Here to discuss their studies and their findings are Dr Payal Sud, associate director, Department of Emergency Medicine at Glen Cove Hospital, Northwell Health, and one of her coauthors, Dr Miles Gordon, resident in emergency medicine at Northwell Health. Welcome, doctors.
Miles P. Gordon, MD: Thank you. Glad to be here.
Patients Are Presenting With Completely Different Symptoms Today
Glatter: Dr Sud, congratulations on a well-done study which certainly highlights unique findings in patients intoxicated with these cannabinoids.
[4] Can you discuss some of the key findings of your study?
Payal Sud, MD: Prior to 2015, the majority of the SC-intoxicated patients that we saw presented with a completely different array of symptoms—very sympathomimetic in appearance, such as hypertension, tachycardia, mydriasis, diaphoresis. Whereas 2015 onwards, patients were presenting with completely opposite type of symptoms. Working in the ED, and as toxicology consultants, we were seeing patients presenting with central nervous system (CNS) suppression, respiratory depression, bradycardia, hypotension, and in some cases, complete loss of upper respiratory drive, requiring intubation.
We proceeded to do a chart review of these patients and try to map out their clinical course. At the same time, when possible, we acquired their blood and urine samples, as well as the plant materials that they came with.
Of course, the concern was whether the plant material they actually brought along was in fact the same one that they consumed. Regardless, we analyzed the plant samples (as well as blood and urine samples from some of these patients) and ran them in the laboratory, and we discovered specific compounds in those three samples.
We compared these samples to some xenobiotics (clonidine, digoxin, opioids) that we thought might be present and could contribute to this array of vital sign abnormalities—respiratory depression, hypotension, and bradycardia. In fact, we did not find any of these contaminants present in the samples that we tested.
Glatter: What exactly did you find? Can you describe some of the compounds and what their significance is to our clinical practice?
Sud: Some of the compounds we saw were SCs, which are extremely potent at the cannabinoid receptor—anywhere between 10 and 800 times more potent than traditional tetrahydrocannabinol (THC) or marijuana. They have certain chemical names, like XLR-11, and are part of the indazole carboxamide (INACA) family. What was key about finding these compounds was that we had come across a new family of SCs that were previously unknown, and the symptoms that we were seeing were because of these new SC compounds rather than other ingestions that we were more familiar with.
Initial Treatment of Patients Presenting With K2 Intoxication
Glatter: For the typical practicing physician who encounters a patient like this, often we think of drug screening by a toxicologist. I know that is something that would not be indicated. I want to get your viewpoints on how you feel about toxicology screens in the setting of these types of ingestions.
Sud: A lot of emergency physicians, as well as other physicians, are used to the UDS (urine drug screen) or the UTOX (urine toxicology screen). What is very important to realize is that the majority, if not all of these compounds in the novel SCs, as well as multiple new drugs of abuse, do not appear on the UTOX, or the serum toxicology, for that matter.
Glatter: Obviously, you have to consider what you can do right now to take care of this patient—looking at his or her airway, their O2 saturation and degree of CO2 retention, whether they need intubation or other medicines for their blood pressure, and so forth.
It can be somewhat overwhelming to all of a sudden get 2-10 people with CNS depression requiring emergent monitoring, to the extent that there is overcrowding in our ED and we had to place these patients in hallways.
Sud: Right. I think the first focus with these patients should definitely be on their vitals, just like with any ill patient in the ED (their airway, breathing, circulation). There is no antidote that we can currently utilize to reverse the respiratory depression that the SC-ingestion patients are presenting with (such as with opioids, we have naloxone). If they are presenting with a respiratory depression and need airway support, that should be provided—either bag valve mask ventilation or intubation. If the patient is on the verge, where you are not quite sure if they are going to lose their airway drive, keep them in a monitored setting. Put them on an end-tidal CO2, and keep an eye on them during your shift while they are metabolizing.
Glatter: Absolutely. Miles, as a resident caring for such patients, I am sure these are challenging patients because of monitoring, availability of space, and capability in a busy ED. I want to get your viewpoint on how it affects you and how you operate in terms of multitasking.
