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USAMRICD PROTECT, PROJECT, SUSTAIN MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES NERVE AGENTS & PRETREAMENT U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL.

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Presentation on theme: "USAMRICD PROTECT, PROJECT, SUSTAIN MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES NERVE AGENTS & PRETREAMENT U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL."— Presentation transcript:

1 USAMRICD PROTECT, PROJECT, SUSTAIN MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES NERVE AGENTS & PRETREAMENT U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

2 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 2 DEFINITION A substance that causes biological effects by inhibiting acetylcholinesterase Acetylcholine accumulates Effects are due to excess acetylcholine

3 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 3 EXAMPLES Carbamates –Physostigmine (Antilirium) –Neostigmine (Prostigmine) –Pyridostigmine (Mestinon) –Sevin (insecticide) Organophosphates –Malathion –Diazinon –“Nerve Agents”

4 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 4 NERVE AGENTS GA (Tabun) GB (Sarin) GD (Soman) GF VX

5 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 5 GA CH 3 CH 2 O O P CH 3 N CN

6 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 6 GB CH 3 O O P F CH

7 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 7 GD CH 3 O OP F CHC CH 3

8 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 8 VX CH 3 O S P CH 2 N CH(CH 3 ) 2 CH 2 CH 3 CH 2 O CH(CH 3 ) 2

9 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 9 HISTORY Germany, WW II, nerve agent munitions Used by Iraq In stockpiles CONTINUED

10 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 10 TERRORIST USE Matsumoto, 1994 –7 deaths Tokyo, 1995 –12 deaths

11 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 11 PHYSICAL PROPERTIES Clear, colorless liquids (when fresh), not “nerve gas” Tasteless, most are odorless Freeze/melt <0º C Boil >150º C Volatility GB>GD>GA>GF>VX Penetrate skin, clothing

12 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 12 TOXICITY LCt 50 LD 50 mg-min/m 3 mg/70kg GA400 1,000 GB100 1,700 GD GF VX 10 10

13 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 13 CHOLINESTERASE Blood –Acetyl (red cell, erythrocyte, “true”) –Butyryl (plasma, pseudo) Tissue –Tissue acetylcholinesterase (at cholinergic receptor sites)

14 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 14 EXPOSURE INDICATORS Inhibition of Acetylcholinesterase (RBC) –most sensitive for nerve agent Butyrylcholinesterase (plasma) –more sensitive for most insecticides

15 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 15 PHYSIOLOGY: NORMAL Electrical impulse goes down nerve Impulse causes release of neurotransmitter, acetylcholine ACh stimulates receptor site on organ Causes organ to act ACh is destroyed by AChE No more organ activity

16 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 16 Nerve Transmission: Nerve to Nerve ACh

17 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 17 Nerve Transmission: Nerve to Nerve ACh

18 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 18 Nerve Transmission: Nerve to Nerve ACh

19 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 19 Nerve Transmission: Nerve to Skeletal Muscle

20 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 20 Nerve Transmission: Nerve to Smooth Muscle

21 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 21 Nerve Transmission: Nerve to Exocrine Gland

22 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 22 Impulse Termination: The Role of AChE ACh AChE

23 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 23 Impulse Termination: The Role of AChE ACh AChE

24 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 24 PHYSIOLOGY: NERVE AGENT Enzyme (AChE) is inhibited Does not destroy ACh Excess ACh continues to stimulate organ Organ overstimulation

25 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 25 Exposure to Nerve Agent ACh AChE

26 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 26 Exposure to Nerve Agent ACh AChE

27 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 27 Effects on Striated (Skeletal) Muscle ACh AChE

28 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 28 Effects on Smooth and Cardiac Muscle ACh AChE

29 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 29 Effects on Exocrine Glands ACh AChE

30 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 30 ORGANS Muscarinic –Smooth muscles –Exocrine glands –Cranial nerves (vagus) Nicotinic –Skeletal muscles –Pre-ganglionic nerves Both –CNS

