Blue Mood 2

Want to know what cocaine has to do with residency hours? What genetic disease can kill you in the operating room? How a missed diagnosis resulted in changes to the training of every American intern and resident afterward? Listen to find out! 

Transcript

This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patient survive this podcast? It’s up to you and the choices you make. Our episode today is called Blue Moon Part 2. Want to know what cocaine has to do with residency hours? What genetic disease can kill you in the operating room? How a missed diagnosis resulted in changes to the training of every American intern and resident afterward? Listen to find out!

If you haven’t listened to Part 1I’d recommend starting there. We are in the midst of treating a 23-year-old woman with fever, altered mental status, clonus and the wet-dog shakes. Quick recap. She has serotonin syndrome, AKA serotonin toxicity. She routinely takes fluoxetine, ie Prozac, then took a few doses of dextromethorphan, ie Robitussin for a cough several days ago. 

Both fluoxetineand dextromethorphan cause elevated levels of serotonin in the brain, likely triggering this reaction. But, you still have some reservations about the timeline and are wondering why the symptoms took 2 days to develop after her last dose of cough medicine. She’s gotten a dose of diazepam, or Valium. The intern says she feels a little better, but not much and wants to give her another, higher dose. You agree with this plan and tell him to check on her again in about thirty minutes.  

While we are waiting to see if the second dose helps, let’s talk about serotonin itself and thena very real, very famous, lethal case of serotonin syndrome. First, it’s the reason serotonin syndrome is widely known. Second, it’s no exaggeration the repercussions of this tragic case affected the medical training of every single intern and resident in the US thereafter. 

What does serotonin do? That’s question number 1. Is it? 

A.                Fight or flight

B.                 Pleasure

C.                 Calming 

D.                Happiness

Answer D. Happiness. Fight or flight is epinephrine, pleasure dopamine and calming can represent gaba. Serotonin has been a buzzword and internet meme, called the “Happy hormone”. There’s some truth to this, but is more an oversimplification due in part to outdated thinking. When SSRIs were originally invented, the thought was depression was caused by low serotonin levels, which these drugs would fix. We now know serotonin itself isn’t the cause of depression and we aren’t clear on the exact therapeutic mechanisms of SSRIs either. 

Serotonin is a neurotransmitter. It’s found everywhere from single celled organisms like bacteria and protozoa, to the human central nervous system. Most of our serotonin, 90-95% is actually located in our gastrointestinal tracts where it promotes motility. In the brain, its effects are very complex. Let me just give you a brief overview.  Serotonin is associated with feelings of well-being and contentment. Low levels correlate in animal studies with increased risk-taking, aggression and violence, leading some to postulate it might be a defensive mechanism when in a nonsafe place. Higher serotonin levels appear to promote patience and waiting for a delayed reward, rather than the instantaneous gratification loop of dopamine. 

A lot of drugs work on serotonin and it’s receptors. Question #2. The mechanism of action of which drug is attributed to increased serotonin. To clarify, many drugs, if not all affect serotonin. I’m asking about the main effect. Is it? 

A.                Hallucinogens

B.                 Opioids

C.                 Alcohol

D.                Sympathomimetics like cocaine

The answer is A. Hallucinogens increase serotonin as their primary mechanism. So LSD, peyote, mushrooms. Also, DMT one of the two ingredients in ayahuasca. In medicine we use serotonin receptor drugs daily. Sumatriptan or Imitrex for migraines is an agonist, ondansetron or Zofran the nausea medicine is an antagonist. 

On this note, let’s go back to March 4, 1984. Libby Zion was an 18-year-old woman home in Manhattan on break from college in Bennington, Vermont. She developed a fever. Her family physician recommend she go to the ED at New York Hospital, currently Cornell. 

There,she noted taking phenelzine, a monoamine oxidase inhibitor, though said she hadn’t taken it for several days. She denied drug use. She was intermittently agitated with jerking movements and continued to be febrile. She was seen by the intern and resident, the case was discussed with the attending, her family physician over the phone.

