Intravenous lidocaine infusion | Revista Española de Anestesiología y Reanimación (English Edition)

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Soto, M. Naranjo González, F. Calero" "autores" => array:3 [ 0 => array:4 [ "nombre" => "G." "apellidos" => "Soto" "email" => array:1 [ 0 => "dr.germansoto@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "?" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Naranjo González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "F." "apellidos" => "Calero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Médico Anestesiólogo, Hospital Escuela Eva Perón, Granadero Baigorria, Argentina" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Médica Anestesióloga, Clínica de Mérida, Mérida, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "?" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Perfusión de lidocaína intravenosa" ] ] "textoCompleto" => "IntroductionPostoperative pain (POP) is a nociceptive stimulus produced by surgery-induced tissue damage, and results in emotional and cognitive experiences. Good pain management reduces morbidity, improves surgical outcomes, and reduces hospital costs. However, estimates suggest that more than 50% of patients undergoing surgical procedures experience moderate to severe pain.<a class="elsevierStyleCrossRef" href="#bib0255">1</a> Persistence of the painful stimulus can even change the plasticity of the nervous system, leading to chronic pain.<a class="elsevierStyleCrossRef" href="#bib0260">2</a> Inter-individual differences in pain thresholds and the use of inappropriate drugs are among the causes of POP.Although opioids are frequently used in pain therapy, they can cause adverse effects, such as respiratory depression, postoperative nausea and vomiting, ileus, urinary retention, hyperalgesia and immune changes.<a class="elsevierStyleCrossRef" href="#bib0265">3</a> Intravenous (iv) perfusion of lidocaine, a drug whose analgesic, antihyperalgesic and anti-inflammatory properties modulate the inflammatory response produced by surgical stress, is an alternative to opioids in pain management.<a class="elsevierStyleCrossRef" href="#bib0270">4</a> Some studies have shown that lidocaine decreases POP and the need for opioids and volatile agents, and rapidly restores intestinal function.<a class="elsevierStyleCrossRef" href="#bib0275">5</a> The antihyperalgesic action of lidocaine reduces allodynia by acting on spinal cord neurons.<a class="elsevierStyleCrossRef" href="#bib0280">6</a> The anti-inflammatory action of the drug, which inhibits cytokine release and polymorphonuclear activation, has been demonstrated in vitro and in vivo.<a class="elsevierStyleCrossRef" href="#bib0285">7</a> The aim of this review is to describe the pharmacology of lidocaine, its indications for use in anaesthesia practice, and its effect on new fields of study, including chronic POP, postoperative cognitive dysfunction (PCD) and cancer recurrence.Mechanisms of actionLidocaine is an amide-type local anaesthetic that acts by blocking voltage-gated sodium channels (VGSC) in neuronal tissues, thus interrupting synaptic transmission.<a class="elsevierStyleCrossRef" href="#bib0290">8</a> VGSCs are composed of an a subunit (Nav1.5, 260kDa) and 1 or more ß subunits (Navß1.1, Navß1.1 a, Navß3.1; 33–36kDa). The a subunit is an integral heteromultimeric protein complex consisting of 4 homologous domains (D1–D4), each of which contains 6 a-helix transmembrane segments (S1–S6). The C- and N-terminus ends and P loops that bind the domains are intracytoplasmic. The S5–S6 segments and the P loop of each domain form the channel pore that penetrates the membrane. In mammals, VGSCs have 9 different a unit isotypes (Nav1.1 to 1.9), some of which are associated with neuropathic pain (Nav1.3, 1.7, 1.8 and 1.9) and others with inflammatory pain (Nav1.7, 1.8 and 1.9). Lidocaine passes through the neuron membrane and is converted to its non-ionised form by the effect of pH. It binds to the S6 portion of domain 4 of the a subunit inside the sodium channel. The affinity of lidocaine for VGSCs varies according to the status of the channel, being high when the channel is open and low when it is closed. Therefore, the greater the neural discharge, the greater the number of ionised lidocaine molecules entering the site of action, thus increasing the analgesic capacity of the drug.<a class="elsevierStyleCrossRef" href="#bib0295">9</a> The analgesic effect of intravenous administration is the result of increased acetylcholine levels in the cerebrospinal fluid, which cause downward inhibition, inhibition of glycine receptors, and increase the release of endogenous opioids. When lidocaine reaches the spinal cord, it reduces the post-synaptic depolarisation mediated by N-methyl-d-aspartate and neurokinin receptors, thus modifying the pain response.