Do lower intraoperative tidal volumes reduce postoperative pulmonary complications?

Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical practices. I'm David Hao, and I'm an anesthesia resident at the Massachusetts General Hospital. This week's episode will be featured on Anesthesiology News. Season two of their podcast, The Etherist, is out now, so definitely give that a listen I'm excited to announce that we've added several members to our team, many of whom you'll be meeting in the coming episodes.

Two special members I'd like to highlight are Ellie Kaplan and Stasia Gribon. They've been working hard to expand our social media presence and a content. So follow us on both of those platforms and let us know what you think. My guest today is Dr. Avery Tung. Dr. Tung is professor of anesthesia and critical care at the University of Chicago.

Quality Chief for Anesthesia, Former President of the Society of Critical Care Anesthesiologists, and Section Editor for Critical Care and Resuscitation for Anesthesia and Analgesia. He did his residency at the University of California in San Francisco Health and his fellowship at Stanford. Dr. Tung, welcome to the show. Thanks, Dr. Howam. Happy to be here.

For our listeners to get to know you a little bit more, how do you spend most of your clinical time at the University of Chicago? I divide my time equally between critical care, which is mostly in our cardiothoracic ICU, and OR anesthesia, which is also mostly cardiothoracic. It also sounds to me like you have a lot of roles outside of your clinical work. What's keeping you busy these days? Well, I do a number of other things.

I run the quality improvement program for our department. Uh I edit the critical care section of Anesthesian Analgesia and I participate in clinical research projects conducted in our department Uh here 's a shameless plug. Uh check out the critical care section of ANA Last Month, a recent article on aspirin and COVID-19 from the University of Maryland. Just reached an altmetric score of 1077, which is higher than last year's Eolia trial, 732, and higher than the Andromeda shock as well. We're proud of that one For our listeners who might not be familiar, that's a very high score.

Eolea was a very important trial back in 2018 that was published in NEJM and explored whether patients with severe ARDS benefited from early initiation of ECMO. Dr. Tung, I know you presented very recently on the topic of this podcast episode at the Year in Critical Care session at the ASA annual meeting. How'd you get interested in exploring the subject? David, that's a good question. Well, having practiced critical care since 96, I've watched the low tidal volume movement evolve from its clinical origins in the RZET trial of 2000 that everybody knows.

Through the extension of LTV philosophy to patients without ARDS and to patients in the OR, having both high and low risk surgery. In fact, the MPOG Data Registry run by the University of Michigan, to which we belong, will add a title volume quality metric to their panel early next year. And given existing evidence, including the trial we're about to discuss, we are currently debating exactly what that metric should measure. So I'm I guess I'm old enough to be familiar with the origins of the physiological rationale for why LTV should improve outcomes. in ventilated patients with ARDS and what that mechanistic explanation should predict for tidal volume effects on outcome in patients who do not have ARDS.

I'll mention we created the year and critical care panel as part of the critical care educational track at ASA back in 2016. This is our fourth year to highlight papers we thought were particularly interesting due either to their methodologies, their findings, or their impact on critical care practice. This presentation was part of the 2020 edition. Over the years, we've touched on anesthetic choice in patients with ARDS, increases in PA catheter use over time. inhibation and survival in cardiac arrest, you know, salt, eolia, and andromeda shock. And if you're interested in critical care paperology, we encourage you to consider attending our 2021 edition at ASA next year.

Considering that both this episode and our last epitho episode with Dr. Charnin were adapted from the Year and Critical Care panel, I couldn't recommend the presentation more highly. Our case today is adapted from Dr. Tung's talk entitled The Arc of History. You're 90 minutes into a laparoscopic colectomy on a 70 kilogram man, and an older colleague gives you a break. When you return, he tells you that he increased the tidal volume from six cc's per kilogram or about 400 cc's to nine cc's per kilogram to quote keep the sats up. You look at the monitor and observe an uh spO2 of 98% on 50% FIO2 with tidal volumes now of about 650.

