This 2021 randomized trial reported a statistically significant reduction in agitation-related events among patients with unhealthy alcohol use receiving mechanical ventilation randomized to high-dose baclofen vs placebo.
Karim Asehnoune, MD, PhD, and Mickael Vourc’h, MD, of CHU de Nantes in Nantes, France present findings from the BACLOREA Trial at the virtual Critical Care Reviews Meeting 2021 (CCR21) on January 21, 2021. An oral editorial from Waleed Alhazzani of McMaster University and a Q&A session follow.
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>> Okay so it is my pleasure to open the scientific [inaudible] with the results of the baccalaureate trial. Joining us from Nant in France we have Corinne Assanune and his colleague [inaudible]. We have from London Kathy Rohen, from Aberdeen Marianne Campbell. From Copenhagen Morgan Highlander-Muller and from Melbourne Chris Nixon. [inaudible] from Hamilton Canada will be delivering the editorial. The baccalaureate trial of [inaudible] for the prevention of the alcohol addicted patient in the - to the prevention of agitation in the alcohol addicted patient in the intensive care unit. So without further ado, over to Corinne and Michael.
>> Thank you. Thank you very much Robert. We're very happy to - to share the results of the baccalaureate trial. In this meeting we are very happy to because the - the paper was just accepted yesterday in the [inaudible]. It's really an honor for us to share the results of the baccalaureate trial, and to discuss of course, with the panel and with the audience about these results. So first of all some background. They are mainly three stages regarding the consequences of [inaudible] views in high social demographic index location. First 2.8 million death were attributed to alcohol use. Second, alcohol is the seventh leading risk factor for pre - premature death. And third there is really a high prevalence of unhealthy alcohol use in high social demographic index location. So what did the definition of - or unhealthy alcohol use? There is a - there is a clear definition which is more than 14 drinks per week for healthy men up to 65 years old. Or, more than seven drinks for women or older men. It includes patients with or without alcohol use or dependents. In this - sorry, yes, in this study from the ICU team of [inaudible] they - they did participate to the baccalaureate trial. They evaluated the consequences of [inaudible] drinking, and they found an increased risk of ICU acquired infection and increased risk of death in the ICU up to one year after discharge. [inaudible] alcohol abuse or dependents, so the first message could be that they are consequences on outcome for patients in ICU when they are [inaudible] alcohol use. We, and other evaluated influence of alcohol abuse on agitate - on agitation, delirium and [inaudible] requirement of patients admitted to an [inaudible] unit. And if we compared the incidents of agitation between the two papers we see important difference. First as you can see - can you see the pointer? Yes, okay. So if you - if you look at the - the agitation between the two papers you can see that for in the - for lower risk alcohol user there is 31% versus 50%. And if we are looking at [inaudible] alcohol user, this is 42% versus 66.8%. So the - the problem here is related with the definition of agitation. What is exactly agitation? Is it patient that bite the tracheal tube or patient with [inaudible] or patient ventilator [inaudible]? It's very difficult - it's difficult to answer if we are looking at the [inaudible]. So another way of looking, is to evaluate the consequences of alcohol use disorder. And in our study we found that the time of - on ventilator was higher and the rate of ICU acquired infections was - was higher in these patients. So considering these evidences it is [inaudible] agitation as major consequence in - on the outcome of ICU patients. First, short - short term consequences [inaudible] care. [inaudible] and extubation, removal of restraint, etc. Big term consequences are increased time of ventilator, ICU acquired infection, long term psychology [inaudible]. So there are clearly consequences of agitation in this kind of patients. So we can consider patient centered outcome to figure out if [inaudible] outcome use as really consequences for these patients. So now the question becomes as - as agitation is frequent, patients with [inaudible] consequence, how can we prevent this complication and take care of this patient? Unfortunately, there is absolutely no answer to this question because there is no - sorry, there is no recommendation for the prevention of agitation delirium in patients with [inaudible] alcohol use in the ICU. But we know that in the molecules currently available Baclofen is a good candidate. And in France since 2014 we have a temporary recommendation of [inaudible] in outpatients up to 300mg per day. This is a recommendation from the French Drug [inaudible]. So the problem is that [inaudible] for using Baclofen is weak. But interestingly if we are looking at these studies the rest of studies for a low dose and the [inaudible] studies are for high dose, I could - as you can see on this - on this slide the two positive studies used the high dose, what we call the high dose sorry, of Baclofen, which is about 150mg daily. But again, we don't have any proof of evidence for using such a dose in ICU patients. So if we want to use Baclofen in ICU, the first step is to evaluate pharmacokinetics and toxicity of the molecule, presumably high dose if we consider studies from the latter slide. This is exactly what we did. We studied 20 patients with [inaudible] alcohol use under the NIAAA criteria, under mechanical ventilation for an expected duration above 96 hours. And we obtain in this - in this pharmacokinetic study two main results. Firstly the validated - I show you the validated pharmacokinetics model we used to adapt the dose of Baclofen to the renal function could be applied to ICIU patient. Suddenly, and this is really interesting. It consists of the incidents of agitation in [inaudible] alcohol users was receiving Baclofen was 25%. A lower incidents as compared to first study without Baclofen use. Where the incidents was 42%. This huge decrease suggests potential effect of the molecule for the prevention of agitation and agitation related events in the population of [inaudible] alcohol users hospitalized in ICU. So overall this is background for performing the baccalaureate trial that Michael will now present to you.
