LABORATORIO DE URGENCIAS

 

Salicylate poisoning: Consensus Guideline for Out-of-Hospital Management

 

                              Peter CHyka, Andrew Erdman,Gwenn Risttistianson,Paul Waxet all                                     
                                      American Association of Poison Control Centers, Washington, District of Columbia, USA

                                                                                Clinical Toxicology (2007) 45, 95-131

 

 

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
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  examination is indicated (Grade D). 
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 nonemergent 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.
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). 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).

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 (1).
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 childresistant 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 f 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,
Dermal products are used for local relief of pain and soreness in muscles and joints.

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 (2). Not all forms of non-aspirin salicylate, such as salsalate (3), 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 (4), and is not considered in this guideline.

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 (5), but the onset of systemic effects can be delayed by 8-12 hours (6). The rate of absorption may be greatly delayed when a large number of tablets are ingested and form tablet bezoars or concretions (7). Dermal formulations of some salicylates, such as 15% methyl salicylate cream (8), 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 halflife 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 (9). This dosedependent, 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 (5,10).

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 (11-14).
Gastrointestinal symptoms of acute ingestion include vomiting, abdominal pain,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 noncardiogenic 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 (15).

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 (14). Neurological findings such as agitation, confusion, slurred speech, hallucinations, seizures, and coma can be the presenting symptoms and can potentially mislead initial assessment (16-19). Often pulmonary edema is present in adults upon admission to a healthcare facility (16). Salicylate poisoning should be considered in adults with acid-base disorders of unknown origin, particularly when neurological symptoms are present (20).
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 (21). Salicylic acid is well absorbed into the bloodstream through healthy skin, and the extent of absorption varies with the concentration and formulation (22). 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) (23). 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

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 (1). 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.

 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.

 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 roomtemperature 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 entericcoated aspirin (Grade C).

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                                                  Clinical Toxicology (2007) 45, 95-131