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 🫁Feb 22, 2023

@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!

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.

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

@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%.