Serum Salicylate Concentration Research Articles

The trajectory of serum salicylate concentrations after ingestion of medicinal oil containing methyl salicylate

Introduction The toxicokinetics of methyl salicylate after unintentional or intentional ingestion of medicinal oil containing methyl salicylate has not been well studied. We aimed to characterize the trajectory of serum salicylate concentrations and to evaluate factors associated with the peak serum salicylate concentration and the time from ingestion to peak concentration. Methods This was a retrospective cohort study of consecutive patients reported to the Hong Kong Poison Control Centre for laboratory-confirmed methyl salicylate poisoning by all local public emergency departments between 1 July 2008 and 30 June 2023. We analyzed cases with at least three serum salicylate concentrations. Multivariable generalized linear regression was used to identify factors significantly associated with the peak serum concentration and the time from ingestion to peak concentration. Results We included 41 patients (median age 81.0 years; 32 women and nine men). The median time from ingestion to the first peak serum salicylate concentration was 5.6 h (IQR: 3.2–10.8 h). Multiple regression showed that gastric aspiration (adjusted regression coefficient [β] − 2.50; 95% CI: −3.93 to −1.08; P = 0.001) and single-dose activated charcoal (adjusted β − 1.22; 95% CI: −2.02 to −0.42; P = 0.003) were significantly associated with a lower peak concentration, after adjusting for patient age, sex, exposure due to intentional self-harm, reported ingested dose, time from ingestion to emergency department presentation, vomiting, concurrent use of aspirin (acetylsalicylic acid) and other medications that affect gastric emptying or gastric acid secretion, blood pH, serum albumin concentration, and creatinine clearance. Discussion The serum salicylate concentration did not peak as quickly as generally believed, highlighting the importance of continued monitoring. Gastric aspiration and single-dose activated charcoal may help reduce gastrointestinal absorption, but their impact on clinical outcomes remains unclear. Conclusions Given the median time of 5.6 h (IQR: 3.2–10.8 h) from ingestion to the peak salicylate concentration, gastric aspiration and single-dose activated charcoal can be considered in patients up to a few hours after medicinal oil ingestion when the airway is protected.

Severe Salicylate Poisoning Due to Teaberry Flavoring Ingestion: A Case Report

BackgroundCurrently there are many commercial uses of methyl salicylate including fragrances, flavoring, topical pain relief, and polymer restoration. Most recorded instances of human toxicity due to methyl salicylate are the result of topical or accidental exposures. However, this is a previously unreported case of an adult patient who intentionally ingested teaberry flavoring causing life-threatening salicylism. Case ReportA 22-year-old man presented to the Emergency Department with the chief complaint of nausea, vomiting and abdominal pain. Triage nursing noted the patient's vomit smelled strongly of wintergreen. Further history indicated the patient had ingested approximately 40 mL of teaberry oil while using it to make ice cream. The initial serum salicylate concentration was 111 mg/dL. The medical toxicology team was consulted, and the patient was given a singular dose of activated charcoal by mouth. He was also administered both an intravenous sodium bicarbonate bolus and sodium bicarbonate infusion. He was admitted to the intensive care unit while the nephrology service was consulted to initiate emergent hemodialysis (hD). After the single hD treatment with concomitant serum and urine alkalization, the patient had progressive improvement of salicylate concentrations. He was discharged on hospital day three in normal condition. Why should an emergency physician be aware of this?Emergency physicians should be aware of novel etiologies of life-threatening salicylate poisoning.

Tracheal Intubation and Mechanical Ventilation in Adults with Severe Salicylate Poisoning

