Chapters Transcript Video Neuro-Sedative Use in the Inpatient Setting Back to Symposium Pharmacist Rhonda Kurz spoke on the variability in use of medications for BPD and variability of individual responses to medications. So our next talk uh will be this, we will be exploring neuro sedative use in the inpatient uh setting. It's my pleasure to call uh Rhonda Kerr. She's one of our critical care pharmacists um um for us in the NICU, um certainly a lifeline for us many times. So with that, uh hopefully a little data, maybe just a little bit. But you can see certainly there's a theme that we have a lack of data for uh all of our pharmacologic interventions here in, in the N IC U for BPD. With that random, please. Thank you everyone for joining us today. Um Both in person and online. So, um I tried to use evidence where there was some but there is some extrapolation. So disclosures I don't have any financial conflicts of interest, but I will be discussing many off label indications of four medications. If only man management of BPD was fill in the blank simple babies, followed what we thought was best for them. It would make my job a lot easier. However, we know that's not always the case. I did find it interesting though that I did find out of this strategy uh published in a Turkish journal that talked about their strategies mechanically in regards to managing the vent. But what jumped out to me was that they targeted, keeping the infant calm without the need for sedatives. I don't know that we actually go into the patient's room thinking that's going to be my goal today. Um, versus lying on relying on other, um, adjunct agents such as neuro sedatives. That's why I think we've seen this before. Um Anesthetics, analgesics and sedatives are one of the top medication classes used in patients. So as a result, we're gonna be discussing delirium and some of the risk factors that may present these patients, uh recognizing the effects of benzodiazepines and examining some of the alternative buro sedatives that may be an option for them. So a little bit of background, um I think some of our goals in general for neuro sedatives are to provide that respiratory stability. So they are able to tolerate what we're doing with the ventilator, promote growth. Ultimately, because we know tincture time and growth is going to be the best thing for these infants. But we also wanna think about the neurodevelopmental impact and provide, you know, minimal or even positive impact when possible. So, thinking of what is an ideal sedative. So you would want it to have lysis, you know, adequate effects, but you wouldn't want it to affect their respiratory drive their airway tone, their hemodynamics and even have positive or neutral development effect on their neurodevelopment, not only long term but also short term. So even sleep patterns because I think that's an under recognized um effect of some of these neuro sedatives. So why do I think sleep is important? So mature maturation of the brain facilitation of learning cognition that conservation of metabolic energy which once again contributes to growth, which there's a lot of circumstantial evidence in relation to sleep um equating to growth. However, I did find one study in term infants that was able to find um an association with um changes in sleep and their growth patterns. And the thought was that growth hormone, you know, is um secreted most with slow wave sleep. So just quick refresher infants up to three months of age, actually don't have differentiated non rem sleep. It's pretty much either um rem or non rem and there's no regular rhythm. I think we can all attest to that, especially if you've had an infant. Um and then three months or older, they start developing those neurologic patterns and um for sleep and it becomes more regular that this is also when they start to develop their circadian rhythm and melatonin releases and cortisol releases uh more by basic. So whenever those things don't go well, we can have patients with delirium. Delirium is often unrecognized in vic. I think it's new and upcoming topic. Um It's an acute disorder characterized by a change in awareness or cognition. So one day you walk in and you hear that, oh, the baby is just out of their mind, we can't do anything for them. Something's changed. It may have been gradual or it may be acute. I think we can all envision that this is gonna be negatively associated with development long term. Um combined with what they're even here for is what's contributing to their delirium. So they underlying severe illness, um environmental disruptions with alarms, frequency and tears, poor sleep quality. Um even the mechanical ventilation that we um expose them to combined with what we try to use to keep them calm neuros iss whether it be opioids, benzos or even anti full energies. So, in my search, I found that the most important modify modifiable risk factor for development of delirium is sedative choice. So if you have a patient and then you suspect having delirium, I think we often go towards the hyperactive aspect, the irritability, the restlessness, um the shaking their head back and forth, we're worried about them excavating. However, that's not the only presentation that they have. And I think some of our