Thank you for the introduction. So my name is Luma Sukkar, I am a clinical pharmacist in the Surgical and Liver Transplant ICU, and today I'll be talking to you about ketamine's growing role in opioid-sparing analgesic initiatives. I have nothing to disclose, but I will be discussing the off-label use of IV ketamine, or intravenous ketamine. The objectives of this section are to describe the role of ketamine for pain management in the perioperative setting, review ketamine's dosing, safety, and efficacy data, and identify barriers and challenges to the use of ketamine. To produce analgesia, ketamine exerts its effect by noncompetitively inhibiting the N-methyl-D-aspartate receptor, or NMDA receptor. We can see in this picture that whenever there's a pain signal, glutamate is released from the dorsal horn and it binds to the NMDA receptor, and ketamine works by inhibiting the binding of glutamate and eventually stopping this cascade from propagating. Ketamine is FDA-approved for induction and maintenance of anesthesia, however it has many off-label uses, including pain management, which will be the focus of the presentation. Most of the pharmacokinetic data of ketamine is extrapolated from its use as an anesthetic agent. It has an onset of action that is quick, of 10 to 30 seconds, with a duration of action of almost 5 to 15 minutes. It also has a half-life of 45 minutes and is metabolized mainly via the hepatic route to norketamine, which is an active metabolite and is 33% as active as the parent compound. Both ketamine and norketamine are excreted primarily through the urine, almost 91%. And then as you can see here, the plasma concentrations of ketamine that are required to produce anesthesia far exceed those required to produce analgesia, which basically is evidenced by the doses that are used to produce both the analgesic and the anesthetic effects. So with analgesia, we would use doses as low as 0.1 to 0.3 milligrams per kilo, whereas for the dissociative effect or the anesthetic effect, the doses are closer to 1 milligram per kilogram. Ketamine is contraindicated in patients with known or suspected schizophrenia, although a recent consensus statement from the American Psychiatric Association did not explicitly state psychosis as an absolute contraindication. It is also contraindicated in patients with increased intracranial or intraocular pressures and in patients with liver injury, particularly those with advanced liver disease such as cirrhosis. Ketamine is also associated with a number of adverse effects, and the ones that I have here are the ones that are more common and more pertinent to the literature that I will be discussing later on. One of the major adverse effects of ketamine is cardiovascular, such as arrhythmias or increased blood pressure. It also has gastrointestinal adverse effects, such as nausea and vomiting, and neurologic adverse effects, such as delirium, confusion, and seizures. So basically, this emphasizes that we need to monitor patients on continuous intravenous ketamine therapy by monitoring blood pressure, heart rate, also doing frequent delirium assessments. The most recent SCCM PADIS guidelines addressed the use of ketamine and recommended its use as an adjunct to opioids in patients in the post-operative setting within the ICU. However, the evidence supporting its use was limited. Also, the American Society of Regional Anesthesia, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published a guideline on the use of ketamine for acute pain. And in this guideline, they identified patient populations that will most likely benefit from the use of IV ketamine. And those patients usually are the surgical patients, particularly upper abdominal and thoracic surgery. This is where most of the benefit is in terms of opioid reduction, as well as lower abdominal, intra-abdominal, and orthopedic procedures. Also, another population that may benefit from the use of ketamine are those that are opioid tolerant or dependent at baseline and are presenting for surgery or with an acute exacerbation of a chronic condition. Looking at the efficacy of ketamine. So basically, what we're trying to address here is, what is the benefit of ketamine in patients who are already on opioids and other agents in the post-operative setting? Is there any benefit to using this medication? And this question was addressed in these four meta-analyses, in which ketamine was used as an adjunct to opioid therapy, mostly in the post-operative setting. And in all of these studies, they found that there is a decreased opioid requirement with the use of ketamine, as well as a reduction in pain scores. In two of these reviews, they also found a reduction in nausea and vomiting as well, which is initially a concern because it's one of the adverse effects of the use of ketamine. However, in none of these reports, they found any increase in adverse effects associated with the use of ketamine. That being said, all of these studies used different post-operative pain regimens. Also, the dosing of ketamine was variable between the different