Salicylate Toxicity from Ingestion and Continued Dermal Absorption (2024)

INTRODUCTION

Salicylates are commonly used for their analgesic,antipyretic, anti-inflammatory and antiplateletproperties. Acute salicylate poisoning is a commonoverdose resulting in high morbidity and mortality.Insidious cases of salicylate intoxication may alsooccur, caused by either ingestion or topicalabsorption, most often in elderly patients withassociated medical illnesses. We present a fatalcase of acute methyl salicylate toxicity from bothingestion and dermal absorption of oil ofwintergreen. This case highlights the point thattopical absorption of salicylates, particularly inpatients with renal failure, can result in severeintoxication.

CASE REPORT

An 80-year-old man with end-stage renal disease had oil ofwintergreen (containing 35% mg/ml methyl salicylate)rubbed regularly on his lower extremities by alive-in attendant. He applied it to the patient’slegs and left the bottle on the nightstand. Thepatient mistakenly drank a mouthful when he mistookit for a beverage. The attendant said the patientvomited the oil of wintergreen immediately. Twohours later, the man was found seizing. Whenparamedics arrived the patient remained unresponsiveand apneic with a wide QRS complex on the cardiacmonitor.

The patient’s medical history included diabetes mellitus,diabetic nephropathy requiring hemodialysis threetimes per week, and severe coronary artery disease.He had a coronary artery bypass graft and apacemaker. He was dialyzed one day prior topresentation and had otherwise been in his usualhealth.

Upon presentation to the Emergency Department, the patientwas unresponsive and apneic. He had a blood pressureof 146/66 mm Hg, a palpable pulse at 55 beats perminute, and depressed respirations requiringassisted ventilation by bag valve mask. Externalcardiac monitoring revealed a wide QRS rhythm. Thepatient smelled of oil of wintergreen. Head and neckexam was normal. His lungs were clear and his heartwithout murmurs. Abdominal and rectal exam wereunremarkable. His lower extremities demonstratedacrocyanosis and were cool to touch. Diminishedpulses were noted, and no reflexes were elicited.His bilateral forearm shunts appeared intact.

Resuscitation in the Emergency Department consisted of oralendotracheal intubation, followed by gastric lavageand administration of activated charcoal. Thepatient initial arterial blood gas on FiO2 100% waspH 6.95, pCO2 34 mmHg, pO2 400 mmHg, and the patientwas given intravenous sodium bicarbonate. The serumpotassium level was 8.6 mmol/L and the patient wasgiven 1 gm of calcium gluconate intravenously. Hiselectrocardiogram showed a wide complex QRS withpacemaker depolarizations at 80 spikes per minute.The patient also developed several runs ofventricular tachycardia, which responded to 1mg/kg(75 mg) lidocaine.

The patient’s chest radiograph demonstrated cardiomegaly withno evidence of pulmonary edema. The endotrachealtube was in good position above the carina. Serumchemistries revealed the following values: sodium134 mmol/L, potassium 8.6 mmol/L, chloride 97mmol/L, bicarbonate 6 mmol/L, urea nitrogen 62mmol/L, creatinine 6.9 mmol/L. He had an anion gapof 31 (normal < 14). His salicylate level was74.8 mg/dl.

Immediate hemodialysis was initiated upon transfer to theIntensive Care Unit. Repeat arterial blood gas after1 1/2 hrs of dialysis demonstrated a pH of 7.37,PaCO2 34 mmHg, and PaO2 147 mmHg. Repeat potassiumwas 4.3 mmol/L.

Approximately nine hours after admission, the patient hadanother generalized tonic-clonic seizure, whichresponded to diazepam. However, because the patientdesired no heroic measures, no resuscitative effortswere performed when he continued to deteriorate.

An autopsy revealed a postmortem salicylate level of 82.6mg/dl; 7.8 mg/dl higher than his pre-dialysis level,and the cause of death was determined to be acutesalicylate intoxication. It was concluded that thecause of salicylate toxicity in this patient was dueto continued dermal absorption of oil of wintergreenin this patient with chronic renal failure.

DISCUSSION

Salicylate intoxication can produce serious morbidity andmortality after accidental or intentional acuteingestion, or chronic over-medication. Percutaneousabsorption of salicylates may also result intoxicity, especially in patients with renalfailure.

Prior to antibiotics, topical salicylates were widely used totreat scabies and impetigo, and toxicity associatedwith dermal absorption was common. One case seriesreported 13 deaths, 10 of them in children,substantiating the severe potential for toxicityassociated with this route.¹ A review of theliterature of topical salicylates reported 17documented cases of toxicity associated withunderlying illnesses, days to diagnosis, and serumsalicylate.² Psoriasis is themain entity still treated with topical salicylates,and there are numerous case reports documentingtoxicity.^1,2Another route of application is with sports creamsused in massage therapy for muscle pain. Local skinnecrosis and interstitial nephritis have also beenassociated with these creams.²

Our patient experienced seizures with a salicylate level of74.8 mg/dl and was hemodialyzed immediately uponpresentation, which should have lowered his serumsalicylate level. However, his subsequent serumlevel was 82.6 mg/dl. Despite aggressive treatmentwith intubation, gastric lavage, charcoal,bicarbonate, and dialysis, his salicylate levelcontinued to increase. It is likely thatpercutaneous penetration of salicylate contributedto his rising level. No efforts were made todecontaminate his skin because it was thought to beinsignificant at that time.

