Is mixing in lidocaine effective for preventing burning with propofol?

Welcome back to Depth of Anesthesia. This is a podcast that critically explores our clinical practice. I'm David Hao, and I'm an anesthesia resident at the Massachusetts General Hospital. This week's episode will be featured on Anesthesiology News, one of the most widely read resources in our specialty. If you haven't checked out depth of anesthesia. com yet, we've partnered with QXMD recently for a fantastic integration in which you can easily access all of the references we discuss in each episode.

So definitely check that out. My guest today is Dr. Stu Foreman. Dr. Foreman is a professor of anesthesiology at Massachusetts General and has multiple roles in our department, including investigator on several NIH-sponsored basic research grants. And he's also co-director of the Harvard Anesthesia Research Training Fellowship. Dr. Foreman, welcome to the show.

Thanks, David. It's a pleasure for me to contribute to this podcast. For our case today, we have a thirty-five year old man who is presenting for an abdominal hernia repair. Prior to induction of general anesthesia, the attending observes the resident mixing lidocaine with propofol in a syringe and The attending asks why. The resident comments that the technique is to prevent burning with propofol infusion.

Here are two questions now for our listeners to think about. What is the level of your agreement with the claim that mixing lidocaine with propofol prevents burning with infusion? And what is the level of evidence for what you believe? So, Dr. Foreman, I'd like to just start by asking you, how did you get interested in exploring the subject of burning with propofol infusion? So um first of all, for as a researcher, I've always been interested in mechanisms of anesthesia And when I was an MGH anesthesia resident, uh way back in the nineteen nineties, propofol uh started to become uh more commonly used.

And I uh like many others observed that patients experience pain when propofol is injected. So a standard practice uh that developed Here was to mix 20 milligrams of lidocaine into the 20 mils of propofol before injection. After that, I began hearing from colleagues that what they called a mini beer block was effective for pro blocking propofol injection pain and this involved injecting forty or more milligrams of ivy lidocaine into the patient after putting up a tourniquet above the IV site, waiting a minute before undoing the tourniquet and then injecting propofol However, for me, lacking both patience and a third hand when I induce, uh, I didn't find this a very satisfying approach. So a number of years ago, uh I thought about this some more.

I did some reading and I developed and started using a different approach uh for using lidocaine to block propofol injection pain. Uh that made sense from a pharmacodynamic and pharmacokinetic perspective. That's super interesting because I've actually witnessed all of the approaches you've mentioned, in addition to many more, so I'm definitely looking forward to exploring the evidence here. Before we discuss propofol specifically, I do want to pose the question, why does injection of anything intravenously cause pain? I did some research for a tutorial in the past.

It turns out that unphysiological osmolality and pH have both been studied as causes. Back in 1991, Clement studied this in seven healthy subjects, and obviously that included the authors and various medical students. Two cannulas were inserted at a proximal and distal puncture site and a vein segment was isolated Each subject then had the vein exposed to varying osmolalities and returned the next week to be exposed to solutions with varying pHs. With osmolar stimulation, pain tended to increase as the osmolar concentration of both saline and glucose solutions increased. And with pH stimulation, acidic and alkaline solutions evoke pain at a pH value of less than 4 or greater than 11, so the extremes.

What's super interesting, however, is that propofol has neither a high osmolality nor an extreme of pH. Sodium hydroxide is added to maintain a pH between six and eight point five, and the published osmolality seems to be about zero point three osmoles per kilogram, which is significantly less than the solutions that they tested in this study. Dr. Foreman, what other potential mechanisms have been explored in the literature? So you're right that propofol is formulated to be uh not terribly uh far from isoasmolar and its pH is unlikely to evoke pain. Um the relevant Pain induction mechanism that has the most research behind it is propofol activation of transient receptor potential vanilloid or trip V receptors.

TRYP V channels are excitatory cation channels and they're also known as capsaicin receptors. So your listeners probably know that capsaicin is the active ingredients in hot chili peppers, and tryp V receptor activation is associated with a burning sensation, which is qualitatively how propofol induced pain on injection is experienced Activation of TRYP channels activates pain-conducting neurons, resulting in action potentials that rapidly ascend through neural pathways into the central nervous system. This also induces local neuronal and immune cells to release neuropeptides associated with tissue damage and inflammation. These include calocrines and calcitonin gene-related peptide or CGRP. The result is both a fast burning pain sensation and a slower, somewhat persistent discomfort in affected tissues.

That's pretty incredible to think that pain with propofol infusion is mediated by capsaicin receptors. What about the concept of the free aqueous fraction of propofol? What exactly is that and how is it relevant? So the free aqueous propofol concentration in the formulation is a is an important and modifiable factor in the mechanism. So remember that propofol is formulated in lipid microparticles called micells, mostly consisting of long-chain fatty acids that are suspended in aqueous buffer.

