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DEC
28

Shallow Hal-dol by Natalie Zink

In a world where Ketamine rules all FOAMed, services without access to this “miraKle drug” often get left out of the conversation on safe chemical restraint. So, Ketamine Warriors, I humbly ask that you imagine for a moment that you don’t have your secret sauce, and you must rely upon……BENZOS AND ANTIPSYCHOTICS.

Image result for american dun gif

I will leave the “favorite benzo flavor” out of today’s discussion and instead shoot for a dissection of a fairly popular prehospital/hospital antipsychotic agent, Haldol. 

Before this past May, I never had access to haloperidol. Knew of it and its general characteristics, of course, and heard a couple “B52!!!”s yelled out in the ER but never had an opportunity to use it. This made for an uncomfortable Natalie when I learned 5mg Versed and 5mg Haldol IM was our chemical restraint concoction of choice, so I dove into the research. 

I must be honest here: I didn’t really like what I found. Long onset, sketchy side effects, significant half-life…..not my ideal characteristics for a sedation agent. Then, add on anecdotally how many patients list Haldol as an allergy because they had such adverse reactions-not thrilling news for someone often administering this drug before we are even able to get a name, much less a full medical history, due to excited delirium, tox, or just downright combativeness. So, allow me to make my case for why we should be taking much more care and consideration before grabbing for the haloperidol as a first line drug…

AN OVERVIEW

Indications: Excited delirium, agitation, psychosis, vomiting, chronic hiccups 

Mechanism of Action: Strong antagonist of Dopamine receptors (D2) AKA inhibits dopamine’s effects

Contraindications: Parkinson’s Disease, hypersensitivity. 

Yes, you read that right. Head injury is not a contraindication to Haldol. Go on and take y’all’s mind-blown selves to the research suggesting no harm in intermittent administration to TBI patients, and holler if you need me.

Side Effects: Extrapyramidal symptoms (Parkinson’s-esque), restlessness, worsened agitation, spasms, drooling, dystonia, hypotension, nausea, vomiting, vision changes, irreversible dyskinetic movement syndrome (especially in elderly women)

Really Scary Side Effects: QT Prolongation > Ventricular Arrhythmias >Sudden Cardiac Arrest

Onset: For IM injections, 20 minutes ‘til peak effects in average population, 34 minutes in schizophrenic

Half-life: Almost 21 HOURS 

Mechanism of Metabolism: Lipophilic and hella metabolized by the liver (only ~1% of original drug in the urine)

Drug Interactions: 

  • Lithium: Cause extrapyramidal symptoms, encephalopathy, coma
  • Tricyclic Antidepressants: Decrease metabolism/elimination of TCAs
  • Quinidine, Buspirone, Fluoxetine: Increase Haldol serum levels
  • Carbamazepine, Phenobarbital, Rifampicin: Decrease Haldol serum levels
  • Warfarin: Increase warfarin serum levels
  • Acyclovir: Increase Haldol serum levels
  • Metformin: Decrease efficacy of metformin
  • Insulin: Decrease efficacy of insulin

So, why does haloperidol work?

The best working theory we have for the positive symptoms of schizophrenia is an over-production of dopamine in the mesolimbic system. That’s to say that the hallucinations, delusions, agitation, aggression, disorganization reside……right here 

The part of schizophrenia that we typically want to treat and control in a prehospital emergency setting is acute agitation and aggression; therefore, BOOM we want that pathway to cool its dopamine jets, which Haldol achieves. 

So then, what’s your problem, Nat?

  1. We aren’t always administering this drug to schizophrenic patients. Yes, sometimes, we find the classic clear-cut case or patient we are familiar with who maybe missed their monthly injection. However, most of the time, we are dealing with complex cases in high-stress situations. I so hope we have all joined the school of thought that severe agitation is indeed a medical emergency, and a fragile, dangerous one at that. We must think swiftly about the safest plan for ourselves, our crew, our patients, and any bystanders. I won’t be discussing defusing or other methods of restraint here, just making a point that urgency in stopping the acute problem of agitation is our first priority on these calls. If the patient is hypoxic, we give oxygen. If they’re hypoglycemic, we give sugar. Yet, if they’re combative, they get an antipsychotic? Interesting. 
  1. Haloperidol is not an effective rapid sedative. Like I just said, in order to move forward in the treatment of this patient, we have to bring them from a Level 10 to at least a Level 6. Why wait 20 minutes (or 34!!!!) to get there? Further delaying the ability to fully assess, not to mention treat this patient. Some of y’all’s services don’t have anywhere near those transport times, so, I mean, you’re welcome to the ER staff, but I still have a clinically agitated dude who is further stressed by my bright, moving, terrifying machine with pokey things. That does not make for excellent care. 
  1. It lasts way too long. I mean waytoo long. A half-life of 21 hours is absurd. For comparison, the half-life of midazolam is about 2 hours. If we have an adverse reaction, just hold on to your hats; we have a BIT until this stuff is cleared out. 
  1. Finally, my real beef with the stuff….it’s not ONLY affecting the mesolimbic pathway!

