NERVE AGENTS & PRETREAMENT

Transcription

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

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

3 EXAMPLES Carbamates Physostigmine (Antilirium) Neostigmine (Prostigmine) Pyridostigmine (Mestinon) Sevin (insecticide) Organophosphates Malathion Diazinon Nerve Agents NERVE AGENTS 3

4 NERVE AGENTS GA (Tabun) GB (Sarin) GD (Soman) GF VX NERVE AGENTS 4

5 GA O CH 3 CH 3 CH 2 O P N CN CH 3 NERVE AGENTS 5

6 GB O CH 3 CH 3 P O CH F CH 3 NERVE AGENTS 6

7 GD O CH 3 CH 3 P O CH C CH 3 F CH 3 CH 3 NERVE AGENTS 7

8 VX CH 3 CH 3 CH 2 O O P S CH CH N 2 2 CH(CH 3 ) 2 CH(CH 3 ) 2 NERVE AGENTS 8

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

10 TERRORIST USE Matsumoto, deaths Tokyo, deaths NERVE AGENTS 10

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 NERVE AGENTS 11

12 TOXICITY NERVE AGENTS 12 LCt 50 LD 50 mg-min/m 3 mg/70kg GA 400 1,000 GB 100 1,700 GD GF VX 10 10

13 Blood CHOLINESTERASE Acetyl (red cell, erythrocyte, true ) Butyryl (plasma, pseudo) Tissue Tissue acetylcholinesterase (at cholinergic receptor sites) NERVE AGENTS 13

14 EXPOSURE INDICATORS Inhibition of Acetylcholinesterase (RBC) most sensitive for nerve agent Butyrylcholinesterase (plasma) more sensitive for most insecticides NERVE AGENTS 14

15 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 Transmission: Nerve to Nerve ACh NERVE AGENTS 16

17 Nerve Transmission: Nerve to Nerve ACh NERVE AGENTS 17

18 Nerve Transmission: Nerve to Nerve ACh NERVE AGENTS 18

19 Nerve Transmission: Nerve to Skeletal Muscle NERVE AGENTS 19

20 Nerve Transmission: Nerve to Smooth Muscle NERVE AGENTS 20

21 Nerve Transmission: Nerve to Exocrine Gland NERVE AGENTS 21

22 Impulse Termination: The Role of AChE AChE ACh NERVE AGENTS 22

23 Impulse Termination: The Role of AChE AChE ACh NERVE AGENTS 23

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

25 Exposure to Nerve Agent AChE ACh NERVE AGENTS 25

26 Exposure to Nerve Agent AChE ACh NERVE AGENTS 26

27 Effects on Striated (Skeletal) Muscle AChE ACh NERVE AGENTS 27

28 Effects on Smooth and Cardiac Muscle AChE ACh NERVE AGENTS 28

29 Effects on Exocrine Glands AChE ACh NERVE AGENTS 29

30 ORGANS Muscarinic Smooth muscles Exocrine glands Cranial nerves (vagus) Nicotinic Skeletal muscles Pre-ganglionic nerves Both CNS NERVE AGENTS 30

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

32 Skeletal muscles NICOTINIC Fasciculations, twitching, fatigue, flaccid paralysis Pre-ganglionic Tachycardia, hypertension NERVE AGENTS 32

33 ACh at Receptors ACh Nicotinic Preganglionic synapses in ANS Skeletal muscle ACh Nicotinic ACh Muscarinic Synapses in CNS Smooth muscle Exocrine glands ACh Muscarinic NERVE AGENTS 33

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

35 CNS Acutely, large exposure Loss of consciousness Seizures Apnea Death NERVE AGENTS 35

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

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

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

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

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

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

42 VAPOR - CARDIAC Heart rate Increase or decrease Blood pressure - increase Not an indicator for care NERVE AGENTS 42

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

44 CONTINUED VAPOR Large exposure Previously listed effects plus... Loss of consciousness Seizures Apnea Flaccid paralysis Death NERVE AGENTS 44

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

47 CONTINUED LIQUID ON SKIN Onset time, penetration Skin site Temperature Moisture NERVE AGENTS 47

48 CONTINUED LIQUID ON SKIN Effects may occur despite initial decontamination Effects may worsen NERVE AGENTS 48

49 MIOSIS Almost always after vapor After liquid on skin: Small: no Moderate: maybe Severe: yes NERVE AGENTS 49

50 MANAGEMENT ABCs Drugs Decontamination Supportive Not necessarily in that order NERVE AGENTS 50

51 CONTINUED MANAGEMENT MOST IMPORTANT Protect self Protective gear Decontaminate casualty Protect medical facility Decontaminate casualty NERVE AGENTS 51

