Selected Toxicological Antidotes

1
Selected Toxicological Antidotes
Joel Turner, CCFP, FRCP (R5) Dept. of Emergency
Medecine McGill University
2
Selected Toxicological Antidotes

• Present 3 cases
• Epidemiology, pathophysiology
• Conventional treatment of each.
• Their limitations
• Specific antidotes
• Mechanism of action
• Indications
• Dosing instructions
• Benefits and side effects

3
Case 1. Lub/Dub
Lub/Dub

• 65 year old male found comatose at home
• En route BP 80/s HR 30 RR 10
• On arrival, he is intubated.

4
Case 1. Lub/Dub
Lub/Dub
1. Atropine 1 mg given ? no response 2. Bolus 500
cc NS ? no response

• Atropine 2mg ? no response
• Pacing Paddles placed ? BP drops
• 5. Dopamine infusion started
• (at 20 ug/kg/min) ?HR at 40

5
Case 1. Lub/Dub
Lub/Dub

• Finally, family member brings in an empty
  bottle of propranalol ( 5 grams missing)

Diagnosis Beta Blocker overdose
6
Beta Blockers
Beta Blocker overdose - epidemiology
2000 1. U.S - 11,064 exposures
(3.6100,000) - 2,829 lt 6yrs (25) - 2,491
intentional (22) 2. Quebec - 247 exposures
(3.5100,000) - 30 in lt 6yrs (12 ) - 121
intentional (49)
7
Beta Blockers
8
Beta Blockers
Treatment of Bradycardia

• ABCs

• Circulatory support

• ACLS guidelines
• hypotension fluids, dopamine
• bradycardia atropine, pacers, dopamine

9
Beta Blockers

1. Atropine limited effects (bradycardia is not
   due to increased vagal tone)

? Increases HR only 22 of the time
10
Beta Blockers

1. Catecholamines (epi, dobutamine, dopamine) often
   are ineffective in treating ?-blocker effect.

? Dopamine 25 effective, Epi 67 effective
Catecholamines
?-blocker
Therefore, must find something that will bypass
this blocked receptor
11
Beta Blockers

1. Glucagon

?Drug of choice for ?-blocker ( CCB) O.D.

• Secreted by pancreas secondary to hypoglycemia
• Glucagon Receptors found in heart muscle
• Acts by stimulating adenylate cyclase.
• independent of ?-receptor

glucagon

?-blocker
Glucagon receptor
12
Beta Blockers
Glucagon

• The final outcome
• positive chronotropic and inotropic effects
  despite ?-adrenergic blockade.
• Onset within minutes, peak levels in 5-7
  minutes, duration of action of 10-15 minutes.

13
Beta Blockers
Glucagon - evidence.

• Many animal studies of Glucagons cardiac effects
• Human Studies
• ?About 15-20 case reports of glucagon benefit,
  when other modalities failed.
• Only two case reports of glucagon benefit where
  glucagon was the sole agent used.
• About 5 cases of treatment failure

No prospective studies exist
14
Beta Blockers
Glucagon - How to give

• Available as a 1-unit (1-mg) or 10-unit (10-mg)
  lyophilized powder accompanied by 1 cc or 10 cc
  diluent
• Initial dose (adults or pediatrics)
• 50ug/kg (3.5 mg in 70 kg) infused over 1 min.
• If ineffective, higher doses (up to 10 mg) can
  be tried.
• infusion
• 2-5 mg/hr in D5W (0.1 mg/kg/hr Peds).
• (response dose/hr)

15
Beta Blockers
Glucagon - precautions

• Diluent contains 2 mg/ml phenol as preservative
• Max 10-h dose of phenol 50 mg 5mg glucagon
• Use sterile water instead of diluent

• Side effects from glucagon include
• dose-dependent nausea and vomiting ? aspiration
• hyperglycemia, hypokalemia (not clinically
  important)
• Some Reports of treatment failure

16
Beta Blockers
4. Insulin??
Shown to have positive inotropic effects on
animal and human myocardium
17
Beta Blockers
Insulin in Acute Beta Blocker OD.
Kerns, et al. Ann Em Medicine. 1997. 29748-757

• 24 dogs, anesthetized and infused with Inderal.
• Hemodynamics before after treatment with
• Normal Saline (n6)
• Insulin (4IU/min) glucose PRN (n6)
• Glucagon (50 ug/kg) infusion (n6)
• Epinephrine (1ug/kg/min) titrated (n6)

