SALICYLATEINTOXICATION

Signifkance of Measurements of Salicylate in Blood in

Casesof Acute Ingestion
Alan K. Done, M.D.
Department of Pediatrics, University of Utah College of Medicine

S ALICYLATES are ingested by children the emergency room of the Salt Lake County
more frequently than any other po General Hospital or in consultation at other
tentially toxic substance. In the emergency local hospitals were studied. With one excep
room of the Salt Lake County General Hos tion (Patient 1, who had a mild upper respira
tory infection), none of the patients had ap
pital, aspirin is involved in 27% of instances
parent organic disease. In each instance, salicyl
of the accidental ingestions of potentially ate had been ingested in a single dose in un
toxic materials by children and in 54% of known or potentially toxic amounts. In four
accidental childhood ingestions involving patients the substance involved was oil of
drugs; it is implicated six times more fre wintergreen (methyl salicylate), and in the re
quently than the second-ranking barbitu mainder it was aspirin.
rates. Moreover, in the experience of this Severity of intoxication was assessed on
institution, salicylates rank second only to clinical grounds without reference to salicylate
barbiturates as a popular choice among levels. Separation of patients into severity
adults and adolescents for attempted sui groups was empirical and a clear delineation
was not always possible. Although specific
cidal poisoning.'
predetermined criteria did not enter into classi
In most cases of acute ingestion, it is im fication, the following major manifestations
possible to determine with any degree of generally were observed in the patients of each
accuracy the amount of salicylate ingested. group:
Methods adaptable for use by clinical labo
symptoms― Occasional
“¿No subjective,
ratories are available for the measurement but not objective, mani
of levels of circulating salicylate. However, festations
considerable discouragement concerning “¿Mild― Mild to moderate h@perp
their usefulness has arisen because of the nea, sometimes lethargy
poor correlation of level of circulatirg sali “¿Moderate― Severe hyperpnea, prom
cylate with severity of intoxication.'-4 Pa inent neurologic disturb
tients have died with salicylate levels of ances (marked lethargy
less than 15 mg/100 ml, while others have and/or excitability) but
not coma or convulsions
been relatively asymptomatic with levels of
“¿Severe― Severe hyperpnea, coma
50 to 60 mg/100 ml.
or semi-coma with or
This communication is an attempt to in without convulsions
crease the clinical usefulness of measure
Adult mongrel dogs were used in preliminary
ments of circulating salicylate in cases of
studies on the removal of salicylate from circu
acute ingestion by clarifying the relation
lation. The animals were fasted for 18 hours
ship between levels of salicylate and the prior to the period of study. Intravenous salicyl
severity of intoxication. ate administration was accomplished by in
jecting sodium salicylate into a leg vein. Oral
PATIENTS AND METHODS
administration was accomplished by pouring
Thirty-eight patients (29 children and 9 an aqueous solution (15 ml total volume, in
adults) who were seen by the author either in cluding wash) of sodium salicylate or aspirin

Supported by research grants from The Institute for the Study of Analgesic and Sedative Drugs, and
the National Institute for Neurological Diseases and Blindness (Grant B-1606), Public Health Service.
ADDRESS: Salt Lake County Hospital, 1940 South Second Street East, Salt Lake City 15, Utah.
PEDIATRICS, November 1960

800

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 @ I I

ARTICLES 801

@
through a tube which had been passed peroral 120 0@01

@ ly into the stomach. Blood specimens were ob —¿.‘

110-
1' IOO@
@> •¿
Na
‘¿
Asp
Snicylate

@90
tained from a leg vein.
Salicylate concentrations were determined
immediately by the method of Trinder,' using
0.5 to 1.0 ml of serum.

