Funding ridiculous studies OR Other Weird/Negative Trials

[SurfingDoctor]

https://www.nejm.org/doi/full/10.1056/NEJMoa1812405

Okay, maybe it’s just because I’m in pediatrics and if you don’t bag a patient who you are intubating in the unit... you’re essentially committing malpractice, but the NIH really needs to stop supporting stuff like this.

The hypothesis was that if you ventilate someone who you’ve sedated and relaxed, their SaO2 stays higher... that can’t be a serious question in 2019.

---

Members don't see this ad.

 

[SpacemanSpifff]

https://www.nejm.org/doi/full/10.1056/NEJMoa1812405

Okay, maybe it’s just because I’m in pediatrics and if you don’t bag a patient who you are intubating in the unit... you’re essentially committing malpractice, but the NIH really needs to stop supporting stuff like this.

The hypothesis was that if you ventilate someone who you’ve sedated and relaxed, their SaO2 stays higher... that can’t be a serious question in 2019.

That does seem like a straight forward question. However, there is disagreement about the relative risks of manual ventilation during the apneic period after RSI (see https://www.nejm.org/doi/full/10.1056/NEJMe1900708?query=recirc_curatedRelated_article). In my relatively limited experience (2 academic MICU, 2 academic ED's) BVM has been used during apnea in 1 of them - the others utilized flush flow non-rebreather plus or minus nasal cannula. The teaching I have received is that withholding manual ventilation during the apneic period, if oxygenation allows, reduces aspiration risk - which isn't supported by this trial.

 

[SurfingDoctor]

That does seem like a straight forward question. However, there is disagreement about the relative risks of manual ventilation during the apneic period after RSI (see https://www.nejm.org/doi/full/10.1056/NEJMe1900708?query=recirc_curatedRelated_article). In my relatively limited experience (2 academic MICU, 2 academic ED's) BVM has been used during apnea in 1 of them - the others utilized flush flow non-rebreather plus or minus nasal cannula. The teaching I have received is that withholding manual ventilation during the apneic period, if oxygenation allows, reduces aspiration risk - which isn't supported by this trial.

Well, maybe pediatrics is just different then because if we followed that rule, then a good number of intubations would end in codes as the primary cause of arrest is respiratory in nature in pediatrics.

Of course, none of this changes the fact that as written, the hypothesis of this study is terrible. There probably should be more transparency in studies where the total cost is disclosed for each study.

 

[deleted547339]

https://www.nejm.org/doi/full/10.1056/NEJMoa1812405

Okay, maybe it’s just because I’m in pediatrics and if you don’t bag a patient who you are intubating in the unit... you’re essentially committing malpractice, but the NIH really needs to stop supporting stuff like this.

The hypothesis was that if you ventilate someone who you’ve sedated and relaxed, their SaO2 stays higher... that can’t be a serious question in 2019.

It’s because you’re in pediatrics. Standard RSI in the ER and the ICU uses no bagging due to concerns of aspiration in the emergent setting. One could argue that bagging and a subsequent aspiration event is malpractice in adults.

 

[SurfingDoctor]

It’s because you’re in pediatrics. Standard RSI in the ER and the ICU uses no bagging due to concerns of aspiration in the emergent setting. One could argue that bagging and a subsequent aspiration event is malpractice in adults.

Except now I guess you can’t argue that.

 

[deleted547339]

Except now I guess you can’t argue that.

This article is definitely practice changing for adult EM and CCM docs.

 

[SurfingDoctor]

This article is definitely practice changing for adult EM and CCM docs.

To each their own I guess.

 

[deleted547339]

https://www.nejm.org/doi/full/10.1056/NEJMoa1812405

Okay, maybe it’s just because I’m in pediatrics and if you don’t bag a patient who you are intubating in the unit... you’re essentially committing malpractice, but the NIH really needs to stop supporting stuff like this.

The hypothesis was that if you ventilate someone who you’ve sedated and relaxed, their SaO2 stays higher... that can’t be a serious question in 2019.

Also, this has no NIH funding....looks like just internal funding from Vandy.

 

[SurfingDoctor]

Also, this has no NIH funding....looks like just internal funding from Vandy.

Where do you think that funding came from? Do you know what a CTSA award is?

Even if someones doesn't know what that is, it says in the text: "Supported by grants (UL1 TR000445 and UL1TR002243) from the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), to the Vanderbilt Institute for Clinical and Translational Research."

 

[deleted547339]

Where do you think that funding came from? Do you know what a CTSA award is?

