A Case of an Intraoperative Iatrogenic Methanol Exposure

Background

ThinPrep Cytolyt is a methanol-based cell preservation solution used to support biopsied cells during transport and slide preparation [1]. Cytolyt is frequently used to fix tissue samples immediately following an endobronchial ultrasound-guided fine-needle aspiration. The reported methanol concentration in Cytolyt is 14% to 25%, suggesting an accidental ingestion can produce methanol toxicity with as little as 25 to 30 mL in a patient weighing 70 kg [2]. Cytolyt otherwise consists of water, magnesium acetate, sodium chloride, potassium chloride, and calcium acetate [1]. Our patient was exposed to approximately 20 mL of Cytolyt. Methanol toxicity is mediated by methanol’s conversion to formic acid, which itself impairs oxidative phosphorylation of all exposed cells via complex IV inhibition. Toxicity can vary depending on the exposure, ranging from mild metabolic acidosis to cardiovascular collapse and death [3]. To date, no published reports describe an iatrogenic exposure to Cytolyt. We report the only known case of an accidental intraoperative administration of a methanol solution, with corresponding plasma concentrations, and subsequent treatment with fomepizole.

Case Report

The patient was a 70-year-old woman, weighing 58 kg. She had a history of stage IIIA rectal adenocarcinoma with metastasis to the regional lymph nodes. Additional past medical history included a diagnosis of hypertension, gastroesophageal reflux disease, and chronic obstructive pulmonary disease. A recent computed tomography scan showed a worsening mass-like consolidation of the right middle and upper lung, with a concern for an atypical infection, versus new metastasis. The patient was referred to the interventional pulmonology service to undergo navigational bronchoscopy, endobronchial biopsy, and bronchoalveolar lavage (BAL) of the newly identified mass.

In the operating room, the patient underwent a standard induction of anesthesia, with 80 mg of propofol, 5 mL of preservative-free 2% lidocaine, 50 mg of rocuronium, and 50 mcg of fentanyl. The patient was successfully intubated with an 8.5-mm endotracheal tube, and maintenance of anesthesia was achieved with continuous infusion propofol at 150 mcg/kg/min throughout the procedure. Other pertinent procedural medications included dexamethasone, ondansetron, and phenylephrine. During the procedure, an Illumisite bronchoscopy under fluoroscopy was performed to visualize and navigate to the lung nodule. An Arcpoint needle was used to perform fine-needle aspirations of the upper lobe mass, with subsequent trans-bronchial biopsies of the node. Following sample collection, a BAL of the right upper lobe was performed. This was achieved by instilling 30 mL of fluid, believed to be normal saline, into the right upper lobe. A 10-mL volume was then aspirated with the purpose of culture collection. Shortly after the BAL, the proceduralist was informed that the aforementioned syringe contained CytoLyt, a methanol-based fixative used for cytopathology, instead of saline. Preparation of Cytolyt specimen bottles occurred at the equipment table, which is not standard procedure, and the clear fluid was left on the table and confused with saline. In our practice, in the absence of a cytopathologist, sample specimens and slides are prepared in the operating room and placed in a designated area on the procedure table. Upon realization of the iatrogenic exposure to methanol, the Department of Medical Toxicology was promptly contacted and recommended obtaining the following laboratory tests: complete blood count, basic metabolic panel, venous blood gas, and methanol level. The patient exhibited no appreciable changes in ventilation, oxygenation, or hemodynamics in the acute period following exposure. The decision was made to keep the patient intubated following the procedure, and she was transported to the Post-Anesthesia Care Unit. Upon arrival, she promptly received a 15 mg/kg dose of fomepizole (890 mg), for treatment of possible methanol toxicity. The amount of time that elapsed from instillation of Cytolyt into the lungs and administration of fomepizole was approximately 45 min. An arterial blood gas was collected, showing the following: pH 7.35/PaCO2 47/PaO2 216/HCO3− 25, with an oxygen saturation of 99.9%.

The patient’s first plasma methanol level, prior to fomepizole administration, returned elevated, at 21 mg/dL. Three hours after fomepizole administration, the plasma methanol level had decreased to 13 mg/dL, and at both 8 h and 18 h, the plasma methanol level was 12 mg/dL. No additional fomepizole was administered after the loading dose, and a repeat arterial blood gas showed no evidence of metabolic acidosis. Overall, the remainder of the patient’s hospital course was uneventful, as she was extubated shortly after arrival to the Medical Intensive Care Unit and ultimately discharged 2 days after her procedure. Aside from having a mild cough following extubation, the patient did not appear to have any significant adverse respiratory symptoms as a result of the inadvertent CytoLyt administration, and interval chest X-rays showed no acute findings.