@
OBSERVATIONS @30
@I8

Figure 1 illustrates the relationship be C',

20
Path@oy
24 hr oolue
10

tween serum salicylate level and the sever 2 4 6 8 0 2

HOURS
ity of intoxication among 38 patients who
were seen at varying time intervals follow FIG. 2. Semi-logarithmic plot of serum levels of

ing the accidental or suicidal ingestion of intravenously or orally administered salicylate in

salicylate. The salicylate levels
in Figure 1 are those obtained at the time
the patients were first seen. In agreement
with the observations of others,24 the cor
relation between salicylate level and the
severity of intoxication in these patients is
relatively poor. The serum salicylate level
at the time of admission was lower in some
patients with moderate to severe (or even
fatal) intoxication than in other patients
dogs. Salicylate levels were measured at 24 hours
indicated in the animals which received salicylate orally in
order to determine whether the slope of the re
gression curve was similar over the first and second
12-hour periods.However, the graph was not ex
panded to include the 24-hour values since this
would necessitate telescoping of the early period,
the period of primary concern here. Instead, the
direction of the curve (“pathway―)
between the
12- and 24-hour points is shown.
(Doses: intravenous, 6 gm; oral, 3 gm. Animals
weighed 20 to 25 kilograms.)

who were asymptomatic or only mildly in

toxicated. greatest influence on the relationship be
The one variable that seemed to exert the tween salicylate level and severity of intox
ication was time since ingestion. A patient
180
with a serum salicylate level of 50 mg/100
•¿CHILD
O ADULT ml 3 hours after ingestion, for example, was
L@METHYL
SALICYLATE less likely to be seriously ill than a patient
60
who had the same level 10 or 12 hours
after ingestion. That is to say that the se
40
-.5 verity of intoxication appeared to be related
to the maximum salicylate level achieved,
20 .
and in the latter instance, the level must
have been considerably higher than 50 mg/
@I00
6
100 ml at an earlier time in the patient's
course.
@80 •¿ rjri If, with passage of time, the level of cir
•¿â€¢â€¢¿ •¿ culating salicylate diminished in a rela
@oo1 •¿o@
00 0
[o@.1i. H •¿H L@ tively predictable fashion, the variable of
: L.JI time since ingestion could be eliminated.
@ 40@
L0iL.@ Studies were undertaken in dogs to deter
mine the pattern of removal of salicylate
20 from circulation (Fig. 2). Following the
intravenous administration of sodium sali
0- cylate or the oral administration of sodium
NO MILD MOD SEJ@QE@W4Z salicylate or aspirin, the regression curve
SYMPTOMS
for salicylate levels in serum assumed early
FIG. 1. Relationship between serum level at time
of admission and clinical severity of salicylate in the characteristics of a first-order reaction.
toxication. Thus, at least beyond 3 hours, the salicylate

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 802 SALICYLATE INTOXICATION

90 That the rates of disappearance of sali

80 cylates among various patients fall within
70 reasonably narrow limits is indicated by the
data of Table I. The half-life values in 17
60@
patients ranged from 15 to 29 hours with a
50- mean of 20 hours (S.E.M., 1.07). The data
are not sufficient to determine whether the
40- rate of removal is influenced significantly by
such factors as age, treatment with alkalin
izing solutions, or the type of salicylate in
gested.
Since the disappearance of salicylate from
circulation is a first-order reaction, the cir
culating salicylate level at a given time in
20
the post-absorptive period can be calculated
from the equation for a semi-logarithmic
curve:
(1) log S = log S0 + bT,
Where S is the salicylate level (mg/100 ml),
S0 is the theoretical (extrapolated) salicylate
10- , , , ‘¿ level at zero-time, b is the slope of the re
4 8 6 24 32 40 48
HOURS SINCE INGESTION gression curve and T is time in hours. The
Fic. 3. Regression of serum salicylate levels in extrapolated zero-time salicylate level can
seven human subjects(6 childrenand 1 adult)with be calculated by transposing equation (1):
salicylate intoxication. Aspirin or methyl salicylate (2) log So = log S —¿
bT
was ingested orally in a single dose. Note that the The mean slope (b) of the regression curves
ordinate (salicylate cone.) is on a logarithmic scale.
for the 17 patients, for whom salicylate half
level declined at a relatively constant frac life was calculated, was —¿ .015. Thus, the
tional rate which did not change appre equation which describes the mean salicyl
ciably over 24 hours. ate regression curve for the patients of this
Figure 3 presents data from serial meas study is:
urements of serum salicylate levels in seven (3) log S@= log S + .015 T
representative patients with salicylate in Although S0 exists in theory only, its cal
toxication. It can be seen that in these sub culation makes it possible to eliminate the
jects the disappearance of salicylate from variable of time since ingestion. Were peak
the serum also approximated a first-order salicylate concentrations achieved almost in
reaction, at least beyond 4 to 12 hours after stantaneously, as by intravenous injection,
ingestion. The rate of removal can, there 5,, and the peak level would be essentially
fore, be characterized by calculating the the same. Where salicylate is ingested orally
half-life of circulating salicylate.° and the peak concentration is therefore
reached gradually, S@ will be somewhat
° The salicylate half-life is calculated as fol higher than the actual peak level. It will,
lows:
S is the salicylate level (mg/100 ml) and T is Then, since
time in hours. S
By definition, the half-life is the amount of time log —¿ log S —¿
log 2
2
required to go from
S Half-life = log 2
log S to log .@ b
The value of b (slope of the regression curve)
Thus, from equation (1) above, isderived from the equation for the regressionline
—¿ log S log(S/2) of best fit, which is calculated by the method of
Half-life = T1 —¿
T2 =
b least squares.

