Remdesivir: NOT a Game Changer

How I wish that this was a positive study. We’re in need of a helpful tool. I’ve thrown every possible treatment including tPA at patients to try to save them and nothing is 100% at this point. I took apart the first Remdesivir study several weeks ago and was not impressed. History is repeating itself.

This study was published to much fanfare and media attention yesterday. It was so good that the Lancet hid it behind the paywall when they had made all their COVID coverage free until this point. Shady shady (EDIT: it is now free to download). I have to credit my partner Kelly for getting me this paper. My NP Cody texted me about it 45 seconds before Kelly. I love my team.

There’s much to go over here. Too much to fit in the limited character count on IG but I’ll try my best. I could be wrong, don’t trust me, read the data for yourself. There are many details I just can’t cover because I’m trying to live my life. Let’s go!

Investigator initiated: they weren’t randomized from the get-go based on certain criteria, someone chose these patients. If your patients have renal failure or are on CRRT, these data do not apply as they were excluded from the study. The placebo group had more males which it’s the sex harder hit by COVID but the Remdesivir group had more HTN, DM, and CAD. These patients were less ill than the prior study. Interpret that as you may.

Remdesivir, 200mg on day 1, 100mg days 2-10 vs. placebo (2:1); n=158 vs. 78

Primary endpoint: time to clinical improvement within 28 days after randomization. What type of vague endpoint is that? Correct me if I’m wrong but that's a very uncommon endpoint. Either way, there was no statistically significant difference. Now, they admit that it’s not statistically significant, but they said there’s a trend that if they started the study drug within 10 days there’s possibly a benefit for faster clinical improvement. That’s a lot of ifs but this is where I figure there should be a benefit if there was to be one. Even with this caveat in mind, there was no difference in mortality if started early or late.

Secondary endpoints that you and I care about: all-cause mortality at day 28; frequency of invasive mechanical ventilation; duration of oxygen therapy; duration of hospital admission. No difference in any of these. There wasn’t even a difference in viral loads. This is an antiviral drug, by the way.

To be honest with you I’m not even going to go over the adverse effect stuff because I’m not convinced this works and I don’t think I can get my hands on it for my patients even if I wanted it. Well, maybe now since others may feel the same way I do and many aren’t going to want it.

The study was stopped early because they didn’t have enough patients to continue. Why not phone some friends and make the study multicentered? I disagree. I’m not a research conducting guy. I don’t want to further expose my ignorance.

I’m tired. This COVID stuff has exhausted me and I’m not even in an epicenter. I sympathize for all my colleagues in busier places than me. I have a strange survivorship guilt thing going on. I’m here for you all.

-EJ

Wang Y Zhang D Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; (published online April 29.)

Addendum: the Lancet now made the paper open access. I can't take the credit for them doing that! 

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Resuscitation and Fluid responsiveness, what is it?

You have a patient who is hypotensive. You want to make them not hypotensive. The first thing the vast majority of clinicians reach for is some sort of IV fluid. We give it and cross our fingers that they won't be hypotensive after the fluids were provided. This is what is done in every single hospital throughout the world.

I've already posted before that even in a healthy person, if they get a liter of fluid, 68% of it will be extravasated within 1 hour. Much more and far quicker will that volume be lost in someone who is critically ill; approximately 80% in 30 minutes. No wonder the "response" to that liter of fluid was so short lived.

Fluid overload has many complications which many of you know of already. Perhaps I'll do a post solely on that. This is just one post of many, so feel free to ask questions below and I will address all of them in full posts in the near future.

The whole purpose of providing a fluid challenge is to increase either the cardiac output or stroke volume, not increase MAP. This excellent paper was written by some resuscitation geniuses who I often fanboy over their work. It's completely free and I suggest you download it and read it for yourself. 

Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Ann Intensive Care. 2016;6(1):111. doi:10.1186/s13613-016-0216-7

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Resuscitation and Fluid Responsiveness: Passive Leg Raising + Stroke Volume

Don't think that I'm anywhere close to being finished on discussing fluid resuscitation and when to stop, I think I could spend a whole career just talking about this once concept. Drowning our patients with fluids is bad, we all know that.

