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Practice Guideline

Salicylate poisoning: An evidence-based consensus guideline for out-of-hospital management

, Pharm.D., , M.D., , M.S.N., , M.D., , Pharm.D., , Pharm.D., , M.P.H. , M.D., , M.D., , M.D., , Pharm.D., , Pharm.D., , M.P.H. , M.D. & , Pharm.D. show all
Pages 95-131 | Received 06 Jun 2006, Accepted 06 Jun 2006, Published online: 07 Oct 2008

Abstract

A review of U.S. poison center data for 2004 showed over 40,000 exposures to salicylate-containing products. A guideline that determines the conditions for emergency department referral and pre-hospital care could potentially optimize patient outcome, avoid unnecessary emergency department visits, reduce health care costs, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected exposure to salicylates by 1) describing the process by which a specialist in poison information should evaluate an exposure to salicylates, 2) identifying the key decision elements in managing cases of salicylate exposure, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses: 1) Patients with stated or suspected self-harm or who are the victims of a potentially malicious administration of a salicylate, should be referred to an emergency department immediately. This referral should be guided by local poison center procedures. In general, this should occur regardless of the dose reported (Grade D). 2) The presence of typical symptoms of salicylate toxicity such as hematemesis, tachypnea, hyperpnea, dyspnea, tinnitus, deafness, lethargy, seizures, unexplained lethargy, or confusion warrants referral to an emergency department for evaluation (Grade C). 3) Patients who exhibit typical symptoms of salicylate toxicity or nonspecific symptoms such as unexplained lethargy, confusion, or dyspnea, which could indicate the development of chronic salicylate toxicity, should be referred to an emergency department (Grade C). 4) Patients without evidence of self-harm should have further evaluation, including determination of the dose, time of ingestion, presence of symptoms, history of other medical conditions, and the presence of co-ingestants. The acute ingestion of more than 150 mg/kg or 6.5 g of aspirin equivalent, whichever is less, warrants referral to an emergency department. Ingestion of greater than a lick or taste of oil of wintergreen (98% methyl salicylate) by children under 6 years of age and more than 4 mL of oil of wintergreen by patients 6 years of age and older could cause systemic salicylate toxicity and warrants referral to an emergency department (Grade C). 5) Do not induce emesis for ingestions of salicylates (Grade D). 6) Consider the out-of-hospital administration of activated charcoal for acute ingestions of a toxic dose if it is immediately available, no contraindications are present, the patient is not vomiting, and local guidelines for its out-of-hospital use are observed. However, do not delay transportation in order to administer activated charcoal (Grade D). 7) Women in the last trimester of pregnancy who ingest below the dose for emergency department referral and do not have other referral conditions should be directed to their primary care physician, obstetrician, or a non-emergent health care facility for evaluation of maternal and fetal risk. Routine referral to an emergency department for immediate care is not required (Grade C). 8) For asymptomatic patients with dermal exposures to methyl salicylate or salicylic acid, the skin should be thoroughly washed with soap and water and the patient can be observed at home for development of symptoms (Grade C). 9) For patients with an ocular exposure of methyl salicylate or salicylic acid, the eye(s) should be irrigated with room-temperature tap water for 15 minutes. If after irrigation the patient is having pain, decreased visual acuity, or persistent irritation, referral for an ophthalmological examination is indicated (Grade D). 10) Poison centers should monitor the onset of symptoms whenever possible by conducting follow-up calls at periodic intervals for approximately 12 hours after ingestion of non-enteric-coated salicylate products, and for approximately 24 hours after the ingestion of enteric-coated aspirin (Grade C).

Introduction

Scope of the problem and importance of the guideline

In 2004, poison control centers in the U.S. reported 40,405 human exposures to salicylates. Of these, 25,239 (63%) were unintentional exposures and 17,659 (44%) involved children under the age of 6 years. Aspirin as a single agent was involved in 18,181 cases (45%), aspirin in combination with other drugs contributed 9,267 cases (23%), methyl salicylate was involved in 12,005 cases (30%), and other non-aspirin salicylates accounted for 952 cases (2%). Exposures to salicylates resulted in 3,804 cases (9%) with moderate toxicity and 524 (1%) with severe toxicity. There were 64 (0.2%) deaths. Aspirin alone was involved in 54 of the deaths; none were young children (Citation1).

During the 1950s through 1970s the drug category most frequently responsible for poisoning deaths in children in the U.S. was salicylates. A combination of factors such as child-resistant packaging, mandatory restrictions on the number of children's aspirin tablets per bottle, the association of aspirin use and Reye's syndrome, decline in market share, and improved critical care have all contributed to nearly eradicating aspirin-related deaths in children after the 1990s. Despite this decline in childhood deaths, poison exposures and toxicity from salicylates still persist as a common problem in all ages. Poisoning can follow the unintentional ingestion of a single large dose or it can follow repeated supratherapeutic doses, particularly in the elderly. Salicylates are also used as a means to commit or attempt suicide. Some salicylates, such as methyl salicylate (oil of wintergreen), are not intended to be ingested but are ingested intentionally or swallowed mistakenly for another product. Chronic dermal application of some salicylate-containing products can produce systemic salicylate toxicity. Due to the number of salicylate exposures, their potential life-threatening severity, and the variety of exposure situations, a guideline on the out-of-hospital management of salicylate poisoning is indicated for consistency in case management by poison control centers.

Background on Salicylates

Salicylate products

Salicylates represent a group of compounds that are derivatives of salicylic acid in which an ester or salt is added to modify its properties in order to make the substance suitable for therapeutic use. Salicylic acid is irritating to mucous membranes and it is only used topically. Although aspirin (acetylsalicylic acid) is the most commonly used salicylate, the salicylates discussed in this guideline are all metabolized to salicylate, which is primarily responsible for the toxicity observed. Since salicylates are used for many everyday maladies such as fever, inflammation, and pain and for cardiovascular prophylaxis, they are found in most homes (). Dermal products are used for local relief of pain and soreness in muscles and joints.

Table 1. Aspirin dosage by indication and age (Citation211)

Several forms of salicylate are available for use as tablets, powders, and suppositories. In addition to regular aspirin, it is also formulated as an enteric-coated tablet intended for dissolution in the small intestine. Dermal preparations of salicylates may be absorbed and cause systemic toxicity. In order to compare the relative toxicity of the salicylates in this guideline, the dose of the salicylates has been standardized to be equivalent to aspirin () (Citation2). Not all forms of non-aspirin salicylate, such as salsalate (Citation3), fully dissociate to salicylate and the extent of this dissociation is variable. Salicylamide does not convert to salicylate, does not cause symptoms of salicylate poisoning (Citation4), and is not considered in this guideline.

Table 2. Relationship of salicylates to aspirin equivalent doses (Citation2,Citation212)

Pharmacokinetics and pathophysiology of salicylate toxicity

Aspirin is readily absorbed from the gastrointestinal tract as both aspirin and salicylate, with peak serum concentrations of therapeutic doses typically achieved in 1 hour. Enteric-coated tablets exhibit variable rates of absorption with peak serum concentrations achieved in 4–6 hours after therapeutic doses (Citation5), but the onset of systemic effects can be delayed by 8–12 hours (Citation6). The rate of absorption may be greatly delayed when a large number of tablets are ingested and form tablet bezoars or concretions (Citation7). Dermal formulations of some salicylates, such as 15% methyl salicylate cream (Citation8), can exhibit less bioavailability when applied to the buccal cavity compared to oral ingestion.

Since aspirin is readily hydrolyzed to salicylate in the gastrointestinal tract and bloodstream (aspirin's serum half-life is 15 minutes), salicylate is principally responsible for the systemic toxic effects. The rate of decline of salicylate concentrations will slow as the amount of salicylate in the body increases. Two major metabolic pathways of biotransformation are capacity-limited (Michealis-Menten kinetics) and lead to accumulation and slower elimination as salicylate in the body increases. Healthy adults begin to exhibit saturation kinetics with acute aspirin doses of 1–2 g (Citation9). This dose-dependent, prolonged excretion increases a person's risk of serious toxicity. Salicylate kinetics are also a factor in chronic and acute-on-chronic poisonings. A small increase in dose or slowed excretion due to evolving renal dysfunction can cause a greatly prolonged elimination time, and a disproportionate increase in serum salicylate concentration with attendant severe toxicity. The Serum Half-Life Of Salicylate Is typically 2–4 hours at low doses, approximately 12 hours with anti-inflammatory doses, and can be prolonged to 15–30 hours or more following overdosage. Approximately 2–30% of salicylate is excreted unchanged in the urine, with less renal excretion occurring in acidic urine or in patients with renal dysfunction (Citation5,Citation10).

