cyanide poisoning 1981

7/31/2019 Cyanide Poisoning 1981

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368 VOGEL, SULTAN, AND TEN EYCK

in Europe, including hydroxocobalamin,cobal t sa l ts , and par t icu-larly aminophenols.

I N T R O D U C T I O N

Cyanide poisoning is an uncommon poisoning f o r the individual pr ac -t i t ioner to encounter. He may be rem inded of i t occasion ally by sp o r-adic, anecdotal reports of fruit pi to r Lae t r i l e inges tions [ 1- 101. Ex-po sur e to cyanide may not be co nsidere d ev en when the clinic al andlabora tory p ic tures are highly suggestive. T h e r e are few surv ivingc a s e s in the l i terature with supportive blood levels.

An increa sing number of nonin dustrial cas esare being reported,mo st l ikely r elate d to the incre asin g availabil i ty of La etr i le and theincreasing awareness that cyanide gases maybe r e l ea sed f rom bu rn -ing synthet ic m ater ia ls [ l l , 121. More sophist icated c r i t i ca l ca re l i fe -support systems may allow patients with what were previously consid-ere d fatal lev els to survive. Because of t ight binding to cytoc hrom eoxidase, even moderate blood levels may reflect severe intoxication.

Cyanide exposure should be added to the differential diagnosis ofse v er e metabol ic / lact ic acido sis and anion gap[131 (Table 1). T hecl inic ian must also fac e the que stion of at what pointa potential lytoxic therapy is no long er indicated.

TABLE 1. High Anion Gap Metabolic Acidoses [76]

I Renal fa i lure11. Ketoacidosis

Diabetic

Alcoholic

In. Lact icCard io re sp i r a to ry f a i l u r eShock

IV. Toxins

Sal icyla tes

P a raldehyde

Methanol

Ethylene glycolCyanide

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CYANIDE POISONING 369

Presen ted here are two c as e s, with th re e instan ces of cyan ide poi-soning, including the fif th reported fatal Laetri le ingestion[1, 4, 5, 71.Pathophysiology, cl inical recognit ion of acute and chr on ic sta te s, cur -rent concepts of therapy, and a review of the l i ter a tu re a r e presented.

C A S E R E P O R T 1

A 31-year-old White ma le biochemist was brought to the Em ergen cyDepartmen t a f ter being found com atoseb y his wife. She reported thathe had a histo ry of alcohol ab use for 15 ye ars and had been drinkingheavily that day. She had la st se en himawake about 1 h p r i o r t o arri-val . Thir ty minutes la te rshe had heart him thrashing around andchoking. She found him un respo nsive o n the floor and called the pa ra -medics . H e was reported to have been i n good health previously exceptfor chronic ulcer disease , t reated with Riopan, and hyper tension, t reat -ed with propranolol.

blood p re ss u re 120/70. The patient was unrespo nsive to deep pain.Pu pils we re mid-dilated, e qual, and rea cti ve to l ight. Examination ofthe lungs revealed bi la tera l ronchi . Car diac examinat ion revealedanS-4. Neurological exam w a s r e m a r k a b l e f o r his al te red s ta te of con-sciou sness and the absence of corne al ref lexes . DTRswere 2+ andsym me tr ica l ; motor tonewas diffusely spast ic .

On init ial laboratory evaluation, glucosewas 313 (patient was given50 cc of 50% dextrose in the field), BUN 9,N a 140, K 3.7, COZ 16, Cl90 (anion gap of 38), Ca 2' 9.3, and Mg 2.0. U rin aly sis showed 3+pro-tein, and complete blood countwas unremarkable . In i ti a l a r te r ia lblood gases, on 2 L of n a s a l oxygen , we re pH 7.32, ~ O Z39, pC0z 11,and ba se ex ce ss of -17.8. Blood alcohollevel was 290 mg% and rou-t ine dru g sc re en was negative . Serum acetonew a s negative. EKGdemo ns t ra ted s inus tachycard ia with occas iona l p rem ature ven t r icu-lar contract ions .

resp i ra tory pa t te rn de te r io ra tedand nasotracheal intubation was pe r-form ed. Ga str ic lavage was subsequently perfo rme d and gene ral sup-po r t i ve measu re s were continued, including 40% 02 v ia a T-tube andforced d iu res i s with Ds 1/2 N.S. O ve r the next half hour the pat ientbegan to respond, became combative, and gradually quieted down withreas su rance . Th ree hou r s a f t e r a r r i va l t he pa ti en tw a s fully respon-siv e to questioning and denied any ingestion other than alcohol. Sixhours af ter admission he s ta ted thath e had ingested potass ium cyan-ide from h i s lab. A specific antidote wa s not given at that t im e be-cau se of the long period of t im e sin ce ingestion, the continued stabil -i ty, and improv eme nt of h i s clinical condit ion. Ser um cyanide lev eldrawn at that t ime was 2.3 pg/mL. Lactic acid level draw n on ad-miss ion was gr ea te r than 100 mg/dL (norm alis 3- 15) . The rem ain -d e r of h i s cl inical course was unremarkable .