Even if someones doesn't know what that is, it says in the text: "Supported by grants (UL1 TR000445 and UL1TR002243) from the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), to the Vanderbilt Institute for Clinical and Translational Research."

My bad. You’re right.

 

[Hook_EM]

To each their own I guess.

Lol. You came in here guns-a-blazing complaining about stupid studies that you don’t think make any sense or should receive funding but you don’t even practice with it’s target population and someone informs you that it’s actually a relevant study and can be practice changing (in which I agree) and you blow it off and then you attack him for not knowing how it’s actually funded.

Are you okay?

 

[SurfingDoctor]

Lol. You came in here guns-a-blazing complaining about stupid studies that you don’t think make any sense or should receive funding but you don’t even practice with it’s target population and someone informs you that it’s actually a relevant study and can be practice changing (in which I agree) and you blow it off and then you attack him for not knowing how it’s actually funded.

Are you okay?

I'm fine. Usually pediatrics relies on adults populations to test good hypothesis just based on a greater "n"... but not always I guess. I also still think the NIH should enact funding transparency to show the public what research like this actually costs.

 

[SurfingDoctor]

My bad. You’re right.

No worries, but there are essentially no large multicenter trials in this country that aren't funded by the NIH (or occasionally foundation) unless it is funded by private industry in the hopes that the product shows great benefit. I think the Marik sepsis cocktail trials are funded by both, the NIH in one study to prove if it helps (or not) and a private industry in another to see if it can be profitable (or not).

 

[SpacemanSpifff]

It’s because you’re in pediatrics. Standard RSI in the ER and the ICU uses no bagging due to concerns of aspiration in the emergent setting. One could argue that bagging and a subsequent aspiration event is malpractice in adults.

Have you seen many people in the ED, ICU get bagged during RSI? I figured there were some out there that are doing it.

 

[deleted547339]

Have you seen many people in the ED, ICU get bagged during RSI? I figured there were some out there that are doing it.

Maybe 20% if I had to guess. But technically that’s not RSI. RSI, by definition, doesn’t bag. Your patients that you can’t preoxygenate well and are already hypoxic mostly are the ones that get a modified RSI.

 

[Hamhock]

This article is definitely practice changing for adult EM and CCM docs.

I agree with your point to the OP that this is not "a ridiculous study" and that perhaps the OP doesn't know what he doesn't know.

However, this is unlikely going to be a practice changing study for me or my colleagues. Without getting to far into the methods and results (which I will likely do soon, when I have the time), from a "big picture" distance, this paper is just showing me that it is very common in ICUs to see very poor "pre-oxygenation" and a near absence of delayed-sequence intubation techniques/concepts. I also suspect (haven't viewed the supplements yet) there was very poor dosing and timing of NMB.

HH

 

[turkeyjerky]

I agree with your point to the OP that this is not "a ridiculous study" and that perhaps the OP doesn't know what he doesn't know.

However, this is unlikely going to be a practice changing study for me or my colleagues. Without getting to far into the methods and results (which I will likely do soon, when I have the time), from a "big picture" distance, this paper is just showing me that it is very common in ICUs to see very poor "pre-oxygenation" and a near absence of delayed-sequence intubation techniques/concepts. I also suspect (haven't viewed the supplements yet) there was very poor dosing and timing of NMB.

HH

Agreed. I'm not changing my usual RSI based on this, except I'll probably incorporate BVM if I anticipate prolonged laryngoscopy or esp high risk of desaturation.

Also, these were ICU patients and (presumably) npo, not trauma patients brought in with a belly full of Big Macs and beer...

 

[Colorado outliers]

While it is a worthwhile study, and something I personally have often wondered about after seeing someone aspirate while getting BVM, I also don't believe this article will change much in the way of day-to-day practice.
To the Peds person that started the thread - I am an adult doc but spent some time as a Med-Peds resident. The pediatric approach to intubations is different, as you said, because most intubations in the PICU are for strictly respiratory issues. Not necessarily the case with adults.

