Hello, and welcome to the multi-professional critical care review course. I am Saurabh Patel. I'm at the University of Chicago, and I work within the adult critical care areas and perioperative space. My main areas of focus and practice include the surgical intensive care unit and the burn intensive care units there on site. I don't have any disclosures for this presentation, however, please note there are a number of medications that are being presented, which are off-label indications for the management of the different syndromes that we're going to be covering in the presentation. Some objectives for the presentation include reviewing the management of alcohol withdrawal, identifying strategies for opioid withdrawal, describing how we can manage patients that are having and presenting with stimulant withdrawal, and then we'll end with looking at strategies for the management of cannabinoids or THC withdrawal as well. So some common withdrawal syndromes in the intensive care unit include alcohol, opioids, stimulants, and THC. The mechanism of action to begin with alcohol withdrawal predominantly revolves around GABA, or GABA receptor hyperactivity. Normally, alcohol would depress cognition and act on the GABA receptor, and there's activity both on nicotinic and serotonin receptors, which likely manifest in what we see in some of the withdrawal symptoms. For example, it's generally described in stages. So in stage one, you could see more hypertension and tachycardia within the first 24 hours, whereas a progression into stage three could be as severe as delirium tremens and seizures. The diagnostic criteria for alcohol withdrawal includes an abrupt cessation of intake and also two more of the following, tachycardia, nausea and vomiting, tactile hallucinations, anxiety, agitation, and seizures. And there's also a mix of symptoms or diagnostic criteria that can be used within section B that I just covered that can also be used for its diagnoses. The mechanism of alcohol withdrawal includes an increase in norepinephrine, dopamine, and N-methyl-D-aspartate or NMDA activity. A combination of these can manifest into the patient presenting with seizures and or the hyperactivity, agitation, and tremor that's commonly observed. The supportive therapies for alcohol withdrawal focuses on patient hydration, so that generally encompasses crystalloids and then also a number of different essential electrolytes, inclusive of magnesium, phosphorus, potassium, and also the B vitamins of B1 and B6, thiamine and pyridoxine, respectively. Therapeutic options for the management of alcohol withdrawal include a number of different agents or therapies that can act on the GABA receptor. That can be inclusive of barbiturates, as you'll see here on the slide, acting right here, or benzodiazepines acting on the other side of the receptor, which are commonly used together as adjunctive therapies. The benzodiazepines can be, again, I wanted to cover three of the more commonly used ones and then noting some specific clinical pearls or highlights regarding their metabolism. So for example, midazolam and diazepam are both extensively hepatically metabolized with active metabolites, and so in patients with liver and or kidney dysfunction, they may not be your best alternatives unless deemed necessary. In contrast, the half-lives of those two different agents is significantly different with midazolam being very short or in hours, whereas diazepam could be up in the words of days. Diazepam is also hepatically metabolized, however, its metabolism is via phase two versus midazolam and diazepam, which are in phase one. The reason why that's important to highlight is that the phase two metabolism or glucuronidation converting the lorazepam into a water-soluble metabolite is less impacted by cirrhosis or in patients with a high MELD score or liver dysfunction. Lorazepam, of course, can also be used not just as an intravenous push, but also an infusion if deemed necessary. Other adjunct therapies is that I wanted to make sure to cover one includes barbiturates or predominantly phenobarbital and phenobarbital has been described in a couple of different studies in a bolus dose of five or 10 milligram per kilogram and also less, I would say, or a more conservative dosing of 260 milligrams times one and then 130 milligrams twice daily thereafter with the taper. Phenobarbital when combined with other adjunctive therapies can also be impacting on sedation and or respiratory depression. And so one of the things to monitor for are going to be those two side effects. Alpha-2 agonists can also be utilized specifically clonidine orally or dexmedetomidine infusion. So additional adjunctive therapies inclusive in that group would include ketamine for alcohol withdrawal and generally what we're observing and what's been described in the scientific literature is ketamine again as an adjunct therapy to benzodiazepines for patients either with really high CEWA scores persistent despite receiving a lorazepam infusion. The patients are often also already receiving phenobarbital as an adjunct therapy as well. So really what you're observing