Physical exam revealed pulse 120, respirations 20 and gasping, and

The pat ient w a s given 0.4 mg of Narcan with no response. H i s

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C A S E R E P O R T 2

A 57-year-old White female , known to have m anic de pre ss iv eill-ne ss and d i ssemina ted carc inom a of the br ea s t , p resen ted to theEmergency Depar tment in a comatose s ta te . The fami ly revea ledthat her husband had died 1 week ea r l i e r of a br ain tum or. She hadbeen hosp i ta l ized on se ve ra l occas ions prev ious ly fo r su ic ide a t temptsby drug overdose. Medicat ions avai lable to he r, according to the fam-ily, were Valium, Librium, Stelazine, Thorazine, Dilantin, Phenophen#3, and Laetr i le , the la t t er d ispensed by ano ther physic ian for t re at -ment of h er b r ea s t ca rc inoma.

Physical examinat ion revealeda com atose woman. The pulse was80, resp i ra t ions 20, empera tu re 97.4, b lood p r e s su re 80/38. The sk inwas p lethoric . Th er ewas no evidence of head t raum a. The eye swerePER LA ; the fundi benign. The neckw a s supple and the thyroid sl ightlyenlarged. A f ir m m a s s 3 X 4 cm w as noted in the r ight breast . An in-d i s tinc t hard m as s encompassed the en t i re l e f t b r ea s t witha 2 X 3 cmfi rm lymph node in the leftaxilla. The lungs were c lear. The card io-vascu la r exam demons t ra teda Grade II/VI sys to l ic e jec tion mu rmu r.The abdomen was obese and demonstra ted a s c a r of previous hystere c-tomy. The ext rem it ies dem onstra ted no cyan osis , c lubbing,o r edema.The neurologic exam showed no focal signs.

14,000 on admission. The sodiumwas 141, he potass ium 4.3, hechlor ide 97, he COZ 13 (anion gap 351, and the glucose 226. The u r ineanalysis showed no abnormal i ty. The chest X-ray revea led cardio-megaly. Ar ter ia l b lood g as es dem onstra te d pH7.05, p C 0 ~ 6, p 0 ~6,and a base e xc ess -12 on 2 L of na sal oxygen. An el ec tr oc ar di og ra mdemonstrated an incomplete r ight bundle branch block and nonspecificSTT wave changes. The se ru m and gas t r i c con ten t toxico logy sc re enwas unremarkable . A small amount of phenothiazine was discoveredin the urine. A cyanide level of 29.0 g /dL , pe r fo rmed on admis s ion ,was re turned a f te r d i scharge .

The admit ting imp ress ion was of mu l t iple dru g overdose. Th e pa-t ient improv ed with symp tomatic therapy. She was subsequent ly t r an s-fe r r ed to another hosp ita l fo r psychia t r ic c a r e andwas discharged 3days la te r.

life and was pronounced dead att h i s t ime. A cyanide level drawn onautopsy was 218 g / d L . Toxico log ie s a t t h i s t ime were o therwi senegative. The autopsy failed to docum ent phy sical cau se of deat h ot he rthan cyanide poisoning.

The hem oglobin was 14.7, he hematocr i t 45.2, and the white count

She re turned to the Eme rgen cy Room 12 d later with no signs of

S O U R C E S O F E X P O S U R E

Suspicion in cr ea se s with aw arene ss , bothof the acute and chroniccl inical synd rom es and of potent ia l so ur ce s of ex posu re[ l , 6, o ] .

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CYANIDE POISONING 37 1

The decision to treat a potentially lethal ingestion with a highly toxic,potentially letha l tre atm ent modality must often rest on circumstan-tia l evidence of exposure. Indust rial uses of cyanides a r e widespread.The sodium and potassium s al ts of cyanide ar e used in metallurgy fo rthe extraction of gold and sil ver met als from ore s. Per hap s the gre at-e s t use of these salts is in electroplat ing and i n the ca se hardening ofsteel [14, 151. Hydrogen cyanide (HCN) exposure oc cu rs in fumiga-tion processes as w e l l a s chemistry lab accidents (acid + salt), blastfurnace gases, and from the gas of burning polyurethanes/nitrocellu-lose [11, 121. Many ca se s of fat al poisoning oc cu rred dur ing WorldWar I because of the extensive use of HCN fo r dest ruc tio n of ve rm in[14]. HCN is absorbed through the skin, gas masks providing inade-quate protection from poisoning.

There are many case re po rt s of poisonings fro m fru it pit ingestions,and inc reasin g numbers of r ep or ts of toxic and fatal L ae tr il e inges-tions [1- 101. Cyanide al so oc curs in consid erable amounts in tobaccosmoke [16].

Ther e ar e sever al rep or ts of cyanide as a mode of suicide [13, 17-201. There are approximately 60 cases reported in the l i ter atur ewith documenting cyanide levels, but the vast majority of these havebeen rep ort ed on postm ortem evaluation. Th ere are few cases ofsurvivors in whom good clinical information and cyanide levels areavailable.

therapy, especially in prolonged treatment where tachyphylaxis re-qu ir es the use of higher dose s than the recommended maximum of 10pg/kg/min [2 1-25].