Here now are two questions for our listeners to think about. What is the level of your agreement with the claim that low intraoperative tidal volumes reduce postoperative pulmonary complications? And what is the level of evidence for what you believe? To add some context to our discussion, SOCA conducted a pre-session Twitter survey on whether low intraoperative tidal volumes conferred a lung protective effect. Of the 17 respondents, 76.5 % reported yes and 23.5 % reported no. Dr. Tung, were you surprised at all by these findings?

Um not at all. You know, as former president of SOCA, I'll highlight the SOCA Twitter feed, which is run by Mike Fierro, who is uh the third member of our urine critical care team and added this to our urine critical care session uh so people could vote so we could see you know the pre-discussion impact of any papers we were going to discuss We actually joked that there should be a another question on the poll, which is would you let Dr. Tung give you another break in the OR again? Or would you refuse that break? Um but any list of interventions proven to improve outcomes in the ICU, I think would have to start with low tidal volumes.

You know, one could argue that in the ICU the use of low tidal volumes enjoys probably the most widespread acceptance of any ICU care strategy. Certainly you know, more than tight glucose control or paralysis or prone positioning or or goal-directed therapy. And unlike those other interventions, no negative trials in Telev have really been published since 2000. In fact, I'm surprised there weren't more yes votes. But this poll was conducted after the carallapolide trial we're about to discuss was published, and it is reasonable for skeptics to wonder whether the extension of LTV philosophy to OR patients who are ventilated for only brief periods and do not have ARDS is clinically relevant.

Plus those who know me know that I am often fascinated by papers that cut against conventional wisdom and often seek them out for panels like these. I think that's going to be perfect because that's exactly the type of literature that we love exploring here on Depth of Anesthesia. We'll start now with a preview of the thought-provoking trial that you just alluded to. It was published in JAMA and titled Effect of Intraoperative Low Tidal Volume versus Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery. Can you tell us a little bit about this trial, Dr. Tung?

Sure. Uh this trial actually dropped very quietly in Gemma on September 1st uh this year in the midst of the COVID pandemic and uh a turbulent election season. And when you watch the Twitter you know response to this trial, it's muted. I think for both of those reasons, because there were other more interesting things to tweet about. But these authors, uh, these Australian authors performed a four-year single-center prospective random I controlled trial Comparing six cc's per kilo versus nine cc's per kilo for patients undergoing major non-cardiac, non-intracranial surgery, lasting more than two hours, and with arterial access for blood gas measurement The primary outcome was a composite of pulmonary complications, and secondary outcomes include intraoperative vasopressors, unplanned ICU admission, ICU and hospital length of stay, and mortality I'd highlight the many experienced Australian trialists in the author list, Dr. Belomo, Dr. Serpanito, Dr. Story, and Dr. Weinberg, to name a few.

These guys are pros at the game of clinical trialism. Now we'll get back to this trial very shortly, but first we're going to chat about one of the seminal articles on title volume that was published in 2000 in NEJM. This study compared lower tidal volumes compared with traditional tidal volumes for acute lung injury and acute respiratory distress syndrome or ARDS. In fact, you know, without this trial you would wonder, and if you were a space alien, you'd wonder why humans care so much about three cc's per kilo uh during mechanical ventilation in the OR. So taken out of context, you should wonder why would a trial measuring such a small difference merit a four-year 1200 patient trial and a JAMA masthead?

You wonder whether other research priorities are more impactful. So the history of that 3cc per kilo difference is key to understanding why this paper is JAMA-worthy. It seems to me that before the NE Jam paper in 2000, it wasn't necessarily clear as to whether low tidal volume ventilation was a slam dunk. Is that correct? Um well it was sorta complicated and you had to have been there.

