SCCM Resource Library-Year in Review: Internal Medicine

Video Transcription

Hi, everyone, and thanks, Bram. I think the goal of this session is to generate audience discussion. So hopefully, I'll keep this brief and just present some of the data.  And at the end of the session, as Bram said, we'll have lots of questions. I have no relevant disclosures for this talk. The objectives of my talk are to go through three trials.  Target temperature management and non-shockable rhythms, that's the Hyperion study. Vitamin D for critically vitamin D deficient patients, that's the Violet study.  And vitamin C for sepsis-associated acute lung injury, which is the Citrus ALI study. All right, the PICO question for the target temperature management and non-shockable rhythms.  In patients with coma after successful resuscitation, so PICO, patient intervention, comparator, and outcomes. So that's the format I have phrased each trial  that I'm going to present in. In patients with coma after successful resuscitation from cardiac arrest with non-shockable rhythms, does moderate hypothermia, defined as 33 degrees  centigrade, compared with targeted normothermia, defined as 37 degrees centigrade, improve neurological outcomes? OK, so the premise of this trial is clear.  Obviously, everyone knows that moderate hypothermia, or at least targeted temperature management, has demonstrated benefit in out-of-hospital cardiac arrest with shockable rhythms.  However, in non-shockable rhythms, the data is equivocal. There have been some retrospective case studies, but the case studies have either shown benefit or harm,  or no effect at all. And moreover, everyone knows that if you have, or if a patient has cardiac arrest from non-shockable rhythm, the neurologically good survival  is absolutely dismal. OK, so this was the methodology of the Hyperion trial. Open label, blinded, outcome assessor, randomized controlled trial in 25 ICUs in France.  Patients with cardiac arrest from non-shockable rhythms of any cause could be included. They could either be out-of-hospital arrest or in-hospital arrest.  Their definition of coma was a GCS of less than or equal to 8. Randomization was to 33 degrees centigrade. It was 33 plus or minus 5 degrees centigrade  versus targeted neurothermia, which was 37 plus or minus 5 degrees centigrade. And some of the major exclusion criterias were a no-flow time of 10 minutes,  or greater than 10 minutes. A no-flow time is the time of onset of cardiac arrest to the delivery of first CPR. CPR to ROSC, which is a return of spontaneous circulation  of greater than 60 minutes. Cardiac arrest to screening time of more than 300 minutes. And epinephrine or non-epinephrine doses at more than one mic per kg per minute.  The outcomes of interest and the temperature management strategies were as follows. So in the hypothermia arm, there was 24 hours of hypothermia with a site-specific protocol.  What a site-specific protocol means was you could use external passive warming, external active warming, oh, sorry, cooling. And or internal active cooling.  And then there was slow re-warming by about 0.25 to 0.5 centigrades per hour to 37 degrees for 24 hours. And the normothermia arm had a temperature of 37 degrees for 48 hours.  Now, please note that in the hypothermia arm, people were either hypothermic or at target temperature for a bit longer than the normothermia arm because  of the slow re-warming process. Outcomes. The primary outcome was survival with favorable neurological outcome, defined as cerebral Pittsburgh,  cerebral performance category 1 or 2 at 90 days. So 1 is mild deficit and 2 is moderate deficit. There is debate whether that is the best outcome to use or not.  But this trial used the cerebral performance category. The secondary outcomes were mortality, mechanical ventilation duration, length of stay,  infections, and hematological adverse events. There were some more. I just listed the major ones. So there were 2,723 patients assessed for eligibility,  out of which 584 were randomized, 284 to the hypothermia arm, 297 in the normothermia arm. Three patients in the hypothermia arm withdrew consent.  And hence, they started out with 287 but were left with 284. There were no baseline differences in groups. About 3 quarters of cardiac arrests were out of hospital  and 1 4th were in the hospital. On the right is the mean body temperature versus hours since randomization graph. And as you can see, there's a clear separation of temperatures.  The one thing to note here is that when people were randomized, everyone had mild hypothermia. So actually, the group that received the normothermia got warmed a little bit.  Again, there was no difference in mortality in this trial. Mortality was exactly the same. Survival was really dismal. But of the people that survived, the people in the hypothermia  arm actually had good neurological function twice as much as the patients in the normothermia arm. And this was the only thing that was statistically significant.  The other things were not. So Pittsburgh Cerebral Performance Category 1 or 2 occurred way more frequently off the survivors, which were very few, in the hypothermia arm.  All right, so one caveat of the study is something called the fragility index. So the fragility index is the minimum number  of participants in a randomized control trial whose status would have to be changed from non-event to event. So non-event not experiencing primary endpoint,  event experiencing primary endpoint. Event experiencing primary endpoint. So in this trial, primary endpoint, neurologically beneficial or neurologically good survival.  And non-endpoint, not neurologically good survival. All right, to turn this statistically significant result to non-significant. So you would probably just need one patient.  The fragility index of this trial was one. So you would just have, if the trial had just one patient, that experience that went from not being good or being  good to bad, the trial would have been non-significant. OK, the takeaways from, or my takeaways from Hyperion. Cardiac arrest from non-shockable rhythms  is associated with the high mortality. Use of hypothermia may lead to more patients with favorable neurological outcomes compared to normalthermia.  And there is, in the appropriate patient, if you really think that you should be doing hypothermia, there is little downside to using hypothermia and non-shockable rhythms as there  was no significant difference in adverse events between the two groups. All right, the next trial, this is the Violet trial. The bigger question is, in critically ill vitamin D  patients at high risk of death, does early administration of high dose vitamin D compared to no administration of vitamin D reduce all-cause 90-day mortality?  