david m. penetar et al- combined atropine and 2-pam ci effects on tracking performance and visual,...

8/3/2019 David M. Penetar et al- Combined Atropine and 2-PAM CI Effects on Tracking Performance and Visual, Physiological,

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12 , PERSONAL AUTWOR(S)-Penetar, David M., Hayrstcrmi-Portnoy, Gunilla, Jones, R~eese T.13s. TYPE OF WOPRT 130. TIME COVERED ~ 4DAE REPORT (YeV,'Month.Dayl 1.AGCOUNTFinal FROM 1=jj TOuj-y 889016 , SUPPLEMENTARY N0OTATION

17, COSATI COOLS -111 -SUBACr TERMS (Cntinue oll m'ten# if flwO1Wy ed~i dAntiA, by "l(Ck nu-mb.FIELD GROUP 5Ue-GROIJp Atropi ne, 2-PAM C 01J 00dbvn, an t idaf-es,, visual functionphysiology~~'psch V~clef s tracki~ porfoi.~.ASRACT Cotne onvw i if nwo.ury and fify ry =c =Wjr AN

Ccoritinations of atropina (up to 4 ing/70 kg) and 2-1PAM ('L(up to 120') tg/70 kg ) were stud~iedfor their effects on a pursuit tracking task, six visual fwu ions, heart rate and bloodpresur, and coginitive functions as me~asured by six psychological tests. Track.ng 1-Ar-formance in both bright and dim light was significantly deqraded up to 3.5 har after-injection. Hi1gh- and low-contrast near acuity ums significantly altered up to 6 hr afterinjftction, wheareus accaimxidation and 1ptpil sizo remained altered for 24 hr. Elevatedpulse rates vai'e observed for 4 hr. Elevated systol ic blood pressures were observed .for2hr. while diaz~tolic prmsisues rceinalad elevaited far 6 h~r. No drug effects were found forthe psychological tests. (Xyerall, the observed effects of these two drugs in cxarbinat ionare qualitatively simi~lar t howe of atropine alone although they are of Tg;eateL nagnitude.On twov treasurcs (accamvtation anyd diastolic blood presstire), 2-PAM CLwas found to Sig-ni.ficimitly potent iate the atropine effect. ' i 'r42

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Rer-' nt & Copyright byAer,, pace Medical Association, Washington, DC

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CL.nbined Atropine and 2-PAM CI Effects onTracking Performance and Visual,Physiological, and Psychological FunctionsDAVID M. PENETAR, Ph.D., GUNILLA HAEGERSTROM-PORTNOY, O.D., Ph.D., and REESE T. JONES. M.D.

PtrNk . M, HAFG'FPSTRa%1--FOTNOY 0, JONES HT Cwombined and acetic acid. With this etnzyme inactivated, exce3-atiop.ie 4! ?.PAAf CI effkcts on trwcin, pe~ftwrmc.anv ai:d visXil. siVc concentrations of acetyleholiue result in respira-physiviv," and ps,-t~holog.t'Vl j'nv'litns, AvIal. Spa~e Einvirozn.pj, an p, u .A. tory distress, gastrointestinal symptoms, convulsions,Combi ons of atyapine (up to 4 mg % 0kg ') and .AMM and death. Two complementary methods tevarse the(up ajI mo 70 kg ') were itv4~ld foe their cfferts on a c.ffects of excess clholinergic stimulation: a) competitivepursuit, ging task, six visual functioen. hoart rate and blood receptor blockade prevents the binding of unhydrolyzedpresstlo, id cognitive functlos as moasufel by six p~ycholo, acetylcholine: and b) the inhibited enzyme is reacti-teal tsao. 1trcklnw porformance in -both bright lighta veoslibihtight w ., cfnilfkantfy degraded up to 3.5 h after Inetn ated by feing it from its orgnophosphat bonds.hilh. an dLtwcontret iear oculty was significantly Olaered up Competitive receptor blockade is achieved by atropinet 6 h 404,# Injection, whereas acon4,.edotlon and pupil also and other anticholinergics whila enzyme reactivation is"Mml"ned altered for 24 h, lleveled putlse rtie0 WeOI awh "d accomplished by oximne nucleophilic agents. such as 2-for 4l h.Slevolod syWst.f. blood prewnus were observed for 2 %whIlt diastolic prmssures r*malned elevated foil hN' O dft PAM Cl (pyridine-2-aldoxime methyl choioiue or prali-effects wo* found 4W tho psychelegl0cl tests. Overall, the oi. doxime) (11,13).erved ,fieit of those " drues 1tte.fefialln re qualte- In order to counter the threat of chenuical nervelively soliler to the".of atropin. alone 6lthIteug they Or of agents. soldiers are issued drig antidotes, which, can hegreeter maglntude. On ftm wmeisures (utcemriwdatien Snd dia. self- or buddy-addministeted if they sspect they nave,efla., tbuedfrohre),OAec been exposed to a chemical nerve agent or exhibitsymptoms. Similarly. atropine ant! 2-PAM Cl are the

standard nerve agent antidotes currently available to( RGANOPHOSPIRAIF. chemical warfai'c agants Air Force and Navy personnel. Soldiers now carry'.Jproduce their toxic effects by irreversibly binding three sets of atropine and 2-PAM CI autoiqjectors. Eachacetylcholinesterase. the enzyme responsible for hydro- set contains a 2 mg auboinjector of atropine and a 600 mgl zing the neurotransmitter acetylcholine into choline autoinjector of 2-PAM Cl. Thus, the total possible self-administered dose for each soklier is 6 mg atropine and1800 mug 24PAM Cl.