Let’s go to the nigrostriatal tract to see what I mean.

Big stuff is going on here…like 80% of the body’s dopamine, NBD. But it’s ok; it’s not like that dopamine is involved in anything important. OH WAIT. MOTOR PLANNING. Without that, well, you kinda...

Image result for blizzard gif meme frozen

Pseudo-Parkinson’s-type extrapyramidal symptoms can occur from the antagonism of the dopamine receptors like dystonia, akathisia, and tardive dyskinesia. Those symptoms can range in severity from tense muscles and restlessness up to difficulty swallowing and breathing. Me no likey. Think about it, though, Parkinson’s patients take Carbidopa to treat their symptoms and increase their dopamine. We are doing the opposite. It can be a bummer. I do wonder if part of the role of the Benadryl in the common B52 cocktail (Benadryl, 5mg Haldol, 2mg Ativan by the way) is to guard against the extrapyramidal symptoms. My literature review was lacking in rationale for it other than generic sedative effects. Anyone care to weigh in?

Now, over to the tuberoinfundibular tract…

Dopamine in the tuberoinfundibular pathway inhibits prolactin release from the pituitary gland. Therefore, inhibiting dopamine increases prolactin. This causes discharge from the breasts and a decrease in estrogen and testosterone which affects fertility, sex drive, and eventually bone density. Also, fairly uncool symptoms for somebody who ended up being a tox patient had we been able to discern that earlier and withhold a dopamine antagonist.

BONUS: Guess what else is really fun! GABA receptors (multipurpose inhibitors in da’ brain) MODULATE Dopamine receptors! So, activating GABA receptors suppresses dopamine receptors. Guess what enhances GABA receptors?! Benzos! So essentially when we 5x5, we are just straight up Hoovering these folks’ dopamine right on out of their mesolimbic systems. Rock on.

SO, NOW WHAT?!

Look, Haldol is a very effective First-Generation Antipsychotic medication for schizophrenia. So far, the literature hasn’t shown increased efficacy of Second Generations (atypical antipsychotics) over First. Haloperidol is the affinity champion on dopamine receptors while Second Generations tend to also antagonize serotonin receptors. The atypicals(i.e. risperidone, olanzapine, clozapine, quetiapine, aripiprazole, ziprasidone), while having a decreased risk of extrapyramidal symptoms, tend to cause more metabolic side effects like weight gain and hyperglycemia. Again, our prehospital purpose is treating time of behavioral crisis, and haloperidol has been proven to be a successful sedative.

On the other hand, I cringe at the thought of Haldol being used as a first line without consideration for its pharmacokinetics. While successful, it is not a simple sedative. It doesn’t really suit the prehospital environment because of its long onset, and it doesn’t suit the average non-dopamine rich patient. If anything, its administration to a non-schizophrenic patient makes me a little worried about airway difficulties from extrapyramidal symptoms, especially when given in conjunction with a respiratory depressant. 

Who knows? Maybe someday I’ll eat these words, but I’m just not too crazy about this stuff being used as a broad sedative (as I’m sure my sass alluded to). I have just one more question…is there still room on the Ketamine train, guys?

SOURCES

https://www.drugbank.ca/drugs/DB00502

http://criticalcare.imedpub.com/haloperidol-use-in-acute-traumatic-brain-injury-a-safety-analysis.php?aid=8802

https://www.liebertpub.com/doi/abs/10.1089/neu.2018.6212

https://www.sciencedirect.com/science/article/pii/S0166432816306817

https://www.news-medical.net/health/GABA-Activation-and-Dopamine-Suppression.aspx

https://www.news-medical.net/health/Haloperidol-Pharmacokinetics.aspx

https://images.app.goo.gl/JNDQSFtsUHxzfbii8

https://psychopharmacologyinstitute.com/publication/the-four-dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096

https://psychopharmacologyinstitute.com/publication/first-vs-second-generation-antipsychotics-2082

 

 

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DEC
16

Serotonin Syndrome by Jace Mullen

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 it’s 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. 

EPIDEMIOLOGY

One of the things that should clue you into 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 under recognition, 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 which 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. 

Second is looking for the presence of inducible clonus. This means you should be touching your patients 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. Hyper-reflexia 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.  

https://www.youtube.com/watch?v=kA7GQ8aCYKo

The eye exam will reveal ocular clonus, differing from nystagmus in that is 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.

 

TREATMENT

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 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 it use. There is also data that atypical anitpsychotics, such as olanzapine, may have benefit.

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 patients clinical course and be ready to treat if you need to.  

TAKEAWAYS

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 in to the diagnosis.

Consider the diagnosis for any hyper-adregnergic patient--stimulants can be a culprit of serotonin syndrome and this should be ruled out on 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 with this piece!

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