 She was treated with meperidine, brand name Demerol for the jerking. Meperidine is an opioid with a lot of side effects. Effects outside the usual opioid toxidrome. First, it has a very high abuse potential. Every EM physician has had patients ask specifically for this drug. Second, it can cause serotonin syndrome and third, it causes seizures, even in therapeutic doses. No surprise it’s fallen out of favor. Anyway, they gave her this and admitted her with a diagnosis of "viral syndrome with hysterical symptoms”. Quite a diagnosis. Not one I’ve ever made, hopefully you haven’t either.

The ER doctors and toxicologists listening know what went wrong here, but for everyone else we haven’t talked about the causes of serotonin syndrome. First and foremost, as we've said, SSRIs. Older generation antidepressants, tricyclic antidepressants like imipramine and nortriptyline. Also, monoamine oxidase inhibitors like phenelzine. Lithium. A few opioids can cause it, not all of them, but fentanyl, tramadol and meperidine as mentioned. Antiemetics for vomiting, including metoclopramide, and ondansetron or Zofran. Harmaline, the secondingredient used to make ayahuasca. Listen to the Bitter Brew episode to hear about this ingenious ancient pharmacology combo. Linezolid, a big gun antibiotic for resistant infections is a classic cause in the hospital. Herbs found in supplements like St. John's wart, Syrian roe, and ginseng. 

It's a huge list with a lot of pitfalls both for patients outside the hospital, taking supplements, over-the-counter medicines, or drugs of abuse. Also, it can happen in the hospital too with patients on SSRIs, unwittingly given other drugs, precipitating serotonin syndrome. It’s not helped by the fact that fluoxetine in particular has a long half-life with a metabolite that may be present for as long as two weeks. 

Libby Zion was taking phenelzine and was then given meperidine, both serotonergic agents. 45 minutes after the meperidine, she became more, rather than less, agitated and tried to jump out of bed. She was placed in restraints, tied to the bed by her wrists and ankles as well as a vest. Question #3. Restraints help patients with serotonin syndrome. 

A.                True

B.                 False

Answer: B False. Restraints may cause more harm than good. We try to minimize use of physical restraints these days regardless. In particular, physical restraints might worsen serotonin syndrome. As I said earlier, the fever is likely due to increased muscle activity. You can imagine someone is fighting against restraints, worsening the situation and potentially increasing their temperature.

The intern was caring for 40 other patients and in the middle of a 36-hour shift. She also ordered haloperidol or Haldol. Zion calmed down, the restraints were removed.

But…Several hours later Libby Zion’s temperature was 107°F or 42 Celsius. She didn't improve with a cooling blanket or cold compresses, and had a cardiac arrest. Resuscitation attempts failed. Her autopsy showed bilateral pneumonia. There was also evidence of cocaine use. What killed Libby Zion has never been definitively proven, most believe it was serotonin syndrome from the combination of phenelzine, her antidepressant, the meperidine given in the hospital and cocaine. 

Libby's father Sidney Zion was extremely well connected. He was a lawyer, and a journalist for the New York Times. Initially, he pressured the Manhattan district attorney to charge the intern and the resident with murder, rather than malpractice which shocked the medical community as you can imagine. Four well -known chairmen of medicine at university hospitals testified they themselves had never heard of serotonin syndrome. The grand jury found no criminal charges. How did this case affect every American resident and intern in the years following? The grand jury issued an indictment of the American medical training system suggesting closer supervision and fewer hours. 

The panel of experts called the Bell Commission was convened. They issued guidelines in New York reducing call to only 24 hours at a time and limited work hours to 80 hours per week in 1989. A law enforcing these rules is often called the Libby Zion Law. Similar rules were adopted nation-wide in 2003. If you are currently and intern or resident, working “only” 80 hours, Libby Zion and her tragic death are the reason why.

