Hello, and thank you for registering for the 2024 SCCM Advanced Pharmacotherapy course. I'm Scott Balesta, and today I'm going to be discussing and talking to you about a topic that's near and dear to my heart and interesting in my area of research, and that's iatrogenic withdrawal. So the title of my topic for today in my lecture is Halting the Domino Effect, Preventing and Managing Iatrogenic Withdrawal Syndrome. I'm a professor in the Nesbitt School of Pharmacy at Wilkes University in Pennsylvania, and I also have a clinical practice in the ICU at Wilkes-Barre General Hospital, part of the Commonwealth Health Medical System, and I am a board-certified critical care pharmacist. So I have no disclosures for my lecture today. Three objectives that I want to cover with all of you, and these include describing the prevalence and incidence of iatrogenic withdrawal from opioids and benzodiazepines and the impact on patient-centered outcomes, to differentiate strategies to mitigate iatrogenic withdrawal syndromes through pharmacologic and non-pharmacologic modalities, and to compare the utility of clinical scoring tools to assess and risk stratify patients with acute withdrawal syndromes in the intensive care unit. So before we start, we know our patients are complex. I just wanted to put a picture up, you know, of what we typically would see as our typical patient in the ICU. A lot of support measures. We have monitoring with the ventilator, monitoring of vital signs, support with additional modalities for renal support, sometimes ECMO and other means of circulation, respiratory and ventilation support, and a lot of medications as well. So this makes our patients, obviously, as we all know, very complex, and this is what makes withdrawal such a complex, or iatrogenic withdrawal, such a complex issue to tease out because there are so many things going on with our patients. Sometimes it's hard to remember that we can actually be causing harm to them by doing some of the things that we're doing to them to actually help and improve their care. So what is iatrogenic withdrawal syndrome? It's a simple definition as defined by withdrawal from opioids and sedatives administered under medical supervision, and this is known as iatrogenic withdrawal syndrome. Typically, the withdrawal that occurs from medications, primarily opioids and benzodiazepines for patients who are naive to these medications prior to coming to the ICU and then needing these medications for part of their care while they're during their ICU stay. It can also occur in patients who are not naive to opioids and benzodiazepines, but usually the doses that we need to provide to these patients, these patients may sometimes experience iatrogenic withdrawal. The prevalence of iatrogenic withdrawal in the ICU is not well documented or known. It's better documented in patients in the pediatric ICU than the adult ICU, and I'll go over that during the lecture today in a few slides. But in general, patients in the pediatric ICU have an incidence or prevalence rather of iatrogenic withdrawal anywhere between 10 and 68%. And this is really not changed over time, it just depends on exactly what study is being conducted to gain or look at this data and what kind of assessment tools are being utilized. One of the differences between being able to determine the prevalence of iatrogenic withdrawal in pediatric ICU patients compared to patients in the adult ICU is that there are validated tools in PICU setting that can specifically be used to assess patients for iatrogenic withdrawal. In the adult ICU population, we don't have any validated tools to assess for iatrogenic withdrawal, but the incidence has been reported to be anywhere between 17 and 35%. However, again, without validated tools, we're really not sure exactly what the true prevalence of iatrogenic withdrawal is in this population. And there are limited prospective studies in the adult ICU population as well compared to the pediatric ICU population. Another thing that clouds the true prevalence of iatrogenic withdrawal in the ICU is, again, not only all the supportive measures that we have going on, all the therapies that we're doing to patients, but it's a conflating syndrome or conflated syndrome in the presence of other neurological abnormalities and deficits that may occur in our patients in the ICU, including delirium, agitation, previously existing or new-onset neurological deficits, and previously existing or new-onset psychological conditions. All within the middle of this, patients could be experiencing iatrogenic withdrawal if they're receiving benzodiazepines or opioids and other sedative medications. But we may not be able to tease this out because of these other confounding factors. So it's really a kind of a—this slide demonstrates how iatrogenic withdrawal is a conglomerate of patients being under-sedated, getting pain medication therapy, and potentially experiencing delirium. And at the center of all this are some of the signs and symptoms that may exhibit not only signs and symptoms of iatrogenic withdrawal, but these other syndromes as well. And so, again, it's hard to exactly tease out or differentiate between patients who may be experiencing delirium, under-sedation, or pain compared to those who might actually be experiencing iatrogenic withdrawal. Now, without knowing this, we're really not sure what we need to treat. Do we need to treat patients for delirium? Do we need to treat them for more pain or provide more sedation? Or do we simply need to try and decrease their opioids and sedatives less aggressively and wean them more appropriately so that patients do not experience these signs and symptoms of iatrogenic withdrawal? Now that we've discussed some of the issues that make it difficult to determine the prevalence of iatrogenic withdrawal, let's take a little bit of a look at some of the studies that have explored the prevalence of iatrogenic withdrawal in various ICU populations. The first one I'd like to go over with all of you is the Evaluation and Exploration of Iatrogenic Withdrawal in the PICU Population, and this was the first study to explore prevalence of iatrogenic withdrawal in this population. The study was published by Fondsmark and colleagues. It included a small number of patients, only 40 patients, and there were no validated tools used in