>> Thank you [inaudible]. So we decided to design this trial and effect of Baclofen on agitation related events in patients with [inaudible] alcohol use were saving mechanical ventilation [inaudible] trial. So this study was around the [inaudible] double blind, placebo controlled study including 18 participant - participating center from university and district hospitals. The main objective of the study was to assess whether high dose Baclofen could reduce agitation in patients with [inaudible] alcohol use and mechanical ventilation compared with placebo. This study including patients from 18 to 80 years old. With expected duration of mechanical ventilation above 24 hours. And weekly alcohol intake, which was classified as [inaudible] according to the National Institute on Alcohol Abuse and Alcohol [inaudible]. Namely more than 14 drinks per week for men or more than seven drinks for women or men older than 65. Patients were included after [inaudible] or emergency inclusion or [inaudible] obtained before intubation. Patients with hospital stay of more than seven days before randomization could not be included. So as patient we [inaudible] impairments, brain or spinal cord injury, or with the expose to Baclofen or with contra-indication to [inaudible]. Patients with - sorry, so after - after inclusion patients with randomized - where randomized - on [inaudible] renal system and randomization sequence was stratified on the participating center. Manufacturing of the treatments was centralized by the pharmacy of North University Hospital. So as Baclofen and placebo could not be differentiated. In the end, clinician, nurses, investigators, the statistician and the [inaudible] monitoring board were blinded to the randomization group. So after randomization, patients receive a low dose of placebo or Baclofen from 50 to 150 mg through the feeding tube according to their [inaudible] rates estimated by [inaudible] question. Then patients receive from 50 to 150mg per day of treatment according to their renal function. You might need [inaudible] from the [inaudible]. At the end of the - of this period treatment was [inaudible] reduced three to six days depending on the renal function. This payout was shortened if extubation of tracheotomy occurred before the 15 and in all cases, the treatment was stopped on ICU discharge. The treatment was temporarily discontinued if the renal clearance was below 15 ml per minute without renal [inaudible] or if the liver enzyme were above 20 times the normal rate or if [inaudible] was below 50 beats per minute. The treatment could also be definitively discontinued if allergic symptoms or [inaudible] occurred, if the heartrate was below 35 beats per minute or if the patient presented delayed [inaudible] namely [inaudible] 72 hours after sedation [inaudible]. So to - and the - sorry, the previous slide to assess retrospectively the residual [inaudible] concentration of Baclofen, blood samples were drawn in 80 persons on day three - on 80 participants on day three and day 10 after randomization. So primarily end point of the study was the [inaudible] rate of at least one agitation related event over the treatment period. Agitation related events were defined as [inaudible] extubation putting out lines [inaudible] and drinks, putting out [inaudible] from the ICU. [inaudible] device removal or self-aggression or aggression toward medical staff. The secondary end points were the occurrence rates of at least one agitation related event by day 28. The total number of agitation related events in age group [inaudible] the [inaudible] agitation scale, the total dose of sedative and [inaudible] the rate of ICU acquired infection, the length of stay in the ICU and death. For the simple size calculation in our two preliminary studies the rate of agitation was 42% in a lengthy alcohol user in [inaudible] in [inaudible]. And compared to 25% in [inaudible] alcohol user receiving Baclofen. As a result we assumed on average reduction of 15% of agitation in Baclofen group compared with the placebo group. We've 5% type one error and the [inaudible] 80% meaning a sampler size of 340 patients. So this slide is difficult, yes. So here are the results of the study. So although [inaudible] 2,146 patient on the medical - mechanical ventilation from 18 to 80 years old identified as [inaudible] alcohol users. After the exclusion of 1,832 patients finally 314 patients were randomized. 159 - 159 in the Baclofen group and 155 in the placebo group. In the Baclofen group one patient [inaudible] one did not receive the treatment because [inaudible] was not [inaudible]. In the placebo group one patient was included twice in the study for two different ICU stays. All randomized patients were interviewed in the final analysis. So at baseline patients were mainly middle aged men with simplified acute physiology score between 46 and 49 points meaning probably [inaudible] death in the ICU between 34 and 46%. [inaudible] alcohol intake was five unit per day, about 15% of the patient [inaudible] alcohol blood test on admission and the two main diagonals in the ICU were acute risk [inaudible] syndrome and septic shock. [inaudible] the primary endpoint so 19.7% of in the Baclofen group versus 29.7% in the - in the placebo group presented at least one agitation related even [inaudible]. This difference was significant. This analysis included all the randomized patients. The missing data for the primary outcome in the one consent [inaudible] and one patient with [inaudible] and viable were [inaudible]. The sensitivity analysis considering [inaudible] event of agitation confirm this significant result. I would show you the accumulative incidents [inaudible] and this results were consistent in the [inaudible] analysis. These are the graphical representation of the cumulative incidents plot for the primary outcome considering death as a [inaudible]. So you have the primary analysis on the left hand side and the political analysis on the right hand side. The [inaudible] access corresponds to the time and days. Regarding the summary outcomes, so the incidents of agitation by the 28 was not different between groups. However, when you compare the number of agitation related events in each groups there were more events of treatment [inaudible] and update 28 in the - in the placebo group than in the Baclofen group. The difference which was also significant. The median duration of mechanical ventilation instead in the ICU was significantly longer in the Baclofen group than in the placebo group. There was no difference in the [inaudible] at any time point. [inaudible] presented the [inaudible] of agitation related events in age group over the treatment [inaudible] so 45 for Baclofen versus 79 for placebo. And day 28, 70 for Baclofen versus 111 for placebo. We are presented the monitoring [inaudible] so there was no difference for the community or the daily doses of hypnotics and [inaudible] between groups by day 28. You will notice that patient in the Baclofen group spent more time with [inaudible] agitation [inaudible] from one point [inaudible] to three points namely patient difficult to arose. Regarding the addition to the protocol, patient received mean 90% of the particular dose of Baclofen or placebo. Treatment was mostly temporarily discontinued in both groups for acute [inaudible] failure with clearance below 50 ml per minutes with our prescription of [inaudible] therapy. The treatment was definitely interrupted for delayed [inaudible] in 14 patient in the Baclofen group compared with three patients in the placebo group. The monitoring of the residual [inaudible] concentration on day three and day 10 after randomization revealed that the concentration would be low, the toxic threshold of 1,100 nanograms per milliliter on all patient who were tested. So it is the first randomized control trial to study the role of Baclofen in order to reduce agitation in the ICU. Moreover Baclofen was used in addition to care which increases the visibility of implementing this molecule in our clinical practice. The mean adherence to the protocol was high and no specific event apart from [inaudible]. Finally, the reduction of [inaudible] appear as a major patient outcome because it has the potential to reduce the incidents of post-traumatic stress disorder of the ICU stay. This is [inaudible] which is ongoing. This study also several limitation. First the 10 difference between groups was less and the study was [inaudible] to detect. This difference appear to be clinically relevant since each agitation pay out involve possible risk of injury. For the patients, but also for the medical staff and can end the medical care. [inaudible] of the treatment was not adjusted to sedation [inaudible] which could explain [inaudible] in the Baclofen group. The study used higher dose of Baclofen that the current recommendation however, it was - it corresponded to the temporary authorization use when the study was designed. And all the Baclofen [inaudible] concentration were below the toxic threshold. Baclofen is Gaba-agonist which may increase the [inaudible] in the ICU, however [inaudible] is uncertain. It was [inaudible] the prevention and the treatment of alcohol withdrawal syndromes, nevertheless no recommendation is available so far. Finally there was no distinction between [inaudible] delirium and agitation without [inaudible] which would require to assess [inaudible] together. So in conclusion, in [inaudible] alcohol users and mechanical [inaudible] high dose Baclofen in addition to [inaudible] reduced agitation related events compared with placebo. [inaudible] this could also increase the depth of sedation, the length of stay in the ICU. Those things should be up to [inaudible] according to the sedation scale and estimation [inaudible] rate. Thank you for your attention.
