SALICYLATE INTOXICATION

By

Harris D. Riley, Jr., M.D.,

and

Lee Worley, M.D.

1)epartinent of Pediatrics, Vanderbilt Uninersity School of Medicine

(Sitbuimittuol jaimiuarv 24, acc(’l)te(i \laro’im 2:3, 1956.)

ADDRESS: (lll),R.) Vanderbilt Uimivcrsity l-Io)spital, Nashville 5, Tennessee.

578

SALICYLATE

INTOXICATION

I

‘ PIll)I3AIILE that miiore acetylsahicyhic

acid! is iligestedl auiuiuallv tliami any’ other

dirug. Iii 1951 the Anienican pol)umlace s1)eilt

1:35 miiilhiomi dollars oii acety!sa!icyhic acid

ilui(I analgesics. However, neither the

mcdi-cal 1)rofessiomi on the laity fumhly appreciate

til(’ Pt1’1ititI toxic effects of this conimonhy

used miledlicamnemit. The dieatil rate from

acci-d!euitti )Oisonumlg o)f all types in children 1

tO) 5 years of age imi the United! States

froiii 1940 to) 1950 is :3.6 Pt” 100,000

popumla-tiOli. i)rugs tccO)tmmlt for one-thlird! of these

accidemitah 1)0i5011 ings, acetylsahicyhic acid

1)eing

tue

miiost COlTmOfl lethal drug.2 The

true imicidlence of salicylate intoxication is

hot knovn; iiO)WeVer, according to the

United States Cemisus Bureau the average

miiortaiitv rate fromii salicvIates is 0.350 per

miiil hiO)ii tOtili )OptuIatiOll, accOumitiflg for 4%

of fatal poisonimigs in

all

age grotmps.2

Despite tile lange role played! by sahicyhates

jul (lrug poisomiing there have been

reha-tively few rel)orts iii time Aunenicami literature

coiicermm ing this pnobiemii. I mi 1949, Lipman,

Krasnoff, dud! Schhess areported that poison-iumg dIne to salicvlates was necord!ed! so

infne-((n1(’hitl’ that omily sevemi previously reported oleatims ere found. In a review o)f the

l)ro)i) kuii imi 1950 Creemibeng fotimid only

88 reported i nstauices of acethsa!icyhic acid

of

all

degrees of severity. Phy-sicians caring for cimild!ren feel the

preva-lence O)f this po)isouiing is comisidienably inore

(OmiilmiOii tiiaui these reports wouihd indicate.

Baiii2 has estiunated that appnoxnnatehy

two-tiiird!s of tile !catiis from accidental

poison-imig \VOllid! i)e \vipedl otit if aspirin, the

bar-i)itturates, kerosene, lead, lye amid! arsenic

were tilia\’ailai)le to small childiremi. NIany

1)ilYsiciitlis comisciel mtiously warmi 1)1rents

iti)d)tlt tiit.’ danger of caustics, insecticic!es,

rodiemiticidleS, (1110! solvemits i)ut iieglect the

(!amlger O)f tue carelessly 1)ilcedi :I111

bottle. Iii addiition to the umiawareness of

the l)Oteiitial d!angers of sahicylates, confu-sion exists comicerning the pathologic

physi-ohogy of salicyhism and its treatment. In

in-fants and children sahicylate intoxication

may result from (1) accidental ingestion of

the drugs, especially acetylsahicyhic acid

(aspirin) or methyl salicylate (oil of

winter-green), and (2) mistaken dosage of

sa-hicyhate on the part of parents or physicians

in the treatment of disease. Intoxication can

also result from topical sahicylate thenapy#{176}

and occasionally from an idiosyncrasy to

acetylsahicyhic acid.

For these reasons, 42 patients with

sahicy-late intoxication in the pediatric age group

observed in a 10-year-period (1945 to 1955)

at the Vanderbilt University Hospital are

presented with a discussion of the problems

involved in this disturbance. In all cases

poisoning was due to acetysahicyhic acid

except one instance of intoxication due to sodium sahicyhate.

TABLE I

SALICYLISM 1945-1955

Iota I cases 4’.

A. Acci(lental 13

B. Therapeutic

a. Febrile 23

1). Itheuniatic

.,,,,,,.,..

6

Table I reveals that of the 42 proven

cases, 13 were due to accidental ingestion

and 29 occurred as a complication of

therapy for some concomitamit disease, in six

instances rheumatic feven.* One patient

was receivimig acetyisalicyhic acid

therapeu-0 There were niany more instances of salicyhism

occurring d!uring treatment of rheumatic fever prior

to) 1945 when milassive sahicyiate therapy’ was

ARTICLES 579

‘i’.iii.i: II

,O;E I)1s’nlolui’ruoN 01’ AO(’mt)ENTAL ANt) ‘I’iIEIOAPEITlC AttO’YLATE INTOXi( ‘TiON 194.5-1955

(Ex’mu:DmNG Rii.F)

0-I Fr. I Fr. ?--i Yr. 4-( Fr.

.\.(‘enietltal 0 2 1(1 1

ilmeral)eut i( I (; 1 I 3 I

ticahly i)ult also imigested! ami unknown

iium-ben of tablets from a carelessly placed!

i)ottle. This 1)atieilt is includ!ed in the

thena-Peumtic groump. \Iamiy cases of salicylate in-gestion wi thoumt intoxication were observed

lendlimig suipport to the contention that sa-licvhismii occurs more commonly in children

thiami has h)een reported!.’ As woumhd he

cx-I)ectei niost of the accidiental cases oc-ctirred! iii chiidremi 2 to 4 years of age-the

age O)f imisatiable cuuniositv and some

meas-umre of imid!cpendence. For reasons which

will i)e discumssed later, therapeutic

imitoxica-tiomi occurred! chiefly in infants h)elow 1

year (if age (Table II); of the hatter groump 11 were below 6 months of age.

PHARMACOLOGY

AND

PATHOGENESIS

Antipyresis is the most commonly sought

effect of saiicvhates I)ut these drugs are also

used! for their analgesic and antinheumatic

effects. A knowledlge of certain fund!amental

)liarmnacologic pnimici)hes is essential for the

rational treatment of salicyhism.

Acetylsal-icyiic acid! is hess irritating to the

gastro-imitestimial tract tiiami sodium sahicyhate but

Pndiumces toxicity moire rapidily. Methyl sa-hicylate 10 to 20 times the toxicity

of either of these and! because of its pleas-ant od!or is especially olangenous in that large amoumits may be ingested by small chihdincml. There is prompt absorption of

sa-licvlates from the gastrointestinal tract,

traces being detectable in the urine 10 to

15 minutes after therapeutic doses. After

single 2 gui doses in adults, maximum

con-centnations in the blood occur some 2 to :3 houmns after ingestion and! do not fall

appreciably for 6 hotmrs. ‘#{176}‘Sod!ium

bicarbo-miate hastens al)5O)rI)tioli as it dlOeS

excre-5 Estenified forms of these drugs are

first hydrolyzed, then absorbed and after

absorption are distributed evenly through-out the body fiuids.’ Sb Fortunately, after

absonptioui, most of

tue

salicylate is bound to) plasma leaving only 25% free to diffuse

into the interstitial fluid!; otherwise the

tox-icity at a given level wotihd be much

greater.’ Approximately 20% of ah)sonhed! sa-licvhate compoumnc!s are destroyed! in the l)ody and 1)robabhy even greater amounts in

tue

patient with rheumatic fever. Of the

remaining 80%, probably a small portion is oxidized to such end products as gentisic

acid, while the majority of the remaining portion is detoxified by conversion to more

easily excretabhe forms such as salicyhic

acid, sahicyhunic acid amid sahicyiglycuro-nides. It is improbable that

au

these end products play a significant role in the

pro-duction of toxicity. ‘ R#{231}mialexcretion is rapid by both fihtnatiomi and tubular excre-tion but renal clearance of free sahicylate is

markedly affected by the pH of the urine.