Gordon: As Dr Sud said, the first thing to do when this patient comes in is assess their ABCs (airway, breathing, and circulation), make sure they are stable, and give them IV fluids as necessary. The scary thing about SCs is that they often present as clusters. At the Long Island Jewish Medical Center, we would see up to 10 people present at the same time with similar complaints and CNS depression. It can be somewhat overwhelming to all of a sudden get 2-10 people with CNS depression requiring emergent monitoring, to the extent that there was overcrowding in our ED and we had to place these patients in hallways. It’s not optimal, but it is one of the challenges that we have to address every single day.
Glatter: That is something I have dealt with too, so I can certainly identify with that. Looking at comorbidity, especially in an older patient in their 50s or 60s, with this type of ingestion is concerning. They have impaired cognition as well.
Gordon: You never know what their comorbidities are, you don’t know what their baseline mental status is, or the slew of other medications that they are on that could be interacting with these SCs and could be causing this CNS depression.
Glatter: Would you typically place IVs and start hydration on most of these patients?
Gordon: I would definitely place at least one, if not two, large-bore IVs, especially if they have altered mental status. Depending on your initial evaluation, do they look fluid overloaded or do they look dry? If they look dry, then I would absolutely start some crystalloid.
SC-Intoxicated Patients Are Now Older and Have Comorbidity Concerns
Glatter: Dr Sud, was there a special area in the ER for these patients when you had this surge, or were they intermixed within a department?
Sud: Unfortunately, they were all intermixed. Like Gordon said, it’s very challenging. In the past, the SC-intoxicated patients we saw were typically young adults, teenagers with a good reserve. Now we see older patients in their 50s or 60s with congestive heart failure, chronic obstructive pulmonary disease, and other comorbidities. You throw in respiratory depression and they definitely require a lot more critical monitoring than younger patients in the past.
Glatter: In your paper, you talked about this cluster of patients from a psychiatric facility.
[4] Some of these patients were on neuroleptics, and that played into the lethargy and the bradycardia that was observed. Can you comment on that?
Sud: Even before their presentation, the patient history was limited because these patients had underlying psychiatric disorders. Was the lethargy because they actually had neuroleptic malignant syndrome and they were altered because of that? There were other considerations that we had to think about and not just zone in on the SC that they came in with stuffed in their pockets.
Glatter: In your study, did you follow patients individually or were the data de-identified or anonymous in terms of outcome per patient?
Sud: It was de-identified and made anonymous.
Glatter: Do you plan any further follow-up on this study in terms of looking at the cohort itself and their long-term clinical situation?
Sud: Based on what we encountered at that time, it largely ended up being a convenient sample, as there were a lot of patients who presented like this. Since that time, thankfully, even though we have had minor surges—knock on wood, so far—we have not had any other major surges; but if we do, absolutely we will look at them.
Superwarfarin in SCs: Bleeding Risks and Vitamin K Shortages Reported
Glatter: I wanted to bring up the point of bleeding. Certainly, this was an issue [reported by the CDC] earlier this spring.
[2] I personally did not encounter any patients with bleeding. Have either of you encountered any?
Gordon: No, I personally have not.
Sud: I have not, personally.
Glatter: In terms of [SCs laced with] long-acting superwarfarins, I would like to briefly discuss how you would manage such a patient—first and foremost, the undifferentiated bleeding in someone who has an altered mental status. That is really something to think about now in clinical presentation that we didn’t have in the past with SCs.
Another question also comes to mind: Why are these agents being added to SCs? Any thoughts on that?
Gordon: Some research indicates that superwarfarin, having a long half-life, when added to these newer SC products has the potential to increase cannabinoid binding and can actually increase the length of the euphoric effect.
Glatter: That is quite interesting, because now this is a very potent way to increase the ability of this mixture to deliver that high, but people do not know the secondary effect, and that is really the danger.
