SALICYLATES

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Acetaminosalol
2) Aluminum aspirin
3) Ammonium salicylate
4) Antipyrine salicylate
5) Aspirin
6) Benorylate
7) Bismuth subsalicylate
8) Bialpirina
9) Bromosalicylic acid acetate
10) Calcium aminosalicylate
11) Calcium carbaspirin
12) Carbamoylphenoxyacetic acid
13) Choline salicylate
14) Cospirn
15) Diethylamine salicylate
16) Ethyl salicylate
17) Fendosal
18) Glycol salicylate
19) Homomenthyl salicylate
20) Lithium salicylate
21) Magnesium salicylate
22) Menthyl salicylate
23) Methyl salicylate
24) Octyl salicylate
25) Phenazone salicylate
26) Phenyl aminosalicylate
27) Phenyl salicylate
28) Potassium aminosalicylate
29) Potassium salicylate
30) Salicylamide
31) Salicylic acid
32) Salsalate
33) Silver salicylate
34) Sodium aminosalicylate
35) Sodium salicylate
36) Sodium thiosalicylate
37) Thurfyl salicylate
38) Triethanolamine salicylate
39) Trolamine salicylate

1) For further information regarding aminosalicylic acid see MESALAMINE AND RELATED AGENTS.

1.2.1) MOLECULAR FORMULA
1) ASPIRIN: C9H8O4
2) CHOLINE MAGNESIUM TRISALICYLATE: C26H29O10NMg

Available Forms Sources

1) Salicylates are available as tablets, capsules, powders, effervescent tablets and liquid preparations for ingestion. They are available as rectal suppositories as a chewing gum. Salicylates are also available as liniments, creams and lotions for topical application. Methyl salicylate is found in many plants.
2) As of November 1997, the FDA requires an alcohol warning on all over-the-counter pain relievers, which includes aspirin, other salicylates, acetaminophen, ibuprofen, ketoprofen, and naproxen sodium, due to a potential drug interaction resulting in upper GI bleed or liver damage.

1) ASPIRIN: CHILDREN's aspirin contains 75 to 81 milligrams per tablet; ADULT aspirin contains 325 to 650 milligrams per tablet.
2) COMBINATION PRODUCTS: Salicylate is often combined with antihistamines and decongestants, or caffeine in cold and allergy preparations (Sainsbury, 1991). Several products contain combinations of acetaminophen and salicylate (Todd et al, 1981; Beringer, 1984).

a) Combinations of salicylate with opioids are common pain relievers (Sainsbury, 1991).

3) SUSTAINED RELEASE preparations of aspirin contain aspirin released over a 12 hour or longer period of time. Prolonged absorption and persistently elevated salicylate levels may occur following overdose.
4) ENTERIC-COATED FORMULATIONS: Designed to dissolve in the alkaline medium of the small intestine, these formulations may cause bezoars and prolonged drug absorption.
5) BISMUTH SUBSALICYLATE is an over-the-counter preparation containing 130 milligram/15 milliliter to 236 milligram/15 milliliter of salicylate for the liquid formulation, 99 to 102 milligrams of salicylate per chewable tablet, and 99 milligrams of salicylate per caplet. It is used in the treatment of diarrhea and prophylaxis for travellers diarrhea (Prod Info Pepto-Bismol Original Liquid, Maximum Strength Liquid, Original and Cherry Tablets and Easy-to-Swallow Caplets, 2004; Anon, 1980; Sainsbury, 1991; Levy, 1993).
6) TOPICAL USE

a) HOMOMENTHYL SALICYLATE (HOMOSALATE) is a sunscreen agent found in many sunscreen products and contains 46% salicylic acid. Homosalate could be hydrolyzed in vivo to free salicylic acid and homomenthol. There are, however, no reported cases of salicylate intoxication resulting from ingestion or dermal application of sunscreens containing homomenthyl salicylate (Personal Communication, 1981).
b) OCTYL SALICYLATE - Measurable salicylate levels and reports of symptomatology have occurred in children after ingesting Octyl Salicylate 5%, a topical sunscreen agent (Quail MT, 1994).
c) TROLAMINE SALICYLATE cream (10 grams of cream contains 500 milligrams of salicylic acid) is used in the management of osteoarthritis (O'Brien, 1982).
d) SALICYLATE in PETROLATUM - A topical 20% salicylate in petrolatum caused salicylism in a newborn with ichthyosis. Salicylate concentration on day 7 was 119 milligram/deciliter (therapeutic: 15 to 30 milligram/deciliter) (Yamamura et al, 2002).
e) LINIMENTS - Various liniments contain salicylates which are absorbed percutaneously (range is 15% to 30% methyl salicylate).

1) METHYL SALICYLATE (OIL OF WINTERGREEN): Commercial preparations are not less than 98% w/w. One milliliter of 98% methyl salicylate is equivalent to 1.4 grams ASA in salicylate potency and its action is the same as salicylates; or one teaspoonful of oil of wintergreen (5 milliliters) is equivalent to approximately 7000 milligram of salicylate or 21.7 adult aspirin tablets (Botma et al, 2001), which could result in serious toxicity in children less than 6 years with an average weight of less than 23 kg (Davis, 2007).
2) It is absorbed through the skin and may be used undiluted or as part of a liniment or ointment (Gordon, 1968); the ointment has also been accidentally ingested by children (Botma et al, 2001).

a) TOXICITY: Salicylism occurred in an elderly adult using several salicylate containing ointments for the treatment of erythroderma (Brubacher & Hoffman, 1995).

3) HERBAL/CHINESE MEDICINES: Asian products containing methyl salicylate include koong yick hung far oil, red flower oil, red oil Chinese, tiger oil, golden lion shield medicated oil, kwan loong oil, pak fah yeow, white flower oil, white flower embrocation, and axe brand universal oil (Davis, 2007; Tam et al, 1995; Chan et al, 1995; Chan, 1996; Baxter et al, 2001).

a) CASE SERIES: In a retrospective study of 24 adults who had ingested white flower oil (n=18) or red flower oil (n=6), no subjects ingesting white flower oil developed symptoms, while 50% of the individuals ingesting red flower oil developed moderate to severe symptoms. Thirty-three percent of those cases required urine alkalinization. Red flower oil usually has a 50% to 60% methyl salicylate concentration, as compared to 40% methyl salicylate in white flower oil. Red flower oil may also contain turpentine oil, cinnamon leaf oil, and eucalyptus oil. All patients recovered except one who died of hospital-acquired pneumonia (Chan, 2002). The authors suggested packaging improvements to decrease or avoid the amount that can be easily ingested due to existing packaging.
b) CASE REPORT: Salicylism was reported in an elderly patient with a history of dementia who ingested Red Oil Chinese which was found to contain methyl salicylate (the product had a concentration of 70% along with turpentine oil, palm olean, and cinnamon oil) (Baxter et al, 2001).

f) Non-aspirin salicylates (NAS) are used in many over-the-counter lotions, ointments, creams, liniments, and sunscreens because of their antipyretic, analgesic, and anti-inflammatory abilities (Quail MT, 1994). Systemic effects have been reported following pediatric ingestions.

7) OTHER SALT FORMS include sodium salicylate as 324 to 650 mg tablets or capsules 325 and 500 milligrams (86% salicylate), calcium carbaspirin as 352 milligram tablets (30% salicylate), magnesium salicylate as 600 milligram tablets (93% salicylate), choline salicylate as liquid 870 milligrams/5 milliliters (57% salicylate), salsalate as 500 mg capsule (106% salicylate), aluminum aspirin as 670 mg tablet (68% salicylate), and potassium salicylate (78% salicylate). Aluminum aspirin, magnesium salicylate, and salsalate are hydrolyzed to 2 molecules of salicylate.
8) ALOXIPRIN is a polymeric condensation product of aluminum oxide and aspirin. 600 mg of aloxiprin is equivalent to 500 mg of ASA.
9) PLANTS: Acacia (flower oil), Aspens, Birches, Calycanthus (leaves), Camellia (leaves), Chenopodium (leaves), Hyacinth, Marigold, Milkwort, Poplars, Spiraea, Teaberry, Tulips, Violets (Shelley, 1964).
10) FOODS (Shelley, 1964):

1) Almonds
2) Apples
3) Apricots
4) Blackberries
5) Cherries
6) Currants
7) Gooseberries
8) Grapes
9) Nectarines
10) Oranges
11) Peaches
12) Plums
13) Raspberries
14) Birch beer
15) Teaberry tea
16) Wines

1) Salicylates are used primarily as antipyretics, analgesic and anti-inflammatory agents. Low dose salicylates are used to inhibit platelet aggregation in ischemic heart disease and cerebrovascular disease.
2) Bismuth subsalicylate is used to treat diarrhea and as prophylaxis for travellers diarrhea.
3) Salicylate ointments are used for the anti-inflammatory effects in rheumatological conditions and for the keratolytic properties in dermal conditions such as ichthyosis and psoriasis.
4) Oil of wintergreen is used as a flavoring for candy (Howrie et al, 1985).
5) Salicylates are used in some teething ointments (Payntes & Alexander, 1979).
6) In Asia, preparations containing menthyl salicylate are sold for a variety of indications, including muscle and joint aches, bruises, cuts, burns, infected wounds, insect bites, abdominal pain, headache, toothache, motion sickness, and colds (Chan, 2002; Chan et al, 1995; Chan, 1996).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Salicylates are used primarily as an analgesic, antipyretic, anti-inflammatory, and antiplatelet agent. Found in many over-the-counter preparations in oral and topical forms. It may also be found in combination with other agents such as narcotics, barbiturates, and caffeine. Topical forms are often used as rubefacients. Also found in some essential oils in high concentrations such as oil of wintergreen.
B) PHARMACOLOGY: Salicylates inhibit cyclooxygenase, thereby reducing the formation of prostaglandins, and cause platelet dysfunction.
C) TOXICOLOGY: Salicylates stimulate the respiratory center in the brainstem, interfere with the Krebs cycle (limiting ATP production), uncouple oxidative phosphorylation (causing accumulation of pyruvic and lactic acid and heat production), and increase fatty acid metabolism (generating ketone bodies). The net result is a mixed respiratory alkalosis and metabolic acidosis.
D) EPIDEMIOLOGY: Common poisoning which can result in significant morbidity and mortality.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: GI upset and tinnitus.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: GI upset, tinnitus, tachypnea, and respiratory alkalosis.
2) SEVERE TOXICITY: Metabolic acidosis, hyperpnea, diaphoresis, fever, altered mental status, seizures, coma, cerebral edema, pulmonary edema and death. Chronic overdoses present more insidiously and may be subtle, especially in the elderly, and may consist primarily of neurologic manifestations such as confusion, delirium, and agitation. Coagulopathy, hepatic injury, and dysrhythmias are rare complications of severe overdose.
3) DELAYED TOXICITY: Onset of clinical toxicity and peak serum levels may be delayed in patients with ingestion of sustained release or enteric coated aspirin, or if pylorospasm or pharmacobezoar develop. Patients should be monitored until serial serum salicylate levels are declining and clinical symptoms have improved.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hyperventilation, mild tachycardia and hyperthermia are common; hypotension may develop in severe overdose.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Ototoxicity has been reported with both therapeutic use and overdose. Effects include tinnitus, hearing loss, and electrocochleographic changes.
2) Salicylic acid in topical wart removers can cause mucosal burns.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common. Hypotension and dysrhythmias may develop with severe intoxication.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Tachypnea and hyperpnea are common. Noncardiogenic pulmonary edema may develop in patients with severe intoxication.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Lethargy, agitation and confusion may be early findings in patients with severe toxicity. Coma and seizures may develop subsequently. Cerebral edema is a common autopsy finding.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Nausea and vomiting are common. Gastrointestinal bleeding, perforation and pancreatitis are rare complications.

0.2.9)

A) WITH THERAPEUTIC USE

1) Hepatic injury has been reported with chronic therapeutic use. Salicylates have been linked with Reye's syndrome in children.

B) WITH POISONING/EXPOSURE

1) Hepatic injury has been reported with chronic toxicity. Salicylates have been linked with Reye's syndrome in children.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Renal insufficiency is an uncommon complication that may develop secondary to rhabdomyolysis or hypotension.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Respiratory alkalosis develops early in the course of intoxication and may be the only acid base disturbance with mild salicylism.
2) Respiratory alkalosis with compensatory metabolic acidosis develops in most adults with moderate intoxication.
3) Metabolic acidosis with acidemia and compensatory respiratory alkalosis develops in severe overdose and is associated with a higher rate of complications and death. In infants respiratory alkalosis may be short lived or not occur at all; metabolic acidosis with acidemia predominates.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Dehydration and hypokalemia are common.

0.2.13)

A) WITH POISONING/EXPOSURE

1) PT prolongation is fairly common; DIC and thrombocytopenia occur rarely. Hemorrhage is uncommon.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis is an unusual complication of salicylate overdose.

0.2.16)

A) WITH POISONING/EXPOSURE

1) Hypoglycemia may develop, especially in children.

0.2.20)

A) Aspirin should not be used during the third trimester of pregnancy. Do not use 1 week prior to or during labor and delivery. Exercise caution with use during the first or second trimesters of pregnancy. Aspirin/butalbital/caffeine, bismuth subsalicylate, and choline magnesium trisalicylate have been classified as FDA pregnancy category C. Carisoprodol/aspirin and carisoprodol/aspirin/codeine are classified as FDA pregnancy category D. Chronic maternal ingestion is associated with an increased incidence of stillbirths, antepartum/postpartum bleeding, prolonged pregnancy/labor, and lower birth weight.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) An initial salicylate level should be obtained and repeated every 1 to 2 hours until a clear peak and decline is observed. Start intravenous fluids. Concentrations greater than 30 mg/dL and rising should be treated with urine alkalinization. The presence of a large anion gap metabolic acidosis or altered mental status indicates a more severe poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients with severe poisoning should be continued on urine alkalinization; hemodialysis should be strongly considered. Relative indications for hemodialysis include: renal failure, congestive heart failure, altered mental status, seizures, evidence of cerebral edema, worsening acidosis despite adequate resuscitation, persistently rising salicylate concentrations despite adequate treatment (greater than 50 to 60 mg/dL in a chronic poisoning or levels greater than 90 to 100 mg/dL in an acute overdose). Patients with an altered mental status may have cerebral edema; a head CT should be obtained. Mannitol can be given for cerebral edema. Severely ill patients may require respiratory support and intubation. Maintain preintubation minute ventilation at the same high respiratory rate because once the patient's respiratory drive is removed metabolic acidosis may worsen

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination with activated charcoal can be considered for large ingestions in patients with normal mental status in whom there will be a delay to definitive healthcare, but a poison center should be consulted first.
2) HOSPITAL: Activated charcoal should be administered to any patient who presents within 2 hours of a significant ingestion, can adequately protect their airway, and has no alteration in mental status. Administer activated charcoal to patients with large ingestions who present after 2 hours, as salicylate absorption can be delayed and erratic. Consider the use of gastric lavage for patients that present with large ingestions within 2 hours.