The premise of the vital trial, of the Violet trial, I'm sorry, was one randomized controlled trial done in 2014 that suggested benefit  of administering vitamin D to critically ill patients. Another meta-analysis which showed that vitamin D may be associated with benefit. Now, this meta-analysis was largely  driven by the data from the Vital D ICU RCT, which I have shown on the left. The methodology of the trial, this was a phase three,  double-brine, multi-center, randomized controlled trial, which gave one single enteral dose of 540,000 international units of vitamin D3 versus placebo.  The inclusions, and please note, I haven't listed all of the exclusion criteria here. I've listed just the main ones. So the inclusions were adults with one or more acute risk  factors for death or acute lung injury contributing to the need for ICU admission, such as pneumonia, sepsis, shock, et cetera, and a 25 hydroxy vitamin D level of less than 20  nanograms per milliliter. So in this trial, if a physician either in the emergency department or on hospital ward, for example, said yes, this patient can go to the ICU  and the patient had risk factors, within 12 hours, the vitamin D3 dose had to be given, and some people actually got it out of the ICU. The exclusions were history of kidney stones,  inability to take the enteral drug, and hypercalcemia. Their primary outcome was 90-day all-cause, all-location mortality in the primary analysis population.  Now, I'll spend 30 seconds explaining the primary analysis population. So the way the folks could be randomized in the trial was you got consent and said the family  member of the patient said, sure, I'll be in the trial. A vitamin D level was checked. And this was either a point-of-care test or a rapid test in the hospital laboratory,  but this had to be confirmed by liquid chromatography tandem mass spectrometry at, I think, a lab, the confirmatory lab was in Washington University.  However, so not all of the people who screened positive at less than 20 milligrams per nanoliter, 20 nanograms per milliliter, actually truly had vitamin D deficiency  when measured by mass spec. So the primary analysis population is just those people that were confirmed by mass spec to have low vitamin D3 levels.  Secondary outcomes were hospital stay, ventilator-free days, and quality of life. This is how the randomization took place. So consent was obtained from over 2,000 patients.  1,360 patients screened vitamin D deficient. Of those, 1,078 actually were proven to be vitamin D deficient. 19 were lost to follow-up, and the rest  were randomized to either vitamin D or placebo. And as you can see, there was no difference in mortality at 90 days, whether in the placebo arm versus the vitamin D arm.  And even if you stratified it by vitamin D levels, again, there was no significant difference in mortality. So Kaplan-Meier graph on the left, all-cause mortality versus time,  and Kaplan-Meier graph, or the graph on the right, is mortality stratified by baseline vitamin D levels. Okay, but the most interesting finding of this study  is that in pre-specified subgroups, and I'm sorry, I did not separate them out into the screen population and the primary population, or the primary enrolled population.  This is sort of in both arms.  If you had pre-existing ARDS before vitamin D was given, if your reason for admission to the ICU was infection, pneumonia, or sepsis, the vitamin D arm had higher mortality.  Okay, so the takeaways. So there was high mortality in the vitamin D arm in patients with infectious causes and illnesses, as well as pre-randomization ARDS.  This was very unexpected. It was counter to the reported immunomodulatory properties of vitamin D, and the results do not support testing or treating vitamin D deficiency  in critically ill patients. All right, my last trial is the CITRIS-ALI study. We've all talked about, you know, negative studies. This is really an exciting trial,  but take the results for what you will. I find the results only to be hypothesis-generating. All right, in critically ill patients,  the bigger question is, in critically ill patients with sepsis-induced acute lung injury, does vitamin C supplementation compared to no supplementation  improve sequential organ failure assessment and biomarkers of inflammation and vascular injury? So this trial was not actually powered to mortality outcomes.  Okay, and obviously the premise is that low vitamin C levels are consistently seen in sepsis. They correlate with high incidence of multiple organ failure,  and they also correlate with poor survival. So the methodology of the study was, multi-center blinded, randomized controlled trial. Vitamin C at a dose of 50 milligrams of KG  was given every six hours for 96 hours versus placebo. The inclusions were sepsis-associated ARDS, and the exclusions, again, some of the exclusions  were an allergy to vitamin C more than 48 hours since meeting ARDS criteria, more home mechanical ventilation in a moribund patient. The primary outcomes, like we said,  were sequential organ failure assessment scores at 96 hours, plasma C-reactive proteins such as thrombomodulin,  sorry, anthromomodulin at up to 168 hours. They had 42 secondary outcomes. Okay, some of the secondary outcomes were ventilator-free days, ICU-free days, hospital-free days to 60,  and all-cause mortality to day 28. Again, a lot of patients were screened. Only 170 were randomized. And in the end, there were 83 in the placebo group  and 84 in the vitamin C group. These are some of the results, the primary analysis results, the average SOFA scores, thrombomodulin, and C-reactive protein.  No differences in either, in both arms. So whether you gave vitamin C or not, or placebo, they were exactly the same. What is really interesting was the arm that got vitamin C  had a better mortality than the arm that got placebo, and this separation actually occurred very, very early during the time that the vitamin C was being infused  during the first 96 hours. There was a clear separation in the Kaplan-Meier curves. Although the ventilator-free days were not different, ICU-free days and hospital-free days  were significantly lower in the vitamin C arm. Now, since this trial, so remember, the SOFA scores that were measured were measured only in survivors, okay? And so the question is,  was there a survivorship bias in this study?  So because the people who died, or the people who got to the floor, you know, the SOFA scores were sort of messed up, and so what this figure demonstrates  is that the people who died were given the worst SOFA score of 20. Now, the worst SOFA score is actually 24 and not 20. In this trial, it is 20 because they excluded bilirubin.  