Crystallization of mixtures of local anesthetics with and without select adjuvants: a semiquantitative light microscopy analysis

Introduction: Injecting mixtures of local anesthetics with or without adjuvants is a common practise in regional and particularly obstetric anesthesia to decrease block onset time and/or augment epidural analgesia for cesarean section. While evidence on the efficacy of this practise is equivocal, little is known about its safety in terms of the pharmacologic compatibility of local anesthetics.

Methods: We assessed the grade of crystallization in individual mixtures of seven local anesthetics (bupivacaine, ropivacaine, lidocaine, procaine, chloroprocaine, mepivacaine, prilocaine) with or without four adjuvants (sodium bicarbonate, dexamethasone, clonidine, fentanyl) using a semiquantitative light microscopy scale (ranging from 0 to 5), repeatedly for up to 60 min and performed correlation analysis between grade of crystallization and initial solution pH.

Results: Of the 50 mixtures tested, 26 showed grades of crystallization ≥4 at admixture and 41 showed grades of crystallization ≥4 after 60 min. The addition of adjuvants to local anesthetic mixtures did not substantially change the grades of crystallization. Bupivacaine has a slightly lower precipitation tendency, compared with ropivacaine. A moderate relationship was found between initial pH and grade of crystallization after 15 min for the adjuvant mixtures (R=0.33, p=0.04), but not at other time points.

Discussion: The preparation of local anesthetic (±adjuvant) mixtures leads to high grades of crystallization, which increase over 60 min and appear independent of solution pH. The risk of mixing medications with unknown physical or chemical compatibility profiles in regional anesthesia should be critically appraised and its clinical significance elucidated in future translational research.