Does spinal anesthesia decrease the risk of postoperative delirium?

Welcome back to Depth of Anesthesia. This is a podcast that critically explores her clinical practices. I'm David Hao and I'm an anesthesiologist at the Massachusetts General Hospital. This episode was produced through the Depth of Anesthesia Podcast Elective that we run here at MGH for our residents. A thank you again to Dr. Shayun Johnson Akeju and Dr. Daniel Saddawi-Konefka for their ongoing support of this educational project.

Our first guest today is Dr. Sam Foxon. Sam is a graduate of the Stanford School of Medicine and he completed his undergraduate degree at Brown. Sam, welcome to the show. Thank you for having me here, Dr. Howe. I'm a big fan of the podcast and really excited to be here today.

Thanks, Sam. Our second guest today is Dr. Mark Newman. Mark is a professor of anesthesiology and critical care at the Perelman School of Medicine. He's also the founding director of the Center for Perioperative Outcomes Research and Transformation and recently gave grand rounds at MGH. Mark, welcome to the show.

Thanks so much, David. It's great to be here. We're definitely looking forward to getting some of your insights as somebody who is actively researching in this space. So thank you again for being here. We'll start with our case today, which is that of a 70-year-old woman with a history of chronic hypertension, hyperlipidemia, and osteoporosis, who is undergoing intramedullary nailing for a hip fracture sustained the previous day during a fall.

Prior to the case, the resident suggests using spinal anesthesia as opposed to general anesthesia because the patient is at risk for postoperative delirium. Sam, what is the claim in this case? So I think the claim in this case is that avoiding general anesthesia by using neuroaxial techniques such as spinal anesthesia decreases the risk of postoperative delirium. So here now are two questions for our listeners to think about. What is the level of your agreement with the claim that neuroaxial techniques such as spinal anesthesia decrease the risk of post-operative delirium compared to general anesthesia?

And what is the level of evidence for what you believe? Sam, I want to get started by just learning a little bit more about why you decided to pick this topic for your elective. So I got interested in this topic mainly from my experiences in residency uh so far. Um I've seen multiple occurrences of patients. particularly elderly patients and sometimes in the postoperative setting that have experienced delirium and it's had a a multitude of negative clinical consequences So some of those consequences would include things like extending the length of their hospitalizations, which subsequently increases them to risk of lots of different complications like nosocomial infections or other a atropinic mishaps that can h happen in the hospital.

I also remember uh during medical school when I was being taught about delirium. Uh it was stressed that it it almost represent represents like a a hit or an assault to the nervous system. Um it was really stressed to me how important it is to try and prevent delirium in the first place. So those experiences uh culminated in me finding an interest in this topic and thinking about looking into ways we can decrease the risk of our patients experiencing delirium in the postoperative setting Yeah, and I think we often hear about sort of the deliriogenic nature of some meds, um, many of which have similar mechanisms like anticholinergic effects or GABA potentiation. So Given that many of the medications given in general anesthesia work by such pathways, I think it stands to reason that some would think general anesthesia would increase the risk of delirium.

Uh before we move into examining the literature for a possible connection or uh maybe a lack thereof, uh I think it'd be wise to establish a baseline definition of post-operative delirium. So I think a good place to start understanding the term postoperative delirium is with the basic definition of delirium, which according to the Diagnostic and Statistical Manuals 5 or the DSM 5. It 's the disturbance of attention, awareness, and cognition, which develops over a short period of time, represents a change from baseline and tends to fluctuate during the course of the day. Adding the term postoperative complicates things just a little bit as different people or different studies might have different ideas of what exactly postoperative means.

And that's something we've encountered going over the studies for this show A two thousand eighteen paper in anesthesiology by Everett et al. However, gives us a a framework for what to consider the postoperative period. The title of the paper is Recommendations for the Nomenclature of Cognitive Change Associated with Anesthesia and Surgery two thousand eighteen. So what they refer to as the post-operative period is the time period that occurs in the hospital up to one week post-procedure or until discharge, whichever occurs first. So putting these pieces together, we can understand post-operative delirium. as the disturbance of attention, awareness, and cognition, which develops over a short period of time, represents a change from baseline, tends to fluctuate during the course of the day. and occurs during the time period that occurs in the hospital up to one week post procedure or until discharge, whichever occurs first.

As we'll see, some of the meta-analyses and the studies that we look at have slightly different definitions of what ex exactly postoperative delirium is, which hinders our ability just a little bit to to pull the research together to kind of come up with a cohesive picture. I do think this reiterates how important it is to actually define the outcome of interest. It sounds like there's been some heterogeneity in terms of what's been used to define post-operative delirium, but I think as a general concept, it's probably useful to just keep the DSM five description in mind. Uh a disturbance of attention, awareness, or and cognition. Which develops over a short period of time, representing a change from baseline and tending to fluctuate during the course of the day.