this study, but they basically looked at some of the signs and symptoms associated with iatrogenic withdrawal and withdrawal syndromes, and what they found was that overall incidence of withdrawal in this small patient population to the medications that you can see listed here, midazolam, morphine, and pentobarbital, was about 35%, 14 of these 40 patients. In a much more recent study in the PICU, Amigoni and colleagues used a validated assessment tool, the Withdrawal Assessment Tool 1, or the WAP 1, to look at the prevalence of iatrogenic withdrawal in all patients 18 years or younger admitted to the PICU who were supported on mechanical ventilation and who received analgesic or sedative therapy for five or more days. They did look at patients who were experiencing or at risk for neonatal withdrawal syndrome, and the study included eight ICUs in Italy. So this study, or this slide rather, looks at the main findings of this study. The study found, as you can see, an overall incidence of withdrawal of 64.6%, 73 out of 113 patients. So again, not a very large sample, but much larger than the earlier study by Ponsmark and colleagues. And again, this was using a validated assessment tool. So this shows you that there was a much higher incidence of withdrawal using this validated tool in a population that, again, we would typically think would be at risk, those patients who received sedatives or analgesics for a long period of time and who required additional support for their organ function. Much larger study than that conducted by Amigote and colleagues, the RESTORE trial also assessed the incidence, or the prevalence rather, of atrogenic withdrawal in the PICU population. And the RESTORE trial wasn't done to look at the prevalence or the occurrence of atrogenic withdrawal, but it was conducted to look at a comparison between protocolized sedation and usual care in mechanical ventilated pediatric ICU patients. And the primary outcome was to look at the total duration of mechanical ventilation time. However, in a subset of patients who required weaning from at least five days or longer opioid use, these patients were monitored for withdrawal using the validated, again, one assessment tool. So there were 1,157 patients who needed to be weaned out of opioids who had been administered for more than five days, and these patients were monitored for the occurrence of atrogenic withdrawal. The results of the RESTORE trial are presented on this slide. So you can see, as I highlight in the box for you here, that the overall incidence of atrogenic withdrawal syndrome, according to patients who had a WAP1 score greater than or equal to three, was 68%. This was the same in both the patients who received protocolized sedation versus patients who had usual care. So again, a very high incidence, much like the trials done by Amigoni and colleagues, but in a much larger cohort of patients who are studied and evaluated prospectively. So those are some of the more robust, and again, early on findings from withdrawal occurrence and prevalence in the pediatric ICU population. But there's very little study, again, using non-validated tools in the adult ICU population that explore the incidence or prevalence of atrogenic withdrawal. This study by Camerano and colleagues is one of the first to look at the incidence of atrogenic withdrawal in a small cohort of ICU patients admitted to the San Francisco General Hospital ICUs in the mid-90s. As a retrospective cohort study, it included only 28 adult patients admitted to the San Francisco General Hospital who had an ICU stay of at least seven days or more. The overall incidence of withdrawal that they found was 32%, so nine of these 28 patients. And they looked at a plethora of medication exposures for these patients, including opioid sedatives and neuromuscular blocking agents. They excluded patients who were not experiencing signs and symptoms of withdrawal using a scoring tool, not a validated tool, but a scoring tool, who experienced these signs and symptoms within their first seven days of ICU stay, because those patients were more likely to be experiencing withdrawal from substance abuse that occurred outside of or prior to their ICU admission. So, actually, a pretty probably more at-risk patient population for atrogenic withdrawal than in some other earlier studies. A recent study to assess the incidence of atrogenic withdrawal in the adult ICU population was conducted by Wang and colleagues. The study was done at two level one trauma centers in Montreal, Canada, and it utilized a small cohort of adult ICU patients who are at least 18 years or older and required mechanical ventilation, but it limited enrollment to patients who received continuous infusion or regular admitted boluses of opioids for at least 72 hours or more. And this has been shown to be a risk factor for atrogenic withdrawal in patients. So they are very exclusive in the type of patients that they included in this study. The overall incidence of withdrawal that they found was 16.7%. So even though it was a small cohort of 54 patients, it gives us a good idea of what the incidence of iatrogenic withdrawal is likely to be in the adult ICU population. But again, a validated tool is not utilized in this study to assess patients for the incidence of iatrogenic withdrawal. A study of similar size and design to that by Wang and colleagues, another prospective observational study has been published, conducted at the University Hospital in Bangkok, Thailand. This included 55 patients in their eventual cohort. So these were all adult patients receiving mechanical ventilation who also received continuous opioid infusions for at least 24 hours or more. And the evaluation tool they used to assess patients for iatrogenic withdrawal in this study was the DSM-5 criteria for withdrawal. Again, this assessment tool hasn't been validated to assess patients in the ICU for iatrogenic withdrawal, but is a validated instrument to assess patients for overall opioid withdrawal in the outpatient setting. So the incidence they found in this study was 23.6%. So slightly higher than the study by Wang and colleagues. And this may be due to other confounders that we can't tease out from this observational study design. But again, it gives us similar results with a good idea of the incidence of iatrogenic withdrawal in the