Aspirin as a Risk Factor in Reye's Syndrome

Waldman, Ronald J.

doi:10.1001/jama.1982.03320470035029

Cited by 183 publications

(72 citation statements)

References 26 publications

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“…The syndrome, usually seen in children, presents as an acute, noninflammatory encephalopathy with cerebral edema and fatty metamorphosis of the liver. Although the etiology of RS remains unknown, epidemiologic studies suggest that the administration of acetylsalicyclic acid (ASA) during the prodromal viral illness increases the risk of development of RS (4)(5)(6). While the association has been questioned, governmental agencies have advised against the use of salicylate-containing medications for children with influenza or chickenpox (3).…”

mentioning

confidence: 99%

Dose-related effect of acetylsalicylic acid on replication of varicella zoster virus in vitro.

Walz-Cicconi¹,

Weller²

1984

Proc. Natl. Acad. Sci. U.S.A.

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Cultivation of human embryonic lung (HEL) cells in media containing acetylsalicylic acid (ASA) at 100 pg/ml and maintenance at this level after inoculation with either cell-free varicella zoster virus (VZV) or virus-infected cells resulted in a 2-to 4-fold increase in yields of cell-free virus released by sonication. The degree of enhancement was dependent upon multiplicity of infection and time of harvest. Enhanced viral yields were not consistently accompanied by an increase in the number of infected cells, nor was VZV plaque formation in HEL indicator cells significantly increased in the presence of ASA at 100 pg/ml. In the presence of ASA at 500-1000 pug/ml, VZV plaque formation was inhibited; this inhibition was partially reversible, depending on concentration and period of exposure to ASA. These findings may bear on the apparent association between ASA ingestion and the development of Reye syndrome after infection with varicella virus. METHODS AND MATERIALSTissue Culture and Virus. Two lines of human embryonic lung (HEL) fibroblast cultures were prepared and maintained on Eagle's minimal essential medium supplemented with 2% fetal calf serum, penicillin at 100 units/ml, streptomycin at 100 ,ug/ml, or gentamicin at 100 ,ug/ml. One line was used in the 4th to the 10th passage and the other in the 22nd to the 39th passage. The strain of VZV was isolated from a patient with varicella and used after 19-55 cultural passages. Stock virus was prepared and cell-free virus was concentrated with polyethylene glycol 6000 as previously described (7).Harvest of Virus. Virus-infected cells were harvested by washing infected cultures maintained in 25-cm2 Corning flasks with phosphate-buffered saline and incubating for 5-10 min with 1.0 ml of 0.25% trypsin in phosphate-buffered saline at 370C; the detached cells were then transferred to 10% fetal calf serum in phosphate-buffered saline to inactivate residual trypsin, centrifuged at 180 x g for 10 min, resuspended in 1.0 ml of Eagle's minimal essential medium, and kept at 40C. Cell-free virus was obtained from three cultural sources: (i) Growth medium. Five milliliters of growth medium was removed from infected cultures maintained in 25-cm2 flasks and centrifuged at 400 x g for 15 min, and the supernatant was kept at 40C. (ii) Glass bead treatment. Infected cells were harvested mechanically by addition of 10-15 glass beads (2-3 mm in diameter) and 0.5 ml of SPGA medium (8) to each flask; after gentle shaking the freed cells were removed and the flask was rinsed twice with 0.5 ml of SPGA; the cells and washings were centrifuged at 600 x g for 15 min, and the supernatant containing virus was kept at 40C.(iii) Sonicated infected cells. The cellular sediment after centrifugation was resuspended in 1.0 ml of SPGA, sonicated in a 40-ml conical centrifuge tube with the microtip of a model W 200 Heat Systems sonicator (60% power, 10-15 sec), and centrifuged at 600 x g for 15 min, and the supernatant fluid was kept at 4°C. The total amount of cell-free virus mechanically re...

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mentioning

confidence: 99%

Dose-related effect of acetylsalicylic acid on replication of varicella zoster virus in vitro.

Walz-Cicconi¹,

Weller²

1984

Proc. Natl. Acad. Sci. U.S.A.

