Blue Mood
Want to know what the wet-dog shakes have to do with humans? What drug reaction causes a temperature so high it can cook the proteins inside your body? What over the counter medicine can cause a potentially life-threatening reaction with SSRIs?
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 Mood. Want to know what the wet-dog shakes have to do with humans? What drug reaction causes a temperature so high it can cook the proteins inside your body? What over the counter medicine can cause a potentially life-threatening reaction with SSRIs? Listen to find out.
Today's episode starts in the emergency department. The intern presents a case of a 23-year-old woman with a fever, which started a few hours prior to arrival. She’s had a few episodes of diarrhea, no vomiting, abdominal pain or blood in the stools. She's had a mild cough for the past few days, though this is improving. In addition, she feels shaky and jittery.
The intern notes a past medical history of depression for which the patient takes fluoxetine, brand-name Prozac in the US. She’s also taking over-the-counter cough medicine, dextromethorphan, often brand-name Robitussin here. He says the patient doesn’t use tobacco, drinks 1-2 drinks per week and occasionally uses marijuana.
Her vitals are as follows: temperature 101.4F or 38.5 C, heart rate 120 bpm, blood pressure 120/80, respiratory rate 20 bpm, pox is 100% on room air. The intern reports the patient was shaky, but the physical exam was unremarkable with clear lungs, a rapid, but otherwise normal, heart rate and no abdominal tenderness.
You ask if the patient has recently been on antibiotics or traveled outside the US, considering risk factors for bacterial diarrhea like e. coli or c. diff. The intern says no. He concludes by summarizing, most likely a viral infection, causing cough and diarrhea. He wants to check lab work, a chest x-ray to rule out pneumonia and urine specimen to rule out urinary tract infection. The patient doesn't have symptoms particularly concerning for either, but you agree, those tests are easy to obtain and therefore often done in patients presenting to the emergency department with fever. He’s already ordered acetaminophen, AKA Tylenol or paracetamol, and IV fluids for her.
You agree with his plan, tell him you have a lot of sick patients to see first, and to let you know when the results are back. I’m going to share with you one thing we EM physicians wish everyone knew. The longer you have to wait to be seen, the less likely you are to be dying. Everyone hates waiting, understandably so. You’ll have my full and immediate attention with no wait if you have a cardiac arrest. Same with a stroke, heart attack, a gunshot wound, stabbing or a bad car accident. As painful as waiting is, and there are few people more impatient than myself, better to be in the category of people who wait then those who don't.
Fever in a young healthy person can be an emergency, but as we've talked about before common things are common and when you hear hoof beats, think horses not zebras. Common diagnoses include viral infections, urinary tract infections, and appendicitis. We could talk for at least week about fever, but fortunately this isn't an infectious disease podcast, it's a toxicology podcast so let's just skip everything else and focus on toxicological causes of fever i.e. hyperthermia. Most are rare and difficult to diagnosis, zebras not horses. In order to do so you have to have a high level of clinical suspicion, if you don’t remember to include them on the list, you won’t diagnose them. In most cases, They are a diagnosis of exclusion, meaning you have to rule out infections and other problems first.
Question # 1. Which of the following toxins can cause a fever?
A. MDMA, ie ecstasy or Molly
B. cocaine
c. Aspirin.
D. diphenhydramine ie Benadryl
E. All of the above.
The answer is E. All of the above can cause hyperthermia. Toxicologic hyperthermia occurs via different mechanisms, many of which we've touched on in other episodes. Aspirin and dinitrophenol uncouple oxidative phosphorylation or energy generation inside cells, meaning energy is released haphazardly, causing an elevated temperature.
Diphenhydramine causes anticholinergic toxicity along with a number of other drugs and toxins. We'd expect an elevated heart rate, present here, but also high blood pressure which she's lacking. Do you remember the Mad as a Hatter pneumonic? Question #2. If she has anticholinergic toxicity her skin would be:
Dry
Wet
Answer A. She should be dry as a bone, which the intern denies.
