Mastodawn

Joanna Poole Feb 22, 2023

More equivocal fluid trial fodder https://ccforum.biomedcentral.com/articles/10.1186/s13054-023-04357-1#icu #icm #criticalcare

Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial - Critical Care

Background In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients. Methods POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA). Results A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2–34.8 vs. 33.9%, 95% CI 29.6–38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results. Conclusion The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it. Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

BioMed Central

Jack Iwashyna 🫁Feb 22, 2023

@jopo_dr it is striking how hard it is to find a robust difference in effect among a broad array of fluid strategies

Maybe there are just several more or less equivalent ways to skin this cat?

RogovtTed Feb 22, 2023

@iwashyna @jopo_dr it’s very difficult to prove a therapy or strategy is effective when our tools for defining the problem we are monitoring are unreliable. No shortage of examples of this in ccm/icm.

Jack Iwashyna 🫁Feb 22, 2023

@RogovtTed @jopo_dr

I thought Mike Sjoding did a nice job of formalizing that intuition in

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015753/

Acute Respiratory Distress Syndrome Measurement Error. Potential Effect on Clinical Study Results

Rationale: Identifying patients with acute respiratory distress syndrome (ARDS) is a recognized challenge. Experts often have only moderate agreement when applying the clinical definition of ARDS to patients. However, no study has fully examined the implications ...

PubMed Central (PMC)

Mathieu Desgroseilliers Feb 22, 2023

@iwashyna @RogovtTed @jopo_dr
Indeed !
That’s the problem with “syndrome definition”. It’s a heterogenous population with different pathophysiology. “one size fits all” approach/strategy is very likely leading to negative results.

Sometimes, we forgot the clinical endpoint of it. Like in the case of fluid resuscitation, it’s rather a matter of tissue perfusion than fluid strategy.

We should ask ourselves more often “if we should rather than if we could” 😂

Jack Iwashyna 🫁

@matdesgro @RogovtTed @jopo_dr

I hear you, sir … yet if every patient is unique, there is no science. Finding the commonalities in our patients is so essential

Mathieu Desgroseilliers Feb 22, 2023

@iwashyna @RogovtTed @jopo_dr
I completely agree.
There’s probably common pattern/phenotypes of clinical presentation according to underlying pathophysiology. Identifying this is key. Once it’s done, there’re will be better population selection in trials & better evidence

At bedside, the challenge will be identifying the path taken by the patient & adapting treatment according to it

We will be able to better personalize patient care that way in sense

Jack Iwashyna 🫁Feb 22, 2023

@matdesgro @RogovtTed @jopo_dr

Thankfully it is not an either/or. Because even though we just discovered endotypes, supportive care for common stuff has really gotten us a long way already.

Joanna Poole Feb 22, 2023

@iwashyna @matdesgro @RogovtTed yea although people demonise syndromes they did allow us to start finding evidence based survival improvements. Biomarkers will still only group rather than individualise therapy. The ultimate experiment is in each patient individual but until we can model a person exactly like jaguar do their race car simulations we have to start somewhere!

Joanna Poole Feb 22, 2023

@iwashyna @matdesgro @RogovtTed Berlin criteria are actually not bad at diagnosing severe ards/diffuse alveolar damage at autopsy

Mathieu Desgroseilliers Feb 23, 2023

@jopo_dr @iwashyna @RogovtTed Agreed, syndromes allowed us to come a way but I feel it might have slowed us down in the lasts years as negative results were accumulating, perhaps in part of selection biais of heterogeneous group

It’s like in oncology, it has evolved quit a bit. Now it’s “treat X cancer having this Y mutation with Z med.” We will be there eventually I hope

But for now, “individualized care” is labelling the patient according clinical/biochemistry features & do our best for them

Jack Iwashyna 🫁Feb 23, 2023

@matdesgro @jopo_dr @RogovtTed

I am curious, is there any population data on what fraction of cancer treatment is truly mutation-specific targeted, and what fraction is old school cytotoxic poison it, surgical cut it, and rad Onc zap it?

Even AML, site of so many brilliant break throughs, still seems to use a lot of classic untargeted 7+3 induction

Jack Iwashyna 🫁Feb 23, 2023

@matdesgro @jopo_dr @RogovtTed and cardiology has clearly made tremendous strides, but that’s still mostly anatomic, non-molecular plumbing and electrical work, right?

Jon Henrik Laake MD PhD Feb 23, 2023

@iwashyna @matdesgro @jopo_dr @RogovtTed I fail to understand the misgivings in ICM. The more I look at ‘precision medicine’, the less precise it seems. In ICM we have generic interventions that cut death by more than half and we have witnessed steady improvement over the decades. We refine and revise according to available evidence, and we contribute during all disasters, theatres of war and in epidemics. Forget about the magic bullets.

