Does BIS monitoring reduce accidental awareness during general anesthesia?

Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical practices. I'm David Hao and I'm now a fellow across town at Brigham and Women's Hospital. It's certainly been a while, and it turns out the fellowship can be even more tiring the residency. But I'm really glad to be back for the new year with our new episode.

A lot of things have happened in the last six months, but one of the most exciting developments is that we've actually created a podcast elective at Mass General. Residents will have the opportunity to dig deep into a dogma and work alongside our team to create an episode. We've already had three residents complete the elective and we're looking forward to starting recording the first episode in the coming months. Today, I'm excited to reintroduce our listeners to Dr. Ashwini Joshi. She joined us for our last episode back in, I think, May or June on the perioperative management of buprenorphine.

She's a current anesthesia resident now at MGH, and she helped a lot with researching and writing this episode. Dr. Joshi, welcome back. Thank you so much for the introduction, David. I'm excited to be back. I learned so much writing this episode, and I'm very excited to share what we found with our listeners.

Thank you, Dr. Joshi. It's been my pleasure to have you on the team. Our guest today is Dr. Brian Glezerson. Dr. Glezerson is a neuroanesthesiologist currently in Montreal, Canada. He completed his residency in anesthesiology at the University of Ottawa, followed by a Neurosurgical Anesthesiology Fellowship here at MGH and Brigham and Women's Hospital, as well as a diagnostic EEG Fellowship at the Toronto Western Hospital.

His Twitter handle is at Brian Glezerson. Dr. Glezerson, welcome to the show. Thanks so much, David, for having me on the show. I feel uh quite honored and uh really excited actually to finally contribute to the show after having been a devoted listener since really the very beginning. Well, I'm grateful for your support and I remember this was one of the things we first connected on when you were here for fellowship.

So I'm super excited you're here today. Now before we get started, I just want to say that I think the literature in this space is actually incredibly fruitful. There's really a natural progression to each study that really builds on the deficiencies of prior studies and I personally came away with the feeling that I had a pretty solid grasp of how I would shape my clinical practice thoughtfully through the evidence that we're about to review today. I agree with that entirely, actually. I think that this was uh this is a topic which we'll discover is of huge importance to anesthesiologists and to patients, gained importantly, a significant amount of kind of media presence and and popular awareness for lack of better term.

And I think that that has helped enormously in the crafting and curating of a reasonable evidence base Absolutely. And so we'll get started with our case today, which is that of a 42-year-old woman who's presenting for a laparoscopic cholesteromy. After induction of general anesthesia and endotracheal intubation, the anesthesia resident applies a BIS monitor to the patient's forehead. The attending observes this and asks what the bismonitor is for. The resident responds that the patient had actually mentioned concerns about waking up under anesthesia and that the BIS monitor would help ensure that the patient was asleep.

Well David, there are certainly a number of themes that are worthy of discussion. But I think the central claim in this case is that the use of the bismonitor is an effective means to prevent accidental awareness under general anesthesia. And importantly, accidental awareness with recall under general anesthesia, which is what the patient actually uh was expressing concerns about At a more fundamental level, the other claim is that the bis itself, that is to say the bispectral index, scales in a one-to-one fashion with a patient's arousal state. But this may be a bit out of the scope of this episode, perhaps So here now are two questions for our listeners to think about. What is your level of agreement with the claim that bis monitoring reduces awareness with recall under general anesthesia?

And what is the level of evidence for what you believe? Well, let's start with the idea of awareness under general anesthesia with recall. How do we define this? Well it's a it's quite a deviously simple question actually, isn't it? In fact, I think it's such a simple question that it's actually worthy of some explicit attention.

To define anesthetic awareness, I'd like to highlight a really incredible study called the NAP V. The Knapp V was the fifth in a series of national audit projects organized by the Royal College of Anesthetists Which set out to understand broadly the epidemiology, natural history, and risk factors for what they called accidental awareness under GA, or accidental awareness under general anesthesia. It's the largest study of the topic ever conducted by some orders of magnitude. Crudely, all new patient reports have accidental awareness under GA, which I'll call AAGA. were systematically reported from all UK NHS hospitals and separately in Ireland to a central secure online database over one year from 2012 to 2013. The database collected detailed information about the event, the anesthetic, the surgical techniques, and any sequelae.

