Is it safe to peripherally administer norepinephrine?

Welcome to Depth of Anesthesia. I'm David Hao and I'm an anesthesia resident at the Massachusetts General Hospital. We're quickly approaching 100 reviews on iTunes for the podcast. As always, thank you for your support and please share the podcast with your friends and colleagues We definitely hope to continue to reach more people and inspire conversation about practices in anesthesia. My guests today are Dr. Jamie Sparling and Dr. Katarina Rusik You may recognize Dr. Sparling from our recent episode investigating Ketorolac and Surgical Bleeding.

Dr. Rusik is a graduate of our Anesthesia Critical Care Fellowship here at MGH, and she's a faculty member. Dr. Sparling and Dr. Rusik, welcome to the show. Thanks for having me back. Thanks for having me here. So our case today is that of a 85-year-old woman with a history of reduced EF at 45%, who's presenting for irrigation and debridement of an infected wound.

She's persistently hypotensive in the operating room, and the resident decides to start an infusion of norepinephrine through one of the patient's peripheral IVs. The attending observes this, however, and tells the resident to switch the infusion to phenylephrine and to actually place a central line if the patient needs norepinephrine. What do you guys think are some of the claims here in this case? So as I see it, the claims are that one The risk of vasopressor extravization is greater through a peripheral IV than a central line. 2. The risk of norepinephrine administration poses a greater risk than that of phenylephrine And three, the benefits of avoiding central line placement outweigh potential risks of peripheral administration of vasopressor.

So to our listeners, what's the level of your agreement with the claim that norepinephrine is not safe to infuse through a peripheral intravenous line? And what's the level of evidence for what you believe? So this is a topic that you guys presented with Dr. Jeremy Mountjoy at Grand Rounds, and as I understand it, it seems like at least from discussion on social media platforms like Twitter. This topic is getting discussed across many institutions. That's right.

Um we thought this was a timely topic to discuss at our Grand Rounds. Because it's a conversation that we have not only within our own department and the ICUs that we cover here, but also with our colleagues in pulmonary critical care, in the emergency room, in neurocritical care and others Um and it it comes up frequently in the operating room. I thought it was entertaining at least that when we were preparing this talk a few weeks ago that I I was of course procrastinating and reviewing my Twitter feed and I came across one of my pulmonary critical care friends who had posted a clinical vignette uh to his Twitter feed uh and polled his followers to see uh what their agreement was with either placing a central line versus startating norepinephrine peripherally.

And so I just think it just highlights that it's not only um anesthesiologists that are considering this level of evidence, but also um physicians from across the spectrum. And we actually pulled the audience at our own grand rounds, right, to gauge the percentage of people who felt that Norapnephron was safe. We we pulled them before and after we presented the evidence actually. And uh beforehand, eighty-five percent of the of respondents believed that norepranephrine was safe to administer peripherally Uh maybe we'll save the results for after the evidence until later on in the podcast. So let's get started by just talking about some of the reasons that people would give uh when they support the peripheral infusion of norepinephrine.

So things you'll hear pretty commonly are, for example, that peripheral administration has been given safely both in the operating room and in the ICU setting. At peripheral concentrations, risks of norepinephrine are similar to that of phenylephrine, and early administration of norepinephrine might be beneficial in certain populations, such as in septic shock. What are some of the reasons that people would give when they oppose the peripheral infusion of norepinephrine? The things that I commonly hear are first that the risk to of First, that the risk of extravization is just unacceptably high with peripheral nepinephrine, and that therefore it's not safe. And secondly, that the literature, which we're about to take a closer look at, is really just not generalizable to our population in the operating room and in the ICU.

It was either done in healthcare patients or in settings with closer monitoring. Um and so I think some people are reticent to generalize those. Got it. So as I understand it, the Food and Drug Administration here in the United States or the FDA uh label on norepinephrine, brand name LeviFed , actually mentions uh site infusion and discusses some of the very concerns that people raise So the FDA label actually seems to assume that you're going to be giving it peripherally. So the site of infusion portion of the FDA label says Well, try to give it in a large vein, particularly the anticubital vein.