31 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 31 EFFECTS Muscarinic –Smooth muscles Airways - constrict GI tract - constrict Pupils - constrict –Glands Eyes, nose, mouth, sweat, airways, GI –Heart, bradycardia (vagal)

32 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 32 NICOTINIC Skeletal muscles –Fasciculations, twitching, fatigue, flaccid paralysis Pre-ganglionic –Tachycardia, hypertension

33 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 33 ACh at Receptors ACh Nicotinic Muscarinic Preganglionic synapses in ANS Skeletal muscle Synapses in CNS Smooth muscle Exocrine glands

34 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 34 HEART RATE Muscarinic (vagal) decreases Nicotinic (ganglionic) increases May be high, low, normal

35 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 35 CNS Acutely, large exposure –Loss of consciousness –Seizures –Apnea –Death

36 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 36 CNS Acutely, small exposure –Minor CNS effects Slowness in thinking and decision making Sleep disturbances Poor concentration Emotional problems Other minor problems CONTINUED

37 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 37 CNS Minor CNS effects –May last for 3 to 6 weeks –May follow any exposure –Not always present –Very slight, subtle CONTINUED

38 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 38 VAPOR Small exposure –Eyes: Miosis; injection; dim, blurred vision; pain; maybe nausea, vomiting –Nose: Rhinorrhea –Mouth: Salivation –Airways: Shortness of breath

39 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 39 VAPOR - NOSE and MOUTH Runny nose –Worse than cold or hay fever –Leaking faucet Mouth –Excessive saliva –May run out corners

40 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 40 VAPOR - RESPIRATORY TRACT Small exposure –Tight chest Moderate exposure –Severe breathing difficulty –Gasping, irregular breathing –Compounded by excessive secretions

41 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 41 VAPOR - GASTROINTESTINAL Exposure to a large but not lethal concentration may cause: –Nausea, vomiting –Pain in abdomen –Diarrhea, involuntary defecation or urination

42 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 42 VAPOR - CARDIAC Heart rate –Increase or decrease –Blood pressure - increase –Not an indicator for care

43 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 43 VAPOR Onset of effects: seconds to minutes After removal from vapor –Effects do not worsen –May improve No late-onset effects CONTINUED

44 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 44 VAPOR Large exposure Previously listed effects plus... –Loss of consciousness –Seizures –Apnea –Flaccid paralysis –Death CONTINUED

45 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 45 LIQUID ON SKIN Small droplet: local effects –Sweating, fasciculations Medium droplet: systemic effects –GI Large droplet: CNS –Loss of consciousness, seizures, apnea, flaccid paralysis, death

46 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 46 LIQUID ON SKIN Onset of effects –Small, medium drop As long as 18 hours –Large, lethal drop Usually <30 minutes CONTINUED

47 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 47 LIQUID ON SKIN Onset time, penetration –Skin site –Temperature –Moisture CONTINUED

48 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 48 LIQUID ON SKIN Effects may occur despite initial decontamination Effects may worsen CONTINUED

49 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 49 MIOSIS Almost always after vapor After liquid on skin: –Small: no –Moderate: maybe –Severe: yes

50 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 50 MANAGEMENT ABCs Drugs Decontamination Supportive Not necessarily in that order

51 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 51 MANAGEMENT MOST IMPORTANT Protect self –Protective gear –Decontaminate casualty Protect medical facility –Decontaminate casualty CONTINUED

52 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 52 DETECTION M256A1 Chemical Agent Monitor M8 and M9 paper M8A1 Automatic Chemical Agent Alarm

53 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 53 PROTECTIVE POSTURE MOPP 4!!!!!!