At

a urinary

pH

of less than 7.0 the

clear-ance is 10 to 15 mh/minute but as the pH

rises above 7.5, excretion rises sharply and may reach values above 100 mh/minute. Thus, if the urine caui be made alkaline,

the kidneys are able to rid the body of

free sahicyhate much more rapidly and this

is the rationale for the stuidiies shoving that

sodium bicarbonate given in comijunction

with salicylate lowers the concentration of sahicyhate in the bhood. However, in clinical

use this effect must be carefully weighed!

against the systemic acid-base disturbance

of salicylism. The major excretion occurs

within several hours but traces appear in

the umnine for :3 days or longer.s

Imi infants the elimination of sahicylate compounds is less efficient than in adults,

which must certainly be related not only

to hepatic and renal immaturity but also to the water deficit so easily acquired by

in-fants and young children. Not only does

sahicylism itself cause dehydration, as has

(‘ase

.)

liners (‘n/il

Onset

Salicylale iii Blood after

!nlerva1s Indicated

(mg/100 ml)

3 2.2 s

58() II I LEY - SALICYLATE INTOXICATION

* fntervai iii hours hat1(tti ingest ioim atid (leteruuuiflatiOti of blood salicylate.

‘i’I uterva Iin hours hat v(en (icterinhtmat ions of blood saIi(’iate. Lci(l is (I (Ieh\’(irLting Oli(’; e.g.. febnile

ill-nesses, (liarnilea dli(l vonhitilig. The

olenion-strated! cumulative effects of sahicyhates are

chiefly due to this relatively slow rate of

excretion.’2’ ‘ It has been shown that 4

houuns foilowimig a simigle diOSe of 65 nig of

acetylsalicylic acid in an infant the concen-tration of salicyiate in the plasma is 3 to 4 iiig/10() mi.’ If 80 mg (“a baby aspirin”)

are given at the ctisto)nianv inten#{188}’aI of every 4 hours pyrarnidling occurs 50) that

concert-tratiomis of 20 to) 24 rng/10() nil may 1)e

reached in the cotirse o)f 24 iioxmrs.

Obvi-ousiy intoxicatiomm vihl supenveiie if this

dose amid! schedule are comitinumed! for any

significant time. It was quite common in our

exl)enience to find! that the parent had

unwittingly given a small infant an

cx-cessive olose of acetylsahicyhic acid!

re-1)eated!iy by administering a portion of an “adult” tablet (0.32 gin) when a smaller

dosage form was not available. Hoffman

regards 35 mg/1(X) ml a toxic

concentra-tion in infants and with concentrations of 45 mg/1(X) ml unmarked! hyperventilation

oc-curs. The toxicity of salicylates is probably

in o!irect relatiomi to the rate of rise of the

concentration of salicyhate ill the plasma

as well #{163}15the actual comicentnation attaiiledl. Obviously iii aiiy patient with decreased! renal excretiomi whether it lie prerenal from

dehyd!ratiomi or dume to intrinsic renal

d!ys-function, the concentration of salicylate in

the 1)100(1 will rise )noportfl)naIIy higher

111(i faster (itle to) fatuity eIimiiimiation of

sahicylate amid imito)Xi catioii \Vi I I OdCI1F inore

read!ily. The loss of water from the lungs

due to hyperventilation and the excessive

sweating further diminishes the amount

available for renal excretion which in toni prevents lowering of the concemitration of

sahicylate in the blood.

Those intoxications resulting from acci-(!eIital ingestion are more satisfactory for

all aspects of analysis than those anisimig

from therapeutic reasons, since the clinical

and laboratory findings are not influenced

h)y an underlying disease, as is the case in

the therapeutic group (although, in the

majority, the primary disease process was minor). Acutely ill children, even before

renal function becomes impaired, do not

tolerate sahicyhates as well as those free of

disease. ‘ In analyzing our accidental

poi-sonings in an attempt to correlate dose,

concentration, and excretion, marked van-ability was encountered.#{176} This is

demon-stratedi in Table III wherein three patients

are presented for comparison. All three

patients were of similar age and weight.

Patients 1 and 2 ingested identical amounts

amid! exhibited! a comparable latent period

(

interval from ingestion to hyperpnea). However, 10 hours following ingestion,

pa-#{176}Methoddescribed i)y Brodie, B. B., et a!. (I.

Pharmacol. & Exper. Therap., 80: 1 14, 1944) was tised for all salicylate determinations.

‘I’ABLE III

lLLtSTtl.TlVE (‘.&ss TO I)EiloNsTio.TE \A10IABILITY OF CoNcENTRA’u’ioN OF’ SALICYLATE m BLOOm)

.lge Weigh! Satmcylate

(ir) (lit) (gr’Th)

27 4.7 4.5

10* lOt

‘2() 12

2 1.6 I ‘ 3.5

14 27

ARTICLES 581

tient 1 had a blood! level of only 49

mg/100 ml while patient 2 had a level of

70 nig/100 ml 20 hours following

inges-tiomi. Both patients were treated in a similar fashion yet 1iatt 1 iild! completely

cleaned! his 1)lasnia of detectable sahicylate

at 10 houmrs while patient 2 had eliminated

omily a))rOxirflateIy one-half his

concentra-tion iii the ilasma in 12 hours. Although the

iuiiotimit iuigested i)y 11tie1it 3 is not known,

his sahicyhate level omi adimissiomi is similar to

that of patient 1 after a comparable time

imiterval followimig ingestion. The similarity

emids here, however, for 27 hours later

pa-tiemit 3 still had a concentration in the blood!

three-fourths tFiat of the adimission

concen-tration while I)itieult 1 showed! no

c!etect-able salicyhate iii the blood in 10 hours.

All three patiemits had! essentially the same

degree (if intoxicatiomi as evaluated by

c!imii-cal standiard!s. \Vliethen these

inconsisten-cies reflect differemit degrees of physiologic

miiatumrity, varvilig stages of hiydnatiomi, or

juidividumal susceptibility to the d!rug

re-niaimis to be clarified.

Severe toxicity at low concentrations of

sahicylate in the bloo! is frequently

en-coumitered as mioted by others.7’ 21, 35 Graham

1mi(! 21 I)articuhar have documented

the great variability of the concentration of

sahicylate iii fhe i)hd)Odl at which 5ym)tOms

appear in oi!ifferent ind!ividuals (Table VI).

Oiie of the more severe intoxications in our series was a 2-rnomitii-old infant who

re-ceivcd! oiiiy 0.58 gui o)f acet!sahicyclicacid

over au interval of 5 days ending 3 hours

before admission for a mild upper

res-PiratorY infection. She was desperately ill vitIi niarked! hyperventilation, a

respina-tory rate of 80 per mintite, l)lOOd! 1)H, 7.3

amid! CO combining power of 8.3 mEq/l.

However, the concentration of salicylate in

the plasma was only 9.0 mg/100 ml, and

althoumgh it had! fallen to 3 mg/100 ml 14

hours hater, she remained in poor condition

with severe hyperpnea. Other instances of

severe toxicity at sahicylate concentrations

O)f 8, 4, dud1 22 nig/100 ml, respectively, were

observed!.

Table IV SilO)W/S the emitire series of the

13 accidental cases. These cases further

emphasize the variabilities just discussed!.

