Do preoperative anxiolytics improve patient satisfaction?

Welcome back to Depth of Anesthesia. I'm David and I'm an anesthesia resident at the Massachusetts Massachusetts General Hospital. My guest today is Dr. Matt Vanneman. Matt's an attending cardiothoracic anesthesiologist here, and he was my guest for our episode on cefazolin in penicillin allergic patients. If you haven't had a chance to listen to that episode, I highly recommend it.

Matt, welcome back to the show. Glad to be here, David. Thanks for inviting me back. So today we'll be talking about the use of preoperative anxiolytics. Our case today is that of a 56-year-old man.

He has a history of hypertension, osteoarthritis. and he's presenting for a total hip replacement. On arrival to the operating room, the r the resident reports to the attending that The patient appeared nervous in the preoperative area and so the resident decided to give that patient two milligrams of midazolam as an anxiolytic. Matt, what do you think are some of the claims here that might be worth looking into I think underlying this statement is the claim that patients who are nervous need intravenous anxiolytics prior to surgery. I've had many people tell me many different reasons, but ultimately it comes down to usually that the patient will be more satisfied with their perioperative experience if they receive some type of anxiolysis prior to their operation.

And what do you think advocates against administering pre-operative anxiolytics would say? So the downside to preoperative anxiolytics is sometimes there's a concern that maybe they may hang around or some cause a delayed wake-up. a delayed packed discharge, a delayed discharge home. And so I've heard people tell me, oh, we shouldn't administer anxiolytics because of this reason. It may cause these delays. So to our listeners, think about your own practice.

What's the level of your agreement with the claims that we just mentioned? And what is the level of evidence for what you believe? For those of you out there on Twitter, our handle is at depth anesthesia. So that's without the depth of anesthesia. It's just at depth anesthesia.

And we conducted a poll a couple days ago asking about routine administration of anxiolytics like midazolam prior to general anesthesia in non-elderly patients. We received about 50 votes in total. 65% of you guys said no. 20% said yes, and 15% said it depends. We'd love to connect with you guys on Twitter. We think it's a great way to reach out and talk to people who listen to the episodes, and we definitely conduct these polls whenever we can. Before we begin exploring the literature, I think we should mention that the literature was fairly heterogeneous with respect to a lot of the outcomes that we studied.

The two claims we specifically intend to address today are the ones that seem to be a little bit more consistently studied. Having said that, as we mentioned before, knowing the absence of literature in itself is just as important All right, Matt, so do you want to get us started with this first study? Yeah, absolutely. So by far the largest study on this topic to date is a randomized trial out of France called the Pre-MedX study. The longer title is Effect of Sedative Pre-Medication on Patient Experience After General Anesthesia.

And what the study did was basically across five different hospitals in France, uh they randomized over a thousand patients to one of three groups. They randomized the patients to either receive two point five milligrams of all lorezepam as one group. A second group received a placebo pill, an oral placebo pill, which had no active ingredient And a third group actually received no pill whatsoever, and this was the no pre-medication group. So the patients that were included in the study were eligible to be enrolled, they had to be younger than 70 years of age They had to be over 45 kilos, they had to be able to complete a self-reported questionnaire, and they had to have no other obvious contraindication to benzodiazepine like a prior allergic reaction or a prior adverse reaction.

What were some of the exclusion criteria in the study? So that's a great point, and I'm glad you brought it up so quickly One of the major exclusion criteria for this study was patients who were undergoing outpatient surgery, meaning that the only people included were patients who were already in the hospital and were planned for surgery. If you were coming in for say like a knee arthroscopy for an ACL repair, you could not be included in this study. And therefore these results may not apply to the larger outpatient population, many of whom we deal with on a daily basis. The other major exclusion we should discuss is it excluded patients who were specifically requesting anxiolytic premedication So if you met someone on their inpatient war and they specifically said, oh doctor, I am very nervous about my surgery tomorrow, is there anything you can give me in order to help me feel better about this?