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“…6,22 Reports of studies in Ohio and Michigan also implicated salicylate. [23][24][25] In 1983, Starko and Mullick reported hepatic microvesicular fat patterns in children with therapeutic salicylate intoxication, findings previously reported with RS. 26 In 1988, clinical risks were reported with increasing daily aspirin doses at all levels below "recommended" (65-80 mg/kg/day) doses and were also associated with dosing on days three and four.…”

Section: Reye's Syndromementioning

confidence: 98%

“…27 Efforts to raise awareness of the link between aspirin and RS included journal publications; warning statements in 1982 by CDC consultants, the American Academy of Pediatrics, and the United States' Surgeon General; and a "Black Box" warning in 1986 advising against administering aspirin to children and teenagers with chicken pox or flu symptoms without consulting a physician. 6,24,25,[27][28][29][30][31][32][33] The British Risk Factor Study found excess aspirin exposure in RS children and a 1986 advisory by the Committee on Safety of Medicines warned against administering aspirin to children under twelve. 34 Warning labeling on aspirin containing preparations was introduced, and modified in 2003 to warn against giving aspirin to children under sixteen without consulting a physician.…”

Section: Reye's Syndromementioning

confidence: 99%

Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

et al. 2012

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Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common

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“…A small increase in dose or slowed excretion due to evolving renal dysfunction can cause a greatly prolonged elimination time, and a disproportionate increase in serum salicylate concentration with 97 attendant severe toxicity. The serum half-life of salicylate is typically 2-4 hours at low doses, approximately 12 hours with anti-inflammatory doses, and can be prolonged to [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] hours or more following overdosage. Approximately 2-30% of salicylate is excreted unchanged in the urine, with less renal excretion occurring in acidic urine or in patients with renal dysfunction (5,10).…”

Section: Pharmacokinetics and Pathophysiology Of Salicylate Toxicitymentioning

confidence: 99%

“…Although therapeutic doses of salicylate can sometimes cause adverse effects in adults and children-some idiosyncratic and some dose-dependentthese cases are not considered. The management of Reye's syndrome associated with aspirin use in children is beyond the scope of this guideline (24). It does not address bismuth toxicity resulting from bismuth subsalicylate ingestion.…”

Section: Objective Of This Guidelinementioning

confidence: 99%

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

Chyka

Erdman

Christianson

et al. 2007

Clinical Toxicology

115

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American Association of Poison Control Centers, Washington, District of Columbia, USAA review of U.S. poison center data for 2004 showed over 40,000 exposures to salicylate-containing products. A guideline that determines the conditions for emergency department referral and pre-hospital care could potentially optimize patient outcome, avoid unnecessary emergency department visits, reduce health care costs, and reduce life disruption for patients and caregivers. An evidence-based expert consensus process was used to create the guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the lead author. The entire panel discussed and refined the guideline before distribution to secondary reviewers for comment. The panel then made changes based on the secondary review comments. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial out-of-hospital management of patients with a suspected exposure to salicylates by 1) describing the process by which a specialist in poison information should evaluate an exposure to salicylates, 2) identifying the key decision elements in managing cases of salicylate exposure, 3) providing clear and practical recommendations that reflect the current state of knowledge, and 4) identifying needs for research. This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. This guideline does not substitute for clinical judgment. Recommendations are in chronological order of likely clinical use. The grade of recommendation is in parentheses: 1) Patients with stated or suspected self-harm or who are the victims of a potentially malicious administration of a salicylate, should be referred to an emergency department immediately. This referral should be guided by local poison center procedures. In general, this should occur regardless of the dose reported (Grade D).2) The presence of typical symptoms of salicylate toxicity such as hematemesis, tachypnea, hyperpnea, dyspnea, tinnitus, deafness, lethargy, seizures, unexplained lethargy, or confusion warrants referral to an emergency department for evaluation (Grade C). 3) Patients who exhibit typical symptoms of salicylate toxicity or nonspecific symptoms such as unexplained lethargy, confusion, or dyspnea, which could indicate the development of chronic salicylate toxicity, should be referred to an emergency department (Grade C). 4) Patients without evidence of self-harm should have further evaluation, including determination of the dose, time of ingestion, presence of symptoms, history of other medical conditions, and the presence of co-ingestants. The acute ingestion of more than 150 mg/kg or 6.5 g of aspirin equivalent, whichever is less, war...

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Aspirin as a Risk Factor in Reye's Syndrome

Cited by 183 publications

References 26 publications

Dose-related effect of acetylsalicylic acid on replication of varicella zoster virus in vitro.

Dose-related effect of acetylsalicylic acid on replication of varicella zoster virus in vitro.

Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR)

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

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