Hello, and thank you again for the opportunity to present and continue this discussion about how the PEDS, PANDEM, and ICU liberation efforts can complement and inform each other. If you missed my earlier session, my name is John Birkenbach. I am a pediatric intensivist at Norton Children's Hospital in Louisville, Kentucky. I served as the co-chair for the Sedation and Analgesia Task Force, and I'm a co-author of the 2022 PEDS, PANDEM guidelines. I will be discussing some of the key recommendations made in the guidelines relating to choice of analgesic, sedative, and neuromuscular blocking agents. While this presentation will focus primarily on pharmacologic choices, it should be remembered that there are several non-pharmacologic interventions for the provision of comfort to the critically ill child as well, and these are discussed in the guidelines and supplemental content. I have no relevant financial disclosures or conflicts of interest. My objectives for this part of the session are twofold. First, I would like to remind you of the importance of providing appropriate analgesia and sedation in the PICU, and follow that with the discussion highlighting specific recommendations related to the choice of analgesic, sedative, or neuromuscular blocking agent. It probably comes as no surprise that pain and agitation are commonplace in the critically ill child, regardless of their reason for admission to the PICU and the invasiveness of the therapies they are receiving. Similarly, it should come as no surprise that pain and or agitation have multiple sources in the PICU patient. I think we're all aware of the obvious causes of pain, such as surgical site pain, traumatic injury, or agitation such as the presence and need to protect, invasive devices, or distress due to just being in the ICU. However, multiple other causes exist that may be underappreciated. We may forget that the underlying inflammatory response associated with critical disease may not just make patients feel unwell, but may be overtly painful. Similarly, pain is described by older patients in the PICU regarding the presence of an endotracheal tube, especially during suctioning. Perhaps even less well appreciated are the pain associated with immobility or reduced mobility experienced by a large number of our patients, or the distress, which is probably cumulative in nature, that the sleep disruption so prevalent in our PICUs can also create. I would advocate, then, that this list serves as a reminder to implement the suggestions made earlier in this panel about the frequent need for assessments of pain and distress in all of our patients. Coincidental with the high prevalence of pain and agitation in the PICU is a need to understand the adverse consequences of inadequately addressing them. In the acute phase, we, quite rightly, focus on patient safety, including the need to prevent inadvertent device removal, and facilitate cooperation with therapies. Just as important, we must remind ourselves of other possibly longer-term adverse consequences to PICU interventions, including the development of withdrawal syndromes, delirium, and post-intensive care syndrome. While these developments are almost certainly multifactorial in origin, our pharmacologic choices likely play a role. Regarding analgesia, I would like to highlight two recommendations that we make for analgesic choices in the PICU. This probably seems like the most obvious question to ask, but was still one that we felt we should address. What class of analgesic is superior for treating pain in the critically ill pediatric patient? Not surprisingly, our recommendation, and it is a strong one, is that IV opiates be used as the primary analgesic for treating moderate to severe pain. This recommendation is based almost exclusively on multiple survey-type studies, all of which reported that IV opiates were, by far, the most commonly used agent for treating most pain in the PICU patient. Additionally, opiates remain the agent of choice for treating moderate to severe pain in the World Health Organization pain ladder. Consequently, despite the lack of comparative studies, we feel comfortable making this recommendation, particularly since no other viable analgesic options exist for longer-term analgesia provision to the ICU patient. One thing our group would have liked to see was evidence comparing efficacy and or safety between opiate agents. Unfortunately, we were unable to find any head-to-head comparisons between opiates in PICU patients, leaving the question of which opiate provides a therapeutic and or safety advantage as an unanswered question. While pharmacologic principles suggest that synthetic opiates may be preferred in the setting of renal dysfunction, the evidence here was, again, insufficient to allow us to make a recommendation. A similar insufficient body of evidence existed for questions relating to the utility of shorter acting agents, such as remifentanyl, to facilitate early extubation. A potentially more interesting question is that of the utility of adding non-opiate adjunct medications to opiate-based analgesic regimens, specifically acetaminophen or a nonsteroidal agent. We are recommending the addition of IV or oral nonsteroidals to improve early postoperative analgesia, and we are suggesting their use to decrease opiate exposure in the immediate postoperative period. In the case of acetaminophen, we are suggesting their addition for the same two outcomes. I should stress that these recommendations apply to early postoperative outcomes and that we are not advocating for longer-term use of either agent. The evidence evaluating these recommendations derived from two systematic reviews and four randomized controlled trials, although I will just summarize the findings of the systematic reviews here. In the 45 discrete studies included in both reviews, addition of a nonsteroidal was addressed in 34. While not all studies addressed the outcomes we were interested in, the majority demonstrated improved pain scores and reduced opiate requirements with nonsteroidal addition. 