From Lctiermn Auviy Institute oReearlh, Smnith.k-keiwcll Eye Biecause of widespread cholinergic innervationsReeAth loundainick. and lait!cy.lorer Neu psyehialrn Instituto throughout the human nervous system, any perturba-of the Univermity or California. San Frwanciwi. A. tion of the cholinergic receptors and enzyme functionslTi%manuwriA wa% eceived For review in November 1987. 1Uiorevisedl nmetasnir was aceejte4 for Ue Iin Nitne IONs. can be expected to have profound physiological andsend rterint requests to MAJ D)avid M.Prnelar tM-artmev or behavioral consequences. The effects of anticholin-Ilehavioral Biology. Walter Reed Army Inttute or RewArch. Wash- ergics and cholinestenar reactivators have been studiediqflN, C0.07-510, whert Isa eswei tie wo % for many years (4). Over the past 2 years, oor labora-lwo # rmarh ,yc:holgt.,t at L~letuan Amly lnititume or"Rtesa~h*U n INtu yh asone. tories have collaborated in a comprehensive evaluationItuaw) vtulnte.cerat/i-ipatie in these studict alter giving their of atropine and 2-PAM Ci on a variety of functions andtree and informted consent. Invesligt adhered to AR 70-2S and tasks. Thi purpose of our studies was to examine theUSAMRDC keg. 10.25 oti the uc of volunteers in rewarch. The cffects of these two drugs, alone and in combination, onhopirs an d are not t a eosine are t vatever ah a visual motor tracking task that requires skills similar


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ANTIDOTE .:lFFI:LCTS--PNI)I'NI.TAR ET. At..mcnl the phyiological changes in heart rate .nd blood injection, at 13 times during the day after injection up topresure, and to analyzc the etffcts these drugs have on 6 h, and at the I day and 2 day followup. Volunteers alsoa number oftcognitive functions and psychological mca- recorded a subjective rating of pain at the injection sitesure%. We have attempted to perform an encompassing and a "high" rating to the psychoactive effects of theset of,,tudies where many tasks and functions ot'general drugs. These ratings were taken 60 min prior to injec-medical interest and military relevaaice are examined lion, five times after injection (15, 30.45 min, 3 and 6 h).together. As aviation skills presume excellent v;, ;on and on the two followup days. In addition. volunteersand unimpaired visual functions. results in those sec- rated themselves-on a 16-item subjective checklist-attion,, will be of particular interest to aviation spcciilists. 1.75, 3 and 5.75 h after injection.We have reported recently the separate effects 6Catro- Psychological Tests: Several standard and widely usedpine and 2-PAM Cl on performance and visual fLnctions psychological tests were employed to determine if there(3.7). We now report their combined effects o;m erfor- were cognitive changes following administration ofmance and vision and additionally on a psychological these antidotes. Tests used were: I) Stroop color-wordtest baltery. form test (administered before injection and four timesafter injection); 2) Five-item acquisition and recall (ad-MATERIALS AND METHODS ministered three times after injection); 3) Forward andTen male civilian volunteers (range 22-33 years) par- backw ard digit span (administered once after injection)-ticipated in a Latin square experiment using saline pla- 4) Short story acquisition and recall (administered threeceho. 2and 4 mg atropine 70 kg 'of body weight, and times after injection): 5) Controlled oral word associa-6t00) and 120M mg 2-PAM Cl 70 kg 1of body weight. tion (administered once after injection): and 6) PacedAlthough before the injections neither experimenter nor auditory serial addition test (administered once after in-volunteer knew the drug(s) or dose(s) of that day. the jection).readily disccrniblc side cffc;tLs of the drugs (atropine'sdry mouth and 2-PAM Cl's pain at the injection site) RESULTSquickly alerted the volunteer that he had received either For ease of presentation and clarity, the figuresor both drugs. Serving as his ow n control, each volun- present the results of 4 mg atropine *70 kg-'. 1200 mgleer received all nine possible injection conditions. 2-PAM Cl * 70 kg-, and the combination of theseDrugs were given by separate injections intramuscularly doses vs. the saline placebo condition. The discussionin the thigh. Injection days were scheduled no closer too is limited to these four conditions except where sig-than 72 h to allow for complete clearance of the drugs nificant effects or important trends were observed withd to prevent possible tolerance or carry-over effects. the remaining drug conditions.Results were analyzed by the nonparametric Walsh Test Tracking:The vertical and horizontal (lead/lag) compo-The Walsh test compares each individual against nents of the tracking task were analyzed as the standardhis own baseline score and then submits these differ- deviation of the absolute angular tracking error ex-to statistical analysis. Significance level was set at pressed in milliradians. This is a measure of variabilityp < 0.05, Results report the comparisons of a particular around a center aiming point and can be thought of as adrug group with placebo or the comparison between two measure of operator steadiness.drug groups. Fo r the horizontal scores, tracking efficiency underTracking:On each day, volunteers performed three sets daylight conditions was significantly degraded at bothof a pursuit tracking task: at preinjection or baseline times after injection by both 4 mg atropine 70 kg-'control, and at I h and 3.5 h after injection. Pursuit alone and its combination with 1200 mg 2-PAM Cl 70tracking was performed within a simulated field bunker kg- 1 (Fig. I). Average standard deviation tracking er-using a laboratory-constructed, viscous-damped optical rors increased to a maximum of about 1.5 times baselinedevice that simulated various Army weapons systems for the combination dose at 3.5 h after injection. Over-(7). Each set of tracking consisted of 20 15-s tracking all, tracking performance was significantly worse undertrials. Half were conducted under daylight conditions, dim light vs. daylight, and greater drug effects wereand half were conducted under dusk/dawn conditions. observed under dim light. Significant drug effects wereVolunteers were required to track a tank operating on a observed for both atropine alone and atropine in comr-rolling course at a simulated distance of 1.2 km bination with 2-PAM Cl at I h after injection. Perfor.and traveling at 5 milliradians per second (mrad e s- I). mance remained significantly affected at 3.5 h after in-equivalent to 20 mph. jection.Visual Functions.: Measurements were taken for: 1) Drug effects on the vertical tracking errors are shownNear (40 cm) and distance (20 ft) acuity for both high also in Fig. I. The decreased effcicncy in tracking was(90%) and low (10%1b) contrast using standard Bailey- significant only at 3.5 h after injections of atropine andLovie charts, 2) Accommodative amplitude in the pri- atropine plus 2-PAM Cl under dim light, Note the dif-mary (straight ahead), upgaze (450), and downgaze (45*); ferences in the ordinate scale used In this figure, Verti-3) Pupil size; 4) Color discrimination with desaturated cal errors were much less than the horizontal emvrsD-15 color cup ranking test; and 5)Stereopsis by means overall.of the Randut test viewed at 40 cm. These tests were Another method of describing tracking performaeadministered tit 30 min before injections and at 1.5, 3.5, Is percent time on target. In our studies, we defitne the6.75, 24 , and 48 h after Injection. central portion of the tank (0.5 mrad square) as the tar.I'leyslolglcnl M,,ltares: Pulse rates and systolic and get, (Overall, the tank subtended a visual angle of 4diastolic bluod pressures were taken 90 min prior to mrad). This can bN thought of a, the catlstrophic,kiI1126 A Nation, Spear, urnd P'n'ImrfnmenfaI-XldhMv eIM-ember, II ,