Those patients were excluded from this trial. So there are a couple limitations on the people that we need to think about when we're applying this study. And I noticed you mentioned that in the interventional arm the patients got two point five milligrams of larazipam. Did the authors of the study mention at all why they decided to select larazipam as opposed to something like midazolam? Yeah, so the authors did talk about this a little bit in one of their supplements.

Basically their major uh motivator was that they wanted to use the Razopam because it had been used in a prior study, which at that time of their study protocol creation was the largest kind of study about sedative me uh sedative pre medication that have been done to date. Now, one important point to mention though, as you mentioned, is that Larazopam is what they is termed an intermediate last uh benzodiazepine, so the effect actually has like a fairly long duration of effect. We think about the anesthesia, so be like six to eight hours or something like this. Whereas in contrast, midazlam is a shorter acting benzodiazepine, the effect is not as long, maybe like two to three hours And we'll see that that probably comes into play a little bit later, but it's an important difference to recognize as we're thinking about the kind of preoperative anxiolysis.

Sounds good. So what was the primary outcome of the study? So the primary outcome that they're looking at was uh patient satisfaction. as assessed 24 hours after surgery by a pre -validated questionnaire that the authors had already published in other domains. And so what the study uh what the excuse me what the questionnaire did was it looked at kind of six domains of different satisfaction and then created a global score ranging from zero to a hundred, um which a higher score would indicate higher satisfaction. The other thing that the authors looked at as a s pre-pre-specified secondary analysis was uh the time to extubation in the operating room as well as the time uh to a c early cognitive recovery amongst the three groups.

And then they also plan to do an a priori subgroup analysis in patients who self-reported high levels of anxiety. So whenever a patient was enrolled into the study, they had them fill out a questionnaire that was basically asking how anxious are you as a person And then they plan to do subgroup analysis of patients who self-reported high levels of anxiety prior to surgery. So Matt, what exactly is the Evan G? And could you just give us a couple examples of some items included on that questionnaire? Yeah, absolutely.

So the MNGE is basically a 26-item questionnaire that patients self-report on, and it's scored on a normalized scale of 0 to 100, with 100 being uh representing higher satisfaction And the survey uh had been previously validated in other studies that the authors had done prior to initiating this study. And so what the authors did was they asked the patients to fill out the questionnaire And the questionnaire was a measure of global satisfaction with the entire perioperative experience. And so it was a metric across many things. So as an example, one of the questions they asked about were how satisfied were you during the pre-operative visit? with the anaesthetist. So that probably is directly related to uh you know anesth satisfaction with the anesthesia anesthetist.

However, um they also ask about things that are not related to anesthesia. So for instance, one of the questions they ask about is Waiting times in the hospitals seem too long, which probably would be aggravating, but aren't necessarily directly related to anesthesia. So the point I want to emphasize is the Evan G focuses on global satisfaction, is not specific regarding satisfaction for anesthesia. I think that makes a lot of sense and that's a good point to clarify. So what were the results of the study?

So I'll I'll get cut right to the chase. The major take-home is that across these three randomized groups there was no difference in perioperative satisfaction as measured by the FNG score across the groups. Or, put another way, patients who received preoperative anxiolysis with oral larynzopan were not more satisfied than patients who received either placebo pill or even patients who received nothing. And what about those patients who had the heightened preoperative anxiety? Because I think there'd be a claim out there saying in patients who have more preoperative anxiety, they might benefit more in terms of their satisfaction from getting a preoperative anxiolytic.

Yeah, that seems incredibly intuitive. If patients are reporting high anxiety, they would probably be the ones to most benefit from anxiolysis. Unfortunately, the study found that that was not the case In their pre-specified subgroup analysis, patients who self-reported high anxiety and received lorzepane were no more satisfied than patients who reported hang high anxiety who received placebo or patients who reported high anxiety and received nothing. There was no difference amongst patients who reported high anxiety who received larazipam, placebo, or nothing in terms of their global perioperative satisfaction Now I know this goes a little bit into our second claim that we're going to investigate about preoperative anxiolytics affecting discharge and recovery, but did this study look at any of those factors So in their pre-specified secondary outcomes, the authors did find that patients receiving lorezeapam had a very slightly increased time to extubation. but clinically I'm not sure how relevant it was.