There were a lot of missing values for bilirubin because clinicians just didn't check bilirubin, so their SOFA scores only went up to 20, and the best SOFA scores of people  who got better and went to the floor were zero, and if you used that methodology, there was a statistically significant benefit in SOFA scores at 96 hours in the vitamin C group.  All right, the limitations of the study were that the secondary outcomes were really not adjusted for the multiple comparisons that were made.  We've already talked about survivorship bias, and perhaps there was an internal selection bias as death and ICU-to-floor transfer rates were very different in both groups.  Okay, so the takeaways for me for this trial is this vitamin C appears to be safe in critical illness. It may be associated with a mortality benefit in sepsis-associated ARDS,  and this data is hypothesis-generating, should be used for design of future trials. There are several ongoing trials of vitamin C,  one that just recently got published from Australia, but we are not talking about that. There are another couple of trials that are ongoing, you know,  and please be tuned for the results, and I thank you for your attention.  Thank you very much, Rahul.  Our next speaker is Dr. Tina Chen, assistant professor at the Albert Einstein College of Medicine, works as a consultant intensivist  at Montefiore Medical Center in the Bronx, New York. Welcome.  Hi, I'm Tina Chen from Montefiore Medical Center. Thank you for giving me the opportunity. So I also have nothing to declare. So coming up with some of the articles to review today,  I wanted to talk about how sepsis research, bring up few sepsis research in 2019. So I'm gonna talk about a study on a patient level,  one on phenotyping and another study on population level. So the first study is by Hernandez et al, and this was done in South America, including five countries with 28 ICU.  They wanted to look at peripheral perfusion targeted resuscitation strategy with serum lactate levels on the 28 day mortality in patients with septic shock.  So this question is important for us as practicing clinician is that when you're on the bedside, the question I always wanna answer is,  have I adequately resuscitated a patient in shock? So the study included patients who are on vasopressor, and that is their definition for shock  to maintain a normal blood pressure of 65. And they wanted to test the peripheral perfusion versus serum lactate, and the surrogate  for the peripheral perfusion is capillary refill time, and a time of less than three second, greater than three second is considered abnormal.  And the study protocol is not as straightforward as just comparing capillary refill time with serum lactate, they really actually had a really stringent protocol  on how the participating clinician treat these patient. So if someone has an abnormal capillary refill time or abnormal lactate while on vasopressor,  they will first perform a fluid responsiveness test. If the patient is responsive, they will get 500 cc fluid challenge, and this goes on.  Once they become unresponsive to fluid responsiveness test, they get a secondary test to see if this person is normally hypertensive at baseline, then the clinician needs to target  for a much higher MAP goal of 80 to 85. And then after that, they would try inotropes to see if they could normalize again the capillary refill time or serum lactate.  They found that there was no difference using capillary refill time as a marker versus lactate as a marker for resuscitation strategy and 28-day mortality.  The absolute unadjusted difference between the two group was favoring the capillary refill time group with 8.5% reduction, but the study was powered to look at 15%, therefore,  they didn't find a statistically significant difference in the two groups. So the takeaway for me is that capillary refill time is easy enough to do,  as easy as putting a sly on your fingers. It's probably a good method for places that have limited resources to check lactate and that the study is under power  to really show a significant difference. So perhaps a bigger study could. So the next study I wanted to talk about is derivation validation and the potential treatment implication  on different phenotypes of sepsis. And this is done by Seymour et al. in Pittsburgh. So the question I had when I picked this one is,  we all know sepsis is a non-homogeneous condition. And can we actually identify these different phenotypes? The primary aim of the study is to derive  and validate these sepsis phenotype. And the first part of the study was to determine if they could use clinically available information early on to define these types.  And they want to validate the types to different biomarkers as well as clinical outcomes. The first cohort they assembled was single center of Pittsburgh  with 12 hospital sites with people arriving with septic shock early, sepsis early by SEP3 criteria. And that helped them derive the phenotypes and validate the phenotype algorithm.  They used 29 clinically available markers like your vital signs, white counts, and such. And then they further validated the phenotypes that they made  with clinical outcomes and biomarker with four other study including the genetic inflammatory marker studies as well as access, prowess, and process.  And all these study had 27 serum markers that they could compare with. So they found that there were four different distinct phenotypes and each type had associated  with different clinical variables that they measured in the beginning of the patient presentation. The first type was alpha type.  And these were more likely to be the less sick patient who had fewer abnormal lab, fewer, less organ failure. Then the beta type who were slightly older, had more renal dysfunction.  Then the gamma who had higher white counts, markers for inflammation that we could get as clinicians. And lower albumin and higher temperature.  And finally there was the delta type which had higher lactate, more transaminases, abnormality as well as hypotension. And these types correlated well with biomarkers.  As you could see on your left-hand side, the group that has less abnormal labs actually had less inflammatory markers that's elevated and less coagulation markers that was a normal  when they compared to the studies that did have biomarker data. And then on the other side, the studies that have high lactate, high inflammation markers,  they also had high biomarkers that's elevated. And not only did it correlate well with biomarkers, these phenotype correlated well with clinical outcomes as well.  The site on your left-hand side, the less sick group had less mortality. And the group that has the highest mortality is the delta subtype.  