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AGE-DIsTRIBu'rIoN OF SALICYLATE HALF-LIFE
(years)1234567Adulthalf
21 17
-life
(hours)16* 1629 22
19Mean 28t
2420
half-iife
(17patients):
* Received intravenous bicarbonate.
t Methyl salicylate.
however, be directly proportional to the
maximum salicylate level.
The value S0 was calculated for each pa
tient of this study using the mean rate of
disappearance of salicylate from the serum
(equation 3, above). Table II lists the symp
toms, observed salicylate levels and cal
culated values of S0 for individual
Figure 4 illustrates the relationship between
S0 and the clinical severity of salicylate in
toxication. The correlation here, in contrast
to the correlation between severity of intoxi
cation and the actual salicylate concentra
tion at the time of admission, is excellent.
With the exception of one patient in the
“¿moderate― group, the only overlap was
among patients who were asymptomatic
mildly intoxicated. This is to be expected,
since patients of these groups usually dif
fered only with regard to the presence or
absence of hyperpnea or lethargy, mild de
grees of which are difficult to identify with
certainty in the disturbed or very young
patient. The separation of patients with
fatal intoxication from those who had severe
intoxication but recovered, is especially
noteworthy. Two of the patients in the
“¿fatal―
group did not receive medical care
intil very late in the course of severe in
toxication. Patient 35 was first seen 32 hours
after salicylate ingestion and died within
2 hours of admission; Patient 36 appeared
moribund when first seen 21 hours after
salicylate ingestion, became apneic 15 hours
later and required artificial respiration for
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ARTICLES 803
TABLE I
VALUES
Age
1615*252218 16
19
20 hr.(S.E.M.,±1.07)
12 hours before death. Patients 37 and 38
died despite intensive treatment instituted
within 12 and 3 hours, respectively, of sali
cylate ingestion. The latter patients had the
highest S@values observed. These observa
tions suggest that with conventional treat
ment a fatal outcome is likely in patients
patients. with an S@value greater than approximately
160 and that measures for accomplishing a
rapid reduction in blood salicylate levels,
such as hemodialysis or exchange transfu
sion, are indicated.
On the basis of these observations, ap
proximate limits were established for pre
dicting the severity of intoxication on the
basis of S0 (Table III). Obviously, not every
or patient will follow this outline since indi
vidual factors such as concomitant illness
and perhaps age may materially influence
the reaction to a particular degree of sail
cylemia. In addition, a value for S@ cal
culated on the basis of the average rate of
removal of circulating salicylate will be in
accurate for patients who eliminate salicyl
ate at a much slower or faster rate than
average. The observations of the present
study suggest, however, that such inac
curacies are not likely to be of sufficient
magnitude to detract appreciably from the
clinical value of the proposed scheme, at
least in patients who were previously well.
The longest salicylate half-life observed in
this study was 29 hours; in this patient the
S@values calculated on the basis of his own
and the average rates of salicylate elimina
 @
@ .@ .@ s @.