BackgroundSalicylate poisoning may lead to critical acid–base disturbances. Tracheal intubation and mechanical ventilation for patients with severe salicylism has been strongly discouraged. Study ObjectiveThis study aims to describe pH trends, complications, and outcomes in a cohort of salicylate-poisoned patients who were intubated. MethodsThis retrospective observational study included adults presenting to the emergency department (ED) with severe salicylate poisoning (serum salicylate concentration >40 mg/dL and admission to an intensive care unit) over a 14-year period (2007–2021). The primary and secondary outcomes were the change in serum pH and the occurrence of severe complications (systolic blood pressure <80 mm Hg, oxygen saturation <80%, or cardiac arrest), respectively, in the 6 h after presentation. ResultsAmong 32 adults with severe salicylate poisoning (median serum salicylate level 64.2, interquartile range 52.5–70.7), 11 (34%) underwent tracheal intubation. The initial mean pH (±SD) in the no intubation group was 7.48 ± 0.07 and was 7.36 ± 0.04 in the intubation group. The mean absolute difference in pH measured before and after intubation was -0.02 (95% confidence interval −0.11 to 0.07). No severe complications were observed during or up to 6 h after tracheal intubation and mechanical ventilation. ConclusionIn our single-center experience managing adults with severe salicylate poisoning, tracheal intubation and mechanical ventilation were not associated with substantial perturbation of serum pH or severe complications. These findings challenge the current paradigm that these interventions should be avoided in salicylate-poisoned patients.

Short-term salicylate treatment improves microvascular endothelium-dependent dilation in young adults with major depressive disorder.

Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [NG-nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before (P = 0.023), but not after (P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline (R2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before (P < 0.01), but not after (P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression.NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.

Coagulopathy and bleeding associated with salicylate toxicity

Introduction: Salicylate toxicity is a common cause of morbidity and hospitalization. Animal and human studies suggest that salicylates cause a dose-dependent inhibition of the activation of factors 2, 7, 9, and 10. However, limited reports of coagulopathy or major bleeding from salicylate toxicity exist.Methods: This is a retrospective study examining subjects from January 1, 2001 to December 31, 2011 in whom at least one serum salicylate concentration was measured above 30 mg/dL. Cases were patients with elevated salicylate concentration and coagulopathy (INR > 1.5). Major bleeding cases were those with elevated salicylate concentration who developed hemorrhagic death; or bleeding from an intracranial, intraspinal, intraocular, retroperitoneal, pericardial, intramuscular site; or hemoglobin decrease of >2 g/dL, or transfusion of at least 2 units of packed RBCs during hospitalization.Results: Twelve percent of all cases of elevated salicylate concentration developed coagulopathy, 6% developed major bleeding, and 3% died. In a multivariate model, duration of elevated salicylate concentration and renal impairment were associated with coagulopathy and no variable was associated with major bleeding. Patients were more likely to develop major bleeding if they had coagulopathy, but not all cases of major bleeding had coagulopathy.Discussion: Coagulopathy and major bleeding during salicylate toxicity has been underrecognized. Renal impairment and duration of salicylate elevation contribute to the risk of coagulopathy, but no factors predict major bleeding. Patients with coagulopathy have a high risk of bleeding but some bleeding occurs without coagulopathy, suggesting that other factors, such as platelet dysfunction, may play a role.Conclusion: Coagulopathy and major bleeding develop in a clinically relevant percentage of cases of salicylate toxicity.

Salicylate toxicity after undetectable serum salicylate concentration: a retrospective cohort study

Background: Salicylates are usually rapidly absorbed and quickly measurable in serum. An undetectable serum salicylate concentration ([ASA]) may occur early after ingestion and may be interpreted as evidence of non-exposure and not repeated. Although cases of delayed salicylate detection are reported rarely, the risk factors associated with this phenomenon are not known.Research question: What factors are associated with an early undetectable [ASA] in salicylate poisoning?Methods: Records from a single regional poison center were searched from 2002 to 2016 for cases of salicylate toxicity treated with bicarbonate and [ASA] > 30 mg/dL. Cases were excluded if initial [ASA] was obtained >4 h after presentation. Case information, serial [ASA], and outcomes were recorded and compared between groups.Results: A total of 313 records met all criteria with 11 initially undetectable [ASA] (3.5%) and 302 detectable [ASA] (96.5%). Time of first [ASA] occurred sooner in the undetectable [ASA] group (89 vs. 137 min, p = 0.011) while time to peak [ASA] was longer (640 vs. 321 min, p < .001). The longest interval between ingestion and undetectable [ASA] was 225 min. Peak [ASA] and reported mean ingested dose were similar in both groups (45 vs. 50 mg/dL, p = NS; 19.7 g vs. 32.9 g, p = NS). Coingestion of agents that delay gastric emptying were similar in both groups (18% [2/11] vs. 25% [76/302], p = NS, chi-square). Hemodialysis was performed in 9% (1/11) of undetectable [ASA] patients and 5.6% (17/302) of detectable [ASA] patients (p = NS, chi-square). A single death occurred in the entire cohort in a patient with an initially detectable [ASA].Discussion: In this series, a small but significant proportion (3.5%) of patients who developed [ASA] > 30 mg/dL had an initially undetectable [ASA]. Those with an undetectable [ASA] were measured earlier after ingestion with a longer time to peak [ASA]. However, neither coingestion of agents prolonging gastric emptying nor reported dose ingested was different between groups. Formulation was infrequently recorded but one undetectable [ASA] did ingest a non-enteric coated product. Limitations include the small number of patients with undetectable [ASA], use of single poison center data and partial data on co-ingestants and aspirin formulation.Conclusions: [ASA] may be undetectable early after an overdose and need for serial [ASA] in the evaluation of salicylate ingestion should be further explored. Additional research is needed to determine any causative factors and the optimal timing of [ASA] measurements.

