Vasopressors in 2022

The intention of this post is going to be to take a deep dive into the states of vasopressors using the best evidence based practices available. It will be routinely updated. This is a work-in-progress blog post on vasopressors. Last updated 02/25/2022.

If you find this blog post useful, and you want to cite it in your own work, please give me credit when credit is due.
Cite this post as: Eddy J. Gutierrez, “Vasopressors in 2022”, eddyjoemd blog, February 25, 2022. Available at: eddyjoemd.com/vasopressors.

Table of Contents of Vasopressors

  • Norepinephrine
    • Is it better than epinephrine for cardiogenic shock?
    • Does it cause immunosuppression?
    • Shock after Cardiac Arrest
  • Epinephrine
    • Why isn’t it a first-line vasopressor?
  • Vasopressin
    • 0.03 vs 0.04U/min: Which should we use?
    • Is vasopressin titratable?
    • Should we wean vasopressin or just turn it off?
    • Uses in Cardiac Surgery for Vasoplegia
    • Selepressin
    • Terlipressin
  • Phenylephrine
    • Can we give pushes to buy time?
    • Would it be beneficial to switch to PE from NE if patient is in a.fib?
  • Dopamine
    • Is renal dose dopamine a thing?
    • Does dopamine belong in the ICU as a vasopressor anymore?
  • Angiotensin II/Giapreza
    • ATHOS-III
    • Post-marketing data
    • ANG-II in Mechanical Circulatory Support
    • ANG-II in Cardiac Surgery Vasoplegia
    • How does ANG-II behave in the real world?
  • Midodrine
  • Methylene Blue
  • Questions we all ask ourselves
    • Early vs. Late Vasopressors in Septic Shock
    • What MAP target should I shoot for?
    • Enteral nutrition for patients on vasopressors
    • Weaning order of vasopressors

Things I will not be discussing

The pathophysiology of vasodilatory shock.

Norepinephrine

Norepinephrine is considered the first-line vasopressor in the majority of shock states. The Surviving Sepsis Campaign has it listed as option number one. I agree with this wholeheartedly.

How Norepinephrine works:

Receptors: primarily α1, α2, and then β1, β2 with less potency.

Upon binding to these receptors, it causes an increase in intracellular concentration and vasoconstriction. The β1 component provides some positive inotropic activity which leads to increasing the contractility of the ventricles.

Norepinephrine vs. Epinephrine in Cardiogenic Shock 2/2 Myocardial Infarction

This is one sexy pilot study about norepinephrine in cardiogenic shock. The authors here decided to take a look at norepinephrine (NE) versus epinephrine in patients with cardiogenic shock s/p MI. They didn’t use dopamine as they had noted an article that I have reference here where I discussed how dopamine actually increases mortality in cardiogenic shock compared to NE.

The rationale why the authors went to NE was because data has shown that the myocardium may have a more favorable effect on myocardial O2 consumption. Epi was believed to cause more deleterious effects. Ultimately, though, none of this had been proven in a trial. Well, here is the trial. 

Over the course of 5 years they included 57 patients. See why I have such respect for these folks who do trials? I have no idea where I am going to be in 5 weeks, let alone 5 years. They measures a ton of parameters and did their statistical jumping jacks that I will not bore you with (but the article is entirely free for those curious minds out there).   

Ultimately, what we are about is how the patients did. With regards to their MAP, CI, and SVI, they were the same. As one would expect, the HR for the patients on epi was higher. Also expected, as epi hits more of the beta receptors, there was an increase in lactate in these patients (which doesn’t mean they need more fluids).

There was an early termination of the study, though, as 37% of the patients on epi went into refractory shock while just 7% of the patients on NE did the same (p=0.008).  The authors acknowledge that it is a small trial but they were able to see a clear difference between the two groups. There are numerous other limitations to the study as well that they acknowledged.

More data on this article HERE.

Norepinephrine and Volume Expansion: Article Shared on IG on 8/22/21

Adda, I., Lai, C., Teboul, JL. et al. Norepinephrine potentiates the efficacy of volume expansion on mean systemic pressure in septic shock. Crit Care 25, 302 (2021). https://doi.org/10.1186/s13054-021-03711-5
Link to Article
Link to FULL FREE PDF

Does Norepinephrine cause immunosuppression?

The thought process brought forth by Stolk, et al. is that norepinephrine contributes to the dysregulation of the immune response to patients who have sepsis. It is admitted that clinical evidence for this is circumstantial but they claim how norepinephrine is a driver of sepsis-induced immunosuppression. How, you may ask?

They discuss how norepinephrine, via its effect on the beta adrenergic receptors, attenuates the production of TNF-alpha and IL-6. Norepinephrine also enhances the release of IL-10, an anti-inflammatory cytokine, and inhibits natural killer cell cytotoxicity.

The point of their evaluation was to consider other alternatives, although my sentiment is that we do not have that many tools in the tool box with regards to keeping people alive who are in septic shock. Perhaps using multimodal vasopressors could be worth considering.

Shock after Cardiac Arrest: Epi or NE?

Epinephrine

Why is epinephrine not the first-line vasopressor?

Epinephrine is not the first-line vasopressor due to increased risk of splanchnic vasoconstriction and tachyarrhythmias. There is also the concern of hyperlactatemia due to the β1 effects. I explained that in detail in my lactic acid post. In 2012, there was commentary by Dünser et al. on how epinephrine was preferred to norepinephrine in resource-limited countries due to cost.

Vasopressin

0.03U/min vs. 0.04U/min in Septic Shock

I had this question when reading the Surviving Sepsis Campaign guidelines where it is 0.03U/min of vasopressin, fixed dose, but then seeing 0.04U/min everywhere I have worked. Some people say that vasopressin is not titratable but the VAAST and VANISH trial have shown us that it is. But is there really a clinical difference between the two doses?

The fine folks over at the Cleveland Clinic performed a retrospective, multi-hospital health system, observational cohort study looking at this question. There are intrinsic limitations to this type of study but they were able to crunch on a very respectable 1536 patients. I definitely recommend you read the study for yourself as it is free but long story short, there was no difference in the measured outcomes such as early hemodynamic response, mortality and length of stay.

