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Crystallization of short-acting and intermediate-acting local anesthetics when mixed with adjuvants: a semiquantitative light microscopy analysis
  1. Elisabeth Hoerner1,
  2. Ottokar Stundner1,2,
  3. Heidi Fiegl3 and
  4. Lukas Gasteiger1
  1. 1Anaesthesiology and Intensive Care, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Department of Anesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medizinische Privatuniversität, Salzburg, Austria
  3. 3Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
  1. Correspondence to Dr Ottokar Stundner, Anaesthesiology and Intensive Care, Medical University of Innsbruck, Innsbruck A-6020, Austria; otto.stundner{at}


Introduction The addition of adjuvants to short-acting local anesthetics (LA) is common practice in clinical routine to speed up block onset and decrease pain on injection. In a previous study, we observed the development of microscopic crystal precipitations after bupivacaine or ropivacaine were mixed with adjuvants; this follow-up study is intended to clarify whether crystallization (A) also occurs in short-acting or intermediate-acting LA-adjuvant mixtures, (B) changes over time, and (C) is associated with the solutions’ pH.

Methods Lidocaine 2%, prilocaine 2%, mepivacaine 2%, procaine 2% and chloroprocaine 2% were individually mixed with clonidine, dexamethasone, dexmedetomidine, epinephrine, fentanyl, morphine or sodium bicarbonate 8.4% in clinically established ratios. For each mixture, we measured initial pH and recorded crystallization patterns at 0, 15, 30 and 60 min using a standardized, semiquantitative light microscopy approach.

Results Lidocaine 2% and mepivacaine 2% plus sodium bicarbonate 8.4%, and mepivacaine 2% plus dexamethasone developed delayed grade 5 crystallization over 1 hour. Prilocaine-based, procaine-based and chloroprocaine-based mixtures showed much less pronounced crystallization, with a maximum of grade 2. Initial pH and grade of crystallization showed weak monotonic relationships at time points t0, t15 and t30 (ρ=−0.17, 0.31 and 0.32, (all p>0.05)) and a moderate relationship time point t60 (ρ=0.57 (p=0.0003))

Conclusions Our study revealed high grades of crystallization in lidocaine/mepivacaine-bicarbonate and mepivacaine-dexamethasone mixtures, although these were previously considered safe for local, perineural or neuraxial use. Our findings cast particular doubt on the safety of preparing these formulations for later use.

  • anesthesia, local
  • regional anesthesia
  • pharmacology
  • drug-related side effects and adverse reactions

Data availability statement

Data (including high-resolution images) are available on reasonable request.

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Data availability statement

Data (including high-resolution images) are available on reasonable request.

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  • Contributors EH is the guarantor for this work. EH, OS, HF and LG developed the research protocol. EH, HF and LG performed laboratory tests. OS, HF and LG provided methodological consultation. EH, OS and LG wrote the initial draft of the manuscript. All authors reviewed the manuscript. All authors helped revise the manuscript.

  • Funding This work was supported solely with departmental sources.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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