The signs and symptoms of salicylate intoxication are related to local irritation of the gastrointestinal tract, direct stimulation of the central nervous system respiratory center, stimulation of the metabolic rate, disturbance of carbohydrate and lipid metabolism, and interference with hemostasis (Citation11–14). Typical gastrointestinal symptoms of acute ingestion include vomiting, abdominal pain, and occasional hematemesis. Symptoms of acute systemic toxicity include hyperpnea, tachypnea, tinnitus, deafness, hyperpyrexia, diaphoresis, lethargy, confusion, coma, and seizures. Complications of salicylate poisoning include dehydration, electrolyte disturbances, mixed and complex acid-base disturbances, gastrointestinal ulcers, hepatitis, cerebral edema, CSF glucopenia, and non-cardiogenic pulmonary edema. Although salicylates rarely produce spontaneous hemorrhage, they can decrease prothrombin formation, platelet adhesiveness, and platelet numbers. Contact to the eye or mucous membranes with dermal preparations of salicylate can be irritating and can cause temporary discomfort (Citation15).

Symptoms of chronic salicylate poisoning are similar to those of acute exposures except that gastrointestinal symptoms may be less pronounced, patients appear more severely ill, and CNS symptoms may be more prominent (Citation14). Neurological findings such as agitation, confusion, slurred speech, hallucinations, seizures, and coma can be the presenting symptoms and can potentially mislead initial assessment (Citation16–19). Often pulmonary edema is present in adults upon admission to a healthcare facility (Citation16). Salicylate poisoning should be considered in adults with acid-base disorders of unknown origin, particularly when neurological symptoms are present (Citation20).

Salicylic acid presents additional and unique toxicities. Salicylic acid is found in creams and liquids (in varying concentrations) for the topical treatment of acne (0.5–10%), psoriasis (3–6%), and warts (5–60%). Concentrations of 3–6% are keratolytic, and concentrations greater than 6% are destructive to tissues (Citation21). Salicylic acid is well absorbed into the bloodstream through healthy skin, and the extent of absorption varies with the concentration and formulation (Citation22). When a salicylic acid-containing product with a concentration greater than 6% is swallowed, tissue may be subject to chemical burns upon contact, particularly from wart removal products (17% salicylic acid and greater) (Citation23). Lower concentrations produce local irritation and erythema. Risks for systemic and local toxicity should be recognized for products that contain salicylic acid.

Definition of terms

This guideline is intended to address exposure to the salicylates found in . Other salicylates may share some of the toxicity of these agents, but they can exhibit different properties and are not included in this document. Since aspirin is the best known salicylate, aspirin equivalent doses (AED) have been calculated for non-aspirin salicylates in this guideline. The AED represents the salicylate content of a substance expressed as a comparable dose of aspirin. The term “out-of-hospital” is defined as the period before a patient reaches a healthcare facility. For the purpose of this guideline, two age groups are defined as either children less than 6 years of age and older children and adults. The older age group is more likely to attempt self-harm and to conceal an exposure. To be consistent with TESS definitions, acute exposures are defined as those occurring over a period of up to 8 hours, and chronic exposures are those that occur over a period of more than 8 hours (Citation1). Acute-on-chronic exposure is an acute exposure in a patient who has already been exposed to salicylate for more than 8 hours, typically as drug therapy of a disease.

Intended users of this guideline

The intended users of this guideline are personnel in U.S. poison control centers. This guideline has been developed for the conditions prevalent in the U.S. While the toxicity of salicylates is not expected to vary in a clinically significant manner in other nations, the out-of-hospital conditions could be much different. This guideline should not be extrapolated to other settings unless it has been determined that the conditions assumed in this guideline are present. This guideline also provides information for poison center staff members and researchers who wish to further develop the information base available for the development of guidelines for the out-of-hospital management of poisoning.

Objective of this guideline

The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected exposure to salicylates by 1) describing the process by which a specialist in poison information should evaluate an exposure to salicylates, 2) identifying the key decision elements in managing cases of salicylate exposure, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research.

This guideline applies to exposure to the specified salicylates alone. Exposure to additional substances could require different referral and management recommendations depending on the combined toxicities of the substances. This review focuses on the ingestion of more than a single therapeutic dose and the effects of an overdose. Although therapeutic doses of salicylate can sometimes cause adverse effects in adults and children—some idiosyncratic and some dose-dependent—these cases are not considered. The management of Reye's syndrome associated with aspirin use in children is beyond the scope of this guideline (Citation24). It does not address bismuth toxicity resulting from bismuth subsalicylate ingestion.

This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment.

Methodology

The methodology used for the preparation of this guideline was developed after reviewing the key elements of practice guidelines (Citation25,Citation26). An Expert Consensus Panel Was Established to develop the guideline (Appendix 1). The American Association of Poison Control Centers (AAPCC), the American Academy of Clinical Toxicology (AACT), and the American College of Medical Toxicology (ACMT) appointed members of their organizations to serve as panel members. To serve on the expert consensus panel, an individual had to have an exceptional record in clinical care and scientific research in toxicology, board certification as a clinical or medical toxicologist, significant U.S. poison control center experience, and be an opinion leader with broad esteem. Two specialists in poison information were included as full panel members to provide the viewpoint of the end-users of the guideline.

Search strategy

Literature searches for relevant articles were performed by a single investigator. The National Library of Medicine's MEDLINE database was searched (1966–March 2004) using aspirin or salicylic acid (exploded as MeSH terms) with the subheadings poisoning (po) or toxicity (to), limited to humans. The MEDLINE database was further searched using aspirin or bismuth subsalicylate or choline salicylate or ethyl salicylate or glycol salicylate or homomenthyl salicylate or magnesium salicylate or methyl salicylate or methylsalicylate or octyl salicylate or phenyl aminosalicylate or phenyl salicylate or potassium aminosalicylate or potassium salicylate or salicylamide or salicylic acid or salsalate or sodium aminosalicylate or sodium salicylate or sodium thiosalicylate or triethanolamine salicylate or trolamine salicylate as textwords (title, abstract, MeSH term, CAS registry), plus either poison* or overdos* or intox*, limited to humans. This process was repeated in International Pharmaceutical Abstracts (1970–March 2004, excluding abstracts of meeting presentations), Science Citation Index (1977–March 2004), Database of Abstracts of Reviews of Effects (accessed March 2004), Cochrane Database of Systematic Reviews (accessed March 2004), and Cochrane Central Register of Controlled Trials (accessed March 2004). Reactions (1980–March 2004), the salicylate poisoning management in Poisindex, and the bibliographies of recovered articles were reviewed to identify previously undiscovered articles. Furthermore, NACCT abstracts published in the Journal of Toxicology Clinical Toxicology (1995–2004) and Clinical Toxicology (2005) were reviewed for original human data.

Four major toxicology textbooks were reviewed for recommendations on the management of salicylate poisonings and for citations of additional articles with original human data in the chapter bibliographies. The Toxic Exposure Surveillance System (TESS) maintained by the American Association of Poison Control Centers was searched for deaths resulting from unintentional salicylate poisoning. These cases were abstracted for review by panel members. All U.S. poison control centers were surveyed in 2004 to ascertain their out-of-hospital management and triage practices for salicylate poisonings.

Criteria used to identify applicable studies

The recovered citations were entered into an EndNote library and duplicate entries were eliminated. The abstracts of these articles were reviewed, searching specifically for those that dealt with estimations of doses with or without subsequent signs or symptoms of toxicity, and management techniques that might be suitable for out-of-hospital use (e.g., gastrointestinal decontamination). Articles that did not meet either of the preceding criteria, did not add new data (e.g., reviews, editorials), or that exclusively described inpatient-only procedures (e.g., dialysis) were excluded.

Data extraction process

All articles that were retrieved from the original search were reviewed by a single trained physician abstractor. The complete article was reviewed for original human data regarding the toxic effects of salicylates or original human data directly relevant to the out-of-hospital management of patients with salicylate toxicity or overdose. Relevant data (e.g., dose, effects, time of onset of effects, therapeutic interventions or decontamination measures provided, efficacy or results of any interventions, and overall patient outcome) were compiled into a table and a brief description of each article was written. This evidence table is available at http://www.aapcc.org/DiscGuidelines/Guidelines%20Tables/Salicylate%20Evidence%20Table.pdf. The table of all abstracted articles was then forwarded to the panel members for review and consideration in developing the guideline. Every attempt was made to locate foreign language articles and have their crucial information extracted, translated, and tabulated. A written summary of the data was created and distributed by the abstractor. Copies of all of the abstracted articles were made available for reading by the panel members on a secure AAPCC website.

Criteria used to evaluate studies and assign levels of evidence

The articles were assigned level-of-evidence scores based on the Grades of Recommendation table developed by the Centre for Evidence-Based Medicine at Oxford University (Appendix 2). Single case reports and case series were classified as level 4.

Guideline writing and review

A draft guideline was prepared by the lead author (listed first). The draft was submitted to the expert consensus panel for comment. Using a modified Delphi process, comments from the expert consensus panel members were collected, copied into a table of comments, and submitted to the lead author for response. The lead author responded to each comment in the table and, when appropriate, the guideline draft was modified to incorporate changes suggested by the panel. The revised guideline draft was again reviewed by the panel and, if there was no strong objection by any panelist to any of the changes made by the lead author, the draft was prepared for the external review process. External review of the second draft was conducted by distributing it electronically to AAPCC, AACT, and ACMT members and the secondary review panel. The secondary review panel consisted of representatives from the federal government, public health, emergency services, pediatrics, pharmacy practice, and consumer organizations (Appendix 3). Comments were submitted via a discussion thread on the AAPCC website or privately through email communication to AAPCC staff. All submitted comments were rendered anonymous, copied into a table of comments, and reviewed by the expert consensus panel and the lead author. The lead author responded to each comment in the table and his responses and subsequent changes in the guideline were reviewed and accepted by the panel. Following a meeting of the expert consensus panel, the final revision of the guideline was prepared.

