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

Link to PDF

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

Link to Article



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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. 

Link to Website

Link to Full FREE PDF

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

Link to Article

Link to FREE PDF

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

Link to 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

Link to PDF

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

Link to FREE PDF

Link to Supplementary Materials



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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


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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)


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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


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Nutrition in the Critically Ill with COVID-19

We can always count on the ASPEN team to come through for us regarding nutritional recommendations for our patients with COVID-19. A hat tip to them. A hat tip also to my pharmacist teammate, Amanda, for sending this to me (and many other literature goodies). This is free so download your own copy and don't trust me.

Let's take a look. First of all, to make one thing clear, there's no RCT on how to provide nutrition particularly to COVID patients. These recommendations need to be extrapolated from other data. This document was updated today. I enjoyed how they took into account preserving PPE in their recs.

The recs:

- start EN within 24-36 hours of admission to the ICU or within 12h of intubation.

- start with trickle/trophic feeds and ramp it up as stated in the document.

- use weight based equations for the correct amount of nutrition

- trophic feeds if patients are on vasopressors (not if increasing VP doses, though). My understanding is that most of these patients are hemodynamically stable. If the patient is getting sicker, do not feed.

- no recommendations regarding patients on paralytics.

- start with gastric feeds, if this fails, try prokinetics, if this fails, feed post-pyloric. I know there are logistical issues with this at different institutions. They also recommend against post-pyloric feeding tubes needing fluoro for placement due to limiting exposure to HCW.

- continuous feeds recommended over bolus feeds (less PPE)

- they make recommendations about TPN that I won't mention here

- they recommend checking triglyceride levels in patients on propofol within the first 24 hours due to a subset of patients who develop secondary HLH. Not going down this road right now.

- they do not recommend checking gastric residuals. This is something I've covered in the past and it will save PPE.

- feeding proned patients: you could feed the gastric chamber. This is something that I have been asked.

It's only an 8 page document. Check it out for yourself!

-EJ

Link to Abstract

Link to FULL FREE PDF

Hydroxychloroquine for COVID-19

This is some actual data regarding the effects of hydroxychloroquine in COVID-19! A hat tip to the authors. This is not the most robust study with the most conventional endpoints but it's something. It is very small but I'd rather it exist than not exist at this juncture. These patients are not ICU level patients. 

Disclaimer: this is a not a peer reviewed article at the time of my writing. This is also my interpretation of the study.

The authors wanted to see the effects of hydroxychloroquine in patients with COVID-19. No azithro was harmed in this study that I can tell.

n=62, RCT
31 received standard treatment PLUS a 5 days course of HCQ 400mg daily
Mean age: 44.7 (not the oldest folks, older tend to be sicker.)
All 62 patients also received antivirals, antibiotics (zero mentions of azithro in the article), immunoglobulins +/- steroids.
Noteworthy excluded patients (cannot discuss all of these): severe and critically ill patients. Renal failure. Others. Bottom line is that these patients are not SICK SICK SICK. 
There's no subgroup analysis to see how the +/- steroids may have influenced the results.

Endpoints and Results (assessed at baseline and after 5 days of treatment)
Time to clinical recovery: body temperature, cough remission time. Fewer patients in the control group had fevers, despite this, fever resolved quicker in the HCQ group. Fewer patients had cough in the control group. Also despite this, fewer patients had cough in the HCQ group. Bottom line, patients with HCQ felt better. This is a strange endpoint.

Radiological results: 

CT scan on day 0 and on day 6. Improved pneumonia in 80.6% of HCQ arm versus 54.8% in the control arm. NNT=3.9. 

61.3% of the patients in the HCQ group had a significant absorption of their pneumonia.

4 patients progressed to severe illness in the control group. That's almost 13% of the group. None in HCQ group.

Adverse reactions: 

in the HCQ group, one patient had a rash, another had a headache. 

The authors concluded that HCQ could shorten the time to clinical recovery and promote the absorption of pneumonia. The mechanisms by which this occurs are postulated in the article. This would support giving HCQ to patients who are not critically ill as we do not know its effects on that population, yet. 

-EJ

Link to FULL FREE Article

Link to Abstract

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 WHO Strikes Back: Droplet and Contact Precautions

The World Health Organization has obtained the paper I referenced yesterday as well as the study in the NEJM that I covered on 3/18/2020. Please read the document for yourself. I have provided links, as always. Please interpret this data yourself. Don't trust me.