You should check for free flow, monitor the site frequently for blanching, um, but it says in bold letters um the risk of necrosis um from prolonged vasoconstriction is apparently very slight. So the FDA seems to assume we're given this stuff through peripheral IVs. It's really interesting. It's literally the first time I've heard of that. I I was blown away by this language in the label when we were researching this So I think to get started, we're gonna do a rough comparison of the dose equivalents between norepinephrine and phenylephrine, just so that we make sure we're actually making a fair comparison.

Yeah, so I have a paper here from anesthesiology in 2017. The author is Nyan Ki, and you'll find that his group has published a number of studies in the obstetric population. where they've been using peripheral norepinephrine prophylactically to treat hypotension related to spinal anesthesia. So in this particular study, they were looking to determine the relative potency of norepinephrine as compared with phenylephrine, both delivered peripherally, and this was specifically in the context of spinal anesthesia for cesarean delivery. The study design I thought was pretty interesting. So they took 180 healthy protrudents that were undergoing elective c section. and they were randomized to either a single norepinephrine or phenoephrine dose.

And then they measured what the response was in terms of the systolic blood pressure before and after administration. This bolus was given when the systolic blood pressure dropped to less than 80% of the baseline, prespinal. And the doses that they received as a single push were a random allocation of norepinephrine between 4 and 12 mics or phenylephrine between 60 and 200 micrograms. To record the response, they cycle a non-invasive blood pressure cuff every one minute And then outside of this dose binding study, they continued to run a norepinephrine infusion. uh peripherally again as needed after the conclusion of the protocol to maintain an adequate uh systolic blood pressure. So single doses and they're measuring the response pre and post based on non-invasive blood pressure.

What they found is there was an approximation of the equivalency, wherein phenophrin, about 13 micrograms, was more or less equivalent to norepinephrine, 1 microgram. And again, this was in healthy perturients that had just received a spinal. So a pretty specific population, but it does give you a number in your head to take home. And Dr. Sparling, I just want to jump in and comment that I like to remember as few fact words and numbers in my life as I can. So I um distill this down to basically an order of magnitude difference instead of 13 to 1.

I always remember roughly 10 to 1 given uh that you don't have valvulopathies or heart failure and things, if you're on a hundred of phenylephrine and you wanted to substitute it out for norepinephrine, you'd probably be on ten of norepinephrine for your hundred of phenylephrine. Yeah, sounds like a good rule of thumb. And what are the uh standard infusions that we typically run here? Because I think that must change from institution to institution. Um here at MGH, uh we typically prepare a peripheral phenophrine infusion of 80 micrograms per ml and the norepinephrine infusions that we prepare range a little bit depending on the provider, anywhere from 4 micrograms per ml to 16 micrograms per ml That's compared with uh central administration, which is 80 micrograms per ml for norepinephrine.

Got it. So I think that's important to note that the The norepinephrine concentration is far more dilute than the phenylephrine concentration that we're using peripherally So now that we have a sense of the rough dose equivalency of phenylephrine and norepinephrine, let's start exploring the Biggest claim I think in this case, which is that norepinephrine is either safer or less safe to give peripherally, specifically due to the risk of tissue extravization and injury So on the theme of this being a hot topic, there was a retrospective study published just last week in Anesthesia and Analgesia. by Pancaro et al. And um they had a final population of around fourteen thousand patients who received norepinephrine at peripheral concentrations of twenty micrograms per ml.

So pretty similar to the concentrations we would use at MGH, maybe a little more concentrated, but ballpark. And they only found in their review drug extravization in five patients, which amounts to 0.035 %. or one to eight events per 10,000 patients, estimated risk. And then of those five patients that did have an extravasation event there were zero complications recorded that required any sort of surgical or medical intervention other than watching. So one of the things I liked about this study is that it's patients undergoing a general anesthetic So this is our population of patients. On one hand, I feel like the risk of extrapization is is higher because you don't have patients that can tell you if the IB is starting to bother you.