Estimation of weight-based dose

When the mg/kg dose was not provided and the child's weight was not stated in articles describing patients under 6 years of age, the mg/kg dose was estimated by the use of pediatric growth charts (Citation27). The 95th percentile weight was used for a particular age and sex. When the sex of the child was not stated, the weight for boys was used. This approach errs on the side of estimating a lower mg/kg dose. Estimated mg/kg doses are italicized throughout the guideline wherever they are presented.

Evaluation of Evidence

Current poison control center practices

The triage and management of salicylate ingestions by U.S. poison control centers appears to vary based on the responses of 16 centers (); two other centers reported that they did not have guidelines for salicylates. The average dose that the responding centers utilize to refer patients to an emergency department is 225 mg/kg, but there is a two-fold difference in the range of doses (150–300 mg/kg) with equal numbers on both sides of the average. Ten of 16 poison centers’ guidelines did not specify whether the dose referred to salicylate or aspirin. This difference could result in a 23% variance in interpreting the dose. The duration for follow-up monitoring was stated by five poison centers as 2, 4, 6, 6, and 24 hours after initial contact. Three centers indicated that ipecac syrup was indicated for ingestions of 150–300 mg/kg, and one center used a dose of 130–300 mg/kg. Three centers recommended activated charcoal at home when 150–300 mg/kg (two centers) or 100–200 mg/kg (one center) was ingested, and two utilized an unspecified gastric decontamination method when the dose exceeded 150 mg/kg. Some centers cited one of two reviews as a reference for their guideline (Citation19,Citation28). In a review of his experiences with pediatric salicylate poisoning, Done indicated that 240 mg/kg of aspirin would be required for moderate severity poisoning and approximately 480 mg/kg for lethality (Citation28). In a general review of salicylate toxicity, Temple stated that doses of 150–300 mg/kg would be expected to produce mild to moderate toxic reactions, 300–500 mg/kg would produce serious reactions, and doses in excess of 500 mg/kg would be potentially lethal (Citation19). Neither of these reviews cited original research as the basis for the recommendations.

Table 3. Acute salicylate ingestion action threshold (mg/kg) guidelines of 16 poison centers, 2004

Review of textbooks

The review of salicylate poisoning chapters in toxicology textbooks revealed variation in their recommendations (Citation11–14). Three books provided no dose guidelines for emergency department referral for acute exposures and one recommended referral when doses exceed 150 mg/kg (Citation11). The acute toxic dose was stated as 150 mg/kg or more by all four texts. Severe toxicity was expected at doses of 300–500 mg/kg (Citation11) or in excess of 500 mg/kg (Citation13). Three books indicated that chronic poisoning was possible with doses exceeding 100 mg/kg per day (Citation11,Citation13,Citation14). The threshold doses were not referenced to reports of original research. It was unclear whether the doses referred to doses of aspirin or salicylate.

Poisindex, a computerized toxicology reference used by poison control centers, indicates that unintentional ingestions under 150 mg/kg can usually be managed at home. Induction of emesis should be considered for doses between 150–300 mg/kg if ingested within the preceding hour. Patients who ingest more than 300 mg/kg should be referred to a health care facility (Citation29). A review article is cited as the reference for these recommendations (Citation19). Poisindex also indicates that chronic ingestion of more than 100 mg/kg/day over 2 days can produce toxicity.

Review of TESS mortality data

An analysis of the American Association of Poison Control Centers’ Toxic Exposure Surveillance System (TESS) database for deaths from unintentional exposures to salicylates during 1985 to 2003 identified 23 deaths (). Aspirin (15 cases) and methyl salicylate (eight cases) were the only salicylates associated with the deaths and the only substances implicated in the exposures. Six cases of acute methyl salicylate poisoning involved ingestions (expressed as mL of oil of wintergreen) of 5–15 mL (AED 7–21 g), 10 mL (AED 14 g, 959 mg/kg), 10 mL (AED 14 g), 15 mL (AED 21 g, 1,438 mg/kg), 60 mL (AED 84 g), and 120 mL (AED 168 g). One case of acute aspirin ingestion involved 558 mg/kg of aspirin. Serum salicylate concentrations were reported in all but two cases. Ten of the cases were elderly adults and nine were young children.

Table 4. Deaths from salicylates with an unintentional reason from TESS, 1985–2003

Review of the literature

There were no articles specifically addressing out-of-hospital management of salicylate exposures, but several articles contained information relevant to out-of-hospital care. Evidence regarding dose, toxicity, and time of onset is primarily limited to case reports and case series (level 4). The literature search did not identify any level 1 articles specifically investigating a toxic threshold dose or onset of effects of any salicylate.

The severity of salicylate toxicity was categorized into one of three categories when sufficient information was available. These categories are used throughout this guideline: mild = not life-threatening local effects (e.g., vomiting, erythema); moderate = not life-threatening systemic effects (e.g., mild acidosis, lethargy, coagulopathy); severe = serious or potentially life-threatening local effects (e.g., hematemesis), systemic effects (e.g., coma, severe acidosis, seizures, pulmonary dema, shock), or clinical effects requiring dialysis. These categories were developed specifically for this guideline but generally are comparable to those utilized by TESS (1).

The evidence is organized into sections dealing with acute ingestions by age group, chronic ingestions by age group, acute-on-chronic ingestions, and dermal exposures. In cases where it was difficult to determine whether the exposure was acute or chronic, the cases were not included. For non-aspirin drugs, the AED was estimated when possible ().

Acute ingestions in patients less than 6 years of age

Aspirin

Several case reports or series (levels 4 and 6) of aspirin poisoning in children less than 6 years of age were found, but many articles did not describe total dose, exact age of the child, or the severity of toxicity. There were two large case series (Citation30,Citation31) and 17 case reports with sufficient dose and effect information (Citation32–39). The lowest dose of aspirin reported to cause toxicity was 99 mg/kg (1,875 mg) in a 3½-year-old boy who developed vomiting, restlessness, and hyperpnea. He was treated with intravenous fluids and had an uneventful recovery (Citation37). A retrospective review (level 4) stated that doses as low as 46 mg/kg produced toxicity, but the authors only described the child as being toxic from aspirin (Citation30). The lowest dose of aspirin associated with severe toxicity was 143 mg/kg (1,944 mg) in a 14-month-old boy who developed vomiting, restlessness, hyperpnea, tachypnea (56 breaths per minute), a temperature of 39°C, cyanosis, and dehydration. He was treated with intravenous fluids and sent home after 10 days of hospitalization (Citation39). The lowest fatal dose from salicylate poisoning was 800 mg/kg in a 20-month-old boy who ingested 10.8 g 19.5 hours prior to admission to a hospital. Within 2 hours of ingestion he was lethargic and irritable. Marked hyperpnea later prompted his transportation to a hospital. Upon hospital admission he was comatose, hyperpneic, tachypneic, and tachycardic with a temperature of 38.3°C. Peritoneal dialysis was begun 21.5 hours after ingestion, but his condition continued to deteriorate and he died 54 hours after ingestion. Salicylate was measured in the urine and dialysate; the serum salicylate concentration was approximately 100 mg/dL at the start of dialysis (Citation36). The only fatality reported to TESS with a known dose of aspirin was a 3-year-old child who ingested 558 mg/kg ().

Bismuth subsalicylate

In the only case report (level 4) identified for acute bismuth subsalicylate exposure, the ingestion of Pepto-Bismol 90 mL (AED 787 mg, 30 mg/kg) resulted in the death of a 4-year-old girl, but an aspirin 325 mg suppository was given at the hospital, which likely contributed to the toxicity. A serum salicylate concentration of 111.2 mg/dL (8.05 mmol/L) was measured approximately 24 hours after ingestion and suggests that a much larger dose was ingested than was reported (Citation40). This case was not included in subsequent considerations of toxic doses.

Methyl salicylate

Fifteen cases of methyl salicylate ingestion were found with sufficient information described in 11 case series or reports (level 4) (Citation41–51). The smallest amount of methyl salicylate reported to cause toxicity was approximately 346 mg/kg (AED 408 mg/kg) in a 5-year-old girl who became “acutely ill” (Citation47). The ingestion of approximately 4 mL of oil of wintergreen (AED 5,600 mg, 378 mg/kg) by a 21-month-old boy resulted in moderate toxicity (Citation45). Ingestion of less than 5 mL of oil of wintergreen (AED 7000 mg, 486 mg/kg) by a 20-month-old boy resulted in severe toxicity (Citation41). The lowest dose of methyl salicylate associated with death was approximately 5 mL of oil of wintergreen ingested by a 2½-year-old boy (AED 7,000 mg, 432 mg/kg) (Citation42). In two other cases of small-volume ingestions of oil of wintergreen, ingestion of a mouthful by a 22-month-old girl led to moderate toxicity and the administration of 5 mL (AED 7000 mg, 1,400 mg/kg) in a 1-month-old girl resulted in death (Citation50). Two fatal doses of oil of wintergreen reported in TESS were 10 mL (AED 14,000 mg, 959 mg/kg) and 15 mL (AED 21,000 mg, 1,438 mg/kg), both in 2-year-old girls ().

