Good morning everyone. Glad to be here in rainy Phoenix. I've been to Phoenix twice in the last 15 years. I think the previous time it was 31 degrees. It was the coldest in decades. So I'm, that's pretty much me. But I am glad to be here in talking to all of you. So just a brief outline. Pat's already given a timeline so I'm gonna move through that fairly quickly. And my my goal was to focus on a decade of literature. But if you'll bear with me I'm gonna extend back about 25 years and we're gonna move quickly. Because I want to show what led to to the 2002 sedation analgesia guidelines. And then you know more importantly to the first decade of literature leading up to the 2013 PAD guidelines. And then I'll talk about some of the major investigations that have been published since since 2018. And then Pat has already highlighted some of the outcome data. I'll go into that in a little bit more detail. This is just you know another sort of sense of the timeline. You can see there was you know really about 25 years ago we started have a sense of ICU acquired weakness and brain dysfunction in critically ill patients. And then that led to some early 2000s focus on delirium screening tools. And then the initial sedation analgesia guidelines which I remember as a resident and fellow. And that's really what we had at the time. What what we based our practice on. And then there was a really active 10 to 15 years various really important randomized control trials that led to the to the PAD guidelines. And then and then onward. And Pat's covered a lot of that. So I won't spend too much time on this. But this is where we started. Certainly what I remember at the beginning of my training. And as I mentioned there was a recognition of the of the harms that we were doing. And certainly patients who were developing weakness and patients who were suffering the consequences of some of our standard practice. And one of the standard practice that I certainly remember as a resident and a fellow was was deep sedation. This is very common at least at the time. Although it's interesting if you go back and look there's some interesting editorials on ICU practices decades before this. And we've definitely gone through different phases where there have been times where there's been less of a focus on sedation and there there are some veteran intensivists who comment on in the 80s actually where there was a focus on turning down sedation. And then we somehow or another at the time in my training we got to a point where everybody was deeply sedated until we came to this recognition that you had all these harms when when patients were deeply sedated all the time. So one of the first trials that I'll just highlight quickly was Cresson colleagues and the New England Journal in 2000 which looked at daily sedation interruption. We've all called it different things. We call it a sedation wake up UCSF but showed that a daily sedation interruption decreased the duration of mechanical ventilation pretty substantially by by about two and a half days as well as decreased ICU length of stay. And this also was an important safety trial. It showed that this practice didn't cause increasing PTSD didn't cause cardiac ischemia. And so in the total incidence of agitated related complications mainly self-excavation was was manageable I would say. And so this was an important safety trial as well. And then the ABC trial and this had a huge impact on on many of our practices certainly in our practice at UCSF. And this really looked at the importance of coordinated care. And I would say in some respects I highlight this trial in part because it was my early recognition and we didn't know it at the time and I didn't call it interprofessional care at the time but it was my sort of early recognition of the importance of interprofessional care in the ICU because it really to do this to pair a sedation interruption of some type with a spontaneous breathing trial you had to coordinate the entire team the provider team the bedside nurses the respiratory therapists all the pharmacists everybody had to get coordinated. And this trial showed really a remarkable one-year mortality benefit as well as benefits in length of stay and in number of ventilator free days. So you can see we're developing momentum here this is building this is post 2000 2000 through 2010. And many of you will recall the men's trial which looked at dexmedetomidine and compared it to a standard practice and the use of a benzodiazepine drip and show that dexmedetomidine was essentially effective more more days alive without delirium or coma a lower overall prevalence of coma and more time within sedation goals as well as also a good safety profile with dexmedetomidine. So another important trial that was guiding our practice. Pat mentioned Bill Schweikert and his colleagues and the work they did in Lancet. So now we're adding on to another piece of the bundle and looking at the impact of early mobility efforts. This is a an important trial in mechanically ventilated patients that showed the benefits of early mobilization 1.5 days after mechanical ventilation versus about 7.4 days in the control group and showed you know you know decreased ICU length of stay and better functional status at hospital discharge. So a very important trial also I would say for many of us in the ICU's really impacted practice and continues to impact