54 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 54 SKIN DECONTAMINATION Early is best, within 1 to 2 minutes –Little benefit after 30 minutes Physical removal is best –Forceful flush with water –Stick, dirt, cloth, M291 Solutions (hypochlorite, etc.) –Detoxify after many minutes

55 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 55 VENTILATION Possibly less need after pyridostigmine None forward of Battalion Aid Station Very high airway resistance until atropine is given

56 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 56 ANTIDOTES Too much acetylcholine –Block excess acetylcholine Enzyme inhibited –Reactivate enzyme

57 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 57 ATROPINE A cholinergic blocking drug –An anticholinergic Blocks excess acetylcholine Clinical effects at muscarinic sites –Dries secretions –Reduces smooth muscle constriction

58 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 58 Atropine at Receptors Nicotinic Muscarinic Atropine

59 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 59 ACh and Atropine at Receptors ACh Nicotinic Muscarinic Atropine Nicotinic Muscarinic Atropine

60 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 60 ATROPINE Side effects in unexposed Starting dose 2 mg or 6 mg More, 2 mg every 5 to 10 minutes Until –Secretions drying –Ventilation improved Usual dose: (severe casualty) 15 to 20 mg –1000s of mgs in insecticide CONTINUED

61 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 61 ATROPINE Not for –Skeletal muscle effects –Miosis, unless used topically Use will cause blurred vision for 24 hours CONTINUED

62 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 62 Action of Atropine on Smooth Muscle ACh AChE Atr

63 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 63 Effects on Exocrine Glands ACh AChE Atr

64 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 64 Effects on Striated (Skeletal) Muscle: None! ACh AChE Atr

65 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 65 OXIMES Effects at nicotinic sites –Increase skeletal muscle strength No clinical effects at muscarinic sites

66 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 66 Action of Pralidoxime Chloride (2-PAM Cl) AChE Nerve Agent 2-PAM Cl

67 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 67 ACTION OF PRALIDOXIME CHLORIDE (2-PAM Cl) AChE 2-PAM Cl Nerve Agent

68 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 68 OXIMES Remove agent from enzyme, unless aging has occurred Aging: agent-enzyme complex changes Oximes cannot reactivate enzyme Aging times: GD 2 min GB 3 to 4 hours Others longer CONTINUED

69 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 69 Aging of the Nerve Agent-AChE Complex AChE Nerve Agent

70 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 70 Introduction of 2-PAM Cl after Aging

71 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 71 OXIMES Other countries have different ones –England: P2S –Some European countries: obidoxime –Israel: TMB4 –Japan: 2-PAMI CONTINUED

72 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 72 2-PAMCL DOSE NAAK (MARK I): contains 600 mg –One or three Combopens; repeat in one hour IV: One gram slowly (20 to 30 min) –Repeat in one hour

73 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 73 SEIZURES Without pyridostigmine –Not prolonged –Anticonvulsant seldom necessary Prolonged after pyridostigmine –Possible brain damage from prolonged seizures –Anticonvulsant needed (diazepam) Give diazepam to any severe casualty

74 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 74 ARRHYTHMIAS Initial, transient from agent, atropine Terminal after hypoxia V-fib if atropine given IV with hypoxia

75 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 75 RECOVERY Severe casualty: –Without complications, conscious, breathing, in 2 to 3 hours

76 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 76 RETURN TO DUTY Dose-dependent, need dependent Could be hours with minor exposure, great need Many days after severe exposure Consider: –Vision –Minor, subtle mental effects

77 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 77 LONG TERM EEG changes not detected in individuals –Minor changes detected in an averaged group –Significance unknown

78 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 78 MARK I Spring powered injectors –Atropine, 2 mg/0.7 ml –2-PAMCl, 600 mg/2 ml

79 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 79 MARK I AUTO-INJECTOR

80 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 80 MILD VAPOR EXPOSURE Miosis, rhinorrhea Rx: Probably none unless rhinorrhea is severe Atropine IM will not help miosis

81 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 81 MODERATE VAPOR EXPOSURE Miosis, rhinorrhea, moderate or severe dyspnea Walking and talking Rx: 1 MARK I (if dyspnea is quite severe: 2 MARK Is)

82 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 82 SEVERE VAPOR EXPOSURE Conscious or unconscious Seizing or post-ictal Breathing or not Or effects in two or more systems (airway, GI, muscular, CNS)