804 SALICYLATE INTOXICATION

TABLE II
SYMPTOMS, OBSERVED SERUM SALICYLATE LEVELS AND CALCULATED VALUES OF So FOR 38 PATIENTS WITh
SALICYLATE INTOXICATION. PATIENTS ARE LISTED IN ORDER OF INCREASING MAGNITUDE OF S0

ml)..@ ManifestationsSerum Sal iej,vlvils(mg‘¿1(X)

Since
@ a. .@ Measured
ingestion L I
E (hrs.)Aaymptomatic
4
@ 0,@.@ Ci@.Interval

if 3 7.40 26 4 35 36
2 21 7.47 24 35 38
3 ‘¿24 7.30 21 2 42 45
4 17 Nausea 2 44 47
.5 ‘¿2 2 46 49
6 3 7.53 27 2 18 51
7 19 Tinnitus 8 47 69
8 2 3 56 62
9 ‘¿2 4 .57 6.5
102 4 .59 68
Ii 17 4 60 69

Mild

12 34 + 14 34 50 56
132 + 3@ 57 65
14 94 ++ 7.41 16 10 47 66
15 24 ++ + 7.26 16 24 32 73
16 ‘¿2 ++ + + 24 69 75
17 2.5 ++ + + 54 64 77
18 14 + + 7.45 16 44 69 81
19 15 + + 7.54 15 64 65 81
20 15 + 7.46 18 89Moderate 9 65

21 11 + + + + 7.43 17 Hypotension 3 76 84
22 21 ++ + Confusion 4 88 101
23t 2 +++ + 7.51 11 Hyper-irritability 5 86 102
24 3 -4--@--4- 7.40 14 Ilyper-excitability 12 67 103
25 2 +++ 15 Staggering gait 20 52 104
26 5 +++ + + 7.37 18 3 94 104
@ 27 +++ + + 7.45 13 16 61 106
28 ‘¿2 +++ + + 24 47 108
29 16 ++ + + 7.44 19 Vertigo 111Severe 16 64

30 14 +++ + + ± + 7.20 9 14 80 130

31 14 +++ + ± + 9 14 82 133
32 4 +++ + + ± 7.22 8 21 66 136
33 2 +++ + + 9 19 73 141
34 2 +++ + + 142Fatal 54 22

@t14 +++ + + 6 Deathin 34bra. 32 55 166

36 2 +++ + + 7.10 12 Reap. failure 36 bra.; death in 51 bra. 21 84 174
37 ‘¿2 +++ + + ++-4- Death in 18 bra. 12 120 182
38f 2 +++ + + Deatb in 9 bra. 3 165 183

Oil of wintergreen (methyl salicylate); all others ingested aspirin.

* Venous blond.

tion were 88 and 103, respectively. In the A nomogram (Fig. 5) was prepared on
patient with the shortest salicylate half-life the basis of the average rate of elimination
among those who were not treated with of salicylate and the observed relationship
bicarbonate (16 hours), these values were between S@and the severity of intoxication.
149 and 130, respectively. This nomogram makes it possible to deter

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 @ @t%@

ARTICLES 805

TABLE III —¿200

@ ISO
.@ I'PIIOXIMATE LIMITS FOR ESTIM AT! NG TI! E Ex ISO-i
PECTEL) SEVERITY OF SALICYI.ATE INTOXI 40
CATION ON THE B.&sis 01.' 120

lOO@
SEVERE
log So=log S@+ 015 Tt
@ 8OH
@ @3 7O-i •¿MOD@'
So \— eo@

<50 Not intoxicated 50 MILD\

@
.50—
So Mild 4O@
80—100 Moderate
>110 Severe N
30- - N - N
>160 Usually lethal \
-- N. -
* S=Serum salicylate in rng/100 ml. 20-
t T=Time in hours. ASYMPTOMATIC

