Funding ridiculous studies OR Other Weird/Negative Trials

[SurfingDoctor]

Lol, we suck at research. Goal directed therapy, Leuven trials, the Marik fiasco, etc.

ICU is meticulously doing the simple things as little as possible.

“More studies are needed to confirm these results”

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[Siggy]

I mean I *get* that these are questions to be answered...but I also would like someone to explain to me how one would suggest a mechanism to improved mortality with haloperidol use or early mobilization. Poor choice of primary outcome. I guess if you can show it's not actively killing people, you can move on to trying to study clinical outcomes that are more relevant to survivors.

Antipsychotics and early mobility prevent delirium (the first has never been proven to do that), delirium is linked to death (correlation ≠ causation though). Therefore haldol and early mobility prevents death.

I played around with the idea of doing a study where we removed the window blinds to half the rooms in the ICU during fellowship. That way the ICU could be it’s own control. Why? Because no matter how often I opened the blinds, family always closed them immediately after… so their loved ones could rest… during the day.

So how to measure this. We could do CAM… but getting a bunch of nurses that are always doubled or tripled to actually do CAM (including the “tap your fingers when I say “A” part) isn’t really realistic.

It’s also not a patient centered outcome like LOS or mortality.

However given a 2 year fellowship and the program not very research focused to begin with, it never got off the ground.

 

[SurfingDoctor]

Ok not a ridiculous study...

https://www.nejm.org/doi/full/10.1056/NEJMoa2212663?query=featured_pulmonary

I actually love this study, mostly because its further evidence to prove the Surivivng Sepsis Guidelines are duuuummmmbbbb.

Give some fluid, give some vasoactive. Does the combination matter?! Nope!

 

[lymphocyte]

Ok not a ridiculous study...

https://www.nejm.org/doi/full/10.1056/NEJMoa2212663?query=featured_pulmonary

I actually love this study, mostly because its further evidence to prove the Surivivng Sepsis Guidelines are duuuummmmbbbb.

Give some fluid, give some vasoactive. Does the combination matter?! Nope!

Critical care research in the last two years: it's all dumb and nothing matters.

 

[SurfingDoctor]

Critical care research in the last two years: it's all dumb and nothing matters.

I mean, I’d rather people be honest instead of pretending that they have some magical treatment to the rare and heterogenous disease that is critical illness.

When your body has taken a beating to the extreme of needing mechanical, invasive support to support your organs in the hopes that it magically heals itself, positive trials should be met with severe scrutiny. Because if the only cure for magical healing is just too much fluids or not enough steroids, that, in reality, is magical thinking.

What can I say…

 

[ShockIndex]

I mean I *get* that these are questions to be answered...but I also would like someone to explain to me how one would suggest a mechanism to improved mortality with haloperidol use or early mobilization. Poor choice of primary outcome. I guess if you can show it's not actively killing people, you can move on to trying to study clinical outcomes that are more relevant to survivors.

The outcome being days alive and out of the hospital is used so that early death doesn’t give the appearance of a positive treatment effect. Thus, mortality is more of a qualifier than an outcome. However you touch on a good point that mortality is a juicy but inappropriate primary outcome in many ICU studies.

 

[SurfingDoctor]

The outcome being days alive and out of the hospital is used so that early death doesn’t give the appearance of a positive treatment effect. Thus, mortality is more of a qualifier than an outcome. However you touch on a good point that mortality is a juicy but inappropriate primary outcome in many ICU studies.

Gotta keep those LTACs in business, amirite?

 

[ShockIndex]

Gotta keep those LTACs in business, amirite?

There are fates worse than death…

 

[SurfingDoctor]

Association of Vitamin C, Thiamine, and Hydrocortisone With Long-term Sepsis Outcomes

This secondary analysis of a randomized clinical trial reports on the cognitive performance, risk of posttraumatic stress disorder and depression, and functional status 6 months after the administration of a treatment regimen consisting of antioxidants and hydrocortisone infusion in adults with...

jamanetwork.com

I. Can't. Even.

 

[JoaoMoutinho]

Not critical care but can I add this one?

