Crystallization of ropivacaine and bupivacaine when mixed with different adjuvants: a semiquantitative light microscopy analysis

Abstract

IntroductionAmino-amide local anesthetics precipitate when mixed with some commonly used adjuvants, carrying the risk of perineural or vascular crystal deposition. The aim of this study was to evaluate whether crystallization occurs with routinely used local anesthetic–adjuvant combinations and if a relation with the solution’s pH exists.MethodsAll substances used in this trial were first visually investigated undiluted under tenfold magnification. Grade of crystallization was assessed using a 6 point grading system.Ropivacaine (0.2%, 0.75% and 1%) and bupivacaine (0.25% and 0.5%) were mixed in a 1:1 solution with the following adjuvants: dexamethasone, dexmedetomidine, clonidine, fentanyl, sodium bicarbonate 8.4% and sodium chloride 0.9%. Subsequently, ropivacaine (0.2% and 0.75%) and bupivacaine (0.25% and 0.5%) were mixed with adjuvants in concentrations commonly used in clinical practice and then serially assessed at several time points up to 1 hour. pH of all substances/combinations was assessed and correlated with crystallization grade.ResultsAll pure substances—except the reference standards sterile water and triamcinolon—showed crystallization grades ranging from grade 1 to grade 4. Addition of adjuvants lead to variable, unpredictable changes in crystal depositions. Addition of sodium bicarbonate 8.4% produced heavy crystallization in all combinations. Grade of crystallization was weakly positively related to the pH of the solution in 1:1 mixtures and clinically relevant concentrations, but not in pure substances.DiscussionOur study showed that crystallization is present in pure local anesthetics and may be increased or decreased by admixture of adjuvants. Higher pH of mixtures was weakly associated with more crystallization. Further research is necessary to translate these findings into clinical practice.

Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis

“…The analysis technique was previously described 8. We assessed five LAs (lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2%) and seven commonly used adjuvants (clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine and sodium bicarbonate 8.4%).…”

“…A light microscope (IX 80, Olympus, Tokyo, Japan) and the microscope camera software Jenoptik Gryphax, V.1.1.4.2, were used to determine grade of crystallization (GoC) according to an established scale, yielding GoC values ranging from 0 (no signs of crystallization/single <10 µm) to 5 (heavy polymorphic crystallization: >100 solid bodies >10 µm, and >1 solid body >50 µm or >1 solid body >100 µm; see table 1). 8 Single particulates <10 µm are commonly found on clean and empty specimen slides and cover glasses as signs of impurities in the material and were, therefore, graded as grade 0 (no signs of crystallization).…”

“…Admixture of substances can lead to unpredictable chemical and pharmacological effects. In a recently published in vitro study, we demonstrated that considerable precipitation occurred after admixture of the long-acting LAs ropivacaine or bupivacaine with various adjuvants in ratios frequently used in routine practice 8. Although the clinical relevance of crystallization and subsequent perineural injection of crystalline deposits is not fully elucidated, doubts regarding safety and justification of such off-label uses arise.…”

Peripheral Regional Anesthesia Using Local Anesthetics: Old Wine in New Bottles?

“…Different drugs are commonly used, including α 2 -receptor agonists, opioids, corticosteroids or vasoconstrictors. However, one should consider that mixing substances of different substance classes creates a new drug that lacks registration, changes their pharmacological properties and may also lead to precipitation [ 72 , 85 ]. In our mind, mixtures should only be created after the strict estimation of their safety profile.…”

“…Given the inconsistent results for dexamethasone’s off-label perineural use, its unclear mechanism of action, its potential to precipitate when combined to long-acting LAs, or its possible increase in LA-induced neurotoxicity, the systemic route should be preferred [ 84 , 85 , 98 , 102 ].…”