Antidotes. Dr Brad Wibrow. From CICM ICU Updates

1. Tox
Antidotes
Bradley Wibrow

2. What do people die from –
50% intentional, 40% accidental
 Carbon Monoxide
 Ethanol
 Methadone
 Morphine
 Codeine
 Zopiclone - unrestricted
 Clozapine
 Helium – euthanasia websites –
suicide bag plastic hoods
 Methamphetamine
 Butane – young, unintentional

3. Recommended by US and
European Tox bodies since
around 2000

6. Fomepizole
 Competitive inhibitor of alcohol dehydrogenase
 Slows production
 Time for liver to process and excrete
 Prevents/improves acidosis and
visual Sx (methanol) or renal dysfxn (EG)

7. Methanol – Mortality 22% ETOH, 17% Fomepizole
EG – Mortality 18% ETOH, 4% Fomepizole
No RCTs, 145 Studies, 897 pts

8. WHO application – compared
with Ethanol
 Equal or more efficacious antidote and practical
advantages
 Standardised dosing
 Easy to administer
 Pharmacokinetics more predictable
 Need to monitor ethanol conc but not fomepizole
 Better adverse event profile
Higher drug cost but ?less hospital costs
$1500
$3000

10. Case - 3yo
 In Garage working on car with Dad
 Country ED – nurse+ doc on telehealth
 Ataxic, drowsy
 Istat – HCO3 20 and pH 7.32, no lactate
 Start ETOH therapy
 Couldn’t blow into breathlyser

11. Case
 ETS/Tox/RFDS – ethanol and transfer


12. At Childrens Hospital:
Hypoglycaemic
BAL 0.16 (bit high)
Calculated Osmolar Gap
as 26

13. At Childrens Hospital:
Forgot Ethanol
Convert mg/dl to mmol/l – divide by 4.6
-> no osmolar gap
And BSL probably ETOH related

14. Suppresses Gluconeogenesis
ETOH metabolism -> Reduces
Oxidised : Reduced NADP

15. Argument for Fomepizole?
Excessive ETOH
Transferring drunk child in plane
Inadvertent dialysis
Application underway in WA

16. DOSING
 Loading dose 15mg/kg over 30 minutes
 Maintenance dose 10mg/kg over 30 minutes
BD for 48 hrs
 If on CVVHDF – give every 4 hours or as a
1mg/kg/hr infusion

17. ‘Tox’
CardiogenicSh
ock
Tox

19. Anaerobic'glycolysis'
2#

20. 30#

21. High-dose Insulin-Euglycaemia
(HIE)
CCB tox inhibits
insulin secretion
+FFA uptake
Directly inotropic
Several Case series
humans. RCT in
animals
FFA = normal
Myocardial
energy

22. Endogenous
CCAs already
high
Inhibit insulin
secretion
anaerobic
glycolysis,
FFA delivery
Peripheral
vasoconstriction ->
afterload
Limitations of catecholamines in
pump failure

23. HIE
 Review 199 patients
 1U/kg – median bolus.
 Median peak infusion 8U/kg/hr
 Up to 18 and case report of 22/kg/hr
 Unrelated to
insulin dose
30%

24. Shocked -
overdose

31. Cardiogenic shock +SAH
 62yo SAH – profound shock
 - neurogenic stunned myocardium
 Norad 0.9mcg/kg/min, lactate 6.2, oliguric, AKI
 HIE as rescue therapy 60 U/hr

34. CARDIAC SURGERY?
 224 patients Placebo Controlled RCT
 Insulin 20U + 10mmol K + 50mls glucose 40%
 Primary outcome = vent dysfunction
 RR 0.41 (CI 0.25-0.66)

35. Levosimendan
 Not really – conflicting rat models
 Case reports but nothing convincing
 Omitted from treatment options in review

37. Lipids
?Salvage Rx..
 Controversial
 Lipid soluble
LA – makes some sense
Ingested tox – when to dose, how
much, ?increase GI absorption

39. Mar 2018 J Med Tox
15yo overdose
 Quetiapine
 Desvenlafaxine
 Amlodopine
 Ramipril
 Fluoxetine
 Promethazine
 Lithium

40. Vasoplegic Shock
 Refractory to high dose pressors
 Methylene Blue given 6.5 hrs post OD –
 within 1 hr reduction in catetcholamines
 BUT…

41. And Half life 38 hours
Serotonin Syndrome 5 days

42. Anything Else?
 Vitamin C
 Hydroxycobalamin
 4-aminopyridine (4-AP)
 Fructose 1,6 diphosphate (FDP)

46. Toxic mechanism – several
 Binds Fe 3+ of cytochrome oxidase
 -> lactic acidosis - correlates with severity
 Release of biogenic amines
 -> pulm and coronary vasoconstriction
 Triggers neurotransmitter release, esp NMDA
 -> seizures and delayed parkinsonism

