Melatonin for Sepsis

You’re following along on my page bc you know I’m trying to find the most cutting-edge treatments and therapies for my critically ill patients. I hope to keep on pumping out eye catching content such as this article on melatonin. Please share with you’re nerdy friends who would also find this nerdy content I put out interesting.

Yes, melatonin. I finished my lecture today on metabolic resuscitation and this article was published just a few days ago. It’s actually free and you can download it from my website, eddyjoemd.com. I have learned a ton of fascinating facts regarding melatonin as to why is SHOULD work. I can see the eyes rolling already. No, there aren’t any double blind, randomized controlled trials on this but one is in the works.

It definitely makes me curious as this is yet another therapy that many of us take during the day to sleep while on night shifts and is benign (based on years and years of studies listed in this article).

Fascinating stuff, right? Did you know that melatonin did all these cool things? I surely didn’t. Now I do... and that’s why I read as much as I do. A 🎩 tip to the authors!

-EJ

Link to article

Link to full free PDF

Colunga Biancatelli, R., Berrill, M., Mohammed, Y., & Marik, P. (2020). Melatonin for the treatment of sepsis: the scientific rationale. Journal Of Thoracic Disease, 12(S1), S54-S65.

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.

Sepsis Killed Approx 11 million people in 2017.

This data was published on January 18th, 2020. Hot and fresh stuff! This represents the most recent estimate of sepsis-related deaths globally. We're doing better from a mortality perspective in the developed world with the mortality, but 11 million people is the, per census data, the entire population of New York City and Chicago combined per year. That's a lot of people. 20% of worldwide deaths. Many of these occur in our own ICU's. We could and need to do better. I understand we are all going to die of something one day, but this is mostly treatable with quick identification, source control, and appropriate and timely antibiotics.

People ask me all the time why I spend so much time and energy on social media educating about the critically ill when I could instead be doing other things. At the time of this writing there are 26,122 people following along in my insanity on Instagram (thank you all, btw). As the number grows, and I may be an idealist on this, we may be able to put a dent into those 11 million deaths by keeping our practices in line with the best evidence available.

Hope you all have a great day!

- EJ



Link to FULL FREE PDF

Rudd, Kristina E et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet, Volume 395, Issue 10219, 200 - 211.

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.

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



Link to FULL FREE ARTICLE


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.

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.

Cardiopulmonary Resuscitation: ACLS in the CVICU

Yesterday, @yournursingeducator created a great post on Code Blue tips. @fobiesme asked a very legitimate question regarding how to proceed in patients who are s/p bypass or any open chest situation in the CVICU. This was something I wondered about myself even as someone who taught ACLS for the AHA at a point in my life. It was hard to find a solid answer. Fortunately, as of 2017, the Society of Thoracic Surgeons put forth this consensus statement and algorithm on how to handle cardiac arrest situations in the CVICU population. Since this is relatively new data (only 2 years ago), I understand that the CVICU nurses out there may not be familiar with nor using this particular algorithm. What we did in my shop is that we printed this out with all its pretty colors, laminated it, and placed it on the code carts. Fortunately, this is entirely FREE!

-EJ

Link to full FREE PDF

Dunning J, Levine A, Ley J; STS Task Force. The Society of Thoracic Surgeons expert consensus for the resuscitation of patients who arrest after cardiac surgery. Ann Thorac Surg 2017;103:1005–20.

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.

IV Vitamin C in Sepsis and "Fictitious Hyperglycemia"

I’m plenty fired up for the VITAMINS trial that’s going to be published on the 17th. That’s the first large RCT looking at Vitamin C, Thiamine, and Hydrocortisone in Septic Shock. If the trial turns out to be positive, which I really hope it does, then we will really need to know about this limitation as our utilization will definitely increase worldwide.

From burn data and providing high dose vitamin C in that population, and I’m taking about doses >50gm/day, they have noted a cross reactivity in certain point of care blood glucose monitors where the ascorbic acid, due to having to do with glucose having a similar molecular structure to ascorbic acid with six-carbon molecules.

This seems to confuse the POC machine and the readings could be falsely >30%. Ultimately, those designing the studies for 1.5gm IV q6 hours have known this and have been checking to see if there’s a difference between the lab numbers and the POC numbers. As of the time of publication, they found no significant difference. We still need to keep this in mind, though. In the burn population someone died of iatrogenic hypoglycemia 😔. A 🎩 tip to the authors and those who answered the questions.

-EJ



Link to Website

Flannery AH, Bastin MLT, Magee CA, Bensadoun ES. Vitamin C in sepsis: when it seems too sweet, it might (literally) be. Chest. 2017;152(2):450–1.

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.

Vasopressors have immunologic activity

This is a post I’m 90% sure you’re going to learn something from because I had NO IDEA this was a thing until I was doing all my research on vasopressors. I’m sure it’s not going to get many likes nor any shares, but it’s cool stuff like this that really gets me excited. Not many know what tumor necrosis factor is and what interleukins are, but they all play a huge role in inflammation and the overresponse of the body in sepsis. I’m going to stay far away from the specifics on this one. We give catecholamines and Vasopressin to our patients almost daily, might as well know the intricacies of these treatments. Cool stuff, right? A 🎩 tip to the authors.

Thanks for following along in my insanity.

-EJ




Link to Abstract

Link to FULL FREE ARTICLE (maybe)

Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M (2016) Potentially inadvertent immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med 194(5):550–558

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.