As a bonus, the authors put together an analysis of the cost of vasopressin. Turns out that using the dose of 0.03U/min instead of the 0.04U/min saves $109 per patient per day. Think of how much vasopressin we all use at our respective institutions. This can be a big deal. A hat tip to the authors and a hat tip to Ryan (one of the pharmacists at my shop) who recently led an initiative to change the dosing of vasopressin from 0.04U/min to 0.03U/min.

Is vasopressin titratable?

What the VANISH trial does shows us, amongst several things, is that the authors used vasopressin as a titratable medication as well as a mono therapy medication (that means not just adding it to norephinephrine when it reaches X dose. Studies like this indirectly guide us to what can and can’t be done moving forward in medicine. If you get into trouble with a patient, one can justify it by saying “the VANISH study showed that it’s safe to use it in this manner”. I’m always worried about the lawyers, I’m not going to lie. Click here for additional details on titratable vasopressin.

The goodies in this article and what I want you to focus on today is not necessarily the conclusions of the article nor all the subgroup analysis, but rather I want you to look at the methods on how they performed the study.

Patients were able to receive titratable doses of vasopressin up to 0.06U/min. That means that they were able to exceed the 0.04U/min you and I use every day.

They also titrated to a MAP of 65 or 75. Note that they did not use a systolic blood pressure. I have covered why you shouldn’t do that unless you have an arterial line on youtube and here in the past.

The MAP of 75 is also important because there’s data that higher MAP’s in patients with chronic hypertension is better for them. I see shops where the MAP goal is 60 and that’s just plain stupid and only acceptable on a case by case scenario.

Patients in this study received vasopressin as monotherapy for septic shock and it did not cause issues.

There is much to be said about the methodology of this trial which I am not going to get into today. I’ll be here forever. Instead, you can hear me take it apart live in Hawaii in May 2020.

Should we wean vasopressin or just turn it off?

The vast majority of us use vasopressin as an adjunct to norepinephrine when we take care of patients who are in septic shock. The doses of norepinephrine at which vasopressin is initiated is determined by the clinician and varies. Fortunately, many of our patients get better and we are left wondering what is the best methodology of discontinuing vasopressin. Further down in this post I discuss whether to discontinue norepinephrine or vasopressin first. Right now I this study is focused on vasopressin. Should we wean it off or just turn it off?

This paper is a retrospective, multicenter look at 1318 septic shock patients with all the limitations one could expect with this type of study. I’m not gong to get into the nitty-gritty of the paper because it’s completely free and you can read it for yourself. What we care about is whether the authors found something that will make us change our practice. Did they? Nope.

Whether they weaned the vasopressin or just flat out turned it off found no difference in “did not reveal any differences in time to ICU discharge, ICU mortality, or hospital mortality.” The evidence by no means is strong but they found that abruptly stopping it led to less duration of infusion of vasopressin. I’m sure we can all figure out reasons why. They did some additional statistical jumping jacks to attempt to find a difference and still couldn’t tease out a solid practice pattern for us. The verdict? Keep doing what makes you happy.

Lam SW, Sacha GL, Duggal A, Reddy AJ, Bauer SR. Abrupt Discontinuation Versus Down-Titration of Vasopressin in Patients Recovering from Septic Shock. Shock. 2021 Feb 1;55(2):210-214. doi: 10.1097/SHK.0000000000001609. PMID: 32842024.
Link to Article and FULL FREE PDF

Vasopressin in Cardiac Surgery for Vasoplegia

Webb, et al. published a systematic review for the utilization of vasopressin in patients with cardiac surgery and I couldn’t believe the paucity of data that actually exists regarding this. In my practice, I reach for vasopressin up to a max dose of 0.04U/min to assist in patients whose cardiac index is acceptable but their systemic vascular resistance (SVR) is on the floor. I have heard of other institutions using up to 0.1U/min but I need to look deeper into the literature to see where this is supported.

Phenylephrine: The “Lite” Vasopressor

Many of us have phenylephrine pushes readily available to buy some blood pressure until the patient either stabilizes, or needs a drip. I will say that if the patient needs a drip of norepinephrine, go ahead an order it. Data by Hawn et al. published in December of 2020 in CHEST proved this to be the case (in a NOT FREE article). If the patient is crashing and burning with septic shock, then by all means. I’m not going to allow my patients to be unstable and hypotensive while getting the norepinephrine hung because of the results of this paper.

Patients here had a higher incidence of reaching hemodynamic stability within 3 hours which is good. The ICU mortality in these patients was worse, though. The confidence interval is wide, though, at 1.10 to 3.21. That being said, the way I interpret this is that if patients need to be rescued with phenylephrine pushes, then there was more of a hemodynamic panic that is likely not captured in the baseline characteristics of patients. If they’re sicker to start, then their mortality will be higher.

Would it be beneficial to switch to PE from NE if patient is in a.fib?

We’ve all taken care of the patient who is in septic shock, on norepinephrine or other vasopressors who goes into atrial fibrillation with a rapid ventricular rate. This leaves us in a conundrum of what to do next. Haiduc et al. sought to tease out the answer to this question. Their team retrospectively looked at 67 patients who were on NE. When they looked at the raw numbers, there was a benefit to switching. When they did their statistical jumping jacks, however, that benefit was lost. They concluded that “a lack of benefit with phenylephrine cannot be excluded”. I’d say it’s inconclusive and we still do not know the answer to this question.