Sodium salicylate

One case report (level 4) was found with dose and effect information for sodium salicylate (Citation52). The ingestion of up to 56,000 mg of sodium salicylate (AED 63,280 mg, 4,219 mg/kg) in an alcoholic solution by a 23-month-old boy led to moderate systemic toxicity.

Unspecified salicylate

A single cohort study (level 2b) was found with dose and effect information on unspecified salicylate ingestions in patients less than 6 years of age. In this prospective study of 38 children with acute salicylate poisoning, specific clinical effects were not listed, but doses as low as approximately 90 mg/kg were noted in two children with mild severity of toxicity (Citation53).

Summary

When the doses for all salicylates within the categories of severity of toxicity () are compared, there is wide variability for all categories. Ranges of 99–5,526 mg/kg for nonfatal cases and 432–2,763 mg/kg for fatalities were evident (see details in and ). The lowest AEDs categorized as moderate, severe, and fatal toxicity were 99, 144, and 432 mg/kg, respectively. The median doses for these categories were 378, 493, and 1,130 mg/kg, respectively. For oil of wintergreen, doses of approximately 5 mL were associated with moderate, severe, and fatal toxicity.

Fig. 1. Acute ingestion of salicylate with aspirin equivalent doses under 1,500 mg/kg and severity of salicylate toxicity in patients less than 6 years of age. See text for definitions. Data from and .

Fig. 1. Acute ingestion of salicylate with aspirin equivalent doses under 1,500 mg/kg and severity of salicylate toxicity in patients less than 6 years of age. See text for definitions. Data from Tables 4 and 6.

Table 5. Guide to information found in

Table 6. Cases with dose information on acute ingestions in patients less than 6 years of age, sorted by drug and dose

Acute ingestions in patients 6 years of age and older

Aspirin

There were two studies (level 2b) that reported dose and effect information for aspirin exposures in patients older than 6 years of age (Citation54,Citation55). Multiple case reports or series (levels 4 and 6) were found in which 66 cases with sufficient detail were reported in 42 articles (Citation31,Citation38,Citation39,Citation56–94). The lowest fatal aspirin dose reported in a patient older than 6 years of age was 13,000 mg in a 24-year-old man who died in 1918. He took the aspirin to relieve flu-like symptoms and died within 2 days after “a large quantity of blood was passed by the bowel.” There was no laboratory confirmation of the presence of salicylate in his body (Citation78). The next lowest fatal dose was 32,500 mg in a 30‐year-old patient (Citation58). In a 1949 report, a 54‐year-old man presented to a hospital in an anuric and stuporous state approximately 12 hours after ingesting 5,000–6,100 mg of aspirin. He died within 30 hours of ingestion, but it is unclear whether the cause of death was aspirin or treatment with “artificial antipyresis and rapidly acting stimulants” (Citation79). The lowest dose associated with severe toxicity was 12,600 mg in a 6-year-old child who developed agitation, hyperventilation, and acute renal failure that required peritoneal dialysis (Citation38). The next lowest dose causing severe toxicity was 19,500 mg in 21-year-old patient who received peritoneal dialysis (Citation63). The lowest aspirin dose reported as moderate toxicity involved a 14-year-old boy who ingested 9,750 mg (195 mg/kg) at home and exhibited vomiting, headache, tinnitus, orthostatic hypotension, and tachypnea within 6 hours of ingestion. At the hospital he had a respiratory rate of 28 breaths per minute and a serum salicylate concentration of 60 mg/dL (4.3 mmol/L). After 9 hours of hospitalization he developed clinical and laboratory signs of hypocalcemia and alkalemia during treatment with a sodium bicarbonate infusion. He eventually recovered following restoration of his electrolyte and acid-base balance (Citation65).

Choline magnesium trisalicylate

There were no reports of acute self-poisoning or unintentional toxicity identified for acute choline magnesium trisalicylate ingestions. One randomized clinical trial (level 1b) involved 24 adult volunteers who received choline magnesium trisalicylate (AED 1,300 mg) as tablets or as an aqueous solution. One subject in each group complained of nausea (Citation95).

Methyl salicylate

There was one retrospective case series (Citation96) and four case reports (levels 4 or 6) with sufficient detail identified (Citation97–100). An 86-year-old woman experienced moderate local and systemic symptoms after the ingestion of 5 mL of Red Flower Oil, estimated to contain 30–67% methyl salicylate (AED 1,770–3,950 mg) (Citation96). The ingestion of 30 mL of oil of wintergreen (AED 42,000 mg) resulted in the death of a 44-year-old man (Citation98). The lowest fatal dose reported in TESS was 5–15 mL of oil of wintergreen (AED 7,000–21,000 mg) in an 88‐year-old patient ().

Salicylic acid

One case report (level 4) of the ingestion of a dermal preparation of salicylic acid was identified. A 13-year-old boy intentionally ingested 9 mL of Compound W wart remover (17% salicylic acid) and experienced burning pain in his mouth and throat. He attempted to induce vomiting and drank some milk. He was evaluated at an emergency department within 4 hours of ingestion and multiple grayish lesions were observed on his tongue and posterior pharynx. His hard and soft palate had multiple erythematous lesions. Endoscopy revealed circumferential burns of the hypopharynx. He eventually had a full recovery. A serum salicylate concentration was not obtained (Citation23).

Sodium salicylate

No reports of acute self-poisoning or unintentional toxicity for acute sodium salicylate exposures were identified. One cohort study (level 2b), in which adult volunteers received 2,000 mg of sodium salicylate (AED 2,260 mg) intravenously, reported moderate systemic effects in several subjects (Citation101).

Unspecified salicylate

One retrospective case series (Citation102) and a single case report (Citation103) (level 4) were found for ingestions of unspecified salicylate products. In a review of coroner's data, the smallest dose of salicylate reported to cause fatal toxicity was 32,000 mg of an unspecified salicylate product in a patient with unspecified age (Citation102).

Summary

A summary of doses for all salicylates associated with the categories of severity of toxicity () indicates wide variability for all categories of 9.75–210 g for nonfatal cases and 13–168 g for fatalities (see details in ). The lowest AEDs categorized as moderate, severe, and fatal toxicity were 9.75, 12.6, and 13 g, respectively. The median doses for these categories were 32, 50, and 56 g, respectively.

Fig. 2. Acute ingestion of salicylate with aspirin equivalent doses under 50 g and severity of salicylate toxicity in patients 6 years of age and older. See text for definitions. Data from and .

Fig. 2. Acute ingestion of salicylate with aspirin equivalent doses under 50 g and severity of salicylate toxicity in patients 6 years of age and older. See text for definitions. Data from Tables 4 and 7.

Table 7. Cases of acute ingestions in patients 6 years of age and older with dose information, sorted by drug and dose

Chronic ingestions in patients less than 6 years of age

Aspirin

There was a single, retrospective cohort study (level 2b) identified with dose and effect information for chronic aspirin toxicity in patients under 6 years of age (Citation104). Several case reports or series with dose and effect information were identified with three of these reports being large retrospective case series (level 4) (Citation30,Citation105,Citation106), and 25 being case reports or series (level 4) which described 45 other cases with sufficient detail (Citation33,Citation36,Citation51,Citation63,Citation79,Citation87,Citation107–125). Due to differences in duration of therapy, regimen for administration, aspirin formulation, presence of underlying medical problems, and the inability to clearly define the time of onset for clinical effects, the comparison of these cases was difficult. In one case series, a total dose as low as 580 mg given over 5 days was reported to cause toxicity in a 2-month-old child (Citation30). Another article reported moderate toxicity in a 7-month-old child after daily doses of 162 mg administered for 7 days (Citation111). The ingestion of 650 mg over 1 day (46 mg/kg/day) by a 19-month-old child resulted in acidosis and a serum salicylate concentration of 36 mg/dL (2.61 mmol/L) (Citation106). There was one clinical trial found (level 2b) in which aspirin was chronically administered to acutely ill patients under 6 years of age. Unspecified toxicity developed in some patients after daily doses as low as 150 mg/kg were given for 3–14 days (Citation126).

Bismuth subsalicylate

One abstract (level 6) described moderate toxicity from the ingestion of bismuth subsalicylate by a 3-month-old boy who developed CNS depression, respiratory distress, tachypnea (66 breaths per minute), metabolic acidosis, increased prothrombin time, increased INR, and a serum salicylate concentration of 74.7 mg/dL (5.41 mmol/L). He had been given a liquid bismuth subsalicylate formulation (1,050 mg/10 mL) in AEDs of 57–84 mg/kg/day for 3 weeks. He recovered uneventfully following general supportive care for 6 days (Citation127).