To be specific, patients who received placebo or nothing were extubated in approximately twelve minutes, and patients who received razepam were extubated in in seventeen minutes. So does this difference of five minutes make a difference? I'm not so sure. That's a fair point. So one of the things I think we should also talk about is that in the method section, I'll quote here for you.

The authors report that upon arrival in the operating room, the anesthetist, who was blinded to the intervention assignment, evaluated the quality of patient cooperation with a VAS Following this assessment, the anesthesiologist in charge could then administer an anxiolative medication if he or she believed it was clinically necessary. What do you think about that? Yeah, so I I'll be honest with you, I didn't really know what to make of that. But uh what I was happy to find when I read the study was that uh things like the quality of patient cooperation, the need for additional anxiolytic, the number of times to start an IV. In fact, all of these variables were the same across all three groups, the Lorazopam group, the placebo group, and the nothing group.

So I'm not quite sure what they were going for here, but it doesn't seem to have made a significant effect on the overall study outcome. Sounds good. So punchline for this, patients undergoing elective surgery under general anesthesia, pre-medication with oral lorazipam. compared with put placebo or no pre-medication did not seem to improve self-reported patient experience based on the Evan G questionnaire. Correct, um which is uh I think a pretty provocative or at least counterintuitive finding. Yeah, definitely.

Alright, so what's the next study we're looking at? So this is another study, much smaller. It's a 90 per patient study of women who are undergoing uh needle leucalization and breast biopsy procedures, and it's titled Benzodiazepine premedication can improve outcome in patients undergoing breast biopsy procedures. And so the patients were women undergoing a breast biopsy. And they excluded patients who were pregnant, breastfeeding, who were already on long-term benzodazipines, or who had allergic reactions to any of the study medications.

And the patients were randomized to three pre-medication groups, right? Yes, correct, David. So the patients received either IV Medazalam. IV diazepan emulsion or an IV saline placebo syringe. And basically the the study medications were given five minutes before going to the radiology department before their breast biopsy.

And then another five minutes before entering the actual procedure room where the breast biopsy would be done. And how was this study set up? So this was a double-blind study, meaning that uh both patients and assessors of the patients were both blind to the study medication that was administered, and so that helps kind of give some external validity to the study. And I just want to clarify, this is not general anesthesia. So this is a critical difference between this study and the prior, the pre-medic study.

So in the pre-medic study, all the patients were undergoing general anesthesia. And so really the question was, how is their periapter satisfaction when you don't remember any of the surgery? The major difference here is all these patients will be receiving monitored anesthesia care or sedation for their procedure. So they will remember the needle localization aspect of the procedure. They will remember people being in the operating room, people talking to them, and that is probably not very pleasant.

So it was probably the patient population that would have the highest yield of anxiolysis because they will actually be awake for the part of the procedure So what were the study's findings? Perhaps not surprisingly, um patients receiving midazolam or diazepane were significantly more likely to report that their premedication was helpful Perfor their needle localization compared to patients who receive the intravenous saline placebo. Additionally, patients who receive the benzodiazepines um we're more likely to rate the worst part of the surgical procedure as being the waiting part of the procedure, the before the procedure Whereas patients who received saline were more likely to rate the actual procedure of the needolozocalization as being the worst part of the procedure.

To think about another way, patients who received the benzodiazepines were probably more satisfied and less anxious during the actual procedure itself compared to patients who received intravenous saline instead. Now, did this study also look at recovery times? It did. And in this small study, only about 30 patients per arm, uh there were no significant differences in times to achieving home readiness and no significant differences in times to the actual discharge from the hospital from these procedures. Punchline for this study, pre-medication with IV benzodiazepines did significantly improve patient satisfaction with the breast biopsy procedure by decreasing levels of discomfort during needle localization and there was no prolongation of discharge times.

