Locked In

Imagine a fever that doesn't break with acetaminophen (i.e. Tylenol or paracetamol). A toxin that leaves you trapped inside your own body. Want to know what your doctor is really thinking when you tell them you take a round white pill? Listen to find out!

Transcript

This is Pick Your Poison. I’m Dr. JP ER doctor, toxicologist, and unapologetic lover of all things poison. 

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Imagine a fever that doesn't break with acetaminophen (i.e. Tylenol or paracetamol). A toxin that leaves you trapped inside your own body. Want to know what your doctor is really thinking when you tell them you take a round white pill? Stay right here to find out.

This is an interactive story. 

Survival isn't guaranteed. 

What happens next depends on you. 
 Will our patient live or die? 

It's up to you and the choices you make. 

Button up your white coat and let's get started! Time to Pick Your Poison.

Tonight, we begin in the emergency department.

The intern presents the case of a 67-year-old man with an altered mental status. The patient was wandering on the highway. 

You picture it: a man, muttering to himself, bathed in the harsh glow of headlights. Cars roaring past, He’s skimming the edge of danger as he lurches along on the shoulder. A startled driver swerving past, calling 911 to get him out of danger before it's too late. 

The intern says the patient is mildly confused, talking about the CIA monitoring radio waves in his head and the government injecting trackers. He is however oriented to his name, the year and month as well as the fact he’s in the hospital. 

The patient complains of mild cough, a runny nose, and pain in his feet for several weeks. Vital signs are as follows: Temperature 100.9 F, 38.2 C, heart rate: 120/80, respiratory rate: 18, Pulse ox: 100% on room air.

The intern says, other than the mental status as previously noted, the patient's exam is unremarkable. Heart and lungs normal, no abdominal tenderness, good strength in all extremities.  His feet have good circulation and no signs of infection. 

The intern ordered lab work including a complete blood count and chem 7. Given the mild elevation in temperature, he ordered a urinalysis, chest x-ray and a flu/covid swab. You agree with this initial workup and go in to examine the patient yourself. 

The patient is disheveled and unkempt, likely undomiciled. He says he has a history of bipolar disease. He denies other past medical history. He’s been taking his medicine, a round white one. 

Question #1. This medicine is most likely 

A.                Acetaminophen, ie Tylenol or paracetamol

B.                 a multivitamin

C.                  a psychiatric medicine

D.                Who the heck knows

The answer here is D. It’s anybody’s guess what the white pill is. If you answered this question, then you got it right, because any of the above can be round and white. Every manufacturer of medicines can make them into whatever size and shape they want. This is especially true once things become generic. Viagra, for example, is famously the little blue pill, but generic forms can be white and round, just like every other medicine. 

We’ll give our patient a pass in this case, since he’s obviously confused, but I hear this description of meds on a daily basis from patients without any mental status issues. We medical professionals do not know which round white pill you're on, so please take a picture of your meds and put it in your phone, or put a list in your wallet, or something, so this important info is available when you need it. 

The patient’s mental status is as described by the intern. He carries on a regular conversation with you but is easily distracted by external stimuli and is at the same time conversing with someone who's not there. Mentally agreeing with the intern's excellent history and physical exam, you leave the room. 

There is no past medical history listed in the patient's electronic medical record. Whether this means he's never been to your hospital before, or if he's been registered under a new medical record number is anybody's guess. It's a little difficult to sort out what's going on here without any collateral information from family members, or correlation with past medical history such as prior ED visits, diagnoses, or medicines. 

The patient says he's heard voices for years, so this isn’t new onset psychosis. You can have psychosis with bipolar disease, though this seems more like schizophrenia, but unclear at this moment. Is this ongoing, underlying disease or an acute exacerbation? Further complicating the clinical picture is the low-grade fever, which could be a cold or something more serious. The workup is a bit of a fishing expedition, you agree with the intern’s plan, and wait for the results.

The patient’s labs come back with a mild white blood cell count and lactate elevation. The white blood cell count usually means inflammation or infection, but mild elevations are very non-specific. These days, we're all concerned about lactate levels because we use them as an indicator of sepsis and septic shock. Therefore, in this case, I would presume that the patient has an infection, treat with antibiotics and IV fluids, and admit the patient to the hospital for further workup and evaluation. 