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with altered mental status may need mechanical respiratory support and orotracheal intubation. If the patient requires intubation, monitor end tidal CO2 and arterial blood gases frequently and maintain the preintubation minute ventilation to prevent severe acidosis.

E) ANTIDOTE

1) There is no specific antidote.

F) FLUID/ELECTROLYTE BALANCE REGULATION

1) Correct dehydration with 0.9% saline 10 to 20 mL/kg/hour over 1 to 2 hours until a good urine flow is obtained (at least 3 to 6 mL/kg/hour). In patients in whom urinary alkalinization is being considered, initial hydration may be with 10 to 20 mL/kg of D5W with 88 to 132 mEq of bicarbonate added. Correct hypokalemia with intravenous potassium boluses and oral potassium. Patients in shock may require more rapid fluid administration. Monitor urine output and pH hourly.

G) ACIDOSIS

1) Administer 1 to 2 mEq/kg NaHCO3 by IV bolus and begin urinary alkalinization. Monitor blood gases and urinary pH to guide frequency and quantity of administration. Patients with refractory acidosis, inability to maintain appropriate respiratory alkalosis, or acidemia should be treated with hemodialysis.

H) ALKALINE DIURESIS

1) Urinary alkalization will increase elimination of salicylates. Place 150 mEq (3 ampules) of NaHCO3 in 1 liter of 5% dextrose to provide an isotonic solution; administer 10 to 20 mL/kg initially as a bolus, then infuse at 2 to 3 mL/kg/hour. Administer 20 to 40 mEq/L of potassium chloride as an intravenous infusion as needed to maintain normokalemia. Oral potassium may be administered as tolerated. Hypokalemia and hypocalcemia may occur with alkalinization and hypokalemia can prevent the development of an alkaline urine. Monitor serum electrolytes (in particular potassium and calcium), serum and urinary pH frequently (ever 1 to 2 hours); goal of therapy is a urine pH of 7.5 to 8.

I) HEMODIALYSIS

1) Hemodialysis efficiently removes salicylate and corrects acid base and electrolyte abnormalities. Hemodialysis is recommended in patients with high serum salicylate levels (greater than 90 to 100 mg/dL after acute overdose, to 50 60 mg/dL with chronic intoxication), refractory acidosis, inability to maintain appropriate respiratory alkalosis, acidemia, evidence of CNS toxicity (i.e., seizures, mental status depression, persistent confusion, coma, and cerebral edema), progressive clinical deterioration despite appropriate fluid therapy and attempted urinary alkalinization, acute lung injury, inability to tolerate sodium bicarbonate (e.g., renal insufficiency, pulmonary edema), refractory/profound electrolyte disturbances, or renal failure. The clinical condition of the patient is more important than the serum salicylate concentration in determining the need for hemodialysis, especially in patients with chronic toxicity or delayed presentation after acute overdose. In patients with early presentation after acute overdose, serum concentrations approaching 100 mg/dL warrant consideration for dialysis even with mild or moderate clinical manifestations of toxicity. Administer a second dose of activated charcoal to patients with persistently rising salicylate levels despite urinary alkalinization and an initial dose of activated charcoal. Consider whole bowel irrigation with polyethylene glycol for patients with large ingestions of enteric coated products if they are alert and able to protect the airway.

J) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with inadvertent ingestions of less than 150 mg/kg or 6.5 g, whichever is less, of aspirin equivalent doses can generally be observed at home with normal follow-up procedures. Consider follow-up at periodic intervals of approximately 12 hours after acute ingestion of non-enteric coated salicylate products or 24-hours for enteric-coated aspirin.
2) ADMISSION CRITERIA: Patients who have a rising salicylate concentration, metabolic acidosis, or alterations in mental status should be admitted to an intensive care setting.
3) OBSERVATION CRITERIA: Patients with intentional ingestions and those with unintentional ingestions greater than 150 mg/kg or 6.5 g of aspirin equivalent doses, whichever is less, should be evaluated in a healthcare facility. For oil of wintergreen (98% methylsalicylate), greater than a lick or taste by children under 6 years of age or greater than 4 mL by patients 6 years of age and older requires referral to an emergency department for evaluation. Patients who have a well defined peak and decline in salicylate concentration and mild to moderate symptoms that resolve with treatment can often be treated and released from an ED observation unit.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for hemodialysis. Women in the third trimester of pregnancy who do not require referral to a healthcare facility for other reasons (ie ingested dose or symptoms) should be referred to an obstetrician for outpatient follow up and assessment of maternal fetal risk.

K) PITFALLS

1) The Done nomogram is not useful, it can both overestimate and underestimate the severity of toxicity.
2) Single determinations of salicylate levels are not sufficient because absorption may be delayed and erratic. Do not discharge patients unless it is clear that serial salicylate concentrations are declining.
3) Sedation or intubation of a patient compromises the patient's own respiratory drive, and has been associated with abrupt decompensation, likely due to worsening metabolic acidosis and increasing the salicylate concentration in the CNS. If the patient requires intubation, it is imperative that respiratory alkalosis be maintained.
4) Hypokalemia will interfere with urinary alkalinization (potassium reabsorbed and hydrogen ion excreted in renal tubules) and needs to be corrected for urinary alkalinization to be successful. In young children, the initial respiratory alkalosis from salicylate intoxication is transient, they often have a predominant metabolic acidosis (and in severe cases also respiratory alkalosis) on presentation.

L) PHARMACOKINETICS

1) Volume of distribution is about 0.1 to 0.3 L/kg. The half-life at therapeutic dose is about 2 to 4 hours. Peak levels are achieved within 0.5 to 2 hours with therapeutic doses. Dermal absorption of topical preparations can be significant especially after repeat applications.

M) TOXICOKINETICS

1) Absorption is often delayed and erratic. Levels may continue to rise for 12 or more hours especially with ingestions of enteric coated products. Elimination becomes zero order in overdose and apparent half-life can be as long as 18 to 36 hours.

N) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis includes conditions that present with an anion gap metabolic acidosis (e.g., iron, methanol, isopropanol, sepsis, alcoholic ketoacidosis). Salicylate toxicity should also be considered in elderly patients with an altered mental status.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Significant toxicity has been reported after chronic topical use of creams and ointments containing salicylates.
2) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

1) ADVERSE EFFECTS: GI upset and tinnitus.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hyperventilation, mild tachycardia and hyperthermia are common; hypotension may develop in severe overdose.

3.3.2)

A) WITH POISONING/EXPOSURE

1) Hyperventilation, hyperpnea, and tachypnea are common findings (Lewis et al, 2006; Baxter et al, 2003; McGuigan, 1987; Done, 1960; Hormaechea et al, 1979; Anderson et al, 1976) .

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA: Mild hyperthermia is common (Pec et al, 1992; Leatherman & Schmitz, 1991; Thisted et al, 1987; Pei & Thompson, 1987; Fisher et al, 1985; Schlegel et al, 1966) .

a) Severe hyperthermia with temperatures above 40 C has occasionally been reported (Levy, 1967; Robin et al, 1959).
b) CASE REPORT: Salicylate toxicity was misdiagnosed as malignant hyperthermia in an 11-year-old boy undergoing an appendectomy whose core temperature rose from 37.2 to 40.2 degrees Celsius during the procedure (Candy et al, 1998). It was later noted that the child was using a topical salicylate cream for treatment ichthyosis; his salicylate level was 4.54 mmol/L (63 mg/dL) (toxic level >2.5 mmol/L).

2) HYPOTHERMIA: Mild hypothermia is less often reported (Thisted et al, 1987).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

3.4.4)

A) WITH POISONING/EXPOSURE

1) SUMMARY - The three most common auditory alterations described by individuals after large doses of salicylates include tinnitus, loss of absolute acoustic sensitivity, and alterations of perceived sounds. Symptoms can occur gradually within the initial few days of therapy or within hours of an extremely large dose (Cazals, 2000).

a) ADDITIONAL EFFECTS: Other possible effects of toxicity include alterations in temporal detection, deterioration of speech understanding and hypersensitivity to noise (Cazals, 2000).
b) MECHANISM: Spontaneous neural activity of the auditory nerve indicates an increase in firings and/or in underlying temporal synchronies. Its suggested that these spontaneous changes might produce tinnitus as they affect mostly neural elements coding high frequencies, can occur without a loss of sensitivity, are dose dependent and progressive, and are reversible.

2) TINNITUS and hearing loss are common complaints in patients with salicylate intoxication (Rivera et al, 2004; Anderson et al, 1976). It is often the first symptom reported and described as a continuous high pitch sound or mild loudness (Cazals, 2000).

a) Tinnitus is frequently associated with blood salicylate concentrations exceeding 30 mg/dL (2.17 mmol/L) (Mongan et al, 1973). However, tinnitus is a nonspecific symptom present in many patients without salicylate toxicity (Halla et al, 1991) and it may be absent in many patients with elevated salicylate levels, particularly those with preexisting hearing loss (Halla et al, 1991; Mongan et al, 1973).
b) The absence of tinnitus cannot be reliably used to exclude the possibility of salicylate intoxication (Halla et al, 1991; Mongan et al, 1973).
c) ETIOLOGY: It has been suggested that aspirin-induced tinnitus occurs at the outer hair cell level (Janssen et al, 2000).

3) DEAFNESS: Audiography may demonstrate hearing loss (Myers & Bernstein, 1965; Bernstein & Weiss, 1967). Hearing loss can be slight to moderate and generally occurs bilaterally in all frequencies with the high frequencies more likely to be affected (Cazals, 2000), usually in the range of 20 to 45 decibels, in patients with salicylate intoxication (Myers & Bernstein, 1965; Bernstein & Weiss, 1967). This effect is reversible on discontinuation of salicylates (Cazals, 2000; Myers & Bernstein, 1965; Bernstein & Weiss, 1967) .

a) Electrocochleographic changes were demonstrated in 2 patients who overdosed on only salicylates (Ramsden et al, 1985).
b) DIAGNOSTIC TOOLS: Janssen et al (2000) also found that distortion product otoacoustic emissions (DPOAEs) and transiently evoked otoacoustic emissions (TEOAEs) were altered (reduced) during the state of salicylate overdose in a young woman with hearing loss and tinnitus(Janssen et al, 2000). The authors suggested that DPOAEs may be a more useful tool in providing quantitative information to evaluate some forms of cochlear tinnitus.

4) CASE REPORTS

a) ADVERSE EFFECTS: THERAPEUTIC - 61 of 134 (45%) rheumatoid arthritis patients who were taking therapeutic doses of salicylates complained of tinnitus or subjective hearing loss. However, 40% of healthy untreated controls reported the same problems. Audiometric testing did not correlate with symptoms, nor did blood salicylate levels (Halla & Hardin, 1988).
b) A three-phase study, carried out with 150 salicylate users and 372 controls, also concluded that ototoxicity symptoms do not correlate well with serum salicylate concentrations (Halla et al, 1991).

3.4.6)

A) WITH POISONING/EXPOSURE

1) Salicylic acid found in topical wart removal products at concentrations up to 17 percent (w/w) can cause mucosal burns if ingested (Sacchetti & Ramoska, 1986; Personal Communication, 1984). Laryngeal edema was reported in an 18-month-old following ingestion of Oil of Wintergreen. The toddler recovered following respiratory support and aggressive treatment (i.e., urinary alkalinization, dialysis) (Botma et al, 2001).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common. Hypotension and dysrhythmias may develop with severe intoxication.

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia is common, but is not usually hemodynamically significant (Watson & Tagupa, 1994; Leventhal et al, 1989; Liebman & Katz, 1981; Thisted et al, 1987).
b) CASE REPORT (INFANT) - A 3-month-old infant presented with vomiting, respiratory distress, CNS depression, and tachycardia (175 beats per minute) following chronic administration of a product containing bismuth subsalicylate, up to 15 mL/day (equivalent to 86 mg/kg of aspirin) for 3.5 weeks. Initial serum salicylate level was 747 mg/L. Despite decontamination with activated charcoal and whole bowel irrigation, the patient's tachycardia persisted (heart rate 110 to 191 beats per minute), along with occasional episodes of bradycardia when coughing. Following continued supportive care with alkalinization therapy, the patient gradually recovered with undetectable serum salicylate levels (< 40 mg/L) and was discharged without sequelae (Lewis et al, 2006).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension is not common but may develop in patients with severe toxicity (Pena-Alonso et al, 2003; Hormaechea et al, 1979; Levy, 1967; Pei & Thompson, 1987; Thomas, 1979; Cauthen & Hester, 1989; Leatherman & Schmitz, 1991; Fisher et al, 1985; Thisted et al, 1987).

C) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) NON-FATAL

1) Abrupt asystole developed in 2 patients who received diazepam, developed respiratory depression, and were subsequently intubated (Berk & Andersen, 1989). Abrupt asystole developed in another salicylate intoxicated patient with postoperative respiratory depression (Austin, 1970). Any intervention which reduces respiratory alkalosis increases the non-ionized fraction of salicylate and increases salicylate distribution to tissues; abrupt decompensation may ensue.
2) CASE REPORT - A 45-year-old woman ingested an unknown amount of aspirin and acetaminophen (serum salicylate concentration: 118 mg/dL (therapeutic: 10-30 mg/dL); serum acetaminophen concentration: 91 mcg/L) and developed nonfatal ventricular dysrhythmias including monomorphic ventricular tachycardia and Torsades de Pointes which lasted up to minutes. The rhythm converted to sinus tachycardia after sodium bicarbonate boluses (total given: 900 mEq of Na HCO3) were given, along with the correction of any underlying electrolyte abnormalities. The patient recovered completely following hemodialysis and veno-venous hemofiltration and was neurologically intact (Kent et al, 2008).
3) CASE REPORT - A 70-year-old woman with no history of cardiovascular disease, presented with confusion, multiple dysrhythmias and chronic salicylism (two different samples showed salicylate serum levels of 48 and 49 mg/dL) (Mukerji et al, 1986). Supraventricular tachycardia, asystole, slow AV junctional rhythm, and atrial fibrillation with slow ventricular response were all noted. All dysrhythmias resolved 30 hours after admission and subsequent electrophysiologic testing was normal.
4) CASE REPORT - Multiple premature ventricular contractions developed in a 77-year-old man with chronic salicylate intoxication (Paul, 1972).
5) CASE REPORTS - Abrupt cardiopulmonary arrest has been reported in adults with chronic salicylate intoxication in whom there was a delay in making the diagnosis (Anderson et al, 1976).

b) Abrupt asystole developed in 2 patients who received diazepam, developed respiratory depression, and were subsequently intubated (Berk & Andersen, 1989). Abrupt asystole developed in another salicylate intoxicated patient with postoperative respiratory depression (Austin, 1970). Any intervention which reduces respiratory alkalosis increases the non-ionized fraction of salicylate and increases salicylate distribution to tissues; abrupt decompensation may ensue.
c) CASE REPORT - A 70-year-old woman with no history of cardiovascular disease, presented with confusion, multiple dysrhythmias and chronic salicylism (two different samples showed salicylate serum levels of 48 and 49 mg/dL) (Mukerji et al, 1986). Supraventricular tachycardia, asystole, slow AV junctional rhythm, and atrial fibrillation with slow ventricular response were all noted. All dysrhythmias resolved 30 hours after admission and subsequent electrophysiologic testing was normal.
d) CASE REPORT - Multiple premature ventricular contractions developed in a 77-year-old man with chronic salicylate intoxication (Paul, 1972).
e) CASE REPORTS - Abrupt cardiopulmonary arrest has been reported in adults with chronic salicylate intoxication in whom there was a delay in making the diagnosis (Anderson et al, 1976).
f) FATAL

1) Dysrhythmias reported in 7 fatal cases of salicylate overdose included asystole, ventricular tachycardia and ventricular fibrillation (Chapman & Proudfoot, 1989).
2) CASE REPORT - A 5-year-old child, with a 6 day history of cough and sore throat, developed hypotension, decreased consciousness requiring mechanical ventilation, and bradycardia progressing to reversible cardiac arrest several hours after receiving one-half of a 500 mg aspirin tablet and an unknown amount of unspecified cough syrup. An ECG showed ventricular tachycardia and, third-degree AV block. A second and third cardiac arrest occurred approximately 4 hours after the first cardiac arrest, with the third cardiac arrest unresponsive to resuscitative measures. A serum salicylate level, taken approximately 36 hours postingestion, was 383.8 mcg/mL. The autopsy showed multiple foci of coagulative necrosis involving the entire thickness of the myocardium (Pena-Alonso et al, 2003). Because there did not appear to be any anatomic cause for the myocardial damage and the pattern of necrosis resembled acute drug-induced toxic myocarditis, it was believed that the myocardial necrosis, in this patient, may have been associated with salicylate overdose.

D) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) QT prolongation, U waves and flattened T waves have been described in several patients with hypokalemia after acute salicylate overdose (Robin et al, 1959).

E) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT - A 13-month-old child developed recurrent episodes of bradycardia 3 to 6 days after salicylate overdose, which were treated with atropine and isoproterenol. Echocardiography on the fifth day after ingestion revealed moderate left ventricular dysfunction without regional wall abnormalities (estimated shortening fraction 23%; normal 27-35%). Chest radiograph revealed pulmonary edema with mild cardiomegaly on day 3 and 4, and was normal on day 7 (Ralston et al, 1995).
b) CASE REPORT (INFANT) - A 3-month-old infant presented with vomiting, respiratory distress, CNS depression, and tachycardia (175 beats per minute) following chronic administration of a product containing bismuth subsalicylate, up to 15 mL/day (equivalent to 86 mg/kg of aspirin) for 3.5 weeks. Initial serum salicylate level was 747 mg/L. Despite decontamination with activated charcoal and whole bowel irrigation, the patient's tachycardia persisted (heart rate 110 to 191 beats per minute), along with occasional episodes of bradycardia when coughing. During sleep, his heart rate would decrease into the 50s, requiring constant stimuli to keep his heart rate within normal limits. Following continued supportive care with alkalinization therapy, the patient gradually recovered with undetectable serum salicylate levels (less than 40 mg/L) and was discharged without sequelae (Lewis et al, 2006).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Tachypnea and hyperpnea are common. Noncardiogenic pulmonary edema may develop in patients with severe intoxication.

3.6.2)

A) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Tachypnea, hyperpnea, and hyperventilation are common findings (Lewis et al, 2006; Baxter et al, 2003; McGuigan, 1987; Leventhal et al, 1989; Done, 1960; Schlegel et al, 1966; Whitehall, 1973; McCleave & Havill, 1974; Hormaechea et al, 1979; Anderson et al, 1976).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Acute lung injury (noncardiogenic pulmonary edema) has been reported with severe salicylate intoxication in children and adults.

a) REFERENCES: (Leatherman & Schmitz, 1991; Cauthen & Hester, 1989; Niehoff & Baltazis, 1985; Pei & Thompson, 1987; Thisted et al, 1987; Kahn & Blum, 1979; Snodgrass et al, 1981; Fisher et al, 1985; Andersen & Refstad, 1978; Hrnicek et al, 1974; Tashima & Rose, 1974; Chapman & Proudfoot, 1989; Hormaechea et al, 1979; Thomas, 1979; Zimmerman & Clemmer, 1981) .

b) ADULTS

1) In a retrospective study of 111 patients with salicylate intoxication, 35% of the patients over 30 years old developed noncardiogenic pulmonary edema (Walters et al, 1983).
2) Adults who develop noncardiogenic pulmonary edema from salicylate intoxication are older, more likely to smoke cigarettes, more likely to have neurological effects, more often have chronic rather than acute salicylate intoxication, and are more likely to have a metabolic acidosis than those who do not develop ARDS (Walters et al, 1983; Anderson et al, 1976; Heffner & Sahn, 1981).
3) CASE REPORT: A 53-year-old woman with a history of acute-on-chronic salicylate toxicity was noted to be in respiratory distress with progressive pulmonary deterioration and a salicylate level of 27 mg/dL (Grabe et al, 1999).

a) A lung biopsy was completed to rule out an infectious cause. The biopsy showed diffuse alveolar damage with hyaline formation and pulmonary edema. The authors suggested that the in vivo histologic evidence supports the respiratory symptoms observed in salicylate toxicity.

c) PEDIATRIC

1) In one study children who developed pulmonary edema from salicylate intoxication had higher initial (1147 micrograms/milliliter {114.7 mg/dL} vs 457 micrograms/milliliter {45.7 mg/dL}) and peak (1148 micrograms/milliliter {114.8 mg/dL} vs 516 micrograms/milliliter {51.6 mg/dL}) salicylate levels and higher anion gaps (28 milliequivalent/liter vs 15 milliequivalent/liter) than children who did not develop pulmonary edema (Fisher et al, 1985).

C) APNEA

1) WITH POISONING/EXPOSURE

a) Respiratory failure or apnea necessitating intubation may develop in patients with aspiration, pulmonary edema or significant alterations in mental status (Thisted et al, 1987; Zimmerman & Clemmer, 1981) (Abdel-Magid & Ahmed, 1993).
b) Abrupt asystole developed in 2 patients who received diazepam, developed respiratory depression, and were subsequently intubated (Berk & Andersen, 1989). Abrupt asystole developed in another salicylate intoxicated patient with postoperative respiratory depression (Austin, 1970). Any intervention which reduces respiratory alkalosis increases the non-ionized fraction of salicylate and increases salicylate distribution to tissues; abrupt decompensation may ensue.

D) SUFFOCATING

1) WITH POISONING/EXPOSURE

a) Aspiration may develop in patients with significant CNS depression (Thisted et al, 1987).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Lethargy, agitation and confusion may be early findings in patients with severe toxicity. Coma and seizures may develop subsequently. Cerebral edema is a common autopsy finding.

3.7.2)

A) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) Irritability, confusion, disorientation, hyperactivity, slurred speech, agitation, combativeness, hallucinations, ataxia, and restlessness may be early findings in patients with severe toxicity (Sainsbury, 1991; Krause et al, 1992; Pei & Thompson, 1987; McGuigan, 1987; Everson & Krenzelok, 1986; Done, 1960; Levy, 1967; Anderson et al, 1976; Brown & Wilson, 1971; Walters et al, 1983; Surapathana et al, 1970) Good & Welsh, 1975; (Liebman & Katz, 1981) .
b) In the elderly the encephalopathy induced by chronic salicylate intoxication may be mislabeled as senile dementia (Gittelman, 1993; Steele & Morton, 1986; Bailey & Jones, 1989) .

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CNS depression may develop, ranging from sleepiness and lethargy to coma in severe cases (Lewis et al, 2006; Fisher et al, 1985; Walters et al, 1983; Anderson et al, 1976; Schlegel et al, 1966; Brem et al, 1973; Dove & Jones, 1982; Quint & Allman, 1984; Shkrum et al, 1989; Snodgrass et al, 1981; Pond et al, 1993; McGuigan, 1987; Thisted et al, 1987; Fiscina, 1986).
b) CNS depression generally follows a phase of agitation, confusion, and dizziness in severe overdoses (Rivera et al, 2004; McGuigan, 1986).

C) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) Cerebral edema and evidence of increased intracranial pressure (papilledema, nuchal rigidity) may develop in severe cases (McGuigan, 1987; Dove & Jones, 1982; Schlegel et al, 1966) .
b) CASE REPORT

1) POSTMORTEM: Evidence of pulmonary edema, cardiac dilatation and venous congestion with acute white matter pathology was present in a woman with a history of mental retardation and fetal alcohol syndrome, following lethal salicylate toxicity. White matter damage was characterized by myelin disintegration and glial caspase-3 activation, which may have a role in the pathological substrate of cerebral dysfunction observed in severe salicylate intoxication. A delay in postmortem exam may have affected histopathology results in this case(Rauschka et al, 2007).

c) INCIDENCE

1) Cerebral edema was found on autopsy in 8 of 26 patients (31%) who died in one series of 177 patients with salicylate overdose (Thisted et al, 1987).
2) Cerebral edema was present on autopsy in 9 of 13 children who died after acute or chronic salicylate intoxication (Starko & Mullick, 1983).

D) CEREBRAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Stroke patients were entered into a prospective case-control study to examine the differences of aspirin-associated intracerebral hemorrhage (ICH) with ICH in non-aspirin users (Wong et al, 2000). Aspirin-users were more likely to develop lobar hemorrhage, 32% versus 10% of nonusers. The authors suggested that further study is needed, but the increase in lobar hematomas may provide some data as to the actual mechanism (e.g., a vascular abnormality such as amyloid angiopathy {occurs more commonly in older patients} and occult angioma) for aspirin-associated ICH. Further study is needed to determine if cerebral amyloid angiopathy is a risk factor for aspirin-associated ICH.

E) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures may develop in patients with severe toxicity (Abdel-Magid & Ahmed, 1994; Cauthen & Hester, 1989; Chapman & Proudfoot, 1989; MacCready, 1943; Done, 1960; Anderson et al, 1976; Thisted et al, 1987) .

F) DYSKINESIA

1) WITH POISONING/EXPOSURE

a) Asterixis has been reported in patients receiving chronic excessive salicylate therapy for rheumatoid arthritis (Ulshen et al, 1978; Anderson, 1981).

G) MENINGITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Aseptic meningitis was reported in a 70-year-old woman with salicylate intoxication (Nair & Stacy, 1993).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Nausea and vomiting are common. Gastrointestinal bleeding, perforation and pancreatitis are rare complications.

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting begin early (within 3 to 8 hours) after acute ingestion and may be persistent in both acute and chronic overdose (Lewis et al, 2006; Pena-Alonso et al, 2003; Done, 1960; McCleave & Havill, 1974; McGuigan, 1987).

B) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) CASE REPORT (DELAYED TOXICITY): A 14-year-old female did not experience any symptoms until 35 hours after the ingestion of 120 extended-release aspirin tablets (81 mg/tablet). Her salicylate blood levels were initially almost undetectable; the levels remained within the therapeutic range (10 to 20 mg/dL) until 35 hours postingestion (46 mg/dL). Following supportive treatment, she recovered without further sequelae. The authors suggested that the delayed aspirin absorption may be due to enteric-coated or sustained-release dosage forms, salicylate-induced pylorospasm, and/or the formation of pharmacobezoars. The authors proposed that serial salicylate levels should be monitored until they are in the nontoxic range. Treatment should not be discontinued until patients are completely asymptomatic (Rivera et al, 2004).

C) PYLORIC STENOSIS

1) WITH POISONING/EXPOSURE

a) Several cases of chronic intoxication from bezoars of enteric coated salicylate have been reported in patients with pyloric stenosis or gastric outlet obstruction (Harris, 1973; Sogge et al, 1977; Springer & Groll, 1980; Halla et al, 1981; Wise et al, 1982).

D) PERFORATION OF INTESTINE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 65-year-old woman without previous peptic ulcer developed gastric perforation one day after acute salicylate overdose (Robins et al, 1985).
b) CASE REPORT: A 48-year-old woman without previous renal or GI complaints developed renal failure and perforated peptic ulcer after acute aspirin ingestion (Christensen & Schmidt, 1987).
c) CASE REPORT: Rectal perforation and stenosis were reported in a 56-year-old woman who used 2 to 4 rectal suppositories per day for 6 years. The suppositories contained both acetylsalicylic acid and acetaminophen (Legallicier et al, 1991).

E) BEZOAR

1) WITH POISONING/EXPOSURE

a) CASE REPORT (INFANT): A 3-month-old infant presented with vomiting, respiratory distress, CNS depression, tachycardia (175 bpm), and tachypnea (44 breaths/min) following chronic administration of a product containing bismuth subsalicylate, up to 15 mL/day (equivalent to 86 mg/kg of aspirin daily) for 3.5 weeks. An abdominal radiograph indicated a possible concretion in the lower colon. Initial serum salicylate level was 747 mg/L. Following continued supportive care with alkalinization therapy, the patient gradually recovered with undetectable serum salicylate levels (< 40 mg/L) and was discharged without sequelae (Lewis et al, 2006).

F) POISONING BY SALICYLATE

1) WITH POISONING/EXPOSURE

a) RECTAL ABSORPTION

1) Severe salicylate toxicity developed in a 43-year-old woman who gave herself an enema containing 700 aspirin tablets dissolved in water (Watson & Tagupa, 1994).

G) PANCREATITIS

1) WITH POISONING/EXPOSURE

a) Two adolescents developed pancreatitis associated with acute salicylate overdose (Cabooter et al, 1981).

H) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) ORAL ULCERATIONS

1) Oral ulcerations and burns have been reported in individuals who leave aspirin products in the mouth for prolonged periods due to the inability to swallow tablets (Ruscin & Astroth, 1998), or with improper administration of powdered aspirin products (taken without first dissolving in water) (Dellinger & Livingston, 1998).

Hepatic

3.9.1)

A) WITH THERAPEUTIC USE

1) Hepatic injury has been reported with chronic therapeutic use. Salicylates have been linked with Reye's syndrome in children.

B) WITH POISONING/EXPOSURE

1) Hepatic injury has been reported with chronic toxicity. Salicylates have been linked with Reye's syndrome in children.