We'll definitely hone in on the relevant definitions as we work through the various manuscripts. So Sam, let's head into our first study, which uh examines the potential link between general anesthesia and postoperative delirium. So the first study we can talk about is by Ravi et al. from 2019 and was published in JAMA Network Open. It's titled Association of Duration of Surgery with Postoperative Delirium among patients receiving hip fracture repair So this is a retrospective population-based cohort study that uses administrative data between April 1, 2009 and March 30, 2017, at 80 hospitals in Ontario, Canada. And it examined the relationship between procedure duration, the type of anesthesia, and the occurrence of postoperative delirium It included 68,131 patients, 65 years in age and older, all receiving hip fracture surgery between 2009 and 2017.

Delirium was identified using ICD 10 codes. So the study found that among the greater than 68,000 patients with surgically managed hip fractures, 7,150 patients experienced postoperative delirium. Results showed that receiving general anesthesia was associated with a slightly higher rate of postoperative delirium compared with not receiving general anesthesia. To the general anesthesia group, eleven percent, which was two thousand nine hundred forty-three patients, uh experienced delirium versus 10.2% in the regional anesthesia group, which was 4,207 patients. This was significant with a p-value of 0.001.

One of the critiques of this study is that relying on ICD10 codes impeded the ability to differentiate post-op and pre-op delirium. There's also concern that patients with delirium may have been more likely to have gone straight to the GA group, as this was an observational study, as it might have been difficult to manage a delirious patient with regional care, and this could have biased the results. Interesting. So we have a retrospective population-based cohort study that's using administrative data of more than 68,000 patients with surgically managed hip fracture. And the authors found that increased duration of surgery and receiving a general anesthetic were associated with increased risk for postoperative delirium.

I'll say that it's also probably worthwhile to comment that even though the conclusion was that receiving a general anesthetic was associated with increased risk, that risk was 11% compared to 10.2% Mark, any other thoughts about this manuscript? This was an interesting study to read. It comes from a big research group in Canada that has, you know, a very unique uh access to health data. And so it's a very powerful database. When I read this study, and I think it's worth noting that that delirium wasn't the that that that anesthesia type wasn't the primary focus of the study was actually duration of anesthesia.

However anesthesia type was something that emerged in the analysis I thought that this was a challenging study to interpret for a couple of reasons. The difference in outcome rates was was pretty narrow between the groups. Eleven percent to ten percent is a relatively small difference, all things considered. in absolute terms. And what makes this a challenging study to look at as definitive is is all the different sources of bias that can arise. The very first one is the ICD9, the ICD-10 codes that they used.

Delirium is notoriously hard to capture in administrative data. It's not reliably coded. And it's very possible that many cases are missed. It's also possible that the cases that are least severe, the ones that are hardest to pick up, might be most likely to be missed. Patients with pre-existing cognitive disorders, those for whom delirium might be hard to diagnose, also might be at risk of being missed.

So it's entirely possible that there could be issues with capture of the delirium data, which is in some ways you know, um a concern because the rates they find are relatively low for a hip fracture population. Uh one thing that that hasn't been mentioned yet is that folks with hip fracture like the the patient in this case are are at high risk for delirium with rates being reported from the twenties to the 50s in terms of percentages postoperatively. Last thing, as Sam mentioned, there's a high possibility that in a retrospective study, you can have patients who are selected for one or another anesthesia type. based on delirium risk factors. So folks who might have cognitive dysfunction or might be agitated at baseline might be less likely to get spinals, thus artificially making the general group look worse.

So I think this is a provocative study. It was an interesting finding, but from the standpoint of clinical practice, I would view this as something that requires a lot of caution before implementing it clinically. Thanks for that, Mark. I think those are all very reasonable perspectives that we have to keep in mind as we consider the potential role of this manuscript in our clinical practice. Sam, have there been any randomized controlled trials that have explored this link any further?

Yes, there have been randomized trials. In fact, we have a 2016 Cochrane systematic review. Published by Gwaiat all, um, that includes all randomized controlled trial trials related to this topic. The title is Anesthesia for HIP fracture surgery in adults. It looks exclusively at randomized trials that compared regional versus general anesthesia for hip fracture surgery in adults and can give us some insight into postdoc delirium rates comparing general anesthesia and regional anesthesia.

So the primary outcomes of the study were mortality from any cause at thirty days, three months, six months, and one year, pneumonia, according to the author's definition in each study, and myocardial infarction Secondary outcomes, of which there were 14, included acute confusional state. So this is probably the outcome that's most relevant to us looking at this question of post-operative delirium So in all, this uh this systematic review included thirty-one studies uh and two thousand nine hundred and seventy-six participants. Regarding acute confusional state specifically, six studies were included with six hundred and twenty-four participants. The systematic review ultimately found that there is no difference in the risk of acute confusional state comparing regional anesthesia and general anesthesia.

Okay, so ultimately six studies with 624 participants with no difference in the risk of acute confusional state with a relative risk of 0.85 and a confidence interval that crosses one. Uh what about the quality of evidence? The quality of the evidence was overall assessed to be very low in the systematic review. Uh one of the reasons from this was marked heterogeneity um amongst the studies uh that were assessing acute confusional state So some of these studies went off the the DSM di uh definition, uh specifically the DSM III, some of some of them were older studies. Some of them use something called mental confusion, which wasn't really defined further Some of them use uh mini mental state exams to define post-op uh cognitive dysfunction or delirium.