That said, infection isn't the only thing causing an elevated lactate. It can be from seizures, chronic alcohol use, medicines, including antiretrovirals and metformin, albuterol in breathing treatments, liver failure or renal failure, or even the nurse keeping the tourniquet on for too long while trying to find a vein during a blood draw. 

Two days later, the hospitalists consult you for a toxicology consult on an inpatient who has become increasingly agitated. You go up to the room and recognize this man as the same patient you admitted two days ago. The resident reviews the hospital course with you. The team looked for signs of infection but thus far haven't found anything. His chest xray, urine and blood cultures were negative. His lactate, only mildly elevated to begin with, resolved rapidly. They're not sure why it had bumped but don't think it's particularly significant at this point. 

Despite the improvement in his labs, he became increasingly agitated. Currently his vitals are as follows: temperature 101.5 F (38.6C), heart rate 115 beats per minute, blood pressure 120/80, respiratory rate 20, oxygen saturation is 100% on room air. 

Let’s see, his temperature is going up despite his lactate getting better and the hospital team not finding any source of infection. They've continued to treat him with antibiotics. His heart rate is elevated, probably due to the fever in this case as they’ve given him a lot of IV hydration. 

The resident tells you they did some digging and found a different chart in the electronic medical record under his name with a different spelling. The old chart confirmed your suspicion he has schizophrenia. He’s been in and out of psychiatric hospitals several times. No other past medical history was noted. He smokes tobacco, but no report of illicit substance use. 

The team restarted his prior regimen of psychiatric medicines in the hope that it would reduce the hallucinations. In the past, he was treated with intramuscular injections of Haldol, an antipsychotic, long-acting depo injections, lasting for a month at a time. They didn’t see recent doses, so they started him on oral Haldol in the hopes of improving his mental status. Despite this, he’s gotten worse, prompting the toxicology consult.

Worried you might have missed something serious in the emergency department, you mentally review your ED workup, but don’t remember any red flags. The inpatient resident continues, “We did a spinal tap for rising fever and worsening mental status. It was normal, some cultures are still pending, but no evidence of encephalitis or meningitis.” 

Question #2. When patients abruptly worsen in the hospital on the second or third day after admission, a common complication is? 

A.    Alcohol withdrawal

B.     Medication error 

C.     Underlying psychiatric disease

The answer is A When patients worsen after two days in the hospital, alcohol withdrawal is always at the top of the list.

“Any history of alcohol?” You ask. 

“Not that we know of.” 

A classic presentation is a patient not forthcoming about the amount of alcohol, admitted to the hospital for surgery, and then two or three days later abruptly becomes worse due to withdrawal.

Is that what's happening to our patient? Worsening confusion and altered mental status, with fever and rapid heart rate absolutely could be caused by alcohol withdrawal. We need some more information, so you go to the bedside for an exam.

Your first thought stepping into the room is that he looks a lot worse than he did in the Emergency department. He doesn’t acknowledge you and is mumbling something about the CIA. You say hi, reintroduce yourself and ask if he remembers you from downstairs. He doesn’t respond. 

His skin is sweaty. You listen to his heart and lungs, other than the rapid heart rate, normal. You ask him to stick out his tongue, to check for fasciculations caused by alcohol withdrawal. He mumbles again. You use a tongue depressor to look inside, no fasciculations. He doesn’t have a tremor in his extremities, either. 

Alcohol withdrawal doesn’t seem very likely at this point. The inpatient team has done a thorough workup for infection, so far negative. Why did they call you for a consult? To consider cases of toxicologic hypothermia. We've talked about this in prior episodes. Alcohol withdrawal is on the list, but doesn’t quite fit here without a history of alcohol use and no tremor on exam.

Malignant hyperthermia, we've talked about in the past, a genetic disease of the muscles. When patients are exposed to things like anesthetic gases, or paralytics like succinylcholine, they develop hyperthermia and muscle rigidity. Doesn’t fit here. 