Clinical syndromes a r e relat ed to the sour ces and amounts of cyan-ide absorbed as well as to the veloci ty of uptake of cyanide. The l a t te ris in turn rel ated to the type, dose, route of ingest ion, and the organ-ism's ability to detoxify [161. It is this latter ability which providesa theoretical bas e for s ome of the hypotheses relati ng cyanide to s ev er -al of the neurological syndromes discussed later.

An additional so ur ce of exposure is iatrogenic, during nitroprusside

PAT H O P H Y S I O L O G Y

The pathophysiology of cyanide poisoning involves the inhibit ion ofthe final st ep of oxidative phosphorylat ion by binding tightly with thecytochrome a-a3 complex, thereby halting aerobic metabolism. Gly-colys is continues and produces 2 mol of pyruvate and 2 mol of ATP/mol of glucose. However, th e pyruvate can no longer produce furt he rATP through the tricarboxylic acid cycle, a pro ces s producing 38 molof ATP/mol of glucose, because of i t s dependence on the cytochrorneoxidase syst em as the final st ep in ene rgy production [26]. Conse-quently, the pyruvate is reduced to lactate, resulting in the rapid ac-cumulation of lacti c acid. The patient ess ent ial ly suffoc ates, not fromthe inability to obtain or transport oxygen, but from the inability tous e it. The median lethal dos e of potassium cyanide in man is 200 mg

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372

[27 ] . Fatal b lood leve ls have been rep orted to be 2 .5-3.0 g / m L [13,191. However, Ber lin points out [28] that blood lev els can be mis lead -ing becau se the toxicity is due to the int racel lu lar concentra t ion. Hefee l s that any blood leve l g r ea te r than 0.2 g / m L sugges t sa toxic re-action, and the best indication remains the clinical condition of the pa-tient.

VOGEL, SULTAN, AND TEN EYCK

D I A G N O S I S

The key point i n the diagnosis of cyan ide poisoning is having a highindex of suspicion in patients with altered level of consciousness andan otherwise unexplained metabol ic acidosis . Potent ia l sou rc es of ex-posu re a r e an important his tor ica l p iece of informat ion. Phy sic ians ,chem ists , pharm acis ts , and other s with easy access ib i l i ty to the com-pound ar e higher r is k groups, especai l ly in suic ide a t tempts . Becauseof poor oxygen utilization, venous blood may retain the bright red colorof ar te ri a l blood [30]. The odor of bit te r alm ond sis useful for physi-cian s who have previously enc oun tered cyanide and know that they a r ecapable of detect ing the odor. Routine toxic scr ee ns do not check forcyanide and, as i n ou r f i rs t case , wi ll be negat ivein pure cyanide in-gestions. A s imple chemical tes t has been reported by Lee-Jones e tal. [29] for the detection of cyanide in ga str ic a spir ate. Unfortunately,mos t emergency rooms do not s t o r e the ma ter ia l s neces sary to per -form th i s t es t.

C L I N I C A L M A N I F E S T AT I O N S - A C U T E

Th e protea n man ifestat ion s of acu te cyanide poisoning a r e fo r themo st par t nonspecific. Th is pr es en ts two types of diagnostic prob -lem s. In patients such as our first cas e rep ort , in whom the diagnosisw a s not suspected, ther e were no specif ic s ignso r sym ptom s to pointtoward cyanide poisoning. The infamous bi t te r almonds odoris ofl imited use because the abi li ty to detect t h is odo ris genetically de-termined and is lacking i n a large portion of the population [13, 201.An equally difficult problem i n known exposures is that the symptomsof se v er e anxiety m im ic the ea rly sy mp tom s of toxicity [18]. Th es einclude headache, tachypnea, tachy cardia, and diz zine ss. The pre sen -tation of th e acutely poisoned patientis dependent on the dose takenand the t im e sinc e expo sure. Cyanideis a very rapidly act ing poison,cap abl e of c aus ing death ina m att er of minutes. Init ial ly the patientexperiences f lushing, tachycardia, tachypnea, headache, and dizziness.

This rapidly prog ress es to a s tuporous, comb at ive phase, and f inallyapnea, gen eralized convulsions, and death[16, 191.Presentat ion with secondary pulmonary edema has been reported

[13, 171. Th e mo st spe cific signi n cyanide poisoning maybe lac t icacido sis in a patient with the above sign s and sym ptom s. Both cas es

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reported here had profound acidosis with a significant anion gap.Th ese findings ar e consisten t with the pathophysiologic action of cy -anide and have been previously reported[131. Th e sp ee d of ons et ofsymptoms depends on the mode of exposure. A maxim al e ffect issee n with int raveno us ad minis t ra t ionor breathing of hydrocyanicacid vapo rs [3 11. O ral o r in t raper i tonea l rou tes a reless rapid be-cau se of a s lower rate of entry into the circulat ion and because t h e ye n t e r via the por ta l sy stem and pas s through the l i ve r, whichis themain s i te of t h e bod y 's detoxif icat ion system . Here cyanide re a ct swith thiosulfate in a react ion cata lyzed by the enzyme rhodanase toproduce the less toxic compound thiocyanate. Consequen tly, o r a lcyanide inges t ions a re m or e l ike ly to p resen t with theearlier symp-toms and be saved if t rea tment is s t ar te d without delay.