52 M256A1 DETECTION Chemical Agent Monitor M8 and M9 paper M8A1 Automatic Chemical Agent Alarm NERVE AGENTS 52

53 PROTECTIVE POSTURE MOPP 4!!!!!! NERVE AGENTS 53

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 NERVE AGENTS 54

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

56 ANTIDOTES Too much acetylcholine Block excess acetylcholine Enzyme inhibited Reactivate enzyme NERVE AGENTS 56

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

58 Atropine at Receptors Nicotinic Atropine Nicotinic Atropine Muscarinic Muscarinic Atropine Atropine NERVE AGENTS 58

59 ACh and Atropine at Receptors Nicotinic Atropine Nicotinic ACh Muscarinic ACh Muscarinic ACh Atropine NERVE AGENTS 59

60 CONTINUED 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

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

62 Action of Atropine on Smooth Muscle AChE Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr NERVE AGENTS 62 ACh Atr Atr Atr Atr Atr Atr Atr Atr

63 Effects on Exocrine Glands AChE Atr Atr Atr ACh Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr Atr NERVE AGENTS 63

64 Effects on Striated (Skeletal) Muscle: None! AChE Atr Atr Atr Atr Atr Atr Atr Atr ACh NERVE AGENTS 64

65 OXIMES Effects at nicotinic sites Increase skeletal muscle strength No clinical effects at muscarinic sites NERVE AGENTS 65

66 Action of Pralidoxime Chloride (2-PAM Cl) AChE Nerve Agent 2-PAM Cl NERVE AGENTS 66

67 ACTION OF PRALIDOXIME CHLORIDE (2-PAM Cl) AChE Nerve Agent 2-PAM Cl NERVE AGENTS 67

68 CONTINUED 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 NERVE AGENTS 68

69 Aging of the Nerve Agent-AChE Complex AChE Nerve Agent NERVE AGENTS 69

70 Introduction of 2-PAM Cl after Aging NERVE AGENTS 70

71 CONTINUED OXIMES Other countries have different ones England: P2S Some European countries: obidoxime Israel: TMB4 Japan: 2-PAMI NERVE AGENTS 71

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 NERVE AGENTS 72

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

75 Severe casualty: RECOVERY Without complications, conscious, breathing, in 2 to 3 hours NERVE AGENTS 75

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 NERVE AGENTS 76

77 LONG TERM EEG changes not detected in individuals Minor changes detected in an averaged group Significance unknown NERVE AGENTS 77

78 MARK I Spring powered injectors Atropine, 2 mg/0.7 ml 2-PAMCl, 600 mg/2 ml NERVE AGENTS 78

79 MARK I AUTO-INJECTOR NERVE AGENTS 79

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

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) NERVE AGENTS 81

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) NERVE AGENTS 82

83 SEVERE VAPOR EXPOSURE Rx: 3 MARK Is and diazepam ASAP Ventilation Rx even after cardiac arrest NERVE AGENTS 83

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

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

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) NERVE AGENTS 86

87 SEVERE SKIN EXPOSURE Rx: 3 MARK Is and diazepam Ventilation Rx after cardiac arrest NERVE AGENTS 87

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

89 35-year-old man Tokyo Subway Victim 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 NERVE profuse AGENTS 89sweating and vomiting

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 NERVE AGENTS 90

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 NERVE Personality AGENTS 91 changes characterized by passivity and shallow affect were also evident

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

94 TERMINAL OBJECTIVE Apply principles of pyridostigmine use in enhancing drug therapy for nerve agent intoxication NERVE AGENTS 94

95 WHY? Major threat agent: Soman Therapy for soman: relatively ineffective NERVE AGENTS 95

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

97 Action of Pyridostigmine AChE Pyridostigmine NERVE AGENTS 97

98 Action of Pyridostigmine AChE Pyridostigmine NERVE AGENTS 98

99 Action of Pyridostigmine AChE Pyridostigmine Nerve Agent NERVE AGENTS 99

100 Action of Pyridostigmine AChE Pyridostigmine NERVE AGENTS 100

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

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

103 PR Study in Rhesus Monkeys Group LD50 of GD PR Control Mark I only NAPP + Mark I 15.3 mcg/kg mcg/kg 1.6 > 617 mcg/kg > 40 NERVE AGENTS 103

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

105 Efficacy Safety Short-term Side Effects Performance Long-term BEFORE USE NERVE AGENTS 105

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

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

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

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? NERVE AGENTS 109

110 PYRIDOSTIGMINE: USE Mestinon : five decades for myasthenia gravis Regonal : anesthesia NERVE AGENTS 110

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 NERVE AGENTS 111

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% NERVE AGENTS 112

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 NERVE AGENTS 113

114 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 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. NERVE AGENTS 115 Limitation: No systematic long-term follow-up MAJ Givoni Israeli Defence Force

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

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 NERVE AGENTS 117

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 NERVE AGENTS 118

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