What about a sympathomimetic toxidrome due to cocaine or meth. It’s easy to find drugs when living on the street. His presentation in the emergency department didn’t fit, no tachycardia or hypertension at that point. His skin exam was normal, not sweaty like it is now. Unless he was taking cocaine or meth while in the hospital, and it should be noted that this is definitely possible, it doesn’t fit either. His current diaphoresis, ie sweatiness, is probably due to the fever. Also, he’s not hypertensive. So, not likely. 

Is this anticholinergic toxicity? We've said before that that can cause fever and altered mental status, but it usually causes dry skin. In addition, they haven't been giving him any anticholinergic medicines, so unless he took a surreptitious Benadryl overdose, it doesn't fit. 

We talked about uncouplers where the cell instead of generating energy and ATP, loses it as heat. ASA and dinitrophenol. These are fascinating drugs. Listen to these Malignant Heat episode for more but again doesn’t fit.

This leaves us with two causes of hyperthermia we definitely need to consider closely, serotonin syndrome and neuroleptic malignant syndrome. Both are caused by drugs used to treat psychiatric disorders. Both look fairly similar, with a few key distinctions. First, let's talk about the similarities. Both serotonin syndrome and neuroleptic malignant syndrome cause fever, altered mental status and muscle changes. 

But they're caused by different mechanisms, different drugs, and the muscle changes are distinctly different as well. Serotonin syndrome is caused by things elevating serotonin, SSRIs for example, selective serotonin reuptake inhibitors, like Prozac and other similar drugs. You ask the intern if they've treated the patient with anything other than Haldol, he says only the antibiotics. There is one antibiotic that can cause serotonin syndrome, and that's linezolid. It's a really big gun antibiotic for resistant infections. He confirms the patient hasn’t gotten this. 

Neuroleptic Malignant Syndrome is also caused by psychiatric drugs. But rather than SSRIs, it's caused by antipsychotics. These drugs primarily affect dopamine, rather than serotonin, and Neuroleptic Malignant Syndrome (NMS) is a problem with dopamine levels. 

One of the key distinguishing features between serotonin syndrome and NMS is in the muscle exam. That's question number 3. Neuroleptic malignant syndrome causes. 

A.                Lead pipe rigidity

B.                 Flaccid paralysis

C.                 Hyperreflexia and clonus

This is a tough one if you aren’t a medical professional. But if you've been listening to prior episodes, you just might know.

Answer: A. NMS classically causes lead-pipe rigidity, meaning the patient's muscles are stiff and difficult to move. Flaccid paralysis is caused by things like botulism and paralytics. Hyperreflexia and clonus are muscle changes caused by serotonin syndrome. This is where the muscles are essentially hyperactive. For example, if you tap the reflex hammer on the knee, the patient’s leg will jerk back and forth several times, instead of once. 

Back to our patient. We know, he takes psychiatric medicines, could this be serotonin syndrome or NMS? 

A good way to start is with his reflexes. You’re not a neurologist or a medical student, so you don't carry a reflex hammer, but you use your stethoscope to tap his knee, his leg barely moves meaning his reflexes are hypo-reflexic. This isn't likely to be serotonin syndrome. 

You ask the patient to raise his arm. He doesn't respond. You raise it up off the bed. It’s hard to move, like he’s trying to resist you but it's clear he's not paying any attention. He’s still looking the other way and mumbling about the CIA. You move his hand back and forth at the elbow, feeling stiff resistance in the joint. This is lead pipe rigidity, so-called because apparently, I’ve never tried it myself, but this is what it feels like to bend a lead pipe. 

There's no test to tell the difference between NMS and serotonin syndrome, so we have to go on history of exposure as well as the physical exam. I'd be pretty confident that this is Neuroleptic Malignant Syndrome because the patient has been on Haldol and his physical exam with fever, altered mental status, and lead pipe rigidity fits.

You ask the intern about the patient's labs. He says, "The basically normal except for an elevated CK.” 

Creatine kinase is an enzyme elevated with muscle damage, this also goes along with NMS. Why? The muscle rigidity is so severe It leads to a muscle breakdown reflected in the elevated CK and can cause rhabdomyolysis and ultimately kidney failure.