Check out my YouTube video on the matter where I break down this study.

Douglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, Kaufman DA, Khan A, Levy MM, Martin GS, Sahatjian JA, Seeley E, Self WH, Weingarten JA, Williams M, Hansell DM, Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial, CHEST (2020), doi: https://doi.org/10.1016/j.chest.2020.04.025.

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Resuscitation and Passive Leg Raise: Don't use the arterial blood pressure to determine fluid responsiveness

Passive leg raising (PLR) is a technique I am going to cover extensively as I am writing a lecture where this will be a hot subtopic. I've covered it before on my blog and instagram. It's all in the effort to NOT drown our patients in IV fluids when they're hypotensive. 

When I was a younger whipper snapper in training, I thought I could perform the passive leg raise assessments by picking up some legs, looking at the BP increase and call it a day. Boy, was I wrong. I learned some further principles behind why I was wrong but today I found the data as to how wrong I was. Needless to say, I was very wrong. Did I mention I was wrong? Glad we're clear. I wasn't born knowing everything and still have a ton to learn.

In this paper they placed a swan in their patients and did some other stuff that I will cover at a later date. As some background and to define certain principles, a person who is fluid responsive is one who receives an amount of fluid, in this case PLR is approximately 300cc, is one who has an increase in their stroke volume or cardiac index/output. It is NOT someone who's blood pressure goes up just because they got fluids. Looking at the sensitivity and specificity of looking at the arterial blood pressure versus the measures generated via thermodilution, you can see how looking at the BP is absolute poop and should not be used. 

I altered a copyrighted photo to help illustrate the area under the curve. I'll take it down if I upset anyone. At the end of the day I'm just trying to save lives. Haney Mallemat @criticalcarenow has done some great coverage on End-tidal CO2 so check out his work on the matter. 

Monnet X, Bataille A, Magalhaes E, et al. End-tidal carbon dioxide is better than arterial pressure for predicting volume responsiveness by the passive leg raising test. Intensive Care Med. 2013;39(1):93–100. doi:10.1007/s00134-012-2693-y



Link to Abstract

Standard BP Measurements in the Critically Ill

Taking a quick COVID break and let's get back to some simple critical care basics: measuring blood pressure. We do this on all of our patients at least hourly for the stable patients and continuously on our unstable patients. Ultimately, though, we need to do this right. After all, this is critical care and the details matter.

I have already detailed my concerns with oscillometric BP cuffs in the past and have even created a youtube video about it meaning I'll skip that here. Ultimately, the values generated by the oscillometric devices leave much to be desired. When someone is sick (everyones definition of what sick is varies) they need an arterial line. Plain and simple. No healthcare professional has ever complained about having an arterial line. Win-win for all involved.

This paper touches on a 5 step approach to using an arterial line.
Step 1. Catheter insertion sites. I am a fan of brachial artery catheterization, ultrasound (US) guided. I tend to look at the radial artery first via US and eyeball the caliber of the vessel. I weigh on complexity of the procedure if they're on jet fuel to keep them alive and quickly scurry up the arm. I don't want to spend 2 hours sticking an artery like we have all done at one point or another. Someone who gloats about how good they are at a-lines hasn't been humbled enough. I asked my nurse colleagues to grab me a dart as well as the femoral line kit. Before anyone gives me a hard time about my preference for brachial artery preference, please note the complication rate is 0.2%. I have placed a number of axillary lines but this is an option of last resort for me. I choose the femoral route in code situations where I knock out a "dirty double" and place both the central line and arterial line depending on what blood return I get from the stick. 

Step 2. Catheter length: I use the 4.45cm catheter for radial arteries and the 16cm catheter for all others. When you place the US probe over the brachial artery you'll quickly see why the 4.45cm catheter won't cut it, especially in an extremity with significant adipose tissue. 

Step 3 is being skipped.

Step 4 and 5 are primarily for my critical care nursing colleagues as they describe the leveling and zeroing of the transducer, as well as checking the quality of the waveforms. They go further into dampening and a number of key concepts that are much better explained by the authors than I can ever do. 