>> Fantastic Karim and Michael. Brilliant presentation. Thanks so much. Very, very interesting data. We'll move on now to the editorial which will be delivered by [inaudible] from Canada, Hamilton Canada. Walid is [inaudible] and a noted Methodologist. And he has led the sedation agitation and pain guideline for SCCM and the surviving sepsis guideline as well. So he is excellently placed to comment on this trial. Walid has provided a pre-recorded editorial, so we'll play that now.
>> Hello everyone. It's a great pleasure to be here today. And share with you my thoughts about an important and interesting clinical trial, the Baclofen trial. I have no conflict of interest that are relevant to this topic. First I would like to congratulate the authors of this trial and other trials presented during this meeting. And just a reminder to all of us in the scientific community and also to clinicians that we always tend and the shoulders of giants. And by giants I mean scientists and researchers, so we can see further and advance ahead. And any thoughts that I'm sharing in this presentation is purely from an academic interest. But I truly appreciate the effort that the authors have put into this trial. Okay the research question, if I were to phrase it. I would phrase it as the following. In mechanically ventilated adults with alcohol abuse disorder, does the use of high dose Baclofen compared to placebo reduce the risk of agitation related events? So is this question a priority? The burden of alcohol use disorder in the ICU is unfortunately not clear. Not too many studies have been done on this topic. So we really don't know, although anecdotally and these patients probably are sicker and some studies have suggested that alcohol use disorder is associated with increased risks of agitation and delirium. I think we can all attest with that as clinicians from anecdotal and dealing with these patients. So it's clearly an understudied problem and I would say yes, this question is of priority. And we really need more studies to address areas of clinical practice that are under studied. Is there a biologic plausibility? Probably. We know that the consumption of alcohol can be suppressed either by Gaba A receptor antagonist, or Gaba B receptor agonist like Baclofen. Unfortunately I could not find any RCT's on this topic in the ICU. So it's became a clear interest to see if this medication would - would work in this context? But if you look at other population, for instance patients with alcohol use disorder as an out patient and there are some small RCT's that showed that Baclofen may improve alcohol abstinence in this population. Guidelines on - on helping clinicians to manage those patients like the SLD guideline list Baclofen as one of the options for this population. So there is some biologic plausibility. But this is in the context of outpatient and a longer term use and with different complete outcomes. One issue that I'd like to bring up most of the time, I do believe and that pilot trials are crucial component of any research program. Pilot - there are many lessons that we can learn from conducting pilot studies, although I couldn't find pilot phase of this particular trial. Authors could have benefitted from conducting a smaller pilot or Van Guard study to address some of the issues before proceeding with a larger clinical trial. We'll talk a little bit about several - several methodological points. We'll start with randomization. We look at the randomization and I think offers the good job selecting central randomization - randomization ratio [inaudible] or affects blocks. It has been used - authors been blinded to - to the blocks. But they also stratified the center so about 18 centers were included. Another way to assess randomization is to look at the table one. This is - when you look closely at table one, you'd see that there are some imbalances, small, not very large but there are some imbalances that you probably shouldn't be seeing with randomizing of 300 patients. For instance, if you look closely at even a gender balance was - was a little bit off. Patients in the Baclofen arm where had higher saps to score, severity [inaudible] scores and slightly higher [inaudible] scores. And more advanced cirrhosis as well was found in the Baclofen group. And even [inaudible] dependents was found in the Baclofen group. While this could be play of chance, just because of small sample size. I would expect the groups to be more balanced. Another possible again, maybe less likely explanation or contributing factor is over stratification with smaller sample size studies it's important to stratify by sensor. However if you have a large number of centers and realizing that in this population is probably difficult to include or finish the trial in one center is - these patients are you know, don't constitute a big proportion of ICU patients. And so it makes sense to involve many trials, sorry many centers. But again as you can see there's a huge variation in terms of recruitment across the centers. Well could have this contributed to the observed imbalances or could it be a play of chance; it's very difficult to say. But it's worth highlighting there is at least numerically some imbalances between the two groups. So that's the first point I'd like to make. Let me go to blinding, I think authors did a great job. They use placebo to blind patients, obviously who are sedated, intubated, investigators, healthcare team. I assume data collectors as well. Although in the article they refer to double blinding, which could mean different things to different people. I'd like to break down blinding by - by groups. I couldn't see any mention of adjudicator so it's hard to comment if there were adjudicators involved and whether they were blinding. When I mean adjudicators, I mean adjudicators of - of the outcomes of the trial. And also wasn't clear to me if data analysts were blinded during the analysis. But overall I have no major concerns that - about blinding. And I think the authors did a great job. After the patients were randomized, you always worry about co-interventions and their affect on the trial outcomes. Authors did a great job promoting a protocolized sedation approach for nurses and - and advocated targeting a [inaudible] score between minus two, to plus one, which is where - somewhere in the appropriate like sedation unless the patient obviously need deep sedation if they were too sick and [inaudible] for example. When you look closely at the medications you use them both [inaudible] sedative agents again, reasonably balanced, maybe numerically more patients in the Baclofen group [inaudible] again could be related to the severity of alcohol abuse that we've seen in table one or could be just again just a fluke from - or just a random observation. I couldn't find the average ras scores post-randomization throughout the conduct of the trial. Maybe it's mentioned somewhere, but I wasn't' able to find it. Authors did provide the RAS score at baseline. However we could look at the Ryker sedation agitation scale as a different surrogate. And they did report the number of days in which patient achieved different scores. Remember the lower the score, the more deep the sedation is. So, score one to three, is anywhere between unarousable to sedated. So kind of a deep sedation, although this is meant mostly for agitation detection. But