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

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

I agree with Joint Commission!

Is this the part of the movie where the villain switches sides and fights with the heroes? 

The PR folks over at the Joint Commission said "now's our chance!!" 

They stated "We must protect those who are working so heroically to care for people afflicted with COVID-19."

That PR team needs a raise!

Here are some key points: Download the PDF over at eddyjoemd.com

"The Joint Commission supports allowing staff to bring their own standard face masks or respirators to wear at work when their healthcare organizations cannot routinely provide access to protective equipment that is commensurate with the risk to which they are exposed."

"No Joint Commission standards or other requirements prohibit staff from using PPE brought from home."

Regarding N95 respirators vs. Surgical MasksThey state that the CDC changing their recommendations from N95 to surgical masks "may have been precipitated by the emergence of PPE shortages". Ohhhhhh burn!

They state that the understand why healthcare workers have concerns about the adequacy of surgical masks.

Regarding wearing a mask throughout the dayThey state "it is reasonable for staff to want to wear a mask throughout the day".

For our ED friends and colleagues: "Staff in the ED are at particularly high risk because of the high number of patients they see who may be asymptomatic carriers of the virus and the fact that they may have to emergently intubate patients and would be at significant risk without a respirator to protect against aerosolized virus".

The Joint Commission is not siding with hospital administrators on this one, team. We will applaud them, once. I'm still going to drink and eat at the nurses station bc that's where the fun people are.

Link to Statement

Link to FULL PDF

ACE inhibitors and ARBs in COVID-19

We've been hearing a bunch regarding ACE-inhibitors and ARBs in COVID-19 infections. The NEJM finally put out an article on it. Let's review it in plain english and see if it can help us treat our patients. Spoiler alert: like they said in the second paragraph of the article :the data in human are too limited to support or refute these hypothesis and concerns".

Okay I read this paper and didn't get much out of it. Data to be determined.

Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19 [published online ahead of print, 2020 Mar 30]. N Engl J Med. 2020;10.1056/NEJMsr2005760. doi:10.1056/NEJMsr2005760

Link to Article

Link to FREE FULL 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.

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.