I have no relevant disclosures and I'm going to be focusing on a couple of studies that relate to the ICU liberation bundle, an area of my expertise. And just as some background, although probably very familiar to this audience, the ICU liberation bundle is the implementation strategy for the PADIS guidelines and encompasses the ABCDEF bundle, A being assessment, prevention and management of pain, B for both spontaneous awakening and breathing trials, C for choice of analgesia and sedation, D for delirium assessment management and prevention, E for early mobility, and then F for family engagement. So I've picked three studies to review with you today, one study that looks at spontaneous breathing trials comparing pressure support versus a T-piece, a trial of early mobilization during mechanical ventilation, and a trial of haloperidol for the treatment of ICU delirium. So the first study that we're going to take a look at is this study in the New England Journal of Spontaneous Breathing Trials with Pressure Support Ventilation, or a T-piece. As a little bit of background, a few years ago there was a study that compared these two methods for doing a spontaneous breathing trial and found that pressure support ventilation SBTs were passed more frequently and earlier than T-piece and led to earlier extubation without an increase in the risk of reintubation. But that earlier study did not include a large proportion of patients who had risk factors or who were high risk for extubation failure. And so this study was looking to evaluate the difference between these two methods in that population. So this was a multi-center, randomized control trial in 31 ICUs in France. They enrolled adult patients who had been intubated for at least 24 hours, were at high risk for extubation failure, and were clinically appropriate for their first SBT. They defined high risk for extubation failure as an age greater than 65 or having the presence of chronic cardiac or pulmonary disease, similar to many of the prior studies. And they excluded patients who had a history of traumatic brain injury, neuromuscular disease, or who had a do not reintubate order after they had already been intubated. They compared pressure support SBT, which was a pressure support of eight, a PEEP of zero, and an FIO2 of less than or equal to 40% for one hour, to a T-piece trial, which was six liters of flow for one hour. They had standardized criteria for when patients were SBT ready and for whether they passed their SBT or not. If the patient passed their SBT, they were put back on their prior vent settings for an hour and then extubated. And if they failed their SBT, they underwent subsequent daily SBTs using the same method that they were randomized to. They strongly encouraged the use of prophylactic non-invasive ventilation and or high flow nasal cannula after extubation, although it wasn't protocolized as part of the study. Their primary outcome was ventilator-free days through day 28. And as you'll see, they looked at a series of secondary outcomes, including the success of the SBT, how many patients were extubated within 24 hours, seven days, and then reintubation rates at seven days. And so here are their primary and secondary outcomes. As you can see, there was no difference in ventilator-free days in the study. The patients who were randomized to the pressure support arm, those patients had a 7.4% absolute increase in their success on their initial SBT, and that translated into a 5.5% absolute increase in extubation after their first SBT within 24 hours, and a 3.3% increase in extubation within seven days in that pressure support group. Here you can see the results visually on the upper left hand. This is a graph that shows the proportion of patients who remain intubated over the first seven days after their first SBT. And I think a couple things to note is, one, that the vast majority of patients who underwent their first SBT were extubated within the first 24 hours. So over 80%. You can see that small difference between the pressure support and the TPs. When you look back from this range, it's very, very small, but it is there. On the right is the rate of reintubation over seven days. They chose to do seven day reintubation rates in this study compared to most prior studies that had done 72 hours because of that encouragement of using non-invasive ventilation post-intubation, and they recommended 48 hours of non-invasive ventilation. They allowed to switch between oxygen therapy and high flow nasal cannula, and in fact they had very high rates, 77 to 80% of patients got prophylactic non-invasive ventilation at the time of extubation. And so you can see that's why they did seven days, and you can see here the seven day reintubation rate was 14.9% in the pressure support group and 13.6% in the TPs group, and that was not significantly different. So my takeaways from this study is that there's no difference in ventilator-free days when comparing SBTs using pressure support or a TPs, but this is the second contemporary trial that reports higher rates of passing a spontaneous breathing trial using pressure support and earlier extubation with pressure support SBT compared to TPs without an increase in the risk of reintubations. Now one key thing is that this trial, they did achieve very high rates of non-invasive ventilation for high risk patients at the time of extubation, so you have to contextualize that in what your practices are in your ICU. If you use it very frequently and you encourage it, then maybe there is truly no difference in reintubation rates, but I think some still wonder for these really high risk patients if you don't use prophylactic non-invasive