Dopamine

Still using Dopamine as a first line agent in shock? (One-Minute Journal Club)

This is a one-minute journal club. This is not medical advice. Read the article for yourself. Norepinephrine is the first line vasopressor for shock. This wasn’t always the case, though. Dopamine was the go-to vasopressor in the past. Although it seems like some are still stuck there. In 2010 a randomized controlled trial compared norepinephrine to dopamine in patients with shock. They recruited almost 1700 patients. The primary outcome was rate of death at day 28. Although there was a trend towards norepinephrine being better, it was not statistically significant. We need to remember that trends don’t mean anything. The adverse effects are where the issues live. Almost 25% of the patients on dopamine developed an arrhythmia. Arrhythmia’s are not good. We all have cardiologist friends who still reach for dopamine as their first line vasopressor. We need to show them that in the subgroup analysis, norepinephrine was superior to dopamine in the Cardiogenic Shock subgroup. How do you use dopamine in your practice?

Still Using Dopamine in Shock?
Still Using Dopamine in Shock?

Renal dose dopamine: taking down a myth

When one looks at the dates where the publications disproved “renal dose dopamine”, you see three articles published in 2000, 2003, and 2004. It’s 2020 and this has not yet been put to bed. Vasopressors 101 here. Now, I’m all worked up about this because I’ve had clinicians tell me that it absolutely works. I saw it in residency, fellowship, and now in private practice. I’m sure some of you see it at your institutions, too.
There’s data that it improves urine output transiently but no data that it improves renal outcomes in critically ill patients. No changes in creatinine. No changes in renal replacement therapy rates. In fact, that whole discussion has been put to bed so much that there haven’t been any comments made on it over the last 15 years. No further trials attempting to prove it works. Is that why we’re still seeing it? Well, it’s time to bring the arguments against renal dose dopamine, or even using dopamine altogether back into the fray.
The data about it being beneficial was from the 60’s in animal and healthy human studies. The latest studies, however, say it doesn’t work and in fact may be harmful. I have attached some of my preliminary slides from my Vasopressors in 2020 lecture. These are some of my preliminary slides. More info will come from me directly as I present these but it should provide you with an idea of why we should rarely see dopamine in our ICU’s anymore. 
Do you still all use dopamine? If so, what for?
I used to use it during codes as it was already packaged in the code carts. We have since gotten rid of these and my badass pharmacy colleagues prep me levophed drips within seconds. 

Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in the modern intensive care unit? Anesth Analg. 2004 Feb;98(2):461-468. doi: 10.1213/01.ANE.0000096188.35789.37. PMID: 14742388.
Link to FREE PDF

Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest. 2003 Apr;123(4):1266-75. doi: 10.1378/chest.123.4.1266. PMID: 12684320.
Link to CHEST Article

Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23-30;356(9248):2139-43. doi: 10.1016/s0140-6736(00)03495-4. PMID: 11191541.
Link to NOT FREE Lancet Article

Keep Dopamine at the bottom of the shelf of vasopressors

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. We need to get better at vasopressors.

De Backer et al. performed a study that 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. I covered this article more in depth here.

Does Dopamine belong in the ICU anymore?

Link to FREE FULL ARTICLE and PDF

Angiotensin II/Giapreza

Angiotensin II is a “synthetic analog of the endogenous human peptide with high affinity for G protein coupled type one angiotensin receptors”. I’ve said this on numerous occasions and I’ll repeat it again. I do not do research (UPDATED on 2/21/22. I have now done two RCT’s serving as the PI). One study published and that’s because I needed to do it to complete fellowship. Outside of that, I’m a boots 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. Including physicians who I have met personally and have great respect for. I’m always excited at the prospects of a new vasopressor or anything to help out my patients in shock. At $1500 a vial, though, we better be seeing some serious benefits.

My Quick Take on the ATHOS-3 Trial

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. Check out my full post on just ATII/Giaprezza HERE.

Post-Marketing Research on ANG-II

In the February 1, 2021 issue of CHEST, Wieruszeski, et al. published a multicenter post-marketing study on Angiotensin II infusion in shock. I have to disclose that I Wieruszeski and I are friendly over Twitter and I’d buy him a beer if I met him in person. He and his team do fantastic work over at the Mayo Clinic. As noted from before, I was not too enthusiastic about using this therapy from the one and only randomized controlled trial today on this medication. Be clear, this is a retrospective study. It is not prospective as we all hope and wish for. That being said, I have to tip my hat to the authors of this important study. The question that the authors were seeking an answer for included the safety and effectiveness of angiotensin II.

I cannot go through all the thorough details about the study so, as always, I recommend that you read it for yourself. They ended up collecting a total of 270 patients. Of which 181 patients were considered to be responders and 89 patients were considered to be non-responders. From a shock etiology standpoint, the majority of patients were those with septic shock encompassing >50% of the population. The second highest group was postoperative vasoplegia with about 10-11% of patients falling into this category. There was a multi-factorial shock ideology group which is many times what we see in our practice and this encompassed about 27 to 28% of the patients in the study.

From looking at the characteristics of the patients, the vast majority were on either two or three vasopressors at the time of initiation of angiotensin two. Over 90% of the patients were on norepinephrine and, even in the non-responder group, over 80% of patients were also on vasopressin. In other words, angiotensin II was not a first line vasopressor in these patients. There is a difference that caught my eye in the baseline characteristics and there is a statistically significant difference between the amount of responders who were on corticosteroids compared to the non-responders. The data is extensive in showing that do utilization of stress dose steroids decreases the time that somebody is in shock. In my opinion, this could be a confounder.

Conclusions of the post-marketing study

The authors ended up finding that, of the 270 patients that were included in the study, 67% of them had a positive affect to the hemodynamics due to angiotensin two. This means that 23% of patients had no response to angiotensin two. Some medication’s just don’t work on everybody, and this is something we should be aware of in most drugs we administer to patients. The people in whom this medication worked on saw a greater increase in the mean arterial pressure as well as a reduction in the dose of the other vasopressors that they were receiving at the time.

Turns out that the patients who had a lower lactate level did better than those who had a high lactate level. This should come as no surprise as there is a correlation between high lactate and mortality. Notice that I said correlation and not causation. Patients also did better with the angiotensin two when they were receiving vasopressin. That is just some data that the authors were able to tease out of this retrospective study. The authors performed some statistical jumping jacks and they were able to determine that “hemodynamic responsiveness to angiotensin two was associated with reduced likelihood of 30 day mortality”.