The reports were then rigorously peer-reviewed and categorized into levels of certainty or specific clinical circumstances, and they categorized them as such: certain or probable anesthetic awareness which they called class A, possible accidental awareness under GA, which was class B, accidental awareness that occurred during sedation, which they called uh class C Accidental awareness under general anesthesia, which occurred in the setting of critical care, which was Class D. Class E was what they called unaccessible. Class F was unlikely. Class G was a specific class uh related to drug errors and a class which they called SO, which stands for statement only, meaning that a patient's statement describing accidental awareness under general anesthesia was submitted. But there were no case notes available to verify, refute, or examine that claim further, often because the case was historical.

And you mentioned that all new reports of AAGA were systematically reported. What were the criteria for an event to be reportable and entered into this online database? So this was indeed quite rigorous. So to be reportable, a report of AAGA had to satisfy two criteria. The first criterion was that it had to be a situation where the patient made a statement that they had been aware for a period of time when they expected to be unconscious.

Thus, a complaint of pain or anxiety alone was not admissible, nor was a desire to have been less conscious, that is to say, to speak of consciousness in any other way but binary during a procedure. The second criterion was that it had to be a report that related to a specific surgical or medical intervention in which anesthetic care was provided. I see. And I imagine the category we're most interested in in is class A, which means certain or probable AAGA. And this is basically a report of AAGA in a surgical setting in which the detail of the patient's story was judged consistent with AAGA, especially where supported by case notes where where report details were verified independently.

A class A report would obviously be an incredibly traumatizing experience for any patient. Dr. Glaserson, what's our current understanding of the incidence of accidental awareness with recall under general anesthesia? Well, I certainly echo that sentiment, David. I think that the successful achievement of unconsciousness during surgery is kind of a central tenant of our specialty and in the observation or the expectations of the public, that's the point, right? The point is to make surgery something that used to be barbaric, not barbaric And so it's entirely understandable that for it to actually happen to you, for you to actually be aware and recall that awareness under uh a situation where you hadn't ought to be.

It's completely reasonable to think that that would be an awful experience for a patient, and even to think about it as just shocking. So to answer your question The incidence of AAGA varies widely in literature based on the methodology used to assess awareness and the patient population studied. So we see figures that range somewhere between one to two in a thousand, all the way to one in twenty-three thousand or sometimes higher. Methodologically, these studies differ tremendously, including amongst them case series, data registries, prospective observational cohort studies, and randomized controlled trials. Well, as you alluded to already, I can imagine there'd be plenty of challenges with attempting to characterize the true incidents of an event like this.

Indeed. There are many, many challenges in reconciling these publications, but one noteworthy difficulty in defining an incidence is that some studies actively screen patients, while others require patients to submit their own report. And in those that screen, the frequency and repetition of screening, as well as the screening instrument use, will differ enormously It appears that in general, having patients report their own complications is associated with a significantly lower incidence, for example, one in 25,000 in the NAP5. than in studies that prospectively screen patients with questionnaires where the incidence is closer to 0.1% or 1 in 1,000. You had mentioned earlier that preventing accidental awareness seems like a fundamental obligation for us. It seems like that sentiment has certainly been shared by others.

Absolutely. You you don't actually have to look back that far. To see that this idea of failure to achieve our primary goal was felt in earnest by our colleagues in yesteryear. So for instance, if you look in 1960 Hutchinson et al. published the first prospective observational study of what we would now call accidental awareness under general anesthesia. And I'll just read a quotation from that paper because I think it's quite poignant.

In that article he writes, every possible effort must be made to ensure complete and continuous unconsciousness during general anesthesia, not only because of the moral obligation of the anaesthetist to provide freedom from physical and mental suffering , but also because of the disproportionate anxiety which knowledge of such a case may induce in other patients. The feeling of responsibility that we have to ensure this does not happen And the idea that this could be of great concern both to the patient who experiences it as well as to patients as a group at large was felt seriously as early as the 1960s and is no different today as it was then. I completely agree. So I think now that we've really established a better understanding of intraoperative awareness, let's move on to talk about the BIS monitor itself.