The group that has highest lactate had high proportion of hypotension, had high in-hospital mortality, as well as ICU admission. But they didn't actually find the use of vasopressor  or mechanical ventilation associated with any specific subtypes. The last step of the study is they wanted to see if this has any implication in the past clinical trial  and how do we carry it forward. So this is an example on one of the studies they applied these subtypes to. So the first panel on your left-hand side is the original  breakdown of process here. It could see the breakdown is pretty even. You have alpha, which is the less sick. The blue, which is the delta, which is the sickest group.  In the study, they found no difference between usual care and early goal-directed therapy. If you change the breakup of these subtypes, meaning here  when they increase the subgroup of the less sick patients, the green part, they actually said that you could potentially find 30% increased chance  of benefit for early goal-directed therapy. On the other hand, when they change it to having most of the breakdown as having the delta type,  which is the sickest group, there's 50% chance to increase harm in using early goal-directed therapy. So for me, the takeaway is that they could use clinically available data early  on in admission to define four different subtypes of sepsis. This could lead to personalized medicine if we could identify which group should get which type of therapy.  And ultimately, if we have the ability to identify these people, will we be able to impact future clinical trial by enriching the right people and the right studies?  So the last study I want to talk about is association between state-mandated protocolized sepsis care and in-hospital mortality with patients, septic patient.  And this is by Con et al., also at Pittsburgh. So the question I had here is, does state-mandated sepsis protocol affect clinical outcome?  So in 2013, New York State put for, implemented a mandate that each hospital needs to have these five things done. Antibiotics for patients who are suspected  of having sepsis within three hours. They need to get fluid within six hours. The hospital needs to have routine training for their staff in terms of implementing these protocol.  The hospital needs to report the protocol adherence as well as sepsis to the state. So what they found is that this regulation actually decreased 30-day in-hospital mortality.  On your left-hand side, it's the unadjusted 30-day mortality comparison. The dotted line in the middle is when the implementation of those five things happen.  So before implementation, New York State actually does have slightly higher 30-day mortality compared to the four-controlled state.  And these controlled states have similar demographic, geographically close to New York except Florida. And after implementation in the unadjusted graph,  you could see that New York State mortality seems to have dropped a little bit. And then on the right-hand side is the adjusted mortality.  And what the dotted line show is what they use adjustment models and model on if everything stays the same, what would the mortality be after implementing,  after the implementation of these protocol. It turns out, as you could see here, the controlled state stays within the predicted mortality.  On the other hand, New York State started dropping and by the third quarter of 2015, the relative decrease is by 3%. And they also found a few other things that they wanted to look  at if ICU admission rate would go up when you implement a sepsis protocol. Which they did not find. And hospital length of stay was not consistently increased either.  There was actually relative decrease in C. diff infection. And one of the reasons why they looked at C. diff infection is when you think of now we're giving everybody antibiotics  with suspected infection, does that increase their C. diff? And in fact, it didn't. And lastly, they did see an increase in central venous line use.  The takeaway is that this is a natural experiment on how policy can impact clinical outcome. And the one question I have is I still wonder which part  of that protocol actually was the major impact and how the change in outcome happened. So that's it. Thank you, Tina.  Our third speaker of the day is Dr. Quad Kiramantang. Quad is an assistant professor at the University of Ottawa, back in Canada where I'm from as well.  He co-trained both in critical care and in palliative care. And is the founder of the Solving Healthcare Podcast. Welcome, Quad.  Thanks, everybody, for having me. First, Bram, thanks for the invite. And I wanted to give a quick congratulations. You had a nice CIHR grant that was awarded.  So congratulations on that. So I'll just jump into it because we only have about 15 minutes. So the central theme of the ones that we chose were  around mechanical ventilation and weaning. So the first paper we talked about was looking at strategies for reducing reintubation amongst high-risk patients.  And, you know, there was a few papers in the last few years that have come out in terms of how can we reduce these rates. So we've seen studies  on non-invasive ventilation post-extubation. We've seen studies on high flow as well. And recently there was one non-inferior study looking  at, you know, non-invasive versus high flow. And so this group in France elected to compare non-invasive and high flow versus just high flow. So this was done in 30 ICUs in France.  And the way they defined high risk was patients that were 65 years old and older with underlying cardiac or respiratory diseases, which we'll point out in a second.  In terms of primary outcomes, it was reintubation at day seven. Secondary outcomes were respiratory failure at day seven with also reintubations up till discharge.  And, of course, mortality. So busy slide, but basically illustrating that they screened over 3,000 patients and ended up randomizing about 648.  The baseline characteristics were equal, but I just wanted to point out once again the underlying chronic cardiac conditions. Ischemic heart disease and AFib  in previous studies weren't necessarily added as high risk patients, but in this study they were. And in terms of primary outcome, we did see a statistically significant reduction  in reintubations at day seven. So that's looking at 18 versus 12% and a reduction of about 6.4% with a p-value of .02. And then amongst the secondary outcomes,  respiratory failure at day seven, reintubation rates two and three days post, and up to discharge, were all statistically significant.  We saw no changes in length of stay or mortality.  Just of note, because a lot of the studies that were done previously with noninvasive ventilation post-extubation were focused on hypercapnic patients, patients with mostly COPD.  