Regarding the NEJM study which concluded that the virus could be in the air up to three hours:

Their take: "the finding of COVID-19 virus in aerosol particles up to 3 hours does not reflect a clinical setting in which aerosol-generating procedures are performed—that is, this was an experimentally induced aerosol-generating procedure."

My take: okay then, can you please give us some data as to how long we could expect it during clinical settings of aerosol-generating procedures to be in the room? Can we have some expert guidance?

Regarding the study I posted yesterday, 3/30.
The WHO provided citations for two studies, one published in JAMA (Ong study) and the other in Infection Control and Hospital Epidemiology to disprove the Santarpia study.

Their take: "It is important to note that the detection of RNA in environmental samples based on PCR-based assays is not indicative of viable virus that could be transmissible. Further studies are needed to determine whether it is possible to detect COVID-19 virus in air samples from patient rooms where no procedures or support treatments that generate aerosols are ongoing. As evidence emerges, it is important to know whether viable virus is found and what role it may play in transmission."

My take: since we don't know with reasonable certainty, then we should err on the side of caution and protect our teams.

Here are the two studies cited by WHO as to why it is NOT airborne.

Ong study: sampled 3 patients, the one who was the sickest noted the virus in the air outlet fans (airborne infection isolation rooms). Per the article, this suggests "that small virus-laden droplets may be displaced by airflows and deposited on equipment such as vents". The limitation stated by the authors includes that "the volume of air sampled represents only a small fraction of total volume, and air exchanges in the room would have diluted the presence of SARS-CoV-2 in the air. Further studies are required to confirm these preliminary results." In this study they also found the virus on the shoe of a physician.

My take: Hardly concrete not definitive.

Cheng study: "air samples were all undetectable for SARS-CoV-2 RNA when the patients were performing 4 different maneuvers (normal breathing, deep breathing, speaking 1, 2, and 3 continuously, and coughing continuously) while putting on and putting off the surgical mask."

It seems based on the discussion that they did this on only ONE patient. They state "we may not be able to make a definite conclusion based on the analysis of a single patient".

My take: inconclusive.

My understanding is that a viral culture is needed to assess viability rather than PCR. Neither of these studies looked at viral cultures. WHO, can you get this for us?

Citations:
WHO Commentary on Transmission Modalities

Cheng V, Wong S-C, Chen J, Yip C, Chuang V, Tsang O, et al. Escalating infection control response to the rapidly evolving epidemiology of the Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong. Infect Control Hosp Epidemiol. 2020 Mar 5 [Epub ahead of print].

Link to Abstract

Link to FULL FREE PDF

Ong SW, Tan YK, Chia PY, Lee TH, Ng OT, Wong MS, et al. Air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient. JAMA. 2020

Link to FULL FREE Article

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.

COVID: Let's call it airborne already. UPDATED on 4/1/2020

Disclaimers before we get this started. The following is my opinion. This article has not been peer-reviewed. I am going to attempt to be said peer. A hat tip to the folks at the University of Nebraska Medical center who have looked into this. They are working to find the answers to the questions we are all asking to take care of all of us. I encourage you to download the article for yourself and read it. There are many details I am intentionally going to gloss over.

Airborne or droplet? That is the question. This paper is quite concerning. Spoiler alert: they recommend the use of airborne isolation precautions.

n=13 confirmed COVID patients.

Some of these patients were hospitalized (NBU unit) and some of these patients were quarantined (NQU) either asymptomatic or with mild symptoms.

They did the best they could to contain the virus regarding PPE, negative pressure, and the like.

They obtained a total of 163 surface and air samples in these rooms combined. Those samples were analyzed by PCR methods.

77.3% of those samples were positive for SARS-CoV-2.

76.5% of all personal items were positive.

- Cell phones: 83.3% positive

- Toilets: 81% positive

- Remote controls: 64.7% positive

- Bedside tables and rails: 75% positive

- Window ledges (how did it get over there?!!?): 81.8% positive


Here's the kicker, though
- Room air samples: 63.2% positive

- They stated a case where the sampler was greater than 6ft away from a patient who was on 1L NC and the sample was positive for COVID-19.

- The highest airborne concentrations noted on patients receiving nasal cannula. They mentioned that these patients hadn't coughed. Again, they were not looking at any other modality of oxygenation.

- 66.7% of HALLWAY air samples had virus-containing particles. People going in and out of the rooms were carrying the airborne virus.