This is done because propofol is too insoluble in water, and that's also known as a hydrophobic drug, to be practical. And effective as an injected aqueous solution. So the volumes of fluid that would be needed if propofol were formulated in aqueous solution alone would be excessive. So almost all of the propofol in the usual lipid suspension is dissolved in the microscopic lipid micells that also give propofol its milky appearance However, under the right conditions, the small amount of propofol dissolved directly in the aqueous carrier itself can diffuse into tissues quite rapidly and at sufficient concentrations to activate the TRIP V channels and produce pain. So I'm guessing there are probably some ways for us to modify the free aqueous propofol concentration.

And this might actually be the origin for some of the strategies out there. So there are several ways we anesthesiologists can modify the free aqueous propofol concentrations that are generated in the cannulated vein. If you read clinical studies of interventions to prevent propofol injection pain, researchers actively try to create conditions where the control group has a high probability of experiencing pain. They typically put an 18-gauge IV into a small hand vein so that the IV cannula occupies most of the vein lumen and obstructs blood flow. Then they rapidly inject propofol to generate maximal free concentrations in that vein.

And the likelihood of pain under these conditions is typically around 60%. To prevent pain, we can do the opposite. I I've also heard that the pharmaceutical industry has attempted to address this problem in the past with various formulations of propofol. Can you tell us a little bit more about that? So some studies have shown that doubling the lipid suspension volume and therefore reducing the propofol concentration, the free propofol concentration by about two fold significantly reduces injection pain.

But of course, this approach is rarely used. Several products have been introduced where propofol has been reformulated with the aim of reducing its free concentration One of these uses medium chain lipids instead of long chain lipids in the suspension, and this results in less pain on injection, presumably because the free propofol concentration is lower. Another propofol formulation is in beta-cyclodextrin instead of lipid micells. However, this doesn't reduce pain, either because free propofol remains high or it unbinds from cyclodextrins rapidly. As a counterexample, there's also a product called aquafol, formulated as an aqueous microemulsion of propofol with no lipids or other components.

And this is a great way to maximize the free aqueous propofol concentrations and rapid diffusion into tissues after injection. Aquafol produces more pain on injection than propofol formulated in lipid micells. Have there been any success stories? A successful drug modification approach was achieved with the propofol pro drug called phospropofol, which was approved for clinical use in 2008. In this drug, a phosphate group replaces the phenol hydrogen of propofol, creating a charged water-soluble compound that is converted to propofol by phosphatases in the circulation a process that takes several minutes.

One advantage of this drug is the absence of pain at the injection site because the Prodrug does not activate TRIP V channels However, well while I never used pro phospropofol myself, I imagine that anesthetists disliked the delay in onset of effect while the phosphatases activate the drug. This makes titrating to affect a much slower process than we usually experience. In addition, release of phosphate into the bloodstream causes a perineal burning sensation in many people who receive IV phosphrophofol. thus creating another negative for patients. I'm not even sure this drug is still being sold. Another drug modification that succeeded in a few small clinical trials is called Beautyfall. which is a propofol analog with sec butyl groups at the two and six positions on the phenol ring instead of propofol's isopropyl groups This structural change results in a drug that is several times more hydrophobic than propofol, which translates into greater potency and also more partitioning into lipid mice cells in the formulation and thus lower free aqueous drug concentrations.

The result is much less pain at the injection site. However, these advantages were insufficient to maintain investor optimism and clinical trials of Beautiful uh were discontinued a few years ago. I'm actually fascinated by how many modifications have been synthesized by the pharmaceutical industry to try to address this issue. I've honestly personally only heard of Foster Propofall. I also sense an opportunity for some puns with Beauty Fall, but I'll stop there.

Now, moving on to our claim, I understand that we have two meta-analyses that look at prevention of pain with injection of propofol. There are actually two meta-analyses that report similar conclusions about the utility of lidocaine to reduce pain on propofol injection, depending on how it's used. The first meta-analysis is entitled Prevention of Pain on Injection of Propofol, Systematic Review and Meta-Analysis It was published in the British Medical Journal in 2011 with Christian Apfel, currently at UCSF, as the senior author. This meta-analysis included data from 177 randomized trials in 25,260 patients evaluating a wide variety of interventions, including several using lidocaine. The second meta-analysis is a 2016 Cochrane Systematic Review entitled Lidocaine for Reducing Propofol Induced Pain on Induction of Anesthesia in Adults.

By Yous Sebon and colleagues at the Bangkok Hospital in Thailand. And they used 82 studies with a total of 10,830 patients. Comparing lidoc lidocaine pre-injection versus pre-mixing lidocaine and propofol for injection. So let's start with the meta-analysis from 2011 with Apfel. What were some of the notable conclusions from that study?

