Crystallization of Local Anesthetic and Adjuvants Mixtures

Patients often receive local anesthetics for small surgical interventions, for spinal or epidural anesthesia, or to provide anesthesia to solitary nerves (regional anesthesia). Many different local anesthetics are available for this purpose, all of which substantially differ in speed of onset and duration of action. Some substances kick in quickly, but wear off quickly too. Some substances, on the other hand, take a longer time to act, but provide a more sustained effect over several hours. It is common practice to mix different classes of local anesthetics for local and regional anesthesia, as both quick onset and long duration of action (signifying longer pain relief) are usually desirable. Additional substances, so-called adjuvants, are sometimes mixed with local anesthetics (e.g. opioids, steroids or bicarbonate) to further improve onset and duration. In some cases, a fast onset is vitally important, for instance for urgent cesarean sections. The practice of mixing local anesthetics and/or adjuvants is contested, as little is known about the safety and chemical compatibility of the multitude of possible combinations. Moreover, very few substances are officially approved for use in mixtures; therefore, their utilization is considered off label. In prior laboratory research, our group discovered that microscopic crystals develop in the local anesthetic mixtures, some of which reach diameters of 100 micrometers and more. Some of these crystals appear immediately after admixture, some develop during a 60 minute latency phase. The chemical composition and behavior of these crystals after injection into human tissue is yet unknown, but their particulate nature could invoke problems. They could hypothetically lead to complications by obstructing small blood vessels, injuring nerves, or provoking inflammatory reactions. Single case reports in the literature have been implying such complications after injection of particulate substances near nerves, however, no connection with local anesthetic crystallization has been made thus far. The aims of our study include a finer classification of crystallization patterns in different clinically established local anesthetic mixtures, analysis of these crystals using specialized microscopy and chemical methods, observation over a longer time period, and finally the preparation of a practical live tissue analysis model. We hope that the results of our project help to better appraise complication risk after use of local anesthetic and/or adjuvant mixtures. This would eventually allow practitioners to weigh their potential benefits (faster onset, longer duration of action) against their potential risks.