Acute respiratory distress syndrome caused by salicylate intoxication.

Key Clinical MessageSalicylate‐induced acute respiratory syndrome (ARDS) is a well‐known entity occurring in 35% of salicylate‐intoxicated patient. Careful history taking, physical examination, arterial blood gas analysis, and measurement of serum salicylate concentration will lead to early recognition to initiate appropriate treatment.

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1-knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (∼1 mmol/L). Salsalate treatment increased VO2, lowered fasting glucose, improved glucose tolerance, and led to an ∼55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.

Absorption of salicylate powders versus tablets following overdose: a poison center observational study

Background: Salicylate absorption following overdose of aspirin (ASA) tablet formulations can be prolonged for greater than 24 h. Accordingly, serial serum concentrations are typically recommended to guide treatment. However, there are little published data on absorption following ingestion of powder ASA formulations, and it is not known if delayed ASA absorption occurs following overdose of powder formulations. The objective of this study is to compare the absorption characteristics of powder and tablet formulations of ASA in patients reported to a single poison center.Methods: Electronic records from an accredited poison center were searched for single substance acute or acute on chronic ingestions of ASA in powder form between 1 January 2002 and 31 January 2014. An identical search for ingestions of ASA tablet products between 1 January 2012 and 31 December 2013 was undertaken as the comparator group. Other inclusion criteria were age >12 years, documented time of ingestion, treatment in a health care facility within nine hours of ingestion and at least two detectable serum salicylate concentrations.Results: 16 of 25 powder and 22 of 49 tablet cases met inclusion criteria for analysis. Repeat serum salicylate concentrations following ingestion of tablets increased or insignificantly changed in 11 of 22 (50%) cases, and median serum salicylate concentrations in followed cases remained elevated for up to 12 h in some cases. In comparison, serum salicylate concentrations following powder ingestions declined in 15 of 16 (94%) cases. One patient, who ingested a powder product, underwent hemodialysis pursuant to an initial serum salicylate concentration of 96 mg/dL.Conclusions: In contrast to persistent concentrations following overdose of tablets, the majority of serum salicylate concentrations declined following ingestion of powder formulations. In this small study population, these findings suggest that prolonged absorption is unlikely following ingestions of ASA powders.

Comparison of three aspirin formulations in human volunteers.

IntroductionThe treatment of acute coronary syndrome (ACS) includes the administration of aspirin. Current guidelines recommend chewing aspirin tablets to increase absorption. While this is intuitive, there are scant data supporting this recommendation. The purpose of this study is to assess which of 3 different aspirin formulations is most rapidly absorbed after ingestion.MethodsA prospective, open-label, 3-way crossover volunteer study at a tertiary university medical center with human subjects 18 years or older. Fasted subjects were randomly assigned to receive aspirin 1,950 mg as (1) solid aspirin tablets swallowed whole, (2) solid aspirin tablet chewed then swallowed, or (3) a chewable aspirin formulation chewed and swallowed. Serum salicylate measurements were obtained over a period of 180 minutes. Pharmacokinetic parameters were determined.ResultsThirteen males and 1 female completed all 3 arms of study. Peak serum salicylate concentrations were seen at 180 minutes in all groups. Mean peaks were 10.4, 11.3, and 12.2 mg/dL in groups 1, 2, and 3, respectively. Mean area under the time concentration was 1,153, 1,401, and 1,743 mg-min/dL in groups 1, 2, and 3, respectively. No measurable salicylate concentrations were seen in 6 subjects in group 1 at 60 minutes as compared to 1 subject in group 2. All subjects in group 3 had measurable levels at 45 minutes. There were no adverse effects in any of the subjects during the study period.ConclusionOur data demonstrate that the chewable aspirin formulation achieved the most rapid rate of absorption. In addition, the chewable formulation absorption was more complete than the other formulations at 180 minutes. These data suggest that in the treatment of ACS, a chewable aspirin formulation may be preferable to solid tablet aspirin, either chewed or swallowed.