Uh but I'd say that there was a num m a large amount of convincing animal data dating back to nineteen seventy-four and You know, clinicians had already trended away from high or twelve cc per kilo title volumes in the mid-1990s. And intensivist practicing the late nineteen nineties, including myself, were already setting 9 to 10 cc per kilo and paying attention to high inspiratory airway pressures and trending away from that. I guess I'd say back then that we all believed that large tidal volumes and or high airway pressures were bad But proving that it made a clinical difference and estimating the magnitude of that difference was a challenge. After all, if you randomize to the low-tidal volume group and the patient desaturates, then you know you've got a crossover event, and what are you gonna do?

So there were a number of attempts to prove a difference that failed, and I think those failed attempts eventually informed the design of the Arznet trial we all remember today from 2000. To make an analogy to the present, you know, many believe that innovative COVID patients are difficult to sedate. They seem to have a high propensity to coughing and ventilator patient desynchrony. And I am definitely a believer myself But proving that is very, very difficult. And we've seen a number of papers in ANA that have tried, but you know, all come short because it's difficult to adjust for the unusual severity of desaturation with coughing episodes you know, leading people to say deeper to prevent those, or reasonable preferences by care staff to sedate more deeply to reduce risky contact episodes.

And also what would be your control group? You know, would you use the literature values or what you normally do? And your protocols would have to be very, very clear. So it was very hard to show. It's very hard to show something like that.

And I think the same was true back in 2000 for low tidal volumes Got it. So it sounds like in spite of the overall perception that large tidal volumes and or high airway pressures were bad Even in the nineteen nineties, what was challenging was proving that low tidal volumes actually made a clinical difference. It sounds like the culmination of basically an era in research on ARDS produced what's known as the alveolar over distension argument. Does that mean that nobody really doubted the basic and preclinical science behind the use of LTV? Well, I don't think anybody publicly doubted it.

For a tight condensation of the 25 years of preclinical work that predates the ArsNet trial, I'd recommend the Tobin editorial that accompanies that Arsnet paper. Easy to look up. The concept is built on several observations stacked on top of each other. That in animals, normal alveoli ventilated at high airway pressures, leads quickly to lung damage. that can be very visible, what we call hepatization of the lung. And that the second observation is that ARDS is a heterogeneous disease And so you can think of the ARDS lung as a mixture of damaged alveoli that do not participate in gas exchange and normal alveoli that do.

An ARDS lung is thus sort of functionally smaller than a normal lung, since the damaged alveoli do not expand normally with positive pressure ventilation. So the normal lung tissue takes all of the tidal volume And thus delivering a normal total volume to a patient with ARDS causes those normal alveoli to overdistend and generates the damage that we uh we believe occurs. So for our listeners, Dr. Tung has an excellent animated visual representing this concept, and I'll make sure it's available on uh the website at depthofanesthesia. com. So now that we've discussed a little bit about the role of lung protective ventilation in patients with acute lung injury and acute respiratory distress syndrome. Do we have any studies looking at lung protective ventilation and outcomes in patients who don't have either of those?

Well, once Arznet was published, that became the million-dollar question. ARDS is a relatively small set subset of innovative patients in the US and elsewhere. If LTV had an effect in patients without ARDS or in the OR, then the potential benefit would be much, much greater. So it was a reasonable next step, in fact inevitable. To extend the LTV intervention to patients without ARDS, see what would happen.

But given the physiological basis for LTV we just described, we could reasonably predict the magnitude of any effect. And the logic would go as follows. And so whether you believe in over-distension per se, or whether you believe ARDS confers some other weakness due to overdistension. It logically follows that any adverse signal of high televiolence would be greatest in patients with ARDS because their lungs are smaller, they're functionally smaller Or put another way that an effect of high title volume in patients without ARDS would be smaller than the effect in ARDS because those without ARDS have larger lungs. Or put another way that the effects seen in ARDS patients should be an upper bound on any effect in non-ARDS patients.