And just to illustrate here that the predominant of, like there was an amplified effect amongst the patients that did have hypercapnia. But once again, those that do not have,  that were nonhypercapnic also had similar improvement in reduction in reintubation rates. So overall, author's conclusions, yes, we are seeing less reintubations with patients  that receive both noninvasive and high flow compared to just high flow. In terms of limitations or, you know, discussion points, obviously this was an open label study.  About a third of the patients actually that were in the control group did receive noninvasive, which would clearly dampen the effect. There was some argument, too,  whether they should have compared instead of high flow using standard oxygen as a comparator. I know certainly at our site, I wouldn't say our standard practice is  to put high risk patients necessarily on high flow. I think our tendency is still to put them on noninvasive. So, or on standard oxygen.  So it would have been interesting to see that as well. Because of the amplitude or the level of like doing in 30 ICUs, the weaning protocols were not standardized.  And the high risk definition was different than previous studies that were established. So, the next paper. Conservative oxygen therapy during mechanical ventilation in the ICU.  So, as many of you guys know, there was a Lancet systematic review looking at conservative oxygen therapy, which showed a significant reduction in mortality.  So, this was a big driver for this ICU ROCS study. This is 1,000 patients randomized in Australia and New Zealand. And in terms of the conservative arm, that was,  they were aiming for oxygen saturations between 70 or 90 and 97%, excuse me. Usual arm was actually, they were quite liberal. So, they allowed for oxygen saturations  above 90% and it was up to the discretion of the team to what level. The primary outcome was ventilator-free days from randomization up till day 28.  Secondary were mortality outcomes, as well as quality of life metrics. So, once again, over 3,000 participants were screened and about 1,000 underwent randomization.  When you look at basically all primary and secondary outcomes, there was no difference. Specifically talking about the primary outcome, 22.3 versus 21.1, 21.0 ventilator-free days  with no difference. And once again, no difference in mortality, no difference in quality of life metrics, and no difference in vasopressor-free days or dialysis.  Here's a capital marker just to illustrate what we just mentioned. And there was no divergence at all throughout the randomization period.  So, in terms of conclusions, conservative oxygen therapy, no difference compared to usual oxygen therapy in terms of the primary outcome of ventilator-free days.  So, in terms of discussion points, again, this is obviously a label study. They didn't standardize the control group. Like, it would have been interesting to say, like,  you know, we want the standard group to have SATs greater than 97%. The, as per their power calculations, they were underpowered to find a difference.  And obviously, in terms of mortality, they would have to be powered even further. Another issue was the clinicians were allowed to increase oxygen  in both groups for specific, some specific circumstances. So, that may have impacted outcomes as well. So, my last paper was the early neuromuscular blockade in ARDS patients.  So, the 2010 study determined that early administration of neuromuscular blockade reflected an improvement in mortality amongst those patients.  So, this was the, but just for this paper, this was over 1,000 patients randomized, once again, to moderate to severe ARDS.  They got continuous infusion of Nimbex and was deeply sedated. And in terms of the usual care, this group was aimed for light sedation, which is a key difference in the studies,  which we'll talk about in a second. And the primary outcome was 90-day mortality. So, the main reason I wanted to put the flow diagram here was  that there was a significant amount of patients, 655 that were, weren't added to the study because they did receive Cysatricurium prior to randomization.  So, obviously, or potentially an influence from that 2010 study. But that's a significant amount of patients that weren't able to participate. Baseline characteristics were similar.  And in terms of primary outcome, no difference in hospital mortality at 90 days. Both groups, intervention group was at 42.5%. Control group at 22 point, or 42.8%.  And in terms of secondary outcomes, once again, they were not significant. The one thing that is worth mentioning, ICU acquired weakness, once again, was not different.  The only one that was different was there was more cardiovascular adverse events, 14 versus 4 with a p-value of 0.02 in the intervention arm,  those that received neuromuscular blockade.  So, amongst patients with moderate to severe ARDS with a higher PEEP strategy, there was no significant difference in mortality at 90 days.  So, here's the key points here when we compare to that 2010 study. I was trying to get Bram to tell me how to pronounce this, but what do we agree on? Acurisis. Acurisis.  Yes. Acurisis. Definitely higher PEEPs in this study, in the 2019 study. The control arm had more light, the sedation was lighter. They had less proning in this study.  There was also earlier enrollment compared to acurisis. And as I mentioned earlier, neuromuscular blockade prior to enrollment, they lost quite a few patients because of that.  And that is all I have, and this is a shameless plug to the show if you guys want to listen to a podcast that will inform you on how to solve healthcare. Thank you. Excellent.  Thank you, Quata. I invite our speakers up to return to the stage, please. And amazingly, we have just over 15 minutes actually for questions. So strongly encourage a sort  of a nice intimate atmosphere, smaller group. If anybody does have questions, please come to the microphone. Perhaps I thought I would start, and my question, Elliot,  we'll get to in a moment, for Tina maybe to start. I know a lot of the feedback after Andromeda was there were differences  within the protocols, both the intervention and the control. And some of it with the cap refill test, it mandated the physicians were  at the bedside checking cap refill test every 30 minutes compared to the lactate arm. I wonder your interpretation of how much maybe the collateral impact  of having a doctor there every 30 minutes might have impacted this, you know, perhaps benefit with cap refill time compared to lactate measures. Great question.  And I'm in agreement as well. When you have someone at bedside, that frequently decision can be different. The other thing is they do have a pretty stringent protocol  after you do an individual test that you have to do a fluid responsiveness test to give additional fluid or increase vasopressor or give inotrope.  