How does Angiotensin II behave in the real world?

Smith et al. published a retrospective, multicenter study looking at 162 patients who received angiotensin II amongst other vasopressors. Amongst their findings, they confirmed that, yes, angiotensin II does increase the MAP. In addition, it decreases the NE-equivalent dose of other vasopressors between hours 0 to 3. They also noted that it takes approximately 16 minutes to kick in with it taking less than 30 minutes the majority of the time. When initiating other vasopressors, we note an effect almost immediately. With angiotensin II, we will have to wait a little while for it to kick in. This is important with our skeptical staff who will almost immediately say “this isn’t working”.

What about DVT’s and Angiotensin II?

One of the questions from the original trial looking at angiotensin II included the risk of deep vein thrombosis. It seems as if there was a higher incidence of this pathology in patients who were receiving angiotensin II. In this particular retrospective study, there were only four cases of DVT’s although the authors needed to do some deep digging into the charts. We all know that we do not regularly screen for DVT’s in the ICU.

Angiotensin II in Patients on Mechanical Circulatory Support?

There was a salvage-therapy retrospective cohort study/case series by Mohamed et al. looking at patients with mechanical circulatory support. In this case: VA-ECMO, VV-ECMO, and Impella/LVADs. This includes combinations of these. The most important thing is that these patients had vasodilatory shock, not cardiogenic. Here are some bullet points on their findings:

  • Hemodynamic response: Five patients (36%) at 3h
  • Median MAP ↑: 61mmHg to 66mmHg at 3h
  • Median NE dose ↓: 0.45mcg/kg/min to 0.2mcg/kg/min at 3h 
  • In-hospital mortality rate: 78.6%

They did see some adverse effects. Remember, this is out of 14 patients. They are also very sick.
Patient 1: Ischemic colitis, in addition to acute liver failure
Patient 3: Sentinel thrombotic event: a thrombus at the pump head inlet of the VV ECMO circuit.
Patient 5: Sharp ↑ in PA pressure & significant ↓ MAP immediately after initiation. ANGII was dc’d: PA & MAP recovered.

Angiotensin II in Post-Cardiac Surgery Vasoplegia?

This is the subset of patients where I feel we may have the biggest use for this medication. Unfortunately, the only study we have on the topic was a post-hoc subgroup analysis of the ATHOS-3 trial. Klijian et al. looked at a whopping 16 patients. Similar to the other groups within the ATHOS-3 trial, an increase of the MAP to 75 took place. Just a reminder, this is a known vasopressor versus a placebo. The benefit they noted included a reduction in catecholamine vasopressors and the adverse effects that come with those.

Is there a place where we can get all the angiotensin II data?

Well, here of course. But also you can try to access the paper by Alam et al. who published a “Review of the Current Literature” in July of 2021. It is unfortunately not free at this point.

Where do I personally stand with Angiotensin II?

Will these data change my practice? The truth is that I would love an independently conducted randomized controlled trial using angiotensin II versus norepinephrine, for example, but the truth is that I do not foresee that in the near future. A quick search on clinical trials.gov did not show anything of this nature in the pipeline. That being said, I am interested in potentially utilizing this medication in the near future for my patients who are in refractory shock, on to vasopressors of which one includes vasopressin, and are also on stress does steroids.

I am quite interested in seeing how patients who have Post pump vasoplegia do with this medication. I have to disclose the fact that I do not have access to this medication at this time and have not used it in my own clinical practice. Check out my YouTube Video with Dr. Rishi Kumar at the bottom of the page where we discuss this further.

Midodrine

Learn all about midodrine in this expansive FULL POST.

Methylene Blue

Methylene Blue in Septic Shock

Check out my full post on this HERE.

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.

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 septic shock? Well, there’s 💩 data for now.

I can’t cover every nuance 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?

Early vs. Late Vasopressors in Septic Shock

Check out my full blog post touching up on this topic.

This is a question that is often asked. Do we give fluids until the patient no longer “responds to fluids” or start vasopressors early? Should we start early vasopressors in septic shock or wait until fluids resuscitation is complete?

Here’s my bias: I dislike arbitrarily pounding patients with fluids. It causes harm. We know this.

I don’t know what people who aren’t doing advanced hemodynamic monitoring of some sort mean when they say “they respond to fluids”. “I gave a liter of fluids and the BP got better” for 30 minutes is not a determinant of fluid responsiveness. Remember, I’ve cited here before that critically ill patients extravasate 80% of that liter of fluids within one hour. What did you really do outside of feeling like you did something? The authors used PPV, SVV, echo with VTI combined with PLR, end-expiratory occlusion maneuvers, and capillary refill time. Did I mention that these authors are legends in the field? Well, they are.

In my opinion, providing pressors early provides a safety net of sorts to the organs to make sure they’re being perfused. You’ve seen it often in your ED and ICU. Patient comes in sick. They’re hypotensive, they get their 30cc/kg and their BP gets “better”. The cuff cycles again 15 minutes later and their BP is now 60/30. How long did those organs go under-perfused? Minutes matter. We NEED to get better at this. After all, we are supposed to be the biggest badasses in medicine, yet we often shrug our shoulders and react when it’s ugly instead of preemptively fixing the issues.

Turns out that very early vasopressors were beneficial to the patients. The definitions of the two groups are defined on my slides. The outcomes are also defined there for the sake of not taking up too much space.

This could be practice changing data. I personally start vasopressors really early in my practice. Some may say, let’s wait for a prospective randomized clinical trial before putting this into practice. To those people I say, there’s no harm in this. Also, you can’t blind the physicians so when that study comes out positive some will say “oh but the physicians weren’t blinded”. Research. Sigh.

Here are the two best papers I’ve found on starting early vasopressors

Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-1034OC. PMID: 30704260.
Link to Article
Link to FULL FREE PDF

Ospina-Tascón GA, Hernandez G, Alvarez I, Calderón-Tapia LE, Manzano-Nunez R, Sánchez-Ortiz AI, Quiñones E, Ruiz-Yucuma JE, Aldana JL, Teboul JL, Cavalcanti AB, De Backer D, Bakker J. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care. 2020 Feb 14;24(1):52. doi: 10.1186/s13054-020-2756-3. PMID: 32059682; PMCID: PMC7023737.
Link to Article
Link to FULL FREE PDF

What MAP goal should I shoot for in patients on vasopressors?