if you look there, patients in the Baclofen arm spent more days in this target range of deep sedation compared to the placebo arm. We're talking about an average of 2.5 days - 2.5 days longer in the deep sedation arm. While - while this could be a result of receiving high dose Baclofen, which has some sedative effect. It's hard to say but it's worth mentioning that these patients were more sedated obviously. You come to the outcome phase. The agitation related events was the primary outcome. The authors looked at this outcome, the primary outcome was throughout the administration of the study [inaudible], is kind of a composite outcome and they did break it down in the supplement very nicely. And as you can see the Baclofen group had less number of events compared to the placebo group and mostly driven by [inaudible] extubations and medical device removal. You want to put this into operspective and numbers, I like to present things visually. It makes it easier to - to understand. So this is an absolute scale and the line in the middle represent difference between the two groups. As you can see the point estimate is suggested by at least 10% absolute reduction in agitation related events. However the confidence interval was extremely wide. Ranging anywhere between an implausible reduction of 20% to a trivial reduction of less than .5%. Usually as the clinicians we set minimally important difference in ideal situation would have asked the audience what they think, but we don't have this luxury by - while presenting online. So I'm going to propose a couple of scenarios. The first scenario where you know Baclofen is considered by clinicians to be toxic or associated with adverse events. And then the minimally important difference need to be larger in order to convince people to use this medication. But even in a scenario where you know, medication is considered to be safe, cheap, available, no downsides and people say okay, we'll accept you know 1% absolute reduction agitation related events [inaudible] even with the very small minimally important difference, the confidence interval still cross that minimally important difference. So there is an element of precision here. And that's only that with time. As the - the secondary outcome, they looked at the same events at 28 days. As you can see the upper limits of the confidence interval crosses the line of unity, suggesting cannot exclude even harm. So there is some element of a precision which is the main - one of the issues. Second question that comes to mind is this high dose safe, just to give some perspective the typical doses of Baclofen and alcohol use disorder at least to my knowledge is anywhere between 15 to 60mg per day. The trial used 150mg a day which is 10 times higher than the lowest dose and at least 2.5 times higher than the maximum dose; so it's a quite high dose of Baclofen. Definitely I personally have never used it with this high dose in the ICU. The authors to the credit of the authors they did a great job of you know, conducting any pharmacologic study and 20 patients with alcohol use disorder in the ICU. And they looked at the pharmacokinetics and toxicity and they found that this high dosing the serum levels were within normal range and no major toxicity. And they also looked at the pharmacokinetics suggesting some [inaudible] doses and critically ill patients which they base their intervention on in the trial. Well what did we - what did they find in the study? As you heard from the authors, adverse events were higher in the Baclofen group. And if you look at it closely just calculating the issue we're talking about 3.5 fold increase in risk of adverse events requiring the discontinuation mostly delayed awakening. Again, consistent with the deep sedation that we've seen the authors described in the table that I showed you before. Other outcomes as well were affected. So, patients who receive Baclofen had longer duration of mechanical ventilation and ICU length of stay. A mean difference of two days longer compared to placebo group. Again the confidence interval could not [inaudible] no difference but the point estimates was not in favor of Baclofen. But looking at mortality again the confidence interval is extremely wide but the point estimate was going the wrong direction suggesting increased risk of death, but again it's uncertain. Again is this related to the fact that the groups were imbalanced is hard to say. When you put everything on a scale to weigh the pros and cons of this intervention, so far if we believe the results about agitation events we're talking about an absolute risk reduction about 10% [inaudible] adverse events of absolute risk increase of 10. But also longer stay and the mechanical ventilator and longer ICU stay. In addition there is uncertainty about mortality and other outcomes. So, things to consider. Well we talked about them - prognostic imbalances that's a possibility given the differences in severity of illness and the table could have - could this have contributed to patients receiving more sedation or is it an effect of Baclofen and could that have contributed to a longer stay in the ICU and longer duration mechanical ventilation is very hard to say. Another question that you ask ourselves is which outcomes matter to patients. Personally I would favor you know, being extubated sooner and being discharged from the ICU sooner you know, over being deeply sedated and extubating myself for instance. Again different patient might have different preferences. And also given the uncertainty about some of the important outcomes. I don't think we have from my personal perspective much to support the routine use of this intervention. So in summary, I think there are several strengths of this trial. The idea is novel, which is great. It addresses clearly an understudied problem. And the trial is randomized design. The analysis which I haven't touched on. I think the authors did a great job with the analysis. In terms of summary, some concerns about as I mentioned before, just having a pilot phase to help design the studies. The significant [inaudible] that we have seen limit the - the interpretation of the results. So we talked quite a bit about the possible prognostic imbalance. Some people may think it's trivial, but it's again hard to say. Also the safety issues that we have seen still acquire probably more studies to before this intervention can be used. I would also say that the effect if you believe it, I think you would agree that the magnitude of effect is still uncertain benefit or uncertain magnitude. I think we all agree that safety of high dose probably needs further studies. Maybe perhaps future studies should use smaller dosing or maybe tailored to effect. Who knows? Thank you for the opportunity to share my thoughts. And again, I would like to congratulate the authors for their fantastic work addressing this topic. If you have any questions and I apologize I'm not there today personally. It's going to be 5:00 a.m. in the morning and Hamilton. If there are any questions, I'm happy to answer them on Twitter or by email. Thank you.
>> Okay. Thank you very much [inaudible] for a fascinating editorial. Hopefully Karim and Michael will have had a chance to listen to that and they might have a moment now to respond to some of the points that Walid has made. Karim and Michael were you able to hear that okay?