This is not actually a technology that we use at Mass General. And it was only after I came to Brigham that I saw people more routinely use it. Dr. Glezerson said, what can you tell us about this monitor and what it's designed for? So the BIS monitor is a device that measures electrical activity in the brain, specifically from the frontal parts of the brain. and turns this electroencephalographic data into what they call the bispectral index, which is a single dimensionless index based on a proprietary algorithm. The range of values for the bis theoretically are zero to a hundred.

A hundred is said to be uh you and I having this conversation, and zero would be, I suppose, a rock. But essentially a number lower than 60 is thought to indicate that a patient does not have awareness. The typical goal for BIS monitoring in the operating room and the intensive care unit is to achieve a BIS value of 40 to 60. By targeting a bis number in that range, in addition to other clinical monitoring, we're able to titrate the level of sedation. Importantly, however, I think it's worthwhile Considering that in general, the BIS monitor falls into a category of monitors called depth of anesthesia or depth of awareness Monitors that are all fundamentally based on the principles of electroencephalography and electromyography And Dr. Joshi, I know you've actually done some research looking into not only the history, but the modern day marketing of the BIS monitor in preparation for this episode.

What can you tell us about your findings? Yeah, so the BIS monitor has actually at this point been around for about 25 years. In 1996, the Bispectral Index, or BIS Monitor, which was initially distributed by Aspect Medical Systems based out of Massachusetts. Massachusetts, now made by Covidian based out of Colorado, received approval from the Food and Drug Administration or FDA in the United States as a monitor with the potential to decrease the incidence of intraoperative awareness. And in fact, if you open up the product guide on the Medtronic website, which I hadn't done until writing this episode, you'll see that There's a PDF that has a number of claims about the value of this BIS monitor.

And the claim most pertinent to us is the statement that Studies show that this technology guided anesthesia reduces awareness with recall by 64%. And in particular, it cites two articles to support this. The first study that this PDF cites is by Miles et al. called Bispectral Index Monitoring to Prevent Awareness During Anesthesia, the B Oware Randomized Control Trial. And that was published in the LANSA in 2004. And the second article that this PDF cites is by Ekman et al. And this article is called Reduction in the Incidence of Awareness Using BIS Monitoring.

And that was published in 2004 as well. Well, I think that's a perfect segue into the first study we'll consider closely today. Dr. Joshi, what can you tell us about the Be Aware trial? So the Be Aware trial was the first prospective randomized control trial looking at the use of the BIS monitor to prevent awareness with recall. The patient population in this study were was um adult surgical patients undergoing what they called relaxant general anesthesia with at least one high risk factor for awareness.

And these high-risk factors included undergoing a C-section, high-risk cardiac surgery, acute trauma with hypovolemia. Rigid bronchoscopy, significant impairment of cardiovascular status and expected intraoperative hypotension requiring treatment anticipated difficult intubation, heavy alcohol intake, or chronic benzodiazepine or opioid use, as well as protease inhibitor therapy And the patients they excluded in this trial really related to an inability to truly understand whether recall had happened. or or to interpret the BIS itself. So they excluded patients with limited English proficiency, prior traumatic brain injury, memory impairment, or EEG abnormalities. And how was this trial set up? So this study uh randomly assigned patients to either monitoring with the bis or routine care.

All patients had a BIS monitor placed on their foreheads, but only the BIS group had them actually turned on. Anesthesiologists taking care of these patients manually recorded BIS monitor values every five to ten minutes. And then after the study, structured interviews were conducted postoperatively with blinded interviewers at three time points after surgery. One was in the immediate post-operative period, two to six hours after surgery. A second interview was conducted 24 to 36 hours after surgery.

And then one final interview was conducted 30 days post-operatively. Okay, so we have a group of adult patients with at least one risk factor for awareness randomly assigned to either BIS or routine care Dr. Glasderson, what were the findings of the study? So this is a really exciting paper. At the end of it all, they had two thousand four hundred and sixty-three patients in the final dataset. Demographics and clinical characteristics were similar between groups, but almost half, forty five percent, of the patients enrolled in the trial, underwent high risk cardiac surgery, and over half of them initially received postoperative care in the intensive care unit.