This is confirmatory for NMS, making this case pretty clear. However, I have to say in real life, it can be tougher to tell NMS from serotonin syndrome when patients are taking both antipsychotics and SSRIs, a not uncommon combo. Another diagnosis further complicating matters is catatonia. In severe catatonia patients can be comatose, with high fever rigid extremities and even rhabdo. These patients are often on antipsychotics for obvious reasons. I’ve had a number of cases in my career, as I’m sure have many experienced toxicologists, psychiatrists, and intensivists, where its’s extremely difficult to tell NMS from catatonia.  

There is one saving grace. Treatment is variable for these overlapping diagnoses, but there is one thing that can treat all three, and that's benzodiazepines, every toxicologist's favorite drug. The resident asks what Benzo to give. Anyone is fine. I often start with lorazepam, brand name Ativan, because that's quick and easy to obtain in most hospitals. I would definitely give it intravenously, our patient is pretty sick. 

Do we expect an immediate response? This is another difficult question. Sometimes, yes. I once had a patient rigid and stiff on the bed completely unresponsive for several days. I told the medicine resident to give a benzo and she called me two hours later shocked, saying the patient was now awake, sitting up and talking. But, the dose can be difficult to titrate because the side effect of benzodiazepines is sedation and altered mental status. We usually start with smaller doses and titrate up to avoid the side effects, but it can be hard to know when you give a low dose if the patient isn't responding because they need a higher dose, or if you're going down the wrong path with the wrong diagnosis. It's the art, rather than the science, of medicine. But in general, if the patient doesn't get worse, then I usually take that as a good sign to give more.

Different benzos have different times to onset. IV lorazepam starts to work in several minutes. The resident gives a dose, you sit down to write a consult note and wait to see what happens. About 30 minutes later, the resident says the patient's temperature is now 101.0. His muscles are still stiff, but he is at least moving a little bit on his own. 

You agree it seems to be helping, and recommend slowly titrating up the dose. You also tell the intern to stop the Haldol. 

So, what is actually happening to this patient and why is it caused by antipsychotics? Neuroleptic malignant syndrome is caused by a lack of dopamine. You need dopamine to move, essentially. And if you don't have enough dopamine, you can't move. As it’s name suggests, its caused by antipsychotics, or neuroleptics they're old name. Most are dopamine antagonists, reducing dopamine levels in the body. NMS can also be caused by withdrawal from drugs that increase dopamine, as seen in patients with Parkinson's disease. We use L-DOPA, i.e. Levo-DOPA, a precursor to dopamine to treat Parkinson’s. If a patient suddenly stops taking L-DOPA, then they can also develop neuroleptic malignant syndrome due to dopamine absence. Some have suggested that this should be called Parkinson's hyperthermia to distinguish the two, but the mechanism is the same. 

We don’t know exactly what causes NMS, its believed to be due to a lack of dopamine secondary to D2 receptor blockade. It’s thought this results in abnormal thermoregulation in the brain and increased calcium release in muscles leading to rigidity.  

NMS is rare to begin with and much rarer than it used to be. It’s estimated to occur in 0.02%-3% of patients taking antipsychotics. It's far less common with newer, atypical antipsychotics rather than traditional first-generation ones like Haldol. Today atypicals are preferred due to better side effect profiles. Because NMS is so rare, it's important for us in the medical profession to discuss it. It's one of those diagnoses like pulmonary embolus, if you don't think about it, you'll never diagnose it.

The other difference we didn't discuss between NMS and Serotonin Syndrome is the time to onset. Serotonin syndrome happens hours after exposure to elevated serotonin, for example if a patient takes an overdose or if two serotonergic drugs are taken at the same time. NMS occurs over days to weeks. It is sometimes associated with an increased dose of a dopaminergic drug, but it can occur anytime.

Did we miss NMS in the emergency department with our patient? Good question, it's difficult to say. It's possible the mild temperature was the beginning of NMS, but difficult to know if he really had an altered mental status or if it was just his baseline mental status due to schizophrenia. Always, it’s a diagnosis of exclusion as there’s no test, as mentioned earlier. Without a doubt, we needed to treat for and rule out infection first. Further confusing the clinical picture, is the tendency of NMS to wax and wane in severity. Maybe we missed it, or maybe he did have a mild viral infection, and the NMS was from restarting his Haldol? It’s impossible to say for certain either way. 