In addition, it can he seemi that no

correla-tioii exists between the amouiit ingested

and the latent period nor betweeii the latent

period and the rate of excretion. There is

only slight conrelatiomi between

concentna-tion iii the blood and! severity of

intoxica-tion and! this d!epends upon whether or not the concentration is obtained!

reason-ably near the time of onset of the patient’s

toxicity. It is well to note, in this regard!,

that symptoms and! signs of severe

intoxica-tion can, and often do, persist after the

concentration of salicyhate in the blood has

fallen to vehi within the thierapeuitic range.

This inay well accoumit for many of the

cases of intoxication which would seem to

have occurred with low conceiitnatioiis of

sahicylate. Thins, a low concemitnation of

sahicylate in a severely hyperpneic and

critically ill patient does not vitiate the

diagnosis of sahicyhism if the last d!ose was

given, say 24 hours prior to admission since

the stimulus to the respiratory center and

the altered metabolism

by

sahicylates may

persist after the concentration in the blood

has decreased significantly. A 2-year-old

child who has received only 0.96 gm of

acetylsahicyhic acid, the last dose being

given 24 hours prior to hospitalization, was

extremely ill with marked hyperventilation,

CO2

combining power of 6.8 mEq/l, but on

examination had only mild otitis media

and a concentration of sahicylate in the

plasma of 23 mg/100 ml.

PATHOLOGIC

PHYSIOLOGY

Sahicylism produces an almost unique

effect on acid-base homeostasis. The hitera-tune is confusing and conflicting as to the

nature of this metabolic effect. The clarified

concept of this aspect of the condition has

been late in coming, not only due to the

failure to obtain determinations of blood!

pH

in conjunction with CO2

concentra-lions but also due to lack of attention to

the age of the patient. Although Odin10

recogmiized the importance of central

hypcrp-I Ilour. hours

. . Resp.

. . I ,mimI front

.#{149}lge II ‘mghi Su1mcyhmc I #{149}Rate

(use IOnaclo; Iimgealmon

)yr) (Ib) (gr. Ib) Ilyperp- to Blood

flea .fna1yst.

I 4.7 1-.’, iO I 60

t I -- ? s I 4 90

:i t

--

? l 7 1

4 ‘t O) ‘9 st mm 3

3 ,, ‘, tmm I 7 H ? 0

to i is m s ? 1 a ‘o

7 .e2, :im 16 It .21 6

8 ‘ ,, :mi in i ? 40

.4rerage Tempera- Leukyles

.‘:; (per aim’)

11 Urine

Kd.

---

--

Blood

‘

Soltcylale

Sal. my 100 ,n/

1(10’ 13,450 .5.5 I +

101mm”

- 49----’O

lO)’ 11,000

-

- +

861mm’

+ .5.5----.17

100’ 101,300 55 +

I i0imr

+ 47---’l.3

ioi’ 9,soo 5.5 +

UI 1mm’ +

mom’ mi,o - - - I

996’ I l0t50 7.0

I i5lr

+ -

‘‘

mom” 13,500 50 ₊ - em

moo’ i,S00 .O’ + +

I

10.5’ t,5(10 Ad’

I 1ilmr

+ + 70---.8i

m0l’ :14,000

11)0’ 3 ,000

o

4.3

I

-ii- +

I - +

i3hr

70----.845

171mm’ 43--- -sm

101’ i5,800 4.5 + +

Ut1mm’

36----.3()

108’ 39,500 &0 + + 4,5

9 mm, :mt 4.7 :i’ tO) 64

Ia t : e; mm ? to .56

mm t21. to ? 7 ‘24 40

it I’ i, ti )‘ moo ti-it 64

em ‘t” ,, ? :; 4 3O) 60

+ POSi(Ist

0 =negatis’m’

- = rmot lime

*Interval 1et sveetm leternmimmatioims of hi a I smlk’ylate.

582 RI LEY - SALICYLATE INTOXICATION

TABLE l\

ALlCYLATE IXTOXI(’tTION DUE TO AccuuExT.kI INOiESTD)N

nea, Dod!d, \Iinot, and! Anemia1 ‘ were

1)rob-ably the first to diemonstrate an elevated!

1)H in

tile h)lOOdI iii tile face of a

simulta-licotis decrease in CO contemit. However,

controversy as to the cause of the lowered CO2 content contimitied!, sonic workers as-cnibimig it to a respiratory ahkalosis1’’ and!

others solely to a metabolic acidosis.hi_lM

That h)Oth mechanisms can and usually do

operate, especially in infancy, is now more

commonly recognized.’ . ia. Clinically,

the two phases are superficially similar

since hyperventilation is present in both.

It has been well established that the

hy)er)miea results frouii stimnumlation l)y

sa-hcyiates of time respirator\’ cemiter’’’2 di-rectlv or reflexlv through cileiiiorecej)tOnS

supplied by the vagus nerves but not

lo-cated in the carotid 21 Graham and

Parker2’ have also shown that the

stimula-tion is one of depth rather than rate and! may reach severe proportions even at low

CO2

pressures. Alexander et al. have

shown that with concentrations of sahicylate

in the blood of the range 12 to 16 mg/10()

ml respiratory sensitivity to the normal

car-hon dioxide-hydrogen ion stimulus is

markedly increased. This hypenventihation leads to an excessive loss of CO2 from the

blood. The concentration of H2CO3 and

BHCO3

are

normally maintained in the

blood in a ratio of 1 :20 such that the blood

pH

is 7.41, pH being equal to 6.1

4-{BHCO.J

lou ‘-- (Henderson - Hasselhalch

ARTICLES

583

equmatioui). This “blowimig off” of CO2 results

ill a d!ecnease of

CO2

content and a resultant increase in

tue

normal 20: 1 ratio with a rise in pH of the blood so that respiratory

alkalosis is now present. If the patient is

seen early and! at this stage, the CO2

con-temit will be miormah or low hut the pH

will i)e elevated! d!espite

tue

apparent

clini-cal picttire of acidosis. Whenever the ratio

of the comicemitrations of

BHCO:I

to H2C03 in the serum is altered!, the bod!y

mmmcdi-atehy calls imito play mechanisms designed!

to return the ratio to

tue

norma! 20: 1, al-though tinder the most ideal conditions

compensatiomi or “ratio repair” is never

complete. Wheui CO2 content is olecreased!,

coml)emisatiomi cami be lnod!ticedl only by a

couicomitant (lecrease in bicarbonate, the kidney promnotimig this by excretion of hi-canh)onate iii the unimie. Theoretically at this

1)Oiuit

tue

tunine SiiOtm!d! be alkaline and

therefore a tmsefuh diaguiostic tool in

d!if-ferentiatimig resj)iratory ahka!osis from

meta-1)Oiic acidosis. Imiitiaily this may be the

case bumt with stmstainc! hyperventilation on

wheti renal function becomes altered, i.e.,

salt d!eI)ietiomi, the urine reaction can vary

gneatly.7 i: The acceleratemJ transfer of

iiyd!nogen ioIis fromn the cells to the extra-cellular flumid! is felt to be another effort to-ward compensation.