Methyl salicylate (oil of wintergreen) contains moresalicylate than other salicylates; 5 ml methylsalicylate is equivalent to five aspirin tablets(325 mg each).

The primary effects of salicylate toxicity are complex andinclude direct stimulation of the CNS respiratorycenter leading to a respiratory alkalosis.Salicylates also uncouple oxidative phosphorylationat a cellular level, producing an increasedmetabolic rate. This results in increasing oxygenconsumption, glucose utilization, and heatproduction.⁴ Salicylates inhibitthe Krebs cycle and alter lipid metabolism and aminoacid metabolism, producing lactic acid and ketoneswith resultant metabolic acidosis.⁴They also interfere with hemostasis by damaginghepatocytes and interfering with prostaglandinsynthesis. These effects cause hyperpnea, tachypnea,tachycardia, fever, hemorrhage, and hypoglycemia,all of which can subsequently progress to alteredmental status and seizures.^4,5

Factors that affect the rate of percutaneous absorption ofsalicylate include: the effect of salicylic acid onthe epidermis, the pathologic state of the skin, thedegree of hydration of the stratum corneum, and thesolvents used.¹ Strakosch studiedthe histological changes of the skin caused by theapplication of salicylate in concentrations rangingfrom 1% to 15%.⁵ His studies wereconducted on the normal skin of volunteers.Depending on the concentration of the salicylate andon the ointment base used, the salicylate ointmentscaused injury to the epidermis within two to 14days. On histological examination, the findingsincluded swelling and exfoliation of the stratumcorneum. He also showed that the addition of 3% or6% sulfur to 3% salicylate accelerated the onset ofswelling and exfoliation of the stratumcorneum.⁶

It is likely that compromised epidermis, by exposing viablecells, is a significant factor in the percutaneouspenetration of salicylates.⁷ In both animalmodels and human subjects, the rate of percutaneouspenetration of salicylate in various ointment baseswas determined by measuring the serum concentrationand urinary output of salicylates.^8,9 Both studiesdemonstrated significant absorption of salicylate,especially in hydrophilic ointment base.

The severity of toxicity can generally be predicted from theamount of drug absorbed. Ingestion of less than 150mg/kg is usually not associated with systemictoxicity; 150–300 mg/kg may produce mild to moderatesymptoms of hyperpnea and neurologic disturbances(lethargy and/or excitability). A dose of greaterthan 500 mg/kg of salicylate can result in severehyperpnea, coma, and occasionally seizures.¹⁰

About 20% of the salicylate is oxidized in the tissues and70% is excreted by the kidneys.³ Because the hepaticenzymatic metabolism becomes saturated as salicylatelevels increase, renal excretion becomesincreasingly important as a means ofelimination.^2,11,12 Therefore, renal insufficiency or renalfailure contributes to further accumulation ofsalicylate.

The treatment of acute salicylate intoxication consists ofdecreasing further absorption of salicylates,enhancing drug elimination, and correcting foracid-base, fluid, and electrolyte imbalances.Gastric lavage has not demonstrated to be betterthan charcoal alone at reducing toxicity in anevidence-based review.¹³ Extra doses ofactivated charcoal may be needed to achieve thedesired ration of 10:1 activated charcoal tosalicylates. Repeated doses of activated charcoalmay enhance elimination through enteroentericrecirculation.¹⁴

Prompt correction of systemic acidosis with sodiumbicarbonate is critical to prevent further transferof unbound salicylate into the CNS. Alkalization ofthe urine with sodium bicarbonate (2–3 mEq/kgloading dose intravenously, and 2 mEq/kg every 3–4hours thereafter to maintain a urine pH above 8)will enhance urinary excretion of salicylate andreduce serum half-life.^7,11Overly vigorous fluid administration can lead topulmonary edema or cerebral edema. Fluid or osmoticdiuresis does not increase renal salicylateexcretion more than urinary alkalization.¹²

Hemodialysis is the most efficient method of removingsalicylates from the blood. Dialysis is thetreatment of choice in salicylate-intoxicatedpatients who have severe renal, hepatic, orcardiovascular disorders, uncorrectable acidosis,comatose, seizing, or are unresponsive to othermethods of treatment.

SUMMARY

Salicylate toxicity from percutaneous absorption can occur,especially with methyl salicylate. Renal dialysispatients are at increased risk for salicylismbecause salicylates are primarily excreted by thekidneys. Physicians should be aware of the potentialrisks of salicylate dermal absorption andtoxicity.

REFERENCES