Hello, my name is Pete Johnson. I'm a professor of pharmacy at the University of Oklahoma College of Pharmacy, and I also practice in Pete's critical care, primarily in the cardiac ICU now at Oklahoma Children's Hospital at OU Health. It's my honor to present how to choose the right analgesia sedation in the pediatric patient. As far as disclosures and conflicts, I have no financial obligations related to the purpose of this presentation. We'll make some references to off-label use of medications. And I guess, lastly, a disclosure is I was a member of the Pete's Pandemic Guideline Task Force, so I'll be talking about aspects related to that. So my objective as it relates to the line of presentations for this content is to identify barriers to optimizing agent selection, facilitators for implementation, rather, education and care, and create a protocol to standardize and monitor success of our patients. So first up, we'll look at barriers to optimizing agent selection. As I was thinking through this, I identified four potential barriers that many of us might encounter on a daily basis in our critically ill children. The first barrier would be drug shortages, which for some of us might be like a four-letter word. It's been a problem in the U.S. for many years, although I feel like over the last 10 to 15 years, it's become even more problematic. There's a lot of different etiologies that are out there. Some problems in quality manufacturing process that can lead companies to halt production. Natural disasters. I know many of us were familiar with some shortages, particularly with fentanyl and opioids as a result of Hurricane Maria in Puerto Rico in 2017 that halted drug manufacturing. And of course, last but not least, is the pandemic. Certainly this resulted into just raw material production issues. People weren't able to be in factories to manufacture products, as well as the difficulties in just sick patients, primarily, at least initially with adults, requiring so many therapies, opioid sedatives, that it just led to a decrease in distribution to other hospitals. I found it interesting that there was a recent survey of approximately 1,400 adults in pediatric health systems in the United States. They looked at drug shortages and answered a number of different questions related to this. In terms of the most common shortages that they noted, it was particularly with albuterol, MDIs, sedative anesthetics, and neuromuscular blockers, which obviously led to a number of clinical issues. So one of them is just confusing among healthcare professionals, not knowing what exactly we have in stock. I can tell you from the pharmacy side of things, sometimes there's confusions between our operations distribution staff and the clinical staff knowing exactly what we have in play, and that can further lead to miscommunication with the medical team. It could require conversion of analgesic sedatives and neuromuscular blockade, and then those factors could lead to an increase in medication errors and adverse events. Another barrier that I sort of thought of is maybe just the patient himself. What about those that have renal or hepatic dysfunction? Obviously, it could require consideration of alternative agents. The PEDS Pandem Guidelines do have some tables that might help you, just as a reminder. So it's Supplemental Digital Content, tables three, 10, and 14, for sedatives, analgesics, and neuromuscular blockade. Just in terms of some general recommendations, one consideration would be those without active metabolites might be better than those with renal dysfunction, as well as those that have hepatic dysfunction, maybe avoiding those that are metabolized through other enzyme pathways other than CYP450. So, as displayed here. Another barrier that I sort of thought of is tolerance. So tolerance could impact the choice of selected agents, generally defined as a decrease in the pharmacodynamic effect that requires an increase in dose for that desired or decreased effect. So there could be a number of etiologies, just with a drug, the PK or PD, so pharmacokinetic or dynamic. So receptor desensitization, mechanistic pathways, pharmacokinetic medicinal structure, so many are familiar with fentanyl as a semi-synthetic short-acting opioid, and is known to have higher degrees of tolerance than morphine or hydromorphone. There could be patient-specific factors as well. The cumulative duration increases the risk of tolerance. Some studies have said those that are admitted for medical, as opposed to surgical diagnoses, may be at higher risk, as well as those with frequent ICU admissions. The problem with all this is that clinical studies often define tolerance as a doubling of a dose. I know a number of studies have looked at fentanyl in particular, or a doubling of their initial dose and bolus dose. The problem is that that definition is a little bit too simplistic and doesn't take into account some of those pharmacokinetic and dynamic issues. As a result, the Peds Pandem guidelines, we do not specifically address this, because honestly, there needs to be a more robust definition that defines exactly what tolerance is for our patients. Another barrier would be obesity. It's estimated between 19 to 22% of children in health systems and PICUs are obese. I know in the state of Oklahoma, this might even underestimate some of our admissions. Obesity can lead to a number of pharmacokinetic alterations, in particular, can affect our sedatives and analgesics and even neuromuscular blockers. It can increase adipose tissue as a result of a decrease in lean body mass, which can in particular affect the volume distribution, the loading dose that obese kids need, as well as their maintenance dose as well. It also can increase their total body clearance, which could affect the renal clearance of some of these medications. So dosing adjustments have definitely been evaluated in critically ill adults, such as adjusted body weight, ideal body weight, lean body mass, and different