You should definitely check out this article for yourself as it is worth your time. Did I mention that it's free?

Saugel, B., Kouz, K., Meidert, A. et al. How to measure blood pressure using an arterial catheter: a systematic 5-step approach. Crit Care 24, 172 (2020). https://doi.org/10.1186/s13054-020-02859-w

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National Institute of Health COVID treatment guidelines

Sorry that I am making you go through my website. I don’t earn any income for what I post on Instagram so think of this minor inconvenience as your way of contributing to the effort I put onto my page. Thanks!

-EJ

Link to NIH Guideline

Link to Aerosolization Article



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Corticosteroids for COVID-19

Some legendary names came out to play for this article. Meduri is the author of the famous Meduri Protocol for methylprednisolone in ARDS and Villar is the author of the article I shared on February 13th (seems like forever ago, really) where they provided dexamethasone for ARDS and showed a mortality benefit amongst many others. I personally like looking into strategies such as corticosteroids as they are inexpensive and available worldwide. You can't really count on third world countries obtaining a -zumab drug. This paper is an opinion piece and is missing formal RCT data. I recommend you read the article yourself and don't trust me. This is not medical advice but I am carefully administering corticosteroids to my COVID patients based on certain clinical and laboratory criteria. It is a custom tailored approach so I can't say exactly what I'm doing. Every patients is different. I am trying to reach for dexamethasone to avoid my team having to go into the room numerous times a day to give a medication. 

Steroids for Cytokine Storm
The authors state that the cytokine storm is what kills COVID patients. I do not disagree with this. You watch the ferritin and CRP spike up and the patient get sicker (we don't have IL-6 at our shop). Their O2 requirement goes up, their renal function starts to worsen. Things get ugly and in a hurry. Some use the -zumab drugs which we have all have a certain allocation of and is expensive, but what if we can reach for plentiful and cheap steroids instead? We all know the adverse reactions to this. The authors cite how the WHO guidelines on steroids is misleading and potentially harmful. 

The Evidence for Steroids in ARDS
We do not have great studies in all this. We have harped on this enough. The authors acknowledge this and pull observational data from Wuhan where there was a decreased risk of death for giving methylprednisolone to the patients in ARDS. They acknowledge that randomized controlled trials are ongoing but that we should not withhold giving patients steroids in the ICU for ARDS in lieu of study results. I know I'm not allowing my patients to wait themselves. 

Simple yes or no question to you all: Are your teams providing steroids to your COVID patients?

-EJ

Villar, Jesús MD, PhD; Confalonieri, Marco MD; Pastores, Stephen M. MD, MACP, FCCP, FCCM; Meduri, G. Umberto MD. Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019, Critical Care Explorations: April 2020 - Volume 2 - Issue 4 - p e0111 doi: 10.1097/CCE.0000000000000111

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Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

ECMO in Adults Training Courses for FREE from ELSO

ELSO, the Extracorporeal Life Support Organization, is now doing free training modules on ECMO (extracorporeal membranous oxygenation), both VV and VA in this COVID-19 time. Take advantage! You need to register, of course. It has been over two years since I did ECMO and this is a good refresher course for me. Check it out for yourself! It's free!

Shout out to Jamie Zink @jamiezink77 for sharing this with me. 

Link to ELSO

Link to Training Modules





Although great care has been taken to ensure that the information in this post is accurate, eddyjoemd, LLC shall not be held responsible or in any way liable for the continued accuracy of the information, or for any errors, omissions or inaccuracies, or for any consequences arising therefrom.

IDSA Guidelines on COVID-19

I typically appreciate guidelines. They do a pretty reasonable job to help us take care of our patients and standardize how we do things. That being said, with all due respect to the Infectious Disease Society of America, I do not like these guidelines. I'd rather they didn't say anything at all. In fact, they do not give any recommendations as to what to do. Seems like they're saying "don't do anything in the absence of a clinical trial". Sorry guys, the RCT days are at a halt. People are dying faster than we can wait for results for clinical trials. We can't just sit back and do nothing while these people get sicker on us. This is all my opinion and download the source material. Do not trust me. 
Here we go with the recs and my interpretation:

Recommendation 1
Hydroxychloroquine (hospitalized patients): give in the context of a clinical trial. What about all the other hospitals who are not in a clinical trial? We are learning that it is not so good in severe/ICU cases with better data but there is still a void and a large absence of adverse effects in this population when patients are carefully monitored (daily EKGs, telemetry). 