C YA N O G E N I C G LY C O S I D E S

La etr i l e and see d poisonings have become the mo st comm onlyre-ported so ur ce s of cyanide poisoningi n t he gene ra l med ica l l i t e r a tu re[ l - o ] . Reports of Laetri le toxicity and documented fatal i t ies[ 1, 4,5, 71 (and Case 2 ) have spawned many ed i to r ia l comm ents , l e t t e r s tothe edi to r, and a number of excellent reveiws [6 , 101.

Lae t r i l e ( 1-mandelo-nitrile-beta-glucuroniside) s a synthes izedfo rm of amyg dalen, a cyanogenic glycoside foundin apricot pi ts andoth er seeds . When hydrolyzed bya B-glucosidase, as found in the gutand in som e foodstuffs , HCN may be re le ase d[2, 10, 161. Laetri lerea lly denote s a c la ss of cyanogenic glyco sides mo re thana s ing lechemica l en ti ty. The i r chem is t ry is rev iewed e l sewh ere [101.

Many foodstuffs consu med by hum ans conta in amygdalin. Th eseinclude, among other s , the se e d s of a pr icot , peach, ch er ry , p ea rand plum. Some le ss commonly consumed in the West a r e je t beads ,chokecherr ies , cassava, and bi t ter a lmonds[ 8 ] . Laet r i l e , then, re -le as e s HCN when exp osed to a B-glucosidase, varyin g am oun ts of

which a r e contained in many nuts (e .g . , a lmond) , s tone f rui t ke rne ls ,app le seeds , f ru i t s (peaches , p lums , e tc . ) , and vege tab les (g re enpeppe r s , mush rooms , l e tt uce , c a r r o t s , c e l e ry, beansp rou t s , e tc .) [9].

C L I N I C A L M A N I F E S T AT I O N S - C H R O N I C

Chronic cyanide poisoning is not widely de scr ibed in the Am ericangene ral medical l i tera ture . Some indu str ia l hygienis tsfeel thatchronic poisoning as a re su l t of occupat ional exposure does not ex is t ,

but that there is pe rhaps a specif ic c l in ic al syndrome following r e -peated attacks of mild cyanide poisoning[141. O t he r s o u r c e s [15, 161leave l i t t le doubt that the re a r e som e indisputable manifes ta t ions ofchronic cyanide exposure .

Thiocyanates were used extensively fo r the t rea tm ent of hy per ten-

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sio n but w er e abandoned be cau se of the ir toxic si deeffects, which in-cluded the occurrence of the goiter[151. Th er e has been a r enewa lof interest i n thiocyanate toxicity since the advent of widespread useof ni t roprusside in cr i t ical care . A s opposed to thiocyanate tox icity,chronic cyanide poisoning has receivedso l i t t le at tention i n the gen-er a l medica l l i t e ra ture tha t the chronic syndrom ewas thought bysom e to resu l t f ro m repea ted subacute exposures .

E l Ghawbi et al. [15] studied 36 workers chronical ly exposed tocyanates in the e lect roplat ing industry. He found incre ase d hemo-globin and lymphocyte counts inall exposed workers . Two wo rkerswith acute psychot ic episodes s im il ar tocases repor ted dur ing theera of therapeutic use of thiocyanates for hypertension[32] c l ea redaf te r exposure was te rminated . In Barn e t t ' s exper ience[32], hio-cyanate psychosis was indist inguishable f rom the toxic psychosis p ro-duced by bromides . Twenty w ork ers had var ia ble thyroid enlargem entwith significantly high er thyroid l 3 I uptakes and unchanged l 3 PBL

Severa l c l in ica l s ta t es have been a scr ibed to chronic up take ofcyanide in sm al l do ses , including tobacco amblyopia , re t r ob ulb ar neu-r i t i s wi th pernic ious anemia ( PA ) , optic atrophy of Leber, and Niger-ian nutri t ion al ataxic neuropathy. The v e ry existe nce of som e of th ese"chronic conditions" is cont ro vers ia l ; they are not in gener al well de-sc r ibed in the Amer ican l i t e r a tu re , and the i r re la t ionsh ip to cyanideintoxication is ba sed on circ um stan tial evidence. Dem yelinating lesio ns

in brain after cyanide intoxication a r e we ll known, but do not ap pea r tobe specif ic fo r cyanide[30],

O P T I C N E U R O P A T H I E S

While the conceptual re la t ion ship of cyanides to sev er al d isea sesta tes- tobacco amblyopia , re t robulbar neuropathy ofP A , and Leber ' sher ed itary op tic atrophy-is intriguin g, th e evidenceis c i rcumstan t ia l .It rem ain s to be proved that chronic low dosage cyanide expo sureh a s

the toxic effects imputed to i t [33].

T o b a c c o ( T o b a c c o - A l c o h o l ) A m b l y o p i a

Tobacco amblyopia (TA ) was first descr ibed by Beer in 1817[34].I ts ex act et iology rem ain s unknown, andit a p p e a r s far l e s s c o m m ontoday than 50 y ea rs ago when Tra qu air w as a ble to de scr ib e o ver 1500c a s e s o r 1% of all eye pat ients presen t ing a t the Royal Inf i rmar y,Edinburgh [35]. Object ive e xper imentat ion is e x t r em e l y r a r e and

most of the l i tera ture is re la ted to uncont ro l led c l in ica l impre ss ions[36]. Current American authors f indit qui te rare [37]. Heaton [38]based the d iagnos is on seven spec i f ic c r i t e r ia , espec ia l ly cen t ro-caecal sco toma with def in ite ch ar ac te r i s t i cs , and sugges tedthat TAand the re t robu lbar ne ur i t is asso cia ted withP A might be identical .