A couple points:

-authors excluded patients from the trial whom the operator felt would be at high risk of hypoxemia without modified RSI w/ BVM
-author also excluded patients deemed to be 'at high risk of aspiration'

So basically they eliminated the two groups at highest risk of hypoxemia and aspiration from the study, leaving a less risky cohort. Not surprisingly, a very small number aspirated, and a small (but higher) number were hypoxemic. Although hypoxemia is 'bad' they don't offer data to determine the clinical significance of the hypoxemia. There was no statistically sig difference in codes, vent days, death, etc

When you're intubating a sick ARDS patient, your hand is usually forced to use modified RSI and BVM to avoid severe hypoxemia. Luckily most of our patients haven't just eaten, as turkeyjerky pointed out, although they may be full of tube feeds. I generally try to bag as little as possible, and go as light as I can with sedation to avoid apnea and bagging prior to intubation...doesn't always work though and maybe it's pointless to try to avoid BVM if your aspiration risk won't really increase (in a population that's low risk for aspiration anyway!).

Looking at the supplement they used pretty standard paralytic doses (1 mg/kg Roc) and sedation (Etomidate 0.2-0.3 mg/kg). Surprised how many got Etomidate (75-80%) as it's fallen out of favor at many places. Generally use Propofol and Ketamine here.

BTW I attend in an ICU similar to that of the study authors' (large academic center)

 

[deleted547339]

While it is a worthwhile study, and something I personally have often wondered about after seeing someone aspirate while getting BVM, I also don't believe this article will change much in the way of day-to-day practice.
To the Peds person that started the thread - I am an adult doc but spent some time as a Med-Peds resident. The pediatric approach to intubations is different, as you said, because most intubations in the PICU are for strictly respiratory issues. Not necessarily the case with adults.

A couple points:

-authors excluded patients from the trial whom the operator felt would be at high risk of hypoxemia without modified RSI w/ BVM
-author also excluded patients deemed to be 'at high risk of aspiration'

So basically they eliminated the two groups at highest risk of hypoxemia and aspiration from the study, leaving a less risky cohort. Not surprisingly, a very small number aspirated, and a small (but higher) number were hypoxemic. Although hypoxemia is 'bad' they don't offer data to determine the clinical significance of the hypoxemia. There was no statistically sig difference in codes, vent days, death, etc

When you're intubating a sick ARDS patient, your hand is usually forced to use modified RSI and BVM to avoid severe hypoxemia. Luckily most of our patients haven't just eaten, as turkeyjerky pointed out, although they may be full of tube feeds. I generally try to bag as little as possible, and go as light as I can with sedation to avoid apnea and bagging prior to intubation...doesn't always work though and maybe it's pointless to try to avoid BVM if your aspiration risk won't really increase (in a population that's low risk for aspiration anyway!).

Looking at the supplement they used pretty standard paralytic doses (1 mg/kg Roc) and sedation (Etomidate 0.2-0.3 mg/kg). Surprised how many got Etomidate (75-80%) as it's fallen out of favor at many places. Generally use Propofol and Ketamine here.

BTW I attend in an ICU similar to that of the study authors' (large academic center)

Etomidate is the tits!

 

[Colorado outliers]

Etomidate is the tits!

I actually don't disagree with you. I used to use it a lot. For whatever reason lately we seem to be using more low-dose Propofol and ketamine.
Just make sure to hang pressors and push a Neo-stick with the Propofol

 

[deleted547339]

I actually don't disagree with you. I used to use it a lot. For whatever reason lately we seem to be using more low-dose Propofol and ketamine.
Just make sure to hang pressors and push a Neo-stick with the Propofol

Yea, I feel like that’s one of the signs of a good intensivist. If I told you that prop, etomidate, ketamine or versed were on shortage, you could still get the patient intubated safely. I used etomidate almost exclusively in residency with some ketamine mixed in, then fent/versed in the MICU and prop in the sicus in fellowship.

We don’t have neo sticks outside of the OR where I practice. Drives me nuts.

 

[Radetzky]

An interesting thing not mentioned is how people bag when they need to in the apneic period- have seen a variety from gentle bag ventilation to looking like they're trying to wring a lemon dry. I'm sure the benefit/risk of oxygenation/aspiration is different depending on the operator.

 

[Hamhock]

We don’t have neo sticks outside of the OR where I practice. Drives me nuts.

Be careful what you wish for...I complained that there were no neo sticks right after fellowship when I started part-time at a community site.

The very responsive admin and P&T committee (it is nice to be at a place that treats docs well) promptly put 1000mcg into 3cc sticks and placed them in the ICUs and ED without consulting me or any anesthesiologist (granted, I am infrequently there). So now I have to run around and explain that -- although I said neo sticks are safe IVP in the peri-intubation period -- 1000mcg is way more than is typically needed....especially if you are intubating with etomidate.

I told them the "stick" was safe and they only see "stick", not 1000mcg.