Um so one of the big issues was just the heterogeneity and these outcomes and the ability to really combine them to get a cohesive picture To sum up the study, this was a systematic review of randomized trials current to March twenty fourteen that compared different methods of anesthesia uh mainly general anesthesia and regional anesthesia for hip fracture surgery and found very low quality evidence that showed no difference in the risk of acute confusional state between the different anesthesia techniques Okay, so we have a systematic review, but it's fraught with limitations. The overall quality of evidence is very low. The optimal information size was not achieved for acute confusional state, amongst other outcomes. And as Sam mentioned, the definitions of acute confusional state were very heterogeneous Mark, any thoughts for our listeners?

Yeah, I mean I think that one thing to keep in mind is that this science of understanding delirium and postoperative confusion is a pretty young science. um you know the folks who've made in some ways the biggest contribution to defining delirium and how to study it are are still you know, they're still out there working and they're and some of them are in the primes of their careers. So this is not something that we've known a lot about for a very long time. So to show a little grace to the prior trialists, you know, they were sort of doing the best with the levels of you know measurement that they could, but but ultimately many of these studies are are looking at Somewhat ad hoc definitions of delirium.

The only one in that 2016 meta-analysis that actually found a difference on its own uh for Spinal Verse General was a 2011 trial by a group led by somebody named Hedari uh um uh from Iran And their assessment of cognitive status was just to ensure that the patient was oriented to person, place, and time in the PACU at 24 hours and 48 hours So this is typical bedside check that we might do, but but is nothing that really rises to the level of a research quality screen for delirium. As a second note, I will just say, having run one of these trials that I know we'll talk about in a second, delirium is extremely hard to measure.

Even in a randomized trial. It's something that is challenging to do at scale in terms of training staff and ensuring quality control. And that's one of the reasons why we haven't had many very large studies looking at this uh in the past. So, you know, I think that the Guaymeta analysis uh provides, you know, initial reassurance that Folks undergoing general anesthesia may not be at additional risk, but for all the reasons that Sam outlined, uh it's just a beginning, what they were able to summarize. Well said, Mark.

So I think we're starting to build a picture here, but the limitations are significant. And perhaps some of this data is more hypothesis generating than perhaps practice changing. I'll note that this review included only randomized trials up to March of 2014. And Sam, I know you have another systematic review that's a bit more recent that includes both randomized and non-randomized trials. This review is titled Effect of Regional versus General Anesthesia on Postoperative Delirium in Elderly Patients Undergoing Surgery for Hip Fracture.

As a quick point of clarification, the authors of this review mention that anesthesia is broadly classified into general or regional anesthesia. regional anesthesia being the use of neuroaxial blocks that, quote, avoid the use of general anesthesia drugs and opioids which have been linked to postoperative delirium, end quote. Yes, so as as you said, we have an additional systematic review uh on this topic. It's by Patel et al. It was published in BMJ Open in 2018. Um and it includes both randomized trials and observational studies. So this systematic review ultimately included one hundred and four studies.

Uh there were seven randomized trials, there were thirty-four prospective observational studies and sixty-three Retrospective observational studies. The primary outcome for the study was post-operative delirium. Secondary outcomes included mortality, length of hospital stay, adverse events, functional outcomes, discharge location, and quality of life. There were twenty two studies included that reported on delirium. These were five RCTs, nine prospective studies, and eight retrospective studies.

Only one of these studies found a statistically significant benefit actually in favor of general anesthesia for post-operative delirium. But overall, when looking at all the studies, there is no evidence of a benefit of one type of anesthesia over another. I think this study has a lot of similar limitations to the previous systematic review we talked about, mainly that there was large heterogeneity in how postoperative delirium was defined and measured. Uh to summarize this study, this is a systematic review of randomized controlled trials and non-randomized controlled studies that investigated the impact of anesthetic technique on postoperative delirium and ultimately it found that there is no evidence to suggest that the type of anesthesia uh influences risk of post-operative delirium.

So again, no evidence to suggest superiority of one anesthetic type as it pertains to the risk of post-operative delirium. And we are challenged again by very similar limitations with respect to significant heterogeneity, both in terms of assessment time points and definition of outcomes. Many of the assessment tools across studies were poorly defined. Only seven out of twenty-two studies used either DSM IV criteria or the abbreviated mental test. And delirium was frequently not a primary outcome, but merely listed as a complication.

Only three percent of the total number of patients included for the primary outcome of delirium were from RCTs and considering the overall small sample sizes, the studies were very likely underpowered. I'll also point out that the authors specifically comment that, quote, detailed reporting of anesthetic techniques was suboptimal, especially for general anesthesia techniques. Regional anesthesia techniques were employed were more commonly reported, but the specific drugs used were not described. End quote. So lots of things to keep in mind.

This episode has been all about systematic reviews. So Sam, let's head into the last and most recent review you found on this topic. Yep, so this next study that we'll talk about is a meta-analysis that can provide some more insight into our question around post-operative delirium. It's by Zangit al. Published in 2020 in BMC Anesthesiology And it's titled Comparative Efficacy of Neuroaxial and General Anesthesia for Hip Braxa Surgery, a meta-analysis of randomized clinical trials So this meta-analysis included nine RCTs with one thousand eighty-four patients and it compared general anesthesia and neuroaxial anesthesia Uh delirium rates were reported in four of the included studies. Um in total there were 400 patients that received neuraxial anesthesia and 409 patients that received general anesthesia.