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Cyanocobalamin improved visual acui ty and re ve rs ed the visual f ie ldchanges in se ve ra l pat ients. Chisholm[391 reported hydroxocobala-min as mo re e ffec tive in t rea tmen t , and o thers ag re e with th i sre-commendat ion [401.

Structu ral changes in the eye include ophthalmoscopical ly vis ibletemporal pal lor of the ne rve heads ( i n so m e case s ) and ove r t a t rophyonly rarely. This is s im i l a r to t he changes s een in r e t robu lba r neu r i -tis of other causes.

one ent i ty of tobacco-alcohol amblyopia o r two se pa ra te ent it ies . Dun-phy has rev iewed the his tory of th is contro versy and the differentpoints of view [41]. Cen trocea cal visua l fa i lu reis also see n in f ami -lial opt ic a t roph ies , lead poisoning, inorganic ar se ni c poisoning,car-bon disulf ide , chloramph enicol optic neuropathy, and oth er di se as es ta tes [37].

in his review feels tha t cen t roceaca l op t ic neuropa thy in male s m ok er swith evidence of impaired nutri t ionis a real syndrom e, qu i te rare,which may or may not be a manifestat ion ofPA.

The role of cyanide as a pathogenic mechanism is cont rovers ia l .Aside f rom th e argumen ts whether tobacco and alcohol amblyopiaarese pa ra te en t i ti es , and whether theyare r e l at e d t o L e b e r P h e r e d i ta r yopt ic a t rophy and PA, th er eis d i s a g r e e m e n t as t o whether t h e r e is a

toxic o r nutr i t ional ( o r both) pathogenesis. Victor [42, 431 fe l t th es erep re sen t ed the sa m e en t ity and were nutr i t ional def ic iencies and nottoxic react ions . He sugg ests the condi t ion should be cal led nutr i t ionalre t r ob ulb ar neuropathy.

Br i t i sh inves t iga tors have cons idered th i s to bea toxic opt ic neuro-pathy and have par t icular ly suspe cted cyanide in tobacco sm ok eas anet iologic o r agg ravat ing fac tor in the development of th e opt ic neuro-pathies of P A and L eb er ' s H eredi ta ry Opt ic Atrophy (HOA). Th eseconcepts can be considered only hypotheses [33, 44, 451.K r i l l feelsL e b e r ' s optic atrophy is often a wastebaske t d iagnos i s fo ra host ofconditions [47].

P l as m a th iocyana te is elevate d by tobac co smo king [46]. The opticneuropathy of tobacco smoking,P A , and Leber ' s HOA all appea r t obenef i t (a t least in so me ca se s ) f rom t rea tm ent with hydroxocoba lamin ,which pre sum abl y binds and detoxifies cyanid e [33].

A s G r an t s u m m a r i z e s [ 3 3 ],the supposit ion in Le ber ' s HOA h a sbeen ba sed on the evidence of a congenital defect in the a bil i ty to de-toxify cyanide by c onver t ing i t to th iocyanate , re sul t ing ina p r e s u m e dincreased suscept ibi l i ty toa toxic action of cyanide absorbed fromtobacco smo ke o r other sources . Pat ien ts with this condi tion have beenfound to have subnorm al p lasm a th iocyana te ra th er than the e leva tedthiocyanate found af ter tob acco smo king in o ther people . In s o m e ( b utnot all) ca ses , t rea tment with hydroxocobalamin wa s con s idered bene-f ic ia l , and therefore was accepted as circumstant ia l evidence of a re-lationship to CN toxicity.

T h e r e h a s been cont roversy over the yea rsas to whether there is

Vitamin BIZ metabol ism in vivo is poo rly understood. Knox [37]

T h e r e are se ve ra l obse rvat ion s in supp ort of the cyanide hypotheses .

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The ro l e of CN, then, is uns u re [37]. Pe rh aps a gene t ic suscep t i -b i li ty o r re la t ive enzyme defic iency tha t re nd ers the re t ina o r op t icne rv e unduly s ens i t ive is re la ted to the pa thogenes i s [47].

N i g e r i a n N u t r i t i o n a l A t a x i c N e u r o p a t h y

The fully developed for m of the disease involves a t rophyof th eopt ic nerve, deafness , and sensory spinalataxia, p r i m a r i l y p o s t e r i o rcolumn myelopathy with o r wi thout per iph era l neuropathy[16, 48, 491.Because of the angula r s tomat i t i s , g loss i t i s , and sc ro ta l de rm at i t i s[50, 511 , sev e ra l au tho r s p roposed t ha t t he d i s ea se migh tbe causedby a vitamin B I Z defic iency. The oc cu rre nc e of the combined symp -

tom s in the Niger ian populat ion led C lark[521 to the supposition thatthe visual impairment in t rop ical amblyopia was caus ed by cyanideintoxication as a res ul t of the lar ge amount of cas sa va consumed inthe d iet . Ca ssav a con ta ins l in im ar ine ,a cyanogenic glycoside, aswell as a hydro lase ( l inase ) , which l ib e ra tes cons iderab le amountsof cyanide i f t he l e aves , s t em , or r o o t s are damaged [16].