And I think that's a way for them to perhaps control some of the things that could be different between the two arms. Excellent. Elliot? I had two questions.  One on the vitamin D study. It's interesting that you're giving vitamin D to people who are septic or infected in one way or another, and those people tend to have a worse outcome.  Did they measure the active 125-hydroxy vitamin D levels in those patients? And, you know, because I wonder if their macrophages were active.  And now you're dumping a bunch of vitamin D in there, and it's just feeding the fire. So I am, they did measure vitamin D levels now.  I mean, and the vitamin D levels were of the majority of the patients that they give vitamin D to were actually returned to the normal range.  There were, I think, about probably a quarter of the patients or even less that the vitamin D levels that didn't return to the normal range.  Now, I'm not exactly sure what, maybe Michelle can, you know, she's part of the PETAL network. So was 125-hydroxy vitamin D measured as well?  I don't remember precisely. We know actually all the examples. We're not on the menu, but we're not sure if they were actually taking that. Yeah.  It might be interesting to just see. They predict in an infection, you might have more active vitamin D, and maybe you get a different outcome in that group.  Then I had another question, just because nobody else is coming up, so I'll go ahead with it.  It's kind of more of a comment, I guess, about the really interesting, about the phenotyping of septic people. I think we all have sensed that there's a difference among them.  But it kind of makes a, how do you interpret that? So people who are less sick, fewer organ failures, benefit more from the sepsis-bundled care  approach. And then the other ones are kind of refractory, maybe too late. So how should we detect sepsis and treat sepsis?  Should we wait until the organs start failing and call it sepsis 3, or should we be trying to detect it sooner and treat them when they're most likely to respond?  I'm kind of guiding you, I guess. I think that's a very deep question, and in some way I feel like it's above my pay grade.  But they were able to type them with very early clinical variables within the first six hours of presenting to the ED.  So in some way, I feel like, I don't want to say your fate is sealed by the first six hours of presenting, but this is a good practice for us to think of patients differently and  modify our treatment and may not be just kind of focused in one way of managing. And then to answer the previous vitamin D question, I wonder if they did have enriched  the trial differently with different phenotypes, perhaps the result could have been different too. Yeah, I guess, and also I think maybe timing.  Could it be that if you wait long enough and you don't treat them, they're going to progress to a different phenotype? The sepsis phenotype is interesting, right?  Because I think we long recognize that sepsis is a syndrome and not just one illness by itself.  You know, the future, I'm an evidence-based guy, but the future probably is personalized healthcare.  And this is sort of a first step forward for identifying those different aspects of sepsis. I think it is really exciting. Haley, I believe, has a question. Sure. Yep.  This is not an insightful question. It's the one that I've heard a lot after the presentation about the targeted temperature management.  And I'm curious, Rahul, with your reading of it and anybody else's, do you feel like some of the distinction, do you think that the study was set up appropriately, meaning  to compare 33 to 37 degrees, I've heard a lot of pushback that the question was never about 37 degrees. It was about 33 versus 36 in other settings.  And do you think that we missed an opportunity to potentially see, you know, harm or something that might have been there? Yeah. So that's an interesting question.  And really, if you looked at the, when you, when everyone started out, they were spontaneously hypothermic. I mean, their average temperature was about 36 degrees centigrade.  And then, you know, and then in the control group, the temperature rose. I'm assuming that whatever they did, they probably warmed the patient to, you know,  at least 37 degrees centigrade. So it is quite possible that the control group, they make the control group look worse. So that is a distinct possibility.  Now having said that, they did, the trial did demonstrate that, you know, there was, there is little downside to doing the hypothermia. I mean, there's very little downside.  And the appropriate patient, of course, you know, we all know, we've seen these people who come in with non-shockable rhythm cardiac arrest and, you know, you go to the bedside  and like, this is a non-survivable injury. They're not going to survive. So in the appropriate patient, it's probably, it's probably okay to do, you should do targeted  temperature management now, whether you should use 36 or, you know, when they're spontaneously  hypothermic, not do anything at all and just let them be there, or whether you should actually put in a, you know, cooling catheter and cool them down to 33.  So that is, I think, that was an opportunity for the trial that, you know, was, that never got to. So. Another question over here. Hi.  I have a question for our third speaker regarding the trial where you had higher levels of oxygen versus lower levels of oxygen and looking at outcomes.  Did they separate out subgroups for, let's say, COPD versus some of the others? Yeah, great question.  As far as I could see looking over the paper, that wasn't, it wasn't, there wasn't a clear group that was, were so, that had a poor prognosis over another.  It was pretty unified that, that there was no difference among the. I'm kind of wondering if you're teasing it out and you're looking at the people that  started out with relatively normal lungs before they took a respiratory hit versus the people that had COPD and were chronically hypoxemic, setting a level of 91 or 92 might  be a lot more reasonable for somebody like that than versus somebody, let's say, who was an asthmatic who then had an aspiration pneumonia. Yeah.  And one of the things I was hoping to kind of see in the paper was how much, like within the conservative arm, it wasn't clear how much time they spent, you know, with higher  saturations. Like, cause all the, all they needed to do was be above 90%. So, you know, what percentage of time were they, you know, having higher levels of SbO2, it wasn't clear.  So, you know, a lot of questions I thought were unanswered. Certainly mega rocks. I'm sure, you know, the plan next step for the Anzigs group is they're going to move  forward with this large 40,000 patient trial. It seems like with no difference, I don't know, I'm a less is more sort of guy and it  seems like probably targeting low to mid 90s in most of our ICU patients, I think is appropriate.  