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ANTIDOTE EFFECTS-PENETAR ET AL.-5 HORIZONTAL 100-

A'.. .. . . W= W LIGHTw aDARKz BC zA *0 .0~

.2- W A LIGHTA

.1 25DARK0.0 PI.ACIO

A 4 .9 .ctop,../7O k9P 1200 -g I-PAM CII?0 kv

0 0 C ccbA.,-2 -.1 0 1 2 3 40 - -1 0 1 2 3 4.2 VERTICAL TIME APFTERNJECTION tho)

Fig. 2. Time tourse of meon perce~nt time an target (N 1).16. The target was defined as the 'A mrad square central portion ofthe tank.

"Z C'4 .12-a W 0 DARK nificantly affected after the 4 mg * 70 kg ' dose. The4c combination of atropine an d 2-PAM Cl is statistically08 the same as atropine alone, although performance is

LIGHT slightly worse. suggesting asynergistic relationship with.04- these two drugs ia the highest doses tested. These drugeffects reach a maximum at approximately 2.5 It afterinjection. with some recovery evident at 1.5 hafter in-0 jection. By testing tracking at t imes different from the-2 -1 0 1 2 3 4 previous study, we now have described atropine's time

TIME AFTER INJECTION (ht) course more completely.Fill, 1. Time course of the Mean standars! devIations of the Visual Functions:aSiolite frackIng earm (N =10). Nate the differenCe Inerdinate it) D~istance~Arnty-The time course of drug effectsSaulest far the hofixentut and virtical stories. Th e tredsing tas shows that atropine alone an d in combination with 2-wasn largely herisoatal In nature and! orns were larger In this IIAM C1 produces small and nonsignificant changes indlmensien. le~gend 0 -aPteoebe A el 4 mg etrepne 70Yg " distance acuity. amounting to about a line on the chartP a 1200 ml 2.PAM C1 *70 kg' 'JC `C"'W"'1en of off*"~ (from 20/16 to 20/20).an d 2-PAM 0; 4-Stgnlificntiy different frem place*o, p C~.0411"*.Sigsiflantly different frem plaerbe asW afteptine, p e 0.05. b) Near A ft-i.4 shows significaint changes inhigh-vontrast acuity after atropine alone and in combi-zone. i.e.. a hit here would destroy the tank, not just nation with 2-PAM Cf. The loss of near acuity produ"-ddisable it. The results show decreas;ing efficiency after 4 by the combination dose (about four lines on the chart,tug atropine -70 kg and the combination dose as t ime fromt the equivalent of 20112.5 to 201/32) is statisticallyafter injection ini~reases (Fig. 2). Significant decrease% signiricant at all three times after injection on the ex-were observed at 3.5 Itafter injection in both the light perimnental day. Recovery isobserved by the followingan d dint conditions for both atropine alone and in coin- day. 1'he drug-induced changes in low-vontrast nearbination with 2-PAM C.' Additionally, the c~ombination acuity are significant up to 6.75 hafter injection for bothdose significantly decreased percent time on target I h the atropine alone and the combination dose. Th e max-after injection in he dint light. imum change of about 0.4 log minimum angle of reso-The previous atropine study (7) ampled tricking pro- lution corresponds to acuity changes f~rom the equiva-ficiency at 30 an d 150 min after injection. From that lent of 20/16.5 to 20/40. The differences betweenstudy an d the atropine alone data in he present study, atropine alone and the combination condition are no tamore complete time course of the drug's effects can be significant. Alone, 2-PAM C1 produced no changes.plotted l'ig. 3). It is evident from these graphs that the c)Accommnodative Amplitude-Accommodation waspoin of maximum tracking degradation occurs 2-3 h measured as the nearest point of clear vision using aholl1owing a4mg - 70 kg dose, with recovery evident small detailed target. The time course of accommoda-at 3.5 h. Tracking ability is affected earlier in he dint tive amplitude in diopters (D)) for the primary gaze islight (40% vs . 