>> The -
>> Yes we just finished to - to hear the video. Yeah.
>> Excellent. Are there any initial comments you'd like to open with in response to Walid's editorial?
>> Yeah, so first of all thank you Walid for this editorial. I think you point very important aspect of this study. So maybe I can - maybe we can take point by point response for these questions. And remarks. So first of all as we - acknowledged that there was no specific pilot study in terms of obligation but the pharmacological study we - we built before [inaudible] this trial was kind of pilot study that again, the number of patient was [inaudible] so 20 patients. You also noticed that patients in the Baclofen group were [inaudible] much higher so - and when you look at the prediction of this [inaudible] mortality was predicted about 30% in the placebo group and 40% in the Baclofen group. So as you noticed, it can explain why there was little difference regarding mortality and also may explain why patients were deeply sedated. So regarding the number of inclusion center, yes you noticed that there was a lot of center including, and some centers are very [inaudible] number of inclusion. And indeed at one point of the study inclusion were quite [inaudible] and that's why we extended the number of - of centers. The [inaudible] analyzes was blinded to the - to the randomization group. The beginning when the - when she discovered the data so it was no education for the primary outcome. So one thing that is quite important is the [inaudible] average [inaudible] and average [inaudible] agitation scale. So to be honest, there was no difference in the mean [inaudible] score between groups. But appear that expressing [inaudible] in groups so one through three are more than four, was [inaudible] for the reader to understand that yes, patient in the Baclofen group [inaudible]. It also mentioned that - one point was that there was no difference for agitation related events, at day 28. That's right, but pre [inaudible] was [inaudible] so if you present at least one, you will be in the group of for yes, you are agitation related event. So the longer you wait, the higher the chance to belong to the group agitation is higher. To [inaudible] one important point is that the number of total events over the treatment [inaudible] day 28 increases with time and the [inaudible] also increases with the time. So -
>> Yes. I would like to - to express some comments. First of all, I would like to - to thank Walid for this terrific editorial highlighting the - the strengths and the limitations of our study. The main issue here I think and I totally agree with Walid is to define if - if Baclofen is beneficial without [inaudible]. I think this is the main point and from the results of our study it's quite difficult to answer - to answer in the straight way. Because our study was powered for the primary outcome agitation. And posteriorly we - we could figure out that the - the level of the rate, sorry of the primary outcome was lower than expected. So maybe we're a little under power, but the study is positive for the primary outcome. If we are looking at the secondary out - outcomes like time on ventilator, I feel like this is not really - this can be considered a side effect, but probably - probably better than it could be considered exploratory outcomes. So if - if I globalize the message, I think that yes the study is - is positive for sure, regarding agitation. Second, it was probably a [inaudible] but the main issue again is to know if this is beneficial, and we cannot answer to this question. I think that to answer to this question, we have to monitor patient centered outcome like PTSD at six months or one year, to know exactly if the administration of Baclofen whether the dose is high or low. I hope that we have clearly demonstrated that the pharmacokinetic study even at higher dose than the dose promoted by [inaudible] we can monitor safely Baclofen in the plasma and adapt it to - to maintain a good safety profile. I think that the step forward will be to - we will do this with our results to [inaudible] from the sub study to know - to know exactly if at six months or one year or two years after the - the - after the ICU stay. There is beneficial - beneficial effect of the - of the drug.
>> Fantastic. Michael and Karim thanks for taking the time to respond to Walid's comments and his editorial. We have time now for some questions from our chat function on the live stream, and also from Twitter. And my colleague Katrina Kelly will join us in the meeting for this.
>> Karim and Michael thank you. And Walid thank you again for your editorial. Several questions, comments on our live feed and one other sedatives and analgesics were excluded. There's been some comment on what other clinicians use, using [inaudible] Clonidine and [inaudible] do you have any comment on that?
>> Sorry, we couldn't - we couldn't hear you very clearly. I don't - I don't know if this is the - could you - could you ask again the question?
>> At some clinicians want to know were other sedatives and analgesics excluded from your study? And some comment they would be regularly using methods such as [inaudible] Clonidine or Dexmedetomidine?
>> Okay, so I am not quite sure I understand all the - so patient allergic to Baclofen were excluded. And also patient with celiac disease were excluded because the kind of [inaudible] is - was present in the drug. So regarding the co [inaudible] and co-analgesia I guess patients with Clonidine or Dexmedetomidine were included and could be included and you are based in the [inaudible] of the - of the article. But regarding the wide [inaudible] of sedative and analgesic, there was no difference regarding the use of this sedative in between groups.
>> I [inaudible] do you remember the percentage of patient Clonidine or Dexmedetomidine at the conclusion?
>> It was less than 10%.
>> You made some comment that some patients had their Baclofen temporarily discontinued. Was that a common event? What were your parameters for [inaudible] Baclofen therapy in that patient group?
>> So your question about was about discontinuation of the therapy?
>> Yeah so in fact in our private study, so kind of pilot study that - in this study which was closely monitored there was no kind of withdrawal syndrome of Baclofen. And we see also in the supplement that the - the [inaudible] score to assess alcohol withdrawal can be - can do a parallel with the Baclofen. Patients were calm and no - very few patient present [inaudible] syndrome. And we have some patient in our center that stop Baclofen on the day of their discharge and on the following day in the - in the medical [inaudible] so it was no issue.
>> Thank you. In some comment about as you alluded to the Baclofen group. And [inaudible] longer time to be liberated from mechanical ventilation and do you feel this is because the group was over sedated and a failure of protocol of other adjuncts that were used to sedate the patient during their stay?
>> Yeah, so [inaudible] about the length of mechanical ventilation. So yes, indeed patient with [inaudible] may have longer - may have longer length of ventilation. But as pointed by Walid so we can't conclude the - anything because it was - exploratory [inaudible] endpoint and the second point is that I don't know if I prefer being ventilated one day [inaudible] one more day and wake up without agitation, without total extubation, without [inaudible] of drains. Or, being [inaudible] one day less and present agitation. So I have no response.
