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! 

Link to Article

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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.

Link to Article

Link to PDF

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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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





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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

Hints on when to anticoagulate your COVID-19 patients

I have written and said this before but I am quite convinced that many of these patients need full anticoagulation. My opinion, not medical advice. This is due to what I have seen in my clinical practice, what others have anecdotally mentioned, and post-mortem data. We need more data to find out when to start it. Obtaining CT scans of the chest and having a radiology tech come in to scan everyone's extremities may not be realistic. This article was published yesterday and I learned about it from Josh Farkas (@pulmcrit). I'll read his take after I put this out. There's ultimately no randomized control trial for anticoagulation in these patients and this is pure clinical gestalt. Please strongly weight risks vs. benefits if you go down this route.

In my practice, I have been keeping track of numerous parameters to try my best to decide when to pull the trigger of when to start anticoagulation. It's a big mystery. As the authors of this paper mentioned, we don't know what is the prevalence of venous thromboembolism in patients with severe COVID-19 infections. They looked at checking d-dimers to predict VTE in these patients.

Retrospective study published on 4/9. They looked at 81 ICU patients in Wuhan, China. They did lower extremity ultrasounds. I am personally reporting that I’ve seen upper extremity VTE's so these could have been missed in the study. They also performed numerous other lab tests.

What they found
25% of patients (n=20) had lower extremity VTE. Again, they didn’t check the uppers.
8 of these 20 patients died.
VTE group: older patients, lower lymphocyte counts, longer PTT (all statistically significant)

What lab value did they find to be most helpful?
D-dimer greater than 1.5mcg/mL.
85% Sensitivity. 88.5% Specificity. 94.7% Negative predictive value.

For some background, an elevated d-dimer is a sign of "excess coagulation activation and hyperfibrinolysis". Once you start anticoagulation, the d-dimer should start coming down. I am seeing this in my practice. I haven't decided where to pull the trigger, though. Anecdotal evidence. Poo poo evidence.

Cui, S., Chen, S., Li, X., Liu, S. and Wang, F. (2020), Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. Accepted Author Manuscript. doi:10.1111/jth.14830

- EJ

Link to Website with Article

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Remdesivir in Severe COVID-19

Let's be quite clear here, there's no miracle drug for all this. I personally have zero experience with remdesivir at this point in time. Hopefully you all can comment on whether you anecdotally think it works or not. This study was published earlier today in the NEJM and is free for you to download and read for yourself. Do not trust me. This is not medical advice. This is industry sponsored but someone had to pay for the medication. 

We've all been hearing about compassionate use but what does it mean? Well, it means that we can give an unapproved (by the FDA in the US) medication has the potential benefit to justify the risks of treatment. In this case, remdesivir has been pulled from the shelf to allow us to try to treat COVID-19 due to its in vitro activity against SARS-CoV-2. It also has numerous other applications that you can check out on your own. 

n=53 (originally 61 but some couldn't be analyzed) 75% were dudes. 57% on vent. 8% on ECMO. 
Patients: sats < 94% on RA or need for O2. Also needed to have kidneys and a liver (that all worked). Symptoms started a median 12 days prior to starting treatment. 
Dose: 200mg IV on day 1, 100mg IV on days 2-10.

What did they do? 
They monitored the patients for at least 28 days and quantified events. No specified end points. It was a "let's see what happens" study. Compassionate use, indeed. Patients were obviously not randomized. No control arm. Sigh. 

What did they find?
68% had an improvement in their O2 support. 15% worsened. It's not 100% but nothing is except death and taxes. Was this because of the medication? We do not know.
Pts on RA or low flow: 100% got better. either they were going to get better on their own or the medication helped. 
NIV or HFNC: 71% got better. Again, either they were going to get better on their own or the medication helped.  

13% of all patients died. 18% of the patients on vents died. 5% of the patients on NIV died. Are these numbers about what we're seeing for patients who end up in our hospitals? 

Did they cause harm?
60% had adverse effects but if you honestly look at these, I can't say they're necessarily the fault of the study drug. 23% had pyrexia (fever) well, duh. And we are seeing renal impairment, AKI, MODS, DVT, ARDS all because of cytokine release syndrome. Can't blame this necessarily on remdesivir. Also, two patients had pneumothoraces. That's definitely not the study drug. 

The limitations are endless and listed thoroughly by the authors. I honestly don't know what to do with this data. It's not like the results are too good to be true. They're just meh. 

-EJ

Link to Article

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FDA definition of "compassionate use"



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Summer heat may help us with COVID-19! (Hopefully!!)