You hear the physician usually choose the number 65 for the MAP goal in patients who are critically ill. Where did that number come from? Does it apply to all patients? The surviving sepsis campaign says to shoot for 65 but why?

LeDoux D, Astiz ME, Carpati CM, et al. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28:27292732. Cited Here

Bourgoin A, Leone M, Delmas A, et al. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33:780786. Cited Here

Thooft A, Favory R, Salgado DR, et al. Effects of changes in arterial pressure on organ perfusion during septic shock. Crit Care. 2011;15:R222. Cited Here

Asfar P, Meziani F, Hamel JF, et al.; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370:15831593. Cited Here

Lamontagne F, Meade MO, Hébert PC, et al.; Canadian Critical Care Trials Group. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42:542550.

Weaning order of vasopressors

This is a post for all my Critical Care Nurses out there! Please tag and share with your friends and colleagues. When you have a patient in shock on norepinephrine and vasopressin and has turned the corner, which vasopressor do you turn off first: norepinephrine or vasopressin? From my hard digging through the internets I have only found three studies which touch on this topic. Also, this seems like a pretty simple RCT that I could actually do at my shop. Anyone interested in joining in on the fun to make it multi-centered?

Here’s what the data says. Spoiler alert: there’s no 100% correct answer.

2010: Bauer, et al. did a retrospective study where the team found that patients did better if the NE was weaned first and the vasopressin was weaned second.

2017: Hammond, et al. also performed a retrospective study which found similar results: patients did better if they weaned off the NE first. So far so good for weaning off NE first.

2018: Jeon, et al. just had to throw a wrench into everything. This was a prospective randomized trial where the results were the exact opposite of the other two. Ugh. Those of you who have been hanging out with me long enough may recognize that I covered this study in March of 2019 when the page was just getting ramped up.

Well what’s the right answer? I guess we just don’t know. Dealers choice of vasopressors. The randomized trial should hold more of an answer due to it being higher on the scale of evidence. The studies are small, hence me considering on doing a trial on this since ultimately it’s not going to cause any harm and I really don’t have a bias. What do you think?

Bauer S, Aloi J, Ahrens C, Yeh J, Culver D, Reddy A. Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study. J Crit Care. 2010;25(2):362.e7-362. e11.
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Hammond DA, McCain K, Painter JT, Clem OA, Cullen J, Brotherton AL, Chopra D, Meena N. Discontinuation of vasopressin before norepinephrine in the recovery phase of septic shock. J Intensive Care Med. 2017:885066617714209
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Jeon K, Song JU, Chung CR, Yang JH, Suh GY (2018) Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care 22(1):131
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Can enteral nutrition be provided to patients on vasopressors?

I have always been interested in the nutritional status of our patients in the ICU and I don’t quite have my mind made up regarding a lot of things. Actually, within the next few months I am going to be asking my registered dietician colleagues here for help with a number of clinical questions.
Truth is that there is a void of solid data regarding nutrition, when to start, how much, how much protein, etc. I understand the ASPEN guidelines have provided some consensus, but much of it is expert opinion rather than actual data. I digress. A topic for another day.

Regarding this article that was published yesterday, the author detailed the vasopressors doses at which one should start feeds (or not start, norepinephrine > 0.3-0.5mcg/kg/min is a no-no), resuscitation markers that should make us feel more comfortable with starting feeds such as decreasing downtrending vasopressor doses.  He also describes the feeding strategy of starting with tropic feeds at 10-20cc/hr.  Lastly, he describes signs of intolerance including residuals > 500cc, note, not 250, not 300… 500.

I have some honest questions for which I personally do not know the answer, though. I need help with this if someone knows the answer. From an evolutionary standpoint, we do not eat when we are ill. Just remember your appetite for a big delicious meal when you last had a significant viral illness. Should we really start to immediately feed these patients? Also, I do not feel that our bodies are accustomed to this whole continuous feeds phenomenon. We normally bolus feed ourselves. Are we shocking the system by doing continuous feeds? See? This is why I need help from some badass registered dietitians.

Wischmeyer PE. Enteral Nutrition Can Be Given to Patients on Vasopressors. Crit Care Med. 2020;48(1):122‐125. doi:10.1097/CCM.0000000000003965
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Citations for Articles on Vasopressors:

Russell JA. Vasopressor therapy in critically ill patients with shock. Intensive Care Med. 2019 Nov;45(11):1503-1517. doi: 10.1007/s00134-019-05801-z. Epub 2019 Oct 23. PMID: 31646370.
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Dünser MW, Hasibeder WR. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med. 2009 Sep-Oct;24(5):293-316. doi: 10.1177/0885066609340519. Epub 2009 Aug 23. Erratum in: J Intensive Care Med. 2016 Sep;31(8):NP1. PMID: 19703817.
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Grignola JC, Domingo E. Acute Right Ventricular Dysfunction in Intensive Care Unit. Biomed Res Int. 2017;2017:8217105. doi: 10.1155/2017/8217105. Epub 2017 Oct 19. PMID: 29201914; PMCID: PMC5671685.
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Hollenberg SM. Vasopressor support in septic shock. Chest. 2007 Nov;132(5):1678-87. doi: 10.1378/chest.07-0291. PMID: 17998371.
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Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM.0000000000002255. PMID: 28098591.
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Norepinephrine Citations