mine, within the limitations mentioned

above, the expected severity of intoxication

@: SINCE
/N@EST/O
J
______________________________“¿@ —¿@
0

froln the salicylate level in serum at a given

time after acute ingestion, without resort ________
to the calculations and use of logarithms
FIG. 5. Nomogram relating serum salicylate con
necessary for the determination of S@. centration and expected severity of intoxication at
It should be noted that both the nomo varying intervalsfollowing the ingestion of a single
gram and the concept of S@ are applicable dose of salicvlate.
only to patients who have ingested salicyl
ate in a single dose. In addition, they are elapsed that the continuing absorption of
applicable only when sufficient time has salicylate does not distort the regression
curve. It is for the latter reason that the
•¿-‘@

L•
80 [@ CHILD nomogram begins at 6 hours. Earlier than
0 ADULT this, the measured salicylate level will ap
@@METHYL_SALICYLATE
60 proximate S@ and can be used directly for
predicting severity of intoxication, once it
40 is established that the peak level has been
reached or passed.
@ 20
DISCUSSION

00

r0
r@ Salicylate
available
measurements
to clinicians
are not as widely
as they should be,
•¿ 01
I 1_. considering the incidence of salicylate in
@8o
•¿â€¢0 toxication and the ease with which the de
60 ri:1 @•¿i terminations
proved
can be performed.
methods, salicylate
With im
measurements
o.• are among the simplest and most satisfac
40
tory of clinical laboratory procedures. For
example, with the Trinder method,5 a very

______
-
20
accurate salicylate determination can be
performed in less than 5 minutes. The
NO MILD MOD J'EVE@QE
,c47.@4L method involves the addition of a single
SYMPTOMS reagent to 1 ml of serum or blood (or a
Fic. 4. Relationshipbetween S0 anti clinical smaller amount diluted to 1 ml with water),
severity of salicvlate intoxication. filtering of the solution and reading it in a

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 806 SALICYLATE INTOXICATION

colorimeter or spectrophotometer. The re of intoxication suggests that individual fac

agent is stable indefinitely at room tern tors are less important than previously sus
perature and results obtained from one time pected in determining the toxicity of salicyl
to the next with one batch of reagent are ates. There are not sufficient data to de
highly reproducible over a period of at least termine whether such factors as age, ante
several months. The method can be adapted cedent illness, type of salicylate and method
to the use of smaller amounts of whole of treatment influence the rate of removal
blood obtained by finger prick. The avail of salicylate or the response of the patient
ability of methods which are so simple, effi to a given degree of salicylemia. However,
cient, inexpensive and accurate leaves little the concepts of salicylate half-life and S@
reason for the failure of hospital labora may be of considerable value in the conduct
tories to provide blood salicylate measure of studies on this question. The half-life
ments. value characterizes the rate of removal of
The data of the present study suggest salicylate from the blood in a manner which
that more meaningful interpretations of the is easily amenable to statistical treatment,
significance of blood salicylate levels can be and its use should facilitate studies on fac
made when the amount of time which has tors that influence elimination of salicyl
passed since salicylate ingestion is taken ates. S@ makes it possible accurately to
into account, either by calculating the the compare patients on the basis of the amount
oretical salicylate level at zero-time (Se) or of salicylate actually absorbed; and its use
through the use of graphs such as the one should facilitate studies on factors that in
presented in Figure 5. It should be empha Iluence toxicity. For such purpose, it would
sized that this provides only a rough guide be advisable to determine the patient's own
to a single criterion of severity in previously S0 from serial measurements of salicylate
well patients. It obviously does not sup level. Studies on factors in the toxicity of
plant clinical judgment, especially when the salicylates are currently underway utilizing
latter suggests that individual factors may these parameters.
be operative in producing an aberrant re
sponse. On the other hand, the scheme de SUMMARY
scribed here has proved to be far better Studies on 38 children and adults who in
than our ineffective and often erroneous gested large amounts of salicylate revealed
earlier attempts to predict the severity of a poor correlation of salicylate level in serum
intoxication from blood salicylate measure with clinical severity of salicylate intoxica
ments. A significant value has been in the tion.
identification of patients who are likely not Serial measurements of serum salicylate
to recover with conventional treatment levels in dogs and in 17 previously well pa
alone. An S@value of approximately 160 or tients revealed that the disappearance of
greater appears to be incompatible with salicylate from circulation is a first-order
life and warrants the use of measures, such reaction in the post-absorptive period. It is
as hemodialysis or exchange transfusions, to possible, therefore, to calculate the half-life
achieve a rapid reduction in the level of cir of circulating salicylate. In the present
culating salicylate.68 It is not meant to im study the mean salicylate half-life in 17
ply that such procedures may not be war patients was 20 hours.
ranted in instances where S0 is less than It is possible to eliminate the variable of
160; rather, it is suggested only that re time since ingestion by utilizing the rate
covery is highly unlikely with more con of removal (half-life) of salicylate to extra
servative treatment in the patient whose S@ polate from the observed salicylate level at
is in the range of 160 or higher. any time following ingestion to a theoreti
The close correlation of S0 with severity cal zero-time salicylate concentration (Se).