>> I think that for more courage news [inaudible] that we have the data or from [inaudible] trial. For a more [inaudible] rate use of Baclofen, probably that we - we should of course, continue to - to monitor the age of Baclofen first. To avoid side effects and in the same time to monitor with scale the level of sedation because as you said probably that some patients were over sedated but as the - as mentioned before we don't have any recommendation for this kind of patients, which render the situation [inaudible] and probably [inaudible] this is - this is because we didn't have any evidence providing good level of evidence from [inaudible] trials before these trials. So I think that we - if we want to use Baclofen in this kind of patients. We should first of course use this age to be sure that this is close to the - the level of the renal function. And in the same time we should closely monitor the level of sedation whatever the sedative drug we use with the scale. Probable. I suppose one final comment is - we mentioned that the average alcohol intake was five units per day. Do you think that would have a dose effect? Or, you know we certainly see patients who have a higher alcohol - much higher alcohol consumption than that? And would you have any comment on that?
>> So some [inaudible] ask us sub group analysis. But when we - when we try to - to find if there was an interaction between [inaudible] alcohol intake so from [inaudible] alcohol use to heavy drinker there was no effect of the amount of the daily, weekly alcohol intake on the primary outcome. So we did not present sub group analysis.
>> Okay, merci. I'll hand you back to Rob, thanks.
>> Thank you very much. Merci.
>> Super. Thank you very much Katrina. We'll move into the panel discussion now. And we will be joined by Marianne Campbell, Kathy Roan, Morton Highlander-Muller and Chris Nixon who I've introduced earlier. We'll maybe start with a clinician in just a moment. One thing that I did see on Twitter, very interesting comment from Jane Esbitt who is a frequent attender at the meeting I'm delighted to say. He's tweeted baccalaureate trial take home. If struggling to achieve adequate sedation in a mechanically ventilated alcoholic patient, patient with alcohol misuse disorder. Baclofen is safe but may result in prolonged ventilation and ICU stay and caution with dosing in renal repairment. Karim and Michael is that fair summary?
>> Yes absolutely Rob. I think it's a fair summary. We don't have answers - answers to all of this, but yes this is a fair summary.
>> Okay great thank you. We'll move into the panel discussion and I'll start with a clinician. Morton, what are your first thoughts on the baccalaureate trial results?
>> Well first of all, congratulations for the completion of a nice trial. And also a nice presentation and - and you're soon to be public - publication in JAMA. So - so what I'm wondering about is the clinical implications. So - so both as a researcher but also as an every day clinical specialist. What do I do in daily clinical practice? Should I start using Baclofen?
>> Yes, Morton very good question. Of course, thank you for the comment. From that point I don't think that we can - the part from expert [inaudible] I feel like we are now experiencing be cause we are working on that for many times and we monitor very tightly our patients. We perform the samples to - to look at the age of Baclofen apart from this [inaudible]. Clearly I don't think now with this dosage of 115mg daily I don't - I don't think that from our results we can recommend daily use of Baclofen even in - even in our population heavy drinker or whatever it is. Because we don't have enough data to - to [inaudible] this kind of statement for sure. Yes. Again the very important point will be if we can demonstrate, not in this study of course. Maybe in our sub study if we can demonstrate a difference between Baclofen group and - and placebo group. Let's say two years after the ICU discharge in terms of I think, PTSD.
>> This is an expectation.
>> Yeah, so - so is it fair to say that you are somewhat worried about the undesirable effects of Baclofen?
>> Not really the worried, but we are not afraid of - about the side effect of Baclofen because the safety monitoring was - was given very positive results. But we should warn clinician that using Baclofen which is probably quite a strength - strong sedative implies that you have to monitor closely sedation, and to adapt all the sedative [inaudible] in order not to have [inaudible] and [inaudible] mechanical [inaudible] so that's the - our response.
>> I fully agree with Michael. Of course, we - we're below the threshold of toxicity. For sure, and large term that - the issue of course that we delay from all results even if it's exploratory we delay probably the winning from ventilation. The - the patients are [inaudible] sedated, so it's a fact. I think.
>> I rather disagree with the fact that you say yes, the primary outcome is positive because the patient were more deeply sedated. But that's - I don't think that's the - that's the reason because - because in fact, when you stop sedation and when you want to win mechanical ventilation [inaudible] sedative are used - you may have agitation related events. So I don't think there is a direct link between the - the sedation and the positivity for the primary outcome.
>> Okay. We'll move on now - we'll stay with the clinicians just for a moment and then we'll move on to Marianne and Kathy in a second. Question for Chris Nixon, it would appear that we get less agitation but more sedation and Michael has just touched on this. Would a similar result be seen with just using more sedation? Have we replaced one sedative with another? Have we just bought more time for the effects of potential alcohol withdrawal syndrome to wear off [inaudible] comment on that and I'll bring Karim and Michael in on that afterwards.
>> Yes, I think that's a really good point Rob and I guess that's something that I was thinking too and I can't say I know - know the answer to that particular question, because I kind of wonder that is a possibility. I guess you know what is Baclofen? It's a Gaba-B antagonist. So what we're kind of expecting there is - sorry agonist. So the - there is this possibility certainly an overdose one of the theories is that it just binds all Gaba receptors and contributes to more sedation and an overdose you know, that's the main side effect that we see over sedation. And that's kind of what we're seeing in this study too. I wouldn't call this an over dose, it's more like 200 mg in one pop is when I would usually be concerned about significant side effects. But there are - so Baclofen is also used in - in maintaining abstinence. So apart from withdrawal but maintaining abstinence, so there's a thought that there's Gaba B receptors that interact with the [inaudible] system and the reward system in the brain. And actually suppresses the urge for alcohol. So there's really two possibilities that Baclofen is a substitute or an additive sedative or that it's doing something else to do with alcohol withdrawal or cravings for - for ethanol. And I'm not 100% sure which it is based on the study because I guess the way it looks on paper, it's possible that if we just turned our power, the sedation maybe we could achieve the same effect. I guess I think of some of the trauma patients that we have where you know you try and sedate them and they wake up scrambled, and you're like "Let's give them another day." Turn up the sedation again. Turn it down the next day and they wake up okay. And it is an interesting outcome. I think it's really fascinating that the authors of the study have really put alcohol and even psychosocial disorders NICU on the map. I think a little bit with this study because it's so neglected. And all of the treatments that we're doing in ICU you know, we don't' really know what any of them do or what the side effects are. So Baclofen, it's - it's an off patent drug. It's probably the reason why we don't have a lot of data on it is that there's not a lot of dollars in it. So I commend the authors for looking at it. But I - I think it is just the beginning of the journey to figuring out exactly what the role of it is.