Pool data from these studies showed no significant difference in delirium rates between the two groups. Uh there's an odds ratio of one point zero five, uh no significant difference. Again, a major drawback of this study is large heterogeneity among the included studies. Um but you know we're getting a similar picture to the previous two systematic reviews that we looked at that really doesn't give a signal for any difference in post-operative delirium rates when you're comparing general anesthesia and regional anesthesia. Thanks, Sam.

Uh as you've alluded to, there's a lot of potential limitations here. Just to mention a couple There were numerous potential confounding factors such as diversity of patient groups, healthcare systems, surgical and anesthetic techniques across studies. Most of the included studies also did not describe whether additional sedation was used in hip fracture patients receiving neuraxial anesthesia. And of course we have our usual limitations in terms of inconsistent definitions of delirium But ultimately, this takes us to three out of three systematic reviews without any significant signal that suggests that anesthesia type affects the rate of post-operative delirium. But as we've alluded to repeatedly, we are limited by the low overall quality of evidence.

So let's get into one of the seminal studies in this space, which was conducted and published by our guest, Dr. Mark Newman Sam, take it away. So we're actually really fortunate to be joined by Dr. Newman, who's the first author of this study that we'll talk about. It's the regain trial. It was published in the New England Journal of Medicine in 2021 and it's titled Spinal Anesthesia or General Anesthesia for Hip Fracture Surgery in Older Adults. So this is a pragmatic, randomized superiority trial that evaluated spinal anesthesia as compared with general anesthesia.

The primary outcome was a composite of death or inability to walk approximately ten feet or three meters, independently or with a walker or cane at sixty days after randomization. Secondary outcomes included death within sixty days, new onset delirium, time to discharge, and ambulation at sixty days. So delirium was assessed as present or absent. uh on the basis of the 3D CAM21 tool. This it stands for three-minute diagnostic interview for confusion assessment method defined delirium. Measurements were conducted before randomization and once daily over each of the first three days after surgery by trained site staff.

Total of sixteen hundred patients were enrolled, seven hundred and ninety-five were assigned to receive spinal anesthesia, and eight hundred five to receive general anesthesia. New onset post-operative delirium occurred in one hundred and thirty of six hundred thirty-three patients, or twenty point five percent assigned to the spinal anesthesia group. And in one hundred twenty-four of six hundred twenty-nine patients, which is nineteen point seven percent assigned to the general anesthesia group. So there's a relative risk of one point zero four with ninety-five confidence ninety-five percent confidence intervals from zero point eight four to one point three So specifically regarding our question of postoperative delirium, this is a large multi-center randomized trial that showed no difference in post-op delirium rates between neuroaxial and germinal anesthesia.

Thanks, Sam. Before we head into a critical appraisal of the study and thinking about some of its findings, Mark, I was actually hoping to learn a bit more about what inspired you to take on this project. Absolutely. Thanks so much for the question, David. Yeah, you know, we were really and motivated to do regain based on the limitations of the work that existed up to this point.

As Sam has really has outlined really well, pretty much the evidence base around spinal versus general anesthesia and the relationship with delirium up to this point. had been either coming from relatively small trials that were typically underpowered to detect real differences in delirium. and most often used assessments for delirium that didn't really meet contemporary standards of quality or robustness. Or retrospective studies, which for the reasons we discussed could be biased either due to selection of patients or issues with outcome ascertainment, particularly when administrative data were used, when things like Discharge diagnosis codes were used. So Regain was a $12 million project that we did with funding from the Patient-Centered Outcomes Research Institute. which is a nonprofit research funding organization in Washington, D.

C. to do a randomized trial. We chose to do a randomized trial because we wanted to take away that potential. For bias from patients being selected one or another into a group based on their clinical characteristics. And we trained all of our staff across 46 hospitals around the country To assess delirium using contemporary best in class tools, we selected the 3D CAM assessment to detect delirium on the first three days after surgery. Last thing I'll mention is because many of these other trials had been done in one or at most two centers, and this goes back to the 1970s.

The data that was available to clinicians to use came from settings that might not be generalizable to where they worked. So we wanted to do a study across a large population that could be. So we aimed to enroll 1600 patients be a large enough sample for us to get some interesting data out of across 46 different hospitals in the US and Canada to show a broad spectrum capturing the type of anesthesia that hip fracture patients might get in North America. So that was the main motivation of the study. And as Sam mentioned, our findings ended up being that we found similar rates of delirium in each group, our relative risk was was pretty much one and the confidence interval was was tighter than the intervals that you've seen in some of these other meta-analyses as well.

So In many ways, we were able to provide a pretty tight estimate that showed um no real differences uh between the groups Well, I appreciate learning a bit more about the motivations behind regain. I do want to transition now to spending some time exploring some of the critiques that have been published in various editorials since publication of this trial. One of the main critiques has been the concern that patients in the spinal group of regain receive sedating medications. The concern being that if sedating medications are associated with postoperative delirium. then giving them to the spinal group would potentially affect our ability to identify a difference in post-operative delirium rates. You know, it's a great question, and it's something that people do talk a lot about.