3.9.2)

A) TOXIC HEPATITIS

1) WITH POISONING/EXPOSURE

a) ACUTE TOXICITY

1) Hepatotoxicity following acute salicylate overdose is rare but has been reported (Starko & Mullick, 1983).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Renal insufficiency is an uncommon complication that may develop secondary to rhabdomyolysis or hypotension.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal insufficiency is a rare complication of salicylate toxicity. It has been reported in 2 patients with rhabdomyolysis after acute overdose (Leventhal et al, 1989; Montgomery et al, 1994) a patient with gastric perforation after acute overdose (Christensen & Schmidt, 1987) and a patient who developed full thickness skin and muscle necrosis after use of a menthol and methyl salicylate containing cream (Heng, 1987).
b) Acute renal insufficiency has been reported in patients with severe salicylate intoxication complicated by hypotension, ARDS and multiorgan system failure (Pei & Thompson, 1987; Leatherman & Schmitz, 1991).
c) Acute polyuric renal insufficiency developed in a 21-year-old man who had ingested 125 grams of buffered aspirin (Rupp et al, 1983). He did not develop rhabdomyolysis or hypotension and renal function recovered rapidly.

B) ALBUMINURIA

1) WITH POISONING/EXPOSURE

a) Proteinuria has been reported in patients with salicylate intoxication and is associated with the development of ARDS (Hormaechea et al, 1979; Heffner & Sahn, 1981).

C) FANCONI SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 17-year-old girl intentionally ingested 12.5 g of acetylsalicylic acid and developed marked albuminuria and glucosuria. A spot urine test indicated generalized proximal tubular dysfunction that was consistent with Fanconi syndrome as evidenced by severe glucosuria (639 mg/dL at 12 hours and 949 at 24 hours), proteinuria, and uric acid wasting. Fifteen days after discharge, no evidence of tubular dysfunction was present, along with no urine abnormalities (Tsimihodimos et al, 2007).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

3.11.2)

A) RESPIRATORY ALKALOSIS

1) WITH POISONING/EXPOSURE

a) Acid-base disturbances vary with age and are a combination of metabolic and respiratory effects.
b) Hyperventilation due to direct respiratory center stimulation produces a respiratory alkalosis in mild overdoses and early in the course of more severe poisoning. A compensatory renal excretion of potassium, sodium, and bicarbonate results in an alkaline urine pH (greater than 6).
c) Patients who only develop respiratory alkalosis have relatively mild toxicity and generally do well (Done, 1960; Chapman & Proudfoot, 1989). Pure respiratory alkalosis may occur after acute or chronic intoxication (Anderson et al, 1976).
d) Infants rarely if ever demonstrate pure respiratory alkalosis (Buchanan & Rabinowitz, 1974).

B) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) RESPIRATORY ALKALOSIS WITH A COMPENSATORY METABOLIC ACIDOSIS - usually with an elevated anion gap, develops subsequently in most adults with moderate salicylate intoxication (Gabow et al, 1978; Krause et al, 1992; Anderson et al, 1976). As potassium becomes depleted intracellularly, hydrogen ions are excreted, resulting in an acidic urine pH (less than 6). Serum potassium levels may be within normal limits, as intracellular potassium moves extracellularly. However, total body potassium is depleted despite a serum concentration that is within the normal range.

1) In young infants respiratory alkalosis either does not occur at all or is very short lived (Buchanan & Rabinowitz, 1974; Abdel-Magid & Ahmed, 1994).

b) PROFOUND METABOLIC ACIDOSIS WITH COMPENSATORY RESPIRATORY ALKALOSIS - and overall acidemia may develop in patients with severe salicylate intoxication. Potassium and bicarbonate depletion are nearly complete and a shift in hydrogen ion to the extracellular space results in an acidic blood pH and acidic urine pH. Acidemia increases the non-ionized fraction of salicylate and increases salicylate distribution to tissues.

1) The development of acidemia is associated with a greater incidence of severe CNS effects, ARDS and higher mortality rates (Watson & Tagupa, 1994; Done, 1960; Proudfoot & Brown, 1969; Anderson et al, 1976; Walters et al, 1983; Gaudreault et al, 1982) .
2) In young infants metabolic acidosis and acidemia is the most common presentation (Musumba et al, 2004; Lewis et al, 2006; Abdel-Magid & Ahmed, 1994; English et al, 1996; Buchanan & Rabinowitz, 1974).
3) In children, acidosis (pH less than 7.32) was noted more frequently in those who were chronically poisoned compared to acute intoxication (Gaudreault et al, 1982).
4) In one study infants with more severe acidosis had a higher ratio of CSF/serum salicylate concentration (Buchanan & Rabinowitz, 1974).

C) CSF: CHEMICAL CONTENT - GENERAL - FINDING

1) WITH POISONING/EXPOSURE

a) The cerebrospinal fluid may also become acidotic (Buchanan & Rabinowitz, 1974; Posner & Plum, 1967).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) PT prolongation is fairly common; DIC and thrombocytopenia occur rarely. Hemorrhage is uncommon.

3.13.2)

A) BLOOD COAGULATION PATHWAY FINDING

1) WITH POISONING/EXPOSURE

a) Prolongation of the PT, PTT, and INR occurs, particularly in chronic intoxication (Lewis et al, 2006; Anderson et al, 1976; Sainsbury, 1991; Gittelman, 1993; Pond et al, 1993). (Brown & Wilson, 1971; Hrnicek et al, 1974; Snodgrass et al, 1981; Mitchell, 1979; Quint & Allman, 1984)

B) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) Prolongation of PT and PTT, thrombocytopenia, hypofibrinogenemia, elevation of fibrin degradation products, and red blood cell fragmentation developed in 5 patients with multiorgan system failure associated with chronic salicylate toxicity (Leatherman & Schmitz, 1991).

C) THROMBOCYTOPENIC DISORDER

1) WITH POISONING/EXPOSURE

a) Thrombocytopenia and prolonged PT and PTT developed in a 5-year-old boy with juvenile rheumatoid arthritis and chronic salicylate intoxication (Everson & Krenzelok, 1986).

D) ANEMIA

1) WITH POISONING/EXPOSURE

a) SICKLE CELL CRISIS: Fatal sickle cell crisis was precipitated by acute salicylate ingestion in a 17-month-old girl (Mullick et al, 1973).

E) PLATELET ADHESION

1) WITH THERAPEUTIC USE

a) Aspirin inhibits platelet aggregation and prolongs bleeding time at therapeutic doses (Weiss & Aledort, 1967).

F) HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Autopsy findings in two cases of salicylate poisoning demonstrated intra-alveolar hemorrhage (Hantsch et al, 1998). The authors suggested a possible idiosyncratic reaction or an unknown pathophysiologic response.

G) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) Salicylate and one of its metabolites, gentisic acid, can induce hemolysis in patients with G6PD deficiency (Shahidi & Westring, 1970).

Dermatologic

3.14.2)

A) SYSTEMIC DISEASE

1) WITH POISONING/EXPOSURE

a) ABSORPTION - Significant toxicity has been reported after chronic topical use of creams and ointments containing salicylates (Dwyer et al, 1994; Galea & Goel, 1990; Raschke et al, 1991; Pec et al, 1992; Abdel-Magid & Ahmed, 1994; Aspinall & Goel, 1978; Davies et al, 1979; Anderson & Ead, 1979).

B) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Diaphoresis is a common finding in patients with salicylate toxicity (McGuigan, 1986; Cauthen & Hester, 1989; McGuigan, 1987; MacCready, 1943; Paul, 1972; Hormaechea et al, 1979).

C) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Allergic contact dermatitis from a topical 3-(aminomethyl)-pyridyl salicylate spray has been reported in 2 females with histories of urticaria. Manifestations included eczema, angioedema, and respiratory symptoms (Camasara et al, 1989).
b) Widespread pustular psoriasis developed in a 6-year-old boy as a hypersensitivity reaction to methyl salicylate from birch trees (Shelly, 1964).

D) SKIN NECROSIS

1) WITH POISONING/EXPOSURE

a) Full thickness skin and muscle necrosis developed in a 62-year-old man after topical application of a methyl salicylate and menthol ointment followed by the use of a heating pad (Heng, 1987).

E) PURPURA

1) WITH THERAPEUTIC USE

a) CASE REPORT - A 60-year-old male developed Henoch-Schonlein purpura after chronic therapy with acetylsalicylic acid (500mg/day for 5 years) (Alberich et al, 1997). A skin biopsy was compatible with leukocytoclastic vasculitis and immunofluorescence studies were positive for IgA deposits, which are characteristic findings. Signs and symptoms rapidly resolved with drug cessation and reappeared with drug rechallenge.

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis is an unusual complication of salicylate overdose.

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis has been reported in 2 patients with acute salicylate overdose (Montgomery et al, 1994; Leventhal et al, 1989) .
b) Rhabdomyolysis has also been noted in combination drug overdoses involving aspirin (Skjoto & Reikvam, 1979; Bismuth et al, 1972).

B) NECROSIS

1) WITH POISONING/EXPOSURE

a) Full thickness skin and muscle necrosis developed in a 62-year-old man after topical application of a methyl salicylate and menthol ointment followed by the use of a heating pad (Heng, 1987).

Endocrine

3.16.1)

A) WITH POISONING/EXPOSURE

1) Hypoglycemia may develop, especially in children.

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Hyperglycemia has also been reported (Buchanan & Rabinowitz, 1974).

B) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Hypoglycemia may develop, particularly in children (Pickering & Ellis, 1968; (Snodgrass et al, 1981; Quint & Allman, 1984; Everson & Krenzelok, 1986) but also in adults (Raschke et al, 1991; Thisted et al, 1987; Arena et al, 1978).

3.16.3)

A) ANIMAL STUDIES

1) HYPOGLYCEMIA

a) Animal studies suggest that brain glucose levels may be decreased in the face of normal serum glucose levels in salicylate toxicity (Thurston et al, 1970).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH POISONING/EXPOSURE

a) Aspirin is commonly involved in allergic reactions, ranging in severity from urticaria or angioedema to acute anaphylaxis (Blanca et al, 1989).

Reproductive

3.20.1)

3.20.2)

A) RENAL FUNCTION ABNORMAL

1) A 20-year-old woman ingested 19 g of aspirin at 2 months of gestation. The child subsequently developed progressive renal insufficiency with water and salt wasting from a diffuse metanephric adenoma (Bove et al, 1979).

3.20.3)

A) RISK SUMMARY

1) ASPIRIN

a) Aspirin should not be used during the third trimester of pregnancy. Do not use 1 week prior to or during labor and delivery. Exercise caution with use during the first or second trimesters of pregnancy (Prod Info DURLAZA(TM) oral extended release capsules, 2015).

B) PLACENTAL BARRIER

1) Salicylate readily crosses the placenta and is found in higher concentrations in the fetal plasma (Garrettson & Procknal JA and Levy, 1975). Chronic maternal ingestion may be associated with an increased incidence of stillbirths, antepartum and postpartum bleeding, prolonged pregnancy and labor, and lower birth weight infants (Corby, 1978).
2) There is no conclusive evidence that salicylate is teratogenic, but large doses taken near or at delivery have resulted in mild to moderate salicylism in the neonate (Lynd et al, 1976; Buck et al, 1993).
3) One study demonstrated an increased incidence of intracranial hemorrhage in infants whose mothers had ingested aspirin during the last week of pregnancy (Rumack et al, 1981).
4) FDA WARNING: All over-the-counter aspirin and aspirin-containing products must now be labelled with the following warning statement: "It is especially important not to use aspirin during the last 3 months of pregnancy unless specifically directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery" (FDA, 1990).

C) CASE SERIES

1) In a case control study, maternal ingestion of aspirin within 5 days of delivery resulted in hemostatic abnormalities in both mother and offspring. Decreased postpartum hemoglobin concentrations, abnormal blood loss, labial hematoma, intraoperative bleeding during caesarean section, and postpartum hemorrhage were noted in mothers, while petechiae, hematuria, and bleeding from circumcision were reported in neonates (Stuart et al, 1982).
2) In a prospective study of 1529 pregnant women, aspirin was taken by 46% during the first half of pregnancy. Maternal aspirin use during the first half of pregnancy was associated with lower IQ scores and attention decrements in offspring. The effect was greater for girls than for boys (Streissguth et al, 1987).

D) CASE REPORTS

1) A 27-year-old severely schizophrenic, bulimic woman admitted to occasional analgesic use during pregnancy. Salicylate levels on cord and maternal blood at the time of delivery were 61 mg/dL and 53 mg/dL, respectively. Delivery of a full-term, 3050-g, female infant was complicated by thick meconium and neonatal bradycardia. Findings after resuscitation included tachypnea, respiratory distress, hypotonia, and metabolic acidosis, all of which resolved by day 7 without specific treatment (Buck et al, 1993).
2) A 22-year-old woman, 8 months pregnant, ingested 32.5 g of aspirin. She presented with tinnitus, emesis, and hyperventilation. Fetus had normal cardiac sounds. Fetal movements were evident at 15 hours post admission, but not at 20 hours post admission. A stillborn fetus was delivered 6 days after admission. Postmortem salicylate blood level was 24.3 mg/dL. Maternal blood salicylate concentrations were 56.8 mg/dL on admission, 21.2 mg/dL at 20 hours post admission, and 4.4 mg/dL at 44 hours post admission (Rejent & Baik, 1985).
3) Salicylate was shown to impair albumin binding of bilirubin in an infant born after her mother had been taking eight 325-mg aspirin tablets daily for several days (Ahlfors et al, 1982). This might necessitate treatment of neonatal jaundice at lower bilirubin levels in salicylate-intoxicated neonates.
4) A 17-year-old woman 37 weeks pregnant presented with pneumonia and spontaneous rupture of membranes and reported she had ingested 50 aspirin tablets daily for one month in an attempt to harm herself and her fetus. She was treated with urinary alkalinization and hemodialysis for chronic salicylate intoxication (salicylate level 620 mg/L (62 mg/dL); pH, 7.34; pCO2, 15; HCO3, 8.8 mmol/L) and recovered. Ultrasound revealed fetal demise. Autopsy of the fetus revealed diffuse petechial hemorrhages of the lungs, heart, thymus, and kidneys (Palatnick & Tenenbein, 1998).
5) A 19-year-old woman who was 38 weeks pregnant intentionally ingested a total of 16.25 g of aspirin. Maternal salicylate level was 31.7 mg/dL on admission with no symptoms of toxicity. Fetal monitoring was begun with distress and bradycardia (heart rate, 60) observed; an emergent caesarean section was performed. Apgar scores of 5 and 7 were recorded at 1 and 5 minutes. A salicylate level of 35.2 mg/dL was obtained immediately after birth. Vital signs were stable after delivery. Laboratory analysis showed a pH of 7.49, pCO2 27 mmHg; electrolytes were normal except for a bicarbonate of 18 mEq/L. Salicylate levels dropped and were 8.1 mg/dL at 101 hours postdelivery. No treatment was reported. The infant was discharged without any evidence of complications (Velez et al, 2001).
6) A 23-year-old woman with chronic alcohol and tobacco abuse delivered a term infant after ingesting 1950 to 3000 mg of salicylic acid daily for 2 weeks. The child had evidence of fetal alcohol syndrome. His postnatal course was complicated by coagulopathy, hematuria, easy bruising, oozing from the umbilicus and venipuncture sites, and intracranial hemorrhage (Karlowicz & White, 1993).