We should see a smaller signal in patients without ARDS. What might be the magnitude of that effect? What is the upper bound? Well, the 2000 R cent trial did not calculate a risk ratio per se, but mortality was 31% in the LTB group and 39% in the control group. A reasonable first approximation for that upper bound in risk ratio would be 0.77 or 31 over 39.

But meta -analyses of papers published between 2000 and 2010 suggested that the mortality effect of low television was the same or even stronger in patients without ARDS. That is, relative risks well below. 77. You know, I refer you to the 2012 JAMA meta -analysis, which reviewed 20 papers published in the first decade of the 2000s and finding a risk ratio of 0.6. And results from OR studies were similar. In particular, the 2013 Futier trial compared 6 to 8 cc's per kilo in PEEP. with 10 to 12 cc per kilo and no peep and puzzled many of us intensivists because of the massive effect of low total volume The relative risk they found was 0.29, so well below any other estimate, on the composite outcome, which was renovation or pneumonia Although the authors found no effect on mortality, it's hard to imagine, at least for me, that a threefold difference in post-op reinhabation and pneumonia didn't somehow affect mortality down the road So I'd say that, you know, in the late 2010s, there was some skepticism in the ICU community as to whether the Futier result could be widely reproduced, which brings us to the rationale for the 2020 JAMA trial.

That's super interesting. So basically what you're saying is that we would expect the adverse signal of high tidal volumes to be highest in patients with ARDS. and we would not expect that effect to be larger in non-ARDS patients. But it sounds like meta -analyses of papers published between 2000 and 2010 suggested that the mortality effect of low tidal volumes was the same or even stronger in patients without ARDS than in those with ARDS We also have a randomized control trial, the Futier trial, that did not demonstrate a mortality difference, but did suggest a pretty massive effect of low tidal volumes on reintubation and pneumonia in non-ARDS patients. With all that in mind, let's head into the 2020 JAMA trial, which explored the impact of intraoperative low tidal volumes versus conventional tidal volumes on postoperative pulmonary complications.

Dr. Tung, what can you tell us about the study design? I'm gonna apologize for potentially mispronouncing the name of the prime lead author, but as I noted above Carolapalai, the lead author of the JAMA trial, conducted a single-centered prospective randomized control trial in 1,200 patients, or 1,236 to be exact. Over four years, his team randomized patients to intraoperative tidal volumes of 6 cc's per kilo, predicted body weight, in the low tidal volume group and 10 cc's per kilo in the control group. The inclusion criteria were fairly standard, more than 40 years of age, surgery more than two hours duration, arterial line access, no cardiac or intracranial neuro, and all patients got five centimeters of PEEP to take that out of the equation.

The primary outcome was a composite of post-operative pulmonary complications within the first seven days after surgery, and this basket of complications is long but fairly standard for this kind of research Pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, unplanned requirement for post-op mechanical ventilation, uh CPAP or non-invasive or invasive ventilation after surgery. This basket was specifically defined to maximize compatibility with other contemporaneous studies of interop ventilation such as ProBase and Propilo. Several secondary outcomes were recorded as I described before, need for ICU admission, hospital into state mortality, sepsis, etc. etc. Got it, so the primary outcome was a composite of post-op pulmonary complications that was designed to maximize compatibility with other studies. And ultimately the groups were randomized to intraoperative tidal volumes of six CCs of predicted body weight in the LTV group and was it nine or ten in the control group?

Nine. Got it. And were there any other pragmatic elements that the authors integrated? That's a good question. Actually, to maximize generalizability, the authors made this trial very pragmatic and did not constrain management decisions that did not involve mechanical ventilation.