I'll give you a small quote from the the results section. By the 30-day endpoint, the number of patients who reported awareness under anesthesia was significantly smaller in the BIS group. than in the routine care group. And the figures are two patients in the BIS group and eleven patients in the routine care group, with an odds ratio calculated as 0.18, which was significant at the 95% confidence interval The absolute reduction in the risk of awareness, therefore, was 0.74%, and the number needed to treat in this trial was 138 patients. There were 22 reports of confirmed or possible awareness in the BIS group, comprising 1.8 %, and 27 reports in the routine care group, which comprised 2.2%.

The two episodes of awareness in the BIS group occurred at BIS readings of 79 to 82 and 55 to 59. Okay, so the study is suggesting here a reduction in awareness in the BIS group. But one thing I do want to point out is that the authors do not explicitly define what constituted awareness. Any thoughts about that, Dr. Glezerson? As we mentioned before, I think that the definition plays a central role in estimating incidents.

And I was similarly concerned when I read this. Of course, I wasn't practicing anesthesia actually when it was published, but when I read it later on, one of the first things that struck me was: could this be simply a question of definition? I think it's also important to consider that the population specifically enrolled high-risk patients, and we don't know as much about the utility of BIS monitoring low-risk patients, and that's something we'll discuss a little bit later on. But this was definitely a very isolated uh subset of the population. And I think it's understandably so.

If you're going about doing the first randomized control trial, you want to sort of, for lack of better terms, stack the deck a bit so that you can enroll a reasonable number of patients and find a signal. And so I don't think it's anything uh I don't think it's a criticism of the study at all. I think it's simply uh a reflection of the fact that the first study had ought to examine the group with the highest proposed incidents. And we knew we've known for quite some time that patients had high at high risk of awareness include those enrolled in the study. So in fact I think that it was a very good launching point for future studies But indeed, one must consider those demographic factors when interpreting this study more broadly than its inclusion criteria.

And I understand that this study really helped to kind of motivate and start the discussion around considering the routine use of BIS monitoring as well as other process EEG devices as a monitoring standard. Dr. Joshi, what can you tell us about the ASA 's position on this? So the American Society of Anesthesiologists or the ASA published a practice advisory in 2006, and I'll share a quote from that practice advisory. They concluded that brain function monitoring is not routinely indicated for patients undergoing general anesthesia. either to reduce the frequency of intraoperative awareness or to monitor depth of anesthesia. They then further stated that a brain electrical activity monitor should be used to assess Intraoperative depth of anesthesia for selected patients, and they agreed with the use of brain electrical activity monitors for patients with conditions that may place them at risk and patients requiring smaller doses of general anesthetics.

In addition to other clinical indicators. There was insufficient evidence at the time that this practice advisory was written to draw conclusions regarding the what they called general clinical applicability of brain monitoring devices and the use of these monitors for specific populations which they then defined as patients undergoing cardiac surgery, cesarean delivery, emergency surgery, trauma surgery, and total intravenous anesthesia. Alright, so to summarize, we have the Be Aware trial, which was the first prospective RCT that demonstrated that BIS monitoring reduced awareness compared to routine care. However, the study had limitations in terms of both defining awareness, and there was also a question of whether the protocol of routinely recording bis values might have actually affected the results due to the potential for increased vigilance in that group Dr. Glezerson, the be unaware trial addressed some of these limitations, is that right?

Absolutely it did. So I mean the central question here is Is the BIS monitor providing useful information beyond that which we already have at our availability at the bedside of a patient undergoing general anesthesia? So the Be Unaware Trial was a study published in 2008 in the New England Journal of Medicine by Michael Avidan and colleagues. And assessed a pa a population of patients who are also high risk. Again, the study excluded patients who had dementia, were unable to provide informed consent for the study or had prior stroke with residual neurological deficits for the reason that it could make the interpretation of their EEG and therefore the internal validity of the BIS in question.