Oh well, it's probably still safe...and now that I have been at this community site for a while, my frequent use of 1.5 ketamine for RSI has the need for neo quickly fading for the ED docs and most of the IM-trained intensivists.

HH

 

[deleted547339]

Be careful what you wish for...I complained that there were no neo sticks right after fellowship when I started part-time at a community site.

The very responsive admin and P&T committee (it is nice to be at a place that treats docs well) promptly put 1000mcg into 3cc sticks and placed them in the ICUs and ED without consulting me or any anesthesiologist (granted, I am infrequently there). So now I have to run around and explain that -- although I said neo sticks are safe IVP in the peri-intubation period -- 1000mcg is way more than is typically needed....especially if you are intubating with etomidate.

I told them the "stick" was safe and they only see "stick", not 1000mcg.

Oh well, it's probably still safe...and now that I have been at this community site for a while, my frequent use of 1.5 ketamine for RSI has the need for neo quickly fading for the ED docs and most of the IM-trained intensivists.

HH

I’m jealous. We’ve been out of ketamine for a while.

 

[jdh71]

Yea, I feel like that’s one of the signs of a good intensivist. If I told you that prop, etomidate, ketamine or versed were on shortage, you could still get the patient intubated safely. I used etomidate almost exclusively in residency with some ketamine mixed in, then fent/versed in the MICU and prop in the sicus in fellowship.

We don’t have neo sticks outside of the OR where I practice. Drives me nuts.

I'd prefer epi "sticks" but I can't get our pharmacy to go in on the "cost" - they'd have to make them and won't buy any commercially.

I was able to get the neo sticks in the ICU where I work by going through the formal channels. You should look into it. They will obviously have them in the OR, you just need to get the anesthesia folks to tell pharmacy you aren't killing patients and it makes sense to get at least one into the pixis. Then you'll need to deal with nursing, and I dealt with them by having a new order with each push of 1mL.

 

[SurfingDoctor]

I thought there was a Marik cocktail thread but this seems just as good a place...

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial - PubMed

ClinicalTrials.gov Identifier: NCT02106975.

www.ncbi.nlm.nih.gov

 

[lymphocyte]

I thought there was a Marik cocktail thread but this seems just as good a place...

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial - PubMed

ClinicalTrials.gov Identifier: NCT02106975.

www.ncbi.nlm.nih.gov

Sleeper trial of the year. I thought there was a strong signal of mortality benefit with no signals of harm. I also thought it was silly that mortality was made a secondary outcome.

 

[SurfingDoctor]

Sleeper trial of the year. I thought there was a strong signal of mortality benefit with no signals of harm. I also thought it was silly that mortality was made a secondary outcome.

Yeah a strong benefit of mortality from an unknown cause since the SOFA scores and all markers of inflammation were the same between the two groups despite the vitamin c. Even the authors had no explanation in the difference in mortality and thus didn’t adjust for it.

I guess the placebo group died of... acute sugar poisoning.

I agree with the lack of harm but that’s not surprising as that has been tested before.

 

[lymphocyte]

Yeah a strong benefit of mortality from an unknown cause since the SOFA scores and all markers of inflammation were the same between the two groups despite the vitamin c. Even the authors had no explanation in the difference in mortality and thus didn’t adjust for it.

I guess the placebo group died of... acute sugar poisoning.

I agree with the lack of harm but that’s not surprising as that has been tested before.

There was no difference in mSOFA scores for the ones that survived at 96 hours -- but if more patients died in the placebo group, presumably the sickest ones, you'd expect to see lower SOFA scores anyways.

I really don't care about the difference in non-specific bioinflammatory markers. I doubt anybody does apart from the NIH.

I agree this was a ridiculous study, but only because of the way it was designed.

 

[SurfingDoctor]

There was no difference in SOFA scores for the ones that survived at 96 hours -- but if more patients died in the placebo group, presumably the sickest ones, you'd expect to see lower SOFA scores anyways.

I really don't care about the difference in non-specific bioinflammatory markers. I doubt anybody does apart from the NHS.

I agree this was a ridiculous study, but only because of the way it was designed.

But if you look at the survival curve, they separate before 96 hours. Yet, all the objective measurements of severity of illness are the same in that time period. So the placebo people are dying at 48 to 96 hours, yet their degree of illness is the exact same as the treatment group. That doesn’t make any sense. Certainly it could be by some random effect or an unknown effect that wasn’t measured, but the authors didn't control for that and by the metrics tested, vitamin c worked early (maybe) by an unknown mechanism that didn’t effect objective measurements.