18
Beta Blockers
Results 6/6 Controls died within 150 min 5/6
Epinephrine animals died after 240 min 2/6
Glucagon animals died 0/6 Insulin animals
died
Kaplan-Meier Survival Curve Insulin vs. Glucagon
(plt0.05) Insulin vs. Epinephrine (plt0.02)
19
Beta Blockers
Insulin in Acute Beta Blocker OD.
Pathophysiology ?
1. May enhance catecholamine release 2. May
enhance myocardial substrate use In
normal myocardium, FFA are preferred substrate.
In poisoned myocardium, glucose becomes
1o substrate 3. May increase cytosolic calcium
20
Questions ??
21
Case 2. Saturday Nights all right for drinking

• 35-year male, brought it to ED, with ataxic
  gait.

• Vomiting , c/o abdominal cramps - smells and
  looks drunk.
• Patients mental status quickly deteriorates
  Vitals remain normal, Physical exam - WNL

What tests do you order?
22
Case 2. Saturday Nights all right for drinking
Anion Gap
32
ABG 7.10/20/10/95
Ca 2.3 mmol/L
ASA, APAP neg ECG - normal
Ethanol 1.1 mmol/L Osmolal Gap 57 !
Imp Toxic alcohol ingestion
23
Ethylene Glycol / Methanol
Ethylene Glycol
Methanol
24
Ethylene Glycol / Methanol
Toxic Alcohol overdose the numbers

• 2000
• U.S.
• - 5837 E.G. poisonings (2100,000)
• - 2474 Methanol poisonings (0.8100,000)
• - 1460 in age lt 6yrs (18)
• - 862 intentional (10)
• Quebec
• - 311 E.G. intoxications (4.4100,000)
• - 732 methanol intoxications (10100,000)
• - 318 in age lt 6 yrs (30)
• - 46 intentional (4)

25
Ethylene Glycol / Methanol
Toxic Alcohol overdose the numbers
Regional Distribution in Quebec
26
Ethylene Glycol / Methanol
Methanol Ethylene Glycol
Alcohol dehydrogenase
Glycoaldehyde
Formaldehyde
Aldehyde dehydrogenase
Formic acid
Glycolic acid
Lactic Dehydrogenase Or Glycolic acid Oxidase
Folate
A-OH-B ketoadipic acid Glycine and benzoic acid
Th
CO2 H2O
Glyoxylic acid Oxalic acid
B6
27
Case 2. Saturday Nights all right for drinking
Bedside pearls (ethylene glycol) i)
hypocalcemia suggests ethylene glycol ii)
urine calcium oxalate crystals (50) iii) urine
fluorescence (w/in 30 min) NOT sensitive (some
antifreezes do NOT contain fluorescein) (Do
not put urine in glass container false
pos) iv) normal gap does NOT rule out toxicity
28
Ethylene Glycol / Methanol

• Initial management
• ABCs (remember the impending CNS depression)
• Initiate specific treatment if ingestion strongly
  suggested Do NOT wait for lab values
• Untreated, lethal dose (apr. 100 cc) will cause
  death in about 24 hours.

29
Ethylene Glycol / Methanol

• Goal of Specific Treatment
• Prevent further metabolism of toxic alcohol
• Eliminate alcohol from circulation

X
Formic, glycolic or Oxalic acid
Toxic Alcohol
ADH
Eliminated (renal, dialysis)
30
Ethylene Glycol / Methanol

• Indications of specific treatment
• Methanol levels gt 6.3 mmol/L
• Ethylene Glycol gt 3.2 mmol/L, or
• Suspicion of ingestion and metabolic acidosis.

31
Ethylene Glycol / Methanol

• 1. Ethanol
• Traditionally been used as antidote for Methanol
  and Ethylene Glycol (never approved)
• Historical Case series/reports only (1st report
  1959)
• Never prospectively/retrospectively studied
• Preferred substrate of alcohol dehydrogenase
• ? therefore inhibits formation of NEW toxic
  substrate

Toxic Alcohol
X
ADH
Ethanol
32
Ethylene Glycol / Methanol
Ethanol How to give.

• What amount will completely block the
  metabolism of methanol/ethylene glycol?