Th e effects of chro nic cy anide intoxication have been studie d inman and experimental animals, and include diffuse demyelination [49,53, 541. T he obse rved pathologic changes in th is di se as eare tho se ofsegmen tal demyel ination [49]. Monekesso[551 stud ied pla sm a thio-

cyanate and vi tamin Blz le ve ls in pat ients with the disea se . Osuntokun[51] surveye d neurological abnorm al i t ies in two Niger ian vi l lag es pr e-sel ecte d for th ei r d i ffer ing consumptionof cas sa va and demons t r a t edthat the degenerat ive neuropathy oc cu rr ed wi th higher f requency in thevil lage where consumptionwas higher. He sug ges t s tha t ea t ing cas -s ava i nc r ea se s exposu re t o cyan ides ,as shown by a r a i s e d p l a s m ath iocyana te l eve l, and tha t th i s (and perh aps o ther fac to r s ) may con-tr ib ut e to th e pathogenesis. An additional study [56] of nine patien tswith t r op ical a taxic neuropathy showeda dec rea se i n su l fu r con ta in -ing amino acids-cysteine and methionine- with no rm alBIZ levels andhigh thiocyanate levels . All patien ts consumeda monotonous d iet ofca ss av a der ivat ives . It was fe l t that " the exce ss i ve cyanide detoxica-t ion ( s ic ) may be respo ns ib le fo r the low concen t ra t ionof t he su lphu rcontaining amino acids," perhaps combined witha nutri t ional deficiency.

As with tobacco amblyopia, evidence con necting cyanide to the patho-genesis of the syndromeis convincing but only circum stantial .

T H E R A P Y - N O N S P E C I F I C

As demons t r a t ed i n ou r f i r s t pa ti en t, i n som e ca se sit is poss ib l efor patients who have ingested a potential ly lethal d os e of cyanide tosur viv e wi th only nonspecif ic support ive me asu res . In th is cas e , theblood level ob tained 6h post ingest ion wa s 2.3 pg/mL. It h a s beendem on stra ted by Bal lantyneet al. [57] tha t blood le ve ls of cyan ide 1 h

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af te r ex posu re to known amountswere 67-83% of th e in itial valu es.Our patient 's peak level , then, would have beenw e l l within the lethalrange. Th er e have been two previo usly repor ted ca se s of potential lyle thal ingest ions of cyanide surviving af ter only supp ort ive t reatm entwithout the use of a specific antidote[13, 181.

Init ial treatment must include airway support , including intubationi f t h e gag reflex is absent , oxygen therap y, car dia c m oni toring, g as-t r ic lavage, and sodium bicarbonateas indicated f or se ve re ac idosi s .Although there h a s been no mechanism descr ibed fora specif ic act ionof supplem ental oxygen therapy against cyanide, som e autho rs sugge stthat such a mechanism exists [58-601. In exp erim en ts on m ice, Sheehye t al. [61] w ere unable to d emo nstra te any s ignif icant protect ive effectof oxygen alone. However, when used in combination with the nitr i te-thiosulfa te reg im en , 100% oxygen doubled theLD50 compared to thenitr i te-thiosulfate alone.

T H E R A P Y - S P E C I F I C

The use of specific antidotes for cyanide poisoninghas been pro-posed s ince ear ly i n this century when Sahlin [62] demonstrated thatmeth ylene blue antagonized the action s of cyanide. Chen e t al. showedni t r i t es to be a more eff icacious t reatment , in i t ia l ly us ing amyl ni -t r i t e [63] and la te r the amyl ni t r i te , sodium ni t r i te combinat ion [64,651. Since that t im e the us e of the El i Lil ly thr ee -st ep cyanide anti-dote package has gained popular acceptance in the United States (Table2). The f i rs t two s teps pro duce methemoglobin witha f e r r i c ( 3 + ) ionwhich com petes with the cytochro me sy ste m f or binding of the cyanideion [66]. Th e ma xim al amount of methemoglobin tha t can be prod ucedwith amyl nitr i te is 5%. This is jus t a temporiz ing maneuver unt i lt reatm ent can be s t ar te d with sodium ni t r i te . Itis des i rab le to keepthe level of methemoglobin clo se to, but under 40%, bec aus e toxiceff ec ts begin to show at this level, with le tha l resu l t s occur r in g a t

lev els of 85% [68]. The final st ep involv es the injection of sod iumthiosulfa te , which provides sulfur g roups fo r the enzyme rh odan aseto con vert cyanide into the rela t ively le ss toxic compound thiocyanate,which i n t u rn can be excre ted f rom the body, This s t epis slow, andthe for m ati on of cyanornethemoglobin allo ws tem po ra ry binding of thecyanide until i t can be exc rete d in the fo rm of thiocyan ate.

Unfortunately, t he us e of spec ific an tido tesi n cyanide poisoning isbased mainly on animal stud ies [31, 69-71] and uncontrolled humancase reports [64, 651.