practice. So this brings us up to 2013 and now this is where I'm supposed to begin my my decade review. So thanks for bearing with me on the 25 year review. But you know this is a very important guideline and certainly something that had a lot of impact on on practice really across the world. The trials that I've already reviewed really the foundation were some of the most important foundations of that of that guideline. But then you know we've what's happened in the decades since so continued to be focused on on mobilization. I'm going to go over a few early mobility trials. This was one of the first trials perhaps the first trial and looking at surgical patients in surgical ICU's basically looked at a protocol again an interprofessional approach to early mobilization. And show to reduce ICU length of stay in similar to the Schweiker trial also showed improved functional status at hospital discharge. So I think if you were an advocate for early mobility and certainly at UCSF we had many advocates we had built up a team we had a growing group of physical therapists. We were all feeling pretty good about this. But a little bit of a pause here. And this is a single trial I'll acknowledge a single center trial that looked at 300 patients with acute respiratory failure requiring mechanical ventilation in this trial with a standardized real rehabilitation protocol did not show any difference in the primary outcome of length of stay. There were some better longer term functional outcomes at six months. But interestingly unlike Schweiker and some other trials didn't show improved functional outcomes at hospital discharge. So certainly something to consider and something that has been considered ongoing. I will say this trial did not have a clear sedation protocol and that may have had an impact on the intervention. Jumping over to another part of the bundle Pat mentioned earlier the Gordon Betty Moore Foundation. This is certainly fundamental to what we were doing with the ICU liberation collaborative and really trying to understand the importance of family engagement and empowerment in the ICU. And this is when we see in 2017 the first SECM guidelines focused on family centered care across ICUs across the age spectrum. So I mean this was really at the time this was published very very much a nascent field of research and I think still there's a lot of work to be done in this area. But I think this at least really focused our attention on the importance of family family presence and family involvement in the care of ICU patients. So again I mean we've talked about early mobility. We've talked about sedation practices. We're sort of building and we're still I think for many of us who are practicing certainly when I was practicing at the time there's still an ongoing focus on are there any pharmacologic interventions that are going to have value particularly in the treatment of delirium and dexmedetomidine at this time and continues to be a drug of great interest and of great use. And this is an interesting trial from 2018 that Janice Grover and her group looked at nocturnal dexmedetomidine. And I'm sure many of you have seen various uses of dexmedetomidine. Certainly at this point we were starting to use some nocturnal dex. Partly it was driven by patient behavior at night. It wasn't necessarily protocolized but this was a protocolized approach that looked at low to moderate dose dexmedetomidine delivered overnight in a protocolized format and showed that there was a greater proportion of patients who remained delirium free. So an interesting study. I brought this up on rounds a couple times. I got very stern looks from the pharmacists in our group but I thought it was an interesting study and continues to be an interesting study. It also did not show any significant adverse events in the treatment group. And then speaking of treatment for delirium, this is I think many of you are aware, a number of trials the REDUCE trial as well as the HOPE ICU trial looking to see whether antipsychotics had any role. And I mean for me and I imagine for many of you this became sort of the standard format in ICU rounds where I would describe all the negative trials of the use of antipsychotics in the ICU and then we would acknowledge all the patients who are getting antipsychotics in the ICU. And the challenge is, one of the challenges we face and you know I think this is interesting to compare these trials and if you compare sort of the use of catepin in the ICU and what led to that. And what I recall led to that was a small pilot study that John Devlin and his group did. And John I think it's very, I've heard John talk about this, it was very much a pilot study. But a very small pilot study led to widespread use of catepin, certainly in our ICUs and I imagine many ICUs and you balance that against many large randomized control trials, multi-center trials that didn't show any benefit. Yet I think we probably all see a fair amount of catepin use in the ICUs. So negative trials in this regard and then I'll, that brings us up to 2018 and as Pat mentioned now we have the inclusion of mobility and sleep and the guidelines which is certainly an important development. But I will say I mean if you look at you know carefully at these guidelines and there are many questions asked and answered in these guidelines, we all still struggle. I mean what's particularly on the issue