Quantification of systemic o-toluidine after intrathecal administration of hyperbaric prilocaine in humans: a prospective cohort study

Abstract

Hyperbaric 2% prilocaine is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Increase of o-toluidine hemoglobin adducts, a marker of o-toluidine ability to modify the DNA structure, was described following subcutaneous injection. In this prospective cohort study we aimed to assess and quantify o-toluidine hemoglobin adducts and urinary o-toluidine after a single intrathecal dose of hyperbaric prilocaine.

10 patients undergoing surgery received 50 mg of hyperbaric prilocaine intrathecally. Blood and urine samples were collected before injection and up to 24 h later (Hospital Braine l’Alleud-Waterloo, Braine l'Alleud, Belgium). Urinary o-toluidine and o-toluidine hemoglobin adducts were measured by tandem mass-spectrometry after gas-chromatographic separation (Institute of the Ruhr-Universität, Bochum Germany). The trial was registered to ClinicalTrials.gov (NCT03642301; 22-08-2018)

Intrathecal administration of 50 mg of hyperbaric prilocaine leads to a significant increase of o-toluidine hemoglobin adducts (0.1 ± 0.02–11.9 ± 1.9 ng/g Hb after 24 h, p = 0.001). Peak of urinary o-toluidine was observed after 8 h (0.1 ± 0.1–460.5 ± 352.8 µg/L, p = 0.001) and declined to 98 ± 66.8 µg/L after 24 h (mean ± SD)

Single intrathecal administration of hyperbaric prilocaine leads to a systemic burden with o-toluidine and o-toluidine hemoglobin adducts. O-toluidine-induced modifications of DNA should be examined and intrathecal hyperbaric prilocaine should not be proposed to patients chronically exposed to o-toluidine.

Clinical trial number and registry URL NCT03642301.

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Funding

This study received fundings from BARA, the Belgian association for Regional Anesthesia, BARA vzw, UZ Leuven – Departement Anesthesie, Herestraat 49, 3000 Leuven (BE), and Association Vésale, Maison des Infirmières – CHU St. Pierre – 322 Rue Haute – Bruxelles (BE).

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Correspondence to Emmanuel Guntz.

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Ethics committee registration number: EC 332, OM 157; B076201836443. This study was presented as a poster at the 38th annual ESRA Congress in Bilbao, Spain, 11–14 September 2019.

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Guntz, E., Carini, A., Koslitz, S. et al. Quantification of systemic o-toluidine after intrathecal administration of hyperbaric prilocaine in humans: a prospective cohort study. Arch Toxicol 95, 925–934 (2021). https://doi.org/10.1007/s00204-021-02973-w

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Keywords

  • Local anesthetic
  • Hyperbaric prilocaine
  • o-toluidine
  • Hemoglobin adducts
  • Spinal anesthesia