Abstracts and Highlight Papers of the 34th Annual European Society of Regional Anaesthesia & Pain Therapy (ESRA) Congress 2015: Invited Speaker Highlight Papers ESRAS-0489 REFRESHER COURSE: THE ROLE OF INTRAVENOUS LIDOCAINE IN MODERN ANESTHESIA Dewinter G. 2 , Teunkens A. 2 , Altmi L. 2 , Van de Velde M. 1,2 , Rex S. 1,2 1 Department of Cardiovascular Sciences, KU Leuven – University of Leuven, Leuven, Belgium, 2 Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium. The role of intravenous lidocaine in modern anesthesia: Lidocaine (dietylamino-2,6 aceto-xylidide), an amide local anesthetic, was discov- ered in 1943 by Nils Löfgren and his assistant Bent Lundqvist. 1 It has anal- gesic, anti-hyperalgesic and anti-inflammatory properties 2 . For over 50 years, lidocaine has been used intravenously for several indications including the im- provement of acoustic function, regional anesthesia, the treatment of arrhyth- mias, and the treatment of neuropathic and central pain. 3 De Clive-Lowe et al. in 1958 and Bartlett et al. in 1962 were the first to describe the intravenous use of lidocaine in the management of postoperative pain. 4,5 Pharmacokinetics and toxicity of lidocaine: The therapeutic plasma concentration of lidocaine ranges between 2 to 5μg/ml, with side effects occur- ring at levels above 6 to 10μg/mL. Lidocaine is metabolized primarily by the liver, only 10% is excreted unchanged in urine. It is degraded to two active me- tabolites, monoethylglycinexylidide (MEGX) and glycinexylidide. The elimi- nation half-life of lidocaine after an intravenous bolus injection is 1.5 to 2 hours. The pharmacokinetics of lidocaine appear to change with prolonged in- fusions, which is attributed to the inhibitory effect of MEGX on the clearance of lidocaine. Lidocaine and MEGX competitively bind to hepatic enzymes. Addi- tionally, congestive heart failure is also a cause of decreased clearance of lido- caine because of a smaller volume of distribution of the central compartment and a diminished cardiac index. Hsu et al. investigated the pharmacokinetics of a 48 hours infusion of lidocaine in patients undergoing cardiac surgery with cardiopulmonary bypass. The authors concluded that weight-dosing is recom- mended to reduce the risk of toxicity and that the infusion rate should be re- duced by 20% after 24 hours of infusion to minimize the risk of toxicity. 6 In most of the studies with intravenous lidocaine, a bolus dose between 1 and 2 mg/kg is administered followed by a continuous infusion of 1.5 mg/ kg/h, which corresponds with a plasma concentration of 2μg/mL. 3 Mechanisms of action of intravenous lidocaine: Although the exact mech- anisms of action of intravenous lidocaine are still not fully understood, several potential mechanisms have been described. The best known action of lidocaine (and of its active metabolite,i.e. monoethylglycinexylidide, MEGX) is the blockade of the peripheral and central voltage-gated Na + -channels at the intra- cellular side of the cell membrane, hereby inhibiting the propagation of action potentials. 7 The prolonged effect of lidocaine is thought to reflect its inhibi- tion of the spontaneous pulse generation arising from injured nerve fibers and from the dorsal root ganglion neurons proximal to the injured nerve. 8 Recently, Wolff et al. have shown that local anesthetics act also on different types of voltage-gated potassium channels. 9 In fact, at low concentrations, lidocaine sup- presses tonic firing neurons by interacting with voltage-gated potassium chan- nels. Contrariwise, the effects on the adapting firing neurons can be explained by interaction with the voltage-gated sodium channels. The different sensitivity to a blockade of voltage-gated sodium and potassium channels in different types of neurons can offer a differentiated approach in pain therapy. It is known that the plasma levels reached with systemic administration of lidocaine are too low to directly block the sodium channels. 7,10,11 There- fore, there must be other mechanisms to explain the effect of intravenous administered lidocaine. It is thought that the antinociceptive effect of lido- caine is partially mediated through an interaction with receptor mechanisms. First, intravenously administrated lidocaine increases the intraspinal release of achetylcholine (Ach), resulting in an increased pain threshold by stimulating inhibitory pathways. 3 This effect of lidocaine on ACh release is mediated through an activation of muscarinic (probably muscarinic receptors of the subtype M3) and nicotinic receptors. 