Hi everyone, my name is Kirsten Cota and I'm a clinical pharmacist in the Medical and Surgical Trauma ICUs at the Mayo Clinic in Rochester, Minnesota. Today I'm going to be giving you a brief overview of purple fall versus dexmedetomidine in the trauma population 1 and Y. This talk is not going to focus on a rehashing of CEDCOM, MENS, or PRODEX-MIDEX because these trials tended to exclude trauma patients or have less than 10% of the population be trauma or non-CV surgical ICU. We'll start with a rapid overview of the potential benefits and risks of each agent in the population, a look at the comparative literature for the two in trauma, and finally identify specific trauma subpopulations that may benefit with one agent versus another. Trauma ICU patients represent a unique critically ill population relative to other ICU types. These patients tend to be younger on average, they have the need for specialty management of their novel injury mechanisms, the shock types can lean more towards hypovolemic and neurogenic as opposed to a more traditional septic shock that we think of, and the phases of illness are distinct entities particularly in the care of patients with traumatic brain injury. These patients also tend to have higher rates of intoxicating agents on presentation than say your standard medical or CV surgical ICU. And finally because this popular patients is unique, we know that specialty care does result in improved outcomes as demonstrated in the BRCA study for 2015. As we consider one of the unique situations in a trauma ICU population, it would be remiss of a me to not discuss secondary traumatic brain injury. This is a result of pathological processes that are started at the time of injury but tend to have a delayed clinical impact, and it's commonly thought of as presenting in two stages. Stage one, initially the damage is happening because of ischemia for the presence of lactic acidosis and the failure of membrane ion pumps to maintain homeostasis. Stage two ends up resulting with a calcium influx into the cell, a terminal membrane depolarization, glutamate release, NDMA activation, increased free fatty acids and free radicals, which then leads to neuronecrosis and apoptosis. So as we're looking at these drugs specifically in TBI, we're trying to modulate these two stages of secondary injury. Propofol and decimetamidine has some theoretical and animal level data in the mitigation of these consequences that we'll explore further. Before we dive into the specific literature regarding trauma patients and sedation, it's worth asking if we have any clarity in the guidelines that would lead us towards one way or another. Unfortunately, that's not the case. The Brain Trauma Foundation only references one study for sedation, and this is the 1999 Kelly et al. study that looked at ICP changes in Propofol versus morphine. Decimetamidine is not discussed. The EAST guidelines make no recommendations, and SCCM's guidelines are more related towards broad critical illness and consider an equivalent utility to Propofol and decimetamidine, regardless of critically ill patient population. So beyond the basic general critically ill patient comparison, what factors should be driving us to use one agent over another? When we consider general characteristics of these two agents, starting with Propofol, it is a GABA-A receptor agonist, and it increases the efficacy of GABA opening, as well as opening the chloride channel directly at higher concentrations, and potentiates activation of other neurons. It additionally inhibits presynaptic glutamate release. Propofol is primarily a lipophilic compound with a very rapid onset of roughly a minute and a half-life ranging from 1.5 to 12 hours. It does have dose-related respiratory inhibition. Decimetamidine is primarily an alpha-2 agonist that's largely hydrophilic. Its onset is a little bit slower than Propofol at 10 to 20 minutes, and the half-life is somewhere around 2 hours. Note that decimetamidine does not have respiratory inhibition. It's also worth remembering that Propofol is amnestic but not analgesic. Well, decimetamidine is analgesic and not amnestic. We typically use decimetamidine to target a lighter level of sedation, whereas Propofol can be utilized for both light and deep sedation. So having considered the specific physiology, particularly in secondary injury for TBI and trauma patients, it may seem that Propofol potentially has a higher benefit versus risk ratio. It's worth noting that a majority of the beneficial effects come from rodent models of TBI, and specific human data with this degree of confirmation is lacking. The theoretical benefit has driven practice, with Propofol being the primary recommendation from trauma guidelines that we referenced earlier. It's thought that Propofol will decrease your cerebral metabolic oxygen demand. Through inhibition of glutamate release, it will increase GABA-A activity and decrease cerebral blood flow. The risks of Propofol include hypotension of bradycardia, metabolic abnormalities, the incidence of Propofol-related infusion syndrome, as well as pancreatitis. In a broad range of a critically ill population, it's been widely established that Propofol decreases ICU length of stay, days of mechanical ventilation, in comparison to benzodiazepines. However, what about human data for Propofol benefits, specifically the trauma population? Gu and colleagues looked at a meta-analysis of four studies that compared Propofol to benzodiazepines, but only two that looked at just severe TBI. For these two studies, they identified no difference in Glasgow outcome score or mortality for Propofol versus benzodiazepines, noting that this was only 57 patients across the two studies. It does appear that Propofol lowers ICP and helps