whether a TPs trial may identify patients who are not ready to be extubated more so than a pressure support. The next trial we're going to look at is another New England Journal of Medicine trial, Early Active Mobilization During Mechanical Ventilation in the ICU. This is from the ANZICS group, and a little bit of background is that prior studies looking at early mobilization have demonstrated that patients who get early mobilization have better functional outcomes at hospital discharge, have reduction in delirium, and may have shorter hospital length of stay. And despite being part of the ICU liberation bundle and being recommended by clinical practice guidelines, there's still lots of questions about when is the appropriate time to start early mobilization, how early, and also what intensity, i.e. what dose of early mobilization is the best for patients. And so this was a multi-center randomized trial across 49 hospitals. They enrolled mechanically ventilated patients who were expected to continue mechanical ventilation through the next calendar day, beyond the next calendar day. They had quite liberal hemodynamic and respiratory parameters to undergo early mobilization. Just to give you a sense, this included things like a heart rate less than 150, respiratory rate less than 45, FiO2 less than or equal to 60%, PEEP less than or equal to 16, and vasopressors 0.2 mics per kilo per minute of norepinephrine. So depending on weight, could be anywhere from 15 or so or higher of norepinephrine. So pretty early on in the phase of critical illness when some of us would say those patients are still requiring a significant amount of life support. They excluded patients if they had any dependency in an activity of daily living at baseline, if they were ordered for bed rest, or if they were admitted with acute brain or spine injury. And they performed mobilization based on the ICU mobility scale. You can see the whole scale to the right, but I just want to orient you to three key spots, which are a scale number three, which is sitting on the edge of the bed, a number four, which is standing, and then seven or higher, which is ambulation. This trial was unique compared to prior trials in that they targeted the highest mobility level that the patient could tolerate for as long as possible. And when they got fatigued, they then dropped down to the next level and kind of continued. And they compared that to usual care. They did daily therapy for the duration of the ICU stay up to 28 days after randomization, and their primary outcome was facility-free days up to 180 days. So that encompasses hospital, long-term acute care facilities, nursing home, rehab. So they're really looking to see, do patients have more time at home comparing these two groups. These are some process metrics that are important to kind of contextualize the trial. And so one of the key things to know from this trial is that they had impressive engagement of their physiotherapists in this trial. You can see in that first orange box that 86.5% of patients were assessed by a physiotherapist on the day of randomization in the intervention group, and 73% in the usual care. So still pretty impressive physiotherapy engagement in the usual care group. The proportion of days when a physiotherapist engagement occurred was 94% in the early mobilization group and 81% in the usual care group. They did achieve a difference. There was 12 minutes more mobilization in the intervention group compared to the usual group. And this resulted in shorter time to achieve key milestones. So patients achieved sitting at the edge of the bed one day earlier, and they achieved standing and ambulating two days earlier. There was a 6.9% increased rate of ambulating while in the ICU in the intervention group that was just shy of statistical significance, but honestly is very likely to be a true finding. Here you can see visually the separation. So what these graphs represent is the proportion of patients on each ICU day that reached a certain ICU mobility level, with the top being the early mobilization group and the bottom being usual care. And what you can see here is that there's a phase shift such that in the intervention group there are far fewer patients who are in the gray box, which is passive exercise, pretty much just laying in bed. And there's an expansion of the group of patients who are in that three to four, the yellow, which is sitting on the other edge of bed or standing. So they definitely did achieve a slight difference in what patients were achieving on each day. And here are their final outcomes. There was no difference overall in facility-free days through day 180. There was no difference in ventilator-free days or ICU-free days through day 28. There was no difference in self-reported health-related quality of life or physical function at 180 days, and they found no difference in delirium, cognition, or mental health. They did track adverse events pretty closely in this trial, given that they were engaging patients quite early in their critical illness. The vast majority didn't have any adverse events, so 91% of patients in the intervention arm had no adverse events compared to 96% in the usual care. So certainly there was a difference in the adverse events with the intervention arm having more adverse events, but overall fairly well tolerated. Cardiac arrhythmia and desaturation were the two adverse events that drove that difference. And when they looked at serious adverse events, there still was a difference with higher rate in the intervention arm, and that was driven mostly by arrhythmias. But there's unfortunately not a great breakdown of whether that's mostly rapid AFib