48. 23yo CN OD arrest
No ABG
No antidote
Lactate 3-5 with RFDS
CN (in Perth) 2mcg/mL

49. Gas inhalation
Intubation & 100% oxygen in severe poisoning
Decontaminate – remove and bag clothes,
soap and water

50. CN Antidotes
 1. Hydroxocobalamin – preferred
 converts -> cyanocobalamin
 2. Thiosulfate – substrate in normal CN metabolism
 Give with Nitrites
 Nitrites induce MetHb. CN binds avidly to MetHb
 3. Dicobalt edetate – cobalt binds cyanide
 4. Cobinaminde? – precursor to cobalamin

51. Cobinamide
 1. greater affinity for CN- and HS- ions
 2. higher rate of complex formation with these ions
 3. neutralize 2CN- and HS- ions instead of one

52. RATS

54. IM Injection

55. Sulphide Gas
Like Cyanide…
SOB, N+V, Confusion,
Coma, Seizures, Acidosis, death

56. Sulphide Gas

57. Sydney – Sulphide plot
>700PPM 2-3 breaths fatal

58. Attractive to terrorists
Highly toxic
Difficult in diagnosing
Easy to produce

59. IV infusion of H2S not
inhalation used
100% survival with cobinamide
0/8 with hydroxycobalamin
But same mg dose - Hydroxycobalamin need 5 x
If needed tomorrow -> O2 + hydroxycobalamin

61. NICOTINIC
 Fasciculations
 Weakness, paralysis
 Autonomic – HTN,
tachycardia, mydriasis
CNS
 Anxiety
 Confusion
 Seizures

62. Novichok
 Synthesized by Russia in 1970s
 2 advantages:
 1. Very toxic – 10x Sarin, more than VX
 2. Binary agent
 Individual agents stable, transportable and within
international treaties

63. Hydrolysis -> HF, HCL, HCN

64.  Skripals >2 months hospital
 2 pedestrians 4 months later
– one dead
Novichok

65. Treatment
 Decontamination, soap and H20
 Airway control and oxygenation
 (no Sux)
 Atropine = immediate, aggressive
 HR>80 and clear chest
Pralidoxime

66. Treatment
 Magnesium -> reduces presynaptic ACH release
 Clonidine -> reduces presynaptic ACH
synthesis/release
 Charcoal? – RCT 1000 pts no benefit

67. 1. Spontaneous hydrolysis
2. Aging
Options for Bound Organophosphate

68. 3.Regenerate with an oxime

69. Pralidoxime
Does it work?
 Not effective once OP aged
 7+ RCTs but still unclear
 Different organophosphates
 Different doses
Does pralidoxime affect outcome in OP
poisoning?
de Silva HJ et al. Lancet 1992; 339:1136-38.
Continuous pralidoxime infusion v.
repeated bolus to treat OP - RCT.
Pawar K et al. Lancet 2006; 368

70. Pralidoxime
 WHO – any OP poisoning needing
atropine (bolus dose slow)
 Continue until atropine not needed
for 12-24 hrs
 2g slow IV 20 min then 3-6 hrly
or 0.5-1g/hr

71. Aging and Solubility
 Diethyl aging – 33 hrs 50%
 Quinalphos, pyrifos
 Dimethyl aging – 3hrs 50%, 12 HRS 94%
 Monocroptophos, fenthion
 Atypical organophosphates – <1 hr 50%
 Profenofos
 Fat Solubility – Fenthion highly fat soluble
 atropine/oximes may be beneficial for days

72. Albany, WA

73. CASE – 2yo
 1500 hrs:
 Drank ‘dregs’ of 50% chlorpyrifos (diethyl)
 2000 hrs:
 Child‘lethargic’
 Admitted to ward – Tox advice -> watch, no need for
antidotes, just atropine if symptoms

74. Case
 0300 hrs:
 Agitated / upset (sleep deprived)
 Myoclonic twitching and diaphoresis
 Normal chest exam
 0545 hrs: Reviewed by ICU consultant:
 Diaphoresis
 Bronchospasm responding to salbutamol

75. Case – deteriorating…
 0745 - Patient more unwell:
 Abnormal LOC
 Vomit x 1
 Wheeze and Bi-basal crackles
 Muscle twitching in neck / upper limbs
 O2 sat. 94% RA

76. Case
 Transfer to HDU for
atropine administration
 On arrival in HDU
 Large vomit
 Aspiration, Sats 80%
 Intubation

77. Case
 Transfer to Perth
 P 150 min
 Basal crackles
 Pupils 2mm
 RBC ChE 1.9 Um/L (reference 8-15)

78. Should she have got
Pralidoxime?
(Diethyl agent)
??Avoid intubation/aspiration

80. THE END