I wonder, Quad, your thoughts and also if there's a certain population that you think we should maybe aim for still 99 or 100 or the higher. Yeah. That's a great question.  So, I mean, based on time, I was going to say, you know, in terms of my clinical practice, this is probably something that I've more adopted to be less aggressive in terms of  trying to get those SATs too high. Like we've clearly seen in mortality, like harm, especially in cardiac patients, but  based on that Lancet paper, but the one population that we still tend to be conservative on is the traumatic brain injuries, the subarachnoid hemorrhages at our site anyway.  So that would be the one group that we would still aim for a more conservative approach. Maybe a population, once we sort of look at the general critical yield population and  show that lower is safer, maybe that's the next step is to look in those higher risk subgroups. Yeah. Absolutely. Any other questions from the audience? One more over here. Sorry.  No problem. Yeah. Yeah. I just had, I guess, two opinion questions or comments. One would be, would the improvement in survival come from a state mandated program forcing  people to define more people as septic where maybe before the less septic people were not defined? That's a very good question.  The way they determine the sepsis for the controlled stay was by ICD coding from CMS. So that could contribute to it. Yeah.  And then the other question is, I always wonder how many people, like the phenotype study, how many people that are in the not so sick group really weren't septic?  They use the SEP3 diagnosis for the derivation of those algorithm.  It seems to me like we identify people who are profoundly dehydrated sometimes as septic because they meet the criteria.  So what they need is fluid resuscitation, not antibiotics, and they're probably going to survive anyway. So anyway. Thank you. Hard to know for sure. Yeah. Yeah.  Another question over here. Hi. It's a question about the ROSE trial.  I think in general, spontaneous breathing is probably better than non-spontaneous breathing.  But I think we've all seen a patient with ARDS with high swings in transpulmonary pressure. And I'm thinking at the bedside, this probably can't be good for this person.  In your clinical practice or in the trial itself, do they assess for that? Or what are your thoughts on measuring that?  I think it's similar to what we were even discussing before is around your spontaneously breathing patients with ARDS, right?  And large tidal volumes, large higher transpiral pressures. Do you tolerate that? Do you paralyze them? Yeah. We legit had that conversation over dinner yesterday.  And I mean, Simon and Bram brought up some good points about like my practice, I tend  to be more conservative and actually not paralyze them, not be if they're breathing spontaneously.  You know, we're talking about the physiology. If you're drawing negative pressure, breathing spontaneously, is that equivalent to getting  that positive pressure that creates that barotrauma? I just personally, you know, if it's not severe ARDS and they're breathing spontaneously and  clinically they're not deteriorating, personally, I would not sedate them more and paralyze them. Great. Great. Michelle?  So if I could comment from being on the writing committee for the ROSE trial. So I think that's a great question. And I tend to agree.  I think there's a couple things that's takeaway that's important about the ROSE trial, okay? One is that the largest number of patients excluded from the study is actually because  they were already started on neuromuscular blockade, okay? So if there was a patient and you get called to see this patient and they're bucking and  the vent and they're like this synchronous and you can't oxygenate them and there's like doesn't seem to be anything else to do, those patients kind of were excluded from the study  because they may have gotten a bolus of neuromuscular blockade and started on the drip, okay? On the other hand, if they didn't need that and they're spontaneous breathing, as you  mentioned, then it's less clear, especially because the ROSE study showed that a large number of these patients, up to like a third of them, doesn't even need deep sedation.  They can continue to be spontaneously breathing and do fine. And with that, actually, they end up having less sedation overall and more mobility towards like the one week mark.  So I think if they look okay in a spontaneously breathing, that might be okay. Hi, Todd, yeah.  Can you give us a sneak peek to that or yeah?  Very interesting That's great So we might have more data soon because this is a population that we all deal with right and I'm often I'm in the same  Conundrum not knowing what's best and I tend to usually follow the same approach where I sort of let them do their thing  Acknowledging that sedation and paralysis is going to lead to more negativity in the long run. But yeah, that's great  Follow up. Yeah, please  Lung strain  So maybe so there is not a you know, so lung strain  requires measurement of initial lung volume and you know in the absence of something like a sophisticated CT scan with you know, some  really good radiologist who can actually tell you what and it and it really requires measurement of  and expiratory lung volume without peep if you believe get an Oni and  That is sort of difficult to do I think  But I think you were looking at baby lungs right some some of the lung is actually has more compliance and others doesn't and it's at the interface right between the  Compliant and the non-compliant that there's all the stretch going on. I think that's the theory but  That is what he was asking whether we can measure lung strain or not And you know, it is difficult if you do not have any regional right it might be micro micro  When you measure strain you're measuring strain of the system and yeah, Elliot's wondering if it's strain  It's regional strain strain in the areas where that's the real problem that we can't measure  Yeah, I don't think there's a good way to measure macro strain as well either in the absent, you know  If you don't do imaging studies, so even get with the regional strain absolutely not but the even the macro strain is difficult to measure  It's great discussion so far any other comments I believe we still have a couple more minutes if anybody does have any more questions  Or if not, we could finish a couple minutes early. That's all right as well  Okay, well I thank you for attending I think our speakers for their excellent input one last applause, please