Alright, so on to our third study. And this is a little bit different because it's a secondary analysis. Yeah, so this is a secondary analysis of a separate study that was initially studying something else But um the data was satisfactory to analyze uh preoperative anxiolysis and patient satisfaction. So this was a study of uh 260 patients who were adults over the age of 18 Um and what the authors did was they looked at the anesthetics all of these patients received and these were these anesthetics were not standardized. So this is a retrospective cohort study, so it's an important point here.

Um and what they found was that patients who received intravenous medazlam were more likely to report either being satisfied or very satisfied with their perioperative experience compared to patients who did not receive intravenous midazalam. Now this wasn't a randomized controlled trial like our prior two trials. So what the authors did to try and adjust for residual or hidden confounding is to do a multivariate analysis to see if there might be any other covariates that could explain these results. And what the authors found was that after adjusting for study site and location, there in fact was no difference in satisfaction between patients receiving medadslam compared to patients who did not receive medadslam. So this study actually probably suggests, at least in this retrospective data, that there wasn't a difference in this cohort.

Um The interesting finding was that there was such variance in satisfaction across locations, but that probably is a little bit beyond the topic of this podcast. All right, Matt. So we've gone through these three studies. What do you think are some of the key takeaways here? And I just want to r review the claim, which is that Those advocating for giving pre-operative anxiolytics will claim that the medication will improve patient satisfaction?

So I think that from the evidence that we have, particularly the pre-medic study At best we could say it's unclear if preoperative anxiolytics would improve patient satisfaction in patients undergoing general anesthesia. Um I just at the moment there's not clear data to suggest that that is necessarily true, and the pre-medic study may in fact suggest that there might not be any difference, although we would probably need more data to support that claim more definitively However, in patients who were receiving monitored anesthesia care or sedation, such as those undergoing the breast biopsies, I think there probably was a pretty solid effect that patients were receiving uh anxiolytics were more satisfied, and I think intuitively that makes sense.

If someone's going to be awake for their procedure, it probably stands to reason that having some degree of anxiolytic to help relax and may improve the satisfaction during the procedure. So I kind of think about it in those two strata Awesome. I think that's a great review of the studies that we just talked about. Now, moving on to the second claim. The second claim is that Advocates against administering preoperative anxiolytics will claim that the medication may delay recovery.

What are some studies that we have either supporting or refuting that? Yeah, so good question, David. So we have a few studies, and then actually there's a very nice meta-analysis on this topic, which I think we'll be able to go over. So the first study we want to talk about It's called pre-operative anxiolysis and postoperative recovery in women undergoing abdominal hysterectomy. So this is a study of women aged 18 to 60 who are undergoing general anesthesia and elective abdominal hysterectomy for fibroids.

Fairly straightforward. Any important exclusion criteria? So major things were patients who had psychiatric disorders such as affective disorders, alcohol and drug abuse, they used psychiatric medications, and also patients who had an ASAP Physical status after more than two. So patients who are ASA 3 or 4 were excluded. So this is kind of a more healthier population So what the investigators did was they randomized these patients into one of two groups.

The first group was a placebo group, and being a double-blind trial, you need to have a placebo arm. And then the other group was an anxiolytic group. And in the anxiolytic group, the patients received on the night before surgery oral lorazopam, which was self-administered. And then on the day of surgery, they received intramuscular midazolam at least 30 minutes before surgery. So the primary outcome of this study actually had to do with postoperative pain, and just briefly the authors found no difference in post-operative pain between the two groups.

But what we were more interested in was the secondary outcomes, and so the The secondary outcomes were the um differ if there were any differences in time to ambulation, bowel sounds, flatus, uh liquid intake, food eating, and uh discharge from the hospital. Because that's the kind of the claim we look to investigate. What did the study find? So the study really didn't find any difference in any of these in these milestones. So basically for any given milestone, like movement from bed, bowel sounds, uh liquid intake, food intake, discharge None of those outcomes were different in patients receiving the placebo versus patients receiving the two preoperative anxiolytics.