I'll just sort of frame my answer by clarifying what our goal was. The goal in this study was to understand how spinal anesthesia, as typically used in practice, compared to general anesthesia as typically used in practice with regard to delirium. This doesn't mean that we claim or aim to study all different possible permutations of those two comparators. You could develop thousands of different ways of looking at this problem, including an anal a comparison that might involve no sedation in one arm for where they get spinal And so from that perspective, our decisions around sedation in Regain were intended to reflect current practice because Providing some sedation for patients is typical in clinical practice for hip fracture patients.

When we looked at the actual sedation regimens people got, They were pretty reflective of I think what I'd consider to be a typical sedation re uh regimen. About 30% of patients got midazolam in the spinal group at 2 milligrams median. A number of patients got a little fentanyl, and most patients got propofol. The rate at which they got propofol was roughly 30 mics per kilo per minute, which for practicing anesthesiologists out there, they'll recognize that as a you know a a a modest dose of sedation. Now for an older patient that might be a lot But at the mean, at the you know, at the average, that's not a gigantic amount of sedation, and it's typically not what we think of as being a general anesthetic level of sedation I'll point out one other thing, which is that Regain was built on prior evidence, which looked at differences in delirium. for higher versus lower sedation regimens.

One of our partners, Fritz Sieber, who's on the paper as a co-investigator, has done excellent work randomizing people to deeper versus lighter sedation regimens with spinal. And has not found consistent results of those sedation -depth choices on outcomes In spite of that data, the the question I guess, you know, one could ask is, well, would spinal with no sedation be better than some sedation, and and I would say that that's a question that's probably outside the bounds of typical practice in the US right now Is probably something that could be explored in a trial. But for us, when we were aiming to understand typical practice, it didn't really seem like a relevant question. So hypothetically, possibly, we can't rule it out, but practically speaking, in terms of the care people are delivering, I think it's somewhat beside the point.

Well, as a pragmatic trial, I think the point is well taken that the sedation regimens should be reflective of real-world practices across these sites. I was a bit surprised to hear about propofol, just considering our typical regimen at MGH in these cases is fentanyl and Versailles or Midazalam, but But either way, I think the question remains about whether avoiding all sedation with spinals decreases risk of post opera delirium compared to GA. Yeah, I mean one of the very interesting things I heard as an aside is after we did this study, I had a couple of people come and say, well, these weren't pure spinals, meaning. No sedation. And I said that's a term I've never heard before.

You know, if you look in an anesthesia textbook, there's no pure spinal method, right And I think that looking at this study, you know, of course, folks who have a prior where they seem to believe that general anesthesia is deliriogenic might look for a cause. But I think the concern about sedation here uh is is really not something that that I'm particularly worried about Uh mostly because the sedation regimens were were pretty modest that we that we saw. Um people were being pretty careful with these patients, as we'd expect for patients enrolled in a randomized trial I think that's a reasonable perspective. And fortunately, we do have another study to discuss which might shed some light on this particular question.

Alright, so the next critique concerns the incidence of preoperative delirium. Of the patients included in the trial, it looks like about 13% were diagnosed with delirium before surgery. which some feel may affect the ability to subsequently diagnose new onset delirium. I was hoping to get your perspective on this Yeah, well, we looked at it a couple of different ways. You know, one thing that we wanted to do in this study was to include as broad a group of patients as possible. Some studies that have looked at hip fracture patients before have deliberately excluded patients who have pre-existing cognitive issues.

And this is a big problem in hip fracture studies because 20% or more hip fracture patients will have some evidence of dementia or cognitive dysfunction when they arrive at the hospital. So we didn't want to exclude those patients. We wanted to give them a chance to be in the study if they or their proxy caregivers agreed to it We did assess delirium before, and that's a key thing to do to assess whether the patient was delirious before they got their anesthetic. And we did find a fraction of our patients had delirium. In the main analysis, when we looked at new delirium, those patients were not included in the denominator.

So in other words, in our main analysis where we Look to see if people developed new delirium, what we report in the New England Journal paper, that was only among people who had no delirium when they showed up. We've subsequently published another analysis focusing on persons who have dementia at baseline or other cognitive disorders. As well as people who don't, there we look at an endpoint of new or worsened delirium, which allowed us to include persons who had a diagnosis of delirium at baseline. And the outcome was whether the ones who didn't have delirium developed it. And the ones who did got worse, and we found largely the same thing.

But in the main paper, the way we handled that is we restricted it to people who did not have delirium beforehand. So I'll make sure to find and include the analysis that Mark is referencing in our show notes for our listeners to take a look at. Alright, so the next critique has two parts, the first pertaining to power calculations and the second pertaining to generalizability. A critique that's been raised uh relates to the power calculation. The concern is that the power calculation was based on a 34.2% rate of the primary outcome. which again was a composite of death and inability to walk at sixty days.

But considering the actual observed percentage, which is eighteen percent, this suggests that the study was likely underpowered especially as it pertains to secondary outcomes such as post-operative delirium. The second concern is the issue about generalizability. So even though 22,000 patients were ultimately screened, only about 1,600 enrolled because many were ineligible or declined to participate. And so the question is raised. about how generalizable these results are. What do you think?