The malpractice case was brought to trial 10 years later in 1994. The jury awarded the Zions $750,000 for pain and suffering, and $1 dollar for wrongful death. They attributed 50% of the pain and suffering to Libby herself for using and not disclosing the cocaine use. Resulting in a $375,000 total.

Serotonin syndrome was identified in the 1960s but wasn’t really known in the medical community until we started prescribing SSRIs in the 1980s and 90s and quite frankly thanks to the publicity surrounding this very tragic case.

In fact, the history of medical training is rife with substance use. Know why residents are called residents? They used to live in the hospital, covering patients at night in exchange for room and sometimes board. We still refer to trainees as house staff for this reason. 

Residency began in the United States in 1889 at Johns Hopkins. At the time they were all single men. They worked every day and every other night under this model. The man who started it, William Halstead is still today a famous surgeon and a tower figure in medicine. He was a bold practiconer of medicine. He operated on his mother on the kitchen table to remove her gallstones and gave his sister one of the first blood transfusions in the US after she hemorrhaged from childbirth, using his own blood. 

He had a serious cocaine use disorder. Yes. Cocaine’s local anesthetic properties had just been discovered. Halsted injected himself with cocaine to experiment. He was famous for the long hours he worked, no doubt thanks to the cocaine addiction he developed. It ended his career in New York. He moved to Baltimore and it was during this time he set up the residency at Hopkins. Those who trained before the residency hour changes have cocaine to thank for the brutality of those schedules. Imagine not just staying awake for 36 hours, but trying not to kill someone while you do so. 

Question #4. Halstead treated his cocaine use disorder with this substance. 

A.                Alcohol

B.                 Morphine

C.                 Nitrous oxide

D.                Cannabis

The answer is B. Morphine. Halstead found morphine helped his cocaine problem, trading cocaine for a life-long morphine addiction, instead. That’s a detour but I remain shocked by how much of medical training is influenced by substances. 

Anyway, back to the patient you are currently treating, the 23-year-old woman. It’s critical to treat her aggressively to make sure she improves and that her temperature doesn’t increase. You ask the intern for an update. After the second dose of diazepam she’s shaking less and has stopped asking repetitive questions about her labs and Tylenol, so some improvement there. But her temperature is 103.5 F or 39.7 C. So it’s still going up. He wants to prescribe more benzos, you agree. 

“Is this definitely serotonin syndrome he asks? You’ve said the timeline doesn’t exactly fit. She took the second serotonergic agent, dextromethorphan 2 days before the symptoms started, when we’d expect it to start a few hours after. What about malignant hyperthermia?”

Good question. I love an intern or resident who keeps asking questions and thinking about the diagnosis, rather than anchoring on the first or easiest answer. 

 Malignant hyperthermia is a complication anesthesiologists fear because it can kill otherwise healthy patient in the operating room. It’s a hereditary problem and the reason they ask every patient about to have surgery if a family member has ever had a problem with anesthesia, because it happens mostly due to general aesthetics.Patients develop hyperthermia and muscle rigidity, specifically masseter muscle rigidity meaning that the patient's jaws clench shut. It's a skeletal muscle disorder with uncontrolled calcium release inside cells, leading to uncontrolled muscle contraction. It’s possible for it to occur outside the OR, one drug we use frequently in the ED a paralytic called succinylcholine can cause it, it can also be triggered by fever or exercise. That said, it’s extremely rare in the OR and even more so in other settings. You note the patient doesn’t have masseter muscle spasm or exposure to anything you’d expect to trigger malignant hyperthermia.  

Which brings us back to her blue urine. At the end of our last episode, she provided a urine specimen. It was bright blue. If you listen to.. not the last episode, but the one before, Fresh Air, I think you can guess what this is. Question 5. Is it?