E) PREGNANCY CATEGORY

1) The manufacturer has classified carisoprodol/aspirin and carisoprodol/aspirin/codeine as FDA pregnancy category D (Prod Info SOMA(R) COMPOUND oral tablets, 2013; Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013a)
2) The manufacturer has classified the combination product of aspirin/butalbital/caffeine as FDA pregnancy category C (Prod Info Fiorinal(R) oral capsules, 2007)
3) The manufacturer has classified bismuth subsalicylate as FDA pregnancy category C (Briggs et al, 1998).
4) The manufacturer has classified choline magnesium trisalicylate as FDA pregnancy category C (Prod Info choline magnesium trisalicylate oral tablets, 1999).
5) Alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths, and neonatal death have been reported with salicylate products. It is recommended that aspirin be used before 30 weeks gestation only if the potential benefit justifies the potential risk to the fetus. After 30 weeks gestation, it is recommended to avoid aspirin use, as premature closure of the fetal ductus arteriosus may occur, which may result in fetal pulmonary hypertension and fetal death. Aspirin use within 1 week of delivery or during labor may prolong delivery or cause excessive blood loss in the mother, fetus, or neonate. Due to the lack of human and animal safety data, it is recommended that the combination be used during pregnancy only if clearly needed (Prod Info SOMA(R) COMPOUND oral tablets, 2013)

F) LACK OF EFFECT

1) ASPIRIN

a) A case-control study was conducted of 3415 children with one of the following congenital abnormalities: neural-tube defects (n=1202), exomphalos/gastroschisis (n=238), cleft lip with or without cleft palate (n=1374), or posterior cleft palate (n=601). There was no association with maternal use of aspirin early in pregnancy and the development of any of these congenital anomalies (Norgard et al, 2005).

3.20.4)

A) BREAST MILK

1) The American Academy of Pediatrics recommends that salicylates should be used cautiously during breastfeeding; a recent review also suggests avoidance of bismuth subsalicylate during lactation because of systemic salicylate absorption (Briggs et al, 1998).
2) A 16-day-old breastfed infant developed salicylate toxicity. The mother was taking 10 grains of aspirin every 4 hours for arthritis. No other source of salicylate exposure was found (Clark & Wilson, 1981).
3) Since salicylate is excreted into breast milk and can cause bleeding in the infant, nursing mothers should avoid aspirin use (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
4) ASPIRIN

a) Discontinue treatment with aspirin or discontinue breastfeeding (Prod Info DURLAZA(TM) oral extended release capsules, 2015).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS18917-89-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

B) IARC Carcinogenicity Ratings for CAS119-36-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

C) IARC Carcinogenicity Ratings for CAS578-36-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

D) IARC Carcinogenicity Ratings for CAS69-72-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.3)

A) CARCINOMA

1) Accumulating data suggests that aspirin may prevent or protect against the development of colon and possibly other types of gastrointestinal cancers (Thun, 1994). There is evidence that colon and rectal cancers tend to decrease with long-term aspirin users. Findings by the American Cancer Society indicated that death rates from colon cancer were reduced in both men and women with frequent aspirin use (16 or more times per month for at least one year).

3.21.4)

A) LACK OF INFORMATION

1) ASPIRIN

a) At the time of this review, carcinogenicity studies with aspirin have not been conducted (Prod Info DURLAZA(TM) oral extended release capsules, 2015).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Serial salicylate levels every 1 to 2 hours until levels have peaked and are declining.
C) Basic metabolic panel every 2 hours until clinical improvement.
D) Arterial or venous blood gas for patients with moderate to severe toxicity, and all patients undergoing urinary alkalinization.
E) Obtain a CBC, liver enzymes, renal tests, INR and PTT in patients with clinical evidence of moderate to severe toxicity.
F) Obtain a CT of the head for altered mental status.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Obtain a serum salicylate level, glucose, electrolytes and blood gases every 2 hours until the salicylate level is consistently falling and acid base abnormalities are improving. Peak salicylate levels may be delayed for 12 hours or more after ingestion of enteric coated products.

a) Follow renal and hepatic function tests in moderate and severe salicylate poisoned patients until the serum salicylate concentration is consistently falling.

B) TOXICITY

1) GENERAL - Toxicity should be assessed by serial salicylate levels, determination of acid base status every 2 hours, as well as, clinical evaluation to determine the severity of an exposure. Other tests should include monitoring of serum electrolytes (i.e., glucose, BUN and creatinine) as indicated.

a) The Done's nomogram has been shown to underestimate and overestimate toxicity after salicylate ingestion (Surapathana et al, 1970; McGuigan, 1986; Dugandzic et al, 1989). Its use cannot be recommended.

2) ENTERIC COATED PRODUCTS - Following ingestion of an unknown amount of enteric-coated aspirin (325 mg each), in a 13-year-old female, salicylate levels did not begin to rise until 8 hours after ingestion and appeared to peak at 14 hours. The reason for the delay in absorption was possibly related to a delay in gastric emptying, failed disintegration of the enteric coating, or desorbed aspirin from the activated charcoal (Elko & Von Derau, 2001).
3) METHYL SALICYLATE - Peak salicylate levels develop rapidly after ingestion of methyl salicylate but may be delayed 6 hours or more following ingestion of tablets (Surapathana et al, 1970; McGuigan, 1986). Peak levels may not be reached for more than 24 hours in patients ingesting enteric coated or sustained release products (Kwong et al, 1983; Wortzman & Grunfeld, 1987; Pierce et al, 1991).
4) CHRONIC TOXICITY - Obtain serum electrolytes, salicylate level, arterial blood gas and baseline renal and hepatic function tests, glucose, INR or PT and PTT. Follow salicylate level, electrolytes and arterial blood gas every 2 to 4 hours until the level is consistently falling and the acid base abnormalities resolving.

C) ACID/BASE

1) Obtain an arterial blood gas in symptomatic patients and follow until acid base abnormalities are improving.

D) HEMATOLOGIC

1) Obtain a CBC.

E) COAGULATION STUDIES

1) Obtain INR or PT and PTT in patients with evidence of moderate to severe toxicity.

F) LABORATORY INTERFERENCE

1) Diflunisal may falsely elevate salicylate levels measured by the TDx(R) fluorescence polarization immunoassay, DuPont aca method or the Trinder colorimetric assay (Duffens et al, 1987).
2) Salicylate may falsely elevate serum carbon dioxide levels using the Technicon RA-1000 system (Shkrum et al, 1989).
3) FALSE POSITIVE TOXIC SERUM SALICYLATE LEVEL - A 45-year-old male with type II diabetes presented with a complaint of weakness and a report of only occasional aspirin use. Neuro exam was normal. Laboratory exam included a serum salicylate of 116.1 mg/dL, serum glucose 534 mg/dL, cholesterol 618 mg/dL and triglycerides 11,004 mg/dL. The blood was visibly lipemic. Post dialysis serum salicylate level was 115.9 mg/dL. A Trinder test on biological fluids was then performed and was found to be negative, and a urine salicylate level was also negative. The authors concluded that the elevated serum salicylate level was likely caused by interference from severe hypertriglyceridemia (Tuckler et al, 2001).
4) PSEUDOHYPERCHLOREMIA - Harchelroad (2008) reported falsely elevated chloride levels in 2 patients admitted for apparent salicylate overdose. Both presented with serum electrolytes and blood gas values that were consistent with acute respiratory alkalosis with metabolic compensation. However, serum chloride concentrations of 174 mEq/L and 146 mEq/L with salicylate concentrations of 8.1 mg/L and 4.5 mg/L, respectively were observed in these patients. Based on previous work, salicylates have been shown to produce falsely elevated chloride levels based on a linear relationship between chloride values and salicylate concentrations. In this report, falsely elevated chloride levels based on another cause were suspected, due to the magnitude of the increase. Previous reports of potentially interference using the Integra 800 ISE have been reported in the literature, and the manufacturer has suggested that the interaction may be due to the "age" of the electrode used. It has been suggested that the chloride ISE should be changed as frequently as every 4 weeks depending on use. The chloride electrodes had been used for at least 5 weeks using the Roche Cobas Integra 800 ion-selective electrode module in this institution (Zimmer et al, 2008).

4.1.3)

A) SPECIFIC AGENT

1) A few drops of 10% ferric chloride added to 1 ml of urine will turn purple in the presence of even small quantities acetylsalicylic acid. False positive results may result from the presence of acetoacetic acid and phenylpyruvic acid (Flomenbaum et al, 2006). Positive results should be confirmed with a serum salicylate level (Broder, 1987).

a) In a study of 155 patients with suspected salicylism or unexplained respiratory alkalosis and/or metabolic acidosis, the ferric chloride test had a sensitivity of 93.8%, a specificity of 75.4% and a negative predictive value of 98.4% in detecting salicylate in urine in patients with serum salicylate levels of 30 milligrams/deciliter or higher (Ford et al, 1994).
b) In a prospective study to evaluate and compare ferric chloride (FC) and Trinder reagent (TR) for the detection of ASA in urine samples, 180 patients with suspected overdose had a serum ASA measured. Of the 20 patients with an ASA concentration above 5 mg/dL (lowest detectable concentration), both reagents were 100% sensitive. Specificity of TR was 73% as compared to 71% for FC. Similar results were reported in 91% of cases for both reagents. A number of cases of false positive results (similar in both groups) were reported and may have been due to the presence of phenothiazines (especially chlorpromazine and thioridazine) or acetoacetate, a ketone. Despite similar findings between the reagents, the authors concluded that FC may be a more practical (i.e., longer shelf life) for use in the Emergency Department. Further study is suggested (Weiner et al, 2000).
c) In a descriptive study to assess the reactivity of ferric chloride with various commercially available salicylate-containing products (ie, regular and buffered acetylsalicylic acid, bismuth subsalicylate, methyl salicylate, physostigmine salicylate, salicylic acid, trolamine salicylate, and herbal tablets with salicin-containing willow bark (Salix sp.)), ferric chloride correctly identified each product as containing salicylate by 3 independent physician reviewers (Hoffman et al, 2002). Limitations of the study include a lack of testing of water-insoluble salicylate-containing products (e.g., salicylate in oil or an emulsion).

2) Laboratory interference has been reported in neonates with hyperbilirubinemia when using the Trinder method. An increase in false-high blood salicylate levels was observed. If salicylate intoxication is suspected during the neonatal period another method to assess salicylate concentrations is suggested (Berkovitch et al, 2000).
3) The Ames Phenistix turns brown when either salicylates or phenothiazines are present in serum or urine. Adding 1 drop of 20 N sulfuric acid fades the color change from phenothiazines but not salicylates. The ferric chloride test is preferred as the color change is easier to detect (Flomenbaum et al, 2006).

Radiographic Studies

1) Obtain a chest radiograph in any patient with hypoxia or severe intoxication to evaluate for evidence of pulmonary edema.

1) In patients with pyloric stenosis, enteric coated aspirin has been shown to remain in the stomach for prolonged periods of time. This can be shown by instillation of contrast media into the stomach followed by an abdominal x-ray (Harris, 1973; Sogge et al, 1977; Springer & Groll, 1980). This procedure should be considered in patients with serum salicylate levels that do not decline or continue to rise.
2) Concretions of bismuth subsalicylate or enteric coated aspirin may be radiopaque on plain abdominal radiographs (Sainsbury, 1991; Hearney et al, 1996).

Methods

1) The following are Qualitative identification methods:

a) A few drops of 10% ferric chloride added to 1 ml of urine will turn purple in the presence of even small quantities acetylsalicylic acid. False positive results may result from the presence of acetoacetic acid and phenylpyruvic acid (Flomenbaum et al, 2006). Positive results should be confirmed with a serum salicylate level (Broder, 1987; Charette et al, 1998).
b) The Ames Phenistix turns brown when either salicylates or phenothiazines are present in serum or urine. Adding 1 drop of 20 N sulfuric acid fades the color change for phenothiazines but not salicylates. The ferric chloride test is preferred as the color change is easier to detect (Flomenbaum et al, 2006).

1) Phenistix(R) use with serum will develop a brown-purplish color with levels of 60 to 90 mg/dL (4.34 to 6.51 mmol/L) and frankly deep purple with levels above 90 mg/dL (6.51 mmol/L) (Done & Temple, 1971).

c) FORENSICS - A method using ferric chloride on methanolic extract of hemolyzed whole blood has been described. The minimum salicylate level this method can detect is 5 mg/dL (Asselin & Caughlin, 1990).

2) The following are Quantitative procedures:

a) HPLC has been used to detect salicylates and metabolites in the plasma. Limits of detection were 0.2 mcg/mL for parent compounds and 0.1 mcg/mL for metabolites (Dadgar et al, 1985).
b) An ADx(TM) Salicylate assay is available. Sensitivity is 5 mg/L; correlation coefficient is 0.996.
c) Other common methods for salicylate determination include a fluorescence polarization assay and a colorimetric assay (Adelman et al, 1991).
d) Salicylate and metabolites can be detected in urine using proton nuclear magnetic resonance spectroscopy (Vermeersch et al, 1988).

3) OTHER

a) BLOOD GAS ANALYZERS - Lacoma et al (1997) evaluated two blood gas analyzers that measure lactate concentration and standard blood gas measurements (Nova Star Profile 9 and Ciba Corning Diagnostics {CCD} 860) to determine possible assay interference by toxic substances known to cause lactic acidosis. No significant interference was noted in either analyzer with plasma samples containing sodium salicylate.

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with major signs or symptoms (metabolic acidosis, dehydration, mental status changes, seizures, pulmonary edema) should be admitted to the Intensive Care Unit regardless of serum salicylate level.
B) Patients with minor symptoms only (i.e., nausea, tinnitus) following acute overdose may be managed in the emergency department with decontamination and alkaline diuresis if the salicylate level is shown to be declining.
C) Admission should be strongly considered regardless of the salicylate level or symptoms in infants, children less than 2, the elderly, in chronic overdose or when the ingested tablets are enteric coated or sustained release.
D) All suspected chronic or deliberate poisonings should be evaluated by a physician.