Patient Perception of Surgeons in Scrub Attire

This survey study involves asking participants about their opinions on positive and negative character traits of male and female clinicians dressed in 4 different colors of scrub suits.

jamanetwork.com

I don't think it's NIH funded, but one of the authors has funding from the NCAA I guess.

 

[SurfingDoctor]

Not critical care but can I add this one?

Patient Perception of Surgeons in Scrub Attire

This survey study involves asking participants about their opinions on positive and negative character traits of male and female clinicians dressed in 4 different colors of scrub suits.

jamanetwork.com

I don't think it's NIH funded, but one of the authors has funding from the NCAA I guess.

Despite this, to our knowledge, no data exist on scrub color and physician perception.

There’s a good reason for that…

 

[SurfingDoctor]

I saw this other day

Transfusion-Associated Delirium in Children: No Difference... : Critical Care Medicine

study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of...

journals.lww.com

“Transfusion-Related Delirium”? I swear, people are just making stuff up now.

 

[chessknt]

Association of Vitamin C, Thiamine, and Hydrocortisone With Long-term Sepsis Outcomes

This secondary analysis of a randomized clinical trial reports on the cognitive performance, risk of posttraumatic stress disorder and depression, and functional status 6 months after the administration of a treatment regimen consisting of antioxidants and hydrocortisone infusion in adults with...

jamanetwork.com

I. Can't. Even.

Too bad they didn't title it
Marik protocol associated with PTSD and delirium with no benefit.

Indeed Marik and his Frontline ilk are so full of **** that it truly threatens our understanding of modern GI physiology.

 

[SurfingDoctor]

https://www.nejm.org/doi/full/10.1056/NEJMoa2212438?query=featured_home

Transplanting re-animated hearts! What a weird and controversial subject.

 

[WheezyBaby]

https://www.nejm.org/doi/full/10.1056/NEJMoa2212438?query=featured_home

Transplanting re-animated hearts! What a weird and controversial subject.

Can't open the article right now, but the rate of primary graft dysfunction doesn't look great. Seems like there would be a mortality/retransplantation/requirement for mechanical support signal in a larger cohort. If I'm having it my way at the BK heart drive through I'd like the brain dead heart thx

 

[SurfingDoctor]

Can't open the article right now, but the rate of primary graft dysfunction doesn't look great. Seems like there would be a mortality/retransplantation/requirement for mechanical support signal in a larger cohort. If I'm having it my way at the BK heart drive through I'd like the brain dead heart thx

Well, it’s a non-inferiority trial. It’s more like if you don’t have a fresh heart, would a reanimated heart be no worse?

It does appear the the graft failure rate was higher in the reanimated group:

But the retransplant at 30 days was no different and the 1 year survival rates are the same:

Definitely needs longer term outcomes.

 

[psychbender]

This was being discussed a little at the Society of Cardiothoracic Anesthesiologists meeting last month. It is basically being sold as a new technique to increase the total number of available organs for transplant, so fewer patients die on the list before a suitable organ becomes available. More long-term followup is needed, and the techniques probably need some refinement, but it certainly seems to be better than no heart transplant at all, so far.

 

[SurfingDoctor]

As much as I hate steroids, data is data.

Hydrocortisone in Severe Community-Acquired Pneumonia - PubMed

Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

pubmed.ncbi.nlm.nih.gov

Even excluding COVID, steroids within the first 24 hrs of ARDS and pnemonia-induced ALI is gonna be the standard of care.

Based on the prior equivocal data stretching to the ARDSNet days, this will be practice changing for many.

 

[lymphocyte]

As much as I hate steroids, data is data.

Hydrocortisone in Severe Community-Acquired Pneumonia - PubMed

Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

pubmed.ncbi.nlm.nih.gov

Even excluding COVID, steroids within the first 24 hrs of ARDS and pnemonia-induced ALI is gonna be the standard of care.

Based on the prior equivocal data stretching to the ARDSNet days, this will be practice changing for many.

There's never been a significant signal of harm with steroids in this case, ever and only signals of benefit. I've been a believer since the second Annane trial.

 

[WheezyBaby]

As much as I hate steroids, data is data.

Hydrocortisone in Severe Community-Acquired Pneumonia - PubMed

Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

pubmed.ncbi.nlm.nih.gov

Even excluding COVID, steroids within the first 24 hrs of ARDS and pnemonia-induced ALI is gonna be the standard of care.