I’m sure this study will be repeated at great expensive though. Maybe after several multi-continent randomized trials, we’ll finally get an answer.

 

[lymphocyte]

I’m sure this study will be repeated at great expensive though. Maybe after several multi-continent randomized trials, we’ll finally get an answer.

Well, here's the first of many to come. VITAMINS.

No survival benefit with everybody getting hydrocortisone vs hydrocortisone + 200mg thiamine BD/1.5g Vitamin C q6. 10% cross-over with thiamine (which was at the treating clinician's discretion -- Vitamin C was not.). Interestingly, the SOFA scores came apart in favour of Vitamin C, but this was a secondary outcome. CITRIS-ALI also used much higher doses of Vitamin C 50mg/kg.

2020 will be the year of Vitamin C with 17 more registered trials to come.

Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone in Septic Shock

This randomized clinical trial compares the effects of treatment with intravenous vitamin C, hydrocortisone, and thiamine compared with intravenous hydrocortisone alone on duration of time alive and free of vasopressor use over 7 days in patients with septic shock.

jamanetwork.com

 

[SurfingDoctor]

Well, here's the first of many to come. VITAMINS.

No survival benefit with everybody getting hydrocortisone vs hydrocortisone + 200mg thiamine BD/1.5g Vitamin C q6. 10% cross-over with thiamine (which was at the treating clinician's discretion -- Vitamin C was not.). Interestingly, the SOFA scores came apart in favour of Vitamin C, but this was a secondary outcome. CITRIS-ALI also used much higher doses of Vitamin C 50mg/kg.

2020 will be the year of Vitamin C with 17 more registered trials to come.

Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone in Septic Shock

This randomized clinical trial compares the effects of treatment with intravenous vitamin C, hydrocortisone, and thiamine compared with intravenous hydrocortisone alone on duration of time alive and free of vasopressor use over 7 days in patients with septic shock.

jamanetwork.com

Hydrocortisone cocktail didn't work?! Wait a minute... I know there's a .gif for this. Where did I leave it?! Ah yes...

But 17 trials you say... oh boy! I'm sure the ability of chance is sure to prove of those trials right.

 

[Colorado outliers]

But if you look at the survival curve, they separate before 96 hours. Yet, all the objective measurements of severity of illness are the same in that time period. So the placebo people are dying at 48 to 96 hours, yet their degree of illness is the exact same as the treatment group. That doesn’t make any sense. Certainly it could be by some random effect or an unknown effect that wasn’t measured, but the authors didn't control for that and by the metrics tested, vitamin c worked early (maybe) by an unknown mechanism that didn’t effect objective measurements.

I’m sure this study will be repeated at great expensive though. Maybe after several multi-continent randomized trials, we’ll finally get an answer.

There is actually a new NIH-sponsored network in development to study Vitamin C, it's called
Clinically Insignificant Trial Repeated Until Sepsis Survival (CITRUSS)

 

[SurfingDoctor]

Well, here's the first of many to come. VITAMINS.

No survival benefit with everybody getting hydrocortisone vs hydrocortisone + 200mg thiamine BD/1.5g Vitamin C q6. 10% cross-over with thiamine (which was at the treating clinician's discretion -- Vitamin C was not.). Interestingly, the SOFA scores came apart in favour of Vitamin C, but this was a secondary outcome. CITRIS-ALI also used much higher doses of Vitamin C 50mg/kg.

2020 will be the year of Vitamin C with 17 more registered trials to come.

Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone in Septic Shock

This randomized clinical trial compares the effects of treatment with intravenous vitamin C, hydrocortisone, and thiamine compared with intravenous hydrocortisone alone on duration of time alive and free of vasopressor use over 7 days in patients with septic shock.

jamanetwork.com

I gotta admit, this is kinda hard to watch, but Marik concludes that all studies on HAT are flawed because he wasn’t consulted.



It does have a good discussion about clinical trials at the end though...

 

[SurfingDoctor]

https://www.atsjournals.org/doi/10.1164/rccm.201908-1543LE

 

[BigRedBeta]

https://www.atsjournals.org/doi/10.1164/rccm.201908-1543LE

What a methodologically piss poor study...

 

[SurfingDoctor]

So many issues with the methods of this study...

What a methodologically piss poor study...

But according to Marik, based on this study, if you don’t give children HAT, you’re committing malpractice.