6.3.1.2) HOME CRITERIA/ORAL

A) A single oral dose of less than 150 mg/kg may result in some nausea, gastritis and vomiting, however clinically significant toxicity is not expected (Temple, 1981).
B) Patients with inadvertent ingestions of less than 150 mg/kg or 6.5 g, whichever is less, of aspirin equivalent doses can generally be observed at home with normal follow-up procedures. Consider follow-up at periodic intervals of approximately 12 hours after acute ingestion of non-enteric coated salicylate products or 24-hours for enteric-coated aspirin (Chyka et al, 2007).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for hemodialysis. Women in the third trimester of pregnancy who do not require referral to a healthcare facility for other reasons (ie ingested dose or symptoms) should be referred to an obstetrician for outpatient follow up and assessment of maternal fetal risk.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with intentional ingestions and those with unintentional ingestions greater than 150 mg/kg or 6.5 g, whichever is less, of aspirin equivalent doses should be evaluated in a healthcare facility (Chyka et al, 2007). Patients who have a clear peak and decline in salicylate concentration and mild to moderate symptoms that resolve with treatment can often be treated and released from an ED observation unit.
B) For children under 6 years of age, ingestions of greater than a lick or a taste of oil of wintergreen (98% methyl salicylate) should be referred to a healthcare facility (Chyka et al, 2007).
C) For patients older than 6 years of age, ingestions of 4 mL or greater of oil of wintergreen (98% methyl salicylate) should be referred to a healthcare facility (Chyka et al, 2007).

Monitoring

Oral Exposure

6.5.1)

A) SUMMARY

1) ASPIRIN: Patients ingesting more than 150 mg/kg or 6.5 g, whichever is less, of aspirin equivalent doses should be referred to a health care facility; activated charcoal can be administered in the prehospital setting if readily available in patients with normal mental status.
2) For children under 6 years of age, ingestions of greater than a lick or a taste of oil of wintergreen (98% methyl salicylate) should be referred to a health care facility.
3) For patients older than 6 years of age, ingestions of 4 mL or greater of oil of wintergreen (98% methyl salicylate) should be referred to a health care facility.
4) Delayed onset of clinical toxicity and peak serum levels may develop after ingestion of enteric coated or sustained release salicylate or if pylorospasm or pharmacobezoar develop.

B) ACTIVATED CHARCOAL

1) Prehospital administration of activated charcoal for acute toxic salicylate ingestions can be considered if it is immediately available and no contraindications are present. Transportation to a hospital should not be delayed in order to administer the activated charcoal.
2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) Activated charcoal decreased salicylate absorption in crossover studies (Dawling et al, 1983; Eisen et al, 1991).
2) In a crossover study of 6 volunteers, activated charcoal reduced aspirin absorption by 67 percent while a milk chocolate-activated charcoal mixture decreased aspirin absorption by 50 percent (Eisen et al, 1991). The addition of chocolate may increase patient acceptance of activated charcoal without significantly diminishing its effectiveness.
3) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

4) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

B) GASTRIC LAVAGE

1) Gastric lavage was effective in reducing salicylate absorption in volunteers (Danel et al, 1988).
2) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

3) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

4) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

5) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

6) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) MULTIPLE DOSE ACTIVATED CHARCOAL

1) Use of multiple dose charcoal is controversial. Two small case series found that salicylate intoxicated patients treated with multiple dose activated charcoal had salicylate elimination half lives that were shorter than other patients not treated with multiple (Hillman & Prescott, 1985) or shorter half lives than previously published cases (Vertrees et al, 1990).
2) In a crossover study in 10 volunteers ingesting 2.88 grams acetylsalicylic acid suspension, a 9% decrease in bioavailability and an 18% decrease in urinary salicylate excretion was noted when 4 doses of 25 grams activated charcoal was administered every 2 hours beginning 4 hours postingestion (Kirshenbaum et al, 1990).

a) These authors felt that they were unable to demonstrate clinically important enhanced salicylate excretion due to multiple dose charcoal therapy in the postabsorptive phase.

3) A controlled, randomized, 3-limbed crossover study in 9 volunteers (2.88 grams acetylsalicylic acid ingested) demonstrated no decrease in AUC after administration of multiple-dose activated charcoal during the post absorptive phase; no cathartic was given (Mayer et al, 1992).
4) Multiple dose vs single dose charcoal has been compared in volunteers who ingested therapeutic doses (650 milligrams every 4 hours x 3 days) until steady state. Multiple dose charcoal resulted in enhanced elimination during the 24 hours after absorption was complete (Yeakel et al, 1988).
5) Multiple doses of activated charcoal, administered over 12 hours, did not significantly increase the elimination of intravenously administered salicylate in male rabbits (Douidar et al, 1992).
6) In a crossover volunteer study the administration of three 50 gram doses of activated charcoal every 4 hours starting 1 hour after ingestion of 24 aspirin (81 milligrams each) decreased the urinary recovery of salicylate more than the administration of 1 or 2 doses of charcoal (Barone et al, 1988).
7) Because of the lack of clear benefit, the routine use of multiple dose activated charcoal is not recommended for all patients with salicylate ingestion. Salicylate has been shown to desorb from activated charcoal in vivo (Filippone et al, 1987); the administration of a second dose of charcoal is reasonable to attempt to counteract desorption.
8) Salicylate absorption may be prolonged after ingestion of enteric coated or sustained release products. Administration of a second dose of activated charcoal should be considered in patients with rising salicylate levels and those who have ingested enteric coated or sustained release preparations. Whole bowel irrigation should also be considered in these patients.

D) WHOLE BOWEL IRRIGATION (WBI)

1) A crossover study in 9 volunteers (2.88 grams acetylsalicylic acid suspension ingested) failed to demonstrate any enhanced excretion of drug following whole bowel irrigation beginning 4 hours postingestion) (Mayer et al, 1992).
2) In another study whole bowel irrigation was more effective in reducing salicylate absorption than single dose activated charcoal begun 4 hours after administration of enteric coated aspirin (Kirschenbaum et al, 1989).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

6.5.3)

A) MONITORING OF PATIENT

1) SUMMARY

a) Obtain serial salicylate levels every 1 to 2 hours until concentrations have peaked and are declining; basic metabolic panel every 2 hours until clinical improvement; arterial or venous blood gas for patients undergoing urinary alkalinization or moderate/severe toxicity. In addition, obtain CBC, liver enzymes, renal function studies, INR and PTT in patients with clinical evidence of moderate/severe toxicity.

2) DELAYED SALICYLATE TOXICITY

a) An adult developed delayed salicylism 17 hours after intentionally ingesting 200 325-mg tablets. He was admitted approximately 45 minutes after exposure and was alert and oriented with some nausea. Fifty grams of activated charcoal and normal saline at 150 mL/hr were administered. An initial salicylate and acetaminophen concentrations were undetectable. Respiratory alkalosis (pH 7.47, PC02 27 mm Hg, PO2 104 mm Hg, and HCO3 20 mEq/L) was observed shortly after admission. A second salicylate level obtained at 3 hours was 33 mg/dL and 35 mg/dL at 7 hours. Following observation for 8 hours the patient was transferred to psychiatric care and was readmitted 17 hours after initial presentation with decreased mental status, diaphoresis, and tachypnea. A repeat ABG revealed a mixed metabolic gap and respiratory acidosis (pH 7.08, PCO2 30 mm Hg, and PO2 73 mm Hg, and HCO3 10 mEq/L) with a salicylate level of 128 mg/dL. The patient had a witnessed seizure and died 20 hours after exposure. Careful monitoring of serial salicylate concentrations until they are in the nontoxic range is important, as delayed absorption may produce mildly elevated salicylate concentrations and initially mild toxicity (nausea and respiratory alkalosis in this patient) that may then progress to severe intoxication (Herres et al, 2009).
b) Delayed salicylate toxicity and no symptoms for the first 35 hours postingestion have been reported in one patient. The authors suggested that the delayed aspirin absorption may be due to enteric-coated or sustained-release dosage forms, salicylate-induced pylorospasm, and/or the formation of pharmacobezoars. If salicylate levels are not decreasing significantly every 4 to 6 hours, this suggests continued absorption or decreased excretion. Serial salicylate levels should be monitored until they are declining and in the nontoxic range. Treatment should not be discontinued until patients are asymptomatic (Rivera et al, 2004).

B) FLUID/ELECTROLYTE BALANCE REGULATION

1) Correct dehydration with 0.9% saline 10 to 20 milliliters/kilogram/hour over 1 to 2 hours until a good urine flow is obtained (at least 3 to 6 milliliters/kilogram/hour). In patients in whom urinary alkalinization is being considered, initial hydration may be with 10 to 20 milliliters/kilogram of D5W with 88 to 132 milliequivalents of bicarbonate added. Patients in shock may require more rapid fluid administration (Temple, 1981).
2) MONITOR urine output and pH hourly.

C) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia should be treated with external cooling.

D) POTASSIUM

1) Correct hypokalemia as needed. Patients undergoing urinary alkalinization may require large amounts of potassium supplementation due to renal potassium wasting.
2) Institute continuous cardiac monitoring in patients with hypokalemia and those requiring high doses of potassium.
3) Do not administer potassium to anuric patients.

E) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
2) Patients with refractory acidosis, inability to maintain appropriate respiratory alkalosis, or acidemia should be treated with hemodialysis.

F) DEXTROSE

1) CASE REPORT/DECREASED NEURO STATUS: A 48-year-old woman with progressive neurological deterioration and a serum salicylate concentration of 4.1 mmol/L received intravenous sodium bicarbonate, potassium, and a 50 mL bolus of 50% dextrose in water (serum glucose 5.4 mmol/L at 1.5 hr after admission) (Kennedy & Telford, 1998). Improved mental status and alertness were noted shortly after glucose administration. In addition, an infusion of 10% dextrose in water was continued for 12 hours with no further change in mental status. At 22 hours post admission, salicylate level was 1.2 mmol/L, potassium 3.4 mmol/L, and glucose 5 mmol/L.

a) Although further study was suggested by the authors, intravenous glucose has been used successfully in animal models, in which salicylate poisoned rodents were found to have low brain glucose levels despite normal serum glucose.

G) ALKALINE DIURESIS

1) Forced diuresis, alkaline diuresis and urinary alkalinization without diuresis have all been shown to increase urinary salicylate excretion (Berg, 1977; Gordon et al, 1984; Prowse et al, 1970; Coppack & Higgins, 1984; Prescott et al, 1982). Alkalinization alone was at least as effective as forced alkaline diuresis in enhancing salicylate removal in one study (Prescott et al, 1982). Alkalinization of the urine (pH of 7.5 to 8) effectively enhances salicylate excretion, but may be difficult to achieve in severely poisoned patients because of depletion of total body potassium.
2) DOSE: A solution of D5W with 132 mEq/L of bicarbonate plus 30 to 40 mEq/L of KCl should be given at a rate of 2 to 3 mL/kg/hour to produce a urine flow of 2 to 3 mL/kg/hour. Monitor serum electrolytes and urine pH every 1 to 2 hours. Adjust potassium and bicarbonate administration as needed to maintain a urine pH of 7.5 to 8.
3) PRECAUTIONS: Alkaline diuresis is a potentially dangerous treatment and meticulous monitoring of urine output, pH, serum potassium, mental status, and pulmonary status must be performed.
4) STUDY: A small comparison study of 9 healthy volunteers was conducted to determine the effectiveness of urinary alkalinization and multidose activated charcoal in salicylate elimination (Ruskosky et al, 1998). Urinary alkalinization shortened half-life by 48.4% (4.741 hours) compared to control (aspirin only administration) and 42.7% (3.767 hours) compared to the activated charcoal phase. Area under the curve was also statistically less for the urinary alkalinization group compared to the control or activated charcoal group.
5) PRECAUTIONS: Hypocalcemia (6.4 mg/dL) and tetany have developed with use of bicarbonate for urinary alkalinization treatment following salicylate poisoning; serum calcium was normal on admission (Fox, 1984).

H) ACETAZOLAMIDE

1) Acetazolamide and tromethamine are NOT recommended as agents to alkalinize the urine due to their potential to cause worsening acidosis. Hill (1971) demonstrated that acetazolamide, in rats, lowered the blood pH, raised the tissue-salicylate concentrations and increased the toxicity of sodium salicylate(Hill, 1971).
2) The combination of acetazolamide and intravenous bicarbonate has been shown to increase urinary salicylate excretion without inducing acidemia in animal models (Reimold et al, 1973) and in adults with salicylate overdose (Morgan & Polak, 1969). This combination cannot be recommended until its safety is more clearly demonstrated.

I) ENDOSCOPY OF STOMACH

1) Serial serum salicylate levels should normally decline with therapy. If they remain relatively unchanged or increase, this may indicate persistent aspirin in the stomach. This is most commonly reported in patients with gastric outlet obstruction after ingestion of enteric coated aspirin. Pills may be visualized by instillation of a contrast media into the stomach followed by an abdominal x-ray (Harris, 1983; (Sogge et al, 1977; Springer & Groll, 1980).
2) Endoscopic removal of the persistent tablets in the stomach should be considered in large, potentially life threatening ingestions (Harris, 1973).

J) ACUTE LUNG INJURY

1) Hemodialysis is indicated in patients with pulmonary edema, as alkaline diuresis may be hazardous in this setting.
2) Maintain adequate ventilation and oxygenation and monitor of arterial blood gases closely. If pO2 cannot be maintained above 50 mmHg with 60 percent oxygen by face mask or mechanical ventilation, then positive-end-expiratory pressure (PEEP) in intubated patients or continuous-positive-airway pressure (CPAP) in non-intubated patients may be necessary.
3) Crystalloid solutions must be administered carefully, avoiding volume overload. Monitor fluid status through a central line or right sided heart catheter.

K) CEREBRAL EDEMA

1) Patients with evidence of cerebral edema require immediate dialysis.
2) CLINICAL IMPLICATIONS

a) Cerebral edema and elevated intracranial pressure (ICP) may occur. Emergent management includes head elevation and administration of mannitol; hyperventilation should be performed if there is evidence of impending herniation.

3) MONITORING

a) Patients will usually require endotracheal intubation and mechanical ventilation. Monitor intracranial pressure, cerebral perfusion pressure and cerebral blood flow.

4) TREATMENT

a) Most information on the treatment of cerebral edema is derived from studies of traumatic brain injury.

5) MANNITOL

a) ADULT/PEDIATRIC DOSE: 0.25 to 1 gram/kilogram intravenously over 10 to 15 minutes (None Listed, 2000).
b) AVAILABLE FORMS: Mannitol injection (5%, 10%, 15%, 20%, 25%).
c) MAJOR ADVERSE REACTIONS: Congestive heart failure, hypernatremia, hyponatremia, hyperkalemia, renal failure, pulmonary edema, and allergic reactions.
d) PRECAUTIONS: Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia. Do not add to whole blood for transfusions; enhanced neuromuscular blockade has occurred with tubocurarine. Keep serum osmolarity below 320 mOsm.
e) MONITORING PARAMETERS: Renal function, urine output, fluid balance, serum potassium levels, serum osmolarity, and CVP.

6) HYPERTONIC SALINE

a) Preliminary studies suggest that hypertonic saline (7.5% saline/6% dextran) 100 ml reduced ICP more effectively than 200 mL of 20% mannitol in adults with elevated ICP after traumatic brain injury(Battison et al, 2005).