of sleep, what's the best approach to sleep? And I think I will say we have wrestled with you know do we develop a protocol for sleep that acknowledges the use of pharmacologic interventions or do we sort of stay wedded to a non pharmacologic approach to sleep? I'd say in my institution we felt like we had to provide some guidance around this because people were using meds for sleep all the time. But the literature certainly is not particularly strong in this area. So what's happened since then? So in the five, six years since then we continue to have more trials on delirium. The MindUSA trial again looked at the use of antipsychotics, both haloperidol and an atypical insoprazidone. A large trial of patients with acute respiratory failure or shock and delirium, although I'll note that 89 percent of these patients had hypoactive delirium. And so they compared haloperidol and insoprazidone and placebo. Did not show any difference in the primary outcome of days alive without delirium or coma. One critique of this trial, I think legitimate critique, was you know is the treatment of hypoactive delirium, which is basically this study group common practice, is the treatment of hypoactive delirium with antipsychotics, atypical antipsychotics in particular, is this common practice. And I would say for many people the answer is probably no. More focused on hyperactive delirium. Another in the same in the same area, another trial looking at pharmacologic interventions for delirium, the 8-ICU trial published just over a year ago. A large randomized control trial that shows that treatment of delirium with haloperidol did not increase the number of days alive and out of hospital at 90 days when compared to placebo. There was some suggestion of a mortality benefit, but I think you need to be cautious of the interpretation. There's a lot of data dropout that may have may have biased the results. I will say it did show a good safety profile. They were given 2.5 milligram IV doses of haloperidol, up to 20 milligrams a day. I believe the average dose was about 8 to 9 milligrams a day for about three and a half days. So how do you make use of this in practice? I think for us we focused on the fact that there wasn't clear benefit. On the other hand, the safety profile was good and certainly for hyperactive delirium I still think it's an option. Although I think you just need to recognize that you are not necessarily treating the duration of delirium, but you may be making things safer for a short period of time. And then shifting over to sedation and some additional trials, again dexmedetomidine is a focus of study in the SPICE III trial that looked at early dexmedetomidine versus usual care within 12 hours of mechanical ventilation. This trial did not show any difference in the primary outcome of rate of death at 90 days. Also important to note there was frequent use of supplemental propofol in the dexmedetomidine group and there were also more adverse events in the dexmedetomidine group. So I think like many trials that look at usual care as you know similar to sepsis trials that look at usual care you see is over time usual care changes. And so I think we see that usual care is different now than it was 20 years ago and that may reflect the absence of difference in this trial. This is an interesting trial. Certainly we've talked about this sort of in the ICU liberation group a lot of times about institutions that practice or try to practice a no sedation approach. And there are certainly institutions that have have made an effort to do this. This was a non-blinded multi-center trial over 700 patients that looked at no sedation versus light sedation and SAT did not show any difference in mortality. I think some important caveats to notice about this trial there were a lot of declination so a lot of people refused to be a part of this trial. I mean that's it was a big part of this or a lot of refusal of consent in older population and also the oxygenation threshold for exclusion was quite low. So they allowed patients to be in this trial that I think many intensives would have said I'm just not comfortable with that. The ratio is way too low. I'm not comfortable. We're not going to include it or synchrony reasons. I'm going to keep this patient on sedation and not allow them to be included. So and also a very high crossover rate for sedation early in this in this trial. To me I mean this came up a lot for us on rounds where I'd have residents and fellows who'd you know go visit another institution or hear another institution that you didn't use a sedation approach and would ask if we could try this and and when this trial came out it certainly was a I think it introduced some caution to the no sedation approach but but certainly a worthwhile trial to consider. And then men's too. Follow-up to men's. We had men's too. We're looking at dexmedetomin dexmedetomidine or propofol did not show any difference in days alive without delirium or coma during the 14-day intervention period and no difference in secondary outcomes. So basically I think showed that both have a role. Both have it's worth noting though that the doses of both medications were relatively low and a fairly high rate of the use of rescue meds in this trial. And then the last trial that I'll just highlight for right now before I move on quickly to outcomes would be the team study. And this this is