We are in deep poop, team.

I know the CDC and WHO are saying something different but that can they provide a similar study to this? Crickets.

-EJ

Link to Abstract

Link to FULL FREE Article



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.



ADDENDUM: The World Health Organization has obtained the paper I referenced above as well as the study in the NEJM that I covered on 3/18/2020. Please read the document for yourself. I have provided links, as always. Please interpret this data yourself. Don't trust me. 

Regarding the NEJM study which concluded that the virus could be in the air up to three hours:

Their take: "the finding of COVID-19 virus in aerosol particles up to 3 hours does not reflect a clinical setting in which aerosol-generating procedures are performed—that is, this was an experimentally induced aerosol-generating procedure."

My take: okay then, can you please give us some data as to how long we could expect it during clinical settings of aerosol-generating procedures to be in the room? Can we have some expert guidance? 

Regarding the study I posted yesterday, 3/30.
The WHO provided citations for two studies, one published in JAMA (Ong study) and the other in Infection Control and Hospital Epidemiology to disprove the Santarpia study. 

Their take: "It is important to note that the detection of RNA in environmental samples based on PCR-based assays is not indicative of viable virus that could be transmissible. Further studies are needed to determine whether it is possible to detect COVID-19 virus in air samples from patient rooms where no procedures or support treatments that generate aerosols are ongoing. As evidence emerges, it is important to know whether viable virus is found and what role it may play in transmission."

My take: since we don't know with reasonable certainty, then we should err on the side of caution and protect our teams. 

Here are the two studies cited by WHO as to why it is NOT airborne. 

Ong study: sampled 3 patients, the one who was the sickest noted the virus in the air outlet fans (airborne infection isolation rooms). Per the article, this suggests "that small virus-laden droplets may be displaced by airflows and deposited on equipment such as vents". The limitation stated by the authors includes that "the volume of air sampled represents only a small fraction of total volume, and air exchanges in the room would have diluted the presence of SARS-CoV-2 in the air. Further studies are required to confirm these preliminary results." In this study they also found the virus on the shoe of a physician. 

My take: Hardly concrete not definitive. 

Cheng study: "air samples were all undetectable for SARS-CoV-2 RNA when the patients were performing 4 different maneuvers (normal breathing, deep breathing, speaking 1, 2, and 3 continuously, and coughing continuously) while putting on and putting off the surgical mask." 

It seems based on the discussion that they did this on only ONE patient. They state "we may not be able to make a definite conclusion based on the analysis of a single patient".

My take: inconclusive.

My understanding is that a viral culture is needed to assess viability rather than PCR. Neither of these studies looked at viral cultures. WHO, can you get this for us?

Citations:
WHO Commentary on Transmission Modalities

Cheng V, Wong S-C, Chen J, Yip C, Chuang V, Tsang O, et al. Escalating infection control response to the rapidly evolving epidemiology of the Coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong. Infect Control Hosp Epidemiol. 2020 Mar 5 [Epub ahead of print].

Link to Abstract

Link to FULL FREE PDF

Ong SW, Tan YK, Chia PY, Lee TH, Ng OT, Wong MS, et al. Air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient. JAMA. 2020

Link to FULL FREE Article

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 as a treatment of COVID-19: An Appraisal on the Study Published on 3/27/20

We have an update now from the same researchers in France regarding hydroxychloroquine and azithromycin in COVID-19. It's a free PDF and I recommend you read it yourself. Don't trust me. 

This study has me scratching my head. Their first study seemed like they rushed it out the door to light the fire for some more research. This study seems like they're deliberately hiding things from us or trying to remain obscure. 

Methods:
This is an observational study, meaning they didn't have any controls.

80% of patients got a CT chest and (almost) every patient had a daily nasopharyngeal swab.
They all got an EKG before treatment and two days after treatment began. They had criteria to not start therapy based on some findings listed in the article. 

Treatment regimen:
Hydroxychloroquine 200mg three time a day for 10 days
Azithromycin 500mg on day 1, then 250 daily for 4 days


End points (these are not your typical endpoints):

Clinical Outcome (oxygen therapy or ICU transfer)
Contagiousness by PCR and culture
Length of stay in the ID ward

Things to know:
n=80
4 patients were asymptomatic carriers (then why were they in the COVID unit?)
92% of the patients were less ill based on their made up NEWS score
52.8% had lower respiratory infections/pneumonia. 