Choline salicylate

There was a single case report (level 4) identified in which a 21-month-old boy developed symptoms of moderate toxicity after a dose of 2,610 mg (AED 1,958 mg) was applied to his gums over 48 hours (Citation128).

Sodium salicylate

Two cases reported in one article (level 4) were found with dose and effect information for chronic sodium salicylate toxicity, but both patients had also received aspirin. The lowest dosage resulting in toxicity involved an 8-month-old child with an upper respiratory illness who was given 70 mg/kg/day (AED 79 mg/kg/day) of sodium salicylate and 60 mg/kg/day of aspirin for 3 days which led to moderate toxicity (Citation108). Two prospective, cohort studies (level 2b) described the effects of chronic administration of sodium salicylate to children under 6 years of age (Citation114,Citation126). Dosages as low as 150 mg/kg/day (AED 170 mg/kg/day) given to acutely ill children for 3–14 days resulted in moderate toxicity (Citation126). A 5-year-old child developed unspecified toxicity after 300 mg/kg/day (AED 339 mg/kg/day) for 4 days (Citation114).

Unspecified salicylate

A cohort study (level 2b) was found that described 112 children, 1 month to 18 years of age, who were hospitalized for salicylate toxicity; 47 cases of chronic toxicity were identified after dosages as low as 32 mg/kg/day (Citation18). Patients’ ages and types of salicylate products were not specified. Two level 4 articles were reviewed with dose and effect information on chronic salicylate toxicity (Citation114,Citation129). The lowest dosage resulting in toxicity was reported in a case series of children who had developed toxicity after being given 65 mg of an unspecified salicylate per year of age per day for variable durations (Citation129).

In a prospective cohort study (level 2b), the chronic administration of salicylates was described in patients (ages unstated) with acute rheumatic fever. Oral or intravenous salicylate doses of 10,000–16,000 mg daily resulted in moderate toxicity in some patients (Citation130).

Summary

The wide variation in dosage regimens that led to salicylate toxicity makes it difficult to generalize any dose associated with chronic toxicity (see details in ). Doses above the upper end of the therapeutic daily dose range (100 mg/kg) for aspirin taken for several days led to toxicity in some patients (Citation126).

Table 8. Cases of chronic ingestions in patients less than 6 years of age with dose information, sorted by drug and toxicity severity

Chronic ingestions in patients 6 years of age and older

Aspirin

Several case reports or series were found with dose and effect information for chronic aspirin toxicity in patients older than 6 years of age. There were 31 cases with sufficient detail reported in 21 level 4 or 6 articles (Citation17,Citation37,Citation82,Citation131–149). In general, there was similar difficulty in comparing doses and effect as described above for chronic exposures in patients under 6 years of age. Several articles reported that the daily ingestion of doses as low as 4–8 “typical tablets” (strength unspecified) led to moderate or even severe toxicity (Citation144,Citation148,Citation149).

Four prospective cohort studies (level 2b) described toxic effects of aspirin when it was chronically administered to adult volunteers or patients older than 6 years of age (Citation101,Citation126,Citation151,Citation152). Daily doses as low as 2,400–3,600 mg caused prolonged bleeding time (Citation151). Daily doses of 3,000 mg of enteric-coated aspirin tablets were found to result in moderate toxicity in some individuals (Citation101). No severe effects were described in these articles.

Bismuth subsalicylate

A daily dose of greater than 360 mL of a bismuth subsalicylate-containing product (product not specified) taken for months produced moderate toxicity in a diabetic patient (level 4) (Citation153). In one clinical trial (level 1b), bismuth subsalicylate was chronically administered to adults. Tinnitus developed in 16% of the subjects at daily doses of 2,000–3,000 mg (AED 1,000–1,500 mg) (Citation154).

Choline magnesium trisalicylate

No reports of chronic self-poisoning or unintentional toxicity from choline magnesium trisalicylate exposures were identified. A clinical trial (level 2b) was located in which adult volunteers developed nausea, drowsiness, and lightheadedness after receiving daily doses of 2,000–3,000 mg (AED 2,600–3,900 mg) for 5 days (Citation155).

Methyl salicylate

There were no reports identified of chronic self-poisoning or unintentional toxicity from methyl salicylate ingestions. One study (level 2b) described adult patients who were convalescing from acute rheumatic fever and who received incrementally increasing doses of methyl salicylate orally. Doses as low as 6,640 mg (AED 7,835 mg) over 10 hours resulted in unspecified toxicity (Citation156).

Salsalate

Three cases (level 4) with sufficient detail were reported in which a daily dose of 3,000 mg (AED 4,200 mg) for an unstated duration resulted in severe toxicity (Citation157).

Sodium salicylate

Four cases with sufficient detail were found in four articles (level 4) (Citation51,Citation107,Citation158,Citation159). The lowest dose of sodium salicylate (based on an estimation of average daily exposure) leading to death was a total of 26,000 mg (AED 29,380 mg) given over 7 days to a 16-year-old girl with rheumatic fever (Citation159). There were three clinical trials (level 2b) in which sodium salicylate was chronically administered to individuals over 6 years of age (Citation114,Citation126,Citation160). Dosages as low as 75 mg/kg/day (AED 85 mg/kg/day) were given to acutely ill children older than 6 years of age, which resulted in toxicity such as hyperpnea, lethargy, tinnitus, seizures, hyperpyrexia, and dehydration in some cases (Citation126). Coagulopathy developed in some patients with acute rheumatic fever who were being treated with daily sodium salicylate doses of 10,000–20,000 mg (AED 11,300–22,600 mg), intravenously or orally (Citation160). Healthy children older than 6 years of age were given sodium salicylate 170–190 mg/kg/day (AED 192–215 mg/kg/day), and some developed symptoms of toxicity such as hyperpnea, coma, dehydration, and seizures (Citation114).

Unspecified salicylate

A cohort study (level 2b) was found with dose and effect information from chronic salicylate toxicity, but the salicylate was not specified. In this retrospective review of 112 children aged 1 month to 18 years who were hospitalized with salicylate toxicity, 47 cases of chronic toxicity were identified after dosages as low as 32 mg/kg/day. The ages of individual patients were not specified (Citation18). Another study (level 2b) reported the effects of chronic administration of salicylates to patients of unspecified age with acute rheumatic fever. In this report, daily salicylate (unspecified type) doses of 10,000–16,000 mg resulted in moderate toxicity in some cases (Citation130).

Summary

The wide variation in dosage regimens that led to salicylate toxicity makes it difficult to generalize any dose associated with chronic toxicity (see details in ). Daily AEDs of 2–3 g, which are near the maximum therapeutic daily dose (4 g), taken for several days led to toxicity in some patients (Citation101,Citation154,Citation155,Citation157).

Table 9. Cases of chronic ingestions in patients less than 6 years of age with dose information, sorted by drug and toxicity severity

Acute-on-chronic exposures

Little information on cases of acute-on-chronic salicylate toxicity was found, and aspirin was the only salicylate identified (see details in ). Four case reports (level 4) were found with dose and effect information for acute-on-chronic aspirin toxicity in patients over 6 years of age (Citation80,Citation120,Citation161,Citation162). The lowest dose leading to toxicity involved a 54-year-old man who died after acutely ingesting 5,000–6,000 mg aspirin after taking 1,300–2,000 mg aspirin daily for weeks (Citation120).

Table 10. Cases of acute-on-chronic ingestions of aspirin with dose information, sorted by toxicity severity

A single case report (level 4) was found with dose and effect information for acute-on-chronic aspirin toxicity in patients less than 6 years of age. In this case, a 2-year-old boy developed severe toxicity after acutely ingesting 15,000 mg (986 mg/kg) after he had received 105 mg aspirin (7 mg/kg) for 6–8 dosage intervals (Citation49).

Dermal exposures

Cases of systemic toxicity after dermal salicylate exposure were difficult to characterize because the doses could not be reliably estimated. These cases were described on the basis of the percentage of the active ingredient reported in the dermal preparation. One case of chemical burns of the tongue, pharynx, and larynx following the ingestion of a dermal preparation of 17% salicylic acid was identified in the literature search and is described in the section dealing with ingestions by adults (Citation23).

Methyl salicylate

Two case reports (level 4) were identified in which patients developed toxicity after dermal methyl salicylate use. A 62-year-old man developed local necrosis 1 day after he applied Bengay (18.3% methyl salicylate, 16% menthol) to his forearms and legs and used a heating pad periodically on the area (Citation163). Another 62-year-old man presented to an emergency department with a 3-day history of tinnitus, diplopia, and shortness of breath with a serum salicylate concentration of 51.5 mg/dL (3.73 mmol/L) and a mixed metabolic acidosis and respiratory alkalosis. He had used a methyl salicylate ointment (concentration unstated) for several weeks on his thigh, twice daily (Citation164).

Salicylic acid

Eighteen case reports were found in 14 articles (levels 4 or 6) with dose and effect information for dermal salicylic acid exposures in patients older than 6 years of age (Citation165–178). The lowest concentration resulting in toxicity occurred in a 10-year-old girl with ichthyosis who developed moderate toxicity 2 days after beginning dermal applications of a 3% salicylic acid preparation every 4 hours (Citation178). The lowest concentration resulting in severe toxicity occurred in a 31-year-old man with HIV and psoriasis, in whom applications of a 30% salicylic acid preparation continuously for 2 days resulted in severe effects. No drug interactions with HIV medications and salicylates were identified to account for this effect (Citation174).