I do like how the hydrocortisone group had no difference in vasoactive free days compared to the “control” group... like the only reproducible result for hydrocortisone in studies... that they couldn't reproduce. Oh well.

 

[lymphocyte]

For those keeping count, CITRIS-ALI, VITAMINS, and now... ACTS, published last month in JAMA.

Multi-centre, blinded, RCT with n=203 randomised to placebo or 50mg/1500mg/100mg q6hrly of hydrocortisone/vitamin C/thiamine. Once again, Vitamin is relatively underdosed compared to CITRIS-ALI (where there was a mortality benefit), but I doubt this is significant based on the preclinical trials.

Interestingly there was over 15% cross over with hydrocortisone. I think overall steroids are a pretty settled question in septic shock. Most practitioner give it, there are almost no signals of harm, and there are lots of signals of benefit.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock

This randomized clinical trial compares the effect of combination hydrocortisone, ascorbic acid, and thiamine (the HAT or Marik protocol) vs placebo on SOFA score–measured organ injury at 72 hours in patients with septic shock.

jamanetwork.com

 

[SurfingDoctor]

For those keeping count, CITRIS-ALI, VITAMINS, and now... ACTS, published last month in JAMA.

Multi-centre, blinded, RCT with n=203 randomised to placebo or 50mg/1500mg/100mg q6hrly of hydrocortisone/vitamin C/thiamine. Once again, Vitamin is relatively underdosed compared to CITRIS-ALI (where there was a mortality benefit), but I doubt this is significant based on the preclinical trials.

Interestingly there was over 15% cross over with hydrocortisone. I think overall steroids are a pretty settled question in septic shock. Most practitioner give it, there are almost no signals of harm, and there are lots of signals of benefit.

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock

This randomized clinical trial compares the effect of combination hydrocortisone, ascorbic acid, and thiamine (the HAT or Marik protocol) vs placebo on SOFA score–measured organ injury at 72 hours in patients with septic shock.

jamanetwork.com

Lots of signals of benefit? You mean reduced vasoactive days? I mean, yeah, but I still think our understanding of sepsis is far too primitive to find much meaningful signal outside a large amount of noise. The mortality is so freaking wishy-washy. Steroids work as a vasoactive medication, that's pretty clear. The rest, I dunno.

Probably not really that relevant to the general field (though maybe), the NIH has funded the SHIPSS trial of randomized hydrocortisone in pediatric sepsis. On the surface, and by that metric alone, the trial is kinda dumb BUT they are prospectively coupling the randomized patients with RNA transcriptomic profiles based on the prior observation that transcriptomic profile could predict steroid responsiveness. That at least adds something meaningful in my opinion to the otherwise hammer and nail debate of steroids.

 

[lymphocyte]

Lots of signals of benefit? You mean reduced vasoactive days? I mean, yeah, but I still think our understanding of sepsis is far too primitive to find much meaningful signal outside a large amount of noise. The mortality is so freaking wishy-washy. Steroids work as a vasoactive medication, that's pretty clear. The rest, I dunno.

Probably not really that relevant to the general field (though maybe), the NIH has funded the SHIPSS trial of randomized hydrocortisone in pediatric sepsis. On the surface, and by that metric alone, the trial is kinda dumb BUT they are prospectively coupling the randomized patients with RNA transcriptomic profiles based on the prior observation that transcriptomic profile could predict steroid responsiveness. That at least adds something meaningful in my opinion to the otherwise hammer and nail debate of steroids.

The first Annane trial, APROCCHES, and ADRENAL all showed benefit, including a mortality benefit in two of the trials. The Cochrane review argues that there is a consistent mortality benefit. I have yet to see a trial that has shown significant harm. In fact, the VITAMINS trial gave everyone hydrocortisone, because they didn't think there would be equipoise otherwise. My personal experience has been uniquely positive (which is worth exactly nothing, but still).

Instead of trying to microtarget people who might benefit from a relatively innocuous drug, why not just adopt a shot gun approach? (On clinical grounds I mean. I agree that it doesn't add much to understanding the disease process itself.)

 

[SurfingDoctor]

The first Annane trial, APROCCHES, and ADRENAL all showed benefit, including a mortality benefit in two of the trials. The Cochrane review argues that there is a consistent mortality benefit. I have yet to see a trial that has shown significant harm. In fact, the VITAMINS trial gave everyone hydrocortisone, because they didn't think there would be equipoise otherwise. My personal experience has been uniquely positive (which is worth exactly nothing, but still).

