/kg/hr infusion
• Duration of Oxime infusion - continued till
  atropine is needed or until irreversible
  clinical improvement is achieved

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..oximes (cont)

• Possible explanation for the ineffectiveness of
  oximes are
• Slow reactivation
• Insufficient dose
• Formation of phosphoryloxime during the
  reactivation process may paradoxically inhibit
  acetylcholinesterase

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Adverse effects of oximes

• Transient increase in neuromuscular block
• Nausea, vomiting following the bolus dose
• Pralidoxime - pressor response and ECG changes
• Obidoxime transient liver damage

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Supportive Treatment

• Vasopressor therapy
• Diuretic pulmonary edema
• Antibiotics
• Temperature regulation

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Criteria for ICU discharge in OP poisoning

• Normal RBC or plasma cholinesterase activity
• No recurrence of symptoms or signs of cholinergic
  excess 24 hrs after discontinuation of oxime
  therapy

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• Medical management of OP poisoning demands close
  observation, timely institution of antidote in
  adequate doses and duration and good supportive
  care

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INTERMEDIATE SYNDROME

• Characterized by absent muscarinic symptoms with
  continued nicotinic symptoms and persistent AChE
  inhibition
• C/f onset 24 72 hrs after acute cholinergic
  crisis
• Pathophysiology inadequate oxime dosing
• -Most likely due to lesions in post synaptic
  striated muscle regions
• - Myonecrosis due to oxidative cellular damage
• Later studies down regulation or
  desensitization of nicotinic ACh receptors at
  post junctional membrane

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Patients at risk

• Poisoning due to OPs with delayed metabolism
• Severe poisoning
• Elevated muscle enzymes
• Delayed or inadequate oxime therapy

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IMS (cont)

• Clinical features NICOTINIC SYMPTOMS
• Paralysis of proximal limb muscles, neck flexors,
  cranial nerves, respiratory muscles, decreased
  DTR
• Rapid onset of difficulty in breathing
• Sensory impairment is not a feature

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Treatment of IMS

• Mainly supportive treatment
• Complete recovery in 4-18 days if adequate
  ventilatory support is provided
• Oximes - preventive

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OP INDUCED POLYNEUROPATHY (OPIDN)

• Delayed mixed sensorimotor peripheral
  neuropathies
• 7-14 days after exposure
• Pathophysiology Inhibition of neuropathy target
  esterase(NTE )
• C/f Symmetric, peripheral neuropathies
• Motor gt sensory
• Ataxia, gait disturbances
• Fate self-resolution / persistent deficits

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Common MISCONCEPTIONS about OP poisoning

• Oximes are of no benefit in OP poisoning
• Oximes are of no benefit if started after 24 hrs
  of onset of OP poisoning

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Carbamates

• Derivatives of N-methyl carbamic acid
• Inhibit AChE by carbamylation of serine hydroxyl
  residue at the enzyme active site
• Spontaneous reactivation of carbamylated enzyme
  within 24 hrs
• No ageing

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• Rapid absorption and biotransformation
• Clinical features
• Rapid onset of mild cholinergic features
• seizures are uncommon as CNS penetration is
  poor
• Life threatening complications rare
• Resolution of symptoms within hours
• Respiratory failure in untreated cases of severe
  poisoning

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Diagnosis and Treatment

• History
• Cholinesterase activity unlikely to be helpful
  because of rapid spontaneous enzyme reactivation
• TREATMENT
• First aid , Supportive t/t same as OP
• Atropine same as OP
• Pralidoxime seldom necessary
• - in severe
  poisoning, dose same as OP
• 
  
  

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KEY POINTS IN OP and CARBAMATE POISONING

• Common poisoning in our country
• Excess cholinergic syndrome
• History and clinical features are main clue to
  diagnosis
• Depending on insecticide s/s may be delayed for
  12 hrs (dermal exposure)
• Resuscitation, decontamination, specific antidote
  and supportive measures is the mainstay of t/t.
• Spontaneous activation depends on chemical
  structure (more with carbamates, dimethyl OP)

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Key points (contd.)

• Oximes are indicated particularly for diethyl OP
• Oximes must be given in sufficient doses and be
  continued as long as atropine is required
• Enzyme activity in carbamate poisoning resolves
  within 24 hrs
• Though Carbamates are less toxic than OP, it must
  not be assumed that they are benign

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ALCOHOL (METHANOL) POISONING
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METHANOL

• Wood alcohol / colonial spirit
• CH3OH
• Colourless, volatile, highly flammable liquid,
  weak smell similar to that of ethanol
• Freely miscible with water, ethanol, organic
  solvents

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Uses of Methanol

• Earlier, obtained from distillation of wood.
  These days it is synthetically prepared
• Widely used as intermediate in manufacture of
  other chemicals and in production of formaldehyde
• Gasoline, antifreeze, windshield wiping fluid,
  paint, solvents for cleaning solutions, dyes,
  varnishes, enamels, paint removers
• ? Alternative energy source in combustion engines

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Methanol - poisoning

• Isolated cases of accidental or intentional
  ingestion
• Epidemics mistakenly substituted for ethanol or
  methanol contaminants are used to ferment wine or
  illicitly distill alcoholic beverages
• Rarely, via dermal and inhalational routes

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Methanol pharmacokinetics

• Rapid absorption following ingestion
• ?
• Distribution analogous to body water
• ?
• Peak concentration within 30-60 mins
• Lethal dose 30240 ml 1g/kg (1.2ml/kg)

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..Methanol pharmacokinetics (cont)
THF 10 formyl THF
Ethanol Fomepizole inhibit
Methanol per se low toxicity Formaldehyde ?
formic acid is very rapid only latter
accumulates
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Pathophysiology

• formic acid accumulates
• ?
• metabolic acidosis
• Inhibits cyt c oxidase in mitochondria
• ?
  