• Can be given IV or PO. (each has its own
  advantages and disadvantages)

• Objective (regardless of route) quickly
  achieve and maintain ethanol level ? 22 mmol/L
• or (100 g/dL)

33
Ethylene Glycol / Methanol
Ethanol (IV or PO) Loading Dose (over 1 hour)
plasma x Vd 1g/L (100 g/dl) x 0.8
g/kg For 70 kg person ? 56 grams
ethanol 280 cc of 20 ethanol (4 cc/kg)
560 cc of 10 ethanol (8 cc/kg) 1120 cc of
5 ethanol (16 cc/kg)
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Ethylene Glycol / Methanol
Ethanol (IV or PO)
Maintenance Dose ? to replace what is being
eliminated 66-130 mg/kg/hr Using 10
Etoh, Average in 70 kg person 5.6 g/hr 56
cc/hr (double in alcoholic) 10 g/hr 105
cc/hour
35
Ethylene Glycol / Methanol
Lots of problems with Ethanol!!

1. Oral Absorption is erratic (and difficult)
2. IV preparations rarely shelved
3. Math is challenging (many reports of errors)
4. Kinematics vary between pts. and in same pt.
5. Causes even more profound CNS depression
6. Need large volumes (1120 cc bolus of 5 etoh)
7. Etoh intoxication can cause hypoglycemia,
   gastritis, pancreatitis
8. Use of Ethanol mandates hourly ethanol and
   glucose checks in ICU
9. Duration can take as long as 100 hrs (depending
   on dialysis)

36
Ethylene Glycol / Methanol
2. Fomepizole (4-methypyrazole)

• Introduced in 1986

• Competitive Inhibitor of Alcohol dehydrogenase
• (in vitro 80,000 times affinity for ADH than
  methanol)

Toxic Alcohol
ADH
Formic, glycolic or oxalic acid
37
Ethylene Glycol / Methanol
2. Fomepizole (4-methypyrazole)

• Introduced in 1986

• Competitive Inhibitor of Alcohol dehydrogenase
• (in vitro 80,000 times affinity for ADH than
  methanol)

Toxic Alcohol
-
Fomepizole
X
ADH
Eliminated (renal, dialysis)
Formic, glycolic or oxalic acid
38
Ethylene Glycol / Methanol
Evidence

• Fomepizole in E.G. poisoning
• 10 Cases prevention or normalization of
  acidosis and renal failure (/- dialysis)
• M.E.T.A. Study group Brent, et al. NEJM 1999.
  340832
• 19 consecutive pts. with confirmed E.G.
  poisoning
• Treated with fomepizole (and dialysis if
  indicated)
• ? 18/19 survived
• ? prevented RF in 10/10 pts with initially
  normal Cr.
• ? eventual normalization of Cr in 6/9 pts with
  ARF

Indications for dialysis -pHlt7.1, worsening
acidosis -Crgt265, worsening ARF -E.G.
gt 8.1 mmol/L
39
Ethylene Glycol / Methanol

1. Fomepizole in methanol poisoning

? Only 4 case reports (first one 1997)
? M.E.T.A. Study group Brent, et al. NEJM 2001.
344424

• 11 consecutive pts. with confirmed methanol
  poisoning
• Treated with fomepizole (and dialysis if
  indicated)
• Outcomes followed formic acid , visual
  acuity, pH
• ? 9/11 patients survived
• visual deficits reversed in 7/7 patients
• Acidosis resolved in all 9 patients

Indications for dialysis -pHlt7.1, worsening
acidosis -methanol gt 15.6 mmol/L -Any
visual symptoms
40
Ethylene Glycol / Methanol
Fomepizole (4-methypyrazole)
? Approved by FDA for E.G. poisoning in 1997,
and for methanol poisoning in 2000
41
Ethylene Glycol / Methanol
Ethanol vs. Fomepizole??