or kind of more concerning arrhythmias. And so overall, this study found no difference in facility-free days when comparing early high-intensity mobilization to usual care. But I italicized usual care there because I think the profound engagement by physiotherapy in this trial in the usual care group with 84% of days having a physiotherapy engagement and an average of eight minutes per day physiotherapy even in the usual care may not be generalizable to all of our different ICUs. There was no difference in self-reported quality of life and function and no difference in delirium coma-free days. But consistent with prior trials, they did achieve earlier milestones. So they were able to stand earlier and walk earlier compared to the usual care. And I think it's really important that you contextualize this trial in particular into your ICU, whether you have this degree of physiotherapy engagement in your ICU. And then I'll just, and we're probably not supposed to do this, but a study just came out yesterday in the Lancet Respiratory Medicine of a early mobilization trial comparing two groups that showed improvement in cognitive function and physical function at one year. So I think when you look at the totality of evidence, I would not leave this year-end review today thinking that early mobilization is still not a very important key component of the ICU liberation bundle. I view this more as a study of diminishing returns, that if you're already doing an amazing job with physical therapy and mobilization, doing it earlier or perhaps more intensely may not give you more bang for your buck if you're already mobilizing patients early and getting them moving. The one other caveat of this trial too is that the prior trials linked early mobilization with minimizing sedation, and this trial did not protocolize that. So perhaps it's the combination of minimizing sedation and mobilizing that gives you the most impact. The last study we're going to look at is the Haloperidol for the Treatment of Delirium in ICU Patients study, another New England Journal of Medicine study. This was a multicenter randomized control trial in 16 ICUs in Europe. They enrolled adult patients who were in the ICU with an unplanned admission with a positive delirium screen. They excluded patients who had a contraindication to Halodol who were chronically treated with antipsychotics or had received an antipsychotic prior to enrollment in the study. The intervention was IV Haloperidol, 2.5 milligrams TID or placebo. Patients could receive PRN doses up to a maximum of 20 milligrams per day. They could be rescued with propofol, benzodiazepines, or alpha-2 agonists. Other antipsychotic use was not allowed as part of the trial. If patients had two consecutive screens for delirium that were negative, the intervention was held. But then if delirium recurred, they resumed on the protocol. And the medication could be continued through ICU stay up to 90 days. Their primary outcome was hospital-free days through day 90. And then they also looked at some secondary outcomes including delirium coma-free days. Here you can just see kind of how separate the groups were. The intervention group received a median dose of 8.3 milligrams of Halodol per day and a median cumulative dose of 32.5 milligrams with a median duration of therapy of about 3.6 days. There was similar use of rescue medications in both groups. And both groups had some antipsychotic use outside of the protocol, about 13%. Overall they found no difference in hospital-free days. Interestingly enough, they found a 6.9% reduction in mortality in the Halodol group that even the authors highlight is difficult to explain. And I'll get into that a little bit more in the conclusions. They found no difference in delirium coma-free days or vent-free days, although the point estimate was on the side of Halodol. And they had similar adverse events in use of rescue medications as I mentioned. So overall there was no difference in hospital-free days or delirium coma-free days comparing moderate dose Halodol to placebo. This is consistent with prior trials, including the MIND-USA trial, which was one of the most more contemporary ones. But this study now extends those findings to a population that had higher rates of hyperactive delirium. The prior MIND-USA study, which compared Halodol to Prazodone and placebo, was about 80-90% hypoactive delirium and very few hyperactive delirium, whereas this study was about 50-50. So much more higher rates of hyperactive delirium. I'd been saying for years for rounds that we needed to study Halodol and hyperactive delirium because maybe we would see some benefit. And now in this study still, it does not appear that there was a benefit. There was a lower mortality in the Halodol group. That's also not consistent with prior trials and really hard to attribute to the Halodol and makes me wonder really why the mortality in that group was different. But I think the one take-home for me is that there was a low rate of adverse events. And so Halodol still may be something in your toolbox that you can use for agitated delirium. I think particularly for patients who have a chondroindication or can't tolerate alternatives that have better evidence base, like dexmedetomidine. And so it's still something that I think you can consider. And perhaps we just need to think about other outcomes that we're interested in besides delirium. Perhaps it's a behavioral outcome or a safety outcome that we should be studying. And thank you very much. And hopefully we'll have some time for questions.

ICU liberation bundle

pressure support ventilation

spontaneous breathing trials

early mobilization

haloperidol