Non-Invasive O-Toluidine Monitoring during Regional Anaesthesia with Prilocaine and Detection of Accidental Intravenous Injection in an Animal Model

Abstract

Regional anaesthesia is well established as a standard method in clinical practice. Currently, the local anaesthetics of amino-amide types such as prilocaine are frequently used. Despite routine use, complications due to overdose or accidental intravenous injection can arise. A non-invasive method that can indicate such complications early would be desirable. Breath gas analysis offers great potential for the non-invasive monitoring of drugs and their volatile metabolites. The physicochemical properties of o-toluidine, the main metabolite of prilocaine, allow its detection in breath gas. Within this study, we investigated whether o-toluidine can be monitored in exhaled breath during regional anaesthesia in an animal model, if correlations between o-toluidine and prilocaine blood levels exist and if accidental intravenous injections are detectable by o-toluidine breath monitoring. Continuous o-toluidine monitoring was possible during regional anaesthesia of the cervical plexus and during simulated accidental intravenous injection of prilocaine. The time course of exhaled o-toluidine concentrations considerably differed depending on the injection site. Intravenous injection led to an immediate increase in exhaled o-toluidine concentrations within 2 min, earlier peak and higher maximum concentrations, followed by a faster decay compared to regional anaesthesia. The strength of correlation of blood and breath parameters depended on the injection site. In conclusion, real time monitoring of o-toluidine in breath gas is possible by means of PTR-ToF-MS. Since simulated accidental intravenous injection led to an immediate increase in exhaled o-toluidine concentrations within 2 min and higher maximum concentrations, monitoring exhaled o-toluidine may potentially be applied for the non-invasive real-time detection of accidental intravenous injection of prilocaine.

Keywords: PTR-ToF-MS; breath gas analysis; drug monitoring; o-toluidine; prilocaine; regional anaesthesia; toxicology; volatile organic compounds (VOC).

Figure 1

Time course of haemodynamic parameters mean arterial pressure (MAP) and cardiac output (CO). Blue lines represent group A (intravenous injection of prilocaine, n = 6) and red lines represent group B (cervical plexus regional anaesthesia with prilocaine, n = 5). Dots mark the defined measurement points as mean value of the entire group with relevant SD values.

Figure 2

Continuous measurement of o-toluidine concentrations in breath by PTR-ToF-MS over 120 min (above) for two single pigs (blue line group A (intravenous injection of prilocaine), red line group B (cervical plexus regional anaesthesia with prilocaine)). Each data point represents mean concentrations over one minute. The diagrams at the bottom show the first 20 min. Bolus was administered at the third minute.

Figure 3

(a) Prilocaine concentrations in blood measured by means of GC-MS, (b) o-toluidine concentrations in the headspace over blood measured by means of SPME-GC-MS and (c) o-toluidine concentrations in breath measured by means of PTR-ToF-MS at defined timepoints (breath data from continuous measurement were averaged over the corresponding minute). (d) Percentage values of methaemoglobin (MetHb) related to haemoglobin (Hb) during the experiment. # indicates statistically significant changes in MetHb versus P0 (0 min) (repeated measures ANOVA on ranks, Dunn’s post hoc test and p < 0.05 was considered significant). Blue plots represent group A (intravenous injection of prilocaine), and red plots represent group B (cervical plexus regional anaesthesia with prilocaine). P0: before prilocaine injection; P1: 2 min; P2: 5 min; P3: 10 min; P4: 30 min; P5: 60 min; P6: 120 min after prilocaine injection.

Figure 4

Schedule of the experimental procedures for both study groups (group A: intravenous injection group B: regional anaesthesia/infiltration). Discontinuous measurements in blood (squares) were carried out for prilocaine by GC-MS and for o-toluidine in the headspace over blood by HS-SPME-GC-MS. Continuous monitoring of breath gas was performed by PTR-TOF-MS (dots).