developmental specialists can attest to, they're just not responding, they're avoiding eye contact, they're not engaging with us. And this can also be detrimental, but it may be more subtle and not picked up on. And then of course, there's next delirium. So if you have a patient that we may suspect they can initiate um the corneal assessment of pediatric delirium or C att for. So this is validated for all ages inclusion are infants and it provides um anger points for various developmental stages for newborns and at one month, um two months and you know, even four weeks out as well as one year. So you can see the questions there. Um How are they engaging with caregivers? What is their movement? Um How did they console? Are they just restless at baseline? And you tally up their score and positive screening for delirium would be a score of nine or great. So what is the impact of delirium? So why do we care? So it can be associated with a longer length of stay, more time spent receiving mechanical ventilation, which is totally counterintuitive to what we're trying to achieve in these patients. And of course, um increase hospitalization cost. So you can treat delirium. Um Most common Asians, atypical antipsychotics, some of you may be very disappointed that I'm not going to talk on this topic today because that's a whole another um level of evidence that isn't really there. Um But Melatonin is a staple as well as uh alpha two agonous. They are coming more in the forefront as um managing delirium. But instead of treating it, why don't we do better at preventing it? So I can speak on some of the pharmacologic reasons um and how you can prevent, but I'm not at the bedside, I'm not an actual provider day to day. So I'd like to uh turn to the audience. What are some physiologic and environmental things you can do to alter their development is delirium 89. Like cycling, like cycling. Ok. Pain limiting restrains promoting therapeutic touches. Awesome. Right. What was that on parental vomiting? Ok. Which actually sometimes whenever we give medications like benzodiazepines, what's an effect of it amnesia? So you may try and promote those positive experiences but then you just wipe them out, you can play therapy. So letting babies be babies as much as possible, they don't wanna be laying there, allow them to move. We don't wanna sedate them toward they can't do anything. Ok? Disability increase their ventilator support. So don't make them work so hard but give them the support they need. So then they may not need to have that extra information. Ok? Anything else I noise, definitely noise and I would say a noise and even promoting that um restful environment, you know, adequate sleep by an environment which depending upon your unit may or may not be possible and just encouraging those non pharmacologic measures as much as possible. So sometimes we do have to use zero sedative though. So what weighs into your choice of selection? Um Some days I'm very popular in the unit because I can provide some, you know, suggestions that may be helpful. Sometimes I'm not so popular whenever I'm like wait, we're on LORazepam scheduled every three or four hours. Yeah, we, we, we shouldn't be doing that. Some people are like, but you don't understand. They're restless, they're a beast. They're gonna extubate. And I'm like, you don't understand, you're feeding the beast, you're making it worse. So, we'll talk about that a little bit. So, actually the FDA issued a warning in 2016, um, related to poor neurodevelopmental outcomes related to benzo exposure to infants and neonatal patients. Um, less than three years of age as well as um pregnant moms and the outcomes of their newborns. So ben um have been associated with neuronal loss and negative effects on cognitive outcomes and this is most associated with repeated or lengthy outcomes or lengthy exposure. Um Midazolam and LORazepam we use and that's included in this morning. Uh Benzos actually have an effect on sleep negatively as well. It decreases rem and slow wave sleep. So you can see once again, uh Laura's pam made a the top five list or medications used in our BPD population. So despite this warning, it continues to creep up. So what is actually the outcomes of issues? So, um looking at secondary analysis from the peanut trial, um with the US study, looking at 19 sites of treatment, infants between 24 and 28 weeks gestation and they stratified it into short duration of exposure to benzos and opioids during their stay is less than seven days or greater than seven days for prolonged exposure. And then they looked at their daily spores um on all three areas down the road. So over half of these patients in this cohort receive both opioids and lympho during their stay. Mm. This cohort did have an instance of severe BPD associated with um their exposures combined with longer hospital stays and then lower uh scores in all three areas most often associated with prolonged exposure. So looking at that, that breakdown, you see in the teal um the cognitive scores, the motor scores in orange and then the Navy has some language and whether it was opioids and those or a combination, long, prolonged exposure, greater than seven days significantly impacted their developmental scores. So what about