So FIO2, respiratory rate, vasoactives, the analogesic plan, including regional anesthesia, antiametics, etc. were left to the individual clinician. You know, I would say this approach is now fairly standard for tidal volume trials and is similar to what was done in the 2019 ProBeast trial, which compared high peep and recruitment versus low peep and no recruitment And the 2014 probehilo trial, which was a similar trial except not in obese patients. You want to be pragmatic because the question is more the real-world magnitude of the LTV effect rather than where it exists, even if that pragmatism might make the signal smaller because you're not controlling things that could affect post-op respiratory complications. That makes a lot of sense and obviously extends to the uh external generalizability of some of these results.

How was the study powered? That's also sort of an interesting quirk, and we'll get to that later. The authors powered their study to a 10% baseline rate of post-op pulmonary complications and an absolute difference of 3.4%. That's interesting because previous trials of ventilation and PPCs in the OR have reported incidences in the 30% range, which is much higher. We'll get to that later.

Now was there anything remarkable in Table 1? Uh not really. Very compatible with contemporaneous trials. The average age was 63. Um 58% was abdominal and 45% of those were laparoscopic. 20% spine, 70% orthopedic, roughly 10% had COPD, and another 10% had asthma, and most of them were ASA2s or 3s.

The actual weight was 82 kilos. The predicted body weight was 63 kilos, which translates into a tidal volume of 6 per cc per kilo, tidal volume of about 380cc. No real differences between groups And what did the study report in terms of the intraoperative variables measured? Well, of course, ventilator settings You know, and this trial differed slightly from others in having arterial access for all patients, so they had blood gas data for all groups, which served as sort of a uh uh a validity assessment As expected, patients in the low title volume group had a lower pH and higher PCO2 values and a higher likelihood of acidosis. Now moving into the results of this study, what were the findings with respect to the primary outcomes?

Well, the authors found no differences in the composite peep uh in the composite outcome of post-op pulmonary complications 38% in the low title group versus 39.3% in the control group, and no differences in any individual component complication. So if you sort of broke out reinnovation as its own component or pneumonia atelectasis, no difference in any individual component of the composite outcome. Got it. So no differences in the composite PPC outcome. And what about any secondary outcomes?

Also no differences. Although I note a numerical difference in the instance of uh SIRS. Which is 1% in the low titom line group and 2% in the control group, a difference that was not significant, but could be hypothesis generating And the authors appropriately described it as such. No difference in length of stay, ICO admission, or mortality. And you can see why, if you were a space alien, you'd say, well, they spent four years, twelve hundred patients Prospective trial, you know, with targeting a 3cc per kilo difference found no difference.

Why did they go to all that effort? And without the history, without the arc of history, you wouldn't know why And I know the authors pre-specified a few subgroups, which included things like type of surgery, approach of surgery, BMI, and risk of complications. Was there anything notable with respect to those pre-specified subgroups? Again, there were no statistical differences, but if you look at figure two, the eye is drawn to the laparoscopic subset, which likely had higher airway pressures with the same tidal volumes Could it be interactive? It's a good question.

And as an editor, I would emphasize that any subgroup signal is hypothesis generating only, and the authors describe this signal as such. But the door is open for someone to do this study in laparoscopic patients, and it's increasingly clinically relevant as the number of robotic and minimally invasive procedures that require insuflation grow. I'll now share some of the key points that the authorized summarized at the conclusion of this paper. The authors observed that in this randomized clinical trial of 1,236 adults, The rate of pulmonary complications within the first seven postoperative days was 38% among those randomized to a strategy of mechanical ventilation with low tidal volume. Compared with 39% among those randomized to a strategy with conventional title volume, a difference that was not statistically significant.

The authors conclude from this that among adults undergoing major surgery, an intraoperative mechanical ventilation strategy with low tidal volume did not significantly reduce postoperative pulmonary complications within the first seven postoperative days. Dr. Tung, where does this now leave us? Which I found surprising given that uh viewed uh skeptically, a paper like this challenges almost ten years of title volume orthodoxy. But I guess I'm not sure whether dogma is being challenged or whether we are gradually clarifying the boundaries uh and magnitude of the LTV effect in OR patients under general anesthesia. I mean, nobody doubts that low tidal volumes improve outcomes in ARDS patients in the ICU.