Serum Concentration-Dependent Hepatotoxicity in Individuals Receiving Oral Salsalate

To the Editor, Salsalate, an older, ‘‘safer’’ oral nonsteroidal anti-inflammatory agent is a nonacetylated dimer of salicylic acid with an established safety profile in treatment of inflammatory conditions. It has been under consideration by the Food and Drug Administration (FDA) for over-the-counter (OTC) sale as an oral analgesic, antipyretic, and antirheumatic drug product since 1972. There is however, renewed interest in this drug as recent studies have shown that salsalate not only improves glycemic and inflammatory parameters in young obese adults but also improves body composition and metabolic alteration in human immunodeficiency virus (HIV) lipodystrophy by inhibiting nuclear factor kappa-B (NF-jB), a central integrator of proinflammatory signals [1, 2]. Since the product is inexpensive and generic, several National Institutes of Health (NIH)-funded clinical trials with salsalate are ongoing to test its effect on subacute inflammation and coronary plaque (TINSAL-T2D; NCT00624923), insulin resistance (NCT00330733), and bed-rest-induced vascular dysfunction (NCT00553995). The usual dosage for salsalate is 3,000 mg daily, given in divided doses. Some of the reversible adverse reactions reported in clinical trials such as tinnitus, nausea, hearing impairment, rash, and vertigo appear to occur more commonly with serum concentration above 30 mg/dl. Although a range of liver test abnormalities from asymptomatic elevation in transaminases to fatal fulminant hepatic failure have been reported with nonsteroidal anti-inflammatory drug (NSAID) use, data regarding salsalate specifically are sparse [4, 5]. These reactions were generally felt to be idiosyncratic in nature and independent of dose. We recently conducted a clinical trial using salsalate and wish to report our experience with salsalate-induced liver injury that exhibited a relationship with serum salsalate concentrations. In order to test the hypothesis that salsalate may improve the endothelial dysfunction that is frequently seen in patients with underlying HIV infection, we conducted a prospective study, approved by our institutional review board [3]. Eleven adults with documented HIV infection (CD4 count C 350/ll) not receiving any antiretroviral therapy and no known underlying liver disease were enrolled into this study. Each participant received 1,500 mg salsalate (Disalcid , 3M Pharmaceuticals, CA, USA) orally twice daily (the maximum daily dose approved by the FDA) with intended duration of treatment of 8 weeks. Serum liver chemistries, serum salicylate levels, and flow-mediated dilation of brachial artery (to measure endothelial function) were measured at baseline, and at 4 and 8 weeks after the initiation of salsalate treatment. The baseline characteristics were: mean age 37 ± 10 years, eight males, mean body mass index (BMI) 26.4 ± 7.8 kg/m, aspartate aminotransferase (AST) 25 ± 5 IU/l, alanine aminotransferase (ALT) 22 ± 9 IU/l, alkaline phosphatase 71 ± 18 IU/l, and total bilirubin 0.8 ± 0.3 mg/dl. During the study period, four patients developed elevated aminotransferases by 4 weeks following the initiation of salsalate whereas another seven participants exhibited no increase in liver biochemistries (Table 1). Two of the subjects with elevated aminotransferases had associated symptoms consisting of nausea, vomiting, fever, fatigue, and abdominal discomfort between weeks 2 and 3 after the initiation of therapy. Serum salicylate concentration measured 24–48 h after stopping the salsalate was R. Juluri S. Gupta R. Vuppalanchi (&) Division of Gastroenterology, Indiana University School of Medicine, 1050 Wishard Blvd., RG 4100, Indianapolis, IN 46202, USA e-mail: rvuppala@iupui.edu

Mechanical Ventilation Was Associated with Acidemia in a Case Series of Salicylate‐poisoned Patients