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 ARTICLES 807

There was found to be an excellent correla and salicylate half-life should facilitate such
tion of S@with the clinical severity of sali studies.
cylate intoxication. A nomogram that elim REFERENCES
inates the necessity for calculating S@ is 1. Kelley, V. C., and Done, A. K.: Poisonings
presented. Calculation of S@or use of the in childhood. Rocky Mountain M. J.,
nomogram provide better means than were 53:291, 1956.
2. Graham, J. D. P. and Parker, W. A.: The
previously available for predicting the se toxic manifestations of sodium salicylate
verity of salicylate intoxication on the basis therapy. Quart. J. Med., 17:153, 1948.
of measurements of blood salicylate. Par 3. Dubow, E. and Solomon, N. H.: Salicylate
ticularly noteworthy was the fact that four tolerance and toxicity in children. PEDI
ATRICS, 1:495, 1948.
patients who died despite intensive conven
4. Riley, H. D., Jr. and Worley, L.: Salicylate
tional treatments had S@ values which intoxication. PEDIATRICS,18:578, 1956.
greatly exceeded those found in patients 5. Trinder, P.: Rapid determination of sali
who recovered. This observation suggests cylate in biological fluids. Biochem. J.,
that an S0 of greater than 160 is essentially 57:301, 1954.
incompatible with life and that measures 6. Doolan, P. D., et al.: Acetylsalicylic acid
intoxication. A proposed method of treat
for rapidly reducing salicylate levels, such ment. J.A.M.A., 146:105, 1951.
as hemodialysis or exchange transfusion, 7. Schreiner, C. E., et at.: Specffic therapy for
should be instituted. salicylism. New Engl. J. Med., 253:213,
The data are not sufficient to permit con 1955.
clusions to be drawn concerning the in 8. Done, A. K. and Otterness, L. J.: Exchange
transfusion in the treatment of oil of
fluence of various factors on salicylate re wintergreen (methyl salicylate) poisoning.
moval and toxicity. However, the use of S@ PEDIATRICS, 18:80, 1956.

MEDICAL CARE OF THE ADOLESCENT, J. R. The volume deals with the many facets of
Gallagher, M.D. New York, Appleton physiologic and psychologic features of adoles
Century-Crofts, Inc., 1960, 369 pp., cence and brings the pertinent material from
$10.00. many fields into focus in terms of the adoles
The establishment of a special unit for cent's special needs. From this volume one can
adolescents at the Children's Hospital in Bos gain a philosophy regarding the care of the
ton encouraged the acquisition of a better adolescent and much practical information. It
understanding of the medical care of the is undoubtedly the best single book on the
adolescent. The present volume summarizes the medical care of the adolescent available to the
experience of a considerable group of physi physician who assumes responsibility for this
cians who participated in this experience. age group.

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