That's uh for 20 years, that's been the standard. But the OR is different. In addition to shorter durations of mechanical ventilation and patients without ARDS, some preclinical data suggests that inhaled anesthetics themselves may have a protective effect. Because previous trials in OR patients targeted different endpoints, the Fruitier endpoint involved only reinhabation and pneumonia, or different ventilator settings like the probes and probehilo trials, this trial did need to be done I do think that these results warn against the uncritical extension of a therapy that works in one domain into another. You know, there's a tenet of clinical research methodology that if you do not see an effect of your intervention then maybe you need to study a higher risk patient population so your signal is bigger.

This trial sort of reverses that tenet. If you see an effect X in a high risk population, the effect in the low risk population should be less than X You know, and to that I'd add another observation that's uh relevant to this question because the um it's been so many years that effect sizes generally diminish over time. And a great example is the use of sedative interruption uh in the ICU to reduce spend literature time and ICU length of stay. That's when you turn off this sedation every morning and turn it back on at half the original dose when you need it, if you need it. When first studied in 2000 at the University of Chicago, the signal was large.

But twelve years later, it was studied again in a large multi-center trial in Canada, and sedative interruption had no effect. And so what happened is the question, and probably we think clinicians adjusted to lower levels of sedation and so the control groups had shifted to be closer to the intervention group. It's actually rare nowadays that a signal gets stronger over time. I think those are some incredibly important observations you just made. So for our listeners who might have missed it, Dr. Tung mentioned that a tenant of clinical research methodology is that if you do not see an effect of your intervention, then maybe you need to study a higher risk patient population.

This JAMA 2020 trial was sort of that tenant in reverse. So if you saw an effect X in a high risk population, then the effect in a lower risk population should be less than X Dr. Tung, we mentioned this briefly, but I'm also curious as to why you think about what you think about why the author overpowered the study. Yeah, that's a good question. It it doesn't affect study interpretation, but it is interesting. I would say from an editor perspective, the much more common move in papers submitted to journals is to underpower the study either by choosing a high baseline incidence or a large effect size for your power analysis.

Both moves result in a lower end which lets you get the study done faster and with less cost. But if your actual incidence is low or your effect size is lower lower than you thought, then you will be forced to conclude no difference statistically even when everybody thinks there was a difference. And there are a number of trials that have popped up with that, you know, observation. Andromeda shock is one, but my favorite is the 2015 proper trial done, you know, comparing one-to-one to one, you know, red cells to FFP to playlists versus one to one to two. product ratios for trauma resuscitation. They powered to a mortality instance that the actual trial did not reach because trauma care had gotten better over the duration that they were planning and then designing and then executing the study.

So they had to conclude no difference between um product ratios in their study even though the general consensus on proper is that one to one to one is better. In this case, overpowering the study helped the conclusion of no difference It always does because it reduces the chance of a type 2 error, which is finding no difference when there actually is a difference. Plus, by overpowering the study, you can increase the chance that any sub-outcome of the study might show a signal So, for example, if you're wondering, was it was their signal in reinhabation? If you overpower, you look at more patients, and so your reinhovation signal gets bigger. Finally, they intentionally chose an endpoint used by other studies to maximize compatibility, and their final instance of PPCs was very similar to both Pro-Base and Pro-Hy-Lo.

Got it. So it it obviously sounds like they put a lot of thought into overpowering this and that ultimately by doing so it really helped the conclusion of no difference by reducing the chance of type two error here. We discussed earlier some of the literature from 2000 to 2010 looking at low tidal volumes in non-ARDS patients. especially the Futier trial, which demonstrated a threefold difference in post op reintubation and pneumonia rates. How do we now interpret these seemingly directly contradictory findings between the Futier trial and the 2020 JAMMA trial? Yeah, that that that that's a good question.