Despite little empiric evidence, mechanical ventilation (MV) in the setting of salicylate poisoning is considered by many to be harmful. When salicylate-poisoned patients are ventilated at conventional settings, the respiratory alkalosis is abolished, more salicylate is able to pass into the central nervous system (CNS), and neurotoxicity worsens. The objective of this study was to identify a relationship between MV, acidosis, and outcome in salicylate-poisoned patients. The authors electronically searched a poison control center (PCC) database (2001-2007) for patients with salicylate poisoning, defined as a serum concentration > 50 mg/dL, who had MV listed as a therapy. For the 7-year study period, a total of 3,144 salicylate-poisoning cases were identified. Eleven patients met the inclusion criteria of having both salicylate concentrations > 50 mg/dL and required MV; only 7 of them had post-MV data available. In all seven patients with post-MV blood gas data, the post-MV pH was < 7.4. In five of six patients with recorded PCO2, the post-MV PCO2 was > 50 mm Hg. Two of the seven patients in the study group died following intubation (two patients died within 3 hours [serum salicylate concentrations, 85 and 79 mg/dL, respectively]). Another patient sustained severe neurologic injury (serum salicylate concentration, 84 mg/dL). The other four patients were ultimately discharged home. In the three patients with the worst clinical outcome, deterioration was reported within hours of intubation. Inadequate MV of patients with salicylate poisoning is associated with respiratory acidosis, acidemia, and clinical deterioration in this series of cases. This supports warnings about the danger of improper MV in patients with salicylate poisoning. A prospective study should be performed.

Salicylate Toxicity Associated with Administration of Percy Medicine in an Infant

Percy Medicine is a nonprescription gastrointestinal suspension containing bismuth subsalicylate as the active ingredient (1050 mg/10-ml dose). A 3-month-old infant with colic developed salicylate toxicity requiring hospitalization in the pediatric intensive care unit (PICU) as a result of continued administration of this medicine. Bismuth subsalicylate has an aspirin equivalency conversion factor of 0.479 (approximately half the strength of aspirin). For 3.5 weeks the infant's parents administered the medicine, which provided the equivalent of aspirin 57-84 mg/kg/day with no reported problems. However, on the day of admission the baby presented with central nervous system depression and respiratory distress. Assessment at a local emergency facility revealed metabolic acidosis; his serum salicylate concentration was 747 mg/L. After acute management, the patient was transferred to our hospital, where he was treated with whole bowel irrigation and alkalinization therapy. Subsequently, the baby required 4 days of management in the PICU and 2 additional days of observation in a general nursing unit before he was discharged home without incident. The parents had chosen Percy Medicine based on the picture of a baby on the front of the package and because of its placement on the shelf next to a drug their family physician had recommended previously. Salicylate-containing products are not routinely recommended for children aged 1 year or younger. The general public may assume that over-the-counter products are safe because they do not require a prescription. Health care professionals must be responsible for educating the public regarding risks associated with over-the-counter products and the need to read and follow label directions.

False-high blood salicylate levels in neonates with hyperbilirubinemia.

Drug assays may yield false-positive results caused by cross-reacting compounds. After finding a serum salicylate concentration of 81 microg/mL by using Trinder's colorimetric method, in a comatose child admitted to the authors' pediatric intensive care unit, in the absence of reported salicylate intake, the authors aimed to compare this situation with the phenomenon involving endogenous digoxin-like substances, which cross-react with the routine assay of digoxin. None of the participants in the study had been exposed to salicylate. Salicylate concentration was measured in all patients using Trinder's colorimetric method and in the second stage of the study also by AxSYM salicylate assay. Salicylate concentration using Trinder's method was 18 +/- 25 (4-81) microg/mL among nine seriously ill children in the pediatric intensive care unit, of whom two children with extensive burns had salicylate levels of 30 and 81 microg/mL, respectively. Salicylate concentrations were 107 +/- 24 (45-143) microg/mL and 60 +/- 25 (28-92) microg/mL, among 18 premature newborns and 18 term newborns, with hyperbilirubinemia, respectively. In the second stage, which involved 22 jaundiced term newborns and cord blood from 21 pregnant women, Trinder's method yielded elevated salicylate blood levels among the hyperbilirubinemic infants: 82 +/- 5 (73-89) microg/mL; however, the AxSYM assay yielded significantly lower blood levels: 2.5 +/- 3.4 (0-10.9) microg/mL (P < 0.0001). Among the pregnant women, salicylate cord blood levels were found to be low-within the limit error of the assay with both assay methods. In conclusion, when salicylate intoxication is suspected, particularly during the neonatal period, it is advisable to measure salicylate levels by immunoassay technology.