In Oldier children and adults witli mild to

moderate toxicity the disturbance may

re-main iii the stage of respiratory a!kalosis

with a slight secondary decrease in buffer

base tmntil the intoxicant is withdirawn,

wiiemi there is a slow return to norma!

re-(t1irimlg rip to :3 iavs. “ On the other

hand, ill imifants and in old!en patients with

severe toxicity, after a variable length of

time and! umsuahly inversely proportional to

the dose, a primary decrease in buffer base

and CO content (metabolic acidosis)

oc-curs. This second amid! more severe

acidi-i)ase derangement is more accurately

speak-ing a mixed respiratory and metabolic

dis-turbance. At this point the CO2 content is

low amid! the

pH

d!nops first to normal, then to a level below 7.4 h)ut seld!Om 1)elow 7.2. #{176}

The exact nietabo)lic niechanismiis for this shift in time acid-imse arrangement are not

entirely clear but are probably related! to

abnormal metabolic production of organic

acids and the secondary removal of fixed

base by the kidiney, dictatec! b’i the

neces-sibj for removal of the abnornial metabolic

end pro(!ucts. Ketones are umsuahiy reported!

ill the urine of these patients and some

workers feel that the acidosis is pnimtnily

diue to a ketosis restilting from a poisomling of the Knebs cycle of carbohydrate metabo-lism by sahicylates with imliiii)itioii of

tue

utilization of lactate. :

,

i Simigen feels that

ili those cases fri which acidosis occurs rapidly, the tisumal type of ketosis is not

responsible non is

the

acid!osis dine to renal failure with accummulation of sumifate amid!

phosphate, as this is a rare and late comn-phication of severe intoxicatiomi. Salicvlate iomis also iia rio sigmiiflcant role. “ It is

1iossible that the niost likely expianatiomi is

iii the changes of interniediany miietabolisuii

at the cellular level with the accuniulatiomi of organic acid! and! metabolites, inc!umd!ing

acids distinct from ketone The

rapid d!evehopment of d!eilyd!ratiomi and

starvatiomi as em1)ilasized h)y Dod!di, Minot

and! Arenau is an adld!itiommai hazardous

factor promoting oiigunia as well as ketosis. Table V illustrates

tue

i)iochemical changes iii five typical cases of sahicyhism.

Intoxication in Ittients 1, 2, andl :3 restuited! from accidental ingestion of acetylsaiiclic

acid by healthy childneii so that the

habona-tory I)icttmne is uncouliplicated! i)y a d!isease process. Patients 4 and! 5 d!evelopcd

sahicyl-ate intoxication d!ue to treatment of mimior

upper respiratory infections.

Of

the 42

l)1-tients, the CO2 combining power was

dc-tenmine! in 39. Thirty-sevemi of the

thirty-nine showed a red!tmced Co2 combinimig

power on admission but timifortunately in

neither of the two patiemits with normal

CO2

values was a dietermimiation of l)IOOd!

pH

obtained!. All I)cltients in whom p1tsuiit

pH

was determined showed an acid!emia

with one exception. This was a 5-month-old!

infant (Case 6, Table V) who received 1.8

gm of acetylsahicyhic acid over a 48-hour

584 HI I EY - SALICYLATE I NTOXICATION

.‘ ‘‘

x

0’- ‘

-_1ic:I

s. x x

I

H;.

H

-‘

.-.‘

i’__

--,--:#:

.- = Ixxx,

-1+ ++++ +

z

I + +++ 1+

:

#{149}

.

-I

:: I

I -x__

“

_

.D I

‘1’

af

-x

0’-,

©

‘,

+1

- -,;

.5,

z

z

z

-z

z :7,

I-5

e5 I

I ‘ “ ‘

-z I

x I

+ 1+

.5,

+ +

.5,

::H

,.C.? C.

-‘

I

I

‘5’.

-r - -

-.5’ ‘5 (, -,. - 1’--‘5’-t

= .5,

- .5,

x

.5’

-.

x

.5,

-I.

.

“5

‘5’

-....

-.

‘‘

s

z

.

:

.t x

-

-- ,

1

-x

, I

++++++

-p - 5

+++++

- , ,, .

-mf

-HEMORRHAGE (I)

SEVERE OYSPNEA (3)

PULMONARY EDEMA (I)

EXCITEMENT, EUPHORIA (2)

CONFUSION (4)

HEMATURIA (2)

ACETONURIA (2)

SEVERE DROWSINESS (4)

VERTIGO (I)

HEADACHE (5) MARKED SWEATING (8)

HYPERVENTILATION (10)

ALBUMINURIA (4)

VOMITING (10)

NAUSEA (9)

DEAFNESS (9)

TINNITUS (9)

ERYTHEMA 3

10 20 30 40

PLASMA SAUCYLATE LEVEL

(MG.S)

50 60

ARTICLES 5(5,-)

‘tABLE VI

‘l’oxmo: N’INtIIIsml toNs ot’ Stto:s’uvi : l’otsoNuN;

‘l’lmese data froumm tue iitcratmmre repro’sent the oo’o..’murrcumce of 87 toxic ummanifestations fromun 58 1)Lti(’lmtS

receiving SO(lillulm Sdiic\ldte for tli(’ tremtmneuit O)f acute rlmetutimatic fever. No)te the g(’tm(’r(tl rO.’iatiOlisiiil)

l)et\\’e(’li time i)io)O)(I i(’veis aul(l tll(’ severity of the signs. \‘erticml litl(’S over the 1)mrs Si1OtVifl ranges

repr(’s(’rlt time ummr’aui. From Winters.

The cO)ncentration of salicvlate iii the l)hood!

W15 20.4 rng/100 miii, p1 7.48 dud1 CO

comnbiuiimig 1)\\’d1 15.9 niEq/h imio!icatimig a

resl)iratorv alkalosis. \Vallacc7 estimates

that 1I)I)rxi uiiately one-hal f of the patients

vitii iiyl)erl)Iiea are iii tue stage d)f

respira-tory alkalosis wlieii rnediical cane is first

souight. The timiie nequiiredi for the transition

to the liliXCd! with its CO mInd!

buffer-base deficit timid! lowered! 1)H is variable

(froni 1 to) S hours), buit iii general occurs

mnuucii miiore rapidily amidl to a more marked degree iii imifants ilid! voting child!remi.’

Because of the relatively large doses

re-CI’i\Cd! b’ roost of our patiemits and! dume

to the referral miature of the ped!iatnic

chien-tele, virtually nomie of the l)atients imi this

report were seen uiiitil 12 or inore hours

after the omiset, which accoumnts for the

pre-diO)iiiiiialice of 1)dtiemlts with acidlemia.

Erganiami et (ll.7im foummid all of their 13

pa-tients to) have rediuctiomi of serum pH when

first seen. That patiemits in the pedliatnic age

group vary greatly in their stmsceptil)ihitv to

sahicyhates is il lustrated! bY coulipanisomi of

I)atiemits 2 amid 6 in Table V. Patient 2, a 2-year-old! gin!, was severely acidotic (pH

7.19 amid! CO 8.2 mEq/l) whemi first seemi

7 hours after ingestimig an immiknowmi auiiouuiit

of acetylsahiclic acid!. Imi contrast, patiemit 6, who W1S 5 months of age, was imi

nes-)iratory alkalosis when first seen after

re-ceiving 1.8 gun of acetylsahicylic acid! over

a 48-hour penioi, the last (lose havimig beemi

given 12 hours before hospitalizatiomi. Iii

p(1tiemit 2, the tinie of ingestion was s1wcifi-cally kmiown buit the exact amiiouimit of

ace-tylsalicylic acid! taken was miot aiu! (if COrtS’

inay be arm important factor ex)laining time

dlifference. It is well kmiown that time onset of

toxic symiiptomiis may be dielaved! for several

hours, and!, when they occur, the conurse

Inlay be rapio! and! fatal. Further contrast

is afforded between I)ItieIitS 8 and! 9 in

the accidental group (Table IV). The ages,

586 RILEY - SAIACYLATE iNTOXICATION

takel I. L11o1 ilItOl”#{188}t1 i)(’t\\’((’Il illg(’stion aimd

O)l1S(t 0)1 SVIii1)tOllis \ver(’ tllilO)St ioiemiticai

iii these two) Pati(’nts However, patient 9

\vas chinical!’ rnumch sicker with higher

fever, letmkocvtosis, greater degree of

hyper-o’uitilatioii, audi vith a iiione severe acidosis.