Uh Futier found a large, big benefit of low title volumes on reinovations and pneumonia. Carolopoli found uh no effect on mortality, renovation, or any other pulmonary complication. Of course, one explanation is that either Futier or Carolopoli were wrong. I guess flukes, if you will. Just because something is statistically significant doesn't mean it's reproducible.

But if you accept both findings as real, paperologists have come up with a few differences between trials that may help explain the divergent outcomes. The first is that uh the two trials studied different interventions and use different endpoints. You know, as described, Futier looked at reinhabations and pneumonia only. But they also studied a bundle of ventilator strategies, six cc's per kilo and peep, five and recruitment maneuvers versus ten cc per kilo and nothing else. So if you unbundle the tidal volume P recruitment package, maybe one of those is the significant element.

Futier also studied a large longer duration mechanical ventilation. You know, he was his was uh 320 minutes versus uh an average in the carilopli trial of 220 minutes, so that's a hour and a half difference. And Futier studied only abdominal surgery and 80% of his patients had cancer, which is very different from the uh all-commerce group that caralopli studied You know, but these differences are small. Ultimately it's hard to imagine that both studies could simultaneously be be true. And I know you were able to connect with Dr. Kara. with Dr. Karolapalai by email.

Could you share some of the highlights of the discussion you had with him? Uh I actually did. I emailed him, you know, because I was curious about you know the design and conduct of the trial, what he thought about the results, and he actually responded. Uh so um I guess uh you know I'm gonna just gonna read exactly what he says so I don't misrepresent him. You know, I said, were you surprised to find no endpoint?

And he said, well, you know, we hypothesized that low tile violence would be associated with a lower instance of PPCs based on the mechanistic understanding of uh ventilator associated lung injury. He said, however, we were not trial , surprised our trial was negative. We had worried that uh the Futier trial, you know, was uh sort of not about title volumes alone since they used a bundle of care with both PEEP recruitment and title volumes We also felt that the high 12cc per kilo of title volume in the absence of PEEP in Futier's control group might have been toxic. I asked him, I said, uh, was there a reason you powered your study to such a low anticipated incidence?

And uh he said, well, the predicted incidence was much lower than we found, but we felt good that you know our incidence of respiratory complications was very similar to other major trials. This uh suggests a generalizability by population. And in fact, as an editor, I concur with that. You know, if you're studying a signal that other people have studied and you find some number that's very different from other people You need to explain why, or we would all worry what exactly was going on with your methodology. In fact, I asked him, I said, you know, you didn't have to study your your basket of complications.

You know Uh the instance of any of your individual outcomes exceeded your 10% threshold. Why did you use the compound endpoint? And he said, well, we used it specifically to be consistent with other major trials You know, we did it deliberately so that deliberately so that our outcomes could be referable to theirs. And finally I asked him, I said, how did you place your crowd in context? Do you think the Futier trial was flawed?

Do you think your intervention was insufficiently large? You know, and he said, well, we worry that the French trial was flawed and that the control group was potentially harmful. We wanted to do a pragmatic trial of reasonable tidal volumes, high versus low. Uh and to compare it to what was current practice in our region, and we felt we've answered this question. We feel that the safe title surgery is between six and ten cc per kilo when PEEP is equal between groups and that there is no protective effect within that band of low tidal volumes.

You say we also take note, you know, that there's a sort of a hint of a signal in the laparoscopic group, you know, and maybe that needs further study And he said that maybe the French study, the Futier trial, wasn't about tidal volume, maybe it was about something else like PEEP or about recruitment maneuvers. So the authors have obviously put a lot of thought into the design of the study, and Dr. Karalapalai seems to confirm many of the observations that you've noted throughout this episode. Well then I guess the question is is it PEEP or recruitment? And what about driving pressure? I know I've heard driving pressure mentioned often in the ICU, so for our listeners who may be unfamiliar, could you briefly review that concept?