As I said, about sixty percent of patients in the control group reported pain on injection of propofol alone. APL also concluded that using a large anticubital vein was the most effective intervention with a relative risk of 0.14 And that has a 95 % confidence interval from 0.07 to 0.3. In other words, the probability of pain on injection was about one -seventh of the control group when a hand vein was used. Apfel also concluded that venous occlusion combined with pre-injection of lidocaine for a minute, that is the mini beer block. was about as effective as using the anticubital vein. The relative risk with this approach was 0.29, representing a three to four fold drop in the probability of pain.

The efficacy of lidocaine mixed with propofol before injection and that of lidocaine pre-injection without venous occlusion were comparable Mixing lidocaine with propofol resulted in a relative risk of zero point four. Ninety-five percent confidence interval was zero point three three to zero point four eight. And pre-injection gave a relative risk of 0.47. Uh the 95% confidence interval was from 0.4 to 0.56 In other words, both interventions reduced the incidence of pain about twofold, which translates into about 30% of the patients they studied were still experiencing discomfort. Interestingly, in this, they also noted that there was no dosage effect observed using lidocaine amounts ranging from 10 milligrams to over 40 milligrams in these studies.

So it sounds to me like the most effective interventions were the mini beer block and then use of an anticule vein. And the whole mixing concept and pre-injection had some effect, but it wasn't as remarkable as uh the beer block or the enticubital vein. Yes, that's that's a good summary. Um the first two are are, you know, reduce the rate of of pain uh by at least threefold and the second two, the lidocaine mixing and the pre injection without without a tourniquet or or occlusion. uh are only about uh only reduce the incidence of pain about twofold. For our listeners and myself, could you review the concept of relative risk?

Sure. Relative risk is a ratio of risks for intervent for the intervention group versus the control group. Where risk is simply the probability of the outcome, in this case, pain on propovol injection. So that risk is calculated as the number of positive outcomes divided by the total study population both positive and so the total study population includes both positive and negative outcomes. The relative risk is easy to understand as the ratio of two outcome probabilities.

If the 95% confidence interval for the relative risk is under 1, then the intervention is effective using a criteria of p less than 0.05. The other thing I noticed is that the term lidocaine pretreatment is used pretty broadly within this meta-analysis. Was there a significant amount of variability in terms of what actually constituted pretreatment? So the standard approach for pretreatment is to inject the drug into a non-flowing IV in the hand. Whether the lidocaine is acting by blocking voltage-gated sodium channels or TRIP V channels themselves, the effect is likely dependent on blood flow around the IV cannula the lidocaine concentration and the volume of the injection, and whether it all enters the vein, because some of it may remain in the IV tubing unless the dead space of the IV tubing is very low.

The doses varied widely in the reviewed studies, as I mentioned, and it's difficult to explain why there was no clear dosage effect, except that lidocaine pretreatment without venous occlusion was generally not that effective. My guess is that efficacy was largely determined by blood flow in the vein. If the non-occluded flow was low, because for instance the um the IV cannula itself was occluding most of the vein lumen, then the lidocaine would stay where it was needed more, resulting in an effect similar to that that you would see with venous occlusion. However, if blood flow around the IV cannula was sufficient to wash the lidocaine away during that minute between its injection and the injection of propofol, then the effect of the lidocaine would also be washed away.

More importantly, these study conditions don't necessarily reflect clinical practice. They certainly don't represent the way I use my IV. Most of us use a running IV to carry propofol and other drugs. into the patient during induction, although stopcocks may result in carrier flow interruption during these drug injections I've seen many trainees who inject lidocaine intravenously, then immediately wash it out of the vein by turning the stopcock and restarting the carrier flow in the IV. I almost never observe residents using a tourniquet or other venous occlusion approaches to improve the efficacy of lidocaine pre-injection. I completely agree, and I've had many of the same observations that you've had in terms of actual clinical practices.

I thought I'd also point out a few interesting comments that the authors make in the discussion. The authors comment that newer studies tended to have a trend towards a lidocaine propofol mixture as opposed to propofol alone as the control group, possibly suggesting that the clinical practice has actually become quite widespread. Additionally, they observed that the funnel plot for the lidocaine probofolide mixture showed significant asymmetry, and they suggested that though efficacious, the treatment effect may actually be well overestimated. Now I know that the meta-analysis also reviewed a significant number of interventions, including various pharmacologic, non-pharmacologic, and combined approaches. Were there any other interventions that were found to be effective?

So to address the prop popularity of pre-mixing lidocaine with propofol, my sense is that it's of just Easy, standard approach, requires a very little time and effort, and can be done before things get very busy during anesthetic induction. As I mentioned, the most invent effective intervention Apfel found was by using a large vein for IV placement. Other modestly effective interventions, and I and I would say these are less than twofold effects uh in terms of relative risk include pretreatment with opioids, ketamine, magnesium sulfate, non steroidal anti inflammatory drugs and other compounds. But some of these were these conclusions were based on really only one or just a few studies, so the repeatability is questionable Some of the findings we discussed from the AppFell meta-analysis seem to be corroborated by a more recent Cochrane systematic review.