Graham e t al. have previously ad dre ssed the iss ue of the lack of

cyanide levels in the patients t reate d with the three -s te p regim en[131.In this paper we have added two additional cases of potentially lethalcyanide poisoning who recovered withouta spe cific antidote. Th is isnot to say that specif ic ant idotes ar e not needed, but ra th er that bet t ercontrol led s tudies are needed to det er m in e which of the num ber of

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TABLE 2. Trea tment Modal i t i es

1. Lilly cyanide kit :

Amy1 n itr at e inhalant, 15-30 /m inStop above when ready to inject300 mg. Sodium n it ra te IV

( 10 c c of 3% solut ion) a t 2 .5-5 cc/min. Ch i ldren 's dose is6-8 mL /m2 (appr oxim ately 0.2 cc/kg) ; do not exceed!

Chi ldren 's dose (hemoglobin 12 g ) is 1.65 mL/kg [72]

2. Kelocyanor (dicob alt EDTA )300-600 mg loading do se IV [30]

3. Hydroxocobalamin (vitaminB I ~ ~ )p to 400 p o l / k g IV [301

4. 4-Dimethylaminophenol [161

12.5 g of sodium thio sulf ate IV (5 0 m L of 25% so lut io n) in adult.

avai lable ant idotes is the sa fe st and m ost efficaciou s. An addit ion alproblem with the cur ren t ly accep ted t rea tm entis its own poten tialtoxicity. It is possib le to induce a fa ta l m ethemoglobinem ia withsodium ni t r i te , especia l ly in chi ldren [72]. The package in se r t[73]w arn s of the po tent ial toxicity. How ever,it r ecommends t ha t c i r cum-

stan t ia l evidence is suff ic ien t to s ta r t t rea tment . A s mentioned e a r l i e r,the sum ptom s of se ve re anxiety mimic the ear ly sym pto m s of cyanidetoxici ty, and a s t r ic t definit ion of c i rc um stan t ia l evidenceis needed toexclude patients with known cyanide exposure who present to the Emer-gency Room som e t im e af ter expo sure awake and aler t . In thes e pa-t ien ts we would propose that a r t er ia l b lood g ase s be se nt and only sup-por t ive t rea tm ent be g ivenas ind ica ted un less they d em ons t ra te anyde te r io ra t ion in menta l s ta tuso r a metabol ic acidosis . Without the sef indings i t is difficult to justify the dia gn osisof a toxic e xpo sure tocyan ide, and treat m en t with a potential ly toxic antido te might not beindicated.

Seve ral ant idotes whichare used in Eur ope include am inophenols ,coba lt sa l ts , and hydroxocobalamin. Like the ni tr i te s, the aminophenolswork by producing methemoglobin. B au m eis ter e tal. [161 reviewedthe evidence in the G erman l i te ra tu re de mo nstra t ing that 4-dimethyl-aminophenol acted m or e rapidly than sodium n i t r i te and producedlessof a dro p in blood pre ssu re .

Dicobalt EDTA is avai lable in Euro pe under the t rad e n ame Kelo-cyan or, and is adminis tered in 300-600 mg loading do ses IV. Th e prod-uct form ed by the cyanide and the co baltsalts is uncer ta in , but it is be-lieved to be co balt icyan ide (CoCNa) which is stable and of low toxicity[31]. The problem with cobal tsalts is t h e i r own inhere nt toxicity,which causes a d rop in blood p re ss u re , c ram ps , vomi t ing , acu te d ia r-rhea, and death due to resp ira to ry fa i lure . Cyanide and cobal t s a l t shave been shown to have a mutual antidotal effect[161. Th is again em -ph asiz es the need fo r certa inty of dia gn osis of cyanide poisoning be-fo re ins t i tu ting toxic t reat m ent [181.

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Hydroxocobalamine (vitamin Biza) w a s proposed as a specificantidote for cyanide by Mushett et al. in 1952 [72]. A s opposed toother modes of treatment, this compound has the advantage of havinglow toxicity, with no toxic effects seen in doses of up to 400 pmol/kgIV [31]. Hydroxocobalamine combines in equimolar amounts withcyanide to form the relative ly nontoxic cyanocobalamine (vit aminBIZ). Subsequent experiments by Rose e t al. showed hydroxocobal-amine to be an effective antidote to letha l dose s of cyanide in dogs[69]. The use of hydroxocobalamine has been labeled as unsuitablebecause of the volume needed to give the recommended dose of 50mg/kg [74], considering that the commercial ly available prepa rat ionscome in a solution of 1 mg/mL. However, hydroxocobalamine i s avail-able, under an investigational license, as a powder which can be pre-pared in an aqueous solution i n an acetate buffer (pH 3.5-4.5) in whicha concentration of 10 mg/mL can be achieved 751.

C O M M E N T S / C O N C L U S I O N / S U M M A R Y

Two patients with th re e exposures a r e presented, including a fatalLae tri le ingestion. In both successful ly treat ed instances, cyanide in-gestion was not considered early, only conventional life support andpoison elimination were provided, and both survived the episodes.