On the other hand, uh it's almost an advantage. So I think about our patients in the ICU that have peripheral pressors running. And they're moving around, they're flexing across where the IV is inserted. And the IV itself is at higher risk to come out of the vein. So I think there's both pros and cons to that.

The other comment that I have about this study is that I I do think we have to be careful. So it is a tiny number that they've reported in the 14,000 patients who had received peripheral norepinephrine. But it relies more or less on QA database. So the individual practitioners had to A recognize an extrapolization event Um so there wasn't necessarily prophylactic monitoring like there have been in other studies. And then they had to self-report, which we know the rate across literature is very low.

They did try to augment that by searching through the medical record for terms like pentolamine, plastic surgery, skin, graft. But I don't believe that those actually added any additional events to those reported through their QA database. So just a couple of caveats, but I do think it's an important study and certainly a large one that warrants uh you know taking a closer look at. So it sounds like there's a strength in this study in the sense that there's a lot of patience, but there's a concern that there may have been under-reporting. Exactly.

So big takeaway? So, based on this database analysis, there's really no significant association found between the use of peripheral norepinephrine infusions and any adverse events. So keeping in mind the inherent problems sometimes with retrospective studies, I know that Dr. Sparling, you have another paper that is a prospective study, correct That's right. Um so this is a paper in the Journal of Hospital Medicine in 2015 by Cardanas Garcia et al. And they looked prospectively at the safety of peripheral administration of norepinephrine, dopamine, and phenolephrine Um they had 734 patients and their outcomes were the risk of extrapization and the need for central venous catheter placement. The protocol that they used, and I think they they had some pretty strict criteria for when they could use a peripheral vein for vasopressor administration I won't detail all of this, but just a few highlights are that they actually examine the vein prior to using it under ultrasound, and they require that the vein be at least four millimeters in diameter.

They required that the position of the peripheral IV um be documented under ultrasound, so injecting a salient bolus and confirming that. It was only done in the upper extremity using an 18 or 20 gauge uh catheter. It was not allowed to be on the hand, the wrist, or the AC, and it had to be contralateral to the blood pressure cuff. So some pretty strict criteria, which I think is important in terms of how we generalize this study. The protocol that they use in terms of the vasopressors use noreprinephrine at a concentration of 32 to 64 micrograms per ml.

Dopamine at a concentration of 1.6 mg per ml, and phenylephrine at a concentration of 160 to 320 micrograms per ml. They checked the site every two hours by nurses, and if there was extravagation noted, they preemptively gave pentolamine as well as local nitroglycerin So Dr. Risik, what was the population that this study was conducted in? So uh the great thing is that these were older patients. 72 years old, plus or minus fifteen years. Uh they were Mickey patients. So while it wasn't an operating room population, they were older sicker patients, uh, which is more akin to who we would be considering peripheral norepinephrine in in the operating room.

And um one other point to make is that the concentration of norepinephrine that they use was actually a little bit more concentrated than our standard mix, which 16 mics per ml and theirs was 32 to 64 mics per ml. Doctor Sparling, what were the results of this study? Of their 734 patients, 506 of them had received peripheral norepinephrine, and of those, 16 had evidence of extravasation. They were all treated with pentolamine and nitroglycerin, and none of them ended up having tissue injury. But again, if you think about this versus the last study. 16 extravizations out of 500 is a much higher rate than the five extravizations in 14,000.

Which probably makes sense what I was saying earlier in terms of the populations. When you have a patient under general anesthesia, they're not going to be moving, they're not going to be flexing the site where that peripheral IV is administered versus in the ICU, um, presuming you have an excavated conscious patient, all of those are risks. And you think about the care, even though the nurses in this protocol were checking the site every two hours Compare that to what we do in the operating room where we are one-to-one with a patient and we're able to continually have that in our sight to be vigilant about the risk of astravization. Those are all really good points.