Instead of trying to microtarget people who might benefit from a relatively innocuous drug, why not just adopt a shot gun approach? (On clinical grounds I mean. I agree that it doesn't add much to understanding the disease process itself.)

What can I say other than the mortality benefit is not a shared consensus (in seems to only happen in France for some reason). And because you are picking a population that already has a relatively high mortality with a pathology we don't really understand, I think it would be hard to show significant harm just for the same reason it doesn’t show significant benefit (which is why the sepsis guideline consensus is essentially equivocal on their use).

I actually don’t really care about steroids and think there are probably people who benefit and likewise probably people who are harmed. Unfortunately, we can’t prospectively identify those cohorts, so we use the shot gun approach and you get a bell shaped outcome curve, where some get better, some get worse and most don’t have either.

And more unfortunately, I think steroids have become like a religious argument in critical illness, you are either a believer or a heretic, that it makes for bad science.

 

[lymphocyte]

What can I say other than the mortality benefit is not a shared consensus (in seems to only happen in France for some reason). And because you are picking a population that already has a relatively high mortality with a pathology we don't really understand, I think it would be hard to show significant harm just for the same reason it doesn’t show significant benefit (which is why the sepsis guideline consensus is essentially equivocal on their use).

I actually don’t really care about steroids and think there are probably people who benefit and likewise probably people who are harmed. Unfortunately, we can’t prospectively identify those cohorts, so we use the shot gun approach and you get a bell shaped outcome curve, where some get better, some get worse and most don’t have either.

And more unfortunately, I think steroids have become like a religious argument in critical illness, you are either a believer or a heretic, that it makes for bad science.

Who is being harmed? Why "probably"? No study has demonstrated clinically significant harm. And yet a review of all the studies argues for benefit.

The argument you're making is one of a therapeutic granularity that I doubt will achieve clinical relevance in our lifetime. Maybe. Watch this space.

 

[SurfingDoctor]

Who is being harmed? Why "probably"? No study has demonstrated clinically significant harm. And yet a review of all the studies argues for benefit.

The argument you're making is one of a therapeutic granularity that I doubt will achieve clinical relevance in our lifetime. Maybe. Watch this space.

I mean, these four recent meta-analysis can't even reach a consistent conclusion:

Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis - PubMed

In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.

pubmed.ncbi.nlm.nih.gov

Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis - PubMed

In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037.

pubmed.ncbi.nlm.nih.gov

Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis - PubMed

The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo use or standard supportive care. More research is needed to associate personalized medicine with the corticosteroid treatment to select suitable patients who are more...

pubmed.ncbi.nlm.nih.gov

Effect of adjunctive corticosteroids on clinical outcomes in adult patients with septic shock - a meta-analysis of randomized controlled trials and trial sequential analysis - PubMed

Future trials are unlikely to detect a reduction in short-term mortality at a daily doses of 200 mg hydrocortisone. More evidence is required to confirm the beneficial effects of dual corticosteroid therapy.

pubmed.ncbi.nlm.nih.gov

Now, they don't include HAT therapy, but they probably would have been excluded anyway given they are multi-therapy trials. And of course, meta-analysis are all susceptible to bias depending on the studies included and excluded and how well those initial studies were conducted in the first place. I agree that steroids have consistently decreased vasoactive infusion days. But again, I have no stake in the fight have been doing this long enough to see that people have very strong opinions on the matter to the point where I am relatively indifferent on the subject.

 

[lymphocyte]

I mean, these four recent meta-analysis can't even reach a consistent conclusion:

Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis - PubMed

In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness.

pubmed.ncbi.nlm.nih.gov

Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis - PubMed

In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037.

pubmed.ncbi.nlm.nih.gov

Association of Corticosteroid Treatment With Outcomes in Adult Patients With Sepsis: A Systematic Review and Meta-analysis - PubMed

The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo use or standard supportive care. More research is needed to associate personalized medicine with the corticosteroid treatment to select suitable patients who are more...

pubmed.ncbi.nlm.nih.gov

Effect of adjunctive corticosteroids on clinical outcomes in adult patients with septic shock - a meta-analysis of randomized controlled trials and trial sequential analysis - PubMed

Future trials are unlikely to detect a reduction in short-term mortality at a daily doses of 200 mg hydrocortisone. More evidence is required to confirm the beneficial effects of dual corticosteroid therapy.

pubmed.ncbi.nlm.nih.gov

Now, they don't include HAT therapy, but they probably would have been excluded anyway given they are multi-therapy trials. And of course, meta-analysis are all susceptible to bias depending on the studies included and excluded and how well those initial studies were conducted in the first place. I agree that steroids have consistently decreased vasoactive infusion days. But again, I have no stake in the fight have been doing this long enough to see that people have very strong opinions on the matter to the point where I am relatively indifferent on the subject.