Serotonin and opiate involvement in the antinociceptive effect of acetylsalicylic acid.

Acetylsalicylic acid (ASA), 400 mg/kg i.p., displayed antinociceptive activity in both the hot-plate and the formalin test. ASA significantly increased brain serotonin (5-HT) content and reduced the number of 5-HT2 receptors in cortical brain membranes 30 min after drug administration. Pretreatment with naloxone abolished the antinociceptive activity of both ASA and morphine in the hot-plate and formalin tests and prevented the increase in cerebral 5-HT concentration and the reduction in 5-HT2 receptors in cortical membranes induced by ASA. The serum salicylate concentrations were not affected by pretreatment with naloxone. These data indicate a central antinociceptive activity of ASA and suggest that ASA may exert its antinociceptive action through serotonergic and opiatergic pathways.

Ototoxicity associated with salicylates. A brief review.

Aspirin, the prototype of the salicylates, is a ubiquitous agent. The availability of aspirin, other salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) as prescription and over-the-counter medications means there is a wealth of clinical experience with these agents. Among the documented adverse effects of aspirin is the potential for ototoxicity. Tinnitus and hearing loss, usually reversible, are associated with acute intoxication and long term administration of salicylates. A range of measured serum concentrations are reported as correlating with documented ototoxicity (19.6 to > 67 mg/dl). Most case reports are based on total serum salicylate concentrations whereas unbound serum salicylate concentrations appear to reflect more closely the risk of ototoxicity. The pathophysiology of toxicity may be related to biochemical and subsequent electrophysiological changes in the inner ear and eighth cranial nerve impulse transmission. Localised drug accumulation and vasoconstriction in auditory microvasculature may be mediated by the antiprostaglandin activity of these agents. Ototoxicity, although not life-threatening, may add to the morbidity of patients taking salicylates or NSAIDs in therapeutic and toxic doses.

Treatment of Kawasaki Disease using the Intravenous Aspirin Anti-inflammatory Effect of Salicylate

Serum salicylate concentrations were measured in 60 patients with acute phase Kawasaki disease (KD), who were treated with intravenous aspirin (IVASP), to evaluate its anti-inflammatory effect in the treatment of KD. Patients with serum salicylate concentrations > or = 150 micrograms/ml showed shorter durations of fever (7.1 +/- 2.0 vs 10.4 +/- 6.6 days; P < 0.05), shorter durations of positive serum C-reactive protein (14.6 +/- 4.5 vs 22.3 +/- 10.6 days; P < 0.01) and lower incidences of coronary arterial involvements (0/10 vs 6/24; P < 0.05) than did patients with serum salicylate concentrations < 150 micrograms/ml. Significant linear correlations were recognized between daily IVASP dosage and serum salicylate concentrations (r = 0.73; P < 0.01), and between serum salicylate concentrations and serum free salicylate concentrations (r = 0.82; P < 0.01). These correlations did not differ between the presence and absence of coronary arterial involvements. Based on these findings we concluded that a beneficial anti-inflammatory effect in the treatment of KD is achieved when the serum salicylate concentration is > or = 150 micrograms/ml, and that such concentrations could be achieved by increasing the daily IVASP dosage to 100 mg/kg per day or more.

Salicylate intoxication in the elderly. Recognition and recommendations on how to prevent it.