Hernández G, Teboul JL, Bakker J. Norepinephrine in septic shock. Intensive Care Med. 2019 May;45(5):687-689. doi: 10.1007/s00134-018-5499-8. Epub 2019 Jan 10. Erratum in: Intensive Care Med. 2019 Apr;45(4):561. PMID: 30631902.
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Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. doi: 10.1164/rccm.201806-1034OC. PMID: 30704260.
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Ospina-Tascón GA, Hernandez G, Alvarez I, Calderón-Tapia LE, Manzano-Nunez R, Sánchez-Ortiz AI, Quiñones E, Ruiz-Yucuma JE, Aldana JL, Teboul JL, Cavalcanti AB, De Backer D, Bakker J. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care. 2020 Feb 14;24(1):52. doi: 10.1186/s13054-020-2756-3. PMID: 32059682; PMCID: PMC7023737.
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Stolk RF, van der Poll T, Angus DC, van der Hoeven JG, Pickkers P, Kox M. Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis. Am J Respir Crit Care Med. 2016 Sep 1;194(5):550-8. doi: 10.1164/rccm.201604-0862CP. PMID: 27398737.
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Stolk RF, Kox M, Pickkers P. Noradrenaline drives immunosuppression in sepsis: clinical consequences. Intensive Care Med. 2020 Jun;46(6):1246-1248. doi: 10.1007/s00134-020-06025-2. Epub 2020 Apr 8. PMID: 32270211; PMCID: PMC7292809.
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Levy B, Clere-Jehl R, Legras A, Morichau-Beauchant T, Leone M, Frederique G, Quenot JP, Kimmoun A, Cariou A, Lassus J, Harjola VP, Meziani F, Louis G, Rossignol P, Duarte K, Girerd N, Mebazaa A, Vignon P; Collaborators. Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction. J Am Coll Cardiol. 2018 Jul 10;72(2):173-182. doi: 10.1016/j.jacc.2018.04.051. PMID: 29976291.
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Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E; CATS Study Group. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007 Aug 25;370(9588):676-84. doi: 10.1016/S0140-6736(07)61344-0. Erratum in: Lancet. 2007 Sep 22;370(9592):1034. PMID: 17720019.
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Cheng L, Yan J, Han S, Chen Q, Chen M, Jiang H, Lu J. Comparative efficacy of vasoactive medications in patients with septic shock: a network meta-analysis of randomized controlled trials. Crit Care. 2019 May 14;23(1):168. doi: 10.1186/s13054-019-2427-4. PMID: 31088524; PMCID: PMC6518735.
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Bougouin W, Slimani K, Renaudier M, Binois Y, Paul M, Dumas F, Lamhaut L, Loeb T, Ortuno S, Deye N, Voicu S, Beganton F, Jost D, Mekontso-Dessap A, Marijon E, Jouven X, Aissaoui N, Cariou A; Sudden Death Expertise Center Investigators. Epinephrine versus norepinephrine in cardiac arrest patients with post-resuscitation shock. Intensive Care Med. 2022 Mar;48(3):300-310. doi: 10.1007/s00134-021-06608-7. Epub 2022 Feb 7. PMID: 35129643.
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Epinephrine Citations

Dünser MW, Festic E, Dondorp A, Kissoon N, Ganbat T, Kwizera A, Haniffa R, Baker T, Schultz MJ; Global Intensive Care Working Group of European Society of Intensive Care Medicine. Recommendations for sepsis management in resource-limited settings. Intensive Care Med. 2012 Apr;38(4):557-74. doi: 10.1007/s00134-012-2468-5. Epub 2012 Feb 14. Erratum in: Intensive Care Med. 2012 Apr;38(4):575-6. PMID: 22349419; PMCID: PMC3307996.
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Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria J; CAT Study investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2226-34. doi: 10.1007/s00134-008-1219-0. Epub 2008 Jul 25. PMID: 18654759.
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Belletti A, Nagy A, Sartorelli M, Mucchetti M, Putzu A, Sartini C, Morselli F, De Domenico P, Zangrillo A, Landoni G, Lembo R. Effect of Continuous Epinephrine Infusion on Survival in Critically Ill Patients: A Meta-Analysis of Randomized Trials. Crit Care Med. 2020 Mar;48(3):398-405. doi: 10.1097/CCM.0000000000004127. PMID: 31789701.
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Ammar MA, Limberg EC, Lam SW, Ammar AA, Sacha GL, Reddy AJ, Bauer SR. Optimal norepinephrine-equivalent dose to initiate epinephrine in patients with septic shock. J Crit Care. 2019 Oct;53:69-74. doi: 10.1016/j.jcrc.2019.05.024. Epub 2019 Jun 3. PMID: 31202160.
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Phenylephrine Citations

Morelli A, Ertmer C, Rehberg S, Lange M, Orecchioni A, Laderchi A, Bachetoni A, D’Alessandro M, Van Aken H, Pietropaoli P, Westphal M. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial. Crit Care. 2008;12(6):R143. doi: 10.1186/cc7121. Epub 2008 Nov 18. PMID: 19017409; PMCID: PMC2646303.
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Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association Between US Norepinephrine Shortage and Mortality Among Patients With Septic Shock. JAMA. 2017 Apr 11;317(14):1433-1442. doi: 10.1001/jama.2017.2841. PMID: 28322415.
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Hawn JM, Bauer SR, Yerke J, Li M, Wang X, Reddy AJ, Mireles-Cabodevila E, Sacha GL. Effect of Phenylephrine Push Before Continuous Infusion Norepinephrine in Patients With Septic Shock. Chest. 2021 May;159(5):1875-1883. doi: 10.1016/j.chest.2020.11.051. Epub 2020 Dec 13. PMID: 33316239.
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Haiduc M, Radparvar S, Aitken SL, Altshuler J. Does Switching Norepinephrine to Phenylephrine in Septic Shock Complicated by Atrial Fibrillation With Rapid Ventricular Response Improve Time to Rate Control? J Intensive Care Med. 2021 Feb;36(2):191-196. doi: 10.1177/0885066619896292. Epub 2020 Jan 2. PMID: 31893966.
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Dopamine Citations

De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NEJMoa0907118. PMID: 20200382.
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Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23-30;356(9248):2139-43. doi: 10.1016/s0140-6736(00)03495-4. PMID: 11191541.
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Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in the modern intensive care unit? Anesth Analg. 2004 Feb;98(2):461-468. doi: 10.1213/01.ANE.0000096188.35789.37. PMID: 14742388.
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Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest. 2003 Apr;123(4):1266-75. doi: 10.1378/chest.123.4.1266. PMID: 12684320.
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Vasopressin Citations