Jon Henrik Laake MD PhD Feb 23, 2023

@iwashyna @matdesgro @jopo_dr @RogovtTed Anyhow, this was my day.

Mathieu Desgroseilliers Feb 23, 2023

@jon_blund that’s really a beautiful way to spend your day ! Hope you enjoyed it & had a great time !

Susan Egbert, PharmD Feb 23, 2023

@jon_blund @iwashyna @matdesgro @jopo_dr @RogovtTed

I actually agree with this. I think the only useful thing in the "precision medicine" sphere I can fight for is pharmacogenomics

Mathieu Desgroseilliers Feb 23, 2023

@lichenlady94 @jon_blund @iwashyna @jopo_dr @RogovtTed from what I heard there’s a lot of potential in this research field

Joanna Poole Feb 23, 2023

@lichenlady94 @jon_blund @iwashyna @matdesgro @RogovtTed the thing about bullets, is until they arrive, best supportive care can and should be given systematically HOWEVER itu syndromes aren’t congenital, there is pathophysiology present, and our tools not being sharp enough to see the detail isn’t a permanent state of existence. Penicillin would have been a bullet for bubonic plague. There are bullets for HIV. mRNA vaccines - 1st viral pandemic in world history to be counteracted within year?

Joanna Poole Feb 23, 2023

@lichenlady94 @jon_blund @iwashyna @matdesgro @RogovtTed imo failure of clinical trials has been hight reliance on animal models of sepsis etc (CRP isn’t even a prominent acute phase response in them) and lengthy trials on heterogenous groups. Newer trial design along with molecular insights and adaptive responses will increase drug development for our patients I think. Still agree with gains from systematic supportive care. Don’t get me started on people not using LPV

Jon Henrik Laake MD PhD Feb 23, 2023

@jopo_dr @lichenlady94 @iwashyna @matdesgro @RogovtTed I don’t think it’s a ‘failure of clinical trials’. First, they provide a load of information, and many define limits of safe care. Second, it would be close to s miracle if any or one of our «bright ideas» proved to be anything more than that. Rather, I think it’s very arrogant of us to suppose that we can come up with solutions based on what, at best, is a very sketchy understanding of physiology.

Joanna Poole Feb 23, 2023

@jon_blund @lichenlady94 @iwashyna @matdesgro @RogovtTed I do think for drug development in translational medicine, clinical trials fail to show efficacy, some for predictable reasons, whether the animal stage, endpoints used, or population used. Icu trials often very underpowered. There is absolutely only a small fraction of drugs developed that make it through to licensing and that is a failure for everyone in my opinion :) expensive!

Mathieu Desgroseilliers Feb 23, 2023

@jon_blund @iwashyna @jopo_dr @RogovtTed very good point. The tings that made the greatest difference were more of “supportive care” rather “magic bullet”

Delirium prevention, early mobilization, A2FBundles, less invasive treatment whenever possible, etc had more impact for largest population than the latest targeted meds for a few ones. This maybe why we are now more focus on PICS prevention, post-ICU QOL for some intervention, etc. “The life after ICU”

Mathieu Desgroseilliers Feb 23, 2023

@jon_blund @iwashyna @jopo_dr @RogovtTed

If what we can do as a community is “just” outstanding supportive care, pretty sure countless lives will be saved

Jon Henrik Laake MD PhD Feb 23, 2023

@matdesgro @iwashyna @jopo_dr @RogovtTed Francois Lamontagne said it best: https://www.nejm.org/doi/full/10.1056/nejmp1411310

Doing Today's Work Superbly Well — Treating Ebola with Current Tools | NEJM

Perspective from The New England Journal of Medicine — Doing Today's Work Superbly Well — Treating Ebola with Current Tools

New England Journal of Medicine

Mathieu Desgroseilliers Feb 23, 2023

@jon_blund @iwashyna @jopo_dr @RogovtTed thank you for sharing this very excellent paper🙏

Though I’m not surprised by the wisdom words of François as I had the chance to round with him in my junior years at CHU Sherbrooke a few years ago (can we say a decade ago count as just a few years🤔)

Jack Iwashyna 🫁Feb 23, 2023

@matdesgro @jon_blund @jopo_dr @RogovtTed

I love that Lamontagne essay so much. I gave it out on the first day of every rotation 2020-2021 to my team

Jon Henrik Laake MD PhD Feb 23, 2023

@iwashyna @matdesgro @jopo_dr @RogovtTed The «drug fetishism» seen during the pandemic just confirmed everything he said.

Joanna Poole Feb 23, 2023

@jon_blund @iwashyna @matdesgro @RogovtTed but ultimately it’s vaccines that got us out of the pandemic and they’re a magic bullet. And dexamethasone that improved outcomes. Just because many places use or experiment with therapies erratically doesn’t mean we will never have answers in the icu, just that we don’t have them yet. Cro magnon humans had a life expectancy of 25 years only - worlds away - us not finding ten cures in a career and deciding are none is arrogance imo (and respectfully!)