adult ICU population. Finally, in the largest and most recent study to date to explore the incidence of iatrogenic withdrawal in the adult ICU population, Fox and colleagues used a prospective observational study design to determine the incidence of iatrogenic withdrawal in patients in their adult ICU. Now, this was patients receiving continuous opioid infusions for 24 hours or more, just like the study in Thailand. But this study used the Clinical Opioid Withdrawal Scale, or better known as the CALS, to assess patients for the incidence of iatrogenic withdrawal. Again, a tool that hasn't been validated for this purpose in the adult ICU population. But interestingly, they found a very similar incidence to the study conducted at the University Hospital in Thailand, with a 25% incidence of iatrogenic withdrawal in their cohort of 92 patients. So again, it looks like the incidence overall in the adult ICU population is roughly somewhere about a quarter of patients who may experience iatrogenic withdrawal. But again, one of the big gaps we still have in research in this area, that is in determining the prevalence of iatrogenic withdrawal, especially in the adult ICU population compared to PICU, is the utility or availability of a tool that's validated to assess patients for iatrogenic withdrawal in this setting. So that brings me to the second part of my first objective, and that is what is the impact on patient-centered outcomes of iatrogenic withdrawal syndrome? The first study, at least in adult patients, to look at the potential outcomes for those experiencing iatrogenic withdrawal was the study by Camerano and colleagues. So we already reviewed this study, and let's look at the prevalence of iatrogenic withdrawal. So it's the same patient cohort, 28 patients enrolled in this study. And you can see that this graph here that they had in their original study goes over some of the duration of therapies that patients were receiving, in addition to two outcomes. In particular, they looked at time on mechanical ventilation and ICU length of stay. And you can see that there's a large difference between these two outcomes in patients who had iatrogenic withdrawal and those who did not have iatrogenic withdrawal based on the criteria they utilized. Only the time on mechanical ventilation was statistically significant, but again, a very small cohort of patients. And remember, all of these patients had to be in the ICU for at least seven days or more as well. So there's a large potential for changes in ICU length of stay if patients who had shorter ICU lengths of stay would have been included in this trial potentially. So let's switch back to the pediatric ICU population now. So this is results from the study by Amigoni and colleagues. So now, not only did they look at prevalence of iatrogenic withdrawal in the pediatric ICU population, but they also looked at some of the outcomes in those eight Italian pediatric ICUs. So this table is the results of some of those outcomes and differences in management in patients who experienced withdrawal versus those who did not. So in this table here, we have patients who had a lot one score greater than or equal to three. Those are the patients who were deemed to have been experiencing iatrogenic withdrawal compared to those patients who had a score less than or equal to three. Again, only 113 patients included in this study, but you can see some pretty big differences here, all of which are statistically significant in some of the outcomes that are relevant or related to the potential of patients having iatrogenic withdrawal. The two biggest of which were lengths of mechanical ventilation and length of PICU stay were much higher in patients who experienced withdrawal than those who did not. And the duration of weaning of opioids and the need for gradual tapering differed as well in this patient group. On these next two slides, I want to go over something that's definitely attributable or related to opioid use in patients while they're in the ICU, but maybe not directly related to iatrogenic withdrawal specifically, but certainly has a tie-in to the occurrence of iatrogenic withdrawal and obviously opioid use during ICU stay. So these are two studies that look at the continued use of opioids in patients after ICU admission for those who are opioid naive prior to admission to the adult ICU. This first one's a small single center retrospective study and included 71 patients who are opioid naive prior to admission. And it looked at the difference in opioid dose prescribing at discharge compared to the previous 24 hour requirements. And what it was looking, what they were looking for these investigators was were those prescription doses in excess of what the previous 24 hours of opioid utilization had been in this patient cohort. What they found was that 36% of, 36.7% of patients upon discharge had those prescription doses written in excess of the pre-discharge opioid requirements. So again, this shows that not only do opioid use or does opioid use lead to withdrawal potentially during an ICU admission, it also leads to continued potential use and probably higher use than necessary in a large proportion of patients at the time of discharge from the ICU. This next study looked at pretty much the same thing, only this was a large registry study, nationwide registry cohort study conducted in Sweden. This study included more than 204,000 patients in the final cohort of those who were eligible for study requirements. So you can see here from the main results that 10.8% of these patients developed chronic opioid use after discharge. And these were patients who survived at least the first initial two months after their hospital discharge. They also found an increased risk or hazard ratio for death at six to 18 months in those who continue to use opioids for this period of time after their hospital discharge. And that was significant at 1.7 times the hazard of death with the confidence interval that was very, very narrow. So again, very potential or disturbing potential outcomes long after ICU discharge for patients who utilize opioids during their ICU admission and were opioid naive prior to coming to the hospital. So in summary, the evidence shows that iatrogenic withdrawal is more prevalent in the PICU than in the adult ICU. But again, we have more validated tools