But also obviously this um uh this study was aiming to specifically look at that outcome. So obviously when you're looking for something, more likely to find it Some I think important caveats to also think about. Just a couple of other points to make. Converting, we're used to using infusions. um norepinephrine infusions in mics per minute at our institution rather than per kilodosing. So their norepinephrine can um concentration for a 70 kilo man would be five mics per minute, whereas the phenylephrine concentrations you were using was 230 mics per minute.

So interestingly of the 500 uh or so norepinephrine groups, 16 had infiltration, and of the 176 phenylephrine, there were no infiltrations. I think you know that it's too small of a numbers game to really comment um too much on the difference between that, but it is interesting that all of the infiltrations were in the norepinephrine group. Again, I don't think we should read too much into that. because that wasn't the point of their their study, but there were none in the phenylephrine group. And then I think another caveat to just keep in mind is how meticulous they were about the IV placement. I mean, as anesthesiologists, I'm sure we're all pretty confident in our IV skills, but we certainly don't ultrasound guide and triple and quadruple check every single IV.

Yeah. And even measuring the the width of the of the veins. Right. That's unheard of. Right.

So quite meticulous IV placement. And maybe that is something to keep in mind when you're considering peripheral norepinephrine and what you've been using for the case is the uh 20 gauge you inherited from the floor that you hope is is in the right place Yeah. I mean not only just the placement of the IV but the protocol that the nurses use, they actually checked for blood return in the IVs every two hours and interrupted the infusion. So again, just goes to speak to the level of material ridiculousness that they that they used. I would say though, um very reassuring that um especially with the use of pentolamine and TNG paste, that they they had no adverse outcomes in their population.

And I think that's a great point that you guys made. It's easy to say peripheral, but clearly not all veins are alike. And when we say peripheral it could really mean very, very shoddy, small IVs in the hands or really solid caliber ones in the AC Yeah, I think that's exactly right. Uh all right, so Dr. Sparling um punchline So in this Pretty well-designed protocol for ICU patients using peripheral vasopressors. There were very few events of extravization, and those that happened were not clinically significant.

Super. And Dr. Rusik, I think you have another prospective observational study for us, right? Yes. This is um by Medley et al. in Journal of Emergency Medicine, January of 2018, that looked at 55 patients that started in the emergency department at a tertiary medical center Uh mean age was around 70 years, so again, older population. And their primary outcome was looking at the incidence of complications, which they broke down into Major and minor, major being something that really impacted your long-term morbidity and mortality, minor being anything else.

So they looked at patients who got started on peripheral vasopressor infusions in the emergency department. norepinephrine at concentrations of 32 mics per mil, which again is about double the concentration of what we standardly use in the operating room And then a handful of patients that also got peripheral dopamine. So the IV site was checked a couple of times a day by research fellows. for the duration of the infusion and then after the infusion was discontinued they continued to have the uh research staff check the site once daily for two more days And so again, the main um outcome that they saw was that they had very few complications. So in the in the whole study Overall, 55 patients.

There were only three complications. Two were local extravagations and one was a thrombophlebitis event None of these they considered particularly serious and none of them required any intervention. So I think the interesting thing about this study is that the protocol was much less strict as compared to the the prior one. And accordingly, the rate of extrapolation for the Norepi group was a bit higher. I think it's really hard to make much of that given the small numbers here with only 50 patients in the Norepi group But this was 6% versus about 3 or 4% in the last one.