83 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 83 SEVERE VAPOR EXPOSURE Rx: 3 MARK Is and diazepam ASAP Ventilation Rx even after cardiac arrest

84 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 84 MILD LIQUID EXPOSURE Localized twitching, sweating Rx: 1 MARK I (agent has been absorbed)

85 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 85 MODERATE SKIN EXPOSURE GI effects: vomiting, diarrhea, cramps Rx: 1 MARK I Watch carefully for 18 hours

86 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 86 SEVERE SKIN EXPOSURE Conscious or unconscious Seizing or post-ictal Breathing or not Or effects in two or more systems (airway, GI, muscular, CNS)

87 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 87 SEVERE SKIN EXPOSURE Rx: 3 MARK Is and diazepam Ventilation Rx after cardiac arrest

88 USAMRICD PROTECT, PROJECT, SUSTAIN MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES NERVE AGENTS A Case Study From the Tokyo Subway Incident U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

89 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 89 Tokyo Subway Victim 35-year-old man Exposed to sarin during the Tokyo subway attack 20 MAR 95 For approximately 7 minutes after exposure: –Had tonic-clonic convulsions –Episodes of dyspnea, during which he needed artificial respiration In the hospital emergency room he was comatose and mildly cyanosed Both pupils were constricted to 1.5 mm Had increased oral and nasal secretions and profuse sweating and vomiting

90 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 90 Tokyo Subway Victim Atropine sulphate and pralidoxime iodide were given intravenously The patient began to regain consciousness 8 hours after exposure Regained full mobility after 54 hours He was, however, disoriented and had an impaired short-term memory His electroencephalogram showed mild slowing of alpha activity, intermittent theta bursts, and the development of delta busts during hyperventilation – disappeared 3 months after exposure CT and MRI imaging showed no focal lesions Plasma cholinesterase activity, which was markedly low at 6% of normal levels after exposure, was normal within 3 weeks RBC cholinesterase activity was normal after 3 months

91 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 91 Tokyo Subway Victim Neuropsychological tests 6 months after exposure showed no global intellectual impairment or defects in immediate recall All his errors on the Mini Mental State were related to recall and temporal orientation Performance was particularly impaired on the Logical Memory and Associate Learning scales from the Wechsler Memory Scale-Revised Ability to copy the Rey-Osterrieth complex figure was normal (36/36) However, when he was asked to reproduce the drawing 3 and 30 minutes later, his performance was worse (18/36 and 3/36, respectively) These results suggest a defect in his ability to consolidate new learning and memory Furthermore, without confabulation, he showed retrograde amnesia that extended to 70 days before exposure to sarin Personality changes characterized by passivity and shallow affect were also evident

92 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 92 Tokyo Subway Victim The extent and consequences of brain injury and incapacity due to nerve gas poisoning in human beings are not understood Patient had amnesia similar to that caused by severe acute hypoxia Hypoxia may have been a factor in our patient during the first 7 minutes after exposure Defects such as retrograde amnesia and character changes might be associated with the direct effects of excess choline Hatta K et al., Lancet 347:1343, 1996

93 USAMRICD PROTECT, PROJECT, SUSTAIN PRETREATMENT FOR NERVE AGENT POISONING U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

94 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 94 TERMINAL OBJECTIVE Apply principles of pyridostigmine use in enhancing drug therapy for nerve agent intoxication

95 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 95 WHY? Major threat agent: Soman Therapy for soman: relatively ineffective

96 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 96 CARBAMATES Transient carbamylation of AChE Protects site from OP (nerve agent) Carbamylation of only small amount of AChE needed

97 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 97 Action of Pyridostigmine Pyridostigmine AChE

98 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 98 Action of Pyridostigmine AChE Pyridostigmine

99 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 99 Action of Pyridostigmine AChE Pyridostigmine Nerve Agent

100 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 100 Action of Pyridostigmine AChE Pyridostigmine

101 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 101 Pretreatment Pretreatment alone, without therapy provides no benefit Pretreatment followed by antidotes after nerve agent: beneficial