Jon Henrik Laake MD PhD Feb 23, 2023

@jopo_dr @iwashyna @matdesgro @RogovtTed Sure, and in countries with efficient public health interventions the pandemic never reached the apocalyotic levels other nations had to endure. Also, I believe a high standard of conventional care saved more lives than all drugs combined (excluding vaccines).

Joanna Poole Feb 23, 2023

@jon_blund @iwashyna @matdesgro @RogovtTed I definitely think bundles etc are essential and agree re standardised safe care but I think it would be very difficult to persuade me and many others not to seek therapies for conditions that approach 20/40/60 % etc mortality, even if 100 years from now. In 1900 Uk infant mortality was 50%!!! It’s less than 1% now ~ combo of hygiene etc and innovation

Jon Henrik Laake MD PhD Feb 23, 2023

@jopo_dr @iwashyna @matdesgro @RogovtTed Add improved living standards and economic well-being to the mix, and we agree 100%.

Jon Henrik Laake MD PhD Feb 23, 2023

@iwashyna @matdesgro @jopo_dr @RogovtTed Another excellent take on this is an editorial by David Bihari in BMJ 20 years ago. https://www.bmj.com/content/322/7300/1437

Preventing renal failure in the critically ill

Few doctors trained in the past 20 years have not learnt of the benefits of “low dose” dopamine in patients developing acute renal failure. The belief that low dose dopamine is beneficial was based on the physiological and pharmacological properties of dopamine and on personal anecdotes, but there is a lack of clinical trials, those available being of poor quality.1 The recent publication of a high quality randomised, double blind, placebo controlled study2 showing no benefit of “low dose” dopamine has, therefore, killed—or at least mortally wounded given that it takes time for cardiac surgeons to catch up—one of critical care's sacred cows. In this study 328 patients (in 23 Australasian intensive care units) with an acute inflammatory response and early renal dysfunction (raised serum creatinine concentration or oliguria) randomly received a dopamine infusion (2 μg/kg/min) or placebo. The primary outcome variable, peak serum creatinine concentration during infusion, did not differ between the well matched groups. Moreover, there was no difference in any other variable studied, including requirement for dialysis. Indeed, urine output and use of frusemide did not differ, suggesting that dopamine was not even an effective diuretic. A possible criticism of the …

The BMJ

Jack Iwashyna 🫁Feb 23, 2023

@jon_blund @matdesgro @jopo_dr @RogovtTed

“recent publication of a high quality randomised, double blind, placebo controlled study2showing no benefit of “low dose” dopamine has, therefore, killed—#or #at #least #mortally #wounded #given #that #it #takes #time #for #cardiac #surgeons #to #catch #up—one of critical care's sacred cows.”

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @jopo_dr @RogovtTed

Good point. As a non-onco folk, I am not uptodate with onco treatment.
I will need to do some research to see if data is available on patient % on targeted therapies.

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @jopo_dr @RogovtTed On the other hand, it could illustrate the point on “precise” medicine & population selection. For exemple, HER-2 positive breast cancer is know to respond to trastuzumab.

If a trastuzumab study include HER2 positive & negative patients, real effect would be diluted. If study include only HER2 positive, these results would give the real effect either positive/negative. Without this nuance, it could be falsely believed that it doesn’t work at all

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @jopo_dr @RogovtTed but as targeted therapies are new-ish in the effervescent onco research field, there’s seems to be a long way before this kind of research makes it way in CritCare from my understanding

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @jopo_dr @RogovtTed All this to say, which was probably my not very well formulated starting point, that syndrome aren’t bad neither good, maybe we just need more precise definition partly based on phenotypes/biomarkers that will continue to be refined as knowledge will grow, this will lead to better data & to better care 🤷‍♂️

“Nanos gigantum umeris insidentes” as it said

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @jopo_dr @RogovtTed
I found some data but I can’t qualify as an expert on this

It seems a growing proportion of patient since 2018 up to ~13% of targeted therapy in 2020 & ~27% of genome informed therapy.

There could barriers to treatment regarding cost though

https://pubmed.ncbi.nlm.nih.gov/29710180/

https://www.targetedonc.com/view/response-to-targeted-therapy-increased-from-2006-to-2020-in-patients-with-cancer

Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome-Driven Oncology - PubMed

Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer. To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug …

PubMed

Mathieu Desgroseilliers Feb 23, 2023

@iwashyna @RogovtTed @jopo_dr
Cannot agree more. Supportive care is a cornerstone of critical care.
As a friend & collègues of mine said “ICU is pretty simple, support the patient to the best of your ability to let time do its thing”