Delayed Salicylate Toxicity at 35 Hours Without Early

Manifestations Following a Single Salicylate Ingestion

Wilfredo Rivera, Kurt C Kleinschmidt, Larissa I Velez, Greene Shepherd, and Daniel C Keyes

OBJECTIVE: To report a case of delayed toxicity following a single ingestion of aspirin, where the initial concentrations were nearly
undetectable and the patient was completely asymptomatic for the first 35 hours.
CASE SUMMARY: A 14-year-old white female was evaluated after a single ingestion of 120 tablets of aspirin 81 mg/tablet hours before
arrival to the emergency department. She denied nausea, abdominal pain, tinnitus, or shortness of breath. She received one dose of
activated charcoal. The first salicylate concentration (4 h after ingestion) was 1 mg/dL. At 35 hours, the patient became symptomatic
(dizziness, tinnitus, epigastric discomfort). Her salicylate concentration at that time was 46 mg/dL. A second dose of activated charcoal
was administered, and intravenous bicarbonate with potassium was started as a continuous infusion for 30 hours.
DISCUSSION: While delayed salicylate toxicity is well reported in the literature, no report was found regarding concentrations
increasing to toxicity 35 hours after ingestion. The delayed aspirin absorption may be due to salicylate-induced pylorospasm or the
formation of pharmacobezoars.
CONCLUSIONS: In cases with known salicylate ingestion, it is important to follow salicylate concentrations every 4 hours until they are
steadily decreasing according to a 4-hour half-life and the patient shows no symptoms of salicylate intoxication.
KEY WORDS: aspirin, salicylate, toxicity.

Ann Pharmacother 2004;38:1186-8.

Published Online, 1 Jun 2004, www.theannals.com, DOI 10.1345/aph.1D575

nalgesics account for 10% (n = 240 747) of the total
A toxic exposures reported in the US to the Toxic Expo-
sure Surveillance System in 2001.1 Absorption of salicy-
late occurs in the stomach and proximal intestine, with
peak concentrations in therapeutic doses occurring 1–2
hours after ingestion for standard preparations and 4 – 6
hours for enteric-coated preparations.2 In overdoses, the
absorption and metabolic pathways may become saturated.
This can lead to delays in peak concentrations and pro-
longed duration of symptoms.3 The approach to manage-
ment of salicylate overdose is to evaluate a combination of
serial plasma salicylate concentrations in relation to the
time of ingestion while assessing the acid–base and the
mental status of the patient.
Delayed peak concentrations up to 60 hours after inges-
tion have been described in the literature after aspirin over-
doses, but there are no previous reports describing patients
Author information provided at the end of the text.
who remain asymptomatic >20 hours after ingestion.3-6 We
present a case of delayed toxicity following ingestion of
extended-release aspirin 81 mg tablets, with initial salicy-
late concentrations nearly undetectable and no symptoms
for the first 35 hours of observation. The patient developed
toxicity after this prolonged asymptomatic period, necessi-
tating urinary alkalinization.
Case Report
A 14-year-old white female was evaluated after a single ingestion of
120 tablets of aspirin 81 mg/tablet, extended-release, and 6 tablets of
ciprofloxacin approximately 2 hours prior to arrival to the emergency de-
partment. Upon arrival, she denied nausea, diaphoresis, abdominal pain,
shortness of breath, or tinnitus. Vital signs were RR 18 breaths/min, HR
100 beats/min, BP 134/74 mm Hg, and T 36.5 ˚C.
The patient received 50 g of oral activated charcoal with sorbitol for
decontamination; no gastric emptying techniques were used. Aceta-
minophen and ethanol concentrations were undetectable. The urine preg-
nancy test and urine screen for drugs of abuse were negative. The first
salicylate concentration, drawn 4 hours after ingestion, was 1 mg/dL
(therapeutic range 10–20 mg/dL). Salicylate concentration 6 hours after
ingestion was 13 mg/dL, and the patient remained asymptomatic. The elec-

1186 ■ The Annals of Pharmacotherapy ■ 2004 July/August, Volume 38 www.theannals.com

