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Crystallization of ropivacaine and bupivacaine when mixed with different adjuvants: a semiquantitative light microscopy analysis
  1. Elisabeth Hoerner1,
  2. Ottokar Stundner1,2,
  3. Guenther Putz1,
  4. Thorsten Steinfeldt3,
  5. Simon Mathis1 and
  6. Lukas Gasteiger1
  1. 1Department of Anesthesiology and Intensive Care, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Department of Anesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University, Salzburg, Austria
  3. 3Department of Anesthesiology, Intensive Care and Pain Medicine, BG Unfallklinik Frankfurt am Main, Frankfurt am Main, Hessen, Germany
  1. Correspondence to Dr Ottokar Stundner, Anaesthesiology and Intensive Care, Medical University of Innsbruck, Innsbruck, Austria; otto.stundner{at}


Introduction Amino-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.

Methods All 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.

Results All 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.

Discussion Our 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.

  • anesthesia, local
  • pain management
  • pharmacology

Data availability statement

Data are available on reasonable request. Raw data/full-resolution images are available on request.

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Data availability statement

Data are available on reasonable request. Raw data/full-resolution images are available on request.

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

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.