Okay, so similar to be aware we have a population of high-risk patients. What about the protocol? The study protocol randomized patients to receiving BIS monitoring versus titration of anesthetic gases according to end title anesthetic gas concentration. Postoperative assessment for awareness took place again at three intervals. First interval at zero to twenty-four hours, the second interval being between twenty-four and seventy-two hours. and the third interval at 30 days after extubation.

This was a large, albeit single-centered study. In the end, they enrolled 2,000 patients. There were two definite cases of awareness in each group. In one case, the bis was greater than 60, and in the remaining three cases, the end title anesthetic gas concentration was less than 0.7 Mach adjusted for age. The mean bis value in this study was 43, continuously less than 60 in 45% of patients, and the entitled anesthetic gas concentration was greater than 0.7 age-adjusted MAC. continuously in 25.5 % of patients.

There was one case of definite awareness that likely occurred when the patient was in the target range for BIS. The conclusion of this study, to quote the authors, was that we did not reproduce the results of previous studies that reported a lower incidence of anesthesia awareness with bis monitoring. And the use of BIS protocol was not associated with reduced administration of volatile anesthetic gases. Anesthesia awareness occurred even when BIS values and n-title anesthetic gas concentrations were within the target ranges. So it sounds like the Be Aware trial helped address some of the prior limitations we discussed by comparing protocols based either on BIS with a target of forty to sixty or n title anesthetic gas with a target of 0.7 to 1.3 mach.

And again, this was in a high risk population. Ultimately, the study showed no difference between the two groups in terms of awareness, and we have an overall incidence of 0.21% for definite anesthesia awareness. Dr. Glezerson, any other thoughts about the study I think this is a very interesting paper for a number of reasons. One, methodologically it was very strong, but also it showed in a very pragmatic sense that the monitors we already had available to us, notably entitled anesthetic gas monitoring, were at some level sufficient. And uh this is not surprising in a way.

The the the original studies that defined Mac by Ted Eager in the nineteen sixties and his colleagues Did a fairly good job of giving us a clinical endpoint that mattered. And it's somewhat by accident that actually the clinical endpoint of immobility correlates quite strongly with lack of awareness. But I think it's interesting to note that uh that monitor, for whatever limitations it has, does actually provide useful information, similar to that provided by a different monitor that uses a completely different technology. I completely agree, and I think this study really contributes another level of understanding beyond the original Beaware trial. Similar to the prior study, the authors were actually pretty careful to comment that there are some concerns relating to all studies that are conducted on anesthesia awareness, specifically that the diagnosis may be subjective and that the awareness interview itself could be invalid because specifically repeated questioning may induce false memories and it's subsequently hard to distinguish those from memories of those events in the operating room versus those in the intensive care unit.

Another aspect that the authors were careful to observe is that the results of this trial should not be extrapolated to patients receiving total intravenous anesthesia, which is as they mentioned, considered a risk factor for anesthesia awareness. One of the other limitations we're seeing now with both of these trials is the wide confidence intervals and overall small numbers. It sounds like the bag recall trial we're gonna chat about now was designed to address this very issue. Absolutely. It's a great fortune that anesthetic awareness is rare.

And so for the trialists, that presents significant challenges for teasing out the incidence and the effect of different interventions on that incidence simply because the incidence is already so low at baseline. So although these studies are large in absolute terms, thousands of patients, in relative terms to the incidence of the primary outcome, they're actually, they were actually quite small. So a second study by Michael Avidan and some colleagues, which was called the Bag Recall Study, was published in 2011 in the New England Journal of Medicine and was titled Prevention of Intraoperative Awareness in a High-Risk Surgical Population. The bag recall study examined high-risk adult patients undergoing elective surgery and excluded patients with dementia, inability to provide consent, and again prior stroke with neurological deficit.

Similar to the be aware study, in that patients were randomly assigned to BIS or control group, both groups received the forehead BIS monitor, but the control group did not see the readings. Practitioners were aware of the groups, but those who conducted and reviewed postoperative interviews were blinded. The premise here is that you can record this values in both groups, but apply an intervention to either group And be able to tease apart whether there was really a difference in the bis value or not. which was N title Anesthesia Agent Concentration, but both groups had the BIS sensor applied, except in the control group the monitors concealed the BIS number. The protocol also integrated alarms for bis values greater than 60 or less than 40, or age-adjusted MAC values less than 0.7 or greater than 1.3.