maintain cerebral perfusion pressure effectively. For neuroprotection, the Hausberg paper referenced here was an excellent summary of current cellular level data on ischemia and reperfusion injury that we extrapolate in theory to trauma patients. This looked at the neuroprotective ability of Propofol in studies that looked at intracranial aneurysm surgery, and they did appear to show some benefit. It appeared that patients with Propofol had decreased oxidative stress and decreased infarction rates, and it's possible that this related to improved functional and cognitive outcomes. Let's first talk about patient-specific characteristics that result in an increased risk of hypotension when Propofol is used as the primary sedative in trauma. Sharon and colleagues conducted a retrospective study of 200 normotensive patients in the trauma bay of their ED. The graph across the top would be the general descriptors of the patients, 80% male, 30% with motor vehicle accident as the mechanism of trauma, followed by assault and falls. About 90% of the patients used Tamidate as the primary RSI med, with about 70% using succinylcholine as the paralytic of choice for RSI. What they found was that for every 10 millimeter decrease in baseline systolic blood pressure for age over 55 years and obesity, you all had higher odds of hypotension with Propofol as primary sedation. The mean age in the study was 39, and the mean Propofol starting dose was 26 mics per kilo per minute. So if hypotension is a concern in your specific patient, paying attention to these typical variables will give you a better sense of their overall risk of experiencing this adverse effect. When we think about other major adverse effects of Propofol, one of the ones that everyone is concerned about would be the Propofol-related infusion syndrome, and it's known that TBI and trauma patients are at a baseline higher risk than other ICU patients. Schreppel and colleagues conducted a study that was a pre- and post-observational assessment of a screening protocol for PRIS at their institution. They identified six patients with suspected PRIS compared to 201 patients that did not have PRIS, and they found that CK and creatinine elevations along with hypernatremia and hyperosmolality were associated with the incidence. The Propofol variables in these patients were a much higher cumulative dose with an average of 50,000 milligrams of Propofol versus 9,000 milligrams of Propofol, and a much longer duration in the PRIS patients with 413 hours versus 65 hours. Schreppel and colleagues used the results of the pre-screening to come up with a protocol for continuous Propofol infusion use, where they would stop the Propofol infusion if patients experienced a creatinine kinase above 5,000 or a lactate greater than 4. They would then switch patients to an alternative sedative agent. Out of 1,038 patients sedated with Propofol and screened, 74 triggered at least one of the criteria. 72 were transitioned off of Propofol. The two patients who were not changed developed suspected PRIS and both died on post-trauma days 5 and 8. No cases of PRIS have been observed between July 2006 and 2014 when the data was reported. Now that we've seen sort of the benefits and risks of Propofol and specifically our trauma population, let's shift over into looking at dexmedetomidine. The benefit of dexmedetomidine would start with having some degree of analgesia, minimal depressive effects, so it's easier to conduct a through neurologic exam, and there is some utility in the paroxysmal sympathetic hyperstimulation syndrome that occurs after somewhere between 20 and 60% of traumatic brain injury. Risks of dexmedetomidine include hypertension and bradycardia, the incidence of drug fever, and there's concern for potentially worsened cerebral perfusion pressure. One of the use cases for dexmedetomidine in a medical ICU population is the facilitation of non-invasive ventilation, or NIV. De La Tombe and colleagues looked at 19 patients and they randomized these patients to placebo-controlled crossover where they received either continuous infusion dexmedetomidine over eight hours or continuous infusion placebo over eight hours. Patients had adjunctive morphine available via PCA and the primary outcome was duration of NIV. What they found, you can see placebo on the y-axis, duration of ventilation, versus the dexmedetomidine on the x-axis, was the dexmedetomidine facilitated a much longer duration of non-invasive ventilation. They also found the dexmedetomidine group had significantly lower RAS scores and patients reported increased comfort. They did not find a difference in pain score or morphine use between the groups. Drug fever is one of the banes of existence of any at practicing ICU and dexmedetomidine unfortunately is implicated in the incidence. There were initially scattered case reports suggesting that fever is potential adverse effect and two studies by Grayson and colleagues looked into this further. The first study in 2017 was a retrospective cohort study of ICU admissions that found a univariate odds ratio of 4.5 increased risk for fever with dexmedetomidine. In a multivariate assessment, this risk was increased with patients with obesity and open heart surgery. In 2021, they conducted a post hoc analysis of the SPICE 3 trial subgroup. In this, their primary outcome was the mean body temperature for five days. Dexmedetomidine resulted in a dose related to higher temperatures and they found the number needed to harm for a fever of at least 39 was 14.5 patients. This did have a fairly wide competence interval of 8 to 76 patients, but it demonstrates that I think this is an underappreciated adverse effect of dexmedetomidine. It's also worth noting that in 2021, Peterson and colleagues