studies and the different study populations. Therefore, it's difficult to isolate or basically detect the absolute effect of the ketamine therapy. However, there seems to be a tendency towards a reduction in opioid consumption, as well as an improvement in pain management with the use of ketamine. Moving on to the dosing of ketamine, this was also addressed in several meta-analyses and reviews. The dosing of ketamine is weight-based. In most of the studies that we looked at, the dosing weight that was used for the patients is their actual body weight. However, in other studies, ideal body weight was used, as well as adjusted body weight. Also, the dosing of the ketamine, as we mentioned earlier, is lower to produce the analgesic effect compared to the anesthetic effect. You will notice here that the doses are much lower than those required for anesthesia. The first three reviews, the doses of ketamine that were used ranged anywhere between 0.002 up to 0.…almost 3 mg per kg per hour, although there is an outlier where they used really high doses in one of the studies. But with these doses, or sub-anesthetic doses, there was a reduction in opioid requirements in all of the studies. In this last study, however, by Groff and colleagues, it was a multi-center retrospective review of ketamine use in the ICU patient population. They looked at almost 20% of the patients who were surgical patients, and this was one of the very few studies that actually looked at the use of ketamine as stand-alone therapy for pain management. And their findings were similar to those of all of the other studies where there was an increase in time spent within the goal pain score and a reduction in opioid requirements. Now the dosing of ketamine in this study was a little more standardized, and it ranged anywhere between 0.1 to 0.5 mg per kg per hour. The study also reported that there were 22 instances where ketamine had to be discontinued for adverse effects that were associated with it, and those were mainly hemodynamic instability. That was the most common, and there was also delirium and agitation. But basically, based on all of these studies, the dosing of ketamine, or the sub-anesthetic dosing of ketamine of 0.1 to 0.5 mg per kg per hour appears to be safe and effective in producing an opioid-sparing effect. Moving on to logistics and some of the challenges associated with the use of ketamine, SCCM sent out a survey to nurses, physicians, nurse practitioners, and they wanted to see how comfortable these people are in using ketamine. And they found some barriers to the use of ketamine, including its adverse effects, lack of familiarity, lack of evidence, as well as lack of institutional guidance on the use of ketamine and its indications, as well as its dosing. Most of the practitioners, however, reported that they feel comfortable using ketamine. However, because of all this variability in practice and in the studies, as well as the dosings that are used, we need a little more guidance. Also, there are challenges from the nursing perspective when it comes to the use of ketamine, such as programming the medication into the pumps, like the Alaris pumps. Obviously, there's a variability in dosing, so there needs to be a certain distinction between anesthetic and sub-anesthetic dosing, as well as accurately entering the patient weight, which may be variable compared to other medications that are on the patient's profile. And then finally, documenting medication waste, because ketamine is a controlled substance, so this needs to be protocolized as well. So all of this emphasizes the need for institutional protocols that will select patients that can actually use ketamine, have dosing recommendations, as well as titration monitoring and weaning parameters. So based on everything that we've discussed, we can basically say that ketamine has an opioid-sparing effect and is helpful in pain reduction in the post-operative setting. However, we need more randomized control trials in order to delineate ketamine's role as well as safety profile in those patient populations in whom it's usually contraindicated at the anesthetic doses, but we don't really have evidence when it comes to the sub-anesthetic doses, such as those with cardiovascular disease, chronic kidney disease, or hepatic dysfunction, and others. And then finally, we need to establish a dosing range that is optimal for sub-anesthetic use of ketamine, either as standalone or as adjunct to opioid therapy, and finally determine whether or not there's a dose-dependent relationship for those adverse effects. So in summary, ketamine provides short-term opioid-sparing effect when used in sub-anesthetic doses in the perioperative setting. The suggested dose for ketamine is anywhere between 0.1 to 0.5 milligrams per kilogram per hour, and with this sub-anesthetic dosing so far, based on what we've seen in the literature, there are no major adverse cardiovascular, hepatic, or neurologic effects in the studies. Thank you for listening.

Luma Sukkar

ketamine

opioid-sparing analgesic

NMDA receptor

pain management