Values o)f j)H iii the 1)10)0(1 Ort adirnission

ranged! from 7.19 to 7.48, the lower values occimrning iii the younger iiifiiits. Sevemi

l)Utiemits slmO\vedi alues for

tue

CO co)ITI-biuiimig I)o)(1 011 adlniission, bctweeii 6 amid

7 mEq/i, 12 i)etweemi 7 and 1:3 niEq/h, 8

i)etween 14 amid! 15 umiEq/l. amid! the

remain-ing 4 11:1(1 ‘aitues l)etweemi 16 and! 21 niEq/h.

AdlmIliSsiO)Ii concemitnations of salicyhate in

time pIisuii1t ranged fromn 70 miig/1()0 ml to

6 liig/100 miii, lilO)st of the valtues falling

i)etWeeli :30 dud! 60 ung/10() miii. The two

highest levels (70 uiig/100 ml) occtmrred! in

ciii 18-niontim amid! a 2-y.:tr-o!d! child!,

re-s1)ecti’(ly, i)o)tii ill the acciolemital group. Cliloridles dud! nonprotein ilitrogen in the

serum were usually iionniah on elevated! on

entry but na1)idily netuiniled! to normal aften

1):ir’miterll flumid! therapy. \Vinter states that iiyierglyceuiiia cami be produiced!

expeni-miiemitallv 1)5/ large oioses O)f sahicyhates and!

this find!ing has beeii reported! iii huirnan

iiitOXKatiOii. Nine of our I)cttiemlts hlad!

die-t(’rlililiatiO)IiS of glucose in

tue

blood and

i!l were witliimi miorma! hiuiiits excel)t two

iii the timerapeuutic grouup with

hypogly-ceuiiic levels wilo had ior d!ietany imitakes

over a 1)eni! of several (lays alid! one fatal a ccidlemitah poisonimig wild) ilad! 1

concentra-tiOll of glucose of 276 mg/100 ml prior to therapy.

Evidence Imas i)een Preselitedi to show that

sahicylates in higii diO5C5 imifluemice the

pitui-tarv-adremial systelli and! its secretions.

fliese (mugs have i)een reported to)

P’#{176}-d tuce ami eosi I mopenia, depletiomi of adrenal asc )rbic llid! cholesterol , dud! histologic

evid!eulce of adiremmal activatio)ml.’’ Iore

re-cently iiumiians and experimnental amiimnahs

vithi sahicylate iiitoxicatid)ii have been found

to have marked!ly elevated! concentrations of

17-hydiroxyconticostenoid iii the plasma, in comitradistimiction to other reports, showing

no elevation in the blood or urine.’

CLINICAL

MANIFESTATIONS

The warning symptoms of early salicyhate

intoxication, which are frequently seen in

adults, such as tinnitus, deafness and

nau-sea, infrequently occur or at least, are rarely

recognized in children. By far the two

most commomi manifestations of salicyhism

iii infants and children are hyperpnea and!

vomitimig. Vomiting clue to local irritation or central iii origin1 frequently occurs 1

to 3 liO)tmnS following dli accidiental

in-gestiomi of a lange over!ose. Nine of the

thirteeim accidlemital cases gave a history of

emesis on were observed to vomit. Vomiting

was frequently present in the therapeutic

grotip also but in view of the frequency of

this symptom in sick infants and! children it was impossible to imicniminate salicylates

as the sole cause. Vomiting usually precedes hyperpnea, which is more likely to occur

from 3 to 8 hours following ingestion.

The onset of hyperpnea is quite variable;

however, as can be seen in Table IV the extremes in our accidental cases were

2 and 18 hours after ingestion. Usually, by

the time the patient is seen by the physician,

and certainly by the time the patient is

hospitalized, hyperpnea is the single

out-standing symptom in children. When severe

it is of a type seen in few other conditions,

l)eing violently deep and rapid ano! remains

so tintil cure or exhatistioii occurs.

With the more common therapeutic

in-toxications the history umsually reveals

pro-longed! administration of presumed safe

doses of acetyhsahicyhic acid in the face of

diminishing fluid! intake, fever, and

fre-quently vomiting and diarrhea. As dehydra-tion progresses, renal excretion of the

sahi-cylates fails and toxic concentrations are

reached. Dodd, Minot and Arenatm1 demon-strated that sahicylates per se cami produce

iiy)erpyrexia and dehydration. It is

en-tirehy possible that some cases of

hyper-pyrexia are exaggerated by the prolonged!

use of acetylsahicyhic acid. All patients in the accidental group (Table IV) showed

temperature elevation, the highest being

105#{176}F. Large doses of sahicylates produce

ARTICLES

587

after the immitial stimulation vlmichi is respomi-siblc for many of the life-threatening

mani-festations. Iii some cases, especially in

in-famits, there may be hyperactivity,

disori-entatiomi , stul)Or, comivulsions, circulatory

Co)iial)Se, conia and respiratory faikmre. Frequicmitlv

tue

leukocyte count is dc-vate!. Temi of the thirteen accidental cases lid(! leukocvte coumits oven 1 1,000/mm.

Io)tIr I)ttieuits had ihuies OVC 20,0()0/mni

amid! two) of these 1)atiellts showed! the

high-(‘st concentnation of salicylate in the 1)100(1

o)f the emitire gro)uup. Ill adi(iitioii, three of

tll(5e four 1)atiemits were the most critically

ill of the accidemital grotup. Otherwise, there

\:t5 1)0) correlation between the

concentra-tiomi of sahicylate and! leumkocyte count. Six

I)cttiemlts ill our series showed! hemorrhagic tendencies varying from melena to bleeding into tile subarachimioid space. Prothnombimi

dletenniinations were carried out on but

two o)f these six patiemits with clinical bleed-ing amId! omily one, a child with petechiae, silo)wed! significant prothrombin reduction.

Aniomig tile group without detectable

bleed!ing omie I)atiemlt was found to have

hy-1)o)I)nthirom1)iu1emi11. Iii vestigation of this i)iiemiouiiemiomi ii:ts revealed multiple mecha-miisnis to 1)e comicerncd. It has been

postu-hated! that salicylates inhibit the formation

0)1 1)rotiiromnhiml in the liver42 amid! the con-cemitratiomi of circulatiiig fibrinogen also falls

1)rcstlm1it1IY d!tme to failure of hepatic syn-thesis.

Time nattire of the acid-base d!istunbances has beemi d!escnibed.

Imi dogs, salicylate poisoning prodtmces a

1)roftmse d!iuresism2 amid! the oligunia so fre-quemitly noted! in human cases is probably a

result of the d!ehyration. Protein, cells, and

cyiindhcah casts are frequently found iii

the urine. Salicylates in the urimie may be dietected! h)y the I)ersisteiice of a positive

fernic chloride test (a purple color) after boiling the uniuie to volatilize the ketones.