It's important to observe that these protocols were specifically designed to increase vigilance and provide warnings of possible awareness. So in addition to the audible alerts, the protocols also include structure education and checklists, and this is something that's fundamentally different from prior studies. In this study, the outcomes were ultimately evaluated at two time intervals with a modified Bryce questionnaire. The study ultimately ended up enrolling a total of six thousand and forty one patients and observed seven events of definite awareness in the BIS group and two in the control group, which did not demonstrate superiority of the BIS protocol. In terms of definite or possible intraoperative awareness, there was a total of nineteen cases in the BIS group. and eight in the control group and again superiority of the BIS protocol was not demonstrated.

Doctor Glezerson, anything else to observe with the study? When compared to those who did not experience awareness, patients who did experience awareness had one additional inclusion criterion and one additional comorbidity. uh which essentially means that they were a higher risk group. And so it comes as no surprise that there is a stratification of risk according to risk factors. You mentioned, of course, that this study enrolled a much larger number of patients, six thousand and forty-one total patients. And that's no uh no laughing matter.

This is Study that took place uh in a multi-centered fashion with a significantly greater power to detect the difference compared to the B unaware trial, and that increased population size. goes a long way to improving our trust in the outcomes of this study. One of the limitations nonetheless though was that the population did not include emergency or trauma surgery. And so there remains a high-risk group that is unstudied in this in this fashion. Perfect. So to summarize, the bag recall trial was a large prospective multi-center RCT that compared BIS to end title anesthetic concentration guided protocols. that ultimately did not demonstrate superiority of the BIS protocol compared to the control group in a high risk population.

This study was substantially larger than prior studies, but seemed to support the findings of the B Unaware trial. Now it seems like all of the studies we've discussed currently have selected for patients who specifically have risk factors for awareness. What evidence do we have for BIS monitoring in the general surgical population? So, David, this brings us to one of my favorite papers by one of my favorite authors, Dr. George Mashur. He published a study entitled Prevention of Intraoperative Awareness with Explicit Recall.

In an unselected surgical population, a randomized comparative effectiveness trial. This was published in the Journal Anesthesiology in 2012. This was a randomized controlled trial of unselected surgical patients at three hospitals of a tertiary academic medical center. 9,460 patients were randomized to the BIS group And 9,376 patients were randomized to the anesthetic concentration group, comprising a total of nearly 20,000 patients. In terms of methodology, operating rooms were randomized every three months based on an even or odd numbering operation So either electronic alerts in the event of a median bis value of greater than sixty or electronic alerts for median age adjusted Mac level less than point five. In the BIS targeted rooms, the BIS values appeared on the main monitoring screen and were automatically recorded, excluding the anesthesiologist as the mediator of that data collection.

In the anesthetic alerts targeted rooms, BIS values neither appeared on the monitor nor were accessible intraoperatively. Okay, so now we have unselected surgical patients randomized to alerting algorithms based on either BIS or anesthetic concentration groups. Before we head further, I do want to clarify some of the unique aspects of this trial. For one, of the 9,460 patients randomized to the BIS intervention, 36 % of them did not have BIS data recorded due to a software interfacing problem. This actually created a third group for the study and the authors decided to use this group as a post hoc control group because it technically had neither intervention.

Dr. Joshi, can you tell us a little bit more about this and the interim analysis the authors plan to conduct? Yeah, so I I think one more important thing to mention in their methods is that they had planned to do an interim analysis during this study. And so at this interim analysis, the incidence of definite awareness was 0.12% or just eleven patients in 9,376 in the anesthetic concentration group. And 0.08 % or 8 out of 9,460 patients who were randomized to the BIS group. And importantly, they in in this interim analysis, they analyzed the data as the groups were randomized and not how they and ended up being monitored, which as we talked about, um about a third of these patients in the BIS group actually ended up receiving routine care without BIS monitoring and with just clinical monitoring alone.