in the PICU population to assess for iatrogenic withdrawal than the adult ICU population where we have no validated tools. Iatrogenic withdrawal syndrome is better studied in the PICU than the adult ICU population. It's been noticed for longer in that patient population and those clinicians are more aware of the potential for iatrogenic withdrawal. So we don't see as more as robust studies in the adult population. And finally, the occurrence of iatrogenic withdrawal is associated with significant morbidity. It's associated with longer times on mechanical ventilation, longer ICU stay. So this is definitely something, a syndrome that we need to pay attention to and be aware of in our patient populations. Now that we've talked about the prevalence and incidence of iatrogenic withdrawal and its impact on patient-centered outcomes, I'll move on to covering the second objective and that's being able to differentiate strategies to mitigate iatrogenic withdrawal through pharmacologic and non-pharmacological modalities. So in general, just to paint a picture of what the risk factors are, and this is a broad brushing scope and look at what those risk factors are that have been identified for iatrogenic withdrawal. It mainly revolves around dose and duration of opioid and sedative use. So dose of opioid and benzodiazepine exposure, primarily total dose accumulated by the time of assessment or the time of iatrogenic withdrawal onset has been associated with iatrogenic withdrawal syndrome, particularly higher doses. Also durations of opioid and benzodiazepine exposure, particularly 72 hours or more of exposure continuously infused or scheduled intermittent bolus dosing has been shown to be a risk factor. Peak opioid dose as well has been determined to be a risk factor. And this would be peak dose received by a patient during any one particular 24-hour period. And then finally, the speed of weaning of opioid and benzodiazepines has been also established to be a well-known risk factor with more aggressive weaning of these agents being associated with the occurrence of iatrogenic withdrawal syndrome. So let's look at some of the agents that have been studied in the treatment of iatrogenic withdrawal. It's not that many. Methadone has been one of the primary agents, although it's been mostly studied in PICU patients, so the pediatric population. It does have a good long half-life with good bioavailability since it's only available orally. It does decrease the time to opioid weaning, but not all studies have shown a benefit. Also alpha-2 adrenergic agonists, primarily clonidine is the only one that's been studied in iatrogenic withdrawal. It has only been researched in very small observational trials. One PICU study has shown no differences in opioid and benzodiazepine withdrawal, and it comes with the potential of hypotension as a severe, potentially adverse effect that can occur in this population. So let's explore some of these in some studies a little further. So this first study here, I know there's just two graphs, but this is a study looking at methadone for fentanyl weaning in a small cohort of patients. So this is a single center study done in hospitals in Brazil, and 75 patients were included who met the criteria. These patients had to be on continuously-infused fentanyl for at least five consecutive days or more before meeting criteria to be enrolled in the study. And what this study did was they used a double-dummy design, actually. So they administered after five consecutive days of fentanyl infusion, either methadone orally to one study group, or they administered placebo capsules to the other study group. On the second day after beginning the oral therapy, patients in the methadone group were prescribed a placebo infusion of fentanyl to have a 20% wean every day, but patients in the methadone group were given a fentanyl infusion to have a 20% wean every day. And you can see the main results here is that there was a significant difference in the time to weaning of mechanical ventilation. So the outcome they looked at was not the time to weaning of the fentanyl, but the time to getting patients off mechanical ventilation. So they achieved a hazard ratio significantly shorter period of time for weaning from mechanical ventilation for those who received the methadone versus those who received the placebo oral medication. Next study was also, again, a single-center study, retrospective cohort design, comparing, again, enteral methadone versus oxycodone. But in this case, it was for weaning patients off IV opioids. So patients that were included had been receiving IV infusion opioids for 72 hours or more. So much shorter period of time. And again, the 72 hours is the kind of the cut point where it's known to be a risk factor for the occurrence of iatrogenic withdrawal. 93 patients included in this study. And what they primarily looked at was the time to weaning of the IV opioid infusions. And patients giving methadone versus oxycodone. You can see from their main results that there was a significant shorter time for opioid weaning of those given methadone compared to oxycodone. And those patients who received the methadone were 1.8 times more likely to have successful weaning using the methadone compared to receiving oxycodone. Now let's look at clonidine for the use of weaning of sedative agents. Particularly, clonidine is beneficial because of its mechanism. Identical mechanisms of action to dexmedetomidine for weaning dexmedetomidine. So this is a small single center study. Prospective observational study, though, that looked at 42 adults who were receiving dexmedetomidine for at least three days. Again, that time period where it's known to be a risk factor for having iatrogenic withdrawal occur. The intervention was that patients who met enrollment criteria received enteral clonidine or continued to receive dexmedetomidine alone. And there was no difference seen in withdrawal symptoms. They didn't use a validated tool. Again, there's no validated tool in adult populations. But they looked at specific symptoms that might be associated with withdrawal, at least occurrence of two or more of these symptoms. And there was no difference in symptoms in patients who received enteral clonidine versus those who had not. However, they did find less time on dexmedetomidine with enteral clonidine