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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Why do we give Corticosteroids during Septic Shock?

Whether you're a med student, intern, resident, or nurse, you've wondered why in the world we give patients who are in septic shock stress dose steroids. This article breaks down in a not-so-easy to understand fashion of the nitty details that are too complex for my post-night shift brain to digest.

The powers that be in Critical Care, SCCM and ESICM, got together for this review with some big guns in the field to write this review discussing Critical Illness-related corticosteroid insufficiency.

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Annane D, Pastores SM, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, et al.: Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 43(12):1781–1792, 2017.

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IV Vitamin C in Sepsis: It Should Help Decrease Vasopressor Doses and Duration

The VITAMINS trial didn’t pan out was not a positive study as it was conducted. I’ve already provided my take on that with my main argument being that they took too long to initiate the study drug (median time >25 hours, not including the time to arrive in the ICU). Sepsis management is expedient, you and I see it every day. Waiting over a day is not being expedient.

I’m seeing a benefit in my clinical practice, as admittedly worthless as my opinion is on the grand scheme of evidence. But when something doesn’t make sense from a results standpoint, you need to go back to the basics and wonder what happened.

Here are some things we absolutely know: 88% of patients in septic shock have hypovitaminosis C and 38% of septic shock patients have severe vitamin C deficiency. What many of you may not know, and I’m here to help you understand why I’m so surprised by the findings of the VITAMINS trial, is that vitamin c is a co-factor to the creation of endogenous catecholamines. That means that without vitamin c, your body isn’t going to produce the appropriate amounts of dopamine, norepinephrine, and epinephrine. It also is necessary for the production of vasopressin. It’s as simple as that. 38% of people will not produce appropriate endogenous catecholamines. The fact that administering exogenous vitamin c did not decrease time that the patients were receiving vasopressors in the study makes me wonder why. I am aware that there was a delay of >24 hours to start the therapies in the study but is there more I'm missing. Hopefully you can take some basic biochem away from this post as to why it should work (although it didn't in the study).

A 🎩 tip to the authors.

-EJ




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Carr, A.C.; Shaw, G.M.; Fowler, A.A.; Natarajan, R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Crit. Care 2015, 19, e418.

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VITAMINS Trial: Timing was overlooked

You all know my bias. It shouldn't be a surprise given my body of work: I wanted this to be a positive study. I wanted patients to benefit from this therapy and SURVIVE. I cannot understand the vitriol I have received in my direct messages when I shared my initial take on the study. I’m prepared to deal with more. Bring it!

Ultimately, there's no difference in the the endpoints, whether primary or secondary. No need to go through them in depth. That’s what the data says, that’s what the study concluded. Hat tip to the authors. It is what it is. I can agree with their conclusions based on the study conducted. But clinicians should not take the study as the end of HAT therapy. It would be scientifically irresponsible to do so. The study had a fatal flaw that doomed it from the beginning. Let me explain why. I practice real world medicine. I am not a trialist. I do the best I can every day with what I have.

Here's a take on how I care for septic shock patients for some perspective. There are plenty of nurses and physicians who work with me currently and have worked with me in the past following along on IG who can vouch for my style of practicing medicine.

This is NOT MEDICAL ADVICE. Do not do what I do because I say so. This post is not all 100% all inclusive for every nuisance. Every pt is different. That is your disclaimer.

1. I get a call from a colleague: ED physician, hospitalist, or surgeon regarding a patient who is in septic shock. At this point they have already gotten antibiotics and fluids bc everyone is excellent at this.
2. I go see the patient IMMEDIATELY
3. I assess, as quickly as possible with my limited tools a guesstimate on their fluid status
4. I start vasopressors EARLY while fluid resuscitating
5. pt arrives in the ICU, central line placed, arterial line placed, EV1000 hooked up.
6. I camp out at the nurses station next to the patient with them in my line of sight.
7. I watch how the patient behaves to my interventions, how the vasopressors go up, if they go up
8. As the vasopressor requirement increases, says NE around 10mcg, I start feeling uneasy. Especially how quickly their requirement increases.
9. I pull the trigger after 10-15mcg of NE to start vasopressin, hydrocortisone 50mg IV q6h, vitamin C 1500mg IV q6h and thiamine 200mg IV q12hours. I hit click, click, click, click, on an order set I created for myself on my EMR.
10. I keep on monitoring the patient closely to assess their response and provide additional fluids and learn more about their physiology.
Thing I do on the side: airway, bedside echo, talk to family and patient, management of other sick patients happen in this time period as needed. This post is not all-inclusive.

Needless to say, all of this happens WITHIN 6 HOURS. One has a general idea, within 6 hours of the patient being in septic shock, a pathology that has a 25-40% mortality rate depending on the study, what is the likelihood of the patient turning the corner.

What can we all agree on regarding management for sepsis: early antibiotics make a difference. Early source control makes a difference. Early fluids are better than late fluids. Early vasopressor administration is showing to be better than late (data for that coming soon).