NMS is a true emergency. It was first described in 1956. Original mortality estimates were as high as 30%, shockingly high. In modern times, it's estimated that the mortality rate is about 16% if associated with first-generation antipsychotics. It’s less severe with second-generation, atypical antipsychotics, with the mortality rate around 3%. Fatalities result from complications of hyperthermia including multi-system organ failure, as well as cardiac arrhythmias, and renal failure. Interestingly, it has a hereditary component that’s not well understood, but if family members have had it, that's a risk factor for development.

 Benzodiazepines are an excellent first-line treatment, we do have other treatments. What are they? That's Question 4. 

A.                Diphenhydramine or Benadryl

B.                 Bromocriptine

C.                 Acetaminophen ie Tylenol or paracetamol

Answer: B. bromocriptine. First and foremost with NMS, is withdraw of the exposure, so stop the medicine or medicines causing it. Or restart l-dopa if it’s been withdrawn. The second step is, benzos as we’ve said. Third, risks and benefits of other medicines can be considered. 

We have a medicine that increases dopamine, a dopamine agonist called bromocriptine. It can only be taken orally or via gastric tube, there’s no IV preparation. It can worsen underlying psychiatric illness, so you have to be cautious, especially if you’ve just stopped antipsychotics. 

Dantrolene has been used. This is the antidote for malignant hyperthermia. It reduces muscle rigidity by counteracting calcium inside the muscles. Some case reports suggest dantrolene may be useful for the muscle rigidity from NMS, though this is far from definitely proven. Dantrolene causes muscle weakness, so if you have a ventilated patient you are trying to extubate, this could be an issue. 

Do antipyretics, ie antifever agents, like Tylenol work? That’s question #5.

A.    Yes

B.     No

Answer, B. No, actually antipyretics don't help at all in NMS. The patients can and do get life-threatening hyperthermia with temperatures above 105F or 40.5°C. Temperatures this high cause multi-system organ failure due to proteins becoming denatured. It's like frying an egg: The temperature causes the egg to change from liquid to solid and the color to change because the proteins are denatured as you cook it. The same thing happens in the body at high temperatures. However, antipyretics like Tylenol don't work to lower the temperature and you may need to put the patient in an ice bath or use mist and fans to cool them and keep their proteins from denaturing.

Whatever treatment you decide to use, it should be tapered off slowly as NMS can last for days to weeks, and a slow taper is best at preventing recurrence. After removal of the offending agent, the natural history, meaning without treatment, is improvement in symptoms over 1-2 weeks. Interestingly, Electroconvulsive therapy has been reported to help, though improvement is reported around the third or fourth of ten ECT sessions in one series. It's difficult to know if this is truly ECT or just a natural course of NMS improving over time. ECT could be useful in patients where there's difficulty telling NMS from catatonia, as I mentioned earlier.

Does NMS occur in antipsychotic overdose? Interestingly, no. It's usually related to sub-acute or acute exposure. And again, this is in contrast to serotonin syndrome. Some psychiatrists like to treat severe schizophrenia with a depo antipsychotic, a preparation given as a shot that lasts for a month, useful in patients with severe disease preventing them from regularly taking their medicines. I can tell you from experience, NMS is really difficult to treat after depot antipsychotic treatment, with symptoms lasting for 30 days.

Back to our patient, the hospitalist team increases doses of benzodiazepines until his fever and altered mental status improve. He's able to move spontaneously, with no more muscle rigidity. They elect not to use Bromocriptine or dantrolene as he is responding well to the benzodiazepines. He stays in the hospital for over two weeks as they titrate the benzos down and restart antipsychotics, this time using an atypical, rather than haldol. Two weeks is the recommended time to wait before restarting. 

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

Last question in today’s podcast. What is the risk of reoccurrence of NMS in our patient? 

A.                > 90%

B.                 Around 30%

C.                 <1%

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.