a trial on the mobility we've talked about and I'm very interested to hear Chris's thoughts on this. This is a randomized control trial 750 patients which compared early active mobilization versus usual care and didn't show any difference in the primary outcome of days alive and out of hospital in 180 days. So what to do with this trial and we can talk about some of this in the question and answer but I do think it's it's interesting it raises the question of what what has happened with usual care. And and if you look at the difference in actual therapy I think was about a 12 minute difference between the the intervention and control group. So certainly the gap is shrinking between a protocolized intervention and what would be usual care similar to what we've seen in in sepsis trials as well. So just very briefly and outcomes I'll just move through this quickly just in the interest of time since Pat's already covered some of this. This was Barnes daily and colleagues study published in 2016 that looked at seven California community hospitals and in bundle implementation and basically just showed that in this prospective cohort quality improvement initiative for every 10 percent increase in bundle compliance whether it was total bundle compliance or partial bundle compliance we saw an improvement in hospital survival more days without delirium and coma. And then this was carried forward. We we those of us involved with the ICU liberation collaborative and Pat mentioned the 68 hospitals 68 hospitals today. My number is correct. And in the work that we did in this collaborative and then this was the study of over 15000 patients involved in in that work and in this show that complete boner performance was associated with with a lower likelihood of of all of these outcomes. I won't read them all but but again showing the benefits of of the A3F bundle and the impact and then just more recently I want to highlight Julia Barr's study that she did with her colleagues that was that was just published a multi center study of 11 adult ICUs at six community hospitals that again showed the value of bundle implementation on a number of different outcomes here and ICU length of stay hospital like to stay. And so I think this is what we're seeing is just these are challenging trials and certainly when we're doing a large quality improvement trials they are vulnerable to criticism. I mean this is and we've all heard the critiques but I think as you see you know study after study demonstrating that that bundle implementation really does have an impact on patient outcomes. I think it's important to highlight these studies. And the one thing that I will mention and I think I'm just going to really I think narrate many of our own experience here is certainly the impact of COVID-19 and in the A3F bundle. I think many of us who who worked in the ICU during that time before I was in my current position I was the director of critical care at UCSF. So I spent a lot of time working with all of our colleagues trying to wrestle with this. What do we do with with the A3F bundle when families aren't allowed to be at the bedside when we're changing our sedation practices because we're out of option because we've been on the vent with a patient for days and days and the triglycerides are 800 and we're back on benzos and the patient's into pressure shock. And I think many of us struggle with this. Certainly both this two day point prevalence study as well as some some survey data suggests that there was certainly reduced compliance and I think that probably matches with everybody's experience. So part of the question is in one of the questions we have at the SCCM is how do we move on from that. So how do we how do we not slide. How do you re-engage your team. And we certainly saw that. I mean it's interesting in getting feedback from various people at the bedside. I think people recognize the need to get back towards bundle compliance but there was also there were some ways in which some parts were easier. You know we used to have 24 hour a day visitation or ICU and then that narrowed down getting back to 24 hours. I mean I had to remind people that prior to the pandemic we were doing 24 hour a day family visitation because in some respects it was just easier. Not always but sometimes it was. And so that was something for instance that we had to wrestle with and still do wrestle with. So my last my last comment here I just want to acknowledge I am co-chairing the the focused PADIS update. Our target is next year at Congress. This is going to be a more narrowed focused update than than previous but certainly we have a lot to consider. We have a terrific a terrific group and various subcommittees looking at various questions related to the 2018 PADIS and then moving forward to the much more focused update. So I think we all look forward to to that in over the next year and I just want to thank everybody. You know there's obviously I've reviewed a lot of trials. There's a huge amount of work that goes into all of these. I mean everybody from the clinical research coordinators to all of the the clinical trialists who have done important work many of whom are here this these last few days. So thank you to all of them and thanks to all of you for your for your attention.

ICU sedation

PAD guidelines

dexmedetomidine

early mobility

ICU Liberation Collaborative

COVID-19 impact