Video Summary

In this session, three trials were discussed. The first trial, Hyperion, evaluated the use of moderate hypothermia for patients with coma after successful resuscitation from cardiac arrest with non-shockable rhythms. The results showed that hypothermia led to more patients with favorable neurological outcomes compared to normothermia. The second trial, Violet, examined the use of high-dose vitamin D for critically ill patients with vitamin D deficiency. The results showed no difference in 90-day mortality between the vitamin D and placebo groups. The third trial, Citrus ALI, investigated the use of vitamin C supplementation for sepsis-associated acute lung injury. The results showed no difference in organ failure assessment or biomarkers, but a potential mortality benefit and shorter ICU-free days with vitamin C supplementation. Overall, the trials highlighted the potential benefits of targeted temperature management and the need for further research on vitamin D and vitamin C supplementation. The session generated discussion on the appropriate use of these interventions and the importance of individualized care for patients with sepsis and other critical illnesses.

Asset Subtitle

Sepsis, Pulmonary, 2020

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2020 Critical Care Congress held February 16-19, 2020, in Orlando, Florida, USA.

Learning Objectives

Identify the extent of the new evidence base in internal medicine critical care
Examine the strengths and weakness of the new evidence base
Explain how new evidence fits in with established published literature

Internal Medicine Review 1

Rahul S. Nanchal

Internal Medicine Review 2

Jen-Ting Chen

Internal Medicine Review 3

Kwadwo Kyeremanteng

Meta Tag

Content Type Presentation

Knowledge Area Sepsis

Knowledge Area Pulmonary

Knowledge Level Foundational

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Membership Level Associate

Tag Shock

Tag Extubation

Tag Fluids Resuscitation Management

Year 2020

Keywords

trials

Hyperion

moderate hypothermia

cardiac arrest

vitamin D deficiency

90-day mortality

vitamin C supplementation

sepsis-associated acute lung injury

targeted temperature management

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