The iiresemice of piiosphates in the urine unav prodiuce a false miegative reaction due to the precipitation of fernic phosphate,

umihess adequate amounts of reagents are

used. In addition to both a true and false

1)O)SitiVC test for acetoacetic 1(i(l, time urine may give a positive Benedict’s test since gentisic acid is a reducing substance. Thus, a patient with sahicylism may prevent the

following

picture

: a dehydrated, comatose

child with hypenpnea, acetone odor to

1)neath,

low

concentratiomi of CO2 in the serum, hyperglycemia, nedtmcing substances

and ketones in the urine. If an occasional improper and potentially dangerous (hag-liosis of dhahetcs mehhitums is to) i)e avoidied,

the possibility of salicylisni must 1)1’ i)oniie

in mind!. Iii such cases, whiemi ami adlequmate

history is miot obtainable, tile concentration of salicylate imi the blood! siioumld be

deter-mined.

One

should

never rely (in a positive test for sahicyhates in the urine since a single

benign

dose

gives

a

positive test, and a

person with diabetes is as likely to be using acetylsalicylic

acid

as anyone.

The

proper

and

safe dose of salicylates

is controversial. A standard textbook of

pharmaco1ogy states, “children are quite

tolerant of salicylates and requlire larger doses than calculated! by their weight and age.” Stevemis and Kaplami17 using the same

relative dose of sodium sahicylate (0.15

gm/kg) safely employed by Cobunn

adults encountered severe intoxication in

childhood. Fashena and Walkenm noted

no toxicity with this dosage but

intoxica-tion rapidly appeared whemi the dose was imi-creased to 0.20 to 0.22 gm/kg. Dumbow and!

SolomonmS found toxicity developed in pa-tients 4 to 11 years of age at a dosage of

0.15 gm/kg/day of sodium sahicyhate but

0.125 gm/kg/day produced satisfactory

concentrations in the blood without toxicity.

The dosages recommended by Marniot and

J

cans39” and Poncher and Unna39t of 0.06

gm

per year of age tip to 5 years no oftener

than every 4 hours and 0.04 to 0.06

gm/hb/d!ay ill rheumatic fever are proba-bly safe for the majority of pmttiemits. How-even, contimiuation of these conservative doses in the face of dechimiing renal fumiction

may head to serious poisoning. If one accepts the majority opinion that sahicylates exert no effect upon the basic cause of rheumatic

(‘torn merit

588 RILEY -

SALICYLATE

INTOXICATION

5ylli)toniatic relief is obtained, and themi gradually ohiscontinno’oI. Es1’ciai consider:i-tion should! h)C givemi to c!ose :111(1 d!tmration

of sahicylate medication iii young infants

because of the greater likelihood of in-toxication (lime to the pnevli)usly m’nentioned!

reasons.

There were five deaths in our series,

all occtmnning in patiemits who received! ace-tylsalicyhic acid! as a therapetitic measure

timese I)ItieiltS it \V15 difficult, even at imecropsy, to h.)(.’ certain whether the (liSease for which the acetylsahicylic acid was givemi

or the sahicylate intoxication itself was the

chief cause of death. In most cases, how-ever, it seemed that the combination of the

two factors was responsible and that the

patient could have survived either of the

insults alone. The fatal cases arc outlined!

below:

ll(’(I.’I)7Ifor .Imount (Ifl(i 1)uration of

((lIt’ .he Sali(’ylate i’reatment toil/i

.1dm ini.lralio,m .leetijlxalieijlic arid

1. 4111(1 “(‘(11(1 1 7 gm’in 24-hour jwrieI Semi-comatose, ‘F 104#{176},hyperneic, lungs clear. CO

(‘ombitmitig power, 1 1 mEq/l, salicylate

coumeentra-tion, 20 tng/100 ml. Expired 8 hours after adunissioum. Necropsy revealed mild interstitial ptmeummmonia not

severe etmough to cause death in OpifliOtm of

patholo-gist.

2. 1yr “flu” Exact aummoutit tutiktmosvtm.

“Received 5 gr every 2 hours

for3-4 days.”

Comatose, ‘F 105#{176},hyperneic, few coarse rales over

both luumgs. C02, 6.8 timEq/l, salicylate coucetmtratiotm,

34 mg/IOO nmi. Expired 6 hours after a(lmission

fol-lowing hematenmesis.

3. .5mittm “(‘01(1 ?30 gm’ AS: in 24 hotmrs prier

to a(Itmlissioti.

Severe Imypernea, dehydrated, ‘1’105#{176}.Lungs o’lear. CO2 counhitming power, 7 ummEq/I, salicylate

conceum-tratioum, tmmg/100 nml. Expired I hour after aolnmissiotm.

Necropsy revealed iniumimal tracheitis and bloody

ocrebrospinal fluid. Tracheitis felt not of sufficient

severity to be fatal.

4. 3 111(1 “cold” 25 30 gr itt 36 hours prior to

adttiissioti.

(‘omuatose, cyanotic, irregular respirations, or’easiotmal

rhotmchi over lungs, T. 104#{176}.CO2 combining power, I I .8 tnEq/l, salicylate (‘otlcetmtration, 24 nig/iOO

nil. Cerelmrospinal fluid normal. After several bouts

of apumea, eXpire(l in 3 hours. No necropsy performed l)ut clituically’ felt to have salieylisnm and questioumable

pneunmonia.

;5. 2 yr utmkmmowmm (;I is gr itt 30 hours and

immgeste(I utmktmomvum amount.

‘I’hought by referring pliysieiatm to have aspirated a

foreigim body or to have diabetes. Comatose, severely

(lyspneic, 1’ 1030. Lungs clear and roetmtgenogram

normal. (1)2 conml)itming power, 8.6 nmEq/1, blood

sugar, 276 ung/100 mi, but (Iropped to 120 mg/1O() ml ill 3 hours, salicylate com’entration, 4.5 mg/IOO mmml.

Expired I1 hours after admission in respiratory

(Ic-pressiotm. Necropsy not permitted but clinically no

concomitant olisease found.

for some concomitant malady.1s One child

ingested an unknown amount of

acetylsali-cyhic acid in addition to that given as treat-ment. Three of the five fatalities occurred

in infants below 6 months of age. In

TREATMENT

The physician caring for children should constantly remind parents as to the dangers

of

salicylate

ingestion

and

remain

aware

ARTICLES

589

Ilsed! dlrugS wimemi emnj)hoyed therapeutically.

\oumlg cii ildremi ingest surprising amnoumits

o)f uuipieasaiit tasting mnateniahs amid some

authorsT feel that the bitter taste of

salicyl-ates is no deterremit to ingestion. However,

a recent survey reveals tiiere has 1)eemi au

actual increase iii the incidence of acetyl-salicylic acid poisoniumgs simice

cand!y-flavored! tablets becauiie generally

avail-di)IC. I 3 recent diinective by the Foo! and!

Drug Ad miiiuiistratiomi requiring a

conspicu-otiS wanmiimig label on most type of

sahicyl-ate 1)reparations for commercial sale should!

1)n\’e h)euieficial iii red!ucing the incidence of sahicvlate )ois0iling. I’

\iihd! diegnees of immtoxication respond

(Iuuickiv to Vithid!rawah of saiicylates. It is diesirable in niost cases to hospitalize the

cliik! ‘iio has accid!entahhv imigested

sahicyl-ates eveii though he is asymptomatic

he-caumse it is umsuahly ini1)OsSihle to know

imii-mli(’dhiatelv the exact amnount of d!rug the

I)atiemlts received!, amid! d!epeiidiemice nitist

oftemi l)e I)l1ced diii uminehiahle factors

sucil as )antiahly emnpty bottles and the

opimiioii (if au excited informant. Each child! varies greatly iii his susce)tibihity to

saucy-lates alid! toxicity, as previously discussed,

imiay occumr at low concemitrations. If the pa-tient is seen shortly after accidental

inges-tioii of a large olose, the stomach should be

iavagedl hiuit sodiituili i)icani)Ouiate, which en-Imances the absorption of salicylates, should!

not l)e tise(! in the lavage sohuition. Since

nietily! salicyhate is slowly absorbed! oven a

period! of houmrs, lavage shouild be carried! oumt eveui if

tue

1)atieuit is seen late followimlg

iulgestio)n. The waslmings sllO)tuld! be saved! for toxicohogic analysis. If hmvpenpimea Ilas Uir(’adlV 1I)1)1m(!, lavage is o)bviotmshy

use-less.

