Serotonin Syndrome (or Serotonin Toxicity) is an uncommon and complex life-threatening condition that is caused by too much serotonin in the synapses (either due to increased release, or decreased reuptake). It is important for EMS providers to be aware of this condition for two reasons. Firstly, the diagnosis is purely a clinical one. This rare disease needs only patient history and physical assessment for diagnosis, unlike many diseases, which rely on the “in-hospital” tools of imaging and labs. Secondly, while it is life-threatening, the initial phases of treatment can be initiated in the field.
To be able to place Serotonin Syndrome on your differential, it is important to understand it, and its presentation, fully. I tell paramedic students that while it is true that when you hear hoofbeats you shouldn’t think zebras; if you have never seen a zebra it’s easy to think “well that’s a funny-looking horse”, dismissing it as an uncommon presentation of an innocuous disease. So let’s talk about what things you should be thinking about when making the diagnosis (yes, paramedics diagnose, get over it) of Serotonin Syndrome in the field, followed by treatment modalities.
Serotonin itself, also referred to as 5-Hydroxytryptamine (or 5-HT) is a neurotransmitter related to happiness, learning, reward, and memory. Humans have 14 types of serotonin receptors, each with their own end effect and associated second-messenger systems.
MAKING THE DIAGNOSIS
The diagnosis of Serotonin Syndrome relies on the history, physical assessment, and the provider considering it as a potential diagnosis. While the history should be the biggest clues for the provider, in the case of intentional overdose, it is not uncommon for a patient to obfuscate their ingestion or to be too obtunded (especially in the case of a poly-pharm overdose) to be able to answer questions regarding their ingestion. The diagnosis is also complicated by the fact that it could easily be “written off” as a patient who “just did a little bit too much meth today”, especially with a nationwide trend towards increased illicit sympathomimetic use. This diagnostic momentum could significantly delay treatment with consequent increase in morbidity.
This figure shows a synaptic cleft. Note the ways that serotonergic drugs can alter the normal function of this system. Serotonin toxicity is achieved when either by increased secretion or by decreased reuptake or metabolism, a dangerous level of serotonin remains in the synaptic cleft.
One of the things that should clue you in to the diagnosis of Serotonin Syndrome is the patient’s history. This may be as simple as the empty bottle of escitalopramin your patient’s hand, or something more subtle like a recent change to their SSRI dose, or recent addition of tramadol to their medications for their migraines. Like every screening criteria or test we do, the pre-test probability is the lens through which we view their presentation and how we interpret those tests. Further, while Serotonin Syndrome is not reported all that frequently, it is thought that this is in part due to underrecognition, even in the ED.
The list of medications with serotonergic activity is long and distinguished, but having a good grasp on home meds, and specifically which ones are SSRIs or SNRIs, will be helpful. In the field, resources like Epocrates and UpToDate (or just plain old Google) should not be underestimated for their role in Just In-time Learning to help tease out which medications may have serotonergic activity.
SSRIs (escitalopram, citalopram, fluoxetine, and sertraline being the most common) are common culprits for Serotonin Syndrome, with recent changes to the dose being worrisome, as well as recently starting the medications. Similarly, new or changes to a patient’s MAOI (MAOIs may in fact be more concerning for the development of serotonin toxicity), SNRI (Venlaflaxine), trazodone, or TCA (amitriptyline) should help spur you to considering Serotonin Syndrome. There are even antibiotics, such as linezolid which have been found as culprits in serotonin toxicity!
Other medications include some migraine medications (tramadol, but also others), lithium, anti-emetics like ondansetron, as well as street drugs like methamphetamine, MDMA/ecstasy, and cocaine. For many of these medications and drugs, Serotonin Syndrome is much more common when more than one serotonergic medication is combined. Beware drug-drug interactions!
PHYSICAL ASSESSMENT FINDINGS
While the history is important to keying in on the diagnosis of serotonin syndrome, and certainly informs how the physical exam is interpreted, the physical exam is really going to be high-yield here.
Serotonin Syndrome is classically described as a triad of Altered Mental Status, Autonomic Hyperactivity, and Neuro-Muscular Changes, all tied together by an exposure to a serotonergic drug; though the neuro-muscular changes will be the thing that really helps narrow in on the diagnosis.
When it comes to mental status changes, while in all but the most severe cases, you are unlikely to find a truly altered patient, more subtle findings such as pressured speech, paranoia, or being easily startled, as well as hypomania should be appreciated. Agitation may also be noted.
The patient will also present with hyperthermia, hypertension, and tachycardia as evidence of autonomic stimulation. It is these things which may be confused for a sympathomimetic toxidrome, and dismissed simply as stimulant use. Similarly, dilated pupils, dry mucous membranes, and flushed red skin are consistent with this picture of autonomic hyperactivity. Though these may be confused for an anticholinergic toxidrome (dry as a bone, mad as a hatter, red as a beet). It is important that these not be confused, and the thing that will be most helpful for differentiating this patient, other than history, is going to be the neuromuscular changes. In particular, the hyperthermia can be striking, and is the finding most highly associated with severe outcomes such as multiorgan failure and death.