Based on the prior equivocal data stretching to the ARDSNet days, this will be practice changing for many.

Anyone in your group extrapolating this or dexards data into any peds populations?

 

[SurfingDoctor]

Anyone in your group extrapolating this or dexards data into any peds populations?

Ha. I’m known as the anti-steroids person in the group. Mostly because I do think that steroids do have some harm (1/2 of pediatric sepsis deaths are immunosuppressed and that correlates with total steroid use) and there’s retrospective data that steroid use in ARDS is associated with worse outcomes in immunosuppressed phenotypes. I mean if you read all the steroids, ARDS/ALI studies, there’s a lot of exclusion populations.

All that being said, I recently did a journal club on this topic for our division (including DEXA-ARDS and the ESCAPe trial). The attendance was poor (mostly because I think most academic intensivists hate learning), but I told the trainees that the data favors early steroid use (any corticosteroid within 24 hours of admission) and they’d be foolish to ignore it.

I mean, this is literally 30 years of data. This isn’t the delirium BS that’s en vogue. People have studied this question since the 1990s. The guidelines for adult severe CAP/ARDS will change based on these most recent studies. The only question remains to me is the duration. I’m gonna guess early (<24 hours) and short duration (<1 week) is gonna be the most effacious.

I’m gonna start doing steroids for pediatric ARDS I admit. I recently admitted an EVALI on 60 L of high flow satting 70% and pulled the steroids card. Dude was on 10 L the next day.

 

[SurfingDoctor]

Ha. I’m known as the anti-steroids person in the group. Mostly because I do think that steroids do have some harm (1/2 of pediatric sepsis deaths are immunosuppressed and that correlates with total steroid use) and there’s retrospective data that steroid use in ARDS is associated with worse outcomes in immunosuppressed phenotypes. I mean if you read all the steroids, ARDS/ALI studies, there’s a lot of exclusion populations.

All that being said, I recently did a journal club on this topic for our division (including DEXA-ARDS and the ESCAPe trial). The attendance was poor (mostly because I think most academic intensivists hate learning), but I told the trainees that the data favors early steroid use (any corticosteroid within 24 hours of admission) and they’d be foolish to ignore it.

I mean, this is literally 30 years of data. This isn’t the delirium BS that’s en vogue. People have studied this question since the 1990s. The guidelines for adult severe CAP/ARDS will change based on these most recent studies. The only question remains to me is the duration. I’m gonna guess early (<24 hours) and short duration (<1 week) is gonna be the most effacious.

I’m gonna start doing steroids for pediatric ARDS I admit. I recently admitted an EVALI on 60 L of high flow satting 70% and pulled the steroids card. Dude was on 10 L the next day.

For those interested…

https://www.nejm.org/doi/full/10.1056/NEJMe2302544

It’s written by one of the authors of the steroids CAP/ARDS Chest guidelines.

 

[WheezyBaby]

Ha. I’m known as the anti-steroids person in the group. Mostly because I do think that steroids do have some harm (1/2 of pediatric sepsis deaths are immunosuppressed and that correlates with total steroid use) and there’s retrospective data that steroid use in ARDS is associated with worse outcomes in immunosuppressed phenotypes. I mean if you read all the steroids, ARDS/ALI studies, there’s a lot of exclusion populations.

All that being said, I recently did a journal club on this topic for our division (including DEXA-ARDS and the ESCAPe trial). The attendance was poor (mostly because I think most academic intensivists hate learning), but I told the trainees that the data favors early steroid use (any corticosteroid within 24 hours of admission) and they’d be foolish to ignore it.

I mean, this is literally 30 years of data. This isn’t the delirium BS that’s en vogue. People have studied this question since the 1990s. The guidelines for adult severe CAP/ARDS will change based on these most recent studies. The only question remains to me is the duration. I’m gonna guess early (<24 hours) and short duration (<1 week) is gonna be the most effacious.

I’m gonna start doing steroids for pediatric ARDS I admit. I recently admitted an EVALI on 60 L of high flow satting 70% and pulled the steroids card. Dude was on 10 L the next day.