\Vimcui intoxication is estal)hishied,

treat-miiemit miiust be iuidiividuahizedi, flexible and

directed! l)y phisiologic pnimiciples. In the

abseuice of vomniting, fluiois shiouk! be forced i)y motmtii iii order to facilitate umninary

ex-d’1’(ti0u1 of the drug. Since hyper)1iea amid!

lo)\Veu’ing O)f time (X) donceimtnation are

usti-:tll I)u’’s’lmt i)o)tiI ill the stage of m’espiratorv

alkalosis dIl(! thu hoter acidlotic pimase, these

tWO) 1)lmlsS C’uI lie (hifiCl’Cfltiate(l vitli

(er-taint)’ only by a blood pH. Serial pH

die-terminations also 1)rovide a vahumable guide in following the course of the patient.

Dc-spite opinions to the contrary2’ the urine

pH

is not a reliable guide to the acidi-base statums because acid! unimie may be prod!ucedl

iii the face of respiratory 2 Spector

and McKhann,1I in several cases of sahicyl-ate intoxication, found the urine reaction

was umsuahly acid although the blood 1)H

was well oven 7.45 in all cases. If the plasma

CO2

content is below 7

mM/h,

the

reduc-lion is sufficient to produce an acid pH

re-gardhess of the degree of ti2

However, aside from this no comiclusiomi

re-gardmg

pH

can

I)e made

on the basis of a

low CO comitemit. Tue use of alkaline

sohu-tions hecaumse (if the reduced CO2

concemi-tration has 1)een avm .2, 3 However,

the tise of such alkalis diumning respirators’

alkalosis, with its cerebral vasodihatation

and! increased intracranial pressure, may

aggravate the alkalosis to such an extent

that compemisation may be impossible and

can lead! to comivulsions amid a fatal

out-7 The imicreased nietal)ohc rate, poly-tinia, dia1)horesis, and! the heed! for

en-hanced urinary volume demand that

ade-quuate amiiouunts (if fluids be provided. Until

serum pH and!

CO2

concentrations

have

heeui determimied, glucose solutions to equal full mnaimitenance and estimated deficit

re-quirernents should be adiministered intra-venously.

If

respiratory alkalosis exists, sahiuie should 1)C added to the parenteral fluids so that salt diel)letion can be avoided!. Convulsions should! be treated by oxygen

since cerebral alioxia may be a factor; tctamiy can l)e coultnohlcd! l)y calciumni gluiconate

or iniialatiouis of 5; CO. Time tramisitiomm

to the mixed state with acidernia shoumki lie anticipated amid comifinuned by determination

of serum pH and CO2 content. If and

when this stage occurs, aikahinizing salts

should he administered. Large doses of

lactate or bicarbonate directed toward com-plete correction of the bicarbonate deficit

are probably contnaindicated since a sudden

1.15(1 iim tills fraction 1lLt\ Prt’cil)it:tte

i’eSI)ira-to)r\’ tlkalosis if the salicviate concentratio)Im

c’ommtinti-590 II I LEY -

SALICYLATE

INTOXICATION

ing hy)er)miea. \Vimmtei advises raising time

bicarbonate concentration initially only 4

to 8 niEq/l, subsequiemit correction

depend-ing on

tue

serum pH amid!

CO

values and! clinical condition of time patiemit. It has been

I)5ttmlc1tei that tile acid!OSis is refractory to correctiomi by one-sixth molar sod!ium lac-tate becaumse of inhibition of lactate

utihiza-tioii I)y saiicylates, 1)tit We have not found

this to 1)e so iii ouur experience. Adequate

amiioumits (if diextrose should! be provided! to

cOml)at the ketoisis viiichi occurs. In

cx-I)enimnemital animals the survival tinie is in-creased! by in’isium of adidied carhohy-(mates.’1

If miieasuirciiient of blo)od! 1)H is

mmo)tavail-able, it is best to pro\’id!e adiequate amounts

of glucose amid! water uuitii 6 to 8 hours have elapsed! or ummitil time

C(.

conceiitnatioii

falls to 7 niM/h, since one can usually be

certain that the shiift toi iilctal)ohic acidosis

has occumrred 1)V this time oi’ at this CO

level.

Shock should! be couiibattcd with whole i)lOOd, albuiiiimi andh plasmiia transfusions,

fresh blood beimig preferred! h)ccause of its

fibriuiogen contemit. Serum albummin also has the thieonetical potemitial of comnbinimig with

the salicyhate comii1)oulids amid! thereby

ren-denitig thiemii less toxic. Vitamin K, and! prob-ably

C,

shoumhd! l)e ad!rnimiisteredi; 1 mg of

vitamimi K will coumiteract ap)noximately 1

gui of sahicylate. On the basis of the findings

of Dod!d and! \iinotm’ hypenprexia should 1)e I)revemltcdl and! controlled by external

cooling, amid! moisture on niist may prevent

ftmrthcn diehydratiomi as the results of

pro-longed! liyperpnea.

Tue use of barbiturates for time hiyperpnea

ills l)eeui \vidielv comidemnhled! following the

‘ork of Rappoport amid! Guest33 in dogs

POiSoulcd! h)y uiiethyl saiicylate. These work-ens diemolistratedi that hypcrpnea could be

abolished! and!

pH

and

CO

concentrations

couldi 1)e maintained within normal range

h)y repeated! injectiomis of sod!ium

pentobar-i)itI!. However, after repeated! injections of

this (mug iumtraveimouslv, scvei’al of the (logs l)ecdmiie d!eel)l\’ co)iiiatose aimdl expired!. They

conel tl(1(’(l tihlt barl)itnrates amid salicylates

had symiergistic toxic amid! depressant actions

oh the central nervous system in dogs and advised! agaimist their use in treatiriemit of

human intoxication. Morphiiie amid panalde-hyde were also found to have d!eletenio)ums effects in experimental poisonimig. Omie of

our patients, a 2-year-old! child with severe

intoxication (pH, 7.19; CO2, 8.1 mEq/h,

sahicyhate concentration 43 mg/100 ml), was by error given sodium phenoharbital

0.16 gun intramuscularly. Iii S houmrs the

respiratory rate dropped from 60/minute to

24/minute with marked decrease in the

depth.

Hen

recovery was clinically more rapid than amiticipated. Another patiemit

with severe sahicyhisni whose course was

progressively d!ownhiil was givemi small doses of barbiturate parenterally with dc-crease in lien hyperpnea and no umitowand

effects. Certainly barbiturates should not be routinely used iii an effort to decrease the hypervemitilation hut might be used as

a last resort iii certain cases.

The

actiomi

of these drugs in human salicylate imitoxica-lion deserves further imivestigation.

Respiratory depression may occur in

cases where the dose of salicylate is

oven-whelniing amid usually ends fatally.

Win-ten,43 in studlying one patiemit, foumid! that the infant rockimig bed lowered! time marked alveolar CO accumulation amid! returned!

the blood!

1)H

towarc! normal range. Iii cases

where

res)irat0ny

failure

has

occurred!, the

tank respirator should be attempted,

al-though there can be little hope for success,

as the failure is probably more central tiiami

I)eriPhenal in origin. Theoretically, clectro-phrenic respinatiomi might be hemieficial.