is an approach of multimodal therapies similar to what's done with pain and any other disease states in order to manage, for example, alcohol withdrawal. The ketamine infusion used in this retrospective analysis was 0.5 milligram per kilogram per hour. What the investigators described was a pre-ketamine infusion rate prior to initiation of 14 milligrams per hour, which is again a fair amount. About 70% of the patients were intubated and they described their ventilator days and ICU length of stay of approximately 5.4 and 8 days respectively. There have been other studies that have evaluated ketamine and severe alcohol withdrawal as well. This was a retrospective, again, observational cohort of approximately 60 patients, about 30 in each group, and these patients actually were admitted to the ICU for delirium tremens, so already deemed to be having severe alcohol withdrawal. Benzodiazepine again was utilized as an adjunctive therapy to benzodiazepines plus or minus phenobarbital, and the investigators also highlighted and described their benzodiazepine requirement in diazepam equivalents. So for example, there are several papers describing an equivalency of approximately diazepam 10 1.5, lorazepam 1.5, midazolam 1 milligram, and phenobarbital 3.3. In this particular study and site, investigators utilized a 0.3 milligram per kilogram bolus followed by a ketamine infusion rate of 0.15 milligram per kilogram per hour. Again, if you're utilizing it as an adjunct therapy, a recommendation would be to utilize the 0.15 milligram per kilogram per hour and then titrate it accordingly. What the investigators observed and found in this study was that in the ketamine-treated patients, the ICU length of stay was clinically and statistically lower, as well as the benzodiazepine dose or dose equivalents overall. One considerable notation was there were more patients, albeit not statistically different, but higher number of patients receiving dexmedetomidine in the ketamine group. But one important finding was that the non-ketamine group was more likely to be intubated and then thus requiring other therapies. In this case, they were on propofol. There have been several comparisons of benzodiazepines, specifically lorazepam and dexmedetomidine infusion. And one interesting kind of highlight or point is that I would strongly suggest dexmedetomidine be an adjunct therapy versus a replacement therapy for benzodiazepines, as it does not have any activity on the GABA receptor. Most of the study, similar to this one, which was from two different hospitals, this retrospective cohort with about 30 patients in each group, was evaluating lorazepam or midazolam and then dexmedetomidine infusion. And what you'll find is that the clinical endpoints they looked at were intubation and seizures and there wasn't necessarily a statistical difference between either of the two approaches or strategies. One highlight was that the patients in the dexmedetomidine group were more likely to demonstrate hemodynamic changes, specifically hypotension and bradycardia. Additional adjunctive therapies, which have been studied in much smaller cohorts or in case reports, include baclofen, valproic acid, and carbamazepine. One recent study that was published earlier this year evaluated baclofen at a dose of 50 milligrams to 150 milligrams in total daily dose for mechanically ventilated patients in the intensive care unit. Their primary outcome was severe agitation or breakthrough agitation and the investigators did demonstrate and find and observe that the patients in the baclofen treated group were less likely to have severe or breakthrough agitation events. However, the dichotomy here or the balance and really the challenge for us is that they also observed an increase in length of stay in the mechanical ventilator, thus a longer stay in the intensive care unit. So even though it was helpful in assisting breakthrough agitation events or severe agitation, it translated into longer time on the mechanical ventilator. Now one aspect that's important to manage when these patients are in our intensive care unit is the titration of the therapies. And normally that would be based upon a clinical institute withdrawal assessment of alcohol or the CEWA scale in non-intubated patients, which includes the following, nausea and vomiting, visual, tactile, and auditory disturbances, agitation, diaphoresis, headache, anxiety, and tremor. However, the challenge for providers and for us on almost a weekly basis is that once that patient is unable to interact and answer questions appropriately with the care team, then utilizing a different scale for monitoring the agitation and titration of therapy safely becomes challenging. The recommendation is to utilize what you've already utilized in your intensive care unit for mechanically ventilated patients on analgesian sedation infusions or intravenous push regimens. And so one example would be the RAS scale. So use the RAS goal setting as your titration of therapies, whether it's to increase or to deescalate when necessary. It will likely provide a much more consistent approach to the titration of