This is my general inclination as well. I may have to do a review of the literature for the division because I'm in significant the minority in wanting to extrapolate the adult data here, and the data is compelling. We operate on a lot less on a day to day basis for a lot of our practice. I generally steroid-biased though

 

[SurfingDoctor]

This is my general inclination as well. I may have to do a review of the literature for the division because I'm in significant the minority in wanting to extrapolate the adult data here, and the data is compelling. We operate on a lot less on a day to day basis for a lot of our practice. I generally steroid-biased though

“This was in adults” is seriously something that so many peds intensivists say and it annoys me to no end.

Someone recently did a journal club on balanced IVF for sepsis and AKI in pediatrics and how great it was. And I said, “What about all the adult studies and a meta analysis of 100,000 patients that say it doesn’t matter”. Their response was “But adults aren’t children and maybe don’t have the same AKI risk in sepsis”.

I was like:

 

[lymphocyte]

“ “What about all the adult studies and a meta analysis of 100,000 patients that say it doesn’t matter”.

Okay, I'll bite. Are you talking about the Hammond meta-analysis?

I think normal saline should be used in only a handful of cases and effectively eliminated on the floor. It's a terrible nephrotoxic drug.

https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100010

 

[Radetzky]

Ha. I’m known as the anti-steroids person in the group. Mostly because I do think that steroids do have some harm (1/2 of pediatric sepsis deaths are immunosuppressed and that correlates with total steroid use) and there’s retrospective data that steroid use in ARDS is associated with worse outcomes in immunosuppressed phenotypes. I mean if you read all the steroids, ARDS/ALI studies, there’s a lot of exclusion populations.

All that being said, I recently did a journal club on this topic for our division (including DEXA-ARDS and the ESCAPe trial). The attendance was poor (mostly because I think most academic intensivists hate learning), but I told the trainees that the data favors early steroid use (any corticosteroid within 24 hours of admission) and they’d be foolish to ignore it.

I mean, this is literally 30 years of data. This isn’t the delirium BS that’s en vogue. People have studied this question since the 1990s. The guidelines for adult severe CAP/ARDS will change based on these most recent studies. The only question remains to me is the duration. I’m gonna guess early (<24 hours) and short duration (<1 week) is gonna be the most effacious.

I’m gonna start doing steroids for pediatric ARDS I admit. I recently admitted an EVALI on 60 L of high flow satting 70% and pulled the steroids card. Dude was on 10 L the next day.

That’s a good point actually.. do we think that if you come in with CAP secondary to immunosuppression that steroids are less efficacious than in an immune competent population?

 

[SurfingDoctor]

Okay, I'll bite. Are you talking about the Hammond meta-analysis?

I think normal saline should be used in only a handful of cases and effectively eliminated on the floor. It's a terrible nephrotoxic drug.

https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100010

Oh, yeah 40,000 patients. Couldn’t remember the exact number.

I just think it’s fascinating that even with 40,000 patients, that there’s a okay chance it does reduce mortality but that they can’t also rule out that the alternative, it increases mortality, is also true. 40,000 patients. Crazy. I mean, it is a meta-analysis and a more recent meta-analysis looking at the most recent trials found no real difference in outcomes (Balanced crystalloid solutions versus normal saline in intensive care units: a systematic review and meta-analysis - PubMed) so whatever.

I mean, I used balanced solutions when I can cause why not, but I don’t pretend I’m saving people lives by using them either. Especially since some of the trials that were used to show an effect were potentially biased to outcomes.

I do think they shorten the length of stay for DKA though.

 

[SurfingDoctor]

That’s a good point actually.. do we think that if you come in with CAP secondary to immunosuppression that steroids are less efficacious than in an immune competent population?

Well, only the ESCAPe trial included immunosuppressed patients from what I recall. The other trials excluded that population. Interestingly, the CAPE COD trial also excluded people with sepsis, ie the population most likely to have ARDS.

There’s plenty of retrospective data that in immunosuppressed patients, steroid use for ARDS has a higher odds ratio of mortality.

So the answer to your question is… maybe .

 

[lymphocyte]

Oh, yeah 40,000 patients. Couldn’t remember the exact number.