So I think that's interesting and probably reflects both the protocol with which the peripheral IVs are placed for in terms of criteria for the vein selection as well as the protocol that they have in place for monitoring. Was there any sort of mention on vein selection, site selection, things like that? So the um uh IV size was mentioned, so they had 20-something 18 gauges, 20-something 20 gauge IVs, so mostly 18 and 20 gauge IVs, but As opposed to the last study we discussed, 20 gauge IVs were allowed. And then in terms of the rates of infusion we're talking about, Um we're we're talking about pretty low, relatively low uh rates, so six to ten micrograms per minute in most of the case.

Um so so we're not talking about peripheral infusions of a hundred um mics per minute of norepinephrine. You know, we're sort of talking about I I guess what we would consider civilized concentrations of Peripheral norepinephrine, where if you were to convert it mentally to phenylephrine , maybe a hundred of phenylephrine or less. Right. Yeah, and the sites of the IVs that they used were a bit different, whereas in the prior study uh they had very specific criteria about it not being over-reflexor surface and not being on the hand In the present study, this emergency medicine study, about 40% were in the anticubital flasum and about 36% were actually in the hand. So I think site selection was quite different I think it's nice to have um this study that's a little bit more representative of real -world emergency department.

What's it like out there in the Wild West where you you inherit whatever IV you inherit from the ED and you you start your emergent case and um it's nice to to see that even with some of these um hand IVs they didn't have a huge infiltration rate So Dr. Rusik punchline? So in a pragmatic, prospective observational study Following patients who started in the emergency department, uh, who got peripheral norepinephrine. There were very, very few extravization events, three out of fifty patients who got norepinephrine and none of them were really clinically significant. So let's shift gears now. We've done a lot of talking about the risk of extravization and I think one of the key branch points here is whether or not to place a central line.

And as we all know, central lines are not without risk, so Do we have literature kind of doing a cost-benefit analysis of placing central lines in the event that peripheral in the event that vasopressors are required? Conveniently we do. So I have a study here from Critical Care Medicine in 2013 by Ricard et al. They actually did a randomized control trial, uh, which was open label and took place in three different French ICUs They included 263 subjects, of which about half received a central line and half were randomized to peripheral administration. And the inclusion criteria for the study I think are pretty interesting. So I interpret this to mean kind of like the gray zone.

So alright, maybe we can make the case to do things with a peripheral IV or maybe we can make the case that they need a central line. Specifically what they used were uh the need for specific drugs that were known to be venotoxic, and they had specific dose ranges in terms of epinephrine infusion, norepinephrine infusion, dopamine or debutamine, etcetera. And then the second major criteria, again which they considered kind of in this gray zone of they may or may not need a central line, was difficulty either in peripheral IV insertion or maintenance. So had nothing to do uh with the drugs that were administered, but just a patient that was repeatedly being stuck for peripherals.

And they included patients that either needed um a third attempt to insert an initial peripheral IV. uh the need to replace a peripheral IV twice a day for two days or once a day for three days. So all of these patients met inclusion criteria and they were randomized to one group or the other And they looked at major catheter-related complications as the primary outcome. And then they looked at minor complications as a secondary outcome, as well as a composite score of staph utilization. So this gets back to I think what is often discussed, at least in in my practice, where say, okay, maybe it is safe to use norepinephrine peripherally, but are we going to really flaw this IV all day? when we could just place a central line and be done in fifteen minutes.

So I I thought this was a great study in terms of examining that. So what were the results of this study? So the primary outcome, remember, was major catheter related complications. And for their overall population for the central venous line group, they reported 87 versus in the peripheral they reported 133. So this was a statistically significant difference with a p-value of 0.02 Of those complications, they included mechanical, infectious, and thrombotic, which we we typically think of the mechanical as being the extravization risk.

They specifically looked at evidence of subcutaneous diffusion greater than five by five centimeters, or necrosis, or blister that was greater than three by three centimeters, and they included that as evidence of extravagation. There were 19 in the peripheral group out of the 128 that were randomized. So a pretty significant number, over 10%. I just want to jump in and stress that we um see from their data that there were more um blisters in the peripheral IV group. What they defined as a blister was three by three centimeters.