8% hange in he bright light at I h), but shown in Fig. 3. Substantial (3-4 D) an d significantthe maximum percent decrease in efficiency is similar losses were observed at th e three test periods after in-for both lighting conditionq (75'% ctinge at 2.5 ht after jection frtr bo~th atrophic alone and in combination. Ac-injection). commodative losses remained significantly affected atInsummary, 2-PAM Cl alone had no effect on track- the 24 h followup (1-2 0)) while complete recovery wasing 1'crfornnance, while 2mg atropine - 70 kg"' did not not observed until 48 h af'ter injection. At 3 an~d 3.45 hsignificantly degrade performance. Efficiency was sig- after the combination dose, four volunteers ha d less


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ANTIDOTE EFFECTS-PENETAR ET AL.75 - LIGHT 20/40 .3- HIGH CONTRAST ACUITY

20/32 .2-50 050- 20/25 .1 = 4 .9 f,*pi.*/70 ko

S 20/ - 1200 a 2-PAM CI/70 kvl A C .... bi-ti..0 Ii'Z 20/20 0.Z 0"4 20/16 -. 1/ go 2 0fw W ......... .....

"2 0,2. 3.m 20/12 -. 2 0 a 1 24 3' 2 40 4-25 '%* *.....*. . . 0) -. 0 8 16t4 2t4 42 1 .20/40 .3' C tOW CONTRAST ACUITY" C.20/32 .2.2

75- DARK 4 f40

Z 20/20 0 0A - Cso0

20/12 -,2A 25- X 20/10 -.3. 0 I 241 32 40I I

1 TIME APTIR INJECTION (kit)Fig. 4. Moon high (90%) and low (10%t) i-eetrt meo multy(40 uim) f.1olowtI drg dmlnhstmileas (N ; 10). Ordisto Ptahbelo theI mlnlim.m angle of remstution meeggred by the-25, -- r- I dy4nend thar Snob. seftlisw equiveiote

0 O.S 1 1.5 2 2.5 3 3.5 4TiME AFTER INJECTION (hts)

Fig. 3. Ti. town of moan pott thong.f fe baseline eof ;hetinofal standard dowllone of Ow ttMklng Wa r 1Wthw"m ofl ne (N -- tO( Deft Ow5e *A2.S orofm apreviews tmeking study (7). Itgendt 0 m .tobw3 2 me anowa.tvpti-7Eel "1'4 to 4 m g tropls" - 70 k.t 6.than I D of accommodative amplitude. Although having ? I...." im'Ano effect by itself, 2-PAM 1C l potentiated the 4 mg ,atropine 70 kg " effect.There was a clear difference in baseline accommoda-

tive amplitude upgaze vs. downgaze (6.5 D vs. 9 D. or 015.4 cm vs. 11.1 cm) verifying the clinical observation Ithat people often need reading additions in the form of bifocals for upgaze before they need it for downgaze. 1Following the combination dose,. accommodative losses 0, - , - , .....fo r the downgaze were greater than either the primnay 0 3 , ,, ,2 40 4-or the upgaze (6.2 Dvs. 4.0 Dvs. 4.3 D, respectively). 1IM1 *9)1e INAC0lON Ih#,These losses inaccommodative amplitude can be ap- F;8. S. im. toM of mwen Co al.m teivees tW"P0.preciated more. perhaps, when the actual distances in sawy to" hieig dru 0dm~ailo (0 a 16). "opd.acentimeters to the point of near vision ar.: examined. .After 4 mg atropine ' 70 k 'I alone, that point was ex-tended on the average by 25 cm. After the combination time that the measurements were taken. Accommoda-dose, tit distance was extended by 40 cm. tive changes arm slow, and ou r previous study appar-The maximum accommodative low; produced by 4 mg ently did not measure at tite poinI (if imxinium loms.atropine in this study is greater than in ou r previous d) Pupil Size and Response-Pupil size measure-study (3). The average naximum loss here was 4.3 D at ments were made using an ophthalmic ruler containing4.5 h while the previous study reported a 3.5 D averaged a series of black halr circles increasing in 0.5-mm steps,maximum loss at 3.25 h. This discrepancy is due to the Measurements were made in office room light, a mod-