The sympathomimetic toxidrome causes fever and tachycardia. From toxins like MDMA, cocaine and meth. Again, elevated blood pressure, missing, and in this case, wet skin or diaphoresis. The resident says her skin is normal
Question 3. Alcohol and benzodiazepine use disorders can cause it. Is it?
A. Overdose
B. withdrawal?
Answer: B. Alcohol or benzodiazepine withdrawal are culprits. She is shaky, which goes along. He said she drinks a few drinks a month and denied prescription drugs, other than Prozac. You remind him patients can obtain benzos on the street, but agree it’s unlikely the cause of her symptoms.
You ask him if he thinks it could be serotonin syndrome or neuroleptic malignant syndrome. He gives you a blank look. Rather than pontificating, you decide it’d be better to examine her and discuss in more detail afterwards.
A few hours later, after treating sepsis, a pedestrian struck by a car and someone with concerning chest pain, the intern flags you down with her results. The lab work including a complete blood count, CBC, as well as chem seven and electrolytes is unremarkable. Her chest x-ray is normal. He asks about sending stool studies for c.diff, other infections. It's overkill in this otherwise healthy patient without risk factors and only 3 episodes thus far. He says he discussed the lab results with her and asked again for a urine specimen as soon as she can provide one. If anyone listening has been a patient in the Emergency Department, can you please tell me why no one can urinate in the ED? I think myself and the nurses have spent at least half of our medical careers asking patients for urine specimens.
With your sick patients stabilized, for now, you have a chance to go examine her. The patient is sitting on the stretcher in a hospital gown with her knees pulled up to her chest, shivering. Your emergency department, like every other ED seems to have a single temperature, freezing. As you enter, the nurse removes a thermometer from the patient’s mouth. “Temperature 102.2,” she reports snapping the machine closed. Increasing now to 39C.
“How long ago did you give the Tylenol,” you ask.
“Two hours,” she answers. Hmm. The patient’s heart rate is still 120 bpm despite the intern ordering a 2nd L of IV fluid. That might be the fever, though the acetaminophen should’ve kicked in by now.
The patient gives you the same history she gave the intern. She asks about her lab results and seems surprised to hear they’re normal. The intern mentioned already discussing them, but nevertheless you review them again.
You move onto the physical exam, agreeing with his heart, lung and abdominal exam. Returning your stereoscope to your pocket, she asks you again about her lab results. Now you’re becoming concerned about her mental status. Sure, patients don't always hear or understand things the first time we say them. But this is perseverating. The nurse says she’s asked repeatedly for tylenol despite having gotten the dose 2 hours ago.
You continue your exam now with fever and altered mental status in mind. You test her neck for meningismus, stiffness, thinking about meningitis. Her neck is supple and she denies headache and neck pain. Reassuring. You check her cranial nerves, the nerves rising from the brain stem. Those are normal as well, then move onto her extremities. She has good strength and sensation is intact.
She continues to shiver during the exam. Specifically in her case, it's shaking rather than a tremor. A tremor could go along with alcohol withdrawal or a lithium toxicity. Patients with fever and chills get shaking, no doubt you’ve had this yourself during an illness. It’s relatively mild and feels better when you get under the covers or a blanket for example. When a patient has truly uncontrollable, severe whole body shivering we call it rigors. Rigoring is often a sign of bacteremia, or bacteria circulating in the bloodstream.
Is that what she has? Possible, but an otherwise young and healthy person doesn't develop bacteremia and rigors out of nowhere. You watch her closely, noting the shaking starts in her head and moves down, like she's a wet dog, shaking off water. She also has intermittent roving eye movements, like she’s watching a disorganized tennis match This is opsoclonus, which we talked about in the Hitchhiker episode. A sign of severe neurological disease or you guessed it, a toxin.
Question 4. This is a tough question more for the medical professionals. The wet dog shakes are associated with what?