Two of the meta-analyses you posted suggested mortality benefit. One uses a statistical technique called TSA to wash-out the positive results from two trials.

Sure.

What's your practice?

 

[SurfingDoctor]

Two of the meta-analyses you posted suggested mortality benefit. One uses a statistical technique called TSA to wash-out the positive results from two trials.

Sure.

What's your practice?

I follow the sepsis guidelines as a CYA.

 

[SurfingDoctor]

Okay, these aren't all ridiculous studies but in the past week, NEJM put out 6 clinical trials in critical care medicine all of them essentially negative.
https://www.nejm.org/doi/full/10.1056/NEJMoa2211868

https://www.nejm.org/doi/full/10.1056/NEJMoa2209083

https://www.nejm.org/doi/full/10.1056/NEJMoa2208415

https://www.nejm.org/doi/full/10.1056/NEJMoa2208687

https://www.nejm.org/doi/full/10.1056/NEJMoa2208686

https://www.nejm.org/doi/full/10.1056/NEJMoa2209041

I don't know how many of these are actually practice changing other that basically we globally don't have a great sense of what we are doing other than less is just as good as more.

Anyway... good times.

 

[BigRedBeta]

Okay, these aren't all ridiculous studies but in the past week, NEJM put out 6 clinical trials in critical care medicine all of them essentially negative.
https://www.nejm.org/doi/full/10.1056/NEJMoa2211868

https://www.nejm.org/doi/full/10.1056/NEJMoa2209083

https://www.nejm.org/doi/full/10.1056/NEJMoa2208415

https://www.nejm.org/doi/full/10.1056/NEJMoa2208687

https://www.nejm.org/doi/full/10.1056/NEJMoa2208686

https://www.nejm.org/doi/full/10.1056/NEJMoa2209041

I don't know how many of these are actually practice changing other that basically we globally don't have a great sense of what we are doing other than less is just as good as more.

Anyway... good times.

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.

 

[SurfingDoctor]

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.

Fair comments. The early mobility study did look at secondary endpoints of delirium prevalence, RASS scores, also which weren't different. That being said, in the early mobility study, the "usual care group" also received early mobility, just less overall contact hours, so in that regard, it was more of a dose response study than an all-or-none study. So less early mobility was just as effective as more early mobility in that regard, but the title would make you think the difference is early mobility versus none, which is not what was tested.

As far as the Vitamin H study, the ICU Delirium website states:

Numerous studies have found ICU delirium to be associated with many negative outcomes such as:

• Increased time on the ventilator
• Longer ICU and Hospital lengths of stay
• Increased costs
• Higher mortality –both in-hospital and after discharge
• Greater long-term cognitive dysfunction

So I guess they were trying to answer that through the lens of a common therapy, eg anti-psychotics. The idea that an anti-psychotic would correct the heterogenous, underlying pathology that leads to delirium is a leap of course, but that's more of a criticism in general of what is delirium.

What I think is clear however that in all these studies, the one-size-fits all approach to the management of critical care patients often does not have the efficacy that would be presumed. So then you are left trying to figure out which patients get the most bang for your buck, which critical trials will be unlikely to ever achieve.

 

[Radetzky]

Yeah the problem with a lot of these is the actual separation of intervention and control groups- ie the early mobility got 20 mins of PT c/w 10.

The only convincing study (SDD) is ironically never going to be accepted.

 

[lymphocyte]

Okay, these aren't all ridiculous studies but in the past week, NEJM put out 6 clinical trials in critical care medicine all of them essentially negative.
https://www.nejm.org/doi/full/10.1056/NEJMoa2211868

https://www.nejm.org/doi/full/10.1056/NEJMoa2209083

https://www.nejm.org/doi/full/10.1056/NEJMoa2208415

https://www.nejm.org/doi/full/10.1056/NEJMoa2208687

https://www.nejm.org/doi/full/10.1056/NEJMoa2208686

https://www.nejm.org/doi/full/10.1056/NEJMoa2209041

I don't know how many of these are actually practice changing other that basically we globally don't have a great sense of what we are doing other than less is just as good as more.

Anyway... good times.

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.