Three case reports (level 4) were found with specific dose and effect information for dermal application of salicylic acid in patients less than 6 years of age (Citation179–181). The lowest concentration resulting in systemic toxicity occurred in a 3‐month-old child with ichthyosis who was treated with a 4% salicylic acid preparation with sulfur (duration and frequency of applications unknown), and later developed vomiting, hyperpnea, metabolic acidosis, convulsions, and coma with a serum salicylate concentration of 67 mg/dL (4.85 mmol/L) (Citation179).

Unspecified salicylate

There was a single case report (level 4) of a patient who developed toxicity after dermal salicylate use, but the product was not specified. In this report, the entire body of a 40-year-old man with psoriasis was sprayed with a Chinese herbal preparation containing salicylate and sulfur and an occlusive dressing was applied. Within 6 hours he developed tinnitus, vomiting, tachypnea, metabolic acidosis superimposed on respiratory alkalosis, and a serum salicylate concentration of 48.5 mg/dL (3.51 mmol/L) (Citation182).

Summary

Dose ranges associated with different categories of toxicity are difficult to estimate (see details in ). Systemic toxicity from these dermal preparations is associated with their application to skin that is typically not intact due to skin lesions or with the use of an occlusive dressing.

Table 11. Cases of dermal exposures with dose information, sorted by toxicity severity

Onset of effects after acute exposures

The expert consensus panel members considered the time of onset for toxicity to develop after salicylate exposure to assist decision-making about out-of-hospital management. All articles with toxicity information were searched for estimates of a time of onset. The available data are summarized herein for acute oral and chronic dermal exposures by the type of salicylate.

Aspirin

The longest reported time to onset of symptoms in a patient less than 6 years of age was 13 hours in a 3½-year-old who had ingested 25 aspirin tablets and was observed at home (Citation37). Three children developed symptoms within 24 hours of ingestion, but the exact time is unknown (Citation33,Citation39). Two reports (level 4) described cases in which effects began 7–8 hours after ingestion (Citation112,Citation183). In a case series (level 4), some children who arrived at a hospital as late as 54 hours after ingestion with symptoms were noted, but their clinical effects had developed at an unknown time prior to arrival (Citation184).

The longest time to onset of symptoms in a patient over 6 years of age after acute aspirin exposure was within 18 hours in a 19-year-old woman, but the exact time was not known (Citation90). The next greatest interval to effect was 12 hours, which was noted in two cases (Citation56,Citation185).

For enteric-coated aspirin tablets, the longest reported time to develop effects was 35 hours in a 14-year-old girl who ingested 120 enteric-coated aspirin 81-mg tablets. She was observed in a hospital and began to developed mild toxicity at that time (Citation86). The published report stated that extended-release aspirin tablets were involved, but a review of hospital records determined that enteric-coated aspirin was ingested (G. Shepherd, personal communication, November 2, 2005). Other reports included intervals of 10–12 hours in a patient over 6 years of age (Citation69) and 12 hours in a 13-month-old child who was observed in a hospital and exhibited an apparent peak serum salicylate concentration at 20 hours (Citation38).

Bismuth subsalicylate

The longest reported time to onset of effects after bismuth subsalicylate ingestion in a patient less than 6 years of age was 3 hours (Citation40).

Methyl salicylate

For patients under 6 years of age, the longest reported time to onset of effects was described as a “few hours” (Citation45,Citation186). In numerous cases, initially mild symptoms of gastrointestinal irritation (e.g., burning sensation or vomiting) were followed by the development of systemic effects up to 15 hours later (Citation41,Citation49,Citation51). In other cases, exact times were not available, but the onset of significant systemic effects appeared to be delayed by several hours after ingestion (Citation42,Citation43).

The longest reported time to onset of effects after methyl salicylate ingestion in patients 6 years of age and older was less than 12 hours in a 44-year-old woman (Citation99).

Salsalate

The longest interval to reported effects after salsalate ingestion was under 45 minutes in an 18-year-old woman (Citation187).

Sodium salicylate

In patients less than 6 years of age, the only reported time to onset of effect was 15 minutes in a 23-month-old boy, but the sodium salicylate had been mixed with alcohol (Citation52).

Summary

The onset of symptoms following the acute ingestion of nonenteric-coated aspirin tablets ranged from 15 minutes to 24 hours (see details in and ). The most frequent time of onset for systemic symptoms was 4–8 hours (41% of 49 cases) after ingestion, followed by 9–12 hours (20%), and 2–3 hours (18%). Liquid forms of salicylate, such as methyl salicylate, exhibited earlier onsets of local and systemic symptoms. Ninety percent of patients () who had ingested a non-enteric-coated formulation had their onset of symptoms within 12 hours of ingestion. Cases that involved enteric-coated aspirin tablets had onsets of symptoms at 9–12 hours (three cases), 4–8 hours (two cases), and 35 hours (one case). One case of an aspirin tablet bezoar was confirmed by endoscopy, but the time for onset or duration of symptoms was not stated (Citation7). In a series of 29 children and nine adults, the frequency of serious or fatal salicylate toxicity generally increased as the interval between ingestion and treatment extended beyond 12 hours (Citation184).

Fig. 3. Onset of symptoms following the acute ingestion of non-enteric-coated aspirin tablets in 49 cases (closed circle) and liquid methyl salicylate formulations in 14 cases (open square).

Fig. 3. Onset of symptoms following the acute ingestion of non-enteric-coated aspirin tablets in 49 cases (closed circle) and liquid methyl salicylate formulations in 14 cases (open square).

Onset of effects with chronic and acute-on-chronic exposures

Time of onset for toxicity from chronic exposures could not reliably be determined, in part due to the insidious onset of symptoms and the late recognition of salicylate as the cause of hospitalization. The shortest interval for the recognition of chronic salicylate poisoning was 1 day for aspirin ingestion reported in four cases (Citation31,Citation36,Citation108). The most frequent times of onset were after 2 and 3 days of drug administration with each day representing 23% of 26 cases (see details in ). Some patients were exposed to salicylate for more than a week before symptoms of toxicity were evident. There were too few cases of acute-on-chronic exposure to make any reliable generalizations.

Onset of effects with dermal exposures

Time to onset of symptoms after dermal exposures was difficult to assess because most patients were subject to chronic, repeated applications over variable periods of time. There were cases in which effects manifested or worsened several hours after the last application of chronic use, or after a single, high concentration exposure (Citation166,Citation171,Citation182). The most frequent times of onset were within 1 day, after 2 days, and after 3 days of drug administration, with each interval representing 29%, 24%, and 12%, respectively, of 17 cases. Some patients were exposed to salicylate for more than a week before symptoms of toxicity were evident. Salicylic acid produced tissue irritation and discomfort shortly after ingestion (Citation23).

Risks during pregnancy

Salicylate crosses the placenta and can result in a concentration in the fetal serum that is higher than that of the mother (Citation188). Acute salicylate overdose during the last trimester of pregnancy can result in fetal death or severe maternal and fetal toxicity (Citation62,Citation64,Citation73,Citation85,Citation92). Salicylates are in FDA pregnancy category C except for the last trimester of pregnancy. Since chronic use during the last trimester can be associated with antepartum and postpartum bleeding and prolonged pregnancy and labor, salicylates during the last trimester are placed in FDA pregnancy category D with positive evidence of human fetal risk (Citation21).

Treatment measures

There are a number of different treatment measures for salicylate poisoning reported in the literature including parenteral sodium bicarbonate, intravenous fluids, intravenous dextrose, acetazolamide, diuretics, lactate, various electrolytes, aminophylline, insulin, vitamin K, vitamin C, antacids, extracorporeal drug removal methods, and supportive measures such as endotracheal intubation, oxygenation, vasopressors, and anticonvulsants. Since most of these measures had little evidence available to evaluate their efficacy and many are unlikely to be available or appropriate in an out-of-hospital setting, only some of these therapies will be reviewed here.

Endotracheal intubation and assisted ventilation should be cautiously implemented and carefully monitored. Abrupt decreases of salicylate-induced hyperventilation and hyperpnea by the effects of CNS depressant drugs (Citation20) or underventilation (Citation189) can lead to life-threatening effects such as severe acidosis.

Several approaches to gastrointestinal decontamination have been reported in the literature. Single-dose activated charcoal and ipecac syrup are decontamination measures that could reasonably be expected to be performed in some out-of-hospital settings and for which evidence was greater than case series or reports. The utility of these measures for a variety of toxins and the shortcomings of the evidence to assess their effectiveness has recently been reviewed (Citation190–192).