identified that 15% of their population on dexmedetomidine experienced a fever greater than 38.5. This is something that we need to be aware of and we need to consider in patients on dexmedetomidine that are experiencing hyperthermia. Another study tried to look at the general use of propofol versus standard dose dexmedetomidine or less than or equal to 0.7 mcq per hour versus high dose dexmedetomidine or greater than 0.7 mcq per hour. The primary endpoint here was looking for hypotension, hypertension, bradycardia, and tachycardia during therapy and the need for intervention. This study included 85% of patients with blunt trauma and 25 to 41% of patients had a traumatic brain injury. Overall, they had similar baseline characteristics with more patients in the high dose dexmedetomidine group having spinal cord injury and thoracic injury than propofol. As you can see here, the duration of mechanical ventilation and need for sedation was much higher in the high dose dexmedetomidine group. Additionally, while propofol loading doses were not really utilized, the dexmedetomidine groups had nearly 50% of patients receive a loading dose, which we would anticipate would result in potentially a higher rate of these hemodynamic adverse effects that they were looking for. This slide highlights the safety outcomes and the need for intervention for patients within each of the groups. Along the y-axis we've got the percentage of patients and along the x-axis we have the individual drugs with blue bar being propofol, red bar being standard dose dexmedetomidine or less than or equal to 0.7 mcq per hour versus high dose dexmedetomidine is the green bar. Between hypotension, hypertension, bradycardia, and tachycardia, there was essentially no difference between the incidence of this adverse effect or the need for intervention between any of the groups, with the exception of nearly 100% of the high dose dexmedetomidine patients experiencing hypotension, as opposed to only 80% of the propofol patients. There were no difference in the number of interventions within each medication grouping for any of these adverse effects. As far as clinical outcomes for this study, there was similar mortality among all the groups and longer ICU, hospital, and time on ventilator for the high dose dexmedetomidine group. Note this group did have a higher incidence of spinal cord injury and thoracic trauma than the other two groups, and so this is thought to be driving the difference in those other outcomes. Another study looked to assess the efficacy of propofol versus dexmedetomidine on reducing duration mechanical ventilation in a trauma population. This was published by Winings and colleagues in 2021. Patients were randomized to propofol or dexmedetomidine based on the area of the ICU that they were admitted to, and there were a total of 57 patients in this study. Broadly, they did not really see a lot of significant difference in between the overall outcomes. There was no significant difference in ventilator duration in hours between the two groups, there was no difference in the cumulative morphine equivalents between the two groups, and there was also no difference in the incidence of delirium. However, it is important to note that in dexmedetomidine, 98% of the time patients were in target RAS as opposed to 92% of the time with propofol. This was the only significant outcome variable with a p-value of 0.02. So between the previous study and this study, it's starting to seem like perhaps on a broad basis, there may not be that much difference in using propofol or dexmedetomidine in the management of patients in the trauma ICU. When we think about TBI specifically out of the trauma population, with the physiologic changes and the consequences of secondary injury, it's useful to have a comparative study to see if there is a difference in the impact on metabolic indices. This eight-patient pilot study gave each patient six hours of each drug with a two-hour washout period in between. It included four TBI patients. They assessed cerebral concentrations of metabolic indicators along with ICP, CPP, and general physiologic variables. They did not find a difference in overall outcome or in hemodynamic or metabolic variables, which suggests that dexmedetomidine may not be actively harmful in cerebral metabolic handling in TBI patients. When we consider the management of severe TBI, it seems like dexmedetomidine may not be an ideal agent. But what is the overall effect of transitioning from propofol or midazolam to dexmedetomidine as you're getting ready to excavate the patient? This study looked at 85 severe TBI patients, 51 of whom were on propofol and 35 on midazolam in the pre-injection period. To walk you through the study, the blue circles are the data collection time frame and the median primary data of interest for the area are in the arrows. There was a median of 63 hours of admission before 24 hours before dexmedetomidine was started. When dexmedetomidine was started, it continued for a median of 32 hours and at the 24 hours post-infusion, the median time to discharge was 15 days. The dexmedetomidine dose was fairly moderate, but note on average this was about 2.5 days into the hospital admission for severe TBI and we would expect either ongoing improvement or worsening at this point. The median dose was that 0.49 mcq per hour and they overall found minimal clinically significant hemodynamic disturbance during dexmedetomidine infusion. They did find a significant MAP decrease, but there wasn't a change in the number of patients who were hypotensive as defined by systolic blood pressure less than 90 during the time frame. They also found that switching to dexmedetomidine resulted in decreased fentanyl requirements from 59 mcq an hour to 