trolyte levels were sodium 138 mEq/L, potassium 3.5 mEq/L, chloride 108
mEq/L, HCO3 19 mEq/L, blood urea nitrogen 10 mg/dL, creatinine 0.6
mg/dL, and glucose 77 mg/dL. The anion gap was 11 mEq/L.
Serial salicylate concentrations were drawn every 4 hours due to the
persistent non-decreasing concentrations: 13 mg/dL at 8 hours, 14 mg/dL
at 13 hours, 14 mg/dL at 17 hours, and 18 mg/dL at 27 hours (Figure 1).
The patient remained asymptomatic until 35 hours after exposure, when
she developed dizziness, tinnitus, and epigastric discomfort. Her salicy-
late concentration at that time was 46 mg/dL. Vital signs were RR 20
breaths/min, HR 80 beats/min, and BP 110/75 mm Hg. Laboratory tests
showed sodium 142 mEq/L, potassium 3.8 mEq/L, chloride 109 mEq/L,
CO2 19 mEq/L, anion gap 14 mEq/L, pH 7.5, pCO2 29 mm Hg, and pO2
96 mm Hg.
A second dose of activated charcoal 50 g with sorbitol was adminis-
tered. A continuous infusion of sodium bicarbonate (3 ampules in 1 L of
D5W) at a rate of 200 mL/h was started for enhanced elimination. Intra-
venous potassium supplementation was also started (40 mEq over 4 h,
then 20 mEq every 8 h). The bicarbonate infusion was continued for ap-
proximately 30 hours (65 h after ingestion) with a steady decrease of the
salicylate concentration to 10 mg/dL 60 hours after ingestion (Figure 1).
The patient’s renal function remained normal throughout the admis-
sion. A flat and upright abdominal X-ray was obtained and showed no
abnormality in the gastrointestinal tract. Endoscopy was unavailable at
the time of the examination. She was observed closely during the obser-
vation period, and no reingestion occurred. Upon questioning, she de-
nied taking any more drugs while in the hospital. She had no complica-
tions and was discharged to a psychiatric facility.
Discussion
The current standard of practice in the treatment of sali-
cylate overdoses combines the use of serial serum mea-
surements and observation for manifestations of the typical
clinical syndrome. While delayed peak concentrations are
well reported in the literature, all previously reported pa-
tients developed toxicity early in their presentations within
20 hours of ingestion.3-6
It is difficult to reliably interpret an isolated salicylate
concentration following an aspirin overdose. Concentra-
tions drawn too early in the overdose may be falsely nor-
mal due to incomplete drug absorption. If obtained later,
they may be unreliably low due to mobilization of the sali-
cylate from the blood compartment. A history of large
amounts of aspirin ingested, increasing or stable salicylate
concentrations, ingestion of extended-release or enteric-
Figure 1. Salicylate concentrations after ingestion.
www.theannals.com The Annals of Pharmacotherapy
coated preparations, and coingestion of substances that de-
crease gastrointestinal motility should alert the clinician to
the need for serial salicylate concentrations.
The cause of delayed aspirin toxicity is unclear. Possi-
bilities include delayed absorption due to enteric-coated or
sustained-release dosage forms, salicylate-induced py-
lorospasm, and/or the formation of pharmacobezoars (ag-
gregates of drug that form a soft mass with limited surface
area exposed to gastric fluids). The interior portion of the
mass has undissolved drug. With time, this mass may dis-
solve, resulting in prolonged drug absorption. The forma-
tion of bezoars has been associated with a variety of medi-
cations. They appear to occur most commonly in patients
with anatomic abnormalities, drugs that alter the function
of the gastrointestinal tract, and/or in patients who ingest
large numbers of tablets.7
Salhanick et al.8 reported the first aspirin bezoar proven
by upper endoscopy in 2002. After the procedure, no esoph-
ageal or gastric abnormalities were found. This supports
the idea that aspirin can form bezoars in individuals with
intact and normally functioning gastrointestinal tracts and
may explain the delayed toxicity in our patient. Alternative
explanations also include the saturation of the absorption
pathways and impaired clearance of the drug.
Summary
In patients with a history of salicylate ingestion, moni-
toring of the salicylate blood concentration is a pivotal in-
tervention. Serial salicylate concentrations, combined with
assessment of mental status and acid–base status, are the
keys to treatment of salicylate ingestion. The formation of
salicylate bezoars, which impairs and delays absorption of
the drug, is a proven complication in these overdoses. For
this reason, serial salicylate concentrations should be fol-
lowed until they are in the nontoxic range. Salicylate con-
centrations that are not decreasing significantly every 4–6
hours are highly suggestive of continued absorption or de-
creased excretion, necessitating further investigation and
more aggressive treatment. Patients should be
completely asymptomatic before treatment is
discontinued.
Wilfredo Rivera MD, Clinical Instructor, Section of
Toxicology, University of Texas Southwestern (UTSW)
Emergency Medicine, Dallas, TX; Assistant Medical