use. And there was a cost savings associated with the utilization of oral clonidine in this population who were able to have dexmedetomidine weaned off at a higher, quicker rate. The last few studies I've reviewed with you included agents specifically that have been evaluated for weaning opioids and or benzodiazepines for the prevention of iatrogenic withdrawal in patients. The next few studies we're going to discuss include protocols that have been utilized or weaning patterns that have been utilized for discontinuing sedatives and benzodiazepines or opioids and benzodiazepines for prevention of iatrogenic withdrawal in patients. This first one is a sub-study of the RESTORE trial. And it was a pre-merandumization phase study that included 145 intubated patients between two weeks and 17 years of age who were receiving mechanical ventilation for respiratory support. They had to be exposed for at least five consecutive days of opioids. You can see there the median time of exposure of opioids was six days. And what they did was they assigned patients once weaning had begun of their opioids to either a steady wean, so a slow and steady kind of wean versus an intermittent weaning pattern, which the intermittent weaning pattern included patients who are being weaned but had the need for at least a 20% or more dose increase during the process at an eight one time of weaning of the opioid. What they found when we look at patients who experienced withdrawal with WOT1 assessments greater than or equal to three was that there was a significantly higher occurrence of biatrogenic withdrawal according to that WOT1 assessment score in patients with an intermittent weaning pattern versus patients who had a steady weaning pattern. You can see there are quite a bit of difference in the percentage of patients who experienced withdrawal with that kind of weaning pattern. And then also the peak WOT1 assessment scores over here, you can see there was a difference significantly and then peak scores obtained for patients who experienced intermittent weaning versus those who underwent a steady weaning pattern with higher scores occurring in those in the intermittent weaning group. This study also included an evaluation in PICU patients or in the PICU population. This is a pre post-intervention design looking at patients and their evaluation of benzodiazepine and opioid weaning prior to initiation of a specific weaning protocol versus those who had experienced weaning utilizing the protocol after implementation of the protocol. And we included patients who are 21 years of age or younger who had undergone surgery for congenital heart disease and were being seen postoperatively. And they included patients who received at least seven days or more of opioids or benzodiazepines prior to initiation of weaning. And again, this is at the very extreme end of where patients would be at risk for opioid and benzodiazepine withdrawal syndrome and antigenic withdrawal. So for the intervention prior to implementing the protocol for weaning of these agents, patients received weaning based on physician discretion. And after the intervention period was begun or after the implementation of the protocol rather, patients received and underwent weaning of these agents based on the protocol itself. So you can see here that the interesting results provided for total duration of opioid exposure, duration of the wean phase, and total equivalence in terms of exposure to both opioids and benzodiazepines were significantly different in patients in the post-intervention group compared to the pre-intervention group. Specifically, the incidence of withdrawal based on the WAP1 assessment was much lower in the post-intervention group versus the pre-intervention group. So again, not only do specific agents potentially mitigate the occurrence of iatrogenic withdrawal, but using a protocolized weaning pattern for opioid and benzodiazepine discontinuation can also help decrease the chance or the incidence of iatrogenic withdrawal, at least so far as we know is in the PICU population for what these studies have shown. Also looking at standardized implementation of pain sedation and withdrawal assessment in the PICU was one of the study that evaluated standardizing this approach to pain management, sedation management, and withdrawal assessment in the PICU. This is a small interventional study in a small 18-bed medical-surgical tertiary care PICU population. And they included 45 patients in each group. And this was, again, a pre-post design. And what they found was there was no significant, statistically significant difference in the morphine or midazolam equivalent doses that were utilized in patients pre versus post-intervention but there was a significant reduction in these doses post-intervention where we had standardized pain management, sedation management protocols, and assessments for withdrawal in this small single-center study. So occurrence treatment strategies in the PICU were also evaluated in a recent large international evaluation of PICU practices for the weaning of opioids and benzodiazepines and assessment for atrogenic withdrawal in this population. So 215 ICUs across 27 countries responded to this survey. And what they found were some very interesting results where 57% of PICUs do utilize a structured weaning protocol for weaning benzodiazepines and opioids. So again, almost about two thirds of those ICUs surveyed. Sedation was stopped without weaning at a maximum of three days. And again, that's typically our cutoff, 72 hours of utilization of continuous opioids or benzodiazepines where we put patients at risk for atrogenic withdrawal. After five or more days of opioids or benzodiazepines, most institutions took a slow and steady approach to weaning with only 10 to 20% of the daily dose being decreased. And that was utilized in two thirds of the PICUs who responded. And then main first line treatment for the occurrence of iatrogenic withdrawal or suspected iatrogenic withdrawal in 41% of PICUs consisted primarily of a rescue bolus of the same medication that was being weaned and also interrupting the current weaning pattern for that particular medication. This is in stark contrast to what was found in a recent evaluation of weaning and iatrogenic withdrawal protocol utilization in the adult ICU population. This was also an