Based on the results of this interim analysis, this study was actually stopped at this point for futility, given that there was no difference between the two groups. in the incidence of awareness under general anesthesia. However, because of this unexpected protocol deviation that produced this third group of about 3,000 patients They then did a post hoc analysis between the cohort receiving no intervention or just clinical monitoring alone and the cohort receiving the BISP protocol. And what they found was that the cohort receiving no intervention had 4.7 times more definite or possible awareness events compared to the cohort receiving the BIS protocol. And that was statistically significant with a p-value of 0.001. And of the patients with definite or possible awareness receiving BIS monitoring Half or 50% had no five-minute epoch of bis values less than 60 during the case, and 50% had at least one five-minute epoch of median bis value greater than 60.

Okay, so basically the trial was terminated due to a pre-specified interim analysis that showed no difference between the BIS or anesthetic concentration guided protocol. But the creation of this third group due to technical factors allowed for a secondary post hoc analysis that showed that the BIS protocol did reduce the incidence of definite and possible awareness when compared to no intervention at all Dr. Gletzerson, what were some other takeaways from the authors? So they conclude essentially that this is a negative trial. And in their own words, they describe that this negative trial could not detect a difference in the incidence of definite awareness between monitoring protocols based on either BIS value. Values or anesthetic concentration.

By their post hoc analysis, however, they conclude that a protocol based on BIS monitoring reduced the incidence of definite or possible intraoperative awareness compared with routine care And they observe that this is in agreement with a Cochrane Review, which was performed around the time of the publication of the study Yeah, and so it sounds like this study supports some of the conclusions from prior papers as well that the BIS monitor may reduce awareness when compared to clinical signs alone But not necessarily when compared to a protocol based on monitoring of entidal anesthetic concentration And I think that that's somewhat logical, isn't it? If you don't monitor something, you have less information than if you do, even if the monitor you use is perhaps flawed Right, and one other thing I'll point out is that the Beaware trial is similar to this trial in that both enrolled patients who are receiving intravenous anesthetics.

And the results from these two studies are consistent in finding bisuperiority compared to routine care for preventing awareness So let's focus in specifically then on patients who are being maintained with total intravenous anesthetics or tivas. Dr. Joshi, any studies looking at this? Yes, there actually was a study based out of China in adults undergoing Tiba. So this study was published by Zhang et al. in 2011. And it was titled Bispectral Index Monitoring Prevents Awareness During Total Intravenous Anesthesia, a prospective randomized, double-blinded, multi-center controlled trial.

This study was a double-blinded multi-center randomized controlled trial, as mentioned in the title. The two groups were a BIS group as well as a control group And in the control group, the monitor screen was covered and was not able to be seen. In the BIS group The clinicians were recommended to keep the BIS between 40 to 60. And again, they administered surveys one day and four days post-operatively. Okay, so now we have a specific Tiva population being randomized to either BIS or control.

What were the results? The results of this study was quite interesting. There were 5,228 total patients, with around 2,900 in the BIS group and around 2,300 in the control group. There were four awareness cases in the BIS group compared with 15 in the control group, and the authors found this to be statistically significant with an odds ratio. for awareness in the BIS group of 0.21 compared to awareness in the control group. They also analyzed the incidence of possible awareness and dreaming, which they said was similar between groups And then they analyzed the awareness cases.

And so a review of six out of the 19 total awareness cases showed light anesthesia defined as a bis value greater than 60 for nineteen to a hundred and six minutes for five of these cases. So four in the control group and one in the this group had these high bis values for prolonged periods of time. And they were further able to analyze 11 of the awareness cases, which and in this analysis, 10 out of these 11 that they were able to analyze showed that awareness was due to light anesthesia. And so they concluded that light anesthesia was the main reason for awareness. And so put putting it all together, they found more awareness in the control group than in the BIS group, and they were able to conclude with by analyzing when this awareness happened that the awareness was due, in fact, to light anesthesia.

Got it. So in this study, specifically focusing on Tiva, BIS monitoring with a level between forty to sixty decreased the risk of awareness compared to routine Tiva. with an overall incidence of confirmed awareness of 0.14% in the bisc group and 0.65 % in the control. All right, so now that we've really covered some of the seminal articles in this subject, Dr. Glezerson, do you want to briefly review what we've talked about thus far? So when we look at these different papers, both the Be Aware trial and the paper published by George Moshur and colleagues that looked at an undifferentiated general surgical population share some methodological similarity in that they included patients receiving intravenous anesthetic infusions.