Summer, my favorite season. It can't get here soon enough. Will it help us with the coronavirus and help terminate this thing sooner rather than later? 

This study was published on April 2nd out of Hong Kong in Lancet Microbe. I believe it may be some good news or I may be too optimistic. This paper is also an exercise in why you need to look up the supplementary material because a lot of goodies live in there. Download it for yourself!

They measured the stability of SARS-CoV-2 at different temperatures. I'm going to break it down in Fahrenheit so that you don't have to ask Siri to convert Celsius to Fahrenheit numerous times like I did. I am completely open to be wrong regarding the following interpretations as looking at virus titers is not something I've honestly ever done. These following numbers do not necessarily mean that they are infective at those titers either. 

At 39.2 degrees Fahrenheit, the virus is extremely stable. It seems to hang around just fine for two weeks, unfortunately. When it starts heating up, however, things become a bit more favorable for us. The temps in NY in Feb/March were 30-50 degrees. 

At 71.6 degrees Fahrenheit, this stability gets cut in half to where it's barely around at one week. 

At 98.6 degrees Fahrenheit, the virus is even more unstable living about just a day. 

I tried to find how this correlates to other viruses such as influenza but this was a wild goose chase with apples to oranges comparisons. Not worth confusing you all (nor myself) with that data.

How this translates to planning for spread in different climates and curve modeling, I don't know. I also don't know how different surfaces will affect this outside of irresponsible extrapolation on my part. I'll leave that up to the epidemiologists. I just know that the virus living in my car that's sitting in the hot Florida sun will be routinely knocked out as I contaminate it with my dirty scrubs daily and my laundry sits in my hot garage.

The paper also discusses the stability on paper, tissue paper, wood, cloth, glass, money, stainless steel, plastic, and masks. Hope you all have a good amount of sterilizing wipes around!

A hat tip to the authors and to my wife who sent me this paper. 

Chin A W H, Chu J T S, Perera M R A, et al. Stability of SARS-CoV-2 in different environmental conditions. Lancet Microbe 2020; published online April 2. https://doi.org/10.1016/S2666-5247(20)30003-3.

Link to Full Text

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Link to Supplementary Materials



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Two phenotypes for Respiratory Failure

Conventional ARDS treatment is not cool anymore, or is it? Gattinoni, one of the authors of this paper, has really made a name for himself during this pandemic as we have learned much from his experience and that of his team. They start off by pointing out that the Surviving Sepsis Campaign guidelines need adjusting. Shots fired! Kidding... ish... Please download the paper for yourself and don't trust me.

In this editorial which has yet to be published in the Intensive Care Medicine journal discusses two phenotypes: L and H. There could be a transition from L to H, by the way. The virus can't make this too easy for us. The type could be identified via CT scan but also looking at the respiratory system elastance and recruitability. The rationales as to why someone would fit into one category or another is dependent on many factors (gray area yet to be determined).

Type L (more than 50% of patients, what they come in with)

- Low elastance (i.e. high compliance)

- Low ventilation to perfusion ratio (loss of regulation of perfusion and loss of hypoxic vasoconstriction/vasoplegia) *I have mixed feelings about this one. 

- Low lung weight (not much generalized infiltrate nor edema)

- Low recruitability (since there's not much infiltrate nor edema)

Tx: Reverse hypoxemia. Try non-invasive options. Try higher tidal volumes (8-9cc/kg) if hypercapnic and intubated. Keep PEEP from 8-10. Prone positioning doesn't really work.

This is where we see the tachypnic patients before they crash. They may improve on their own or worsen. They describe patient-self inflicted lung injury (P-SILI). Perhaps decreasing their work of breathing could buy the patient time to recover before transitioning to type H.

Type H (20-30% of patients)

High elastance (lots of edema in there)

High right-to-left-shunt

High lung weight

High recruitability

Tx: treat like severe ARDS, high PEEP, prone positioning, ECMO if needed.

My take is that this paper is missing some components on the microthrombi and leading to some of the shunt physiology we are seeing leading to the refractory hypoxia. I feel that rather than vasoplegia we are seeing the effects of micro thrombi creating shunts. I could be totally wrong.

Gattinoni L. et al. COVID-19 pneumonia: different respiratory treatment for different phenotypes? (2020) Intensive Care Medicine; DOI: 10.1007/s00134-020-06033-2

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Anticoagulation in COVID-19

Should we anticoagulate COVID patients? Simple question, not so simple answer.