>> Thanks Chris. So Karim and Michael. I think this is - this would be a really key message to come out of this trial and for people to understand this trial correctly. Can you comment again just on the increase in sedation? Maybe buying time with Baclofen versus just turning the usually IV sedative up?
>> Okay. Thank you for this comment because it varies two types of response regarding sedation. So - so let's imagine you give - very high dose [inaudible] to your patient compared with placebo. I'm not quite sure that this patient when you stop with [inaudible] because of delayed awakening. I'm not quite sure this patient will not present agitation. Because in fact, it will wake up when we have clear this [inaudible]. So this is the second response, so maybe various specific effect of Baclofen on the agitation. And - and as you mentioned that's one of the possibilities that [inaudible] studying abstinence expose as a - on high [inaudible] - so they may be specific effect of Baclofen [inaudible]. Because patients were under sedation so we've quite deep sedation in - and also [inaudible] like [inaudible] and analgesics. And the abstinence side of this drug was given by the sedation so can conclude on this point. And that's why we try as a secondary outcome to monitor the withdrawals of the patient in this - in the seven days following the extubating. But because we have - we have not only patients with alcohol dependence then also alcohol abuse without dependents or just [inaudible] without dependents. So in this case was probably not perfectly - does not - not perfectly fit our population to show if there was a difference of -
>> Great, thank you. We'll - we'll move to the statisticians and methodologists Marianne Campbell and Kathy Roane. Marianne is amongst her many duties, a statistician in Aberdeen. She's also a methodologist and a trialist. Kathy Roane leads [inaudible] and the [inaudible] clinical trials unit as a vast experience in running trials. Marianne I'll turn to you first. You've read the protocol. You've seen the stats plan for this. Just a very quick run through. How did it all look to you as it was presented?
>> Thanks very much. And first of all, really to thank the investigators as it's been said, really putting this clinical indication on the map. And there really isn't much evidence before this trial around this area. The first of all, real congratulations for - for doing that. There are a couple of things that spoke to me as I read the protocol and I - I heard the results of the trial. And you know one was really what the authors alluded to, which was actually that first of all the absolute risk reduction was much lower than they had expected. So it was 10% as compared to 15. But on top of that the baseline rate in placebo was much lower than they had planned for. So it's almost a dual difference I guess. My question would be first of all is this still the same patient population you expected because the baseline rate you originally expected for agitation was 42%. But actually what you saw on the trial was done at 29%. So that's exaggerates the possible influences from the protocol with what you saw in the trial. And added to the fact that then the difference in the absolute risk reduction just makes me question a little bit the underlying assumptions and whether you really feel that the trial as run, was the trial you thought you were trying to run. And does it some differential in the patients that has led to this? So that's the first thing. And then the second thing I would like a little bit of comment on is obviously the confidence interval for the effect size is really wide. And so it runs I think I took note of it, it runs from 0.34 right up in really a tiny different potentially 0.98. And so again [inaudible] the fact that things changed from the protocol, how confident are you as investigators that this is the [inaudible] effect and I'm not potentially just [inaudible] effect because that is really near the null effect and given the consent about mortality I guess one would want to really explore that [inaudible]. Just a couple of comments which I'd like the investigator to comment on.
>> Thank you very much Marianne. This is - this is two major point from statistical perspective. And from the design of every clinical trial. So Michael maybe you can start with the answers to this question. This is pharmacological study is exactly the same that in the - in the - in this trial that the population in which we found approximately 2% agitation related event included also patient without mechanical ventilation in the - in the role [inaudible]. So that - the - the explanation of the when university hospital [inaudible] also - also include patient without ventilation. So that's why maybe can explain why the incidents of agitation was not quite the same between these two [inaudible]. So the second - for the second question, so yes [inaudible] there was wide confidence interval for the primary outcome. That with quite confident regarding the clinical [inaudible] of this result because of the secondary outcome which were the number of agitation elated event [inaudible] because yes, [inaudible] this is binary outcome, so it does not - it did not reflect the [inaudible] member of event. And when you look at the total number of events in the placebo group in day 28 so that's quite huge. So more than 110 events or 160 patients, so it's for this point if you like the confidence interval is why.
>> I would like to compliment because I think this is a case problem of the [inaudible] confidence interval. First answer I reasonably confidence that not enthusiastic but all results. But as my [inaudible] said reasonably confident because the secondary outcome even if descriptive kind of confirmed the primary to - to me. Come back to the - the percent of primary outcome - that was lower than expected. This is something that we'll observe another study we performed. For example [inaudible] published in [inaudible] to - 2011. The - the [inaudible] study, we had exactly the same - the same issue. I think that there is probably a secular trend because when we design the study and we had some - and we had some percentage of the primary outcome in a group of patient quite similar to the population in the [inaudible] trial. And when we perform the study of course I think we proved the care of patients even if it's only two years after, so maybe there is a kind of secular trend explaining that. I don't know if you agree with that but it's [inaudible].
>> It had to happen, speak with the mute function on. So Kathy, Walid mentioned a point about baseline imbalance. Can you comment how important that might be in this trial? Of course this - the counter argument as well that there are other cohorts that aren't measured and which may balance these out. Could you just make a quick comment on that please?