1. While often undiagnosed initially, cyanide ingestion survival ispossible (in those patients that r each the hospital) because ofincreasingly sophisticated cri ti cal car e life-support sys tem s

2. Cyanide should be added to the li s t of substances causing se veremetabolic/lactic acidosis and anion gap

3. More ca se s will be seen with ea s ier availability and wider pos-session of Laetrile

4. Further study is needed regarding at what point no activetherapy is needed, whether alternate and perhaps less toxic

forms of intervention should replace the current antidotekits, and whether the prophylactic use of hydroxocobalaminewould be of benefit to patients on nitroprusside treatment.

A C K N O W L E D G M E N T

The authors wish to thank Laura Balin for her help in preparingt h i s manuscript.

R E F E R E N C E S

[ l ] K. Braico et al., Lae tri le intoxication: Report of a fatal case,N. Engl. J. Med.,

-00, 238-240 (1979).

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1113 (1964).V. Herbert, The nutritionally and metabolically destructive"nutritional and metabolic antineoplastic" diet of Laetrile pro-ponents, Am. J. Clin. Nutr., 32, 96-98 (1978).R. D o r r and J. Paxinos, Thecurrent status of Laetrile, Ann.Intern. Med., 89, 389-397 (1978).I. S. Symingtoret al., Cyanide exposure in fires, Lancet, 2, 91-92 (1978).S. R. Mohler. A i r crash survival: Iniuries and evacuation toxic

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poisoning via a reaction with'hemoglobin, J. Chem. Exp: Ther.,191. 557-563 (1974).-ditorial: Controlled intravascular sodium nitroprusside tr ea t-ment, Br. Med. J., pp. 784-785 (1978).

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,_ _ _ -J . M. Heaton, Tobacco amblyopia: A clinical manifestation ofvitamin BI Z deficiency, Lancet, 2, 286 (1958).J. A. Chisholm et al., Hydroxoco3alamin v er s u s cyanocobalaminin the trea tme nt of tobacco amblyopia, - - ancet, 2, 450-451 (1967).F. Walsh, Clinica l Neuroophthalmology, Vol. III, 3r d ed., Wil-liams and Wilkins, Baltimore, 1966.E. Dunphy, Alcohol and tobacco amblyopia: A historical survey,Am. J. Ophthalmol., E, 569-578 (1969).M. Victo r, Tobacco-alcohol amblyopia, Arch. Ophthalmol., -0,M. Victor and P. M. Dreyfus, Tobacco-alcohol amblyopia, Arch.Ophthalmol., 74, 649-657 ( 1965).F. Wokes, T o E c c o amblyopia, Lancet, 2, 526 (1958).

P. J. Vinker and G. H. Bruyn, Handbook-of Cl in ical Neurology.Vol. 28, Metabolic and Deficiency D is eas es of t he Nervous Sys--em, Par t II, North Holland, New York, 1976, p. 172.W. S. Foulds, Serum thiocyanide concen tra tio ns in tobacco am-blyopia, Nature, 218, 526 (1968).

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A. E. Kr i l l , H ered i t a ry Re t ina l and Choro ida l D iseas es . Vol.III,

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t r i t ion a l a t ax ia neuropa thy, B r. Med . J., 3, 647-649 (1968).B. Ballantyne, J. Bright , and P. Wi l l i a m s TA n e x p e r i m e n t a la s s e s s m e n t of d e c r e a s e s i n m e a s u r a b l e c y a n id e l e v e l s i n b i o-logical f lu ids , J. Forens ic Sc i . , 13, 111-117 (1973).R. Smith and R. E. G ossel in , C urr en t conc epts about the t re a t -men t of s e le c te d poisonings: Ni t ra te , cyan ide su l f ide , ba r ium,and quinidin e, Annu. Rev. Ph arm ac ol. To xicol. , pp. 189- 99(1976).G. Co pe, Im po rta nc e of oxygen in the t r ea tm en t of cyanide poi-soning, J. Am. Med. ASSOC.,B ( 2), 1061-1064 (1961).J. L. C. Dall and W. Hannah, Wxygen therapy in cyanide poison-ing, Br. Med. J., 2, 33-34 (1964).M. She eh y an d J. %. Way, E ffect of oxygen on cyanide intoxica-t ion, J. Pharmaco l . Exp . Ther. , 161, 63- 168 ( 1968).B. Sahlin, Skand. Arch. Physiol. , 47, 284 (1926).K. K. Chen, C. L. Ro se , and G. H .C low es , Amy1 ni t r i te andcyanide poisoning, J. Am. Med. Assoc., g( 4), 1920- 1922 ( 1933).K. K. Chen and C. L. Rose , N i t r i te and th iosul fa te the rap y incyan ide poisoning, J. Am. Med. ASSOC.,149, 13 (1952).K K. Chen and C. L. Ro se , T re at m en t of ac ute cyanide poisoning,J. Am. Med. ASSOC., 162, 1154 (1956).

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1977).Anderson e t al., Reming ton ' s P h a r m a c e u t i c a l S c i e n c e s, 1 5 thed. . Mack. Easton. Pennsvlvania. 1975. I). 59.R. E. Scui ly (ed . ), C a s e r i c o r d s ' o f t h e M GH, C a s e38- 1979,N. Engl. J. Med.,

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