Director, North Texas Poison Center, Dallas
Kurt C Kleinschmidt MD, Associate Professor,
UTSW Emergency Medicine
Larissa I Velez MD, Assistant Residency Director
and Assistant Professor, UTSW Emergency Medicine
Greene Shepherd PharmD, Director and Clinical
Toxicologist, North Texas Poison Center; Clinical As-
sistant Professor, UTSW Emergency Medicine
Daniel C Keyes MD MPH, Associate Professor and
Chief, Section of Toxicology, UTSW Emergency
Medicine; Medical Director, North Texas Poison Center
Reprints: Wilfredo Rivera MD, Section of Toxicology,
UTSW Emergency Medicine, 5323 Harry Hines Blvd.,
Dallas, TX 75390-8579, fax 214/590-5008,
wilfredo.rivera@utsouthwestern.edu
■ 2004 July/August, Volume 38 ■ 1187
W Rivera et al.
References
1. Litovitz TL, Klein-Schwartz W, Rodgers GC Jr, Cobaugh DJ, Youniss J,
Omslaer JC, et al. 2001 Annual report of the American Association of
Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg
Med 2002;20:391-452.
2. Davison C. Salicylate metabolism in man. Ann N Y Acad Sci 1971;179:
249-68.
3. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated
aspirin overdose. Ann Emerg Med 1987;16:434-6.
4. Bogacz K, Caldron P. Enteric-coated aspirin bezoar: elevation of serum
salicylate level by barium study. Case report and review of medical man-
agement. Am J Med 1987;83:783-6.
5. Dove DJ, Jones T. Delayed coma associated with salicylate intoxication.
J Pediatr 1982;100:493-6.
6. Pierce RP, Gazewood J, Blake RL Jr. Salicylate poisoning from enteric-
coated aspirin. Delayed absorption may complicate management. Post-
grad Med 1991;89:61-2, 64.
7. Michael T, Ku RP. Bezoars. In: Clinical toxicology review/bezoars. Vol
18, No 9. Boston, The Massachusetts Poison Control System, 1996.
www.maripoisoncenter.com (accessed 2004 May 20).
8. Salhanick S, Levy D, Burns M. Aspirin bezoar proven by upper en-
doscopy (abstract). Clin Toxicol 2002;40:688.
EXTRACTO
OBJETIVO: Reportar un caso de toxicidad retrasada de aspirina en el cual
la concentración inicial fue casi indetectable y la paciente no tuvo
ningún síntoma por las primeras 35 horas.
RESUMEN DEL CASO: Una paciente de 14 años fue evaluada en el hospital
luego de que ingiriera 120 tabletas de aspirina de 81 mg por tableta. Ella
negó tener náuseas, dolor abdominal, “tinnitus,” o dificultad respiratoria.
Una dosis de carbón activado fue administrada por boca. La primera
concentración de aspirina (4 horas luego de la ingestión) fue 1 mg/dL. A
las 35 horas, la paciente comenzó a desarrollar síntomas (mareos,
“tinnitus,” y dolor abdominal). La concentración de aspirina en ese
momento fue 46 mg/dL. Una segunda dosis de carbón activado y una
infusión continua de bicarbonato de sodio fueron administradas. En
adición, una infusión de potasio también fue comenzada.
1188 ■ The Annals of Pharmacotherapy ■ 2004 July/August, Volume 38
DISCUSIÓN: Aunque hay varios reportes en la literatura de toxicidad
retrasada de aspirina, no encontramos ningún reporte con toxicidad a
más de 30 horas luego de la ingestión. La absorción retrasada de
aspirina puede deberse a espasmos del píloro inducido por salicilatos o
la formación de farmacobesores.
CONCLUSIONES: En casos en los cuales hay certeza de que hubo ingestión
de aspirina, hay que hacer niveles consecutivos de aspirina en sangre
hasta que los mismos estén disminuyendo acorde con una vida media de
4 horas y el paciente no tenga ningún síntoma de intoxicación.
Wilfredo Rivera
RÉSUMÉ
OBJECTIF: Rapporter le cas d’une toxicité retardée suivant l’ingestion
d’aspirine, alors que les concentrations initiales étaient pratiquement
indétectables et que la patiente est demeurée complètement
asymptomatique pendant 35 heures.
RÉSUMÉ DU CAS: Une jeune femme de 14 ans s’est présentée à l’urgence
environ 2 heures après l’ingestion de 120 comprimés d’aspirine 81 mg à
action prolongée. Elle se plaignait de nausées, douleur abdominale,
tinnitus, et dyspnée. Elle a reçu une dose de charbon activé. La première
concentration sérique de salicylate (4 heures après l’ingestion) était de 1
mg/dl. Trente-cinq heures après l’ingestion, la patiente est devenue
symptomatique (étourdissements, tinnitus, et inconfort épigastrique). La
concentration sérique de salicylate était alors de 46 mg/dl. Une
deuxième dose de charbon activé lui a été administrée et une perfusion
intraveineuse de bicarbonate et potassium a été débutée.
DISCUSSION: La toxicité retardée aux salicylates est bien rapportée dans la
documentation scientifique. Toutefois, aucun cas n’a été retracé avec des
concentrations sériques qui sont devenues toxiques plus de 30 heures
suivant l’ingestion. L’absorption retardée de l’aspirine peut être due au
spasme du pylore induit par les salicylates ou à la formation de
pharmacobézoards.
CONCLUSION: Dans les cas d’une ingestion connue de salicylates, il est
important de suivre les concentrations sériques aux 4 heures jusqu’à ce
qu’elles décroissent et que le patient ne démontre aucun signe
d’intoxication aux salicylates.
Esthel Rochefort
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