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373. PMID: 18305265.
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Gordon AC, Russell JA, Walley KR, Singer J, Ayers D, Storms MM, Holmes CL, Hébert PC, Cooper DJ, Mehta S, Granton JT, Cook DJ, Presneill JJ. The effects of vasopressin on acute kidney injury in septic shock. Intensive Care Med. 2010 Jan;36(1):83-91. doi: 10.1007/s00134-009-1687-x. Epub 2009 Oct 20. PMID: 19841897.
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Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485. PMID: 27483065.
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Bauer SR, Sacha GL, Lam SW, Wang L, Reddy AJ, Duggal A, Vachharajani V. Hemodynamic Response to Vasopressin Dosage of 0.03 Units/Min vs. 0.04 Units/Min in Patients With Septic Shock. J Intensive Care Med. 2020 Nov 28:885066620977181. doi: 10.1177/0885066620977181. Epub ahead of print. PMID: 33251906.
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Webb AJ, Seisa MO, Nayfeh T, Wieruszewski PM, Nei SD, Smischney NJ. Vasopressin in vasoplegic shock: A systematic review. World J Crit Care Med. 2020 Dec 18;9(5):88-98. doi: 10.5492/wjccm.v9.i5.88. PMID: 33384951; PMCID: PMC7754532.
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McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, Lamontagne F, Healey JS, Whitlock RP, Belley-Côté EP. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock: A Systematic Review and Meta-analysis. JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528. PMID: 29801010; PMCID: PMC6583502.
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Jakowenko ND, Murata J, Kopp BJ, Erstad BL. Influence of Timing and Catecholamine Requirements on Vasopressin Responsiveness in Critically ill Patients with Septic Shock. J Intensive Care Med. 2022 Feb 23:8850666221081836. doi: 10.1177/08850666221081836. Epub ahead of print. PMID: 35195486.
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Terlipressin Citations

Zhu Y, Huang H, Xi X, Du B. Terlipressin for septic shock patients: a meta-analysis of randomized controlled study. J Intensive Care. 2019 Mar 12;7:16. doi: 10.1186/s40560-019-0369-1. PMID: 30923620; PMCID: PMC6419496.
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Wang H, Liu A, Bo W, Feng X, Hu Y. Terlipressin in the treatment of hepatorenal syndrome: A systematic review and meta-analysis. Medicine (Baltimore). 2018 Apr;97(16):e0431. doi: 10.1097/MD.0000000000010431. PMID: 29668606; PMCID: PMC5916651.
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Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, Gonzalez SA, Mumtaz K, Lim N, Simonetto DA, Sharma P, Sanyal AJ, Mayo MJ, Frederick RT, Escalante S, Jamil K; CONFIRM Study Investigators. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021 Mar 4;384(9):818-828. doi: 10.1056/NEJMoa2008290. PMID: 33657294.
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Schultz J, Andersen A, Lyhne MD, Arcanjo DDR, Kjaergaard B, Simonsen U, Nielsen-Kudsk JE. Terlipressin Increases Systemic and Lowers Pulmonary Arterial Pressure in Experimental Acute Pulmonary Embolism. Crit Care Med. 2020 Apr;48(4):e308-e315. doi: 10.1097/CCM.0000000000004243. PMID: 32205621.
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Selepressin Citations

Russell JA, Vincent JL, Kjølbye AL, Olsson H, Blemings A, Spapen H, Carl P, Laterre PF, Grundemar L. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017 Aug 15;21(1):213. doi: 10.1186/s13054-017-1798-7. PMID: 28807037; PMCID: PMC5557574.
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Laterre PF, Berry SM, Blemings A, Carlsen JE, François B, Graves T, Jacobsen K, Lewis RJ, Opal SM, Perner A, Pickkers P, Russell JA, Windeløv NA, Yealy DM, Asfar P, Bestle MH, Muller G, Bruel C, Brulé N, Decruyenaere J, Dive AM, Dugernier T, Krell K, Lefrant JY, Megarbane B, Mercier E, Mira JP, Quenot JP, Rasmussen BS, Thorsen-Meyer HC, Vander Laenen M, Vang ML, Vignon P, Vinatier I, Wichmann S, Wittebole X, Kjølbye AL, Angus DC; SEPSIS-ACT Investigators. Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial. JAMA. 2019 Oct 15;322(15):1476-1485. doi: 10.1001/jama.2019.14607. Erratum in: JAMA. 2019 Nov 12;322(18):1830. PMID: 31577035; PMCID: PMC6802260.
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GIAPREZA/Angiotensin II Citations

Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hästbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM; ATHOS-3 Investigators. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430. doi: 10.1056/NEJMoa1704154. Epub 2017 May 21. PMID: 28528561.
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Wieruszewski PM, Wittwer ED, Kashani KB, Brown DR, Butler SO, Clark AM, Cooper CJ, Davison DL, Gajic O, Gunnerson KJ, Tendler R, Mara KC, Barreto EF. Angiotensin II Infusion for Shock: A Multicenter Study of Postmarketing Use. Chest. 2021 Feb;159(2):596-605. doi: 10.1016/j.chest.2020.08.2074. Epub 2020 Aug 31. PMID: 32882250.
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Smith SE, Newsome AS, Guo Y, Hecht J, McCurdy MT, Mazzeffi MA, Chow JH, Kethireddy S. A Multicenter Observational Cohort Study of Angiotensin II in Shock. J Intensive Care Med. 2022 Jan;37(1):75-82. doi: 10.1177/0885066620972943. Epub 2020 Nov 24. PMID: 33231111; PMCID: PMC8559525.
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Klijian A, Khanna AK, Reddy VS, Friedman B, Ortoleva J, Evans AS, Panwar R, Kroll S, Greenfeld CR, Chatterjee S. Treatment With Angiotensin II Is Associated With Rapid Blood Pressure Response and Vasopressor Sparing in Patients With Vasoplegia After Cardiac Surgery: A Post-Hoc Analysis of Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Study. J Cardiothorac Vasc Anesth. 2021 Jan;35(1):51-58. doi: 10.1053/j.jvca.2020.08.001. Epub 2020 Aug 7. PMID: 32868152.
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Alam A, Sovic W, Gill J, Ragula N, Salem M, Hughes GJ, Colbert GB, Mooney JL. Angiotensin II: A Review of Current Literature. J Cardiothorac Vasc Anesth. 2021 Jul 16:S1053-0770(21)00602-9. doi: 10.1053/j.jvca.2021.07.021. Epub ahead of print. PMID: 34452817.
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Mohamed A, Berry TP, Welge JA, Thomas EL, Zhurav L, Kozinn J, Haines MM. Angiotensin II in Patients With Shock on Mechanical Circulatory Support: A Single-Center Retrospective Case Series. J Cardiothorac Vasc Anesth. 2022 Jan 7:S1053-0770(22)00002-7. doi: 10.1053/j.jvca.2022.01.002. Epub ahead of print. PMID: 35144869.
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Midodrine Citations

Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care. 2020 Jun;57:148-156. doi: 10.1016/j.jcrc.2020.02.011. Epub 2020 Feb 19. PMID: 32145658.
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Levine AR, Meyer MJ, Bittner EA, Berg S, Kalman R, Stanislaus AB, Ryan C, Ball SA, Eikermann M. Oral midodrine treatment accelerates the liberation of intensive care unit patients from intravenous vasopressor infusions. J Crit Care. 2013 Oct;28(5):756-62. doi: 10.1016/j.jcrc.2013.05.021. Epub 2013 Jul 8. PMID: 23845791.
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Whitson MR, Mo E, Nabi T, Healy L, Koenig S, Narasimhan M, Mayo PH. Feasibility, Utility, and Safety of Midodrine During Recovery Phase From Septic Shock. Chest. 2016 Jun;149(6):1380-3. doi: 10.1016/j.chest.2016.02.657. Epub 2016 Mar 4. PMID: 26953217.
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Rizvi MS, Trivedi V, Nasim F, Lin E, Kashyap R, Andrijasevic N, Gajic O. Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series. Crit Care Med. 2018 Jul;46(7):e628-e633. doi: 10.1097/CCM.0000000000003121. PMID: 29613861.
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Santer P, Anstey MH, Patrocínio MD, Wibrow B, Teja B, Shay D, Shaefi S, Parsons CS, Houle TT, Eikermann M; MIDAS Study Group. Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial. Intensive Care Med. 2020 Oct;46(10):1884-1893. doi: 10.1007/s00134-020-06216-x. Epub 2020 Sep 3. PMID: 32885276; PMCID: PMC8273663.
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Costa-Pinto R, Yong ZT, Yanase F, Young C, Brown A, Udy A, Young PJ, Eastwood G, Bellomo R. A pilot, feasibility, randomised controlled trial of midodrine as adjunctive vasopressor for low-dose vasopressor-dependent hypotension in intensive care patients: The MAVERIC study. J Crit Care. 2022 Feb;67:166-171. doi: 10.1016/j.jcrc.2021.11.004. Epub 2021 Nov 18. PMID: 34801917.
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Frequently Asked Questions Citations

Bauer SR, Aloi JJ, Ahrens CL, Yeh JY, Culver DA, Reddy AJ. Discontinuation of vasopressin before norepinephrine increases the incidence of hypotension in patients recovering from septic shock: a retrospective cohort study. J Crit Care. 2010 Jun;25(2):362.e7-362.e11. doi: 10.1016/j.jcrc.2009.10.005. PMID: 19926252.
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Hammond DA, McCain K, Painter JT, Clem OA, Cullen J, Brotherton AL, Chopra D, Meena N. Discontinuation of Vasopressin Before Norepinephrine in the Recovery Phase of Septic Shock. J Intensive Care Med. 2019 Oct;34(10):805-810. doi: 10.1177/0885066617714209. Epub 2017 Jun 15. PMID: 28618919.
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Jeon K, Song JU, Chung CR, Yang JH, Suh GY. Incidence of hypotension according to the discontinuation order of vasopressors in the management of septic shock: a prospective randomized trial (DOVSS). Crit Care. 2018 May 21;22(1):131. doi: 10.1186/s13054-018-2034-9. PMID: 29784057; PMCID: PMC5961479.
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Hammond DA, Sacha GL, Bissell BD, Musallam N, Altshuler D, Flannery AH, Lam SW, Bauer SR. Effects of Norepinephrine and Vasopressin Discontinuation Order in the Recovery Phase of Septic Shock: A Systematic Review and Individual Patient Data Meta-Analysis. Pharmacotherapy. 2019 May;39(5):544-552. doi: 10.1002/phar.2265. Epub 2019 Apr 15. PMID: 30893494.
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Lam SW, Sacha GL, Duggal A, Reddy AJ, Bauer SR. Abrupt Discontinuation Versus Down-Titration of Vasopressin in Patients Recovering from Septic Shock. Shock. 2021 Feb 1;55(2):210-214. doi: 10.1097/SHK.0000000000001609. PMID: 32842024.
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Vadiei N, Daley MJ, Murthy MS, Shuman CS. Impact of Norepinephrine Weight-Based Dosing Compared With Non-Weight-Based Dosing in Achieving Time to Goal Mean Arterial Pressure in Obese Patients With Septic Shock. Ann Pharmacother. 2017 Mar;51(3):194-202. doi: 10.1177/1060028016682030. Epub 2016 Nov 25. PMID: 27886982.
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Russell JA, Gordon AC, Williams MD, Boyd JH, Walley KR, Kissoon N. Vasopressor Therapy in the Intensive Care Unit. Semin Respir Crit Care Med. 2020 Aug 20. doi: 10.1055/s-0040-1710320. Epub ahead of print. PMID: 32820475.
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