international study including 229 ICUs from 11 countries and only about 39%, almost 40% of ICUs utilized a weaning protocol for weaning benzodiazepines and opioids. However, in patients who were eligible admitted to those ICUs that had a protocol in place, only 36% of the patients in those ICUs on the day that the patients were evaluated were utilizing that protocol. When we looked at iatrogenic withdrawal or when this study looked at iatrogenic withdrawal, 10% of ICUs use an iatrogenic withdrawal protocol. But again, the patients who are admitted to those ICUs only 16.7% were actually utilizing the protocol when they had been receiving opioids or sedatives for more than 72 hours. So very low compared to the PICU population implementation of weaning and iatrogenic withdrawal protocols and even lower utilization of those protocols in patients who are eligible and had been admitted to those ICUs. We also, in this study, they looked at, the investigators looked at weaning practices in adult ICUs. And this pie chart on the left here shows when the protocols were initiated based on duration of opioid or benzodiazepine utilization. And you can see that the majority of ICUs who had a protocol in place began weaning within less than 72 hours of utilization of those agents and it got a little smaller from there between 24 to 96 hours. But the most interesting finding was that a lot of ICUs, more than half of them, did not define when the weaning protocol should be initiated or when weaning should be started based on the duration of opioid or benzodiazepine use. When we look at degree of weaning, we found almost a pretty even split between ICUs who had a protocol in place where they weaned by either a percent dose reduction, an absolute dose reduction, or an other pattern of weaning. However, almost 30 percent of ICUs didn't specify the degree of weaning in their protocol and left it to provider or physician discretion. So one other interesting study besides some of the patterns that are occurring regarding weaning and iatrogenic withdrawal assessment in both the PICU and adult patient population is what role the pharmacist may play to help mitigate iatrogenic withdrawal and help wean patients off opioids and sedatives during their ICU stay and prevent delirium. So this is a very interesting single-setter study that looked at, again, a pre-post intervention where they had pharmacists managing weaning of sedative and opioid agents in a post-intervention phase compared to standardized approach of care with provider or prescriber weaning of agents and directed there and directed those weaning prescriptions. What they found were some really interesting results. You can see that across the board for most of their, in fact, almost all of their primary outcomes, there was a statistically significant reduction in patients' mean time to receiving continuous sedatives, benzodiazepine drip numbers, total number of sedative drips, and especially ICU length of stay. So there was a significant decrease in all of these in the post-pharmacist intervention group compared to the standard of care group before implementation of pharmacists providing some of these weaning management services. The only significant outcome that didn't have a statistically significant difference in the post-intervention phase was the time that patients were on mechanical ventilation. It was lower, but it did not reach statistically significant difference in the result. They did look also at, you can see here, return to mechanical ventilation or need to restart mechanical ventilation and death, but the number of patients who experienced these outcomes were likely too low to show a significant difference. They also looked at cost in this study, and you can see in particular there was a 42% nearly reduction in total patient expenses. There was also a 43% reduction in direct hospital expenses and a 43% reduction in drug expenses as well when pharmacists helped with or managed weaning of sedative and opioid agents in patients in the ICU. So now let's look at what the history of the guidance from the guidelines from the Society of Critical Care Medicine of the state about iatrogenic withdrawal. I want to put this up here and share this with you for historical context to see how this has changed over time and how it's changed in the guidelines and what's recommended might surprise you. So let's go back and look at the 2002 SCCM guidelines for pain, sedation, and delirium management. And from that guideline, we can take a quote where a recommendation was that the potential for opioid benzodiazepine and propofol withdrawal should be considered after high doses or more than approximately seven days of continuous therapy. Dosage should be tapered systematically to prevent withdrawal symptoms, and they gave us a greater recommendation to be at the time. Looking at the PAD guidelines from 2013, what was mentioned is a quote from the guidelines stating, although specific recommendations are lacking for the prophylaxis or treatment of opioid or sedative withdrawal in ICU patients, opioids and or sedatives administered for prolonged periods, in other words days, should be weaned over several days in order to reduce the risk of drug withdrawal. So a little more less specific in terms of the agents, but a little bit more tight on days, although they don't specifically define what that is compared to the prior iteration of the guidelines. And then finally, looking at the most recent 2018 PADIS guidelines, they don't have any quotes or recommendations regarding atrogenic withdrawal. All they do is that they note that opioid withdrawal is an example, the potential safety concerns associated with the use of opioids, and that protocol-based pain management may require further study. So they don't really provide any recommendations because, again, there's not a lot of literature out there, especially in the adult population. So let's explore what the 2022 pediatric guidelines for pain and sedation recommend. So this is a stark contrast to what the adult PADIS guidelines recommend. So they have very specific recommendations regarding iatrogenic withdrawal syndrome and the pediatric SECM guidelines. They suggest opioid replacement therapy for opioid-related iatrogenic withdrawal syndrome, and they give us a conditional recommendation based on low levels of