therapies and result in less time on the mechanical ventilator. The next group of agents I want to cover in terms of management of withdrawal includes opioids, now be inclusive of heroin, morphine, methadone, and fentanyl, inclusive of the illicit forms as well. One of the key aspects of management of opioid withdrawal as well, similar to the others, is identifying the substance as accurately as you possibly can. That will be helpful in identifying the half-life or estimated half-life of the substance or substances if it's a poly ingestion and also help titrate therapies in terms of our management and monitoring the patient. Common signs and symptoms of opioid withdrawal include fever, tachycardia, nausea, vomiting, and diarrhea, and different stages of agitation. The management of opioid withdrawal includes alpha-2 agonists, which are again initiated at a low dose and titrated very slowly, and to keep an eye on the hemodynamics during this process and time. There are different strategies described for detoxification and again I wanted to stress a slow titration, but even more importantly to consult and review your state legal requirements in terms of who can actually prescribe methadone and establish in your intensive care unit a safe transition plan so that the patients can be effectively and safely managed outside the intensive care unit and more importantly outside the hospital. Diphenoxylate can also be utilized to help manage severe and extreme forms of diarrhea when necessary and so that should be utilized as well. Now methadone is of course one of the cornerstone therapies, so if you have a patient being admitted to your intensive care unit that has verbalized or a family member has verbalized that the patient is on methadone, it's essential to engage the pharmacist on your team so that we can assist in identifying the clinic and confirming the dose and the last pickup of the medication to have a safe transition. Now with the methadone having a longer half-life as you can see here it takes several days to reach steady state and hence it will take essentially several days for it to wear off, but more importantly that the titration of therapy occurs at a very controlled and slow rate. One of the adjunct therapies that has become helpful in managing opioid withdrawal has also been gabapentinoids, specifically gabapentin, and again it's a lower dose of a hundred milligrams three times a day that's slowly titrated to response again monitoring for sedation during the titration phase. Another therapy that has been utilized and is becoming a little bit more integrated into the addiction and substance abuse team's protocol is suboxone. Now suboxone is a combination therapy of buprenorphine and naloxone, buprenorphine being your partial mu agonist, and so again it's intended mechanistically to help balance any side effects secondary to respiratory depression. The ratio of receptor activity or the components rather of buprenorphine and naloxone is approximately four to one and it's in a sublingual preparation to facilitate fast absorption. There are some drug interactions related to suboxone specifically with cytochrome 2d6 and 3a4 so I wanted to make sure to mention that as well. There is a requirement of patient counseling and education with the drug and so as deemed appropriate on your medical team it's important obviously to ensure that takes place and the medical team is aware and the patient is aware of the therapy that they're starting on. Now as it requires monitoring one of the things I did want to highlight is under the Drug Addiction Treatment Act and that's because when working with your team and working with your addiction team and substance use providers in your intensive care unit it's really to ensure that we have a qualified provider writing for these agents and monitoring and titrating the therapies effectively and safely. The next group of withdrawal agents I want to cover in terms of substances include stimulants and that's inclusive of cocaine, methamphetamine, amphetamine and what we received an increase in admissions just and within the last week here locally in Chicago secondary to Lollapalooza and that was ecstasy or MDMA. The mechanism withdrawal includes hyperactivation of dopamine norepinephrine and the serotonin receptor activity and again similar to opioids it's very dependent on our management strategy in monitoring that we're familiar or are aware of an estimated half-life of the substance so for example cocaine has a fairly short half-life whereas methamphetamine or ecstasy can have a prolonged half-life of hours and some some of the substances going out as far as a day or two. The withdrawal symptoms include agitation hypertension and thermo dysregulation most commonly presenting as an accelerated or high fever so mechanistically cocaine and amphetamines do differ slightly in their activation of the neurotransmitter norepinephrine as an example even though the end result is very similar of hypertension for example in tachycardia if we're talking about the autonomic nervous system so if we look at the diagram for example on the left there with cocaine