A.                Digoxin

B.                 Propofol

C.                 Methylene blue

Answer: C. methylene blue. Digoxin toxicity causes blue halos in the vision, but not blue urine. Propofol causes green urine. It's methylene blue that causes bright blue urine. 

If you listened to Fresh Air, you know it's used as an antidote for methemoglobinemia. And that it's recently become Internet famous due to supposed, but unproven claims it can cure everything from memory loss to Parkinson's disease to aging. 

Methylene blue causes serotonin syndrome. One of the ways we know this is from some fascinating cases in the anesthesia literature. Methylene blue is used in OR to look for tumor cells, to determine if structures like the ureters are leaking amongst other things. Several patients became altered post-op in the PACU and a woman died post-op after her temperature shot up to 43.1 C or 109.5 F. 

Back to our patient. She’s much improved after the third dose of diazepam. She’s no longer shaking and her temperature is back down to 101.2 F or 38.4 C. She says she drank several glasses of methylene blue over the past three days, believing it would help her cold and improve her cognition. It’s pretty clear at this point the combination of fluoxetine, dextromethorphan and methylene blue was too much serotonin and tipped her over the edge. You’re glad she’s improving and admit her to the hospital for ongoing treatment and monitoring.

Millions of people worldwide take SSRIs. How many of them get serotonin syndrome? The true incidence is almost impossible to predict. It’s a spectrum of disease from really mild symptoms like vague discomfort or tremor all the way up to lethal symptoms like cardiac arrest and death. The vast majority of mild cases likely go unrecognized or misdiagnosed. 

We discussed treatment with benzos. There’s another option, an anti-serotonin drug called cyproheptadine which also helps. Why didn’t we start with that? It’s only available orally, so the patient has to be eitherwell enough to swallow it, or sick enough to have an nasogastric tube to put it down. 

Fortunately, we made the diagnosis early enough in our patient, before she progressed to critical illness. What would we have done if she did have a life-threatening case like Libby Zion’s? Of course, lots of benzos. But you might need to do more. Muscle relaxation and cooling are the top priorities. If our patient hadn’t responded to benzos, the next step would be intubation and paralysis. As mentioned several times, the elevated temperature is from muscle activity. If you give paralytics, you have no muscle activity, so that can help in serious cases. 

What do patients actually die of? Often, severe hyperthermia, temperatures >106 F or 41C, leading to multisystem organ failure, seizure, coma and death. Why? Remember the old commercial with an egg in a frying pan saying this is your brain on drugs? An egg changes from liquid and clear to white and solid because heat denatures the proteins, causing them to change shape. What happens when your body temperature gets too high? The exact same thing. All the proteins in your body, denature and stop working. Therefore, aggressive cooling is necessary with ice baths, mists and fans. 

Back to our patient after several more doses of diazepam, the next day she has normal vital signs and is asking how soon she can leave the hospital. It’s a relief we caught this early. A combo of clinical acumen, and honestly, good luck. The hospitalist recommends holding fluoxetine for a week to make sure all the methylene blue clears from her system. Variable half-lives are reported for oral methylene blue, but it can be as long as 24 hours. The patient says she’ll never take dextromethorphan or methylene blue again.  

This is a fictional case, as are all our cases, to protect the innocent. But it is based on real poisonings.

The last question in today’s podcast. Serotonin is synthesized in the body from what precursor? Hint for the think Thanksgiving.

A.                Tryptophan

B.                 Melatonin

C.                 Glutamate

D.                Glycine

Bonus, if you can guess which of the above serotonin is itself is a precursor to. Think sleep. 

Follow the Twitter and Instagram feeds both @pickpoison1 for the answer. Remember, never try anything on this podcast at home or anywhere else. 

Thanks for listening. It helps if you subscribe, leave reviews and/or tell your friends. Transcripts are available at pickpoison.com. 

 While I’m a real doctor this podcast is fictional, meant for entertainment and educational purposes, not medical advice. If you have a medical problem, please see your primary care practitioner. Until next time, take care and stay safe.