A. Lithium toxicity.
B. Neuroleptic malignant syndrome.
C. Serotonin syndrome.
D. Parkinson's disease.
The answer is A. serotonin syndrome. Lithium causes a tremor, not whole body shaking. Same with Parkinson's. We will come back to neuroleptic malignant syndrome in a few minutes. Wet dog shakes are a vivid description of otherwise hard to describe, fairly subtle physical exam finding. It's almost pathopneumonic, for serotonin syndrome, meaning almost exclusively associated with it.
What is serotonin syndrome? It’s also called serotonin toxicity, which describes it more clearly I think for those who are less familiar. It's too much serotonin in the brain and central nervous system, but the exact mechanism isn’t well understood. It can occur with toxins inhibiting serotonin reuptake, decreasing its metabolism or increasing its release to name a few, but exactly how this occurs, why it happens in some patients not others, isn’t clear.
Too add to this, we don't actually know how many antidepressants work, including drugs like fluoxetine a selective serotonin reuptake inhibition, an SSRI. Originally the belief was increasing serotonin relieved depression, however studies have since mostly disproven the correlation between serotonin levels and depression. So we’re not entirely sure.
Back to SSRIs, like fluoxetine ie Prozac. As I’m sure you know, they are extremely commonly used worldwide, for depression and anxiety. The reason is because they have relatively minimal side effects, especially in comparison with older generation antidepressants, like tricyclics, imipramine and monoamine oxidase inhibitors, like phenelzine. Also, they are much less lethal in overdose. It’s possible to develop serotonin syndrome from a single serotonergic drug like an SSRI, but it’s really rare. Typically, it results from a combination of drugs or toxins.
How do we test for serotonin syndrome? We can’t. There's no test and if you don’t think about it, you’ll never diagnosis it. More on this in the next episode when we’ll discuss a famous, lethal case of undiagnosed serotonin syndrome. One that changed internship and residency for every single physician in the US.
There are several different diagnostic criteria, the most commonly used is the Hunter Serotonin Toxicity Criteria. I don’t want to belabor this, you can look up specifics if you’re interested. Essentially you need a combination of the following. Exposure to a serotoninergic agent, along with some combination of fever, altered mental status and muscle changes. Muscle changes include tremor, shaking, hyperreflexia and clonus. Hyperreflexia is when you tap the patient’s knee with a reflex hammer and the response is so sharp they almost kick you in the nose. Clonus is an extension of this when their leg continues to swing back and forth in a rhythmic fashion after just one tap.
You call the intern to the bedside for a more through physical exam. You start to ask him a question at the bedside, then change your mind a tell him to step out instead. Good move, because when you ask if he thinks this is neuroleptic malignant syndrome or serotonin syndrome. He says “Uhhhhh. Ummmm.”
Is he the world's worst intern? Nope. This is actually a tough question which can fool the best of us. Both of these conditions are frequently missed or missed diagnosed. I think we have enough information about our patient to make the distinction but let me touch on the differences briefly because it can be confusing to clinicians at the bedside, as well as to test takers on board exams.
Neuroleptic malignant syndrome, or NMS, is a completely different disease, but looks similar and occurs in a similar patient cohort. It causes fever, altered mental status and muscle changes. The issue isn’t serotonin excess, but rather dopamine deficiency. Dopamine is essential for movement. Parkinson’s disease is due to a lack of dopamine. If you don't have enough dopamine, you get rigidity, in NMS called lead pipe, or cogwheel rigidity. When you move a patient’s limb it feels like there is resistance with each inch. It’s not volitional.
NMS can be caused by withdrawal of Parkinson’s medicine l-dopa if you stop taking it suddenly. Neuroleptic is the old term for antipsychotics and these medicines are by far the most common cause. It’s not uncommon for patients with severe psychiatric disease to be on both SSRIs and antipsychotics. Patients with both syndromes can have severe altered mental status with agitation and even coma, so the history of exposure can be difficult to obtain or completely lacking. Thus the reason a high level of suspicion is necessary to diagnose this zebra.