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ANTIDOTE EFFECTS---PENETAR ET AL.erate photopic illumination condition of 860 lux. Four duce significant and long-lasting effects on near visionmilligrams of atropine and its combination with 1200 mg acuity, accommodation, pupil size and function, and2-PAM CI* 70 kg-I produced significant enlargements stereopsis. Atropine's persisting effects observed hereat the three measurements made on the injection day are in contrast to clinical mydriatics and cycloplegics,(Fig. 6). The changes are small compared to dilations where visual functions recover within 2-4 h. This is dueproduced by topical mydriatics and are unlikely to be of likely to the different routes of administration (intra-practical significance in an indoor environment. No sig- muscular vs. topical). Although we report no new ornificant changes were observed after 2-PAM Cl injec- unexpected ocular effects of atropine and 2-PAM Cl,tions. the magnitude, time course, and possible synergistic ef-A dynamic infrared pupillometer was used with two fects are described here in detail for the first time.volunteers. Following the combination of the highest Physiological Measures:doses of the two drugs, pupil latency and speed of a) Pulse Rate-Changes in pulse rates after the high-change in response to a penlight stimulus remained un- est dose of 2-PAM Cl were the same as after saline (Fig.affected, whereas the amplitude of response decreased 7). Pulse rates showed a rapid rise after atropine injec-from a 2 mm change to a 0.6 mm change. This loss of tions. Four milligrams increased rates from an averagedresponsivity to light may be of practical significance, baseline of 70 beats per minute (bpm) to a maximum ofcoupled with the cycloplegia observed, since a bright 98 bpm at 70 min after injection. The combination ofdaylight condition can produce dazzle under these con- atropine with the highest dose of 2-PAM Cl further in-ditions. creased this maximum to 10 0 bpm. Both the atropinee) ColorDiscrimination-The desaturated D-15 color alone and its combination with 2-PAM Cl are signifi-vision test (1)was given before and after injection under cantly different from baseline, but not significantly dif-appropriate lighting (Illuminant C provided by a Mac- ferent from each other. These increases remained sig-beth easel lamp). A color confusion index was calcu- nificantly elevated at 4 h and were within baseline levelslated from the error scores. No significant changes were at 6 h.found in this index after injection, demonstrating that b) Systolic Blood Pressure-Changes in blood pres-discrimination between pale (desaturated) colors is un- sure following atropine or 2-PAM CI alone were non-affected by atropine and 2-PAM CI alone or in combi- significant (Fig. 8) . Their combination, however, pro-nation. duced significance increases at all time points betweenf) Steropsis-The Randot test was given at a dis- 45 and 90 min inclusive.tance of 40 cm. This test presents random dot figures c)DiastolicBloodPressure-Atropine and 2-PAM Clvisible only using stereopsis as a cue. The disparities are produced similar increases in diastolic pressures al-presented through the use of Polaroid filters. At this though 2-PAM's effect was slower-acting and not asdistance, the smallest disparity is 20 s. Changes oh- long-lasting (Fig. 8). When the drugs were combined,served 4.5 Ihafter the highest combination dose were diastolic pressures were synergistically increased by ansignificant, The loss of stereopxis was very pronounced average of almost 30 mm between I and 1.5 h and re-in three volunteers, who lost all ability to perfortm the mained significantly elevated at 4 h. The elevation at 6test. The retason for the loss of stereopsis was blur h was not significant.caused by the volunteers' inability to accommodate suf- d) "High" Rating-Atropine is known to produceficicutly to resolve the detail in the disparity targets. No psychoactive effects (8), although its time course andchanges in ocular alignment were obscrved. magnitude have not been previously documented. Ing) S.Vemmary-Atropinc's primary action on the eye of this study. volunteers gave a "high" rating to their sub-inydriasis and cycloplegia has bcc shownihere to pro-

:00.

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S.......... 040 * 0 1 4 37 40 41

tIIM l t INJItIION (h.o1I1W AWNI INJIVcION 1kol flg.7. Time coew"e of mWWa eart rotes duapsl the expe"eIus,-

Fig. 6. Time re of W" pup si e dlug edM&k,el de" .*iewla dragadmidshtmeea (14 = 10). Lopd"d hawlasttalem (N a I%). Leeend "lt f.i. Iig. hA v'sthin. .Space. and I,fbiNrn'ntaI Alediine . Dircmber. 19&1M 1129


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ANTIDOTE EFFECTS-PEN ETAR ET AL.IO SYSTOLIC cardiovascular effects with rapid onset (15 mini) an dpeaking at 45-60 min. Ratings of up to 23 were recorded10COCO following atropine and atropine plus 2-PAM Cl. The14 o p rating remained elevated for 3 h. Differences betweenc';PPPZ>% I P, atropine alone an d in combination with 2-PAM Cl were*130- 1~ " C %% no t significant, nor were the slight elevations (ratings of120Pb A, the equivalent of two drinks of alcohol produced ratingsU~p20 2% 'P*'.... t.5 mA enatr2PMC ln.I opno~ A "~.o of 50-60 on this scale (2).