I just think it’s fascinating that even with 40,000 patients, that there’s a okay chance it does reduce mortality but that they can’t also rule out that the alternative, it increases mortality, is also true. 40,000 patients. Crazy. I mean, it is a meta-analysis and a more recent meta-analysis looking at the most recent trials found no real difference in outcomes (Balanced crystalloid solutions versus normal saline in intensive care units: a systematic review and meta-analysis - PubMed) so whatever.

I mean, I used balanced solutions when I can cause why not, but I don’t pretend I’m saving people lives by using them either. Especially since some of the trials that were used to show an effect were potentially biased to outcomes.

I do think they shorten the length of stay for DKA though.

My issue with the meta-analyses is garbage-in/garbage-out.

The PLUS trial, for example, had, something like 60% in the balanced solution group getting a significant volume of normal saline prior to enrollment. And there were a very large number of protocol deviations too (greater than 10% in the balanced solution group).

Still, even if the effect size is very small, when it's multiplied across every single patient that gets IV fluids (i.e. almost every single critically ill patient), it adds up. There are so precious few interventions that matter in intensive care; I think we take all the help we can get.

 

[SurfingDoctor]

Still, even if the effect size is very small, when it's multiplied across every single patient that gets IV fluids (i.e. almost every single critically ill patient), it adds up. There are so precious few interventions that matter in intensive care; I think we take all the help we can get.

That's fair. My issue is really that I feel people often look for a signal when its all mostly noise or exaggerate the effect because it makes them feel like there are doing something of benefit, when it's all a wash. Like if people want to waggle their finger at someone because they used saline instead of LR (because let's be honest, there are definitely people who do that in case reviews and M&Ms) then so be it, but it seems like mostly nonsense to me.

 

[Radetzky]

The issue is average treatment affects. These trials enroll a heterogenous population in order to achieve numbers. If you look at balanced vs unbalanced specifically in ESRD or renal transplant you find quite sizable treatment effects in favour of balanced. OTOH if you look at brain injured patients, balanced solutions are harmful.

Similarly with these steroid trials. Thus far they have been investigating ARDS which is a made up garbage diagnosis. But if you look by actual diagnosis, it now seems that the benefit is in bacterial pneumonia and COVID and not so much other conditions

 

[SurfingDoctor]

The issue is average treatment affects. These trials enroll a heterogenous population in order to achieve numbers. If you look at balanced vs unbalanced specifically in ESRD or renal transplant you find quite sizable treatment effects in favour of balanced. OTOH if you look at brain injured patients, balanced solutions are harmful.

Similarly with these steroid trials. Thus far they have been investigating ARDS which is a made up garbage diagnosis. But if you look by actual diagnosis, it now seems that the benefit is in bacterial pneumonia and COVID and not so much other conditions

I don't know if the bolded is necessarily true. While diseases are heterogenous, the response to them is remarkably similar. Like the differences are so small, they are probably irrelevant. There was some interesting studies starting back in the late 1990s, early 2000s when RNA profiling and proteomic analysis were just cutting edge. These studies were under the umbrella NIH program called the Glue Grant. It was essentially trying to see if the heterogenous types of critical illness had genomic/proteomic signatures that could clearly be delineated and that could potentially lead to personalized medicine for critical illness. It was interesting because globally, the project failed relatively speaking, enough so that the NIH cancelled the project after a decade or so. I mean it generated a lot of data, but all that data essentially said was that if you get shot, lit on fire, go through a windshield, have the flu or get necrotizing fasciitis, your body's response (ie the RNA profiles) are like ~90% the same. In fact, even to this day with array profiles looking at thousands of genes, you can still find lots of papers looking for single candidate "biomarkers", which is just another way of saying a vast majority of the human body's response to stress and critical illness is the exact same... so much so that we can't tell the difference.