• No human studies comparing EtOH vs. Fomepizole
• Only 2 animal studies
• In dogs, fomepizole increased urinary excretion
  of E.G. compared to ethanol (Toxicol Lett.
  1987.35307)
• In Cats, Fomepizole was less effective than Etoh
  in preventing ARF if given 2 hours after
  intoxication with E.G. (dosing issues) (Am J Vet
  Res. 1994. 551771)

42
Ethylene Glycol / Methanol
Fomepizole - How to Give
Can be given PO or IV

1. Loading Dose 15 mg/kg
2. Maintenance 10 mg/kg bolus q12 h x 48 hrs
3. Maintenance 15 mg/kg bolus q12 h until end

Endpoint Methanol levels lt 6.3
mmol/L Ethylene Glycol lt 3.2 mmol/L
43
Ethylene Glycol / Methanol
Change in dialysis recommendations with
Fomepizole? Historical indications for dialysis
with E.G. 1. pHlt7.1, or worsening acidosis
despite treatment 2. Crgt265, worsening ARF 3.
E.G. gt 8.1 mmol/L
Borron S, et al. 1999 Lancet. 354831 Following
E.G. ingestion (Median 16.5), 7 patients
with initial normal Cr and no acidosis were
treated with Fomepizole and NOT dialyzed ? No
adverse effects
44
Ethylene Glycol / Methanol
Change in dialysis recommendations with
Fomepizole?
For E.G. intoxication, ? In the absence of
metabolic acidosis, patients who present with
normal renal function would not be expected to
require hemodialysis, regardless of the EG
concentration. Sivilotti, et al. 2000, Ann Em
Med. 36114
45
Ethylene Glycol / Methanol
Change in dialysis recommendations with
Fomepizole?
Historical indications for dialysis for
Methanol 1. pHlt7.1, or worsening acidosis
despite treatment 2. Any visual symptoms 3.
Methanol gt 15.6 mmol/L
Megarbane, et al. 2001. Int. Care Med.
271370 Following methanol intoxication ( gt
15.6) 4 patients without visual impairment or
acidosis recovered fully after fomepizole (no
dialysis)
46
Ethylene Glycol / Methanol
Fomepizole Advantages

1. Does not require separate preparations
2. Therapeutic levels are reliably achieved
3. No Change in mental status
4. No risk of hypoglycemia, hepatotoxicity
5. Hemodialysis not needed in subgroup of patients

Main Disadvantage Cost!
Apr. 1000 US per 1500 mg vial Suggested shelf
life of drug 3 yrs U.S. Manufacturer (Orphan
Medical) will replace drug at no charge
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Questions ??
48
Case 3. Gimme Sugar
54 year old male brought in by police because of
extreme agitation. While being subdued, patient
becomes lethargic, and begins to show bizarre
focal neurological deficits.
Vitals BP 120/80 HR 110 RR 20 T37.5 gluc
1.3 After 1 amp of D50, patients neuro findings
resolve, and he becomes more alert.
49
Case 3. Gimme Sugar
But

• After an hour on a dextrose drip, patient again
  becomes lethargic and agitated.
• Repeated gluc 1.7
• Another D50 given with resolution of Sx
• This cycle of hypoglycemia-induced symptoms
  returns several times

50
Case 3. Gimme Sugar

• Inside patients pocket is an empty bottle of
  glipizide XL

Diagnosis Sulfonylurea overdose
51
Sulfonylureas
Mechanism of action

• Lower blood sugar by stimulating pancreatic
  islet cells and facilitating the release of
  preformed pancreatic insulin

52
Sulfonylureas
Gen. Generic name Trade name Time to peak (hr) Duration of Action (hr)
First Chlorpropamide Diabinase 2-7 60
First Tolbutamide Orinase 3-4 6-12
Second Glipizide Glucatrol (XL) 1-3 (6-12) 12-24 (24)
Second Glyburide Micronase DiaBeta 2-6 12-24
Third Glimepiride Amaryl 2-3 16-24
53
Sulfonylureas
Sulfonylurea overdose the numbers

• 2000
• U.S
• - 6910 O.H. poisonings (2.3100,000)
• - 2493 in age lt 6yrs (36)
• - 1284 intentional (19)
• Quebec
• - 73 intoxications (1100,000)
• - 15 in lt 6yrs (20 )
• - 30 intentional (40)

54
Sulfonylureas
Initial Managements

• Dextrose
• Initial management for all hypoglycemia.

• BUT
• Glucose itself stimulates release of insulin.
• Results in recurrent, rebound hypoglycemia.
• Requires ICU monitoring, blood glucose
  measurements q 20-60 minutes
• Duration of treatment can be very long (gt2-4
  days)

55
Sulfonylureas

• Glucagon
• Raises glucose levels by stimulating
  gycogenolysis.
• Effective only if sufficient glycogen present,
  has no effects in starvation, chronic
  hypoglycemia.
• Since it stimulates Insulin secretion, it is
  detrimental and contraindicated in Sulfonylurea
  O.D.