references have cited different factors might be needed to be used in certain medications versus others. But really there's a lack of universal definitions in particular with lean body mass in children. My colleagues and I actually evaluate the top 20 infusions that critically ill obese children received in the PICU and the cardiac ICU. So we found almost half of them were a sedative and analgesic or neuromuscular blocker agent. We also did a literature search. So we only found three of these agents that there were PK studies that really have evaluated the impact of pharmacokinetics with obesity, but a number of them have not been studied. So there are a number of unanswered questions. The Peds Pandem notes these questions with neuromuscular blockers in particular, we don't comment on the lack of data or the need of data for sedative and analgesics, but it definitely is there. And so there really is a paucity of studies in impacting the right dose, maybe the right agent to use in some of these children. So now that we talked some of the barriers, I don't know if I had answers for all the barriers, but just highlighting what some of them are for agent selection, et cetera. Let's look at considerations for protocol creation. So what's the state of need for this? Well, as noted in the Pandem guidelines, we referenced this particular study. So this was a survey in which they set out to assess sedation, sleep promotion, and delirium practices among Peds critical care providers. It was a survey of World Federation of Pediatric Intensive and Critical Care Society members over approximately a six month period. In terms of results, they had 341 respondents, the majority from North America, but there was representation from all across the world. 70% of the respondents notarized that they use patient specific sedation goals. However, only about 42% of them actually implemented that in terms of their daily rounds or patient care goals themselves. So even though they were having these goals, maybe not necessarily doing much with them, I hate to say. Also, they looked at some other things that I think are important to note, whether institutions had a unit wide or written protocol for all mechanically ventilated children. So as you can see, there are significant differences between North America and other countries across the world, as well as who is the driver of that sedation protocol. As you can see in the United States at that time, the majority of respondents noted nurses were versus other countries, primarily physicians as well. So basically a lot of heterogeneity in this topic. So what are some considerations of protocols? So some that I, when I was thinking about this topic, I approached it by each sort of category of agents. So analgesia and sedation, obviously we recommend scoring tools for pain and sedation. So that should be a part of this protocol consideration. Selection of agents, no specific recommendation for first line opioid. We do recommend dexmedetomidine for first line and then give considerations for second line and adjunct agents as well. So that could be helpful in designing your protocol if you haven't already done so. In terms of neuromuscular blockade, we do provide recommendations for depth of blockade, selection of agents, which basically we don't recommend one over the other, as well as other supportive care considerations like routine passive eyelid closure with eye lubrication. In terms of additional consideration, you know, if you work in a facility that has a PICU and a cardiac ICU, you might need unit specific protocols. You might need to make room for adjustments that, for patients that don't really fit the norm. Maybe those that have a high degree of tolerance or multiple admissions or other genetic anomalies that make selection and dosing of these agents a little bit different than the normal PICU or cardiac ICU population. What about continuous infusions versus intermittent infusions? In the PANDEM guidelines, we don't necessarily recommend one over the other. Although I will say, if you can get away with doing intermittent dosing of agents, that's of course always best. And then another layer of complexity is PRN analgesics and sedatives. So the joint commission has implemented what is called medication management standards rather for on medication orders and administration. And they require specifically an objective indication of PRN agents. So for example, for opioids, a pain score of four to six, they require sequence administration. So if they're getting acetaminophen plus morphine, providers must illustrate or elucidate what they want to give first. And then also in nursing instructions as well. So this can make it a little bit complicated in terms of creation of your own protocol. So let's look at one possible way around this or one way to address this. So there was a group from Johns Hopkins that set out to address this issue. They conducted a quality improvement project in which they studied pre versus post design of the protocol that was compliant in terms of the PRN sedative analgesic and neuromuscular blocker orders for those issues like we identified on the previous slide. So their method was they first conducted a complex mode on PRN orders on those three requirements that we discussed. So the indication, the timing, and the nursing instructions for analgesic sedatives and paralytics, and then also some additional supportive care consideration for analgesics. They created an example of smart lists that they created with medications and the potential PRN indications as you can see depicted on this slide that was designated for their electronic medical record. So they implemented education on the joint commission requirements themselves as well as implemented the protocol. So the way that they did this is the first period that they assessed was before they did education, before they implemented this order set. Period two was after they implemented the education, but it was before 17 weeks before the protocol