>> Sure. What a wonderful thing to be having a discussion like this, isn't this wonderful what's critical care reviews, ability to present your trial and - and we get a good discussion. And congratulations guys. I think it's a great trial and I really like to see a subject that we probably haven't looked at enough being brought to the fore. So - so yeah I got a couple things that actually link into that imbalance. One would be I noticed that 2,146 people met your inclusion criteria. And 314 ended up in your trial. That's about 14%. You told us about the 1,832 that didn't get in. It would be really interesting to understand the exclusion criteria, Marianne has talked about your who get excluded and the exclusion criteria that they meet. The other thing that I'm really intrigued by this trial is this kind of sort of significance in that primary outcome that's lost in the secondary outcome. And forgive me, I'm not clinical so here we go. You had a small imbalance in the table, so the Baclofen group were more alcoholics or forgive me, they seemed to - to have more alcoholic problems as I understood it. They then go into the trial and we hear that sort of they go on to receive greater doses of sedation. Now as I understand it you can't have an agitation related event if you're heavily sedated, if that makes sense. It's in the period you're coming out of sedation that you get agitated and you may then be able to have an agitation related event. So I suppose this problem I'm just wondering whether as you go out to 28 days, there's a question around where you're second - what's your primary outcome and your secondary outcome to 28 days in ICU? If I pulled devices off on the wall after ICU, were you measuring that because then this longest stay of the Baclofen group in ICU, if it is measured in ICU might mean that you just shifted the window from measuring agitation related events in the Baclofen group because they're more sedated for longer, if that made sense? So I'm just wondering whether the transition of seeing a difference and then not seeing a difference is actually a shift in one group for the period when they were sort of oxidation and able to be agitated and have an agitated related event. So that's sort of my main feeling about this. Generalizability for those 1,800 because I want to know whether the alcoholics in the United Kingdom you know, it's generalizable to them, you know as being a very nation of not drinkers. And then obviously this motion of whether actually what you saw was a later kind of opportunity to capture the agitation related events in the [inaudible] group because of the greater [inaudible] but the longer stay, the longer mechanical ventilation. But congratulations nonetheless.
>> Thank you. Thank you very much.
>> The second question is the [inaudible] I will start with the first one. So you were right there is quite a lot of [inaudible] so sometimes it is - you can be seen as a - a side of study but [inaudible] the drug urgency - the drug [inaudible] which is very odd for clinical trial, ask us to exclude high number of patient with mainly medical problem in the medical story, such as - is offering the - such as patient with Parkinson's disease because we - we wanted to use very high dose of [inaudible] they were worried about the interaction between the personal equipment and Baclofen so that's one reason why -
>> We didn't want to exclude all these patients. But we had no choice.
>> But the second - the second point yes, you [inaudible] is that maybe agitation at day 28 is not different between groups because in fact, the treatments is stopped. So the - the effects become - become more - less important. So that - that's a possibility and the also one is that at day 28 in the ICU there was less patients because the mean - the mean duration of stay in ICU and in the participating center is about seven to 10 days in fact. So at day - at day 28 there was less patients, so because this outcome as mentioned in the supplemental data was only [inaudible] in the ICU so we have less number of patient.
>> Well [inaudible] patients in the ICU at 28 days than not.
>> The mean length of stay was as mentioned in the [inaudible] two bits longer. But at day 28 I don't remember exactly the data, but I - I [inaudible]
>> Okay great, we're coming to the end of the session. It's been absolutely fantastic talking about the baccalaureate trial results. I'll finish with one quick question for each of the four clinicians. So [inaudible] and Chris. We've heard the results, should we now start using Baclofen? So France, first over to Nant?
>> Yes, okay. Yes. The question as you mentioned is of use for the audience. As I mentioned before from the results of this trial even if it's the first randomized multi-centered trial, that topic and even if I feel - if I feel like we have good evidence regarding [inaudible] kinetics regarding safety of the drug. As I mentioned - as I mentioned before the statistical analysis showed that the studies positive. But as it was mentioned before with some pitfalls of course, regarding the - the power of the study, regarding the [inaudible] interval and regarding the secondary act - outcome we don't know exactly why it is specific or not, the fact that the patients, the Baclofen group are longer ventilated, are deeper sedated. They are a little bit more severe from the table one, but we can't be sure of that. They are a little bit more alcoholic, we can't be sure of that. They are some issues about the exact level of sedation, so my feeling is that no we cannot today, say to the audience please use the Baclofen to your alcoholic patients in ICU. Regarding ICU because in England we have some patients with alcohol - alcoholic issue. We use Baclofen because we work on that topic for many years. But no of course, all data are not enough to provide - to provide this kind of recommendation.
>> Okay and Michael I presume you would agree with that then?
>> Excellent. Okay. So Chris Nixon [inaudible]
>> Yeah, I had to add anything different to what I think the office of the study of which - which I think is a very circumspect and considered answer which this is the hopefully the beginning of I'm finding out new stuff about how to manage alcohol withdrawal in ICU. And there may be a roll for Baclofen. But I think there's at least another study there before we should be changing practice.
>> Yes fully agree with that. Thank you Chris.
>> Excellent. And we will finish in Copenhagen with Morton where we started our panel discussion. Morton I presume you won't be using this given the three answers we've had before?
>> No, I fully agree with the comments. So I think we need more firm data, confirming this finding. We also need to interpret the findings in light of the excess thing evidence based and maybe update the existing evidence. And then finally I think it's important as alluded to by Walid that we ask patients what do they prefer. Increased sedation or - or other things. So we need to ask them I think. So more research needed also here.
>> Excellent and I'm sure Kathy and Marianne would agree with the more research needed on - on that front. Okay I'll need to draw the session to a close. We have just gone over time a little bit. I would particularly like to thank Karim and Michael for a beautiful presentation of the baccalaureate trial results. And a very, very considered explanation and description of the interpretation of that trial. Chris, Morton, Kathy, Marianne thank you all very much for joining us in the panel discussion. And Walid in Hamilton Canada, thank you so much for taking the time to put the editorial together. I'll finish with just one last thing, Karim you mentioned the publication. Can you just let our audience know where that's coming - when that's coming?
>> Yes, we are - the paper was just accepted yesterday. So of course I - I don't know the date of publication and [inaudible] but is accepted in the [inaudible] since yesterday.
>> Fantastic. Something to look forward to. So in the next few weeks keep an eye on JAMA. Thank you very much everyone.
>> Thank you.
>> Thank you very much.
>> All of you thank you for the great discussion. Bye bye.
>> Cheers, bye.
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