evidence. They also suggest benzodiazepine replacement therapy for benzodiazepine-related iatrogenic withdrawal syndrome, and they just give this recommendation of good practice. So they don't have this based on any evidence. And again, there's not any evidence out there for this, specifically for benzodiazepines. As we explored a little earlier, there is for opioids in this population, but not benzodiazepines. They also give a good practice recommendation for the utilization of alpha-2 agonist replacement therapy when alpha-2 agonist- related iatrogenic withdrawal syndrome occurs or is suspected. Again, utilization of clonidine for dexmedetomidine withdrawal has been studied in the adult population, but not in the pediatric population. And then finally, they suggest use of standardized protocols for analgesia and sedation weaning, and they give us a conditional recommendation with low levels of evidence. But again, this has been studied in the pediatric ICU population and shown to have some benefit. So to summarize this evidence for mitigating the occurrence of iatrogenic withdrawal, methadone and clonidine have been studied for weaning of opioids and benzodiazepines. The evidence is weak, and again, we cannot apply it to all patient populations. Patterns of weaning and protocols can reduce the occurrence of iatrogenic withdrawal, but it hasn't been validated across the board in all patient groups or populations as a beneficial intervention. Weaning protocols are currently implemented more broadly in PICUs and adult ICUs, and we saw that from some observational studies that were international, including a large number of ICUs across a large number of countries. And so there's a gap to fill, especially with the adult population, where the need for more study into the occurrence, risk factors, and prevalence of iatrogenic withdrawal can be done. And then only pediatric ICU guidelines provide recommendations for weaning and iatrogenic withdrawal syndrome practices, and that's again because of the gaps in the evidence for the adult population. So now that we've discussed mitigating strategies to prevent iatrogenic withdrawal, let's look at our last objective of comparing the utility of clinical scoring tools to assess and risk stratify patients with acute withdrawal syndromes in the intensive care unit. As I mentioned several times already, there are no validated assessment tools for iatrogenic withdrawal syndrome in the adult ICU population. However, there are some validated tools in the pediatric ICU population. The most utilized tool in the pediatric ICU population has been the withdrawal assessment tool version one, or the WOT one. There's also the SOFIA observation symptom scale and the neonatal abstinence syndrome score, both of which have been validated outside of ICU populations as well. Other tools that can be utilized but are not validated include DSM-5 or the Diagnostic and Statistical Manual Mental Disorders 5th edition, and that's just for general withdrawal from opioids or substances of abuse or misuse. There's also the opioid and benzodiazepine withdrawal score, or the OBWS, and there's also the SOFIA benzodiazepine and opioid withdrawal checklist. But again, none of these have been validated for the assessment of iatrogenic withdrawal in either the pediatric or the ICU population. So the WOT one assessment tool, let's take a little bit more of a detailed look at that. So it's been validated in PICU populations. It's based on 11 symptom-based criteria items, and it requires two daily nursing assessments conducted throughout the day, generally ideally at least 12 hours apart. It has an 87 percent sensitivity and an 88 percent specificity when patients have a score greater than or equal to three, and that's why you've seen that score utilized in some of the studies we discussed today. However, it cannot differentiate opioid and benzodiazepine withdrawal, so you can't distinguish between the two of them if patients are on both agents. In comparison, the SOFIA observation symptom scale has some advantages over the WOT one assessment, but also some disadvantages. It has been validated in the PICU population, but it's based on 15 symptom-based criteria compared to the 11 of the WOT one, and it needs to be performed ideally by nurses every eight hours. So it's a bit more cumbersome to implement at the bedside than the WOT one assessment tool. It has an 83 percent sensitivity, but a 93 percent specificity, so a bit higher than the WOT one when scores are greater than or equal to four, and an advantage of it over the WOT one is that it is able to assess opioid and benzodiazepine withdrawal, but still can't distinguish the difference between the two of them. There has been a study actually comparing the WOT one tool to the SOS tool in 60 PICU patients who were being weaned from opioids and benzodiazepines, and this was conducted by Amigoni and colleagues, the same author group who conducted one of his prevalence studies and outcome studies in patients in the PICU setting for iatrogenic withdrawal syndrome. So they found in this particular study that 37 percent of patients presented with iatrogenic withdrawal syndrome who had WOT one scores greater than or equal to three, and they found that the SOS scores correlated or were associated with the WOT one scores with a significant p-value. So now that you know the WOT one and the SOS tools are both validated for assessment of iatrogenic withdrawal in the pediatric ICU population, what's actually being used? So this is the same study looking at, again, 215 patients in 215 ICUs across 27 countries, PICUs, and this is the data that shows what kind of assessment tools are currently being utilized across those ICUs. So 62 percent of PICUs currently use and monitor iatrogenic withdrawal with a validated scale. The most frequently used scale is the WOT one. 53 percent of PICUs use this structured tool, and this was a 39 percent utilization rate among these 215 PICUs overall. 