implementation. And period three was that 13 week period after order set in education was initiated. So what they found was that there was significant increase in order compliance with PRN medications for the joint commission requirements from their first period. So before any education to after they implemented some education. And then after they implemented the education and the protocol, compliance was somewhere around 90%. And it stayed that way through the end of the study. So I think this illustrates having a protocol, educating your team on why this is important and why we have to do this definitely helped them achieve that 90% goal. So I think just the conclusions that they had is development of an order set increased compliance that you need to develop a unit specific protocol and then implement educational strategies. Well, let's look at considerations for implementation and then education and care specifically. We talked about barriers to agents, but there are also barriers to protocol implementation. Just with the culture of an institution itself, training on specific standard assessment tools, maybe a transfer may be needed to form providers to nurses depending on what your protocol looks like. A greater emphasis on using analogous sedation. So less sedation and maybe using the backbone of opioids may be a different practice than some are familiar with. And then definitely the introduction of early mobility could throw a kink in how people approach this. There also could be a lack of agreement of providers on how they want the protocol to look, what they wanted to do, et cetera. And then familiarity of the protocol design as well. In terms of education and implementation, I definitely would recommend selecting a physician champion and interprofessional leadership. So from nursing, but I'd also argue involve your clinical pharmacists just with all the implications as we've already talked about from joint commission requirements to dosing to other considerations as well. Identify some sort of plan for education. So education is nice, but how are you gonna do it? Are you gonna have online modules, face-to-face didactic sessions, Zoom in this day and age? Identify those key champions. So from bedside nurses to sort of your key people that might be then enabled to in turn educate others. And those are people are necessary to ensure sustainability of a protocol. One example that I thought was interesting that I just pointed out is the Sandwich Trial, which many may be familiar with. It was a multi-center step wedge cluster RCT in 17 cities in the United Kingdom. And they assessed sedation and veneration, liberation protocol in approximately 9,000 children. And just what I wanted to highlight here is their education plan. So if you haven't implemented a protocol, maybe you're thinking through the best way to do it. They did just what I presented on the previous slide. They had an online course that included seven different modules. People had to make a certain score. They had some champions, but they also implemented face-to-face training, knowing that that online module may or may not have been a full or a good way to engage our adult learners. So what about protocol sustainability? Some of you may have implemented a protocol, but is it sustainable? So this particular study is published a number of years ago. They compared a duration of sedatives and other outcomes immediately post after they implemented a protocol over a several year timeframe back in the 2008 to 2009 versus five years later after the protocol had still been used, they wanted to assess, is it still working? So some of the education and implementation considerations. So in early 2008, when they implemented the protocol, the staff received detailed training, in-person training, but following implementation, new staff just received education via that online module, not as the face-to-face in-depth engagement that was done initially. And no changes were done in the protocol during the study. So what they found was the Cox Proportional Hazard Model found controlling for severity of illness and diagnosis that more patients in the following, the five-year period following, were more likely to be sedated and had a longer PICU ICU stay. So kind of showing that maybe that protocol initially did some good things, but after it had been out for a number of years, didn't necessarily have as dramatic of results as they initially found. The one positive is that they did note a reduction in visited isopine exposure that remained throughout the different study periods. So what about some additional sustainability considerations? Identify ongoing educational strategies. So I would argue from that previous study, having a face-to-face communication is really necessary versus just an online module. Development of some sort of data collection and ongoing audit and assessment to identify how sustainable are the outcomes, maybe initially had great outcomes, but you find out through that audit that things are not going as well and need to re-strategize how to sustain a protocol success. Need to also obtain ongoing feedback with sedation practices. Maybe as your unit gets bigger, you have more of some types of subsets of critically ill patients, you might need to tailor your protocol to meet their needs. And then I would argue, again, a continued need for interprofessional leadership with nursing, pharmacy, respiratory, physical therapy, et cetera. In conclusion, there are definitely several barriers that we discussed in terms of just analgesias, sedatives, and neuromuscular blockers themselves. There are numerous factors involved with protocol creation, as well as some barriers to implementing that protocol and its sustainability in the future. Thank you for attending this presentation. I hope you at least give you some things to think about for creating or evaluating the sustainability of your own protocol.

analgesia sedation

pediatric patients

agent selection

protocol

scoring tools