Gordon: In general, the concern with all of these synthetic materials is that you don’t know what you are getting. Looking through the research, there is a wide range of concentration seen in these products, as well as a wide range of the actual type of cannabinoid. Whether it is the XLR-11, CIDs [carboxamide indazole derivatives] or the INACA compounds, you really have no idea what you are getting.
Glatter: It’s like Russian roulette; every time you try SCs, it’s an unknown possibility.
In terms of managing an overdose of such a patient, what would be the first thing to consider, and how would you proceed when someone comes in bleeding and their international normalized ratio (INR) is 50 or 60?
Sud: Like with any other patient, the ABCs are going to be essential. It is very challenging to manage patients who have overdosed on these superwarfarins because, like what Gordon alluded to, these have a very high affinity for the vitamin K epoxide reductase and they have a very prolonged half-life—weeks to months. They require extraordinarily large amounts of vitamin K and any kind of four-factor prothrombin complex concentrate that you have available at your facility.
After the patients are stabilized and go home, they need to be on vitamin K for weeks to months to counteract the effect of the superwarfarin that they have ingested. That adds a huge cost to the patient as well.
Glatter: I think that is a big concern that you bring up. Pharmacists are overwhelmed by orders for patients who need to be on 30 mg a day of vitamin K for 3-4 months. I think straining of resources is a concern.
Concerns Raised Over SC Compounds Readily Available on the Internet
Glatter: Are there any other aspects that you would like to mention, either about your paper or bleeding risks in patients?
Gordon: We do not want our paper to be viewed as an epidemiologic study (ie, if you use synthetic cannabinoids, 10% of them are going to be hypotensive, 24% are going to be bradycardic). It’s not like that. It’s more about what we said before—you have no idea what is going into these mixtures.
Another concerning factor is that on the Internet, you can now buy just the liquid solution, not the plant material. Patients have no clue how much they are using. I am scared that as people are using these liquid concentrations, they are going to be showing up to the ED in clusters and high numbers.
Glatter: I think that is a great point you bring up. We will have to alert the public about that.
Sud: Gordon is absolutely right. Unfortunately, the people who are manufacturing these products are a step ahead of us. We are encountering patients who are presenting with the after-effects of these products. We have to stay up-to-date, willing to embrace new possibilities.
We initially were faced with synthetic cannabinoids that presented sympathomimetic, and when this cluster that we presented starting presenting, we initially were not sure. Is this synthetic cannabinoid? What is this? We just have to be aware that there might be completely new novel presentations out there and not get hung up on trying to diagnose right away in real time what the specific SC is, by ordering a UTOX or serum toxicology.
You have to treat the patient in front of you: their vital signs, lab abnormalities, and risk of bleeding. Because at the end of the day, whether the UTOX is positive or negative, or whether the serum toxicology shows something or not, doesn’t matter. We have to manage these patients.
Glatter: I think parents need to have a discussion with their children. Many kids want to try this to avoid a positive urine drug screen, but this could end up in death. It’s not worth the risk. As cannabidiol (CBD) comes more into focus in research and legalization occurs throughout the US, I think the discussion is going to expand more about the use of these synthetic drugs versus true cannabis or CBD.
Gordon: I will mention one positive sign. In the early 2010s, we saw synthetic cannabinoid use skyrocket in the youth population; in high schools it was the second most commonly used drug. Over the past several years with our public relations, signs in subways, and the news reporting on the detrimental effects of SCs, we are seeing the number of teens using these drugs actually going down, which is great.
Sud: What has become more challenging, I think, like our study has shown, is that we did not have a lot on teens and young adults who were exposed, but it was actually older patients coming in with their slew of comorbidities. When you throw in a respiratory depressant, an SC that is contaminated with a superwarfarin, or have patients who are on anticoagulants to begin with for other medical problems, that could really muddy the waters even more and make the patient population even more challenging to manage.
Glatter: Absolutely. Overall, more public messaging needs to be initiated so that the message truly gets out. Obviously, your work, Dr Sud and Dr Gordon, has been instrumental in helping to add to the body of literature about these dangerous substances.