Recommendation 2
HCQ/Azithro combo: give in a clinical trial. I'm cool with this. Two QTc prolonging agents is a time bomb. 

Recommendation 3
Lopinavir/Ritonavir: give only in a clinical trial. We have learned via an NEJM article I posted that this doesn't work in severe patients but what about the mild/moderate camp? Remdesivir is hard to get a hold of these days. 

Recommendation 4
Steroids in patients without ARDS: recommendation against. I tend to agree with this.

Recommendation 5
Steroids in patients with ARDS: give in the context of a clinical trial. Yeah, sure. And what am I supposed to do for the cytokine storm if I'm not in a center that enrolls patients in a clinical trial? Can the IDSA then, since they're not helping, facilitate the PI contact info for these clinical trials?

Recommendation 6
Tocilizumab: only in the context of a clinical trial. Should I sit on my hands as I watch the inflammatory markers skyrocket? Sigh.

Recommendation 7
Convalescent plasma: in the context of a clinical trial. Well at least this is something you can ONLY get in a clinical trial so there's that.

I'd like to invite these fine folks to step out of the Ivory tower, and into the front lines with us in non-academic centers/community hospitals to practice some real world medicine. I trained in an Ivory tower institution myself. The vast majority of us are not in the Cleveland Clinic, Bringham and Women's, Vanderbilt, Mass Gen, Northwestern, Mayo Clinic, and Johns Hopkins. 

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Plasma Exchange for COVID-19

Let's straighten out some nomenclature first. We all have questions about what is what and there is much confusion. I personally like the say all these words roll off the tongue. Makes you sound smart when you say it. There's more to it than what I am going to mention here, of course. 
Plasmapheresis is to remove, treat, and exchange blood plasma for other plasma or something else (i.e. albumin). I am going to focus on the exchange component called "plasma exchange" or even sexier: PLEX. This is typically used to treat various disorders of the immune system like TTP, Guillain-Barre, etc. 

Could this work for COVID? 
First of all, this is not a treatment for the virus itself. This will not be a viral load monitoring type therapy. This is intended to treat the cytokine storm and systemic response. What PLEX does is "remove inflammatory cytokines, stabilizing endothelial membranes, and resetting the hypercoagulable state".
The paper, which you should download and read for yourself, states that PLEX was used in a small number of patients during the H1N1 outbreak which had a full recovery. The authors are trialing this modality at the moment and have a paper that's cooking and is currently undergoing peer-review for publication. I tip my hat to the fact that they propensity matched their s/p PLEX patients to similar patients with similar illness who received standard of care. I wish the HCQ/azithro studies, remdesivir, and FFP studies to date would have done this but they didn't. Sigh.
Based on the experience of the group, they are using PLEX earlier in the disease course rather than later for better outcomes. They're working on a larger trial as well. Seems hopeful. 

Cons:
Adverse effects/Caveats/concerns: patients will need a dialysis catheter. More bleeding when placing the catheter versus a traditional line but given that most patients end up on renal replacement therapy anyway, this may not matter. These prothrombotic patients may potentially clot off this circuit.
This is also a big machine that needs to be placed in a patients room. Concerns exist for cleaning the machine.
Some patients also develop hypotension and transfusion reactions. 

As an aside, the Critical Care Medicine world is TINY! The author of the cited article trained at the same fellowship program I did and I interviewed at a place where he used to work. He's one brilliant dude. Everyone always loved working with him and sung his praises left and right. I picked up on his great energy myself immediately upon meeting him in person. 

Keith, P., Day, M., Perkins, L. et al. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care 24, 128 (2020). https://doi.org/10.1186/s13054-020-2836-4

This data is current as of 4/13/2020

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Link to Pre-pub article