you'll see it specifically blocks NET which is the norepinephrine transporter which is responsible for shuttling norepinephrine back into the neuron for metabolism and further synthesis. The end result of the blockade of the NET transporter is hyperactivation or an excess of the neurotransmitter on the effector cell postsynaptically resulting in increased blood pressure and heart rate. In contrast on the right side you have amphetamines which are there highlighted in those black circles and you'll see norepinephrine in the red kind of dots or circles and what you'll find and what's been described very well is that the amphetamine is transported just like norepinephrine back into the neuron going back out and activating the postsynaptic receptor site resulting in hypertension and tachycardia. So again slightly different where one is resulting in a cocaine is resulting in an excess of already existing norepinephrine due to blocking of internal transport whereas the amphetamine is directly activating those receptors postsynaptically. Now the management of stimulant withdrawal encompasses a number of different therapies. Agitation usually acute and severe is generally best managed with benzodiazepines, IV push, and obviously watching the sedation and titration of these agents very slowly is critical and key. The two recommended agents could be diazepam or lorazepam depending on what you would prefer and need in the clinical scenario for onset and duration of activity. Gabapentin can also be used adjunctively as an oral therapy and titrated slowly once the patient is able to take oral medication. Hydration can be managed with crystalloids and then if there is an urgent or emergent hypertensive episode that requires an infusion, diltiazem can be used or diltiazem or verapamil IV push to help manage these patients in addition to a nitrate or nitroglycerin infusion and you'll see here one particular group of drugs that was not listed necessarily for stimulant withdrawal in regards to hypertension and that is a pure beta blockade. One of the consequences of pure beta blockade can be unopposed alpha activity, thereby resulting in an increase in blood pressure. Therefore even though it is controversial in the literature, the receptor phenomenon is very real and so when possible to utilize both an agent that would have alpha and beta blockade activity. So as an example a drug like labetalol injection could be an option. Other adjunct therapies that are slowly titrated and then weaned outpatient could include methylphenidate and its derivatives and again my recommendation and suggestion is to engage your substance abuse and addiction teams in managing these patients so that we there is a safe and effective transition outpatient. The last group of agents I wanted to cover are the cannabinoids or THC. This would be inclusive of both illicit synthetic forms of THC or cannabinoids and now with the accessibility to the public this has become a little bit more of a focus in the intensive care unit as well. Based on the substance the half-life again could help approximate the monitoring and our strategic approach as the CB1 activity on the central nervous system and its psychotropic effects of the cannabinoid or THC. The DSM criteria for cannabis withdrawal is one or more of the following that has been observed and documented within one week of cessation which is generally inclusive of aggression, nervousness, insomnia, decreased appetite and mood, restlessness, and patients will often present with abdominal pain and discomfort. The management of THC withdrawal is inclusive of noradrenergic agents and again even though the trial designs are limited and the studies are limited, bupropion has been described in the literature but is not a recommended option due to that limited scientific literature that we have in safely utilizing the therapy. Other serotonergic agents include buspirone and then gabapentinoids have been described as being helpful with a low dose of a hundred milligrams three times a day and then again titrated very slowly if need be based on your clinical scenario or situation. Other adjunctive therapies could be inclusive of CB1 receptor agonist and that agent is dronabinol. Now typically the drug is labeled or prescribed at a 5 milligram twice a day dose and that's been as an adjunct for the appetite and or nausea and vomiting in hematology oncology patients so you'll see this is a much higher dose than what we've typically seen. For severe acute agitation episodes you'll see benzodiazepines and dexmedetomidine infusion also described and again the key here is to taper monitor the patient taper the therapies appropriately and discontinue them as safely deemed possible. These are my slides specifically in regards to the references for this presentation and again I wanted to thank the Society of Critical Care Medicine for this opportunity to present to you today on the management of drug withdrawal syndromes in the intensive care unit. Thank you.

Dr. Saurabh Patel

Withdrawal syndromes

Intensive care unit

Alcohol withdrawal

Opioid withdrawal

Stimulant withdrawal

THC withdrawal