3,12 Second, already in 1993, Biella et al. have suggested a glycine-like action of lidocaine in the central nervous sys- tem. 13 Glycine is, besides γ-aminobutyric acid, the major inhibitory neuro- transmitter in the central nervous system where it binds to and activates glycine receptors to cause hyperpolarization. 14 In addition, glycine is also an excitatory neurotransmitter by its action as co-agonist of glutamate at the N-methyl-D-aspartate (NMDA) receptor. The glycinergic neurons contribute to the inhibition of nociceptive signaling and have important roles in segre- gating nociceptive and non-noxious information pathways. 14 The synaptic gly- cine concentration is regulated by two glycine transporters (GlyT). 15 The GlyT1removes glycine from the synaptic cleft and the GlyT2 mediates the glycine reuptake into the nerve terminals. It is not lidocaine itself, but its major metabolites mono-ethylglycinexylidide (MEGX) and glycinexylidide, that cause the inhibition of the GlyT1-mediated uptake of glycine. This inhi- bition of the GlyT might provide a novel molecular mechanism for the anti- nociceptive effect of systemic lidocaine. A third possible mechanism to explain the analgesic effect of lidocaine is the inhibition of glutamatergic neurotransmission. Glutamate is the most important excitatory neurotransmitter in the central nervous system and binds to several receptors, one of which the NMDA receptor. It is known that the activation of the NMDA receptor can lead to postoperative hyperal- gesia and central sensitization. Both Hahnenkamp et al. and Gronwald et al. showed that local anesthetics inhibit the NMDA receptor in a concentration- dependent manner. 16,17 Finally, lidocaine exerts anti-inflammatory effects by inhibition of nuclear factor κB activation and decreased up-regulation of pro-inflammatory cyto- kines. 18 Lidocaine attenuates the production of inflammatory cytokines such as IL-1, IL-6, IL-8 and stimulates the production of IL1-receptor antagonist. 11 The inflammatory response is an important determinant of outcome after surgery, as an excessive stimulation of the inflammatory cascade can lead to a systemic inflammatory response syndrome, organ dysfunction and pain. 19 The analgesic effect of lidocaine in abdominal surgery: During the last decade, the use of systemic lidocaine as a co-analgesic has gained renewed in- terest for the treatment of acute postoperative pain. Four meta-analyses (Sun et al. 2012, Marret et al. 2008, Mc Carthy et al. 2010 and Vigneault et al. 2011) showed that the use of intravenous lidocaine perioperatively in abdominal surgery decreased postoperative pain intensity, reduced opioid consumption, ac- celerated the recovery of gastro-intestinal function and shortened hospital stay. 2,20,21,22 In a randomized, placebo controlled, double-blind study, Kaba et al. showed for laparoscopic colectomy that patients receiving systemic lidocaine perioperatively required 50% less opiate medication during the first 24 hours postoperative my. 23 Likewise, Tikuišis et al. investigated systemic lidocaine in laparoscopic colon surgery 24 and found significantly lower pain scores both in rest and during movement. Kuo et al. compared the use of thoracic epidural analgesia and intravenous lidocaine in patients undergoing colonic surgery and reported that intravenous lidocaine can be an alternative for an epidural catheter to improve postoperative pain relief. In abdominal surgery other than colonic surgery similar results have been reported with regard to postoperative pain relief and opioid consumption. 25 Kang and Kim reported for patients un- dergoing inguinal herniorhaphy significantly lower pain scores and opioid con- sumption the first 12 hours postoperatively in the intravenous lidocaine group. 26 Yon et al. investigated the effect of intravenous lidocaine on postoperative pain in patients undergoing subtotal gastrectomy. Their results demon- strated that the VAS scores were significantly lower in the lidocaine group the first postoperative 24 hours and the fentanyl consumption was lower for the first 12 hours. 27 Also after laparoscopic bariatric surgery systemic lidocaine reduced pain scores and opioid consumption and therefore improved quality of re- covery. 28 Koppert et al. examined the effect of perioperative intravenous lidocaine on postoperative pain and morphine consumption after major abdominal surgery. He included several types of abdominal surgical procedures in his trial and found that intravenous lidocaine reduced postoperative pain and morphine consumption. 29 Although the majority of trials on intravenous lidocaine in abdominal sur- gery confirms the analgesic effect of lidocaine, several other studies failed to ABSTRACTS Regional Anesthesia and Pain Medicine • Volume 40, Number 5, Supplement 1, September-October 2015 e1