Mixing local anesthetics - yay or nay?

Dr. Erik Hofmeister, Professor of Anesthesia at Auburn University College of Veterinary Medicine, Deputy Editor for Veterinary Anaesthesia and Analgesia, and The Vetducator (vetducator.com) blogger, discusses the practice of mixing short- and long-acting local anesthetics.

Dr. Hofmeister is a veterinary anesthesiologist extraordinaire!

I think I was in my residency (early 2000s) when I first heard someone talking about mixing lidocaine and bupivacaine for a local anesthetic block. It seemed like a reasonable plan - you get the best of both worlds: fast onset from the lidocaine and long duration from the bupivacaine.

However, by that time, I had learned enough about the pharmacokinetics of local anesthetics to think, “This doesn’t sound right…”

Mixing lidocaine with bupivacaine is an oft-touted way to deliver local anesthesia. It is ubiquitous on the internet, and even in scientific publications. You would think, therefore, that it is a scientifically-validated, pharmacologically rationale approach.

However, you would be wrong.

To understand the problem, you need to learn a bit about the way local anesthetics work. You probably already know that they block the fast sodium channels which propagate action potentials. This blocks conduction of a pain signal from the periphery to the spinal cord. There are three important considerations for this effect that may be influenced by mixing drugs: concentration gradient, pKa, and protein binding (Becker & Reed 2006).

In my opinion, the biggest problem with mixing lidocaine and bupivacaine has to do with the concentration gradient. Assuming you use regular 2% lidocaine and 0.5% bupivacaine and combine them 1:1, the concentration of each of these is halved. Therefore, you end up with 1% lidocaine and 0.25% bupivacaine in your mixture. Penetration of the drug into the nerve, where it can bind to the sodium channels is, at least in part, due to the concentration gradient. By mixing them, you have diluted your drug and reduced the concentration gradient, so less drug will enter the nerve where it needs to work.

Only the ionized form of local anesthetics is is able to bind to the sodium channel. But it is the non-ionized form that can cross the cell membrane to access the binding site.

Local anesthetics can only enter the nerve in a non-ionized state. That is, if they have single H+ ions attached to them, they can’t get through the lipid layer of the nerve, so they can’t block the sodium channels. How much drug exists in a non-ionized form is dictated by the pKa. When the solution pH is the same as the pKa, 50% of the drug is ionized and 50% is non-ionized. Raising the pH (making it more basic) pulls H+ ions off the drug, creating more non-ionized drug, allowing more to enter the nerve.

Most local anesthetics come in an acidic solution to maintain stability and shelf life. Lidocaine 2% has a pH around 6 (Frank & Lalond 2012) and bupivacaine 0.5% has a pH around 5.33 (Stephens et al. 1999). That pH difference accounts, at least in part, for the difference in onset time.

So what happens when you mix them? You make the lidocaine more acidic, which delays onset, and you make the bupivacaine more basic, which may promote precipitation.

Finally, the protein binding is important. Protein binding dictates the duration of local anesthesia. The more protein binding, the longer the drug lasts. Again, the concentration is important here. If you have half as much bupivacaine bound to protein, there isn’t as much of it, so it won’t last as long.

OK, there’s the theoretical basis for the problem. Let’s look at the evidence. There is extremely compelling evidence from human medicine that combinations are not an improvement, and this has been known for over 20 years! (Ribotsky et al. 1996, Sepehripour & Dheansa 2017)

The mixture of short- and long-acting local anesthetics does NOT improve onset time and actually shortens the length of action, compared to a long-acting local anesthetic alone. Consider using bupivacaine by itself.

There is also evidence from veterinary medicine. In 2009, Lawal & Adetunji published a study looking at the effects of mixing lidocaine and bupivacaine for spinal anesthesia in cats. The onset time was no faster when adding lidocaine to bupivacaine compared with lidocaine alone or bupivacaine alone. So mixing lidocaine did not achieve one goal - to improve onset time. Further, the duration in the lidocaine/bupivacaine mixture was shorter than in the bupivacaine group alone. So mixing lidocaine with bupivacaine actually resulted in a shorter duration than bupivacaine alone.

In 2013, Lizarraga et al. published a study comparing saline, lidocaine, lidocaine/bupivacaine, and bupivacaine blocks for the metacarpi of rams and then did sensory testing. Duration in the lidocaine/bupivacaine group was shorter than the bupivacaine group, and the time to onset was not different.

Also in 2013, Vesal et al. published a study comparing lidocaine, lidocaine/bupivacaine, low dose bupivacaine, and high dose bupivacaine. The onset time was no better for lidocaine or lidocaine/bupivacaine compared with high dose bupivacaine, and the duration was longer in the high-dose bupivacaine group.

So, there you have it. Mixing local anesthetics does not produce a faster onset and reduces the duration. It’s not the best of both worlds - it’s the worst of both.

Do you mix lidocaine and bupivacaine? Why? Have you tried just using bupivacaine?

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References:

Becker DE, Reed KL

Essentials of Local Anesthetic Pharmacology

Anesth Prog. 2006 Fall; 53(3): 98–109.

Frank SG, Lalonde DH.

How acidic is the lidocaine we are injecting, and how much bicarbonate should we add?

Can J Plast Surg. 2012 Summer;20(2):71-3.

Stevens RA, Chester WL, Grueter JA, Schubert A, Brandon D, Clayton B, Spitzer L.

The effect of pH adjustment of 0.5% bupivacaine on the latency of epidural anesthesia.

Reg Anesth. 1989 Sep-Oct;14(5):236-9.

Ribotsky BM, Berkowitz KD, Montague JR.

Local anesthetics. Is there an advantage to mixing solutions?

J Am Podiatr Med Assoc. 1996 Oct;86(10):487-91.

Sepehripour S, Dheansa BS.

Is there an advantage in onset of action with mixing lignocaine and bupivacaine?

J Plast Reconstr Aesthet Surg. 2017 Dec;70(12):1782.

Lawal FM, Adetunji A. A comparison of epidural anaesthesia with lignocaine, bupivacaine and a lignocaine-bupivacaine mixture in cats. J S Afr Vet Assoc. 2009 Dec;80(4):243-6.

Lizarraga I, Janovyak E, Beths T.

Comparing lidocaine, bupivacaine and a lidocaine-bupivacaine mixture as a metacarpal block in sheep.

Vet J. 2013 Aug;197(2):515-8.

Vesal N, Ahmadi M, Foroud M, Imani H.

Caudal epidural anti-nociception using lidocaine, bupivacaine or their combination in cows undergoing reproductive procedures.

Vet Anaesth Analg. 2013 May;40(3):328-32. doi: 10.1111/vaa.12000. Epub 2012 Oct 20.