7) ELEVATION

a) Elevation of the head of the bed to approximately 30 degrees decreases ICP and improves cerebral perfusion pressure (Meixensberger et al, 1997; Schneider et al, 1993; Feldman et al, 1992).

8) MECHANICAL DECOMPRESSION

a) Early surgical decompression, ventriculostomy with CSF drainage, or craniectomy may be useful in patients with persistent elevation of ICP (Sahuquillo & Arikan, 2006; Sakai et al, 1998; Polin et al, 1997; Taylor et al, 2001). Most experience with these modalities has been in patients with traumatic brain injury.

9) HYPERVENTILATION

a) SUMMARY: Hyperventilation has been associated with adverse outcomes and should not be performed routinely (Muizelaar et al, 1991). It is indicated in patients who have clinical evidence of herniation or if there is intracranial hypertension refractory to sedation, paralysis, CSF drainage and osmotic diuretics (None Listed, 2000a).
b) RECOMMENDATION:

1) The PCO2 must be controlled in the range of 25 torr; further lowering of PCO2 may create undesirable effects secondary to local tissue hypoxia.
2) End-tidal CO2 tension, correlated with an initial ABG measurement, provides a noninvasive means of monitoring PCO2 (Mackersie & Karagianes, 1990).
3) Most authorities advise that hyperventilation should be considered a temporizing measure only; SUSTAINED hyperventilation should be avoided (Am Acad Neurol, 1997; Bullock et al, 1996; Kirkpatrick, 1997).

L) RESPIRATORY FAILURE

1) Extreme caution must be taken when performing an intervention which might decrease the patient's respiratory alkalosis, such as sedation or intubation. Any intervention which reduces respiratory alkalosis increases the non-ionized fraction of salicylate and increases salicylate distribution to tissues; abrupt decompensation may ensue.
2) A small retrospective study of salicylate-poisoned patients was conducted to determine the relationship between mechanical ventilation, acidosis, and patient outcome. As previously described in the literature, the use of mechanical ventilation with salicylated-poisoned patients using "standard" settings can diminish the relatively compensatory effect of respiratory alkalosis. This can result in worsening neurotoxic effects. In this study, 7 salicylate-poisoned patients who received mechanical ventilation were identified, 2 patients died within 3 hours of being intubated with serum salicylate concentrations, of 85 and 75 mg/dL, respectively, while another patient developed severe neurologic impairment (serum salicylate concentration 84 mg/dL); 2 of these patients had also ingested cocaine. Mechanical ventilation was associated with worsening acidemia, as noted by post-mechanical ventilation pH levels of 7.14, 7.14, and 6.79, respectively in these patients. Although a cause and effect cannot be determined, of the patients in this study with pre- and post-mechanical ventilation blood gases each had a stable pH and PCO2 prior to mechanical ventilation. The authors concluded that inadequate mechanical ventilation in patients with salicylate toxicity can be associated with respiratory acidosis, acidemia and clinical deterioration. A further prospective study is suggested (Stolbach et al, 2008).
3) Abrupt asystole developed in 2 patients who received diazepam, developed respiratory depression, and were subsequently intubated (Berk & Andersen, 1989). Abrupt asystole developed in another salicylate intoxicated patient with postoperative respiratory depression (Austin, 1970).

M) BLOOD COAGULATION DISORDER

1) Salicylates can interfere with coagulation mechanisms, therefore, patients with evidence of active bleeding or coagulation disorders require laboratory monitoring to include prothrombin time (PT) and INR. Give blood or blood products (fresh frozen plasma) if bleeding is excessive. Vitamin K may be beneficial in the presence of a prolonged PT or INR.
2) VITAMIN K DOSE: ADULT: 2 to 25 mg orally or SubQ; the dose can be repeated in 8 (parenteral) or 12 (oral) hours depending on the response. Doses of more than 25 mg are rarely needed; however doses up to 50 mg may be given (Caravati, 2004).

a) PEDIATRIC DOSING: OLDER CHILDREN: 5 to 10 mg/dose orally or parenterally. INFANTS: 2 mg orally or parenterally (Caravati, 2004)
b) GENERAL: Monitor PT to determine further drug dosing. Injection by the SubQ route is preferred. Intravenous administration is NOT the route of choice; when it is considered unavoidable, the drug should be injected slowly, not exceeding 1 mg/minute (Prod Info VITAMIN K1 injection, 2004).

N) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL ABSORPTION

1) Significant toxicity has been reported after chronic topical use of creams and ointments containing salicylates (Davies et al, 1979; Anderson & Ead, 1979; Dwyer et al, 1994a; Galea & Goel, 1990; Raschke et al, 1991; Pec et al, 1992; Abdel-Magid & Ahmed, 1994).

B) DERMAL DECONTAMINATION

1) Wash skin thoroughly with soap and water.

Enhanced Elimination

1) Hemodialysis rapidly increases salicylate clearance and corrects acid base, fluid and electrolyte disturbances (Kleinman et al, 1988; Levy, 1967; Winchester et al, 1981). Salicylate clearances of 86 milliliter/minute have been achieved (Jacobsen et al, 1988). Because hemodialysis enhances salicylate clearance and corrects acid base derangements, it is the procedure of choice to treat severe salicylate intoxication.
2) Hemodialysis is recommended in patients with high serum salicylate levels (greater than 80 to 100 milligrams/deciliter after acute overdose, 50 to 60 milligrams/deciliter with chronic intoxication), refractory acidosis, inability to maintain appropriate respiratory alkalosis, acidemia, evidence of CNS toxicity (seizures, mental status depression, persistent confusion, coma, cerebral edema), progressive clinical deterioration despite appropriate fluid therapy and attempted urinary alkalinization, acute lung injury, inability to tolerate sodium bicarbonate (eg, renal insufficiency, pulmonary edema), refractory/profound electrolyte disturbances, or renal failure. The clinical condition of the patient is more important than the serum salicylate concentration in determining the need for hemodialysis, especially in patients with chronic toxicity or delayed presentation after acute overdose. In patients with early presentation after acute overdose, serum concentrations approaching 100 mg/dL warrant consideration for dialysis even with mild or moderate clinical manifestations of toxicity.
3) CONSIDERATIONS

a) CASE REPORT: An adult who took two separate overdoses of aspirin received hemodialysis and ineffective alkalinization for the first exposure, and alkalinization only for the second episode (Higgins et al, 1998). It was found that the rate of decline in salicylate concentration was faster with alkalinization within the first 4 hours of therapy and that by 24 hours salicylate rates were similar for both therapies. The authors suggested that if hemodialysis treatment is considered following salicylate poisoning that treatment with alkalinization should also be given early in treatment to prevent acidemia and to facilitate elimination of salicylate via the kidneys.

1) Peritoneal dialysis does not clear salicylate or correct acid-base and electrolyte abnormalities quickly enough to be useful for severe salicylate poisoning. It has been used in the past to increase salicylate clearance and correct acid-base, fluid and electrolyte abnormalities when hemodialysis was not available (Buselmeier et al, 1977; Etteldorf et al, 1961; Schlegel et al, 1966; James et al, 1962; Winchester et al, 1981).
2) Salicylate removal is more rapid when a dialyzing solution containing 5% albumin is used (Schlegel et al, 1966).

1) Hemoperfusion is effective in increasing salicylate clearance but not in correcting fluid and electrolyte abnormalities or acid-base disorders (Fantozzi et al, 1981; Brookings & Ramsey, 1975; Widdop et al, 1975; Winchester et al, 1981).

1) IN VITRO STUDY: An in vitro model was used to evaluate hemofiltration as a treatment for salicylate poisoning, using a Hospal AN69 filter and 500 milliliters of 4% bovine serum albumin (BSA) as the carrier solution. Three different salicylate concentrations (300, 600 and 900 mg/L) were used with hemofiltration performed for 180 minutes at a BSA flow rate of 150 mL/min (the ultrafiltrate was replaced with deionized water). The mean total amount over the 180 minutes for the 300 mg/L runs was 53% (+/-8%); 69% (+/-12%) for the 600 mg/L runs and 70% (+/-2%) for the 900 mg/L runs. Although further evaluation was suggested, this represents the removal of a clinically significant amount of salicylate using this procedure (Dargan et al, 2001).

PROCEDURE	APPROXIMATE MEAN HALF-LIFE DURING PROCEDURE	APPROXIMATE MEANCLEARANCE DURINGPROCEDURE
Hemodialysis	3.5 hours	47 ml/kg/hr (Kallen, 1966)86 ml/min (Jacobsen, 1988)
Hemoperfusion	-	81 ml/min (Jacobsen, 1988)
Peritoneal dialysis without alkalinization	16 hours	10/ml/kg/hr (Summitt, 1964)
Peritoneal dialysis with alkalinization	5 hours	28 ml/kg/hr (Summitt, 1964)
Peritoneal dialysis	14 hours (Ettledorf, 1961)	-

1) INFANT: A 4-month old was treated successfully with exchange transfusion after persistent toxicity including acidemia, aciduria and severe hypokalemia. An initial salicylate concentration was 85 mg/dL. Shortly after presentation, 5 semi-dissolved tablets were found in the stool. Double volume exchange transfusion with 180 mL/kg packaged red blood cells that was reconstituted in fresh frozen plasma was infused over 6 hours. The procedure reduced the serum salicylate concentration from 70.1 mg/dL to 34.4 mg/dL (51% reduction) in 8.5 hours. All laboratory parameters normalized within 48 hours of the exchange transfusion. The infant was extubated 36 hours after the procedure, and was discharged with further follow-up by Child Protective Services. Development was appropriate for age at 1 and 2 month follow-up (Manikian et al, 2002).
2) TODDLER: Exchange transfusion was performed on a 2-year-old male who had ingested methyl salicylate. 542 milligrams of salicylate were eliminated from the blood. The elimination rate attributable to the exchange transfusion was 152 milligrams/hour (Done & Otterness, 1956).
3) ANIMALS: Dogs given 125 milligrams/kilogram of intravenous sodium salicylate were then treated by exchange transfusion, peritoneal lavage, or hemodialysis to determine which technique could remove the most salicylate. Exchange transfusion removed approximately 18% of the administered dose, peritoneal dialysis about 15%, and hemodialysis about 50% (James et al, 1962).

Abstracts

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) ASPIRIN

1) EXTENDED-RELEASE

a) The recommended dose is one 162.5 mg capsule ORALLY once daily (Prod Info DURLAZA(TM) oral extended release capsules, 2015).

2) IMMEDIATE-RELEASE

a) Adults/Adolescents: Oral, two 325 mg tablets every 4 hours, not more than 12 tablets in 24 hours (Prod Info BUFFERIN(R) oral tablets, 2007); two 500 mg tablets every 6 hours not more than 8 tablets in 24 hours (Prod Info BUFFERIN(R) extra-strength oral tablets, 2007).

B) CARISOPRODOL/ASPIRIN

1) ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg); MAXIMUM DURATION OF USE: up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
2) OVER 65 YEARS OF AGE: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

C) CARISOPRODOL/ASPIRIN/CODEINE

1) ADULTS AND ADOLESCENTS 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg/codeine phosphate 16 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg/codeine phosphate 128 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013).
2) OVER 65 YEARS OF AGE: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013).

7.2.2)

A) ASPIRIN

1) ACUTE ISCHEMIC STROKE

a) 1 to 5 mg/kg orally once daily as initial therapy until dissection and embolic causes are excluded (non-sickle-cell-disease related acute ischemic stroke (AIS)) or as secondary prevention after anticoagulation has been discontinued. Prophylaxis for at least 2 years is recommended (Monagle et al, 2012; Ng & Ganesan, 2011; Bernard et al, 2008; Roach et al, 2008; Strater et al, 2001).

2) KAWASAKI DISEASE

a) HIGH-DOSE (ACUTE PHASE): 80 to 100 mg/kg/day (divided every 6 hours) orally; continue therapy until afebrile for 48 to 72 hours or until day 14 of illness and afebrile for at least 48 hours, followed by low-dose therapy (Monagle et al, 2012; Newburger et al, 2004; Falcini et al, 2002; Litalien & Jacqz-Aigrain, 2001).
b) Controversies exist regarding the dose of aspirin used in the acute phase of Kawasaki disease. Study data have shown that lower doses may be just as effective as higher doses and may be more appropriate during the acute phase of illness (Lang & Duffy, 2002). Lower initial doses of aspirin (30 to 50 mg/kg/day) are used in some countries, particularly in Asia, to decrease the risk of aspirin toxicity (Rowley & Shulman, 2010; Lang & Duffy, 2002).
c) LOW DOSE: 3 to 5 mg/kg orally once daily until no evidence of coronary changes, usually 6 to 8 weeks after onset of illness. Continue low-dose aspirin indefinitely for patients with underlying coronary abnormalities (Monagle et al, 2012; Rowley & Shulman, 2010; Newburger et al, 2004; Hsieh et al, 2004; Falcini et al, 2002; Litalien & Jacqz-Aigrain, 2001).

3) THROMBOSIS, PROPHYLAXIS

a) 1 to 5 mg/kg orally once daily (Monagle et al, 2012; Monagle et al, 2011; Li et al, 2007; Israels & Michelson, 2006).

1) Higher doses (6 to 10 mg/kg/day) have been used in children undergoing heart surgery (Monagle et al, 2012; Cholette et al, 2010; Li et al, 2008).

4) EXTENDED RELEASE FORMULATION

a) Safety and effectiveness of the extended-release formulation have not been established in pediatric patients (Prod Info DURLAZA(TM) oral extended release capsules, 2015).

B) CARISOPRODOL/ASPIRIN

1) 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND oral tablets, 2013).
2) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND oral tablets, 2013).

C) CARISOPRODOL/ASPIRIN/CODEINE

1) 16 YEARS AND OLDER: The recommended oral dose is 1 or 2 tablets (each tablet contains carisoprodol 200 mg/aspirin 325 mg/codeine phosphate 16 mg) 4 times per day. MAXIMUM DOSE: 2 tablets 4 times per day (total daily dose, carisoprodol 1600 mg/aspirin 2600 mg/codeine phosphate 128 mg); MAXIMUM DURATION OF USE: Up to 2 or 3 weeks (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013).
2) LESS THAN 16 YEARS: Safety and efficacy have not been established (Prod Info SOMA(R) COMPOUND with CODEINE oral tablets, 2013).

Minimum Lethal Exposure

1) CHRONIC

a) A 52-year-old man ingested an estimated 96 grams of aspirin over nine days and died despite emergency treatment (Kearney, 1989).
b) An 18-month-old boy died after receiving one baby aspirin every 4 to 6 hours for two days (Snodgrass et al, 1981).
c) A 64-year-old woman died after inadvertently receiving 7,100 milligrams of enteric coated aspirin daily for 10 days (Shkrum et al, 1989).