Yeah, two great questions. One thing I will mention, and we're talking about delirium today, delirium was a secondary outcome. It wasn't our primary outcome. So in truth, Our delirium findings should be seen primarily as you know exploratory initial findings, and our hope is that that they are validated in subsequent work. I would say in terms of the power issues, you know, it's a very interesting conversation we've seen because with all respect to folks who commented on the paper.

I think it's a bit of a misunderstanding of what we use power calculations for and how to interpret power in a study that's been published A power calculation is a planning device. It's used to try and figure out how big a sample one might need to recruit under a set of assumptions to be able to say something meaningful about a difference. But once a study is done, the power calculation itself becomes something of an after-the-fact kind of thing. That's sort of no longer really the critical issue The critical issue in the study, when you have the final result, is what is the confidence interval around the primary outcome comparison or a secondary outcome comparison in this case?

The reason that's the place we want to look is that ultimately, if a study is underpowered in reality, once it's done, it'll have a large, very wide confidence interval. Whereas a more adequately powered study will have a relatively narrow confidence interval. So the real fundamental question when you're looking at a trial is not Necessarily did they achieve the assumptions they made in the first pass, but rather does the confidence interval I'm looking at exclude clinically important, meaningful differences? And I think when we look at the confidence interval for regain, we can have a couple of different perspectives on this. The relative risk is pretty close to one, so no real difference.

The lower bound of the confidence interval is 0.84, the upper bounds 1.3. So looking at that, it means that our study gives fairly good evidence that effects outside those bounds can be confidently ruled out. But within those bounds, 0.84 to 1.3, we can't say a lot. And that possibly does include some clinically meaningful differences if that's one's perspective on it. So could it be that doing a larger study to get a narrower band Could yield some useful information?

Possibly. I would say that some perspective on this though is gained by looking at these other meta-analyses. Because if you look at our confidence interval, Compared to all the other confidence intervals that have been generated around this, it's much tighter than what's existed before. So I think rather than saying the study's not powered enough, I think what we can say is the study provides, you know the tightest range of plausible estimates that we've had to date. Could we do a bigger study and find a tighter range?

Sure. I don't know if that's a worthwhile exercise given that our estimate was one. Right? So this would be a different story if we were like a relative risk of 0.8 and we had a somewhat tight conference rule that just happened to cross one. This is a pretty precisely estimated null effect.

So I think it's a matter of one's perspective, but when I look at it, I feel this is fairly convincing evidence of a null effect. And if you look at it qualitate quantitatively using Bayesian methods, for example, to quantify how strong the evidence might be here based on the sample size and what we found It's pretty convincing. There was a JAMA paper that came out recently about quantifying null effects, and Rigain was one of those And we basically fell into the middle of the pack. We were reasonably strong evidence. We weren't the absolute strongest, but we weren't on the margin Well, you've made a number of thoughtful points that I think address the question of power.

Secondary outcomes are those inherently more exploratory in nature, and we'll get into another manuscript soon where delirium is indeed the primary outcome. I'm wondering what you think about the second question uh regarding generalizability. You know, this was an industrial effort to screen and enroll the number of patients that we did. We had many patients who declined participation. In a study where we get participant informed consent, it's simply something that we can't we can't do anything about aside just from trying to recruit uh more and more patients who who might be willing.

The majority of patients who were excluded didn't meet eligibility criteria, and the largest group of those were patients who received anticoagulation. Now those patients are unlikely to be suitable for spinal anesthesia due to current guidelines. A question has been raised about whether Regain speaks to people who are getting anticoagulation and And my response to that is that that's not really in the United States as we practice today a clinically relevant question, given that those patients have a contraindication. to one of the treatments. There were other patients who were excluded based on other considerations, but anticoagulation or coagulopathy were the two most common reasons. I think that what we try to do in Regain is we try to be really rigorous in reporting our screening and enrollment process.

And this is a place in trials that actually is pretty hard to get just right. So that top box, you know, we really wanted to represent the full population. So in some ways these numbers look big because we tried so hard to report everybody who came through the door. What's really reassuring to me though is when we look at table one, it reflects what we would expect for a typical hip fracture population. The median age for hip fracture patients in the United States is 83.

We weren't quite there, but we were at about 78 years old. The split between men and women is about what we'd expect, and the distribution of comorbidities is about what we'd expect. One aside here is that we don't really have great estimates on what a population of people might look like. Who are eligible for spinal, right? But that said , in general, this looked fairly reassuring that we weren't drastically off from what we'd expect a typical population to look like.

That said, generalizing from any trial always involves something of an act of imagination, right? We're always trying to use our you know use our inference to see whether the trial result might apply outside the trial. I'm reassured by what we saw. But again, you know these are things that are in some ways matters of judgment. So one critique that I've I've seen come up in a couple of uh different editorials um relative related to the study has to do with uh crossover between groups.

Um so for example In the the group that was assigned to receive spinal anesthesia, looks like about fifteen percent of them ultimately received general anesthesia There's some concern that this high amount of crossover could confuse some of the statistical analysis in the study. So just curious to get your thoughts about um that crossover and what that ultimately means when interpreting the results of the study. Thank you for that question. It's a great question. And it's true.