Autopsies have found occlusion and microthrombosis formation in the small vessels of the lungs. We all know that people have just decided to drop dead for one reason or another after looking fine. Could this also be happening in the heart and kidneys? Can we at least band-aid this by anticoagulating somewhere in the course?

75% of the COVID ICU patients I've personally cared for have developed DVT's of some sort during their hospital course and are currently on full anticoagulation. But could we have predicted this was going to occur and have been proactive when it comes to all this micro and macro thrombi we are seeing? By the way, I have reached out to some hematologists I know and trust for their opinions and no one really knows. Even though I started writing this post yesterday, Josh Farkas beat me to the punch today.

Let's look at the data.

The paper I’m covering today was published on March 27th and came out of China. I'm late to the game. It is a retrospective study. They described "sepsis-induced coagulopathy" based on PT, platelets, and SOFA score.

They found that if the the SIC score was greater than or equal to 4 and the patients had received heparin, there was a decrease in their 28 day mortality from 64.2% to 40%. The number needed to treat with all its limitations was just 4.1 If the SIC score wasn't elevated, it really didn't make a difference. The D-dimer also held its own if it was greater than 6. When this is the case, patients who received heparin had a mortality of 32.8% versus 54.8% without it (NNT=5.1). This isn't the best data in the world and has numerous limitations that you can look at yourself to help you better interpret the study, but I know I will personally be formulating some anticoagulation strategies for these patients in the absence of a large clinical trial. Potential benefit has to be greater than the risks, of course.

It is important to note that the dosing utilized in this paper is comparable to our DVT prophylaxis doing. My curiosity ultimately stems from the utility of full dose anticoagulation. Could that hypothetically lead to even fewer deaths? I don't know.

Has anyone seen any data where patients who are chronically anticoagulated have less severe COVID? I'm curious.

A question for someone smarter than me:

Would there be a difference between using heparin, enoxaparin, or moving straight to the DOACs? I would like to limit the exposure of my nurses in titrating heparin drips.

- EJ

Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy [published online ahead of print, 2020 Mar 27]. J Thromb Haemost. 2020;10.1111/jth.14817. doi:10.1111/jth.14817

Link to Abstract

Link to FREE PDF


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Respiratory Management Protocol of Patients with SARS-CoV-2

First of all, a big hat tip to the authors:

Aurio Fajardo C; MD. Medicina Interna. Unidad de Paciente Crítico. MsC en Ventilación Mecánica, Universitat de València. MsC en Medicina Intensiva. Grupo Ventilación Mecánica Chile - Drive Flow Org. Viña del Mar. Chile. @drive_flow_org

Alberto Medina V; PhD. MD. UCIP. Hospital Universitario Central de Asturias. Oviedo. España @alberto_medina_villanueva

Angelo Roncalli; PT. MsC. Hospital Escola Helvio Auto Maceió. Brasil @angelo.roncalli

Enrique Monares Zepeda; Médico Intensivista. Ciudad de México. @enriquemonareszepeda

Federico Gordo-Vidal; MD. Hospital Universitario del Henares. Coslada- Madrid. Grupo de Investigación en Patología Crítica. Francisco de Vitoria, Madrid. España. @fgordo5

Vicent Modesto A; MD. Jefe Clínico UCIP Hospital Universitari I Politècnic La Fe. València, España.

Rodrigo Adasme J; MsC, Pt, CRT. Terapia Respiratoria Hospital Clínico Red de Salud UC-Christus. UNAB. Santiago, Chile.


This is a great review of 45 references to help us take care of patients with COVID-19. There is much left to be learned about this horrendous disease, but we can take cues from prior experience to help us guide our management of the ventilator to cause as little harm as possible. The group of experts listed above, using their multinational expertise, developed this evolving document including algorithms as well as guidelines that will be updated as we learn more. Best of all, it's free to us all. Thank you!

Link to Article

Link to PDF in English

Link to PDF in Spanish


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.

Ivermectin for COVID

This paper was sent to me by @itskatiesway, @bug_drugs, @sanamoh92, @sy_doctornetwork, @paul.neil95, @nascarnora. Thank you all for sending data to me. Also, I am getting somewhere around 50-100 messages per day from the community. Much love to you all. I cannot answer every single question bc I wouldn't be able to live my own life. Thanks for understanding.


Let's get started. It bears repeating that I like simple and cheap stuff. Ivermectin, has been around since 1998 and many of us learned about it as a treatment for scabies. It's about $5 a tab per UpToDate. This paper is quite different than what I am used to reading (since I mainly read clinical trial data which is written a particular way). This is far more science-y than what I am accustomed to understanding. Even this nerd has his limitations.