All right. Well let me try to unbundle those issues and you know talk a little bit about driving pressure. You know, in the ICU we've uh looked at the probe hilo trial which looked at uh you know, PEEP versus no PEEP in recruitment uh versus no recruitment in tidal volume, you know, which really found no difference between PEEP levels of two and ten. So if there is a PEEP effect, you know, it's somewhere outside the two to ten band Studies showing with no peep are still coming out, and those studies consistently show an outcome. So maybe there is some no-peep effect, you know, that can be seen in some populations With respect to driving pressure, that's the difference between the plateau pressure during inspiration with mechanical ventilation in positive pressure and the end expiratory pressure or PEEP in positive pressure ventilation.

In the ICU, driving pressure associates more strongly than any other ventilator variable with outcome. You know, very early meta-analyses in the OR suggest that the driving pressure response to PEEP Uh really when you add peep whether your um lung becomes over or understanded or moves into the sweet spot may affect outcomes. So if you Apply PEEP and your driving pressure goes down, then you've moved into the most compliant zone for the lung and that's good. If you apply PEEP and your driving pressure goes up, that means you've moved into an overdistended position. on your lung where your driving pressures are higher and that's bad. But all of what I just said is very preliminary and we're gonna it's gonna take prospective work to uh suss out.

All right, Dr. Tung, that was certainly an extensive and very thorough review of not only this paper, but a lot of the surrounding literature that puts this recent article in context. Can you try to summarize some of what we discussed today? Okay, it's a long summary, but let's try this distillation here. All right, uh abundant preclinical data going to almost a quarter century suggests that overdistending alveoli in animals and in humans worsens lung inflammation. In ARDS, the amount of functional lung is smaller due to heterogeneous lung damage.

So if you don't want to overdistend the normal part of the ARDS lung, you need lower tidal volumes And clinically, limiting tidal volumes to prevent overdistension of normal alveoli in patients with ARDS improves outcomes. We're pretty sure that's true. In principle, extending the same therapy to patients without ARDS, such as those in the OR, should produce a smaller effect, as those lungs are not small. They don't have ARDS. And yet, many studies have found strong effects of low tidal volume even in non-ARDS populations.

This trial clarifies the magnitude of that effect by finding no effect of tidal volumes on post-outpulmonary complications across a 6 to 9 cc's per kilo range and is the largest prospective randomized trial in the OR to date Along with ProHilo and Probeast, which studied various combinations of PEEP and recruitment maneuvers, the weight of recent trials suggests a limited benefit, if at all, to intraoperative ventilator settings within PEEP values ranging from 2 to 12 And tidal volume values ranging from 6 to 9 cc's per kilo, and that's predicted body weight, which is different from ideal. It's often lower The mechanism for these divergent outcomes is unclear, but a metric that may predict outcome better is driving pressure, and that's going to need further study.

Well put, Dr. Tung. Here now are two questions for our listeners to think about from the start of our show. What is the level of your agreement with the claim that low intraoperative tidal volumes reduce postoperative pulmonary complications? And what is the level of evidence for what you believe? Dr. Tunk, thank you so much for taking the time out of your busy schedule to join me on the show today.

This episode was chock full of truly incredible and insightful information. and I know that many of our listeners will benefit from your perspectives. Well thank you, Dr. Howe. It's my privilege. To our listeners, we have an assembled and ambitious team of individuals who are committed to critically exploring our clinical practices together. If you want to help us on our mission, please consider supporting us on our new Patreon.

Your support will help us cover the growing costs of producing and hosting this material. And you can go to patreon. com slash depth of anesthesia. I'll be sure to include a link in the episode description as well. Thank you again for taking the time to join me and for thinking deeply about your clinical practices. You are all making an incredible difference out there.

Stay hungry and keep asking questions. So there's a very spanning spellout, there's a big spazu, but the spirit spanish music.