Activated charcoal, single-dose

There were 13 clinical trials (level 1b) that examined the effect of activated charcoal on aspirin absorption (Citation193–205). None of these studies was performed as out-of-hospital care. In a randomized controlled trial in 339 overdose patients (10 of whom involved aspirin), the efficacy of gastric lavage plus activated charcoal was compared to lavage alone. There was no benefit to the addition of activated charcoal to lavage based on the proportion of patients whose serum salicylate concentrations continued to rise after the intervention. The number of aspirin patients was small and the serum concentrations were low, indicating non-serious poisoning (Citation194). The other 11 clinical studies involved adult volunteers who received non-toxic doses of aspirin prospectively. Although these 11 studies varied in aspirin dose, aspirin product (enteric-coated versus regular), time to activated charcoal administration, sample size, and methodology, all studies showed a reduction in aspirin absorption with activated charcoal given 0–4 hours after aspirin ingestion. One study showed it to be more efficacious than ipecac syrup (Citation195), but another study found that both treatments were equally efficacious (Citation196). The addition of magnesium citrate to activated charcoal had little effect on the efficacy of charcoal in two studies (Citation198, Citation205). The addition of sorbitol improved the efficacy of activated charcoal in one study (Citation200), but reduced it in another (Citation202). Use of whole bowel irrigation after activated charcoal administration reduced the efficacy of activated charcoal (Citation204). Food had a variable effect (Citation203). These studies were performed with non-toxic aspirin doses making their applicability to the overdose patient unknown. There was one controlled trial in volunteers (level 2b) that found that activated charcoal reduced the absorption of three forms of aspirin (regular, enteric-coated, and aspirin in solution) when given up to 3 hours after ingestion (Citation206).

There were no level 1–3 articles identified on the effects of activated charcoal single-dose on salicylates other than aspirin. Numerous case series and reports (levels 4 and 6) were reviewed in which single-dose activated charcoal was used for various salicylates, but the efficacy or effectiveness of activated charcoal could not be determined without a control for comparison.

Ipecac syrup

There were two clinical trials (level 1b) that investigated the efficacy of ipecac syrup in reducing aspirin absorption in which ipecac was given 1 hour after the administration of non‐toxic doses of aspirin to adult volunteers. The studies demonstrated a reduction in aspirin absorption equal to that achieved by activated charcoal (Citation196), or less than that of activated charcoal (Citation195).

A study (level 1b) compared the efficacy of ipecac syrup and gastric lavage at recovering ingested salicylate. Twenty patients with acute aspirin overdoses were randomized to receive gastric lavage followed by ipecac syrup or ipecac syrup followed by lavage. The authors concluded that the use of ipecac syrup led to more salicylate recovery than gastric lavage based on the ratio of salicylate recovered by each method (Citation207). Another study (level 1b) was identified, but it was not designed to investigate the efficacy of ipecac syrup. The authors estimated 0–81% recovery of ingested salicylate in 22 patients with acute aspirin overdose (Citation208).

Numerous case series and reports (levels 4 and 6) were reviewed in which ipecac syrup was administered after the ingestion of a salicylate, but its effectiveness could not be measured in these case reports. Ipecac syrup was used in one level 2b study and a level 3b study, but its efficacy was not evaluated in either study (Citation209,Citation210).

Limitations of the literature

Literature based on case reports can be inherently difficult to evaluate because patient histories can be unreliable and are often obtained during a period of extreme emotional stress for patients and caregivers. The exact product, salicylate content, patient weight, patient age, or specific effects were often not known or not documented. There were infrequent mentions whether the accuracy of the history was confirmed by outside sources (e.g., caregivers or witnesses) or objective evidence (e.g., empty product containers or serum concentrations); however, most cases had serum salicylate concentrations reported or salicylate detected in the urine, indicating exposure to salicylate. A statement of whether confirmation of the exposure was obtained is included in the data summaries ().

Wide dosage ranges were observed for all groupings of toxic severity. Besides interpatient variability, the dose ranges could also be attributed to spontaneous emesis in some cases, time of onset for treatment, and inaccuracies in the history of the exposure. Advances in critical care in the past five decades have likely had an influence on the assessment, treatment, and outcome of salicylate poisoning. This influence could not be gauged but should be considered in the interpretation of the literature.

Some proprietary products were not sufficiently described and the contents could not be verified in domestic or foreign references. In some reports, only tablet counts were provided without any statement of tablet strength. Some reports did not specify the salicylate and only stated that the dose or product referred to “salicylate.” Some reports of case series indicated a percentage of patients with salicylate toxicity and the range or mean of doses, so that specific doses resulting in toxicity could not be determined. When clinical effects were listed as percentages of exposed individuals, it was impossible to determine which effects were associated with a particular dose.

There were inherent difficulties in quantifying exposures to salicylate-containing dermal products. The amount of salicylate in the product, the condition of the skin, surface area of the skin affected, whether occlusive dressings were used, whether the skin was intact, and the frequency and duration of application affected the dose estimation of salicylate.

For the interval to the onset of symptoms, in most cases it was only possible to establish an upper limit of time to onset because often only the time of presentation to a hospital was noted, and effects were often present by that time. Few reports documented an exact time of onset after exposure. The times recorded in the summary tables are estimates of the maximum possible delay to onset of symptoms. The data in refer only to the time of first effect and do not give information on the time to achieve maximum effects or the total duration of effects. The practice of documenting essential data (e.g., dose, patient weight, and time since ingestion) for all salicylate exposures should be reinforced at poison control centers, emergency departments, and in published reports.

Conclusions

Key decision points for triage

The expert consensus panel chose to emphasize the importance of information that would be needed in order to make a sound triage decision for a patient with a known salicylate poisoning. These variables include the patient's intent, dose and formulation of the product, the presence of symptoms, time of ingestion, and pregnancy status. The expert consensus panel agreed that in each case, the judgment of the specialist in poison information, the poison center medical director, or other poison center-affiliated clinicians might override any specific recommendation from this guideline.

Patient intent

The panel concluded that all patients with suicidal intent or in whom a malicious intent was suspected (e.g., child abuse or neglect) should be expeditiously transported to an emergency department regardless of the dose ingested. Patients without these characteristics (e.g., adults with definite unintentional ingestion or children below the age of 6 years in whom abuse is not suspected) are candidates for more selective referral to healthcare facilities.

Dose and formulation of the salicylate

The estimation of dose is based largely on the patient's history and the type of product and its packaging (when available for evaluation). If precise data for the ingestion are unknown or unclear (e.g., package size, unit size, or number of units ingested), poison centers often utilize a method in which the maximum potential dose is calculated. For example, if the actual dose ingested cannot be ascertained, the amount of the drug product that is missing from the container is multiplied by the concentration of the formulation.

For asymptomatic patients with acute, unintentional ingestions of salicylates, the expert consensus panel concluded that home observation might be suitable for some low-dose exposures. However, the panel recognized that a definite threshold dose for toxicity, based on a large-scale, prospective study, has not been established. After a thorough review of published case reports, recommended therapeutic dosage regimens, current poison control center practices, and expert experience, the panel concluded that the acute ingestion of an amount that exceeds 150 mg/kg or 6.5 g, whichever is less, of aspirin or aspirin equivalent doses warrants referral to an emergency department. Ingestion of greater than a lick or taste of oil of wintergreen (98% methyl salicylate) by children under 6 years of age and more than 4 mL of oil of wintergreen by patients 6 years of age and older could cause systemic salicylate toxicity and warrants referral to an emergency department. The 6.5 g aspirin equivalent dose represents the ingestion of 20 aspirin 325 mg tablets or 4.6 mL of oil of wintergreen. For oil of wintergreen, 4 mL is below the 5 mL amount reported to produce moderate, severe, or fatal toxicity. The panel considered these threshold values to be internally consistent among the salicylate products and to provide some measure of safety. The thresholds chosen for this guideline are more conservative than some current poison center practices. Prospective study might provide more definitive data and could result in adjustments of the recommended threshold doses.

Presence of symptoms

In a patient with a demonstrated unintentional salicylate ingestion, medical evaluation in an emergency department is warranted if the patient is significantly symptomatic. Symptoms such as hematemesis, tachypnea, hyperpnea, dyspnea, tinnitus, deafness, lethargy, confusion, and seizures might individually or together suggest evidence of significant acute or chronic salicylate toxicity. All patients with these symptoms, whether or not attributed to salicylate exposure, should be referred to an emergency department regardless of the dose ingested. The importance of each of these variables can be difficult to judge in a telephone conversation, but a low threshold for emergency department evaluation is considered prudent at this time, particularly for very young and elderly patients.

Time of onset of toxicity after overdose

The onset of symptoms following the acute ingestion of non-enteric-coated aspirin ranged from 1 to 24 hours. Gastric discomfort and emesis may occur shortly after ingestion, but symptoms of systemic toxicity typically begin between 4 and 12 hours after acute ingestion. The expert consensus panel concluded that asymptomatic patients who unintentionally ingest more than the referral dose of a salicylate within 12 hours (24 hours for enteric-coated tablets) of contacting the poison center, warrant consideration for medical evaluation in a healthcare facility. However, if the ingestion occurred more than 12 hours (24 hours for enteric-coated tablets) before contacting the poison center and the patient had never been symptomatic, the patient could remain at home because the risk of toxicity beyond this time is small.