Let's start off with the first and glaringly obvious limitation to this study. It works in vitro. No data that it work in vivo. Made simple means we have absolutely zero data that it would work in a human body.


Basically they infected cells with SARS-CoV-2 and then added ivermectin. They followed up later to see if there was a reduction of viral RNA at different time points and there was! They noted that "a single dose was able to control viral replication within 24-48 hours" in their system. Don't get too excited now. Again, this is in vitro. They provide some mechanisms which are way over my head.


They recommend trying multiple regimens on COVID-19 patients to assess for a clinical response. At least could postulate, perhaps erroneously, that we could see a change in 24-48 hours. I am not holding my breath but this seems like something that should be attempted early in the disease course, like plaquenil, and may not have too much benefit once the patient is in my hands in the ICU. I can't wait for a good. The best thing is that the Australians discovered this and the know how to put together some great trials with their ANZICS group. A hat tip to the authors!

- EJ

Link to Article

Link to FULL PDF (this link may not work extremely well, go to the article and sort it out there)


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.

Hydroxychloroquine and Azithromycin in Severe COVID-19 Infection

For those of you new to the page/blog, I am a Critical Care physician. My team and I are usually the last line of care patients receive. Many of you are part of my extended team working in ICU's throughout the world. I would honestly love for this combination of HCQ and azithro to work. This study makes us further curb our enthusiasm.

A bit of background:
The two French studies that "showed a benefit" as well as the Chinese study I posted that "showed a benefit" were conducted in patients who were NOT critically ill. This paper was published on March 30th. I'm late to the party, I know. But it correlates with the anecdotal experience I've noted from various facilities who are taking care of critically ill patients.

We get another small study here. n=11. They weren't critically ill when they started the data collection but within 5 days, 1 died and 2 were transferred to the ICU.

Regimen: HCQ 600mg daily x 10 days + Azithromycin 500mg on day 1, 250mg on days 2-5.

Results: 8 patients still had positive RNA at days 5 to 6 after treatment initiation.

Bottom line: in this subset of patients, there was no rapid clearance of COVID-19 by giving this combination. It wasn't as 100% as the Gautret/Raoult studies that I have taken apart in the past. This study is also fraught with flaws. No control group, small, no baseline characteristics. They do not define what made these patients "severe" as opposed to mild or moderate. They could have also waited the full 10 days of therapy. I guess they were in a rush to pump out data or they're going to publish the full data in a couple days and have two publications for their CV instead of just one. Sigh.

I am personally not excited about the HCQ/Azithro combo in my critically ill patients.

Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N, No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection, Me ́decine et Maladies Infectieuses (2020), doi: https://doi.org/10.1016/j.medmal.2020.03.006

Link to Abstract

Link to FULL FREE PDF


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.

The Cytokine Storm and the -mab

One of the beauties of practicing in the ICU is that although many of my patients take up a lot of resources, the pharmacy-cost component of it isn't too high. I like my cheap IV fluids, norepinephrine, run-of-the-mill antibiotics, heparin, PPI's, tube feeds, sedation meds, etc. None of these are too outlandishly expensive. People generally do well. Reading the ongoing studies regarding COVID-19 I have come across tocilizumab over and over again. Some people around here may already take it or know someone taking it for for their rheumatoid arthritis. Time to take a quick dive into this. This medication is currently being used off-label.


Tocilizumab is an IL-6 receptor antagonist, a monoclonal antibody (hence the -mab at the end of the name). Per UpToDate, this "leads to a reduction in cytokine and acute phase reactant production." Sounds good, right? It's supposed to treat the "cytokine storm" or more formally "cytokine release syndrome". Let's simply define that bad-boy while we are here. We still have a lot to learn and clinical trials are ongoing.


Cytokine release syndrome is a "supraphysiologic response to immune therapy (in this case we're looking at it in COVID-19) that activates or engages T cells and/or other immune effector cells. The systemic reaction is associated with increased levels of inflammatory cytokines and activation of T lymphocytes, macrophages, and endothelial cells" -UpToDate.

The postulation is that this CRS is what is causing people to decide to die. "In more severe CRS, patients may have hypotension and uncontrolled SIRS with circulatory collapse, vascular leakage, peripheral and/or pulmonary edema, renal failure, cardiac dysfunction, and multiorgan system failure." Sounds like what is being described in the COVID literature.

Labs:

Elevated labs: CRP, ferritin, IL-6, and other nonspecific markers of inflammation. I plan to trend these daily.


