Fortune Favors the Prepared Mind: The First Use of IV Dantrolene to Treat Malignant Hyperthermia in an Adult Patient

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  • Todsaporn “Bob” Rodbumrung, MD
| Mar 07, 2022

Bob brodbumrungThe CSA Committee on the History of Anesthesia congratulates Dr. Todsaporn “Bob” Rodbumrung, the 1st place winner of the 2022 CSA History of Anesthesia Essay Contest!

Dr. Rodbumrung, a CA-3 resident at Stanford, is from Houston, Texas. He worked as a high school chemistry teacher for four years before attending medical school at the University of Texas Medical Branch. He enjoys cooking Thai food (his native cuisine) and exploring the Bay Area by hiking, biking, and taking day trips with his wife. 

As I sat in Dr. Jay B. Brodsky’s office on an early May morning, I looked around the room taking in the eclectic mix of objects. There were tomes of anesthesia texts dating back to the 1960s, pictures and mementos from international trips to different medical institutions, and an endless number of other items that were soon to be packed up. Dr. Brodsky’s retirement was nearing in the summer of 2021. I wanted to ask him so many things about his practice of anesthesia spanning over 40 years at Stanford University Hospital, but I was there for a particular story—one that would not have been found in some older medical references. Specifically, I wanted to understand his experience with malignant hyperthermia (MH), and how he came to be one of the first anesthesiologists to treat it using intravenous (IV) dantrolene.1

Dr. Brodsky described the scenario beginning as routinely as any morning an anesthesiologist would find: an attending and resident scheduled for what should have been a straightforward case. He and his resident, Dr. Clifford Friesen, were scheduled to perform anesthesia on a 77-kg “athletic” 28-year-old man scheduled for arthroscopy of an injured knee. Relevant past medical history included essential hypertension and an “innocent” cardiac murmur. The patient had undergone a tonsillectomy under general anesthesia at age six without difficulty, and there was no family history of anesthetic complications. On admission he had an elevated blood pressure with a mild systolic murmur. He was induced with intravenous sodium thiopentone, halothane, and nitrous oxide, and paralyzed with succinylcholine. He was intubated without difficulty and was subsequently breathing spontaneously.

However, 45 minutes after induction, the patient became tachycardic to 150 beats per minute and hypertensive to 200/100 mmHg. Halothane was initially increased but discontinued when the patient developed premature ventricular contractions (PVCs). Lidocaine and phentolamine were administered, and the PVCs disappeared, but tachycardia persisted. The patient’s temperature rapidly increased to 38.0°C from an initial 37.2°C, and the soda lime canister and rubber tubing felt extremely hot to the touch. The MH protocol was initiated, consisting of iced IV solution, surface cooling with ice, IV chlorpromazine, and ventilation with a non-rebreathing circuit.

A crucial addition was made to the protocol by Dr. Brodsky—a runner was sent to fetch IV dantrolene, a medication routinely used by Stanford’s neurology department for muscle spasticity in disorders like cerebral palsy or spinal cord injuries. A total of 250 mg was reconstituted and administered. Five minutes passed, and the patient’s temperature defervesced from a peak of 39.4°C to 36.5°C. He was extubated, taken to the ICU for closer monitoring, and discharged five days later with a serum creatine phosphokinase (CPK) level that had declined to 5260 units/liter, with the normal range being 15-90 units/liter.

Regarding the ad hoc deviation from protocol, I asked Dr. Brodsky how he knew that IV dantrolene would be the right move for saving this man’s life. Although unprecedented, Dr. Brodsky said he was aware of dantrolene’s utility in MH-susceptible swine, something that was studied years before. In fact, malignant hyperpyrexia syndrome, as it was initially called, was first described by Dr. Michael Denborough in Melbourne, Australia, in the 1960s.2 Dr. Denborough’s patient was also a young man with an orthopedic injury who had a remarkable anesthetic family history. Interestingly, this patient was more worried about his anesthetic regimen than his injury because ten of his family members had developed uncontrolled hyperthermia and had subsequently died after receiving general anesthesia with ether.

At the time, the patient’s anesthesiologists decided to proceed with general anesthesia using halothane, a recently developed anesthetic agent. Within ten minutes, the patient began developing tachycardia, hypotension, hypoxemia, and hyperthermia—all classic symptoms of MH. The halothane was discontinued, and the patient was packed with ice (as was the treatment at the time) and subsequently recovered. Being an internist and geneticist, Dr. Denborough studied this man’s family history and later determined that serum creatine phosphokinase levels were elevated in many of the family members. He later suggested that an inherited syndrome could be the cause of an anesthetic-induced fatal hyperthermic crisis. After this discovery, subsequent studies by Drs. Keith Ellis and Gaisford Harrison on dantrolene and its use for MH in swine showed dantrolene to be a promising treatment.3-4

In a written correspondence with anesthesiologist Dr. Kirk Hogan regarding great innovations and advances in our specialty, Dr. Brodsky maintains that his role in the case was “completely serendipitous.”5 Indeed, it seemed fortuitous that over a decade after Dr. Denborough’s findings, the newly graduated Dr. Brodsky encountered a similar situation as his predecessors. However, as Dr. Hogan asserts, I believe “fortune favor[ed] the prepared mind” that day.5 As a rising anesthesiology resident (Class of 1975), Dr. Brodsky had been tasked with presenting an interesting topic or study relevant to anesthesiology to his colleagues during a residency seminar. He had chosen a formidable topic with MH, at that time a well-described and highly lethal complication of anesthesia without a proven antidote, and reviewed the current literature thoroughly between his studies and fulfilling his clinical duties as a resident.

Despite the growing fund of knowledge and research regarding the disease, nothing in the literature had reported successful treatment of MH in humans with IV dantrolene. There were no easily accessible resources like UpToDate or PubMed to search for guidelines or expert opinions, nor would it have mattered since no published cases on the matter existed. In what would be considered an exceptional example of off-label use by today’s FDA standards, Dr. Brodsky acted quickly that day in obtaining and administering dantrolene to save his patient’s life. Although he still describes this case as serendipitous, it clearly demonstrated a key ideal in our field: preparedness of mind to act when necessary—a trait that all of us in anesthesiology aspire to maintain to the highest standards.

References

  1. Friesen CM, Brodsky JB, Dillingham MF. Successful Use of Dantrolene Sodium in Human Malignant Hyperthermia Syndrome: A Case Report. Canad Anaesth Soc J. 1979; 26:319-321.

  2. Denborough MA et al. Anesthetic Deaths in a Family. Brit J Anaesth. 1962; 34:395-396.

  3. Harrison GG. Control of the Malignant Hyperpyrexic Syndrome in MHS Swine by Dantrolene Sodium. Brit J Anaesth. 1975; 47:62-65.

  4. Ellis KO et al. A Comparison of Skeletal, Cardiac, and Smooth Muscle Actions of Dantrolene Sodium - a Skeletal Muscle Relaxant. Arch Int Pharmacodyn. 1976; 224:118.

  5. Hogan K. Malignant Hypercompliance. Anesthesiology. 2017; 126:759-762.

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