2) ACUTE

a) OIL OF WINTERGREEN

1) Five milliliters of oil of wintergreen is equivalent to approximately 7000 milligrams of salicylate (Botma et al, 2001). Fatalities have been reported in children following methyl salicylate exposure with the lowest reported dose being 4 mL in 2 children (17 months and a 2-year-old) (Davis, 2007)
2) A 2-year-old boy ingested approximately 7.5 milliliters of oil of wintergreen and died. He died before receiving treatment (MacCready, 1943).
3) A 21-year-old man died after ingesting 6 mL of oil of wintergreen (Davis, 2007).
4) A 44-year-old man died after accidentally ingesting 30 milliliters of oil of wintergreen (Cauthen & Hester, 1989).

b) PEPTO-BISMOL

1) A 4-year-old girl died after ingesting 3 ounces of Pepto-Bismol(R) (Fisher et al, 1985).

Maximum Tolerated Exposure

1) ACUTE

a) The acute ingestion of less than 150 mg/kg or 6.5 g of aspirin equivalent, whichever is less, is not expected to cause significant toxicity. For oil of wintergreen (98% methylsalicylate), greater than a lick or taste by children under 6 years of age or greater than 4 mL by patients 6 years of age and older may cause toxicity and requires referral to an emergency department for evaluation (Chyka et al, 2007).
b) Acutely, less than 150 mg/kg of ASA will result in mild to moderate GI symptoms and mild irritability. Moderate intoxication can occur after ingesting 150 to 300 mg/kg and serious effects are likely after ingesting greater than 300 mg/kg (Temple, 1981).

1) OIL OF WINTERGREEN

a) Oil of wintergreen, a flavoring agent, is approximately 98% methyl salicylate and has caused severe toxicity and death in both adults and children.
b) PEDIATRIC: A 2-year-old girl survived after ingesting 15 to 30 milliliters of oil of wintergreen. She was treated with fluid therapy only (MacCready, 1943).
c) CASE REPORTS: There have been several reports in the literature of young children (2 to 3.5 years old) surviving an estimated oil of wintergreen ingestions of 30 to 60 mL, but these children underwent aggressive therapy including exchange transfusion or peritoneal dialysis (Davis, 2007).

2) TOPICAL SALICYLIC

a) CASE REPORT: A 2-month-old infant, with crusta lactea, developed salicylate toxicity after inadvertently being treated with an occlusive dressing containing 50% salicylic acid applied for 3 days. Laboratory evaluation showed metabolic acidosis (pH 7.33, base excess -13 mM/L), a normal calculated anion gap (3.5 mM/L) and hyperchloremia (chloride 129 mmol/L). A salicylate level of 42.5 mg/dL was obtained 48 hours after the last topical application. The infant recovered completely following forced diuresis and urinary alkalinization. In this case, the diagnosis of salicylate toxicity was initially difficult due to a falsely elevated chloride level which was caused by laboratory interference in the presence of an elevated salicylate level. Its suggested that some ion-selective electrodes may be more susceptible due to a loss of selectivity of the chloride electrode following chronic use and possible competition between salicylate and chloride ions to bind to albumin (Vazquez Martinez et al, 2015).
b) CASE REPORT: A newborn with ichthyosis (characterized by excessive scales on the skin) was treated with salicylic vaseline from day 1 through the 9th day of life and developed salicylate toxicity. A topical 20% salicylate in petrolatum was applied twice daily over most of the body. Salicylate concentration on day 7 was 119 mg/dL (therapeutic: 15 to 30 mg/dL). Following supportive care, including peritoneal dialysis and mechanical ventilation, the infant was discharged with no neurologic deficit except for moderate abnormal auditory brainstem response on day 57 (Yamamura et al, 2002).

1) The most serious salicylate poisoning results from too frequent or excessive administration of the drug for therapeutic purposes (Done & Temple, 1971; Done, 1978). Chronic salicylism is associated with greater morbidity in adults (Anderson et al, 1976) and children (Gaudreault et al, 1982). All suspected chronic poisonings should be evaluated by a physician.
2) Chronic ingestion of greater than 100 mg/kg/day over 2 or more days is thought to be associated with toxicity (Temple, 1981).
3) Doses of 150 mg/kg and 95 mg/kg used for 2 weeks have been associated with toxicity in children (Evereson & Krenzelok, 1986) (Quint & Allman, 1984).
4) CASE REPORT (INFANT): A 3-month-old infant developed vomiting, tachycardia, tachypnea, metabolic acidosis, and CNS depression following chronic administration of a product containing bismuth subsalicylate, up to 15 mL/day (equivalent to 86 mg/kg of aspirin) for 3.5 weeks. Following supportive care, the patient gradually recovered and was discharged without sequelae (Lewis et al, 2006).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CHRONIC

a) Plasma levels do not correlate well with clinical toxicity in chronic exposures. Clinical determinations such as acid base status and mental status should be used.
b) Plasma concentrations greater than 15 milligrams percent (1.08 millimoles/liter) may be associated with salicylism in chronic exposure (Segar, 1969).

2) ACUTE

a) In one study examining features of 2204 cases of acute salicylate overdose in adults over an 11-year period, 90 patients survived despite peak salicylate concentrations of 700 milligrams/liter or greater (Chapman & Proudfoot, 1989). The seven patients who died did not have significantly higher peak salicylate concentrations, but were older, more likely to present late, and were more likely to have acidemia, coma and pulmonary edema than those who survived.
b) A 34-year-old woman died after ingesting 30 to 35 aspirin pills (estimated cumulative dose was greater than 15 g acetylsalicylate) 3 days prior to admission. Serum salicylate was 668 mg/L on admission and the patient died 6 hours later from refractory asystole (Rauschka et al, 2007).
c) A 23-year-old woman died after ingesting an unknown amount of salicylate (Ferguson & Boutros, 1970). Peak salicylate level 10 hours after ingestion was 115.2 milligrams percent.
d) According to a study conducted to compare salicylate plasma concentrations from ingestion of 1 mL Oil of Wintergreen (1060 mg salicylate) with ingestion of 6.7 g of 15% methyl salicylate cream (900 mg salicylate; "low dose") or ingestion of 20 g of 15% methyl salicylate cream (2700 mg salicylate; "high dose"), the mean peak plasma concentrations (Cp) and time to maximum concentrations (Tmax) were as follows:

Treatment	Tmax (hr)	Cp, max salicylate (mg/L)
Oil	2.4	70
Low dose	2.4	42
High dose	7	145

1) The relative bioavailability following ingestion of the low-dose cream was 0.5 as compared to ingestion of the oil of wintergreen, thereby resulting in a lower Cp at the same Tmax. The difference in the Tmax values indicate slower absorption of the high dose treatment as compared to the other two treatments, suggesting a dose-dependent absorption rate (Wolowich et al, 2003).

e) OIL OF WINTERGREEN

1) A "swallow" of oil of wintergreen by a 21-month-old male infant produced a blood salicylate level of 81 mg/dL 6 hours after ingestion. Signs included hyperpnea and restlessness, and he was treated with aggressive fluid administration with a good outcome (Howrie et al, 1985).
2) A 44-year-old man who died after accidentally ingesting 30 milliliters of wintergreen oil had a blood salicylate level of 78.3 milligrams/deciliter (Cauthen & Hester, 1989).
3) Accidental ingestion of Oil of Wintergreen by an 18-month-old girl produced a blood salicylate level of 4.8 millimoles/liter (12 hours post-ingestion) (Botma et al, 2001).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) SALICYLIC ACID, ACETATE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 167 mg/kg (RTECS, 2001)

2) LD50- (ORAL)MOUSE:

a) 250 mg/kg (RTECS, 2001)

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 1020 mg/kg (RTECS, 2001)

4) LD50- (INTRAPERITONEAL)RAT:

a) 340 mg/kg (RTECS, 2001)

5) LD50- (ORAL)RAT:

a) 200 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Toxicologic Mechanism

1) Nausea and vomiting is mediated via both local gastric irritation and stimulation of the medullary chemoreceptor trigger zone (Smith, 1960).

1) The major manifestations of salicylate intoxication result from the deleterious effects on cellular metabolism. Salicylates uncouple mitochondrial oxidative phosphorylation (Miyahara & Karler, 1965) and inhibit specific Krebs Cycle dehydrogenases (Kaplan et al, 1954). Increased metabolism and peripheral demand for glucose have been demonstrated.
2) The overall effect is hyperthermia, increased production, accumulation and excretion of organic acids resulting in an anion gap metabolic acidosis (Schwartz & Landy, 1965).

1) Salicylates stimulate respiration directly and indirectly. Salicylates directly stimulate the CNS respiratory center in the medulla and is independent of the aortic and carotid chemoreceptor areas (Smith, 1968).
2) Salicylates also uncouple mitochondrial oxidative phosphorylation (Miyahara & Karler, 1965) resulting in an increase in oxygen consumption and CO2 production, primarily in skeletal muscle. The increased production of CO2 stimulates respiration.
3) A compensatory increase in renal excretion of base in the form of bicarbonate ensues in an attempt to normalize arterial pH (compensated respiratory alkalosis).

1) Thurston et al (1970) found that large doses of salicylate profoundly decreased brain glucose concentrations in mice despite normoglycemia and may explain some of the CNS disturbances following intoxication.
2) Seizures may occur as a consequence of severe intoxication (Done, 1960). The exact etiology is unclear but may result from excessive accumulation of carbon dioxide in the CNS (Smith, 1968), decreased brain glucose concentration (Thurston et al, 1970), or a direct toxic effect.
3) CASE REPORT: Evidence of pulmonary edema, cardiac dilatation and venous congestion with acute white matter pathology was present in a woman following lethal salicylate toxicity. She had a history of mental retardation and fetal alcohol syndrome. White matter damage was characterized by myelin disintegration and glial caspase-3 activation, which may have a role in the pathological substrate of cerebral dysfunction observed in severe salicylate intoxication. Histopathology results may have been affected by a delay in the autopsy (Rauschka et al, 2007).

a) The authors suggest that the potential pathophysiology associated with white matter damage following intoxication include: the induction of mitochondrial permeability transition by opening pores in the inner membrane leading to an uncoupling of oxidative phosphorylation and metabolic acidosis and may also release proteins such as apoptosis inducing factors or cytochrome which can initiate the caspases cascade. Other effects may include tissue acidosis which is known to induce selective glial cell death and directly destabilizes myelin sheaths due to direct salicylate toxicity.

1) Small doses of aspirin increase bleeding time significantly (Weiss & Aledort, 1967). A single dose of 650 mg reportedly doubled the mean bleeding time for a period of 4 to 7 days in normal humans and is due to inhibition of platelet cyclo-oxygenase (Gilman et al, 1980).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

Clinical Effects

11.1.6)

A) Signs may include fever, hyperpnea, seizures, respiratory alkalosis, metabolic acidosis, methemoglobinemia, gastric hemorrhage, kidney damage, centrolobular liver necrosis, and bleeding diathesis (Abrams, 1987). Fever and hyperpnea are often the initial signs (Herrgesell, 1967).

Treatment

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOG

a) Activated charcoal 1.5 g/kg followed by gastric lavage followed by a repeat dose of charcoal reduced plasma salicylate levels by 48%, compared to 37% with a single-dose charcoal/lavage regimen and 17% with charcoal alone in dogs given an overdose of aspirin (Burton et al, 1984).

11.2.5)

A) GENERAL TREATMENT

1) Intravenous sodium bicarbonate is recommended to promote urinary excretion of salicylate. Overly aggressive bicarbonate therapy led to hypocalcemic tetany in a cat (Abrams, 1987).
2) Methylene blue or ascorbic acid (preferred in cats) may be given for methemoglobinemia.

Range Of Toxicity

11.3.1)

A) CAT

1) Doses of 25 mg/kg/day produced serum salicylate levels in the therapeutic range and did not result in any adverse effects when given for up to 4 weeks (Eder, 1964).

11.3.2)

A) CAT

1) Doses of 5 grains (325 mg) twice a day were lethal to cats (Herrgesell, 1967).

B) DOG

1) Erosive gastritis has been seen after a single 5 grain dose (Fishler, 1963).

Continuing Care

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOG

Kinetics

11.5.1)

A) LACK OF INFORMATION

1) There was no specific information on absorption at the time of this review.

11.5.4)

A) CAT

1) The half-life was found to be dose-dependent, similar to humans. The apparent elimination half-life was 21.8, 26.8, and 44.6 hours after doses of 5, 12.5, and 25 mg/kg, respectively (Yeary & Swanson, 1973).

References

General Bibliography

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

178)

179)

180)

181)

182)

183)

184)

185)

186)

187)

188)

189)

190)

191)

192)

193)

194)

195)

196)

197)

198)

199)

200)

201)

202)

203)

204)

205)

206)

207)

208)

209)

210)

211)

212)

213)

214)

215)

216)

217)

218)

219)

220)

221)

222)

223)

224)

225)

226)

227)

228)

229)

230)

231)

232)

233)

234)

235)

236)

237)

238)

239)

240)

241)

242)

243)

244)

245)

246)

247)

248)

249)

250)

251)

252)

253)

254)

255)

256)

257)

258)

259)

260)

261)

262)

263)

264)

265)

266)

267)

268)

269)

270)

271)

272)

273)

274)

275)

276)

277)

278)

279)

280)

281)

282)

283)

284)

285)

286)

287)

288)

289)

290)

291)

292)

293)

294)

295)

296)

297)

298)

299)

300)

301)

302)

303)

304)

305)

306)

307)

308)

309)

310)

311)

312)

313)

314)

315)

316)

317)

318)

319)

320)

321)

322)

323)

324)

325)

326)

327)

328)

329)

330)

331)

332)

333)

334)

335)

336)

337)

338)

339)

340)

341)

342)

343)

344)

345)

346)

347)

348)

349)

350)

351)

352)

353)

354)

355)

356)

357)

358)

359)

360)

361)

362)

363)

364)

365)

366)

367)

368)

369)

370)

371)

372)

373)

374)

375)

376)

377)

378)

379)

380)

381)

382)

383)

384)

385)

386)

387)

388)

389)

390)

391)

392)

393)

394)

395)

396)

397)

398)

399)

400)

401)

402)

403)

404)

405)

406)

407)

408)

409)

410)

411)

412)

413)

414)

415)

416)

417)

418)

419)

420)

421)

422)

423)

424)

425)

426)

427)

428)

429)

430)

431)

432)

433)

434)

435)

436)

437)

438)

439)

440)

441)

442)

443)

444)

445)

446)

447)

448)

449)

450)

451)

452)

453)

454)

455)

456)

457)

458)

459)

460)

461)

462)

463)

464)

465)

466)

467)

468)

469)

470)

471)

472)

473)

474)

475)

476)

477)

478)

479)

480)

481)

482)

483)

484)

485)

486)

487)

488)

489)

490)

491)

492)

493)

494)

495)

496)

497)

498)

499)

500)

501)

502)

503)

504)

505)

506)

507)

508)

FeedBack

SALICYLATES

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

General Bibliography