C e) Pain Rating-Injections of 2-PAM Cl have been110 reported as painful (12). In this study, volunteers ratedthe pain at the injection site on a scale of 0-4 (Fig. 9).100___r_----__7-----r-__ Atropine and placebo produced negligible effects while100 ~ ' ' I 2-PrAM alone or in combination significantly elevated-2 -1 0 1 2 3 4 5 6 the rating for up to 6 h after injection. Some volunteersreported "tenderness" at the injection site 24 h later.

110- 0:z PLACEBO f) Subjective Sensation Checklist-Volunteers ratedDIASTOLIC Co A "4 Fog oopino/7Okho themselves (numerically 1-5) on 16 items (Table 1). Noco P2 1200 my 2.PAM C1/70 hg significant changes were observed for placebo or 2-100 ICo C 2 combination, PAM CI alone. Administration of 4 mg atropine -70*+\!kg Iand its combination with 1200 mg: 2-PAM Cl - 70go0*t. *$* co kg- produced significant increases in ratings of dryC A.P moiith, dry skin, an d "high" ratings, an d significant

II~~A *"%.decreases in distant an d near vision at all three timesso- , after injection. These ratings returned to normal the fol-C PM'1O' kP, P 0 lowing day. Balance an d coordination were affected up

70 - to 3 h after injection for atropine alone an d up to 5.75 h0 0 after the combination. All volunteers reported fatigueafter the 4 mg atropine - 70 kg-' dose and significantly60-1, reduced concentration after the combination dose up to

-2 -1 0 1 2 3 4 5 6 4.5 h after injection. The combination dose also causedthe subjects to report feelings of restlessness at 1.75 hTIME AFTER INJECTION (hr) after injection even though atropine or 2-PAM Cl alone

Fig. 8. Time course of mean blood pressures during the exper- produced no change on this item in these ratings. TheImental day following drug administrations (N - 10). remaining sensations of temperature, tension, depres-sion, anxiety, confusion, an d forgetfulness were unal-tered.jective feelings of euphoria on a scale of 0-100, where g)Summary-The physiological changes observed af-100 is he highest they have ever been on any drug. This ter atropine injections in this study are consistent withrating was in addition to the 1-5 "high" rating already those previously reported throughout the medical an don the subjective check list (Table 1)which wa s given at research literature (4). The duration of effect of atropinedifferent times. This 0-100 rating closely followed the alone and incombination with 2-PAM CI isstriking and

TABLE 1.SUBJECTIVE RATING SHEET.Mouth Moist 1 2 3 4 5 Dr ySkin Moist 1 2 3 4 S DryDistance Vision Clear I 2 3 4 5 BlurredNear Vision Clear I 2 3 4 5 Blurred"~Hioh" Not high I 2 3 4 5 As high aslIhavoever beenTemperature Cold I 2 Normal 4 5 HotBalance Worse I 2 Normal 4 S BetterCoo~rdination Worse I 2 Normal 4 3 BetterTension Worse I 2 Normal 4 5 BetterRestlessness More 1 2 Normal 4 5 Los"Depression More 1 2 Normal 4 5 LessAnxiety Worse 1 2' Normal 4 5 BetterFatigue Worse 1 2 Normal 4 5 BetterConcentration Worse 1 2 Normal 4 .4 BetterConfusion Worse 1 2 Normal 4 5 BetterForgetrulneis Worse I 2 Normal 4 5 DotterVolunteers were handed atubjective rating ilheet at 1,75, 3. nd 5.75 ht fller Injetkin and aiked tocircle the number Indicating how they felt at that moment.

1130 A'iininn, Vpgerr, and Envlrrrnmona'I erdikne 9Dieemberr, 190


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ANTIDOTE EFFECTS-PENETAR ET AL.4- were given two letters (one at a time) and asked to nameas many words as they could that started with that letterwithin a 60-s time period. This test was administered3 approximately 3 h after injection and measures the abil-ity to use semantic memory. No significant differenceswere found.

- 0) Paced Auditory Serial Addition Test (PASAT}-2 - The PASAT is a test of auditory vigilance not associated/ , . with intelligence or mathematical ability. The test is/r* C~ sensitive to concentration problems, such as those pro-duced by sedative drugs (5). Approximately 3 h after// injection, volunteers listened to a tape recording of

&.-u-, numbers read sequentially with a specific internumber* # Ainterval. Their task was to add the last two numbers.o Four rates of presentation of 60 numbers were tested:-2 -I 0 1 2 3 4 5 6 one number every 2.4 s, every 2 s, every 1.6 s, and

TIME AFTER INJECTION hi.) finally every 1.2 s. No significant differences wereFig. 9. Time course of mean subjective pain ratings during found.