102 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 102 Protective Ratio PR = PR of 1.0: No effect PR of 5.0 desirable for the battlefield PR of antidotes against GD: 1.6 LD 50 (treated) LD 50 (untreated)

103 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 103 PR Study in Rhesus Monkeys GroupLD50 of GDPR Control 15.3 mcg/kg 1.0 Mark I only 25.1 mcg/kg 1.6 NAPP + Mark I > 617 mcg/kg > 40

104 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 104 UTILITY OF PRETREATMEN T Helpful against: GD, GA No added benefit: GB, GF, VX

105 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 105 BEFORE USE Efficacy Safety –Short-term Side Effects Performance –Long-term

106 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 106 SHORT TERM Side effects: <5% of those taking it Performance: No decrements in military tasks (including shooting, flying, driving, physical tasks)

107 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 107 LONG TERM Animal studies Myasthenia gravis patients –Starting dose usually 60 mg q8h, can go much higher –Usual course of treatment is years, not weeks

108 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 108 DOSE REGIMEN Dose: 30 mg –Based on RBC-ChE –Inhibition Interval: 8 hours –Based on pharmacokinetics of pyridostigmine Dosing: 30 mg every 8 hours Commander starts, stops use

109 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 109 WHAT DO YOU SAY IF YOUR COMMANDER ASKS: How long after I order pyridostigmine do I have to wait until my troops are protected? How soon after I order them to stop taking it can I consider them at risk?

110 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 110 PYRIDOSTIGMINE: USE Mestinon  : five decades for myasthenia gravis Regonal  : anesthesia

111 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 111 PYRIDOSTIGMINE Insignificant binding to plasma proteins Bioavailability after oral dose: 8 to 29% Elimination: <75% in urine Maximal plasma concentration: 1.5 to 2.0 hours Elimination half time: 3.5 hours

112 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 112 PYRIDOSTIGMINE: USE IN GULF WAR Compliance unknown High incidence (>50%) of side effects Most related to pharmacology of drug –GI >50% –GU 5 to 30% Medical assistance 1% Discontinuance drug <0.1%

113 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 113 Israeli Study Effects of Pyridostigmine on troops in field conditions –Done under FTX conditions at basic training on 80 troops –Half of them given pyridostigmine 30 mg q8h or placebo –Studied before and after 8-day period on drug or placebo –Study design is double blinded but not crossover

114 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 114 Results of the Israeli study Pyridostigmine-treated soldiers had “mild” GI symptoms in most cases Pyridostigmine-treated soldiers had changes on order of 10% in their scores on vertical addition and four-choice (perceptual speed) tasks. –Other neuropsychiatric parameters were unaffected. The two groups had no difference in their endocrine or stress tests including cortisol

115 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 115 Conclusions: Soldiers did as well functionally with as without pyridostigmine Functional significance of neuropsychiatric changes is unclear Commanders and their troops had no complaints and those with mild changes were functionally unaware of them. Limitation: No systematic long-term follow-up –MAJ Givoni Israeli Defence Force

116 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 116 PYRIDOSTIGMINE After pretreatment, nerve agent, antidotes: breathing and seizures continue Potential brain damage Anticonvulsant (diazepam) needed (10 mg via auto-injector)

117 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 117 Effects of Long-term Administration In vitro and in vivo evidence of myopathy Complaints of weakness, fatigue, etc. U.K. 60-day study U.S. doctrine does not advocate long-term use

118 NERVE AGENTS USAMRICD PROJECT, PROTECT, SUSTAIN NERVE AGENTS 118 PYRIDOSTIGMINE: SUMMARY Pretreatment, not a substitute for treatment “Hides” or protects a fraction of AChE (creates a “reserve force” Increases the amount of nerve agent a person can be exposed to and survive Causes predictable side effect profile Does not interfere with military function

119 USAMRICD PROTECT, PROJECT, SUSTAIN SUMMARY ANY QUESTIONS? MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE


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