Discussion

Methanol (methyl alcohol) is a toxic alcohol found in a variety of commercial agents, and toxicity is well established via ingestion, dermal absorption, and even inhalation [4]. Administration via BAL has not been previously documented; however, some degree of systemic absorption would be expected via this route. Cytolyt is a tissue fixative utilized in cytopathology and has a methanol concentration ranging from 14% to 25% [1]. Formalin, a combination of formaldehyde and water, has similar applications and generally contains approximately 37% formaldehyde and 6% to 15% methanol as a stabilizer. Other tissue fixatives can contain varying amounts of formaldehyde. Formaldehyde is an intermediate metabolite in the conversion of methanol to formic acid and causes a toxicity similar to that of methanol. As formaldehyde is located downstream of the site of action of fomepizole, its toxicity is not affected by alcohol dehydrogenase inhibition [5].

Aside from possible direct irritant effects, the biggest concern with this exposure to Cytolyt was the potential for systemic methanol toxicity, considered to be a risk at plasma methanol concentrations of 20 mg/dL or greater. Doses of at least 100 mg/kg of methanol can cause toxicity, and deaths have been reported with ingestions ranging from 20 to 150 g [6]. Methanol mediates its toxicity via generation of metabolic acidosis due to accumulation of its carboxylic acid metabolite, which is further exacerbated by formic acid’s inhibition of the electron transport chain and oxidative phosphorylation. Methanol toxicity can have a varied presentation initially depending on the route of exposure; however, severe systemic toxicity can develop via any route and presents similarly [3].

Patients will exhibit metabolic acidosis with potential for blindness, hemodynamic instability, and possibly death if untreated. Clinical symptoms correlate more with the severity of the acidosis and less with the actual methanol level at any one time [7]. With any methanol exposure, the necessary steps are to determine the degree of systemic absorption, inhibit conversion of methanol to formic acid, and determine the need for extracorporeal elimination. Fomepizole (4-methylpyrazole) inhibits alcohol dehydrogenase and is a mainstay of treatment. It should be administered early when exposure to methanol is suspected and in any confirmed case in which the plasma methanol concentration is greater than 20 mg/dL. The loading dose of fomepizole is 15 mg/kg, followed by 10 mg/kg doses every 12 h for the next 48 h. If additional doses are required, dosing should revert to 15 mg/kg after 48 h, as fomepizole induces its own metabolism [4]. As it is dialyzable, fomepizole should be administered every 4 h during hemodialysis. Fomepizole should be administered until the plasma methanol level is less than 20 mg/dL [8]. Our patient demonstrated clear methanol exposure but did not develop systemic toxicity. The patient may not have developed systemic toxicity even without fomepizole administration; therefore, the therapeutic benefit of fomepizole is unclear in this specific case.

In our patient, exposure to methanol was detected almost immediately, allowing for the expeditious initiation of antidotal therapy. A plasma methanol level drawn prior to initiation of fomepizole therapy was elevated, at 21 mg/dL. Given the rapidity of fomepizole administration as well as the only mildly elevated methanol level, the patient did not develop any signs of systemic toxicity. The initial decline in plasma methanol concentration from 21 mg/dL to 13 mg/dL can likely be attributed to metabolism occurring prior to fomepizole administration. The slower clearance that occurred following fomepizole administration is to be expected, given that methanol is primarily eliminated via exhalation once alcohol dehydrogenase is inhibited, with a prolonged half-life of 43 to 96 h [3]. We do not suspect that the medications administered for anesthesia during the procedure significantly affected the metabolism of methanol. Subsequent plasma methanol levels were less than 20 mg/dL; therefore, there was no indication for repeated dosing of fomepizole.

Taking steps toward preventing medical errors is key in ensuring optimal patient care and decreasing adverse events. Communication failures are frequently the root of mistakes in the operating room [9]. Closed loop communication involves acknowledging receipt of information and confirming the message with the sender and has been a reliable method in decreasing miscommunication in the operating room [10]. Furthermore, confusion of solutions during a procedure can cause medication errors as well. Therefore, clear labeling of solutions, particularly clear solutions, and using prefilled labeled vials and syringes can decrease mistakes [11]. Part of our error was filling Cytolyt on the operating room table near the active procedure. Therefore, clear organization of the table would also contribute to mitigating these errors. Our hospital staff took this event as an opportunity to correct processes in the operating room with focused steps in improving the above-mentioned factors.

Conclusions

We present the case of a patient who developed a potentially toxic plasma methanol level following iatrogenic bronchoalveolar administration of a methanol solution. The patient was treated with fomepizole and did not develop systemic toxicity. Providers utilizing CytoLyt and any similar products should be aware of this potential error and approach the possibility of methanol toxicity as they would other routes of methanol exposure.