• histotoxic hypoxia
• (Optic N,retina have fewer mitochondria ?
  particularly susceptible )

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Inhibition of cyt c oxidase is greater as
acidosis increases
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Clinical features

• Mild CNS depression (confusion,lethargy)
  ? latent
  period 12-24hrs

VISUAL CNS GIT
Blurred vision Headache Nausea , vomiting
Photophobia Vertigo Abdominal pain
Weak pupillary reflex, fixed dilated pupils Convulsions Pancreatitis
Hyperemia of optic disc Coma
Visual field contraction Parkinson like syndrome
Retinal edema
Permanent blindness in 25-33
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• Coma, shock, persistent acidosis, anuria are
  serious prognostic signs
• ?
• Death

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Diagnosis

• History amount, concentration, time, visual
  symptoms, ?mixed with ethanol
• Examination vitals, CNS , pupil examination,
  fundoscopy
• CBC usually normal
• ABG metabolic acidosis
• KFT BUN, Se.electrolytes,Se.creatinine
• Amylase

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..Diagnosis (cont)

• Osmolal gap (OG) measured osmolality(OM )
  calculated osmolarity (OC )
• Normally, OG -10mOsm/kgH2O
• For every mg/dl ? in methanol, OG ? 0.34
  mOsm/kg. May reach 20mOsm/kgH2O
• Formic acid does not contribute to this
• Anion gap (Na K ) (HCO3- Cl- )
• Normally 12-16mmol/L
• Formic acid and lactic acid contribute to
  this
• As poisoning progresses, OG decreases and
  anion gap increases

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..Diagnosis (cont)

• Serum formate normally lt1.2mg/dl
• gt20-30mg/dl
  visual symptoms
• Serum methanol rise after peak absorption
• gt20mg/dl-
  significant
• Imaging NCCT b/l putamen necrosis
  

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TREATMENT

• Gastric decontamination not beneficial
• Activated charcoal methanol not adsorbed
• Aggressive treatment of metabolic acidosis
  NaHCO3 if pH lt7.3
• Improvement in visual symptoms, shock
• Fomepizole or Ethanol inhibit ADH

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treatment (cont)
American Academy of Clinical Toxicology Practice
Guidelines on the Treatment of Methanol
Poisoning. Clinical Toxicology 2002
40(4)415446
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treatment (cont)
FOMEPIZOLE ETHANOL
Prevents visual dysfunction and acidosis Prevents visual dysfunction and acidosis
Easy to administer Complex dosing
Longer duration of action Short duration
Lab monitoring not required Required
No CNS depression, hypoglycemia CNS depression, hypoglycemia, flushing, hypotension
Does not reinforce dependence May do so
CI in known hypersensitivity reactions Avoided/caution in liver disease, GI ulcers
Expensive Cheaper
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Fomepizole

• Diluted in NS, dextrose
• Loading dose 15mg/kg iv over 30 mins, fb
  10mg/kg iv every 12 hrs for 4 doses, fb 15mg/kg
  iv every 12 hrs if needed
• Given till blood methanol lt 20 mg/dl, pH is
  normal
• Reduces need for hemodialysis

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Ethanol

• Dose - Bolus dose of 0.6g/kg
• maintenance -66 -154 mg/kg/hr iv or oral
• Blood ethanol level monitored every 1-2 hrs.
• Recommended level of 100mg/dl
• Continued until Se.methanol lt20mg/dl and pH is
  normal
• Hemodialysis removes ethanol. Maintenance dose
  should be doubled during hemodialysis

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Hemodialysis

• Indications
• persistent pH lt7.25-7.3
• Deteriorating visual signs despite treatment
• Renal failure
• Serum methanol gt50mg/dl
• Continued until serum methanol lt20 mg/dl and
  acidosis is corrected
• If blood methanol levels are not available, HD
  must be done for at least 8 hr

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Supportive treatment

• Folinic acid precursor of folate
• favours formic acid ?
  CO2 H2O
• - Dose 1mg/kg iv every 4-6 hrs
• IVF, vasopressor therapy
• Correction of electrolyte disturbances
• Visual function assessment by opthalmologist

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SUMMARY

• Common errors in methanol poisoning is delayed
  diagnosis.
• Any case of metabolic acidosis of unknown cause
  should be suspected as methanol poisoning.
• Ethanol during hemodialysis must be doubled.

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References

• Brent, Wallace, Burkhart, et al. Organophosphorus
  and carbamate insecticides, Methanol poisoning.
  Critical care Toxicology.Diagnosis and management
  of the critically poisoned patient. Philadelphia,
  Elsevier Mosby, 2005 pp 937-947.
• Irwin RS, Rippe JM. Alcohol poisoning, OP
  poisoning.Intensive care medicine pp 1469-1486.
• Joshi S et al. Management of organophosphorus
  poisoning. Update in Anaesthesia 2005.
• Eddleston M, Buckley NA, Eyer P. Management of
  acute organophosphorus pesticide poisoning.
  Lancet 2008371597-607.
• American Academy of Clinical Toxicology Practice
  Guidelines on the Treatment of Methanol
  Poisoning. Clinical Toxicology 2002
  40(4)415446