• Diazoxide
• Direct inhibitor of insulin release
• Increases hepatic glucose output
• Effective in several case reports and chart
  review
• Cumbersome, may cause hypotension, hypernatremia

56
Sulfonylureas
Octreotide

• Long-acting somatostatin analogue
• suppresses hormone release
• GH, gastrin, glucagon, and, most interestingly,

INSULIN
57
Sulfonylureas
Octreotide to treat sulfonylurea overdose
Case reports and case series
About 9 isolated case reports - Intoxications -
Insulinomas - PHHI
58
Sulfonylureas

• 1. Boyle PJ. J Clin Endocrin Metab. 1993
• 8 normal subjects received O.D. of glipizide on 3
  occasions.
• D50 dextrose infusion
• D50 octreotide (30 ng/kg/min)
• D50 diazoxide (300 mg q4h)

• Number of patients with hypoglycemic episodes
• Frequency of rebound hypoglycemia after
  treatment end

• Dextrose requirement significantly lower in
  octreotide group (plt0001)
• Rebound hypoglycemia occurred in all patients
  receiving dextrose or diazoxide, but only 2/8 in
  octreotide group.

59
Sulfonylureas

• 2. McLaughlin, et al Ann Em Med, Aug. 2000
• 9 patients treated with Octreotide for
  sulfonylurea-induced hypoglycemia
• Before Octreotide therapy
• Number of rebound hypoglycemic events (lt3.5)
  28
• Number of amps of D50 given 25

• Following the administration of Octreotide (SC)
• Number of hypoglycemic events 2
• Number of amps of D50 given 2

• NO MAJOR SIDE effects reported!!

60
Sulfonylureas
Octreotide - How to give

• Can be given IV or SQ
• Initial dose 50 ?g q 6 hours
• (Infusion doses 100 ?g /hr)
• Pediatric dose 1.0 ?g /kg (single case report)
• End point 24-48 hrs (remember PO intake is the
  optimal glucose source)

61
Sulfonylureas
Octreotide Advantages/Side effects

• Can be given both IV or SC.

• Very inexpensive, ? 11 for a 100 ug vial

• Highly efficacious and safe in multiple studies
  
• argued that the use of octreotide can prevent
  admission to the ICU

• NO MAJOR SIDE effects reported

62
Summary

• Beta Blocker Overdose
• Bradycardia may not respond to usual ACLS
• Glucagon drug of choice
• Insulin novel antidote?

• Toxic Alcohol overdose
• Must prevent metabolism of benign alcohol into
  toxic metabolite.
• Do not wait for levels to start specific Rx
• Ethanol is efficient but very difficult to use
• Fomepizole very efficient and reliable, and may
  avoid need for dialysis - but expensive.

63
Summary

• Sulfonylurea overdose
• Dextrose treatment will cause recurrent rebound
  hypoglycemia
• Glucagon is contraindicated
• Octreotide is simple, inexpensive and reliable
  (can prevent ICU admission)

64
Questions ??
65
Thank you.
66
Beta Blockers
67
Beta Blockers

• Brief Review
• 3 types of Beta receptors ?1, ?2, ?3
• ?1 found in heart muscle
• Stimulation causes increase contractility,
  conduction velocity and automaticity
• ?2 Smooth muscle of lung
• Stimulation causes bronchodilation and secretion

Beta blockers are classified as selective or
non-selective
68
Beta Blockers
69
Beta Blockers
Treatment of Bradycardia

• Airway protection, and ventilation
• GI decontamination
• Activated Charcoal effective
• Emesis /- lavage are contrainidicated
• increase vagal tone and worsen bradycardia
• pretreat with atropine

• ACLS guidelines
• hypotension fluids, dopamine
• bradycardia atropine, pacers, dopamine

70
Case 2. Saturday Nights all right for drinking
Bedside pearls (ethylene glycol) i)
hypocalcemia suggests ethylene glycol ii)
urine calcium oxalate crystals (50) iii) urine
fluorescence (w/in 30 min) NOT sensitive (some
antifreezes do NOT contain fluorescein) (Do
not put urine in glass container false
pos) iv) normal gap does NOT rule out toxicity
71
Ethylene Glycol / Methanol
Pathophysiology/Clinical effects