We we worked very, very hard to keep our crossover rate down. But this is one of the trade-offs we dealt with in that again we wanted to have a big group of hospitals who could participate. That meant we worked with lots of different places and we tried to take as many patients as we could. We we discouraged you know cherry picking for just the perfect candidates because we wanted this to reflect real practice. The consequence of that though was that for certain patients we were unable to get spinals or the patient may have changed their mind. on the way to the operating room or after being positioned.

Or a clinical status change occurred. We had patients where they had acute events that prevented them From getting spinal anesthesia. And all of these things are part of real practice. One of the really interesting things is even prior to regaining, we didn't even know uh what a crossover rate might look like because people just don't report this stuff. So one of the really interesting things is that a side benefit of regain is for the very first time We have an inkling of how often people have to change their plans, which again we we never really knew in a systematic way before.

The consequence of crossovers is that it has potential to decrease study power, and that's the reason that we worked very hard to keep people in their groups. Um what I will say is that the 15% rate, I thought Again, for the spinal group, I had wished it had been lower, but given the size and complexity of our trial, I think we did a good job. The closest comparator I have is a single center study in the UK, which is one of the few I could find that reported their rates They were at about 8% of crossovers in one center with treatments delivered pretty much by one anesthesiologist. Well, we were at 46 centers across the whole country. and we kept it to 15.

So I think that's a pretty excellent result. In terms of the actual data, And what it means for our findings, what we did was what you call a per -protocol analysis that tried to model how the data would have looked if everybody had gotten the treatments that they were initially assigned. And again, while that's mostly sort of a thought experiment that we go through and it's a model that we can look at to gauge what the bias might have been from this, the results were extremely reassuring in that the the findings were were no different for the primary outcome. Um and based on, you know, how this adjustment works. we can be pretty sure that the delirium result would have would have had the same uh the same kind of showing in our per protocol analysis.

So again, you know, could somebody do another study aim to get a similar sample size with a tighter Adherence rate? Possibly. I think that's a mountain that has not yet been summited. And hopefully someday somebody tries. But for now, I'm reassured by what we found.

Well Mark, thank you for entertaining all the critiques that Sam and I had for you. The trial itself is clearly an impressive undertaking. I do think our listeners will greatly benefit from learning about how it was conducted. and from your perspectives on the results and its limitations. Sam, I know several of the editorials uh we have been disperipherally discussing mentioned the Raga Delirium trial. This was published in early 2020 in JAMA, and I think it's an interesting study because it actually looks at postoperative delirium as a primary outcome.

What can you tell us about this study? So the Raga study is by Lee et al. It was published in 2022 in JAMA and it was titled The Effect of Regional versus General Anesthesia on Incidents of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery. the RAGA randomized trial. So this trial had 950 patients aged sixty-five years and older with or without preexisting dementia and they had a fragility fracture that required surgical repair Patients were taken from nine university teaching hospitals in southeastern China. These patients were randomized to receive either regional anesthesia, so this could be spinal, epidural, or both techniques combined. um without any sedation. So this was 476 patients, or they were to receive general anesthesia.

This could be intravenous, inhalational, or both. And this was 474 patients. The primary outcome was the incidence of delirium during the first seven postoperative days. Delirium was assessed using the confusion assessment method. This was assessed daily by blinded observers, and it was combined with nursing and medical notes from the preceding 24 hours to diagnose delirium.

Okay, so we finally have our study looking at the fabled pure neuroxial, no sedation whatsoever, and we have a primary outcome that is delirium within the first seven post-op days using the CAM or confusion. assessment method. We also have a couple secondary outcomes including severity and subtypes of delirium that were based on the delirium rating scale. For both groups, the study protocol actually highly recommended application of a single injection or continuous infusion of a peripheral nerve block technique, things like fascia iliaca blocks. And benzodiazepines and ketamine were completely prohibited as they were, quote, medications known to impair cognitive function. All right, Sam, what were the results?

Postoperative delirium ultimately recur uh occurred in 29 patients in the regional group, so this is 6.2%, compared to 24 patients in the general group, so this is 5.1%. There's an unadjusted relative risk of delirium of 1.2 with a 95% confidence interval of 0.7 to 2 with a P of 0.57. So essentially showing uh no significant differences uh between the two groups. Well, this study certainly has its strengths. Uh it is the largest study to date that looks at regional anesthetics without sedation for hip fracture surgery.

There are relatively broad inclusion criteria that include preoperative dementia and delirium. So this manuscript seems to be the answer for some of the questions that we thought regained might not be able to answer directly. Mark, I am curious what you think about this. You know, I think it's uh it's an important study. It's a hard study to interpret.

This is something that we knew was going on alongside Regain. We had contact with some of their investigators along the way and shared some lessons learned from our side and heard about their experience. I think this would be a study that'd be pretty hard to pull off in the United States. It would be difficult for me to envision consenting my patients to a regimen where they wouldn't be allowed to get sedation for spinal anesthesia. And the experience of the listeners may may differ from that.