That's huge. So I wonder how many smaller blisters than that that they might have also had. Just some food for thought. Absolutely They also looked at the severity in terms of the complication rate, and they rated this according to a classification scheme. It's called the Common Terminology Classification for Adverse Events.

And with this, they reported for the peripheral group, all grades being uh 1.54. uh risk ratio compared to 0.89 for the central group, which was highly significant. And this was also highly significant when they looked only at grade one and two So overall in basically all of the outcomes that they looked at, the peripheral group had a higher rate of complications. And Dr. Sparling, I I remember you mentioning something about composite composite staff utilization. What's that mean and what's the relevance of that to the study? So the authors in this group, they looked at the time consumption for both the physician team as well as for the paramedical team, meaning the the bedside nurses and other um other members of the staff.

And they rated this on a scale of one to five for each of those groups, uh, depending on which group the patient was assigned to. And then they took the composite score and compared them. They saw a composite score again on a range of 1 to 5 in the peripheral group of 3.2 versus 1.8 in the central line group. Again, this was highly significant with a p-value less than 0.001. So the takeaway from this composite score is that the central line group was much less labor-intensive, both from a medical and a paramedical perspective.

So jumping in again, um, this makes me wonder if some of these numbers are totally applicable to our anesthesia practice Um because we're pretty facile both with peripheral IVs and central line placement. And um other populations may actually be more facile with central line placement than peripheral IV. So while, as you mentioned, you know, there is that patient you come across where you're flogging the IV again and again and you wonder, Am I gonna spend all day on this IV? where you could just place a central line. I I wouldn't say my personal experience in placing any IV or any central line in all comers is that the that the central line is definitely the less labor-intensive choice.

Mm-hmm. I I think it does go back to y you and I were critical care fellows together, uh the the the recurring story where the I see a nurse comes to you asking for a central line again and again And and when I think through their workflows, so things like drawing labs, so if you don't have a central line, you have to poke the patient each time, which is uncomfortable, probably takes more time, maybe difficult, and they would have to come get a provider And then other things like CVP monitoring, the other advantages that the paramedical professionals may be seeing with central lines that are not available with a peripheral. Yeah, these are all really good discussion points and I think speak to the nuances of any of these studies and its applicability.

So Dr. Sparling, what's the takeaway from this paper? So in this group of ICU patients that maybe had a gray zone indication for a central line, there does seem to be a at least significant trend towards a higher rate of complications in the peripheral administration group. And furthermore, uh it seems that the peripheral group uh is probably more labor intensive when we look at the overall medical team, um both physicians and paramedical. Got it And I remember we were talking about it earlier, central lines are certainly not without their own inherent risks. Do we have any literature discussing those?

That's correct. And we even see case reports out there of extravization events that occur with central lines. So certainly I think it begs the question of how safe is is placement and doesn't warrant the the risks inherent in that. There's actually a pretty well-designed study in the New England Journal of Medicine from 2015 by Perienti et al. And they looked at the incidence of mechanical, infectious, and thrombotic complications for central lines uh by site. It was a multi center randomized control trial um and enrolled over three thousand patients.

Um The high-level takeaway is that they looked at these three types of complications for subclavian versus internal jugular versus femoral lines. And the overall rates that they saw were about 3% for subclavians, about 4% for internal jugular, and about 3% for femoral. So overall very low. The lowest risk was with subclavians, so these are probably the safest of those. Most of the complications were mechanical, i. e. pneumothorax, but the rate of infectious and deep vein thrombosis were much lower than for the other two.

Any stipulations on who was allowed to do them, how they were allowed to do them, things like that? They did require that operators had some experience with placing central lines. Uh the threshold they required were 50 prior central lines. I think most of us that have completed anesthesiology training have done many more than that. And the other thing that I'll comment on is that they weren't necessarily ultrasound guided.

