Joanna PooleDec 16, 2022
Alkaline phosphatase seems to have remarkable efficacy in sepsis AKI - inactivates LPS (one reason ALP increases in inflamm?) - anyone think this will become common clinically? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004577/ #AKI #ICM #MOF #nephrology #intensivecare
Effect of alkaline phosphatase on sepsis-associated acute kidney injury patients: A systematic review and meta-analysis

This systematic review and meta-analysis were performed to evaluate kidney function in patients with sepsis-associated acute kidney injury (SA-AKI) on alkaline phosphatase (AP) therapy.PubMed, Embase, and the Cochrane Central Register of Controlled Trials ...

PubMed Central (PMC)
Show threadJoanna PooleDec 16, 2022
@Charlotte_Summers do you think the results of trials so far seem too good to be true? ^^
Show threadMahesh RamananDec 16, 2022
@jopo_dr History of magic bullet trials in sepsis warns us to be very careful with these sorts of findings. Having said that, on a cursory glance, the numbers are hard to ignore completely.
Show threadJoanna PooleDec 17, 2022
@maheshramanan yes my gut says nope nope but it has seemed promising - apparently a follow on trial called Revival has been stopped for futility of 90 day primary endpoint though! Would like to see more info about that however!
Show threadJoanna PooleDec 17, 2022
@maheshramanan here - phase 3 stopped for primary endpoint futility which was mortality at 28 days - but renal parameters improved markedly. I’m wondering, probably naievely, if the component it reduces is the CkD pathophysiology?
Show threadAndrew Conway MorrisDec 17, 2022
@jopo_dr @maheshramanan the phase II trial was negative on that end point, but in a somewhat convoluted and post-hoc analysis showed an improvement in mortality that wasn’t explained by the supposed mechanism of action. The premature closure of the phase III suggests this is not going to be a goer as a treatment to me. Perhaps if they can find a diagnostic to identify a group who may benefit, but not the clinical criteria that have been used to date.
Show threadMahesh RamananDec 17, 2022

@Mozza @jopo_dr Yeah it's pretty much history repeating itself.

My opinion- without some attempt at enrichment, we should not do any more single intervention drug trials in critical care.

Show threadAndrew Conway Morris
@maheshramanan @jopo_dr I think there is a strong case for that- though we must remember‘inclusion criteria’ are already designed to enrich. Post Covid we are seeing more single pathogen studies (e.g. REMAP-CAP flu study) which is again enrichment. But we need a revolution in near-patient diagnostics for stratification and enrichment of trial populations.
Dec 17, 2022 at 10:35amWeb
Show threadJoanna PooleDec 17, 2022
@Mozza @maheshramanan I do dream of near patient subtyping! Some kind of INR for the inflamm cytokines would be dreamy!
Show threadGabriele PollaraDec 17, 2022
@jopo_dr @Mozza @maheshramanan +1 to that on bedside inflammatory stratification that guides therapy (not even just on ICU). Quite a long way off still sadly, but in a way that personalised medicine is broadly the way things are heading.
Show threadMahesh RamananDec 17, 2022

@Mozza @jopo_dr single pathogen or single disease are absolutely acceptable forms of enrichment. The utility of molecular phenotyping will hopefully be proven and realised during my lifetime, but it feels like we're still far away.

But the days of sepsis or ards trials should be over. There's little justification for those sort of syndrome trials anymore.

Show threadAndrew Conway MorrisDec 17, 2022
@jopo_dr @maheshramanan single pathogen is here, especially for pulmonary infections. The host side is more complex, and will need more work but are not too far away. The issue is demonstrating they are needed, with both industry and research funders unwilling to invest in the technology until benefit is demonstrated- chicken and egg
Show threadProf Tamas Szakmany MBEDec 18, 2022
@Mozza @jopo_dr @maheshramanan we need to be able to show that severe inflammation markers can be reliably used. We have some promising mRNA data but need confirmation on a wider population. Could this be one of the routes for enrichment?
Show threadAndrew Conway MorrisDec 18, 2022
@maheshramanan @jopo_dr @iamyourgasman definitely- assuming a suitably parsimonious group of transcripts, designing a qPCR panel for these would be relatively straightforward. A growing range near-patient and lab devices are available allowing for near automated PCR.
Show threadJoanna PooleDec 19, 2022
@Mozza @maheshramanan @iamyourgasman would be amazing to see these used in actual patient trials…
Show threadMahesh RamananDec 20, 2022
@jopo_dr @Mozza @iamyourgasman And then prove to be useful in improving outcomes.... the holy grail of personalized medicine