Medical Aspects of Chemical Warfare (2008) - The Black Vault

Incapacitating Agentsconditions and when administered in the open airunder simulated field conditions, showed it to be approximately60% as effective as when given orally orparenterally. When breathing is regulated at 1 L perbreath, 15 breaths per minute (the typical volume ofrespiration for a moderately active soldier), approximately80% of 1-µm aerosol particles (the optimal diameter)is retained by the lungs. Of this quantity about75% is actually absorbed; the remainder is inactivatedwithin the lung or bronchial lining. 93,94Most absorbed BZ is excreted via the urine afterhepatic metabolic processing. Edgewood chemist AlbertKondritzer studied the brain distribution of BZand found it to be eliminated in three stages, roughlyin parallel with the clinical phases of BZ symptoms. 95It appears to be most persistent in the hippocampusand other regions that control memory and cognitivefunctions.BZ produces anticholinergic drug effects similarto those produced by atropine and scopolamine, asdo many related synthetic belladonnoids. To makequantitative comparisons of the growing number ofrelated compounds subjected to testing, it becamenecessary to establish operational definitions of suchparameters as the minimal effective dose and the incapacitatingdose, as well as onset time, duration, andother important attributes. After much discussion, thefollowing definitions were adopted:• Minimal effective dose: dose required toproduce mild cognitive impairment in 50%of the exposed population. The thresholdfor a minimal effect is two successive scoresbelow 75% of baseline performance on the NFtest. 39• Incapacitating dose (ID 50): dose required toproduce two successive scores below 10%of baseline (at which point incapacitation isclinically obvious). 93• Onset time: time of first NF score below 25%of baseline, which for BZ is approximately 4hours.• Partial recovery time: time at which twosuccessive scores return to 25% or higher insubjects exposed to the ID 50. 94• Duration: number of hours between onsettime and partial recovery time in subjectsexposed to the ID 50.• Peripheral potency: dose required to elevateheart rate to a maximum of at least 100 beatsper minute. This heart rate was found to bethe most reliable indicator of a significantperipheral anticholinergic effect, regardlessof baseline heart rate. 94• Relative central potency: ratio of peripheralpotency to ID 50. This ratio was found to be usefulin estimating the median lethal dose (LD 50)of the belladonnoids, because peripheralpotency (manifested by heart rate increase)at the incapacitating dose is a predictor ofbelladonnoid lethality. 96Other operational definitions include full recoverytime (the percentage of patients returning to above75% of baseline for cognitive testing using the NF test),prolongation time (increase in duration at double theID 50), and dose-onset factor (degree to which onsettime is shortened as a function of dose).Features of BZ-Induced Delirium. Delirium is anonspecific syndrome. 90 Before the systematic study ofanticholinergic delirium, however, the clinical featuresof delirium had not been correlated with performanceof cognitive and other tasks under controlled conditions.In the following discussion, aspects of deliriumproduced by anticholinergic agents will be describedin relation to associated impairment in cognitiveperformance as measured by the facility test alreadydescribed.Following the administration of BZ at the minimumeffective dose, delirium appears in its mildestform, represented by a drowsy state, with occasionallapses of attention and slight difficulty followingcomplex instructions. Recovery is usually completeby 24 hours.Moderate delirium generally is manifested bysomnolence or mild stupor, indistinct speech, poorcoordination, and a generalized slowing of thoughtprocesses, along with some confusion and perplexity.Although sluggish, the subject remains in contact withthe environment most of the time, with occasional illusionsbut rarely true hallucinations. NF test scoresdecline by about 50%. Recovery occurs within 48 hours,and amnesia is minimal.Individuals receiving the ID 50or higher usuallydevelop the full syndrome of delirium. There is verylittle variation from person to person in their responseto BZ (or other belladonnoids), perhaps because thesedrugs operate more directly on the “hardware” of thebrain—neuronal systems where all-or-none activityis more characteristic. Drugs such as LSD, in contrast,act directly at specific serotonin and glutamate receptorsand indirectly on others, including dopamine,norepinephrine, and opioid µ-receptors, with effectsthat vary in relation to the prevailing mood, arousal,and motivational state of the subject.During the first few hours, subjects show increasingconfusion but remain oriented. When delirium ispresent in its full-blown state, however, the individual423