Aspirin (acetylsalicylic acid) and its salicylate derivatives are effective antipyretic, analgesic, and anti-inflammatory agents that are still very widely used by the elderly despite the advent of newer, potentially safer nonsteroidal anti-inflammatory drugs (NSAIDs). However, none of the new NSAIDs have been proven to be more effective than aspirin or salicylic acid. Chronic salicylate intoxication which is most common in the elderly, may occur with therapeutic doses. Increased toxicity in older patients often appears due to inadvertent overdosage. Dual prescribing or additional use of nonprescription salicylates are some causes of unwitting long term toxicity. According to some studies, systemic clearance of salicylate (mainly by hepatic metabolism) is reduced with age, as is renal elimination. These changes are of increased importance in the elderly using high therapeutic doses of salicylates when metabolism is saturated and more unchanged drug is available for renal excretion. In the face of renal impairment, the risk of toxicity is increased. The diagnosis of acute salicylate intoxication generally does not pose diagnostic problems. Patients often present with a history of intentional overdose, with hyperventilation, fever, and nausea. The diagnosis can be confirmed by measuring serum salicylate concentrations. Chronic intoxication often poses a diagnostic dilemma with atypical presentations mimicking other disease states such as diabetic ketoacidosis, delirium, cerebrovascular accident, myocardial infarction or cardiac failure. The diagnosis of salicylate intoxication should be borne in mind when an older patient presents with recent deterioration in activities of daily living with no known cause. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there is no documented history of salicylate ingestion. The risk of salicylate nephrotoxicity is also increased with age, and upper gastrointestinal haemorrhage is associated with increased mortality in older age groups. Treatment of acute toxicity consists of prompt recognition of salicylate intoxication, use of activated charcoal, correction of acid-base abnormalities, general supportive measures, and if concentrations are extremely high, dialysis can be effectively used. Chronic toxicity, which can occur even with marginally high salicylate concentrations, is treated with drug withdrawal and supportive therapy. Chronic salicylate toxicity can be averted by prescription of conservative doses of drug, avoidance of concomitant use of different salicylate preparations, and therapeutic monitoring to guide dosage. Renal function should be monitored to detect nephrotoxicity from chronic salicylate therapy. Patients should be regularly screened for evidence of gastrointestinal bleeding.(ABSTRACT TRUNCATED AT 400 WORDS)

Symptomatic salicylate ototoxicity: a useful indicator of serum salicylate concentration?

A three phase study was designed to define further the sensitivity and specificity of symptomatic salicylate ototoxicity (primarily tinnitus) for serum salicylate concentrations. In phase one 260 patients with osteoarthritis and 112 with rheumatoid arthritis, none taking salicylates, were interviewed about their ear symptoms. Their responses were not significantly different from those of 134 salicylate treated patients with rheumatoid arthritis previously reported. In the second phase 56 patients who were taking salicylates, and who volunteered the complaint of tinnitus, had serum salicylate concentrations measured while symptomatic, and 30 (54%) had concentrations less than 1.3 mmol/l. Few tolerated an upward salicylate dose adjustment. For phase three, 94 patients were found to have a salicylate concentration above 2.2 mmol/l on one or more occasion, and these subjects were interviewed. Fifty two patients (55%) had no tinnitus, and tinnitus correlated with the blood salicylate concentration in only 28 (30%). Audiological evaluation of most of the symptomatic patients was carried out, and results were abnormal in the majority, even in those patients not reporting tinnitus. Symptomatic salicylate ototoxicity is too nonspecific and too insensitive to be a useful indicator of serum salicylate concentration.

Salicylate treatment in Kawasaki disease: high dose or low dose?

Salicylate is the basic therapy for Kawasaki disease, however its optimal dose is controversial. We investigated the therapeutic efficacy of high dose (100 mg/kg per day, n = 30) versus low dose (30 mg/kg per day, n = 30) salicylate. Duration of fever, SGPT, serum salicylate, plasma thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) levels were compared before enrollment and on days 4, 7 and 14 of treatment. In the high dose group, duration of fever was significantly shorter than that of the low dose group (3.2 +/- 0.3 versus 5.4 +/- 0.8 days, P less than 0.05), however, SGPT levels were significantly elevated (157 +/- 34 versus 48 +/- 11 IU/1, P less than 0.05). No differences in the incidence of coronary artery lesions were observed (5/30 versus 7/30). Plasma TxB2 production was completely blocked in both groups, and plasma 6-keto-PGF1 alpha levels in the high dose group on day 14 was lower than that in the low dose group (39 +/- 8 versus 159 +/- 65 pg/ml, P less than 0.05). SGPT and plasma 6-keto-PGF1 alpha correlated with serum salicylate concentration. These data suggest that high dose salicylate therapy may be disadvantageous as anti-thrombotic therapy, and supports the notion that low dose therapy is safe in the acute stage of Kawasaki disease.