So even for the internal jugular, some of them were done by landmark. Take away from the study? Overall, the rate of complication with central line placement is very low, and of the three sites studied, uh subclavian is the lowest. Alright, so I think we've taken a pretty good look at this issue from a safety perspective. Switching gears now, going back to our case.

One of the points that I think we should emphasize or or start to explore is why not just use phenylephrine every time? Is there actually an advantage to norepinephrine in certain situations, and what situations would those be? Dr. Wysik, any thoughts? Well, there are plenty of podcasts and review articles on this topic alone, but just thinking pharmacologically, keep in mind that phenolephrine is a pure Alpha agonist, whereas noreprinephrine is often referred to as a quote-unquote balanced presser where you have alpha agonism as well as beta-1 agonism. So you can think of lots of scenarios where that might be more favorable, having a little bit of that beta one kick, someone with a weak heart.

Someone with mitral regurgitation where you don't want to be giving them just a pure afterload of phenylephrine, etc. etc. But I think one situation uh most people are probably familiar with is sepsis and the the um surviving sepsis guidelines where norepinephrine rather than phenylephrine is your presser of choice. People have talked a lot about the study published May of 2019 in Chest, the sensor trial. Which explores the concept of early use of norepinephrine in septic shock. So in this single-center randomized, double-blind, placebo-controlled trial in Thailand um 310 adults. There was an early norepinephrine group versus a standard treatment group where the early group rolled in the door and basically as soon as possible you tried to give them um a background norepinephrine infusion at point oh five mics per kilo per minute or for those calibrated to um mics per minute for a 70 kiloperson that's about three and a half mics per minute of norepinephrine whereas the control group got sugar water is the same infusion and then beyond that you would um resuscitate people using standard protocols, just that one group got started on the norepinephrine as soon as they rolled in the door, regardless of whether quote unquote they needed it or not.

And what they found was that what they defined as something called shock control rate, which was a map greater than 65 millimeters of mercury and urine output of greater than half a MIG per kilo per hour for two hours, or a decrease in lactate of 10% from baseline by 6 hours The shock control rate was better in the early norepinephrine group. 76.1% versus 48.4 % with a p-value of less than 0.001 There was no difference in 28-day mortality. And interestingly, there was less cardiogenic pulmonary edema. Uh and new arrhythmias in the norepinephrine group, even though they ended up getting the same amount of fluid ultimately as the control group But one key takeaway was that for many patients in this study, the norepinephrine was actually administered peripherally at 16 mics per ml by flora and ward nurses.

That's the same as our own concentrations here at MGH, right? Yeah, that's the same concentrations we use. This would definitely buy you an ICU bed uh at MGH, but interestingly a lot of this was done on the general wards. through peripheral IVs. The other population that I wanted to bring up in addition to septic patients is going back to one of the initial trials that we looked at. So again Keyes group out of the University of Hong Kong has actually studied pretty extensively the use of prophylactic neurepinephrine in parturients under spinal anesthesia for C-section.

And they've shown not only maintenance of the blood pressure, but equivalent or improved neonatal outcomes and better uh sustain uh cardiac output in heart rate as compared with phenoephrine. So that's another group where I think it warrants at least the consideration of early norepinephrine Another study worth just mentioning two sentences about is the impress trial in JAMA in 2017. This was a French study. that looked at anesthetized patients um and thought about the question of whether individualized blood pressure control was going to be better than standard blood pressure control. So in the individual treatment group, you shot for keeping their systolic blood pressure within 10% of their baseline versus the standard treatment group you really only treated once their systolic was below eighty millimeters of mercury or below forty percent of their baseline. their primary outcome, which was a composite of having SURS criteria plus dysfunction of at least one organ system seven days after surgery was significantly lower in the group that got treated more aggressively for maintaining them close to their baseline blood pressure I think the thought is that probably the blood pressure control was the crux of what made the patients benefit, but the pressure that they used in the trial to achieve that was norepinephrine, so We don't know if maybe it's something about the norepinephrine itself that that contributed to part of that effect So I think what you guys are saying from the from mentioning these studies is there definitely seems to be a role for early administration of norepinephrine, and that might you know, counter the argument that phenylephrine is adequate until you're able to have enough time or or get to the appropriate setting to place a central line.