42 studies addressed the addition of acetaminophen, and while the trend in results was similar to that seen with nonsteroidal agents, the proportional improvements were smaller, leading to conditional recommendations only. While there are several more recommendations related to sedative choice, due to time constraints, this section will be limited to highlighting three. Similar to with analgesics, the first question we felt we needed to ask was if there was evidence to support a preferred sedative choice for the critically ill child requiring mechanical ventilation. While multiple agents are available to the critical care practitioner, survey-based studies have reported that benzodiazepines have long been the sedative class of choice in the PICU. Despite that, and based on available evidence, we are suggesting that alpha-2 agonists be used as the primary sedative class. We found five randomized controlled trials comparing sedative efficacy between alpha-agonists and benzodiazepines, all reporting no difference between the two classes. However, four smaller RCTs comparing opiate requirements during sedation with these two classes all reported less opiate exposure in alpha-agonist versus benzodiazepine sedated patients across multiple PICU populations. While greater mean reductions in heart rate and blood pressure have been reported with alpha-agonist use, the need to intervene for overt bradycardia and or hypotension has not been reported to be increased compared to benzodiazepine sedation. These data, combined with the growing evidence of an association between benzodiazepine exposure and delirium development, further informed this recommendation. Related to the above, we specifically evaluated the question of benzodiazepine versus alpha-agonist sedation in postoperative cardiac surgical patients, as this population was thought to perhaps be more sensitive to the sympatholytic effects of alpha-agonists. However, the evidence suggested that this was not the case, and we recommend alpha-agonist over benzodiazepine-based sedation for postoperative cardiac surgical patients in whom early extubation is planned, and we suggest the use of dexmedetomidine sedation to reduce the risk of postoperative tachydysrhythmias. These recommendations were supported by data from two systematic reviews and two additional RCTs. Regarding early extubation, one systematic review and one RCT reported earlier extubation with dexmedetomidine use, with the other RCT finding no difference. This question was not addressed by the second systematic review. Both systematic reviews, however, concluded that the incidence of postoperative tachydysrhythmias was lower with alpha-agonist versus benzodiazepine sedation. As this remains an ongoing topic of debate within our discipline, the task force felt we needed to address the question of propofol use and associated risks. Despite its highly attractive pharmacologic properties, concerns regarding the development of propofol-related infusion syndrome, or PRIS, remain real. For that reason, our group spent probably more time evaluating the evidence here than for any other question. In the end, we are suggesting that propofol infusions be limited to a combination of less than 4 milligrams per kilogram per hour and for less than 48 hours to reduce the risk of PRIS development. Unfortunately, the available data informing propofol dosing recommendations is limited. While the initial developments of PRIS are almost 30 years old now, data addressing the role of propofol dose and or duration and PRIS development remain limited. The suggestion to limit propofol dose and duration were based on data from five prospective observational case series. In all of these series, propofol dosing was limited to either less than 4 milligrams per kilogram per hour and or a 48-hour duration in the vast majority of participants. And no cases of PRIS were reported in patients in whom propofol use was below these dose and duration limits. What remains unknown and has yet to be adequately studied is what the risks of PRIS development are when using propofol at higher doses and or for longer durations. This is especially relevant as we have a greater understanding of the early signs of PRIS and how to more effectively screen for it than when the syndrome was initially described. Therefore, this remains very much a topic in need of further study. I'll conclude this session with a brief look at one recommendation regarding neuromuscular blockade use. While neuromuscular blocking agent use remains relatively common amongst the sickest of critically ill children, the data surrounding their use and impact on outcomes is sparse. Therefore, the only question we were able to find sufficient data from which to make a recommendation regarding neuromuscular blocker use was what are the necessary sedation and or analgesia requirements during neuromuscular blocker use. While the evidence here is also limited, the best we could do is make a suggestion that analgesia and sedation should be adequate to prevent awareness during neuromuscular blockade. Before addressing the actual recommendation, I want to note that the task force asked many other questions regarding neuromuscular blocker use, including their benefits and impacts on outcomes, especially in the setting of severe respiratory disease, which is when neuromuscular blocking agents are most commonly utilized. Available evidence remains insufficient to address these questions. Within the PICU, there is also a paucity of literature evaluating the degree of sedation and or analgesia required during neuromuscular blocker use, other than an intuitive feeling by most practitioners that awareness during neuromuscular blocker use would be unacceptable. The data supporting our recommendation comes primarily from the fifth audit of the Royal College of Anesthetists of the UK and Ireland, which found that accidental awareness under anesthesia is as high as 1 in 135 procedures when children were directly questioned following their procedure. Methods to mitigate this result remain understudied. While the practice of neuromuscular blocker holidays during their use is gaining popularity, published data remain insufficient to address whether this practice truly reduces the incidence of unintended awareness. Similarly, while EEG-based monitoring, particularly with the BIS monitor, has demonstrated efficacy in terms of trending sedation depth in the PICU patient, data regarding their application during neuromuscular blocker use remain insufficient to make a formal recommendation. This therefore remains very much as well a topic for which further study is desperately needed. With that, I will conclude and thank you for your attention. I will again note that additional drug and non-pharmacologic interventions are addressed in the guidelines, but could not all be addressed here due to time constraints, and I refer you to the full guidelines and associated supplemental content for additional information. I also encourage you to post your questions or comments using the chat function and look forward to addressing them later in the session.

PEDS

PANDEM guidelines

analgesic choice

sedative choice

neuromuscular blocking agents