Could you tell us a little bit more about this review? So the the more recent review focuses on lidocaine uh as in both mixed with uh propofol as well as pre-injection. And the major conclusion of the Cochrane review is similar to the BMJ meta -analysis. And essentially there was no discussion of efficacy of venous occlusion combined with lidocaine pre-injection. Maybe of some interest to your list The Cochrane Review rewarded odds ratios, which are the ratio of odds of a positive outcome for intervention versus control groups.

The odds are calculated as the ratio of positive over negative outcomes for each group. Once again, if the 95 % confidence interval for the odds ratio is less than one. . then the intervention is considered effective using a criteria of P less than point oh five. Is there anything we should be keeping in mind when comparing relative risk and odds ratios? Relative risk and odds ratios provide similar insights into the effectiveness of interventions, but it is important to remember that they are calculated differently. and the odds ratio can make effects seem larger than they would using relative risk. For example, if the control group probability of the outcome is fifty percent, which is an odds ratio of one, and drops To 25%, which gives you an odds ratio of 0.33 with that intervention, then the relative risk is the ratio of probabilities, which is 0.5 , And the odds ratio is 0.33.

In other words, there's a two-fold drop in risk, but a threefold drop in odds Okay, I got it. So because of the way the relative risk and odds ratios are calculated, the odds ratio approach can actually cause effects to seem larger than when using a relative risk approach. Now in terms of the Cochrane Review, were there any other notable findings? So the overall conclusion I drew from the Cochrane Review report is that um Both mixing lidocaine with propofol and pre-injecting lidocaine before propofol are effective at reducing the incidence of pain on injection. However, it it's much more difficult because of what I just discussed about the odds ratio as the uh metric that they used to draw any clear conclusion about just how much uh the incidence of pain is is dropping in these studies.

I think a lot of studies tend to use statistics in different ways and and it's important to understand how those are being used for us to draw the correct conclusions. I know that you've been exploring uh an easy variant of lidocaine pre-injection. This is obviously something that hasn't been tested in clinical trials, but it sounds like this is something that you're interested in continuing to possibly research. Yeah, I'm very happy to to describe it for your listeners. And if there's somebody out there interested enough to uh try a clinical trial, I I'd be delighted.

So my approach addresses some of the variable issues evident in the literature. So basically the technique is that I preload lidocaine Usually uh at a dose of one milligram per kilogram using two percent as the uh uh as the solution concentration into the dead space of the IV between the stopcock and the cannula And I use the stopcock to intentionally halt carrier flow after injection of lidocaine. Then When I inject propofol, it's pushing this lidocaine bolus through the IV and then the vein immediately ahead of the propofol. After propofol injection, I open the IV as usual to allow it to flow. The workflow is simplified And the only thing that requires a bit more intent attention is that if I'm administering a pre-induction opioid, I need to be conscientious a bit about making sure it's fully flushed into the patient. before I inject that lidocaine into the IV tubing and stop the carrier flow.

So from a pharmacodynamic uh perspective This approach assures that a high low lidocaine dose at a high concentration is administered to the targeted tissue in the vein. Pharmacokinetically, the lidocaine flows through the targeted vein immediately before propofol hits, and this allows that high concentration of lidocaine to reach the nerves and surrounding tissues and block transmission of pain. That's super interesting, and I definitely look forward to possible studies about it in the future. Dr. Foreman, would you be able to briefly summarize some of the main findings in the literature that we've discussed today? First, pain induced by propofol is associated with its free aqueous concentration and varies by formulation, and most evidence indicates that the mechanism of pain is a is through activation of TRIP V capsaicin receptors That mediate the burning sensation.

If you want to avoid pain on propofol injection, the two most effective measures described in the literature are to place your IV in a large anticubital vein. or to inject 40 milligrams or more of lidocaine into an occluded vein and wait a minute before injecting propofol. So here again are two questions from the start of our show for our listeners to think about. What is the level of your agreement with the claim that mixing lidocaine with propofol is effective at preventing burning with infusion? And what is the level of evidence for what you believe? Dr. Foreman, thanks for joining us on the show.

I thought this was a super insightful conversation, and I really appreciated some of the basic science and pharmacodynamic perspectives that you shared with us. Well David, thank you for again for inviting me to share this information with your listeners. And if anybody out there wants to learn more about my approach to this pharmacological challenge, Uh I'd be delighted to hear from them. Feel free to connect with us on Twitter at Depth Anesthesia or email us with any comments or questions at depth of anesthesia at gmail. com. Stay hungry and keep asking questions.

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