That is to say, they didn't they didn't exclude patients simply because they were not receiving volatile anesthetics. The results in these two papers were consistent in finding that the BIS monitor was superior to routine care in the prevention of anesthetic awareness with recall, and in fact the outcome is shared with a study that Dr. Joshi just described from China in patients receiving total intravenous anesthesia alone. The B unaware and bag recall trials, in contrast, were restricted to patients receiving inhaled anesthetic agents in which N-tital anesthetic gas concentrations could be monitored. Neither of those trials found that the BIS was superior to monitoring of entitled anesthetic gas concentrations. In a review article published by George Moshur and Michael Avidan, In twenty thirteen in the journal Anesthesiology, entitled Prevention of Intraoperative Awareness with Explicit Recall Making Sense of the Evidence, they state the following Based on the current evidence derived from randomized controlled trials, it could be argued that the BIS monitor plays a role in reducing intraoperative awareness in patients receiving heterogeneous anesthetics that include sedative hypnotic infusions while the entitled anesthetic gas concentration protocol is a cost-effective alternative for patients receiving potent inhaled anesthetics.

And I think that that m more or less summarizes the state of the evidence based on the studies that we've discussed so far. Thank you so much, Dr. Glezerson. I'll wrap up this episode today with a brief discussion of one final paper, which is a Cochrane review that was published in 2019 titled Bispectral Index for Improving Intraoperative Awareness and early post-operative recovery in adults. This review included 52 studies, and of these 50 were RCTs and two were quasi-RCTs looking at BIS and intraoperative anesthetic depth or recovery time. Notably only three recruited participants at high risk of intraoperative awareness, all of which we have covered today.

All the outcomes were graded to have low certainty evidence due to factors we've already touched on today, including the low incidence of intraoperative awareness, leading to imprecise effect estimates, bias because clinicians were not necessarily blinded to the monitoring method used, and general disagreement between studies on how awareness was defined or measured. So when BIS was compared with clinical signs, things like blood pressure and heart rate, the authors of this study found low certainty evidence that BIS-guided anesthesia may reduce the risk of intraoperative awareness. in a surgical population that was unselected or at high risk of awareness. However, events were largely rare and they found that the incidences of intraoperative awareness when BIS was used was three per 1,000 compared to nine per 1000 when anesthesia was guided by clinical science.

When BISC was compared with N title Anesthetic Concentration Again, events of intraoperative awareness were extremely rare, and the authors found no evidence of a difference in the incidences of intraoperative awareness when anesthesia was guided by BIS or N title. Overall incidencies of intraoperative awareness were one per 1,000 in both groups, but only three of the five studies reported events. So I think the findings of this Cochrane review largely mirror our discussion today. Let's head back to the central claim in this case. What is your level of agreement with the claim that BIS monitoring reduces awareness with recall under general anesthesia?

And what is the level of evidence for what you believe? Dr. Glauzerson, thank you so much for joining me today. It was great to catch up, and I'm so glad we got to do this together. Thank you so much for having me. It's really been great fun talking about this topic.

I think it's something that's central to the practice of anesthesiology and something that everybody should have a reasonable understanding of in order to provide good care and answer questions that we receive actually quite commonly from patients. So thank you very much for organizing this extremely useful and extremely relevant podcast episode. And Dr. Joshi, thank you for all your help with putting this episode together. We honestly couldn't have done it without you. Thanks again for having me on the show.

I and I couldn't agree more that this is such an important topic. And as somebody who's starting to learn about the practice of anesthesiology, this will really help me provide care to my patients and explain why we're doing what we're doing. And so for all the trainees who are listening to this show, hopefully this has been helpful. Thanks again, David. To our listeners, thank you for joining me on the very first episode of 2020.

I am grateful for all of your support throughout the past few years. In other exciting news, Dan Saddawi-Konefka and I are going to be presenting a live session of Depth of Anesthesia at the upcoming IARS meeting. We're going to be presenting virtually, so if you register for the conference, please consider joining us for the session. As always. Please stay hungry and keep asking questions.

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