I'm not certain. But But I know when we consented folks for regain and and and often in clinical practice being able to receive some sedation for comfort was an important part of their willingness to get spinal. The other thing that I would mention that I think makes this study a little tricky to interpret is the delirium rate they found. We talked about differences in outcome rates from what folks plan you know our delirium rate was around 20 percent and and we found that to be you know within reason but but frankly a little lower than we'd expected For this study to find something in the 5 to 6% range, that's a pretty low rate of delirium, particularly for a hip fracture population.

As I mentioned, typical delirium rates for hip fracture patients are in the 30 to 50 range when we look at all comers. And granted, the folks who are eligible for spinal anesthesia might be a little different, but 5 to 6% is a pretty low rate So I think we're still figuring out how to interpret this study. I think one could take this as corroborative evidence of regain. uh indicating perhaps that a regimen without sedation uh does not uh offer the types of advantages that people might you know theorize. But I think this is another good example of a place where you know additional studies to corroborate and extend the findings, you know, particularly across different kinds of populations or countries could really be very helpful.

I'd add a note to say that, you know, uh uh an additional need would be to Look at this type of thing among people who might be at highest risk. For example, people with dementia. You know, that's something that neither Ragain nor Raga set out to do primarily. We did some work on it in a secondary analysis, but I still think that there's opportunities to learn more about how to best take care of those patients in the operating room. Mark Wellput, this study was conducted with the majority of participants recruited from a single hospital in China, so it's certainly challenging to generalize to the broader US population.

But it's definitely a valuable addition to the ongoing uh literature in this space. We've covered a significant amount of literature today on this topic. The podcast is coming up to almost an hour. And considering the recent randomized controlled trials and the number of systematic reviews on this topic, I think it's fair to say that this is of great value and interest to our specialty. Sam, could you summarize some of your key takeaways?

So my main takeaways uh from studying this topic is that you know there seems to be a good deal of scholarship on this topic of Uh looking at the risk of post-operative delirium with general anesthesia compared to other anesthetic techniques, uh particularly recently with both the regain and raga randomized trials being conducted in the last few years. Prior to researching this topic, I I would definitely thought that genital anesthesia would increase the risk of postoperative delirium, just given that many of the medications uh using genital anesthesia have mechanisms that you might think might increase the risk of delirium. My main takeaway from multiple systematic reviews and large randomized trials that we've looked at today is that we really don't see a signal that indicates that general anesthesia increases the risk of postoperative delirium relative to regional anesthesia.

One important thing to keep in mind though is that most of the studies on this topic are conducted in older adults that were undergoing hip fracture surgery. So it's difficult to know how generalizable this research might be to other populations or other types of surgeries. Ultimately, I think the decision to use general anesthesia or regional anesthesia has to be made in the appropriate clinical context and setting and has to take into account all the different patient factors. Thanks for that, Sam. Here again are two questions from the top of our show for our listeners to think about.

What is your level of agreement with the claim that neuroaxial techniques such as spinal anesthesia decrease the risk of post-operative delirium compared to general anesthesia. And what is the level of evidence for what you believe? Any closing thoughts, Mark? Yeah, you know, um I'm really happy to be able to be part of the conversation and and you know it means so much to me to have this work discussed in a forum like this. I think the main takeaway that that I hope people will hear is that is is maybe a little bit less about the clinical decision and a little more about the science and what's possible in our field.

You know, in anesthesia we don't have a very robust tradition of doing uh big randomized studies. Uh but what I've What I believed in going into regain and and what I continue to believe having completed it is that there's really no other approach that that gives us the kind of powerful evidence we can get from a randomized trial when it's possible to do one. What I hope is that perhaps not all of your listeners, but at least a few of them out there, think a little more when they look at a study like Rudan about what they might be able to accomplish in their own careers. terms of things they want to build or do, especially if they're interested in doing research, uh, because we certainly need more of it So I hope folks take this away, take away maybe a dose, a little bit of inspiration from this, because I really think that it's all about what comes next for the specialty and what we can start building in the future.

I really appreciate those thoughts. We're always talking about evidence on the show, and it's a real treat to have a guest on who's undertaking a project to generate high-quality evidence in a space where it's certainly needed. It's been wonderful to be able to pick your brain about the process of running a trial and to ask some clarifying questions about uh limitations about regain in particular. So Thank you again for taking the time to join us here on the podcast and for sharing your insights with our listeners. Oh, it was an absolute pleasure and uh thanks for the opportunity.

To our listeners, thank you for taking the time to join us today. This was a long episode, so I appreciate all of you who tuned in for the entire show. If you enjoy our work here, please leave us a rating and a review on Apple Podcasts or Spotify. Again, my sincere appreciation to the MGH Anesthesia Department for the support of the Depth of Anesthesia Podcast Selective. We've had a productive year, including two recent publications that were inspired by work conducted on this podcast elective.

In other news, I've also had several listeners reach out to me about show notes. As it stands, I can use an automated service generate a transcript, but it's a bit of a jumble and a lot of the author names are probably going to be transcribed incorrectly. So If there's someone out there who wants to help me clean it up, please reach out to me at depth of anesthesia at gmail. com. Thanks again for tuning in. Stay hungry and keep asking questions.