Pregnancy

The panel concluded that a woman in the last trimester of pregnancy who does not have other conditions for referral and ingests less than the dose for emergency department referral, should be directed to her primary care physician, obstetrician, or a non-emergency healthcare facility for evaluation of maternal and fetal risk.

Potential out-of-hospital management

The expert consensus panel concluded that skin and eye decontamination should be instituted as soon as possible to reduce the risk of local effects, if so exposed. Out-of-hospital gastrointestinal decontamination offers potential benefit, but the potential risks and overall benefit were difficult to determine. Induced emesis with ipecac syrup carries the potential risk of pulmonary aspiration of gastric contents if the patient becomes lethargic, has a seizure, or develops tachypnea; moreover, ipecac-associated drowsiness could confound evaluation of a patient's symptoms of salicylate poisoning. Use of ipecac syrup would likely delay or prevent the use of alternative, potentially more effective treatments such as activated charcoal. Members of the panel concluded that ipecac syrup does not provide sufficient benefit to warrant its use for the treatment of salicylate ingestions. Activated charcoal was determined to be a potentially useful treatment in some cases for which it could be administered in out-of-hospital settings, but its administration is not without risk. Since salicylates are irritants of the gastrointestinal tract that can produce vomiting, the benefits of activated charcoal administration should be weighed against the risk of aspiration of gastric contents secondary to vomiting. The panel agreed that transportation to a healthcare facility should not be delayed in order to attempt administration of activated charcoal, and that local guidelines for its use should be established.

Recommendations

  1. Patients with stated or suspected self-harm or who are the victims of a potentially malicious administration of a salicylate, should be referred to an emergency department immediately. This referral should be guided by local poison center procedures. In general, this should occur regardless of the dose reported (Grade D).

  2. The presence of typical symptoms of salicylate toxicity such as hematemesis, tachypnea, hyperpnea, dyspnea, tinnitus, deafness, lethargy, seizures, unexplained lethargy, or confusion warrants referral to an emergency department for evaluation (Grade C).

  3. Patients who exhibit typical symptoms of salicylate toxicity or non-specific symptoms such as unexplained lethargy, confusion, or dyspnea, which could indicate the development of chronic salicylate toxicity, should be referred to an emergency department (Grade C).

  4. Patients without evidence of self-harm should have further evaluation, including determination of the dose, time of ingestion, presence of symptoms, history of other medical conditions, and the presence of co-ingestants. The acute ingestion of more than 150 mg/kg or 6.5 g of aspirin equivalent, whichever is less, warrants referral to an emergency department. Ingestion of greater than a lick or taste of oil of wintergreen (98% methyl salicylate) by children under 6 years of age and more than 4 mL of oil of wintergreen by patients 6 years of age and older could cause systemic salicylate toxicity and warrants referral to an emergency department (Grade C).

  5. Do not induce emesis for ingestions of salicylates (Grade D).

  6. Consider the out-of-hospital administration of activated charcoal for acute ingestions of a toxic dose if it is immediately available, no contraindications are present, the patient is not vomiting, and local guidelines for its out-of-hospital use are observed. However, do not delay transportation in order to administer activated charcoal (Grade D).

  7. Women in the last trimester of pregnancy who ingest below the dose for emergency department referral and do not have other referral conditions should be directed to their primary care physician, obstetrician, or a non-emergency healthcare facility for evaluation of maternal and fetal risk. Routine referral to an emergency department for immediate care is not required (Grade C).

  8. For asymptomatic patients with dermal exposures to methyl salicylate or salicylic acid, the skin should be thoroughly washed with soap and water and the patient can be observed at home for development of symptoms (Grade C).

  9. For patients with an ocular exposure of methyl salicylate or salicylic acid, the eye(s) should be irrigated with room-temperature tap water for 15 minutes. If after irrigation the patient is having pain, decreased visual acuity, or persistent irritation, referral for an ophthalmological examination is indicated (Grade D).

  10. Poison centers should monitor the onset of symptoms whenever possible by conducting follow-up calls at periodic intervals for approximately 12 hours after ingestion of non-enteric-coated salicylate products and for approximately 24 hours after the ingestion of enteric-coated aspirin (Grade C).

These recommendations are summarized in Appendix 4.

Implications for Research

The panel identified the following topics where additional research is needed or analysis of existing databases might be useful.

  1. A careful analysis of existing poison control center records to further clarify the effect of different salicylate products, onset of systemic toxicity, ingested dose, and outcome is needed.

  2. Large-scale, prospective studies of unintentional acute and chronic salicylate poisoning should be conducted to better characterize the nature and care of patients in the out-of-hospital setting.

  3. The effectiveness and safety of using activated charcoal for the out-of-hospital gastric decontamination, specifically for salicylate ingestions, are unknown and need further study.

  4. A large case series of patients who ingested salicylic acid dermal preparations might better characterize the risks from this type of exposure.

Disclosure

There are no potential conflicts of interest reported by the panel regarding this guideline.

Notes

*Guidelines for the Management of Poisonings. Supported in full by Cooperative Agreement 8 U4BHS00084 between the American Association of Poison Control Centers and the Healthcare Systems Bureau, Health Resources and Services Administration, Department of Health and Human Services.

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Appendix 1

Expert Consensus Panel Members

Lisa L. Booze, Pharm.D.

Certified Specialist in Poison Information

Maryland Poison Center

University of Maryland School of Pharmacy

Baltimore, Maryland

E. Martin Caravati, M.D., M.P.H., F.A.C.M.T., F.A.C.E.P.

Professor of Surgery (Emergency Medicine)

University of Utah

Medical Director

Utah Poison Center

Salt Lake City, Utah

Gwenn Christianson, R.N., M.S.N.

Certified Specialist in Poison Information

Indiana Poison Center

Indianapolis, Indiana

Peter A. Chyka, Pharm.D., D.A.B.A.T., F.A.A.C.T.

Professor, Department of Clinical Pharmacy

College of Pharmacy

University of Tennessee Health Science Center

Knoxville, Tennessee

Daniel J. Cobaugh, Pharm.D., F.A.A.C.T., D.A.B.A.T.

Director of Research

ASHP Research and Education Foundation

Bethesda, Maryland

Former Associate Director, American Association of Poison Control Centers

Daniel C. Keyes, M.D., M.P.H., F.A.C.E.P., F.A.C.M.T.

Medical Director

Pine Bluff Chemical Demilitarization Facility

Associate Professor, Southwestern Toxicology Training Program

Dallas, Texas

Anthony S. Manoguerra, Pharm.D., D.A.B.A.T., F.A.A.C.T.

Professor of Clinical Pharmacy and Associate Dean

School of Pharmacy and Pharmaceutical Sciences

University of California, San Diego

Former Director, California Poison Control System, San Diego Division

San Diego, California

Lewis S. Nelson, M.D., F.A.C.E.P., F.A.C.M.T., F.A.C.C.T.

Associate Professor of Emergency Medicine

New York University School of Medicine

Associate Medical Director

New York City Poison Control Center

New York, New York

Kent R. Olson, M.D., F.A.C.E.P., F.A.A.C.T., F.A.C.M.T.

Medical Director

California Poison Control System, San Francisco Division

Clinical Professor of Medicine & Pharmacy

University of California, San Francisco

San Francisco, California

Elizabeth J. Scharman, Pharm.D., D.A.B.A.T., B.C.P.S., F.A.A.C.T.

Director, West Virginia Poison Center

Professor, West Virginia University School of Pharmacy

Department of Clinical Pharmacy

Charleston, West Virginia

Paul M. Wax, M.D., F.A.C.M.T.

Attending Toxicologist

UT Southwestern Medical Center

Dallas, Texas

Alan D. Woolf, M.D., M.P.H., F.A.C.M.T.

Director, Program in Environmental Medicine

Children's Hospital, Boston

Associate Professor of Pediatrics

Harvard Medical School

Boston, Massachusetts

Appendix 2

Grades of Recommendation and Levels of Evidence

Appendix 3

Secondary Review Panel Organizations

Ambulatory Pediatric Association

American Academy of Breastfeeding Medicine

American Academy of Emergency Medicine

American Academy of Pediatrics

American Association for Health Education

American College of Clinical Pharmacy

American College of Emergency Physicians

American College of Occupational and Environmental Medicine

American Pharmacists Association

American Public Health Association

American Society of Health-System Pharmacists

Association of Maternal and Child Health Programs

Association of Occupational and Environmental Clinics

Association of State and Territorial Health Officials

Canadian Association of Poison Control Centres

Centers for Disease Control and Prevention – National Center for Injury Prevention and Control

Consumer Federation of America

Consumer Product Safety Commission

Department of Transportation

Emergency Medical Services for Children

Emergency Nurses Association

Environmental Protection Agency

Food and Drug Administration

National Association of Children's Hospitals and Related Institutions

National Association of Emergency Medical Services Physicians

National Association of Emergency Medical Technicians

National Association of School Nurses

National Association of State Emergency Medical Services Directors

National Safe Kids Campaign

Teratology Society

World Health Organization International Programme on Chemical Safety

Appendix 4

Triage Algorithm for Salicylate Poisoning

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