experimental day following drug administrations (N = 10). g) SummarY-The results indicate that atropine inScale was O.no pain to 44ntense pain. Legend as for Fig. 1. doses up to 4 mg 70 kg- I alone and in combinationwith 1200 mg 2-PAM Cl 70 kg. - has no significant

could be important in the management of emergency effect on memory or the cognitive functions required bymedical situations or critical care. The increase in blood these tests 3 h after injections.pressure. especially diastolic pressure. is of clinical sig- DISCUSSIONnificance in the management of hypertension.PsychologicalTests: We have measured atropine's and 2-PAM Ci's effectsa) Stroop Color/WordFormTest-This test measures on a wide range of tasks and functions relevant to to-the ability to inhibit an overlearned response (reading a day's military operations. Atropine has been shown toword naming a color) in order to say aloud the correct produce effects on vigilance tasks and tasks requiringcolor of the printed word. This test is sensitive to diffuse immediate recall or consolidating newly acquired infer-brain dysfunction and frontal lobe dysfunction (5). No mation into memory (6.9,14). Our psychological testsignificant differences were found for any drug or drug battery was tailored to incorporate several differentcombination. Atropine alone or in combination with 2- psychological tests known to be sensitive clinically forPAM Cl did not produce any more or any less interfer- assessing these types of cognitive processes (5). Fromence than placebo at any of the testing times after in- previous studies, one would have predicted drug-jertion (45 min. 3.5 h, 24 It, 48 h). induced decrements in the Five Item Acquisition andb) Five Item Acquisition and Recall-Approximately Recall. the Forward and Backward Digit Span Recall,3 h after injection, a list of five words was read aloud to lie Short Story Recall, and the Paced Auditory Serialthe volunteer and he was given three chance% o repeat Addition Tust, with little effect on the Stroop and Con-the words correctly (immediate recall). No significant trolled Oral Word Association tests, We were unable todifferences were found itt the airblity to acquire or recall differentiate drug from placebo using these tests, how-(5 min, 24 h, 48 h) after any of ho drug doses or coin- ever, No significant differences amiong conditions werebinations at anytime tested . observed. One possibility for this lack of a significantc) Forward and hacrp "".. -c'. it Span- Approx. difference is that the test battery was administered be-Llately 3 h after injection, this test ofattention span was yond the point of maximal drug effect. Depending onadministered. Volunteers had to repeat digit sets. ini- the variable, nmaxinal drug effects were observed in thislially three digits long, and then increasing by one. Test- study at different times. Physiological measures peakeding was continued until an error was made. Sets were at 60-90 min while ocular changes and visual-motor per-repeated forward and then backward. Th e length of the formances are most affected 2.5-3.5 h after injection.longest set correctly repeated is the score. No differ- These results agree with previous studies (9,14,13).ences in performance from placebo were observed for Wetherell (14) reported short-term memory effects 60-any drug or drug combination. 90 min. but not at 120 rmin, after injection. This furtherd) Short Story Acquisition and Recall-Approx- supports the conclusion that we assessed cognitiveiniately 3 h after injection, each volunteer listened to a functions beyond the optimum time. Additionally, asshort story consisting of 20 details. Immediately after ou r volunteers were obviously fatigued at the time ofhearing the story, he had to repeal in his own words as the cognitive tests, there is a possibility we were ob .much as he could remember. lie was asked to recall the serving an anticholinergic effect on the general state ofstory again in 5 min, at 24 h. and at 48 h. Scores con- the individuals, or so-called tonic arousal. Phasicsisted of the total number of details recalled. No ,dignif- arousal, however, was unaffected 3 h after atropine be-icant differences between placebo and any of the drug cause, when required to do %o. he volunteers were ableconditions were observed, to concentrate, attend, and recall material.0) Contnrvhed Oral Word Association-Volunteers TIh results of the tracking task reveals the magnitude