Angiotensin II/ Giapreza

I’ve said this on numerous occasions and I’ll repeat it again. I do not do research. I have one study published and that’s because I needed to do it to complete fellowship. Outside of that, I’m a boot on the ground doc. I feel bad criticizing but here we are.

Now that that’s out of the way, I can’t believe that so many huge names in critical care research are listed on this study that has sooooo many issues.

I’m always excited at the prospects of a new vasopressor or anything to help out my patients in shock, but at $1500 a vial, we better be seeing some serious benefits.

Here’s my take and I’m over simplifying: they took real shock patients who were on norepinephrine and gave them either the study drug, known since the 1930’s to cause an increase in BP, or a placebo. Basically giving a hungry person food or air and seeing which one made them feel full. Obviously the delicious meal group felt full. Oddly enough, 23.4% of the pts who received placebo had an increase in their BP. And then people try to tell me this is good data? Want to have some air?

There was also a change in their CV SOFA score. I had to look this up but it means the patients had a decrease in pressor requirement. Well, isn’t that the point? How about having the patient on NE and adding Vasopressin in one group and adding Giapreza in the next? Wouldn’t that world out better? Oh, yeah, this study was sponsored by La Jolla. They created softball endpoints. That’s lame. So you mean to tell me that a $6 dose of vitamin c is garbage but have no qualms with this study? Get out of here.

Ultimately, you should check out @pulmcrit (Josh Farkas) post on this from two years ago. It’s much better than mine: https://emcrit.org/pulmcrit/angiotensin-ii/

- EJ



Link to Article

Link to FULL FREE PDF

Khanna A et al. "Angiotensin II for the Treatment of Vasodilatory Shock". New Engl J Med. 2017. 377:419-30.

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.

Keep the Dopamine at the bottom of the shelf

Does your friendly neighborhood cardiologist or intensivist start your Cardiogenic Shock patient on dopamine? Do you ever ask them when was the last time they read a study? I don’t mean to be harsh but this data is now almost a decade old.

This study placed dopamine far down on the vasopressor selection totem pole. They looked at patients who were in all types of shock, hypovolemic, septic, and cardiogenic on norepinephrine or dopamine and checked a bunch of outcomes.

What did they find? Well, no difference in mortality EXCEPT in those patients in Cardiogenic Shock. (p=0.03). Also, dopamine caused more severe arrhythmias than norepinephrine: 6.1% vs. 1.6%.

24.1% of the dopamine patients had arrhythmias and 12.4% in the norepinephrine group. That’s a lot of time managing side effects. No thank you.

Also, I need to find more data on this “renal dose dopamine” nonsense. This study showed an increase in urine output in the first 24 hours but then it evened out. They had an equal fluid balance when all was said and done. Although there was no statistically significant difference (p=0.07) in renal function and the norepinephrine group trended towards having better renal function. I know seeing urine makes us feel all warm and fuzzy inside but if it’s providing false reassurance than what is it worth?

Still want to use dopamine? I hope not.

-EJ

Link to Article

De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779–789. doi:10.1056/NEJMoa0907118

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.

Methylene Blue in Sepsis Increases the BP

When the CITRIS-ALI study was published just a few months ago they used plasma biomarkers as a method to prove that ascorbic acid in this patient population worked. You know, the study where they gave Vitamin C to patients with acute lung injury and it failed to show its primary endpoint which was SOFA/biomarker changes but..... had a statistically significant decrease in mortality and people scoffed that that since it wasn't the primary endpoint. The study that I am posting today provided methylene blue to patients with severe sepsis and measured TNF-α, IL-1, IL-2 receptor, IL-6, IL-8. As I typed this I realized that I am such a nerd. It's a Sunday and I'm typing about interleukins. I digress. Those endpoints weren't changed by giving these patients methylene blue. You know what did change? The mean arterial pressure on these patients. You know what makes patients survive? Requiring small vasopressor doses and having an improved blood pressure. By no means does this small study mean I'm changing my practice, but I am at least going to think outside the box a little more often in my refractory shock patients who absolutely cannot die on me.
-EJ



Link to Abstract and Article

Memis D, Karamanlioglu B, Yuksel M et al (2002) The influence of methylene blue infusion on cytokine levels during severe sepsis. Anaesth Intensive Care 30(6):755–762.

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.

Methylene Blue in Septic Shock

I don’t know about you all but I’m constantly working on finding new ways to treat my septic shock patients who, based on the numbers from larger studies, have a mortality rate between 25-35%. I have used methylene blue on various occasions for post-CPB vasoplegia but would it possibly work in sepsis? Well, there’s 💩 data for now. I can’t cover every nuisance regarding methylene blue on this post, team, but I chose to share this pilot study from 2001 as it was the first study on the matter (to my knowledge). The third slide in a sneak peek to the lecture I’m creating on metabolic resuscitation.

Has your shop ever used methylene blue for this indication?

I’ll be presenting this data in Hawaii and Portland in 2020.

If you like the content I’m taking apart and posting, please share it with your friends and colleagues. Who knows, maybe it will inspire someone to conduct the larger RCT we need to decide whether this actually works or not.

- EJ



Link to Abstract

Kirov MY, Evgenov OV, Evgenov NV, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med. 2001;29(10):1860–1867. doi:10.1097/00003246-200110000-00002

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.