Adverse effects:

We need to recognize that we are effectively knocking out the immune system to an extent with this medication and could potentially cause harm. There's a black box warning about this. Increased LFTs are commonly noted here (less than 36%). For the nurses, we can see a local site reaction as well.


Cost: it's expensive.


Not FDA approved: currently there is a phase III clinical trial as of 3/26. There are other clinical trials ongoing that have beat the FDA to the punch. Hopefully we will have that data sooner rather than later. There are numerous studies listed on clinicaltrials.gov.





https://www.drugs.com/price-guide/actemra

Link to UpToDate

Chinese non-peer reviewed data

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.

Proning patients on NIV or HFNC

Disclaimer: I am a consultant for a company mentioned in this paper but I am not being compensated in any way, shape or form for this post.

People have asked if it is safe to prone patients who are in ARDS and use either non-invasive ventilation or high flow nasal cannula. In this paper, which is completely FREE for you to download looked at 20 patients who were in ARDS (causes listed on the paper). This was not a randomized trial. It was an observational cohort. They included patients with with moderate ARDS per the Berlin Criteria.

Important teaching point is the Berlin Criteria for ARDS (PaO2/FiO2)
Mild P/F 200-300
Moderate P/F ≤200
Severe: P/F ≤100

Also important to know that moderate ARDS has a mortality of 32% and severe ARDS has a 45% mortality.

55% of patients avoided intubation (it's a small study). But when you consider the fact that these patients with COVID generally stay on the vent for more than 10 days anecdotally, require significant sedation and perhaps paralytics, and eventually move on to be trached, it may be worth consideration. 3 of the 9 patients who were intubated moved on to needing ECMO.

The short answer without me giving away any bias for the aforementioned reasons is that it could be done. The data supporting it is in this article. No, it is not a magic bullet. Not everyone will dodge the endotracheal tube. But one could start asking their patients to do this even in their Emergency Department.

Also, I cannot comment on the concern of aerosolization of the virus by NIV or HFNC at this juncture. I honestly don't know the answer. What I do know is that we may run out of vents if we intubate everyone early. Always wear as much PPE as you can reasonably get your hands on.

Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020;24(1):28. Published 2020 Jan 30. doi:10.1186/s13054-020-2738-5

-EJ
Link to Abstract

Link to PDF

Link to Berlin Criteria

COVID-19 Eval and Management in the Emergency Department

I have to tip my hat on this one to my wife who found this and sent it to me but also to the authors. I agree with mostly everything on here. A link to this article and everything else I've ever posted is on eddyjoemd.com, on my stories, and on my highlights under "COVID-19".

Key take-aways from the Emergency Medicine News guideline of sorts for COVID-19 patients.

With regards to the labs:

- check a CMP, with magnesium and phosphorus.

- here's why. First of all, checking LFT's is necessary for calculating SOFA scores. In the setting of rationing off ventilators (hopefully it never gets to that), SOFA scores are going to be used for this. LFT's are part of the CMP.

- There's very poor data regarding Mg levels and QT intervals but repleting this electrolyte early does not cause harm and makes us feel all warm and fuzzy inside. Phos is also very important for respiratory muscle function. These patients have potentially been sick and not eating well. They may be hypophosphatemic. No data to prove this.

- D-dimer. Hopefully this will be the clinical turning point where people stop thinking about d-dimer only as a rule in or rule out of a PE. Sigh.


Poor prognostic factors:

Listed in the website but important to keep in mind.

Imaging:

I understand that in the ED you need to obtain some baseline imaging. But for those of us taking care of patients in the ICU and wards, we really need to consider how it's going to change the management of the patient. Remember that the radiology techs are being exposed as well. We need to take care of them, too.

Fluids:

PLEASE I BEG OF YOU DO NOT GIVE THESE PATIENTS FLUIDS FOR THEIR LACTATE! I have provided a body of data on this page to support not doing this. They also support starting vasopressors earlier. I have also provided data to support this practice and I do it myself.

I also despise maintenance fluids. If you're a doc or nurse on a COVID unit and you have patients receiving 0.9% saline at 125cc/hr, you really really need to consider the fact that you may be causing harm. Especially when the thought process at this moment for the renal failure is microangiopathic. DO NOT give fluids to try to flush out the kidneys and make the numbers pretty. This does not work like that.

Intubation and O2 therapy.

They make a lot of valid points here. Please check them out for yourself.

Definitely worth reading on your own time.

-EJ

Link to Website