Akitrihm. Spare. and Environmental


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ANTIDOTE EFFECTS--PEN ETAR ET AL.and duration of the antidotes' effects on psychomotor The use of such paradigms is crucial for a full under-performance. Performance was degraded in terms of standing and prediction of performance effects follow-accuracy and steadiness, and was more affected as the ing antidote injections. Our cognitive tests were unabletask became more difficult under dim light. These re - to indicate a drug effect even when volunteers weresuits suggest caution for military tasks requiring steady, visibly fatigued and reported a decreased ability to con-accurate hand-eye coordination in firing antitank weap- centrate. The results from Williams et al. (15) indicateons systems or flying aircraft. Such tasks can probably that more subtle types of cognitive impairments can bebe accomplished at the expense of more target misses expected following atropine use. Injections of both an-and decreased ability to perform more complex maneu- tidotes produccd large and prolonged physiological andvers. visual changes. Interaction of these effects on cognitiveThe visual changes observed following drug adminis- functions is posed as a critical but unexplored area intration, although of less magnitude than observed clin- the chemical defense field.ically following topical applications of cycloplegics andmydriatics. are nonetheless profound and long-lasting. ACKNOWLEDGMENTSAccommodation does not fully recover until sometime We express appreciation to Mark Adams. Charles Barba, Markbetwen an8h . his oss in ddiionto te aro- Brown, Helen Ford, and Jerry Molchany for their skillful technicalpine effects on low contrast near acuity, presents prob- ~ 'sitacelems for tasks such as map reading where contrast is REFERENCESlow and acuity requirements are high. I Adams AJ, Rodic R.Use of desaturuted and saturated versions ofPhysiological changes of heart rate and blood pres- the D-15 tests in laucoma in laucomia-suspect patients. DoM.sure have been extensively reported previously (4). Of Ophthalmol. Proc. Series Colour Vision Deficiencies VI 1982;33:419-24.particular interest to the medical community from our 2. Brown B,Adams AJ, Haegersttom-Portnoy G, ones RT. Flomfindings is the apparent synergistic rise in diastolic MC. Effects of alcohol and marihuana on dynamic visual acu-blood pressure following the combination of 2-PAM Cl ity: I.Threshold measurements. Perception Psychophys. 1975;with atropine. These rises of approximately 30%/ fo~r 1-2 18:4416..h an 1615%r h ac tlerble n halth, yung 3. Huegerstroi- Portnoy G. Jones R. Adams AJ., Jampoisky A. Ef.-h an 1115%for4re oleabl in ealhyyoug tects of atropine and 2-PAMI Cl on vision and performaance inadults. Inolder service members, however, where pres, humuns. Aviat, Space Entviron. Med. 1987; 58:47-53.sures already may he elevated or labile due to a variety 4. Headley Dl). Effects of atropine sulfate and prolidoxirne chlorideof reasons, there is cause for careful observation fol- on visoul, physiological. performance, subjective. and cogni.lowing the use of these drug*. tive variables inman: A eview. Mfilit. Med. 1982. 147:122432.5.Lenik,WNt. Neuropsychological awssessnent. New York: OsfordIn summary. we predict few performance decrements Uni Pr%% 1983,or physiological complications from 2-PAM Cl alone or 6. Moylan-Joncs RI, The effects of a large dose of atropine uponincombination with tup to 2mg atropine , 70 kg --1 4 mg the performance of routine task%. Dr. J,Ptiarmacol. 3969; 37;atropine alone or in combination with 1200 nmg of 2- )01-5PAM Cl is the point at which a host of physiological, Penetsr D-M. Beatrice ES . liffects of atropine on human puriuitvisul. nd isua-moorfecs bcoms sinifcan .frocking performance. Aviat, Space Vinviron, Med. 19M.;the benign environment of the laboiratory, It remnains to W.entt~Ar Mt. I-etICngflel#11d J11"Nychoactivity Of MtOphic Innor-b~e seen what effects these drugs will have upon visual- Mal volunteers. Phiariwiol. MochchM. Rehav. 19m6; 24: I1-1,mototr petl'ornilatce and cognitive abilities in military 9. Seppala T.Vlwakorpil R, sychophyslological measurement* afteroral atrophic InMant.cta Pharniscol. Toxicol. 194); 41:W874.opeatinswh~ere soldiers are sleep-ered phs- (. Siegel 8. d. Nonparametric iktatistics. No w York: Mc~raw-Hilll.cally exhausted. hungry. thirsty. and subjected to heat 9%or cold stress. A recent study by Williams el al. (15) 11. iTaylor P.Arnichofinestcrust agents, In: Gilman AG. Goodmanaddressed thcse quecstions in part. They assessed the 1.S. Gilman A. dt, Th e pharmacologicl ha0%ntf therapautdcs.effctsof mgofroinealoe ad i cobintio 1' 6th Eid. Now Yofk,: Macmillan it Co.. 1980:100-19.effet% f 2ing(ifroinealoe ad incominaion 1-2Vojvodlic V, flo4kovic 0. A comparative: study of pratidoxinie.with sleep deprivation and physical exercise on tests o~toid~me. and triinedoxime In ealthy "ten volunteers and inrequiring perceptual functions. Signal detection capabil- rats. In: Medical prctection agnlust chemical warfare agents.itics were assessed in a visual target recognition para- Stockholm: Alnqi~u~i find Wiskell lat. 191406-73.1digma avid in ito auditory vigtilance task. Signal detection 03 . Weiner N. Atropisne, %copolamine, an d related antimusesrinichatierdrugs. In: Gilman AG. (loodmart L-S. tuilniant A. d% . Th e phurwits impaired in the visual targct recognition 1.5 h fe aological bais o4 theapeutics. 6th Id. Ne w York: Muc.a 2 ing dose. Thi%effect was potentiated by 24 h of sleep Milian &Co.. 19110:1203-31.deprivation but not by moderate exercise. Through a 14. Wethetrell A.Sonic eftectsof tdrophic oh AW-li~etm meMory. ar.sophisticated analysis of these and other tests. they con- 1 C'imn Plaramcol. 1460; 10:62148.cluded that atropine produces a selective imipairivent of 15 . Widliat% 111L,arney 2. Hfolloway FA . Atropine. stress. sd hu-ma n performance. Footiericli. Frederick, hill: USA Medicalinput perceptual functions rather than of output motor Researel &D~evelopmnent C'ommnrad. Annual Report (o r Can-functions, such as response, selection and execution. tract No. DAMI) 174l3oZ-)l94, 1967.

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