Both as mentioned have fever and altered mental status, the key to differentiating them is two things. The timing and the muscle exam. Serotonin syndrome usually occurs in within a day, often within hours. NMS occurs more gradually over days, even a week. As we said, serotonin syndrome causes hyperreflexia and clonus. In contrast, NMS causes rigidity.
Back to the intern. You spare him further embarrassment by answering your own question and telling him you need a muscle exam. He says I left my reflex hammer a home. You suppress a smile, remembering the reflex hammer you carried everywhere in medical school, now collecting dust in the back of a closet. “Use your stethoscope,” you say. He has the patient sit up on the side of the bed and taps her knee with the bell. She almost reflexively kicks him in the nose, and her leg swings for 8 counts. Positive clonus.
We’ll continue the workup, continue to rule out infectious causes, but we have enough to make a presumptive diagnosis and start treatment. She has exposure to serotonergic agents, more than one. Fever, altered mental status, the wet-dog shakes and clonus. This is serotonin syndrome until proven otherwise.
You discuss this with the patient. She responds, “What do you mean I've been taking Prozac for 10 years without an issue.”
What do you think? Question # 5 We made the wrong diagnosis.
True.
False
The answer is B. false. I don't think we’re wrong. There is another serotonergic substance in her history. Question 6. Was it?
A. cough syrup, dextromethorphan
B. Marijuana.
C. alcohol
The answer is A. dextromethorphan. Yes, cough syrup. The patient says that she hasn't taken any dextromethorphan for two days since her cough was improving. What do you think now? Are we on the wrong track? Well, hmm. This information bothers me a bit. There’s a case report or two of delayed onset serotonin syndrome, but typically as I said symptoms start within hours and almost always a day. Still, her clinical picture is consistent, serotonin syndrome is a serious, potential lethal disease so I wouldn’t let it stop me from treating her.
Question 7. What is the treatment?
A. Benzodiazepines, like lorazepam or diazepam, i.e. Ativan or Valium.
B. Methylene blue.
C. NAC, i.e. acetylcysteine.
The answer here is A. benzodiazepines. If you’re a regular listener of the podcast, you’ve probably realized this is the right answer to almost every question. We toxicologists love to use benzos.
The hyperthermia in serotonin syndrome is likely due to excessive muscle activity, producing heat. Therefore, sedatives like benzos are useful to counter act this. NAC is the treatment for acetaminophen toxicity. And if you said, methylene blue uh oh you just made the patient worse.
You tell the intern to order an IV dose of benzodiazepines, it doesn’t matter which one. We often use lorazepam and diazepam in the ED. Treatment requires titrating the dose to the patients’ symptoms, so we’ll give a dose, then wait about thirty minutes or so to see her response.
A few minutes later, the nurse walks into the doctor’s station holding up a biohazard bag with a urine cup inside. She says, “We finally got a specimen, I wanted you to see it before I send it to the lab.” It’s hard to miss. The urine is blue.
We will have to stop here for today. Listen to episode 2 to find out the cause of the blue urine and what it means for our patient. If you’ve been listening to previous episodes, I bet you already know. This is a fictional case, as are all our cases, to protect the innocent. But next time, we’ll also discuss the very real and very tragic death of an 18-year-old woman from serotonin syndrome and how the repercussions affected the medical training of every American intern and resident afterward.
Last question and today’s Pop Culture Consult. In the 1990s and early 2000s, Prozac was featured in Time magazine and references were found across genre’s in books, movies and music. Which of the following didn’t mention Prozac?
American psycho
South Park
Sex and the City
The Sopranos
Breaking Bad
Follow the Twitter and Instagram feeds both @pickpoison1 for the answer. Remember, never try anything on this podcast at home or anywhere else.
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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.