Severe but reversible renal dlamage results from severe sahicylate intoxication. Tue

anti-ficial kidney has been reported to clear the blood of sahicylates in a rapid and efficient fashion.’ The occurrence (if early damage

to the

cemitnal nervous systeni suggests that

rapid removal of sahicylates is highly

de-sirabhe.’ “ We have entertained! the

pos-sibility (if using exchange transfusions in

tecim-ARTICLES

591

uuique, which comistituites a I)l45mn1 as ‘well as a ned cell exchange, has been rel)Onted to be successful imi i)onic acid poisoning.5#{176} It

VOuild! 5CCili tilat a chiuiictl trial with this

thenapeumtic rneasuire is warranted iii

se-lectedl cases of salicylate

SUMMARY

Foi’tv-two cases of salicvhate intoxication

iii infants Umid! childnemi observed over a 10-\ear-period! are reviewed!. The majority of

the 1:3 cases of poisonimig diud to acci(!entah

imigestion occurred! in the 2- to 4-year age

m.amlge \vilereas

tue

29 imitoxications result-imig froiii therapeumtic adiiiiiiistratiomi of

sali-cvhates occurredl chiefly iii infants.

Accumu-lative therapy imitoxication is niore likely to occuir ui infants rather than old!er

cliii-dreui miot only becatise of au umiawareness

of tile damigens and! of the proper dose of acetvlsahicvhic acid!, but also because of the

(Iecreased! nemial excretion of sahicyhates dine

to renal im uiiatunits’, and I)ne-re1i1l azotemia

due to (lehVdhratiOui resumlting fromn the

dis-(tSC for which

tue

(mug is given. Time

niarked! variability in time response of an

ifl(!ividitm al to) salicylates is enl1)hiasized.

Evemi in poiisomiimig nesultimig from accidental

ingestion, where tue effects of an undenly-ing disease diO iiot have to be comisidened,

the 1)ilsmlia concentration of sahicylate, cliii-ical response, degree of toxicity at a given

commccntration of salicylate, amid! time re-quiredi for remmal excretion varied! greatly for

ciiildlreml of time same age and size who

in-gcstedi coiuiil)arable amnouints of salicylate. Severe intoxication at how concentrations of

salicylate iii

tue

iilasumm:m was observed. H’-Per\’entiltlti1m audi voumliting are tile mmiost COlllIil(iil chiiiical manifestations of salicyl-isuli hiut a hemorrhagic d!iathesis mine to

hiypo)nothromhimlemia, hypen)yrexia,

d!e-hinium or conia, circulatory collapse, amid

respiratory failure may be observed. The

unique effect of sahicylates on acid-base

hal-ance with an initial respiraton’ ahkalosis

progressing to a nietabohic acidosis is

dis-cussed!. A treatment prograni based! omi

phys-io)iogic 1)niumcil)ies is outhine(!. Time

im-1)ortant role of dnmg ingestion, es)eciahly

acetylsahicylic aCi(I, as a cause of dicath is

re-emphasized and! a plea is mnade for l)etter

education and attention to the potential damigers of sahicylates.

ACKNOWLEDGMENT

AI)Precic1ti011 is itme lrs. \V. Frakes iii

PreI)aratioml of miiamiuscnipt.

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592 RiLEY -

SALICYLATE

INTOXICATION

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dl1d1 sediuiiemutatioim mate iui m’hmeuimatic

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28. Foreign Letters: Mode of eimdocrine

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29. Dome, A.

K., Ely,

R. S., and Kelley, V. C.:

Studies of 17-hydroxycorticosteroids.

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30. Smith, M.

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H., Gray, C. H., and Lunnoum,

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Text-ARTICLES

59:3

1)00k d)f Pediatrics, 5th Ed., edited by

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ri’

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50. Boggs, T. R., and Anrode, H.

G.

: Boric

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SUMMARIO

IN

INTERLINGUA

Intoxication

a Salicylato

intoxication a sahicylato es on del pluis

commm-mmmuum ty1)OS d!e immvemmeimaiiieimto dirogal in

iii-fatmtes. Es presentate tom revista de 42 casos de

iumtoxication a Sdlicvlat() ium imifantes e juveniles,

observate ill he curso die tin periodo de 10

aimumos al hospital del Universitate Vanderbilt. Dece-tres casos involveva intoxication per in-gestion accidemital. Le majoritate de iste casos

concerumeva patientes de immter duo e quatro

aumumos die etate. Le altei’e 29 casoiS die

immtoxica-tion (‘SS(”S’L effectuate 1)t1’ Ic a(ilnilmistration

tim(’I’7t1ietItiO..’ (IC Salid’Viatd)S. Iste gruppo

con-istea prim mo.’iI)ahIllcImte de hiabies, Dece-un de

illes habeva minus oiue 6 menses die etate. Le salicvhatos es absonbite rapidemeimte per Ic vias gastroiumtestinah, sed Ic excretion, que se effectua quasi imitegremeimte per le via reumal, es nelativememite lente. Iimtoxicatioim therapeum-tic cumulative occurre plus frequentemente in

babies diUd in juveniles de etates plus avanti-ate. Le ration es mion solmente que mtilte per-sonas cognosce ni he peniculos ni le correcte doses de acido acetvhsalicvlic sed etiam qume

ih ha in babies un reducite excretion urinari del salicylatos (debite a immaturitate renal) e azotemia prerenal (debite a! dishydratation

que resulta del morbo contra Ic qual Ic droga

es administrate). Quando Ic functiommes renal es disrammgiate, he excretiomm es retardate e Ic concentration in le sanguiume accresce rapide-mente. Es sublineate Ic mancate variabihitate

del respoumsas individual sub Ic effecto del

sali-cylatos. Mesmo in casos de invemmeumameulto accidental, i.e. in casos in ciue nulle effectos de

Un morbo subjacente esseva invoivite, grande vaniationes esseva notate inter patientes del

mesme etate e del mesme peso e comm ingluti-tiones de comparabile quantitates de sahicvlato, in tanto he tempore post (jtie Ic svmptomas se

declarava como etiam in he commceumtration de sahicyhato in he plasma, in Ic nesponsa chinic, in

he grado de toxicitate correspondente a un date

concentration de sahicylato in le sanguine, e in he tempore requinite per he processo del

excre-tion remmal. Grados sever de intoxication esseva

observate iii he presentia de basse

concentra-tiones de salicylato in he samiguine.

Hyperveum-tilation e vomito es he plus comniun manifes-tationes de sahicyhismo, sed etiam diathese

hemorrhagic pote esser oi)servate como effecto de hpoprothrombinemia, e lmperpvrexia,

dehinio o coma, collapso circulatoni, e

disfalli-mento respiratori. Occurreva cinolue mortes,

ommmes in Ic gruppo therapeumtic, e Ic studios

Imecroptic revelava salicvlismo esseva he

causa pnimani del morte in omne casos.

Sahi-cvhatos ha un effecto tiumic simper he balancia d!e aCid!o C base. Le hyperveumtihation, resuiltammte ab Ic stimulation del cemmtro respiratori he

sa!icylatos, produmce uum perdita excessive de

CO2

in he pnime phases del intoxication con comisequente alcahosis respiratori . Effortios

compeumsatoni, pniumcipalmente per Ic excretion renal de bicarbomiato, es initiate, sed he

pro-CCSS() resulta usualmeimte iii tin acidosis

nietabo-lie debite a! nedluctio)lm pritliari dICI base

taumi-poimh e del conteimto die CO. lit coumsequiemmtia