The reason I mention that is that one of the CAP/ARDS studies excluded influenza because of data with worse outcomes in steroids. Yet, for some reason, it works for COVID and sepsis and aspiration and EVALI, etc. etc. When you think about it and put it in the context of the data that shows the body doesn't care, it's all inflamed, you 1) start to question the validity of the hypothesis that influenza is different just because and 2) realize that steroids are used so commonly because to some degree in inflammatory critical illness, the hammer of steroids makes at least a little sense since all the body does is generate a whole bunch of non-specific nails. Now, what is different is timing and duration of onset. If you been hospitalized for X,Y,Z and then you get pneumonia, you're immune system is in a much different state then if you get pneumonia walking in off the street. That's where every single ICU study, ever, has failed to discriminate.

 

[Radetzky]

I don't know if the bolded is necessarily true. While diseases are heterogenous, the response to them is remarkably similar. Like the differences are so small, they are probably irrelevant. There was some interesting studies starting back in the late 1990s, early 2000s when RNA profiling and proteomic analysis were just cutting edge. These studies were under the umbrella NIH program called the Glue Grant. It was essentially trying to see if the heterogenous types of critical illness had genomic/proteomic signatures that could clearly be delineated and that could potentially lead to personalized medicine for critical illness. It was interesting because globally, the project failed relatively speaking, enough so that the NIH cancelled the project after a decade or so. I mean it generated a lot of data, but all that data essentially said was that if you get shot, lit on fire, go through a windshield, have the flu or get necrotizing fasciitis, your body's response (ie the RNA profiles) are like ~90% the same. In fact, even to this day with array profiles looking at thousands of genes, you can still find lots of papers looking for single candidate "biomarkers", which is just another way of saying a vast majority of the human body's response to stress and critical illness is the exact same... so much so that we can't tell the difference.

The reason I mention that is that one of the CAP/ARDS studies excluded influenza because of data with worse outcomes in steroids. Yet, for some reason, it works for COVID and sepsis and aspiration and EVALI, etc. etc. When you think about it and put it in the context of the data that shows the body doesn't care, it's all inflamed, you 1) start to question the validity of the hypothesis that influenza is different just because and 2) realize that steroids are used so commonly because to some degree in inflammatory critical illness, the hammer of steroids makes at least a little sense since all the body does is generate a whole bunch of non-specific nails. Now, what is different is timing and duration of onset. If you been hospitalized for X,Y,Z and then you get pneumonia, you're immune system is in a much different state then if you get pneumonia walking in off the street. That's where every single ICU study, ever, has failed to discriminate.

Good points. However even very tiny differences in rna expression could have significant clinical difference. To stick with the steroid theme.. COPD of any severity responds extremely well to steroids compared to other respiratory diseases despite all being driven by “inflammation”. And in other conditions that are good targets for “inflammation” such as TBI, SCI and pancreatitis steroids have been shown to be inefficacious and even harmful.

I feel that critical care has strayed too far from medicine by studying made up syndromes such as ARDS, sepsis and AKI, rather than studying the clinical diseases that are actually making people ill.

 

[SurfingDoctor]

Good points. However even very tiny differences in rna expression could have significant clinical difference. To stick with the steroid theme.. COPD of any severity responds extremely well to steroids compared to other respiratory diseases despite all being driven by “inflammation”. And in other conditions that are good targets for “inflammation” such as TBI, SCI and pancreatitis steroids have been shown to be inefficacious and even harmful.

I feel that critical care has strayed too far from medicine by studying made up syndromes such as ARDS, sepsis and AKI, rather than studying the clinical diseases that are actually making people ill.

As to the bolded, I wish that were true. I used to believe that, but having personally done RNA sequencing myself, it mostly just exposes that we don’t know anything. Without getting into specifics, we found differences in RNA expression patterns between inflammatory stimuli in humans and tried to modulate them through targeted therapies. It made some things better, but it also made some things worse. Essentially, if a gene is changed and one is critically ill, we don’t know if that change is detrimental or protective. Honestly, we may never know for that individual.

As for the rest, I kinda agree to a degree. It is helpful to try to define syndromes so that people can approach it in a structured manner. But I will also say people, particularly in academics, want to be known for something and leave their mark. That’s where you get somewhat irrational ideas like ICU psychosis and tight glycemic control. It just is another way of saying when you’re sick as stink, glycolysis revs up and you get cerebral dysfunction, but that’s less note worthy. Defining that I don’t think really helps anyone, but I suppose it highlights the challenges we and patients face, so in that regard, it is kinda helpful.