**2.1 Safety of local anaesthetic**

Local anaesthetic agents are toxic at certain levels in systemic circulation. With any use of local anaesthetic, care must be taken to ensure LIA mixture is not injected directly into the patient's circulation. Local anaesthetic will inevitably be transported into circulation at a small concentration. However, it has been shown that the volume of local anaesthetic used in LIA technique is safe, and their levels in blood tests show sub-toxic concentration [18–20].

Fenten et al. took multiple plasma samples after LIA and torniquet release for TKA (at 20, 40, 60, 90, 120, 240, 360 minutes and 24 hours) [18]. The mix comprised of 200 mL 0.2% ropivacaine and 0.75 mg epinephrine 1:1000. Maximum ropivacaine concentration (total and unbound serum concentration) remained well below the assumed toxic threshold at all serum plasma samples. Stringer et al. studied LIA with the use of pain pump infusions for 48 hours post-operatively and measured ropivacaine concentration in THA and TKA patients [20]. The mixture contained 350-400 mg ropivacaine and defined their safe threshold concentration of 1–3 microg/mL intravascularly. Their intra-articular pain pump infusion commenced 12 hours post-operatively. Ropivacaine concentration was below 2 microg/ mL with LIA intraoperatively. Once intra-articular pain pump infusion commenced, peak ropivacaine concentration reached 0.65–4.36 microg/mL, however none of their patients experienced clinical signs of toxicity.
