Why We Hate Toxicology Cases
A teenage male presented to a local ED with a history of polysubstance overdose. The patient has a history of anxiety, depression and previous overdose attempts. Per the ED, the patient ingested an unknown amount of Tylenol, glipizide/metformin combo, atorvastatin, amoxicillin, Zofran, cimetidine, ibuprofen 800 mg, prednisone, aspirin, and 1 pint of alcohol. He was transported by ambulance somnolent, vomiting, hypothermic with core temperatures 34-35°C, tachypneic with systolic blood pressures in the 90 mmHg range. Initial laboratory results revealed a urine drug screen (UDS) positive for THC, benzodiazepines and amphetamines with a blood alcohol content (BHC) well above the legal limit. An arterial blood gas (ABG) revealed a widened anion gap metabolic acidosis with a serum lactate of 7.9 mmol/L and hypokalemia. In the ED he was intubated and his hypotensive shock was managed with crystalloid and pressors. He was then transferred to the Intensive Care Unit (ICU) where he continued to deteriorate hemodynamically. His serum lactate rose to 15 mmol/L and required phenylephrine, vasopressin, epinephrine, norepinephrine, and dopamine infusions in order to get his mean arterial pressure (MAP) at or slightly above 60 mmHg. He also needed significant electrolyte supplementation for hypokalemia and hypocalcemia, as well as dextrose for serum glucose instability. He was then placed on hemodialysis for concerns with end organ failure as evidenced by rising creatinine levels and liver enzymes.
The Challenge
This was a case where the referring hospital appropriately and aggressively managed a gravely ill patient. Despite their arguably herculean efforts, the patient continued to deteriorate. This prompted them to request the services of the regional academic children’s hospital and the transport team was activated.
The fundamental question for the transport team to answer was “how can we adequately stabilize this patient from a hemodynamic standpoint in order to safely move him?” Despite all current efforts, his blood pressure continued to drop. He was suffering from a profound metabolic acidosis with a rising lactate arguably due to a combination of liver failure and cellular hypoperfusion.
Upon the transport team’s arrival to the bedside, the patient was on high doses of the aforementioned pressor agents, a sodium bicarbonate infusion as well as an acetylcystine (mucomyst) infusion. He was also given stress-dose steroids (100 mg of Hydrocortisone). He was agitated, tachypneic and continued fighting the efforts of mechanical ventilation. In addition to current sedation / analgesia attempts (midazolam and fentanyl infusions), he was given bolus doses of ketamine. The patient’s inherent minute ventilation was supported with the ventilator in order to assist him with his worsening acidosis. In order to combat the hypotension refractory to all current therapies (MAP now 50 mmHg), the transport team dug deep into their distributive shock algorithm (BELOW) and requested that the patient be given intravenous Methylene Blue. After a quick follow up with the referring intensivist and the receiving physicians in the Pediatric Intensive Care Unit (PICU), a weight appropriate dose (1 mg/kg) was ordered and administered.
Within 45 minutes of administration of the methylene blue, the patient’s MAP rose from the high 50’s to near 90 mmHg. With more generous sedation and analgesia, ventilatory management became more effective in combating his metabolic acidosis and he was at the point where transport could be safely attempted. All current therapies were continued enroute, including aggressive electrolyte supplementation and the patient was safely transported to the regional PICU without additional incident.
How it Works
In current literature, it can only be hypothesized that methylene blue is the “miracle cure” for severe hypotensive shock that is refractory to standard therapies. While this case does provide some compelling data to this point, it is difficult to find a study that will definitively confirm a direct correlation between the use of methylene blue in severe vasoplegic shock and a rise in mean arterial pressure (MAP). With that said, methylene blue’s only FDA-approved indication is for acquired or drug-induced methemoglobinemia. It is considered “off-label” in the management of severe vasoplegia during cardiac surgery. Survival Flight is currently approved to utilize methylene blue with appropriate medical direction and for the purpose of managing vasoplegic shock (regardless of etiology) that will not respond to standard high-dose vasopressor therapy.
It is thought that vasoplegia can occur due to instances that cause alterations in the regulation of nitric oxide (NO). This dysregulation can affect the endothelial lining of blood vessels, causing an unwanted drop in systemic vascular resistance (SVR). In these cases, it is thought that methylene blue can be effective in inhibiting this particular pathway without causing unwanted effects like myocardial depression. A typical dosing regimen for this medication is 1-2 mg / kg injected into a 100 ml 0.9 NS bag and administered intravenously over a minimum of 10 minutes. Onset can vary and redosing may be required.
Of the many substances ingested by this child, one of particular concern was Metformin (Glucophage). Metformin intoxication causes dysfunction in cellular mitochondria, causing anaerobic metabolism, high serum lactate levels, metabolic acidosis and hypoperfusion. Methylene blue can be effective in this case as it will reverse the smooth muscle relaxation caused by the effects of these aforementioned physiologic alterations.
“Take Home” Points
Following the review of this case, the Survival Flight nursing staff made several comments that stuck with the author of this post. While we make every attempt to allow science and evidence drive our decisions, sometimes the best course of action is whatever will allow us to safely transport a patient to definitive care. While we have only used methylene blue less than a handful of times since it was incorporated into our shock protocols, it is one medication that could possibly help us temporarily manage severe vasoplegic shock. Additionally,
- In ANY case where the patient is attempting to compensate for severe metabolic dysfunction or acid-base imbalance, DON’T take that away from them. Provide support but allow their normal physiology to steer this. Our team did an excellent job of this!
- Toxicology cases are particularly challenging. Do not underestimate the effectiveness of global (or general) supportive care.
- The approach to shock and hypotension has several common management principles that are “normally” effective, regardless of shock state or etiology. In this case, they were all exhausted.
- Methylene blue should definitely be considered in the case of a polysubtance overdose where the patient is suffering from a high lactate level and severe hypotensive shock.
References
Chiew, A. L., Wright, D. F., Dobos, N. M., McArdle, K., Mostafa, A. A., Newth, A., … & Isbister, G. K. (2018). ‘Massive’metformin overdose. British journal of clinical pharmacology, 84(12), 2923-2927.
Heredia, D., Mancl, E., Sayegh, B., & Simpson, K. (2014). Successful use of methylene blue for hemodynamically unstable metformin toxicity. Chest, 146(4), 253A.
Hosseinian, L., Weiner, M., Levin, M. A., & Fischer, G. W. (2016). Methylene blue: magic bullet for vasoplegia?. Anesthesia & Analgesia, 122(1), 194-201.
McNamara, K., & Isbister, G. K. (2015). Hyperlactataemia and clinical severity of acute metformin overdose. Internal medicine journal, 45(4), 402-408.
Scheffer, A., Bahr, T., Patel, S., & Willis, B. (2018). 250: Methylene Blue Treatment Of Vasoplegic Syndrome In Pediatric Patients. Critical Care Medicine, 46(1), 107.