Did the authors mention why they decided to do a pharmacologic intervention the night before surgery as well as the morning of surgery? Because I'd say that in the majority of cases that I've seen, we usually do not routinely give medication the night before surgery. Yeah, excellent question. I think uh it sounds like from the article the authors had done a prior study um which uh had been only exclusively uh anxiolysis on the day of surgery and had found no difference in their outcomes. So to try and magnify the treatment effect, uh the authors then try to include a second uh intervention on the night before surgery. to really try and ensure a maximum axiolysis for the patients in order to try and find a difference in what their primary outcome was, which in this case was post-operative pain.

Gotcha. So what's the punchline for this study? So to me, the well the way I take away from this is in patients undergoing abdominal hysterectomy um the administration of preoperative anxiolytics both before and the night before and the day of surgery really didn't have very much of a clinical impact in terms of most of the milestones we think about in terms of patients progressing and recovering from their surgery. Alright, so the next study that we'll be talking about is one that's included in the Kochman review. So we'll talk about this study and then we'll talk about what the actual review uh discovered.

Yeah, that sounds like a great idea. So this next study that we're going to talk about is a study that enrolled women who were undergoing laparoscopic tubal ligation as outpatients who are ASA ones and twos, and then randomized them to receive either intravenous menazalam prior to their surgery or intravenous saline as a placebo group The major outcomes that the authors were looking at for the study were functionally discharge readiness. They basically looked at how long does it take the patient to go from the end of surgery to the end of phase one of the PACU And then how long did it take the patient to go from the end of phase one packy to the end of phase two pacu or just discharge home?

So what do they find? So what they found was that patients who received midazolam uh had an equivalent time to recovery uh as patients who received the intravenous saline. So patients who got midazolam had the same phase one pacutimes, they had the same phase two pacutimes, and there was no difference in recovery times in the patients receiving intravenous midazolam or intravenous saline. Alright, so pretty straightforward punchline for this. No differences in recovery times in pretty healthy ASA 1-2 women scheduled for outpatient laparoscopic tubal ligation Yeah, I think that's pretty s fair that we can say in this population.

And we had mentioned how this study that we just talked about was included in a Cochrane review. So let's go ahead and talk about that Cochrane review Yeah, that seems like a great idea. So the Cochrane Review basically amalgamated 17 studies across a fairly wide time period. The most updated version of this is published, I believe, in 2009 Uh and this Kochner view basically combines 17 studies assessing the use of pre-medication for anxiety during adult day surgery. So the view is limited to patients undergoing outbreak Patient day surgery doesn't necessarily talk about inpatients getting surgery.

And what they did was they looked at specifically a few things, but one of them was the time to discharge And what they found was that seven studies specifically looked at the time to discharge question that we were talking about earlier. And they found that uh none of those studies actually found that there's any delay in discharge in patients who received uh enxolytic medication prior to their day surgery. Did the study look at any other outcomes? Yeah, so the review did look at some other things. Specifically, they looked at um some of the studies looked at tests of psychomotive function um after surgery.

And what some of these studies did find was that uh in some patients there was a small delay in recovery of psychomotor function after receiving intravenous anxiolytics as compared to patients who did not receive those anxiolytics. So they do things like digital subtraction tests and other cognitive tests and found that patients who received benzodiazepines did have a little bit slower recovery to recover that type of cognitive function Now what's important to mention though is most of those studies actually also looked at discharge times and found that those patients uh who had that slightly impaired cognitive uh recovery did not have any delay in their discharge from their hospital or ambulatory surgery center, implying that the delay in recovery was probably a transient phenomenon and may not have been clinically Uh so important because there was no delay in discharge.

And the study that we just talked about, that was one that used both clinical measures and tests of psychomotor function. We didn't go into it specifically, but they found impaired performance on a couple of uh cycle motor function tests, but again, as we just talked about, there was no evidence of a difference in time spent in in the post-anesthesia care unit or time to discharge readiness. That's correct, which implies that this transient delay in recovery may not necessarily be extremely clinically important. Now, I think the authors of this study go to great lengths to talk about some of the limitations of the studies included. Do you want to talk about that a little bit?