delirium in our patient population? So there's not a lot of good evidence about benzos and delirium in the neonates. However, looking to our picking colleagues, there is some evidence. So here's a site um that look prospectively screening for delirium and then retrospectively, they looked at what their benzodiazepine exposure was, you think, ok, may or may not be applicable to us. However, they did show a high association with delirium in patients that received benzos and this was even after they adjusted for co-founders of mechanical ventilation or opioids. So I do believe that some of this evidence is relatable to us because of their 580 admissions. A quarter of those were under a year of age. So you can think of your chronic BPD patients and um nearly half of them have respiratory insufficiency or failure. Um opioid days um compared to benzo days were greater. However, predictors of delirium were still if they received benzodiazepines the day prior, um or opioids the day prior or invasive ventilation, which I think in our head, you know, those three all go together. However, if they already had delirium and they controlled for that, just the exposure to benzo is more than double their chance of delirium the following day. And opioid exposure was not independently associated with that delirium. After controlling for opioids and the mechanical ventilation, benzodiazepine dosage remained a significant predictor to that development of delirium. So looking at that for actually every one long increase in the dose exposure of the benzodiazepine, there is a 43% increase in the risk of delirium the next day. And their benzo dose was expressed in normally milligrams per kilo per day equivalent, whether it was, you know, my dad's lamb or moan, they and they concluded that Benzodiazepines are an independent and modifiable risk factor for delivering. So, what would be your ideal sedative once again? Does it have any effect on the respiratory drive and positive or neutral effect on neurodevelopment? Hopefully, we can conclude. Now, the benzodiazepines may not be the ideal sedative for our patients. So, is there anything better? So looking at the alpha agonous dex meat tomaine, so reported um affects are angios with some sedation, analgesia. Um the analgesic effect is moderate but it does potentiate the effect of other opioids when used in association. So what are some reported benefits in the literature? So whenever you use sinoamadi, there are reports, multiple of decreased duration and dose of other neuro sedatives. So I describe this as polypharmacy with a purpose instead of just polypharmacy and adding on to something else, you're actually adding something that's an adjunct to lower the use of something else. Um Multiple reports of decreased incidence of emergent emergency delirium in various patient populations. Also, it may offer neuro protection actually, um and improve developmental outcomes especially in the HIV patient population. Um There's been much research around this and anesthesia. It actually does not alter your respiratory drive or your tolerance to internal feedings because it does not slow down your gut motility and it does not alter your eeg. So what about safety cause? We have to think, ok, just because it may be good, doesn't mean it's gonna be safe. So there are adverse adverse effects associated with it. Most commonly hypotension and bradycardia. These are usually resolved with decreased dose or discontinuation. Um Heart block is actually uh postmarking reported and we have experiences in our unit in some of our smaller patients. This was reversible with discontinuation. It's very interesting though in the literature that the airway tone um that is very similar to that during natural sleep. And this comes from evidence, looking at um obstructive sleep apnea studies in those patients. So how do we apply this to practice? So, actually nationwide did A Q I project trying to decrease their opioid exposure in post trait patients using Dex measom. So they looked at 14 DNA um and the average week gestational age was 51 and they added DEXAmet toad and then looked at what their need for other agents was during that time with the addition of DEX, they were able to decrease the average duration of opioid from 24 days down to less than a week. And benzodiazepines from three weeks down to um right around nine days and that was statistically significant. So once again, patient evidence in our patient population, it would be applicable that it can actually decrease your need for other agents. So, not necessarily our patient population, but um the effects on sleep in a picky, once again, looking at Children six months, up to 17 years, I figured that six months to one year population was relevant. They were also receiving mechanical ventilation for acute respiratory failure and then they did sleep studies and looked at their results. And so sleep um time was above average um for the normal warfarin's range in patients that did receive DEX menas. And um the sleep stages noted were in street um that N one N two, which may be related to growth hormone release. So another new incoming um agent is gabapentin. So gabapentin um commonly started a seizure med however quickly grew interest um related to its