Results:
We don't have any controls to know if this is the normal course of the infection or if the hydroxychloroquine actually worked or not. I forgive them for not having controls in the prior study but this is now too much. 
93.8% were discharged with a low NEWS score. Don't forget that 92% had a low news score to begin with!
3 patients still ended up in the ICU. 

The nasopharyngeal viral load fell. Sure. Cool. Thanks. But does this normally fall at this rate without treatment? We need controls. Is the decrease in contagiousness the normal evolution or the drugs working? We don't know. No controls. 

I'm tired of reviewing this study. You all get my point. I am in favor of trying it, but I feel like there's some academic dishonesty happening here. 

I really want this to work. I really really do. We need some good news but we also need to solidify our management with better data. 

-EJ

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.

Plasma to treat COVID-19: First Update

Several days ago I posted about the FDA approval to start clinical trials to see how convalescent plasma of patients who had already beat COVID-19 would hopefully help patients who are currently suffering from COVID-19.

This paper was published in JAMA yesterday states that there was an "improvement in clinical status" in the population it was provided for. Sweet, but let’s start off with a reality check before we get enthusiastic.

This is a report on only five patients. Five. Cinco. We clear? Good. This is also NOT a randomized clinical trial. It’s case series. You know, like if I were to publish the Vitamin C data from my shop, no one will believe it bc it’s full of my bias. Same thing applies here.

Important takeaways:

These patients did not improve overnight which should provide us with some preparation as to when we could see our own FDA approved trials result.

Generally speaking, it took 7 to 12 days to start seeing some benefits on the vent.

These patients were all on the vent for more than 10 days which is what we are seeing here in the US and also quite terrifying. They had all been hospitalized for 10-20 days before this was provided.

The length of stay for all five of these patients was greater than 50 days when all was said and done.

The largest concern is that there was only one patient with a SOFA score greater than 10. That patient actually got worse before he got better and was actually on ECMO.

I really wish they had done some matching with non-plasma receiving patients to learn how these patients behave at baseline.

The viral load was also difficult to predict the efficacy of plasma on. Seems as if there was, at least in my opinion, a large variety of when they cleared the virus.

Multiple interventions: all of these patients were on steroids, 4/5 were on the lopinavir/ritonavir combo which was shown to not have benefit in an NEJM study, and other meds. Obviously they were throwing the kitchen sink at these patients.

Given that it's just five patients, its really hard to know whether the plasma worked, whether it was one of the other meds, or whether they got better on their own. It's too soon to say whether this works or not.

We're in deep poop, team. The largest value of this study is to just see how these five patients behaved overall. The worst is yet to come. Rest up and be prepared.


Link to Abstract

Link to FULL FREE PDF

Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783



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Multiple Patients on a Ventilator: FAIL

Sometimes medicine behaves like the stock market; a whole bunch of enthusiasm followed by a realistic pullback. This has now occurred with the concept of using one ventilator for multiple patients. I agree that we need to use some ingenuity in this crisis, but this one never sat well with me, hence me not commenting on it at all until now. Too many nuances go into oxygenating and ventilating patients with ARDS. I understand trying this to hold down the fort in a severe crunch, and I tip my hat to those who created the articles and YouTube videos. I'm not trying to be a contrarian or a Debbie Downer.

This statement was put out by the Society of Critical Care Medicine (SCCM), American Association for Respiratory Care (AARC), American Society of Anesthesiologists (ASA), Anesthesia Patient Safety Foundation (ASPF), American Association of Critical-Care Nurses (AACN), and American College of Chest Physicians (CHEST).

Amongst things mentioned here, all patients would need to be paralyzed for this to maybe work. What happens after the 48 hours of paralytics runs it course and they can't play nice on the vent anymore? One always needs an exit strategy. This is something I always teach when taking care of patients in the ICU. I digress, the list provided shows some other safety reasons.

We need to continue thinking outside the box, though, to save all the lives we can. I have never seen our community come together so well. We have done a great job supporting each other. Many have said it already and I agree with them, many of us are going to come out of this psychologically altered. Many of us are, what some would call, jaded in things of life and death. It's part of our daily lives in Critical Care. But this is taking that to another extreme. I appreciate the support that I have received from the community as well. Hope to keep providing you all with great content.

-EJ



Link to ASA Position Statement

Link to SCCM Position Statement

Link to PDF

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