The history needed to identify patients at risk for serotonin syndrome is all pretty standard information to gather for paramedics, and while there is nothing about the autonomic symptoms or AMS which should slip undetected by the vast majority of paramedics. In contrast, the neuromuscular changes are things which you really have to go looking for, and which could be potentially very easy to miss. By the same token, they are also the symptoms that will really help differentiate Serotonin Syndrome from other disease states and nail down the diagnosis. In fact, the Hunter Serotonin Toxicity Criteria hinges largely on physical exam. Severity of toxicity is directly correlated with severity of signs of physical exam.
The physical exam, when focused on the diagnosis of Serotonin Syndrome should have a few things that may not be typical of your standard physical exam (or maybe you are just a better paramedic than me and do these on everyone). These are based off the Hunter Serotonin Toxicity Criteria with an 84% sensitivity and 97% specificity:
First is looking for spontaneous clonus, which can be difficult to distinguish from a tremor. Know that clonus is related to large muscle activation.
The second is looking for the presence of inducible clonus. This means you should be touching your patient's feet, sharply dorsiflexing them to look for the presence of clonus. 2-3 beats of clonus may be normal; this is a good place for pre-test probability to help you interpret the results of a borderline exam. I’ve attached a video of how to perform this test and what to look for. While you are down at the feet, it is useful to test for muscular rigidity by attempting to bend at the knee joint. While clonus and rigidity may be seen in the arms, it is more commonly seen in the lower extremities. Hyperreflexia is common in these patients, but not something I typically test in the field because it’s not something I do enough to feel comfortable interpreting the results. I also don’t have a reflex hammer and hitting your patient with a stethoscope has poor optics.
The eye exam will reveal ocular clonus, differing from nystagmus in that it doesn’t have a fast and slow component and that it is not directional, it will be seen in whatever direction a patient is moving their eyes.
If you have a thermometer, a temperature may be useful, with any temperature >38 C in a patient you are suspicious of Serotonin Syndrome being suspicious. A patient who is obviously hot to the touch is another worrisome sign.
Like most toxicological emergencies, treatment is centered around supportive care. In the case of Serotonin Syndrome, benzodiazepines are the mainstay of treatment. In this case, cardiac monitoring, and a fluid bolus are good starting points. Agitation needs to be treated with benzodiazepines, as not only can it cause harm through rhabdomyolysis, or trauma from fighting restraints, the hyperthermia of Serotonin Syndrome is related to skeletal muscle thermogenesis which is treatable with benzodiazepines. The endpoint is going to be cecassion of the majority of this excess muscle contraction, which may require higher doses than EMS is typically comfortable with. There is a role for online medical direction if you don’t have protocols that allow for these high doses. Though remember, this hyperthermia is from skeletal muscle thermogenesis, not from mitochondrial uncoupling so benzos WILL be effective at reducing hyperthermia. If you have RSI, and a profoundly ill patient, this may be an indication for paralysis to control agitation and hyperthermia (literature suggests 41 C as an indication for RSI).
Serotonin Syndrome can be a quickly progressing process, so rapid control of agitation and temperature are important for reducing complications such as seizure, DIC, profoundly acidotic states, and multiorgan failure. There is also a role for external cooling in these very ill patients. One method that can be used on even the most poorly-equipped ambulances is a standard sheet, covered in saline or water placed over a naked patient. If you have the hands, fanning with whatever is handy may increase the efficacy of the evaporative cooling, otherwise blasting the AC may be sufficient.
While likely untenable for the vast majority of EMS systems, it is worth noting that there is an antidotal treatment for Serotonin Syndrome, cyproheptadine. Though like many things in the toxicological world, there is not a robust quantity of evidence supporting its use. There is also data that atypical antipsychotics, such as olanzapine, may have benefits.
Lastly, it is worth noting that not all serotonin syndrome will need treatment in the prehospital setting. Mild cases may present with flushing, some paranoia, abdominal cramping or diarrhea, and some slight inducible clonus. While they will not need pharmacological therapy from you, know that this is a rapidly progressing disease and take an appropriate aggressive posture towards the patient's clinical course and be ready to treat if you need to.
Serotonin Syndrome is life-threatening and easy to miss if you are not looking for it.
Assessing for clonus, muscle rigidity, and oculomotor changes in the setting of potential exposure to a serotonergic drug will best clue you into the diagnosis.
Consider the diagnosis for any hyper-adrenergic patient--stimulants can be a culprit of serotonin syndrome and this should be ruled out in these patients.
Treatment is supportive care with benzodiazepines for agitation and temperature management. RSI may have a role in the sickest serotonin syndrome patients, along with active cooling.
Author’s note: Dr. Iwanicki (@DrJ4747) is a Toxicologist with Rocky Mountain Poison and Drug Center and is an Emergency Medicine attending at Denver Health. I would like to thank her for her critical eye, helpful suggestions, and kind feedback on this piece!