Here’s my main problem with the study:
- Time for patients to get randomized: I CAN'T FIND THIS DATA
- Time from ICU admission to randomization: 13.7 hours (IQR 7.1-19.3 hrs).
- Median time for patients to receive study study from randomization: 12.1 hours (IQR, 5.7-19 hours).
13.7 + 12.1 = 25.8 hours PLUS time for patients to get randomized!
For those who don't know what IQR means: click here

Why in the world did they take so long to start the study drugs?

That's my problem with the study. My larger problem with the study is the fact that, since it was published in JAMA, a very high impact factor journal, clinicians are going to take it as gospel and dismiss the therapy entirely. If they would have provided the study drugs appropriately, there may have been a difference in outcomes. Since they didn't, patients who could have potentially benefitted will not.
Or maybe I'm just wrong.

-EJ



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Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. Published online January 17, 2020.

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Stress dose steroids for septic shock: bolus dosing or continuous infusion

This study published just this month, November 2019, suggests that providing bolus dosing of hydrocortisone, 50mg IV every 6 hours shortens the time a patient needs to be on vasopressors compared to 200mg IV through a continuous infusion every day.

Stress dose steroids are clearly in my armamentarium in the treatment of septic shock. I tend to reach for them when I’m starting my second vasopressors, usually Vasopressin when the norepinephrine hits around 10-15mcg. I also ready for the vitamin C and thiamine at that point, too. Actually, I have a quick little bundle in the EMR where I just check off all these goodies. Sometimes I stray in different directions, of course. Every patient is different and this is not a recommendation on how you should practice. I haven’t gotten on the fludrocortisone train yet, have you?

Either way, the shock reversal is faster with the bolus dosing. This should make all my nurse followers happy as they won’t have a channel and lumen bogged down with this medication and all the compatibility questions that arise with it. Whether bolus or continuous dosing you won’t see a difference in mortality, ventilator days, adverse effects, length of stay, etc.

Also not yet another study where they don’t check cortisol levels before initiating this treatment. I’m not a fan of checking cortisol levels myself. I see it done and I ask, why?

A 🎩 tip to the authors.

-EJ

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Corticosteroids and GI bleeds: Do We Really Need To Worry?

Link to Abstract

Butler E, Møller MH, Cook O, et al. The effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in critically ill adults: a systematic review with meta-analysis. Intensive Care Med. 2019;45(11):1540–1549. doi:10.1007/s00134-019-05754-3

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Thiamine, Ascorbic Acid and Corticosteroids: The Mechanisms by which they should help in Sepsis

Want some nerdy stuff? Well this is some nerdy stuff! I'm taking a nice deep look at this figure. I am not going to lie to you at this moment, October 19th, and tell you I know what all this means, because I don't. But people who are more intelligent that I am have suggested that these are the mechanisms by which thiamine, ascorbic acid, and corticosteroids should help in the treatment of septic patients. I have a lot to learn.

I hope I don't get dinged for copyright stuff but honestly if this offends you, let me know. I will take it down. I will likely go deeper into this article at a later time. Wanted to share this image with you right now, though.





Link to Abstract

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Moskowitz, A.; Andersen, L.W.; Huang, D.T.; Berg, K.M.; Grossestreuer, A.V.; Marik, P.E.; Sherwin, R.L.; Hou, P.C.; Becker, L.B.; Cocchi, M.N.; et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Crit. Care 2018, 22, 283.

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Ascorbic Acid, Thiamine, and Steroids in Septic Shock: Propensity Matched Analysis

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Another day, another Vitamin C article. This one came out just two weeks ago, it’s not free, and the results are a bit strange. There are larger trials in the works. If I were part of the group of these authors, I’d be itchy to get my data out ASAP as well. Just 31 patients in each arm of this trial. Heck, even I could replicate this trial in my 20 bed MSICU if I wanted to over 1.5 years. The problem is that my bias admittedly is for the cocktail to work. I am wide openly admitting that, everyone. I have a bias. I want it to work bc I want my patients to live.  

There are numerous parts of this study that seem strange to me. 

1. the ICU mortality of the control arm is 42%. This number should not be quite as high based on the latest data. That could lead the p-value of 0.004 to be perhaps a bit too small. But considering that they used the same strategies to manage septic shock these pts in both arms, it’s still valid for that institution. 

2. The duration of the vasopressors were longer in the experimental arm. This makes NO sense as Vitamin C is a co-factor in the endogenous creation of catecholamines. Heck, even the authors admitted this was strange. 

3. There was no significant difference in hospital mortality. They probably needed a high n to get this to show a difference. The hospital medicine and palliative teams must be great at getting code status’ changed so that people don’t bounce back to the unit. 

4. Pts did not get off of the ventilator faster. Word on the street is that there’s preliminary data suggesting that it helps this process that just isn’t out yet. Stay tuned. 

Lastly, everyone is worried about renal failure. No difference in AKI here, folks. In fact, I am yet to see one report in any of these trials talking about renal calculi secondary to vitamin C in sepsis. 

What are your thoughts on the matter? Is your shop using this yet? Are you a believer or a skeptic?

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Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation

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The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

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