I'd agree with that. Alright, so I think we got through all of the literature. And uh Dr. Sparling, do you want to start with just a big summary of some of the issues that we talked about with respect to this uh subject Sure. So based on a a number of well designed both retrospective and prospective studies, it seems that the rate of extrapization, infiltration, with peripheral administration of norepinephrine is relatively low. That being said, we also looked at some of the data for central line complications and is similarly low.

I think it really raises the question of What populations do we really need to be proactive about starting vasopressor administration? Is there a a good consensus on whether that should be norepinephrine versus another presser? And what are the conditions both in terms of patient population monitoring and setting being ICU, OR, or emergency room, under which we should be considering this? And Dr. Brusick, any other thoughts? I think uh with this subject, the really the devil is in the detail.

And we saw that in the studies that we looked at, the lowest rates of complication were uh in the cases where you had extremely meticulous IV placement and monitoring, where it was uh a big IV and a big vein that you placed carefully under ultrasound and uh monitored um nonstop. So that's something important to keep in mind that while the rate of complications seem to be very low You might want to think twice before starting your peripheral norepinephrine in the 22 gauge you inherited from the ED and the pinky toe. I think a second really important caveat to think about is this relative safety, quote unquote, of norepinephrine that we've been talking about is pound for pound comparing to phenylephrine.

So When we're talking about, you know, we feel okay about a hundred of phenylephrine, we're talking about ten of norepinephrine that we quote unquote feel okay about not a hundred of norepinephrine running peripherally. So keeping in mind that when you're at those higher doses of norepinephrine, you are in a data free zone and that these papers were looking at more modest lower doses of norepinephrine. And I think a third really important caveat that both Dr. Sparling and I experienced just finishing a year of ICU fellowship is If you find yourself in the operating room and you're finishing your case on 15 or 20 of norepinephrine, I think the really important question to ask is why?

And um And does this patient need an ICU bed? And and maybe they need a central line because they have other reasons to also need a central line. And uh there's probably more at play than just your your sevo fluorine coming off. Yeah. I I think to that point and and this is a whole nother podcast for a different date, but Thinking back to that norepinephrine FDA label, it actually says specifically that the use of norepinephrine is contraindicated to maintain blood pressure in the in the presence of a an existing volume deficit.

So as good anesthesiologists, we should all be thinking about what the volume status is, and as Dr. Brusick is pointing out what is the reason for this norepinephrine requirement and should are there things that need to be addressed before I I worry too much about the details of how I'm administering it? Awesome. Love the talk. Just for our listeners again, the claim was norepinephrine is unsafe to administer peripherally. So for that claim, again, what's the level of your agreement and what's the level of evidence for what you believe?

And Dr. Sparling, I know you have a little bit more information about a poll that we conducted at Grand Rounds after your talk. Yeah, the poll that we used, of course, didn't have all of the nuances that we just discussed, but we had asked participants up front and then after the debate that we did what their feelings on whether norepinephrine was safely administered peripherally. And before the talk, 85 % of respondents were in agreement with that, and after the talk, uh 90% were. So examining a similar base of literature as we did today, uh, I think at least a few people Uh took that under consideration and and are willing to make changes to their practice.

Dr. Sparling and Dr. Rusick, thank you for joining me on the show. I thought this was an excellent discussion and I hope that this uh spark some conversation throughout institutions uh across the country. Thanks, David. Thank you so much, David. To our listeners, thanks again for joining us.

You know, we always re really appreciate when you reach out to us either on Twitter or by email Our handle on Twitter is at Depth Anesthesia and you can reach us on Gmail at depth of anesthesia at gmail. com. As always, stay hungry and keep asking questions. Spread