23 mcq an hour. Intracranial pressure control is another mainstay of management in TBI and sedation can play a role in this. In 198 adult TBI patients who've required ventilation for more than 24 hours, this study assessed the impact of dexmedetomidine, dexmedetomidine propofol, or propofol alone or neither agent on mean maximum ICP on days 1 through 4. On the graph below you can see that ICP in millimeters of mercury is displayed along the y-axis and the x-axis would be each individual day. Stars here are statistically significant differences. As you can see, dexmedetomidine alone appears to not be adequate for the control of ICP, especially early in the hospital stay. Now no overall difference in outcome was observed. Dexmedetomidine was associated to be with a greater time in target RAS than propofol alone and the number of ICP observations was much greater than propofol alone group. But based on these findings, personally I would not rely on dexmedetomidine for ICP control early in the hospital stay. However, there is another study by Schomer and colleagues that appears to show benefit of adding dexmedetomidine onto existing sedation with propofol and fentanyl for refractory intracranial hypertension. So while we shouldn't be using it first-line for elevated ICP, it could be a reasonable adjunctive agent. Trauma patients tend to have a higher need for opioid utilization than patients in other ICUs, particularly medical ICUs, and in theory dexmedetomidine's analgesic effect should minimize their car doses of opioids. Note that said common men's did not demonstrate differences in a broader population and in specifically a trauma population. In this study of 21 adult trauma patients in the 48 hours around the time of ventilator wean, they did not find a difference in mean fentanyl micrograms per day at 24 or 48 hours between propofol and dexmedetomidine. So perhaps the analgesic effects of dexmedetomidine in a trauma situation aren't as beneficial as we'd hoped. One of the unique facets of trauma would be the relatively higher incidence of intoxicated patients on presentation. In these studies specifically we're looking at cocaine and methamphetamine. What I've done here is pulled out comparative results from Cram and colleagues and Chang and colleagues that both looked at UDS positive for stimulants versus negative in a trauma ICU. Across all the graphs the blue bar would be patients positive in the Cram study, red bar is patients negative in the Cram study, green bar is patients positive in the Chang study, and the red bar purple bar is patients negative in the Chang study. On the left side of the graph you can see that the percentage of patients is on the y-axis and there wasn't a difference in the use of any of the sedatives that was statistically significant between any of the groups which goes against what we would have anticipated just thinking about the fact that someone's coming in intoxicated with methamphetamine. Over on the right side of the graph you can see the relative doses required of probofol on the top and dexmedetomidine in the bottom and between patients that whose UDS was positive and negative there appeared to not be any difference in the overall sedation dose required. So potentially there's not really a benefit for one versus another in the trauma population. Now you may say what about ICU delirium? Is there data that shows that trauma patients have a different response to one versus another? There is preliminary data that suggests that dexmedetomidine has protective effect for delirium incidents but this is primarily in a CV surgical population. Additionally in a lot of these studies there is adjunctive dexmedetomidine in addition to propofol that's confounded. Dexmedetomidine is used in patients who feel propofol and there's also higher antipsychotic use reported in the trauma population. Directly comparative studies are challenging. In the other studies that we've discussed from a comparative standpoint the delirium incidents has not been observed to be significantly different. For the special population of patients with burns this really is more relevant to the chronic phase of burn care. It has been found that patient-controlled dexmedetomidine or weight-based dosage prior to dressing changes improves outcomes with fewer hemodynamic excursions and improved anxiety and pain. So this is something you consider in that population of patients. And the other big-picture population I'd like to just briefly touch on, although this is worth a talk all on its own, would be the management of paroxysmal sympathetic hyperstimulation. Both drugs mechanistically would be helpful options. Recall that earlier slide in the talk on the physiochemical sequelae of traumatic brain injury. The timing of use may be the biggest consideration for the scope of my talk today. It does seem like PSH is very common in the trauma ICU and isolated data for both propofol and dexmedetomidine exists. Mechanistically both are effective and really the choice should be based on the overall clinical status of the patient. My personal opinion is that propofol is more appropriate earlier on the hospital stay when you're dealing with the need for deeper levels of sedation and that dexmedetomidine should be attempted when ventilator weaning is happening or the patient is extubated. In summary, propofol and dexmedetomidine are both reasonable choices in the trauma ICU population. Propofol is positively more beneficial in early TBI management. There's actually no apparent difference in opioid use or need for delirium treatment and we really should be individualizing selection of propofol or dexmedetomidine to the to the needs of our patients.

propofol

dexmedetomidine

trauma population

ICU

sedation

clinical status