64 percent of PICUs assessed signs of iatrogenic withdrawal more than once daily. So, again, if you remember, the WOT one actually recommends assessing iatrogenic withdrawal using that scale twice daily, and the SOS recommends or is validated with assessments three times a day. And finally, iatrogenic withdrawal syndrome assessments conducted by nurses primarily in 83 percent of these PICUs. So you can see nurses are the primarily predominant provider at the bedside doing the assessments using these validated tools, but some other providers are doing the assessments as well. So now that we know what can be used, at least in the pediatric ICU population, it's interesting, again, going back to what I mentioned earlier on in this lecture of the overlap between some of the assessments being done for iatrogenic withdrawal and delirium. There's a lot of overlap between these two syndromes in the population in the ICU. In this study, particularly explore the overlap between the validated tools to assess iatrogenic withdrawal and the validated tools to assess delirium in the pediatric ICU population. And you can see based on the graphic here, even though I know it's a bit busy, the solid more solid bold lines here show lots of overlap between assessment tools for delirium and iatrogenic withdrawal, especially in motor movement states, behavioral states, and so forth for pediatric ICU populations. So there's definitely some still variability in terms of identifying correctly iatrogenic withdrawal versus delirium depending on the assessment tool that's being utilized. So what do the guidelines recommend? So again, I've talked mostly about assessment of iatrogenic withdrawal and validated tools in the pediatric ICU population, because again, we don't have any validated tools in the adult ICU population. So the 2022 pediatric SCCM sedation guidelines recommend the WAP1 or the SOS tool for assessment of iatrogenic withdrawal due to opioids or benzodiazepines. And they give this a strong moderate level of evidence. They also suggest routine iatrogenic withdrawal screening after three to five days of higher dose opioids or benzodiazepine doses. They only give this a conditional recommendation with moderate levels of evidence. And you can recall one of our big risk factors is utilization of high doses of these agents for up to the 72-hour cut point, so the three-day cut point. They also finally recommend, with a good practice recommendation, alpha-2 agonists iatrogenic withdrawal assessment using symptoms and a validated tool for opioid or benzodiazepine withdrawal. But again, these tools haven't been validated in patients for withdrawal from alpha-2 agonists, only for opioids and benzodiazepines. One final thought I want to leave you with, since I've talked mostly in terms of assessment of iatrogenic withdrawal in the pediatric ICU population using validated tools, is what is out there that's validated in the adult ICU population? So currently nothing, but there has been one or two studies, and this is probably the best and largest one out there, that's looked at validating of a tool for iatrogenic withdrawal in the adult ICU population. It's a very small study conducted in 52 adults in two Canadian trauma ICUs, and they looked at looking at the validity and reliability of the WAP1 in a critically ill adult population. So the median age of their cohort they included was 52 years of age. And they used very stringent inclusion-exclusion criteria, and the enrollment in this trial, because of those stringent inclusion-exclusion criteria, was very limited. If you looked at the screening that went on, they only were able to whittle it down to 52 patients. For their results, they had eight patients, and their comparator tool was the DSM-5 criteria. They had eight patients that tested positive for withdrawal using the DSM-5, but they had 19 who showed positive signs and symptoms of withdrawal using the WAP1. So this only gave them a sensitivity of 50% for the WAP1 and a specificity of 66%, roughly. So they concluded, basically, that the WAP1 is not a valid or reliable tool to be utilized in critically ill adults on mechanical ventilation for assessment of iatrogenic withdrawal. And again, this is where it leaves us with a huge gap in being able to determine the prevalence, incidence, and assess patients for iatrogenic withdrawal in the adult ICU. So the big key takeaways I want you to learn and take from this is that iatrogenic withdrawal is prevalent in critically ill patients. We really can't account for or identify the true prevalence of it in the adult ICU population because we have a validated tool, or a lack of a validated tool, rather, in that population. I also want you to take away that opioid use in the ICU affects both short- and long-term patient outcomes. So remember, not only do we have the risks of iatrogenic withdrawal and other potential serious adverse effects and side effects from opioids with its use during the ICU stay and hospital admission, but a good portion of those patients, some studies show, will go on to be discharged on opioids who no longer need them or who would get discharged on doses higher than what they were utilizing at the time of their hospital discharge. There's also sparse data on effective methods for prevention of iatrogenic withdrawal. And so we do have some studies showing that maybe validated protocols or weaning procedures and so forth might be valid. And certain agents might be useful. But again, where and in which patient population specifically these have been shown to be validated in have not completely been studied. And finally, a standardized approach is needed in the ICU for opioid-incentive weaning and withdrawal assessment using validated tools. We have good guidelines and recommendations for this, but not based on strong evidence in the pediatric ICU population, but very, very limited data in the adult ICU population with no recommendations or guidance to utilize in our treatment of these patients and our assessment of iatrogenic withdrawal. And with that, I thank you all for your attention and time listening to me discuss this topic that I'm very passionate about of iatrogenic withdrawal syndrome. And I hope you do some more exploration on your own, in your own patient population in your ICU and consider maybe helping fill in some of those gaps in the literature in the adult ICU population and the pediatric ICU population in terms of our need to understand and study iatrogenic withdrawal syndrome more.

iatrogenic withdrawal syndrome

pediatric ICU population

pharmacologic modalities

non-pharmacologic modalities

Withdrawal Assessment Tool 1

SOFIA Observation Symptom Scale

methadone

clonidine

weaning protocols