um pain properties. So it's actually a GA analog, but it does not bind to any gata receptors or insulin synthesis or uptake of gata. So, it's thought to exert its effect um via voltage dependent calcium ion channels. So it's most commonly gonna be used um for visceral hyperalgesia, especially in those G I or neuro complex patients where you don't know exactly what's going on, but they may have had bowel surgery. And you think that there may be a gut pathology that visceral hyperalgesia or um neurologically impacted and they can't verbalize or, you know, um exert normal developmental responses. And so it can actually decrease the irritability and there's reports of an improving sleep as well. Um because of its effects, if there is a G I associated reason for their irritability may actually improve their ability to feed because it's taking away that stomach um A per se and there are reports of it decreasing cardio and respiratory events and provide a little bit more stabilization. However, what about safety? So it can cause bradycardia um once again, reversible discontinuation of the drug as well as nice stags, which I think we've seen in some of our patients as well. This is new what could be contributing. Um I think it's key to know that patients can exhibit withdrawal from this, um especially with abrupt discontinuation and so weaning it slowly is important and then we really don't know about the neurodevelopmental outcomes of this. I know there may be some concerns because in the adult literature, a couple of years ago, there's some evidence showing um decrease of cognitive and some physiologic changes in the adult brain with prolonged exposure, gabapentin, uh talking to my adult uh neurologist friends, they haven't seen that for all inflammable practice, but it is something to be mind blow. We don't know what the effect will be long term. So looking at a case series, um this actually did involve nine patients with BPD. It was retrospective looking at um 16 patients at a single site that did use gabapentin. Um They started at 2.5 to 5 minutes per kick per day and titrated every few days up to a maximum of around 35 megs per gig per day, which I would say that's typical with what and how we use it here at our institution. Um And then they looked at just what their experience was and they achieved their goal dose approximately a month after initiation. But you can see some patients were on a a prolonged period of time. Um Not surprising to me. However, of interest patients on multiple neuro sedatives, they were able to wean down um on the number of neuro sedatives patients needed. The most impactful was their impact scoring that they um published on 13 of their infants. So on the left hand side, you'll see the patient characteristics table. But on the right hand side, their impasse scores from two days prior to starting up to 28 days, post starting. And you can see a significant difference in their impasse scores gabapentin because of its uh PK parameters. It doesn't impact uh scores immediately. It requires a few days to take effect. But you can see um gradual improvement in their scores, long term limitations to this. Of course, it was retrospective. So they cannot directly attribute all of the results to the gabapentin. They can just publish that. This is what they found in that patient population as well as this was not used in a protocol fashion, but just at the discretion of the para. So talking about how does it affect sleep, it's actually been most studied in the adult population as a treatment strategy for insomnia. So looking at two different studies, one was an open label four week trial, another was another one was a randomized double blind, single dose placebo control. Um given right before bedtime, you can see that in both studies, um it improved their slow wave sleep as well as the frequency and quality of that sleep as well. So never enough time to talk about everything we always want to talk about. So just a quick call out for opioid considerations as well. Um There is a role for opioids in these patients when used judiciously for pain management, um consider nonopioid adjuncts when able. So dex meaty acetaminophen. So, going back to um nationwide's experience with decreasing um opioids and benzos in their treat patients, we also have a fair amount of um patients who require treat placement. And our strategy is post. Um They get dex meat tomaine as well as scheduled acetaminophen for a couple of days and then opioids as needed. And I, we've had great success minimizing their needs with that strategy. Um There is a lot of evidence showing decreased long-term neurologic effects um with prolonged use. So once again, limiting the exposure as much as possible, and then melatonin, it not only plays a role in prevention of delirium as well as treatment. So in summary, whenever you start something, know what you're using it for and define those goals up front, um less is more consider delirium as a source um for change in their clinical presentation, uh minimize exposure to benzodiazepines as much as possible. Hopefully, representing some of this evidence is people thinking a little bit differently and then we may have some new uh alternatives to utilize. Published January 2, 2024 Created by