Absolutely. So there are a couple of major limitations. So one is that the across this group of studies there is a lot of heterogeneity So for instance, uh there is a lot of differences in the specific axiolytic drugs that each study may have used. So some studies or most many studies use benzodazipines Others use beta blockers, some used opioids, and one study even used in herbal medication. So there's a lot of heterogeneity in this cock review, which kind of makes it a little hard to draw strong conclusions.

The other major limitation is that across the different studies, there's many different anesthetic techniques. There are different anesthetic drugs used. Some use things like Calothane or enflorane, probably medicines that we don't use very commonly in this era. So that kind of also limits its applicability to current modern anesthetics. And the authors mentioned that the actual clinical question they wanted to answer was, does anxiolytic premedication delay discharge after adult daycase surgery?

And what do you think about this as an outcome measure? So I think it's an admirable outcome measure that we should be thinking about, but in the s Studies that are included in this Cochrane review, it's very hard to necessarily draw conclusions. The problem is there are many, many, many factors which affect patient discharge. Things like are there PACU beds available? Are there enough people to discharge the patient?

Is the patient still nauseated, or do they have any pain? And those all those factors can have significant variance across both location as well as surgery type. So to specifically pin discharge timeliness, on benzodiazepine or any kind of anxiolytic premedication can be fairly difficult. And I think that that is the one thing that the review is trying to get at is that despite their amalgamation of 17 different studies It's still hard to say the exact role that benzodazapines are playing in either delaying or not delaying patient discharges. And so our takeaway from this is based on this Cochrane review, there seemed to be no evidence of any differences in time to discharge in patients who had received anxiolytic pre-medication.

But as the authors mentioned, any sort of inferences for day-to-day practice should be made with caution, specifically because there was so much heterogeneity between all the studies that they've included Yeah, I think that seems pretty reasonable. I think that at the moment we don't have any evidence to suggest that there's a delay in discharges. But it's possible there are specific circumstances which have not yet been studied where the benzodiazepine may have more of an impact. Alright, Matt. What about ERAS?

Yeah, ERS, the hot topic of the day. ERES. So um so the ES Society has actually released some guidelines on this topic as well And I actually think the society has done a nice job of summarizing some of these studies and formulating them into more reasonable guidelines So we looked up the US guidelines. These are a little bit older. I think they're from 2015.

And they basically said that uh short acting anxiolytics and analgesics uh can be used, particularly if it's to do something like a procedure, like a re-anapidural or something, if it's uh done in a dose appropriate and age appropriate fashion The only major thing the society recommends against is using long-acting sedatives and narcotics, um mostly related to the thought that this may uh hinder recovery or uh sh uh uh delay discharge, those kinds of things. Um but the society does suggest that short-acting benzodiazepines can be appropriate in the appropriate patient. The only thing the society really suggests against is administering short-acting benzodiazepines to older patients over the age of 60 And what's cited in their recommendations is that these may be associated with things like delirium.

Sounds like another claim we should investigate in the future, huh? I definitely think that it would be interesting, and if there's more evidence we should uh probably look into it. Alright, so going back to the two claims that we initially sought to investigate, our first claim was that advocates for giving pre-operative anxiolytics. will claim that the medication may improve patient satisfaction. Our second claim that we investigated is that advocates against giving preoperative axialytics will say that the medication may delay recovery. So again, to our listeners, think about your own practice and now that we've reviewed the evidence, what's the level of your agreement with those claims?

And just as importantly, what is the level of evidence for what you believe? Matt, thanks a bunch for coming back on the show. I think this is another hot button topic, and I'm really glad that you were here to help us review the evidence. Well, thanks a lot for having me. I had a really great time.

To our listeners out there, thanks for joining us this week. We really enjoyed having you. If you enjoyed the show, be sure to leave us a five-star review on iTunes and Go ahead and share the links to any of these episodes with people you think might enjoy the content that we review. If you have any controversial topics in mind, please send us an email at depth of anesthesia at gmail. com. And again, our Twitter handle is at depthia. anesthesia.

To our listeners out there, thanks again for your support and stay hungry and keep asking questions.