• Initial clinical effects of all alcohols are
  similar
• Ethylene Glycol and Methanol are themselves not
  toxic therefore goal is to minimize metabolism
• Methanol Formic acid formation causes severe
  acidosis and retinal toxicity (snowstorm vision)
• Ethylene Glycol Glycolic Acid formation causes
  severe acidosis. Oxalic Acid formation causes
  calcium oxalate deposits in all tissue (esp
  kidney)

72
Ethylene Glycol / Methanol
Evidence
No randomized controlled trials Consistent
results in Case Reports and Multicentred Case
Series All prevent toxic sequelae of Toxic
alcohol ingestion May avert need for dialysis in
EG intoxication who have no acidosis
() Pediatrcs isolated case reports similar
results
73
Isoniazid
Clinical Findings

• Asymptomatic pts. should be observed for at
  least 6 hr (toxicity usually develops by then)
• Initial s/sx nv, dizzyness, Temp, BP
• Generalized seizures will occur within 2 hours
• Ingestions of
• 20mg/kg usually associated with seizures,
• 140 mg/kg usually fatal
• Metabolic acidosis secondary to Lactic acid
  accumulation (type B)

74
Case 4. A whole lot of Shakin Going On.
24 year old woman brought in to ED,
unconscious Found unconscious in apartment by
brother. On the way to hospital, she had
tonic-clonic seizure On arrival,
130/90, 100, 12, 38.4 No trauma found, neck
supple, PERL, GCS6 Intubated for airway
protection, IV, monitor, bloods sent BUT
75
Case 4. A whole lot of Shakin Going On.

• Had another generalized seizure
• Valium 5 mg IV ? No response
• Valium 5 mg IV ? No response
• Phenobarbital 500 mg ? No response

Chemstrip 5.7
ABG 7.32/32/90
Anion Gap
ECGNST (QRS n)
30
76
Case 4. A whole lot of Shakin Going On.

• We have a patient with
• Repeated seizures refractory to normal
  anticonvulsants.
• Coma
• Metabolic Acidosis

These are hallmarks of toxicity to
77
Isoniazid
Introduced in 1952, cornerstone for therapy and
prophylaxis of tuberculosis Use of INH
dramatically increased in past 10 years. With
increase use, comes increase abuse. U.S 1996 -
507 cases of INH-related poisonings Among 5 most
common causes of drug-induced seizures in U.S.
78
Isoniazid
Isoniazid overdose the numbers

• 2000
• Quebec
• - 8 exposures
• - 1 lt 6yrs (12 )
• - 4 intentional (50)

79
Isoniazid
INH
Pyridoxine (Vit B6)
INH
Urinary elimination
PPK
INH
Pyridoxal 5-Phosphate
End Result Severe Pyridoxine Deficiency
80
Isoniazid
Why should we care about a vitamin deficiency?
81
Isoniazid
Treatment

• As with all seizing patients, ABCs
• (airway protection, IV fluids)
• BDZ (Valium, 5-10 mg iv) initial approach.

• BUT BDZs and Barbs when used alone, often not
  effective
• They require presence
• of GABA to be
• effective

82
Isoniazid
Treatment
Problem is NOT inadequate GABA channel
activation, but inadequate GABA

• Dilantin (Na-channel blocker), not effective and
  not recommended.

83
Isoniazid
PYRIDOXINE (VIT B6) IS THE ONLY ANTIDOTE FOR INH
TOXICITY
Pyridoxine reverses the INH process by activating
glutamic acid decarboxylase and increasing
formation of GABA
84
Isoniazid
Pyridoxine - How to give

• Actively seizing patients should immediately be
  given pyridoxine IV in a gram-to-gram dose.

• If ingested amount not known, start with 5 grams
  pyridoxine

• Rate of 1 gram q 2-3 minutes

85
Isoniazid
Pyridoxine - How to give

• Repeated dosing for persistent seizures

• If iv form not available, can be given as a
  slurry using crushed tablets via NG

• Pediatric dose 70 mg/kg (IV or PO)
• max dose 5 g

86
Isoniazid

• Side Effects
• Very little
• Reports of irreversible sensory loss when given
  in mega doses (gt 130 g)

Recommendations 10-15 g of Vit B6 should be
available in stock in hospital