<a class="elsevierStyleCrossRef" href="#bib0300">10</a> N-methyl-d-aspartate blockade inhibits protein kinase C, thus reducing hyperalgesia and postoperative opioid tolerance. In animal models, lidocaine acts during the early stages of systemic inflammatory response, modulating the marginalisation, adherence and diapedesis of polymorphonuclear cells towards the site of the lesion, thus inhibiting the production of reactive oxygen species and the release of histamine. This immunomodulatory effect of the drug is achieved by blocking G protein-coupled receptors, since polymorphonuclear cells do not contain VGSCs.<a class="elsevierStyleCrossRef" href="#bib0305">11</a> Through G protein-coupled receptors, lidocaine inhibits inflammatory processes, such as the sensitisation and lysosomal degradation of neutrophils, the production of reactive oxygen species, and the secretion of cytokines in both macrophages and glial cells. On the other hand, it can also inhibit leukocyte adhesion and migration through the endothelium by inhibiting intercellular adhesion molecules, altering the cytoskeleton, or attenuating the release of chemotactic factors. Lidocaine blocks the release of interleukin (IL) 1, IL-1ß, tumour necrosis factora and IL-8 in polymorphonuclear cells. It also decreases circulating IL-6 and phospholipase A2 levels, both of which are involved in the disruption of the blood-brain barrier, inflammation and brain damage.<a class="elsevierStyleCrossRef" href="#bib0310">12</a> Lidocaine also inhibits the production of thromboxane B2 by inhibiting platelet aggregation, which reduces the risk of venous thrombosis. Finally, lidocaine has been shown to exhibit antioxidant properties by inhibiting the production of reactive oxygen species due to its interaction with phospholipid membranes and interference with mitochondrial radical formation.<a class="elsevierStyleCrossRef" href="#bib0315">13</a>Pharmacokinetics and toxicityStandard dosage is an initial bolus of 1mg/kg-1 followed by continuous perfusion of 0.5–3mg/kg-1/h-1. The most widely used and best described dosage is continuous perfusion of 2mg/kg-1/h-1.<a class="elsevierStyleCrossRef" href="#bib0320">14</a> When administered intravenously, lidocaine is distributed in highly vascularised organs such as the kidney, brain and heart, and then to less vascularised organs. Around 40% of the dose is extracted temporarily by the lung, where pH is lower than in plasma. This reduces the risk of accidental toxicity in the early stages of iv administration.<a class="elsevierStyleCrossRef" href="#bib0275">5</a> When lidocaine is administered in a 1 mg/kg bolus followed by continuous infusion of 2mg/kg-1/h-1, plasma concentrations of approximately 2µg/ml-1 are obtained. Plasma concentrations of more than 5µg/ml-1 are considered toxic. These concentrations are sufficient to attenuate the sympathetic response and reduce pain and the need for inhalational agents and opioids.<a class="elsevierStyleCrossRef" href="#bib0300">10</a> In pharmacokinetic simulations, continuous perfusion with no initial bolus takes between 4 and 8 h to reach equilibrium, with a context-sensitive half-life of 20–40 min when the infusion is completed. Lidocaine is metabolised in the liver by the P-450 system. The liver's monoethyl-glycine-xylidide and glycine-xylidide metabolites are less effective at blocking the sodium channel. Monoethyl-glycine-xylidide has the same potential for causing antiarrhythmia and convulsions as lidocaine; however, it is rapidly metabolised to glycine-xylidide. Glycine-xylidide is less active than lidocaine and its metabolite is metabolised and excreted in urine.<a class="elsevierStyleCrossRef" href="#bib0320">14</a>Adverse effects and toxicity are extremely rare in controlled infusions.<a class="elsevierStyleCrossRef" href="#bib0325">15</a> Circulating plasma concentrations of lidocaine are affected by dose and rate of perfusion, acid-base status, hypoalbuminemia, and liver and kidney function. Toxicity manifests with plasma concentrations of over 5µg/ml-1, and affects the CNS and the cardiovascular system. In awake patients, toxicity manifests as numbness of the tongue, metallic taste, dizziness and tinnitus. Convulsions progressing to coma appear with concentrations greater than 10µg/ml-1. Cardiovascular symptoms in awake patients are rare due to the lower cardiotoxicity of lidocaine compared to bupivacaine, and include QRS and PR interval prolongation, bradycardia and hypotension.<a class="elsevierStyleCrossRef" href="#bib0320">14</a> Toxicity will require supportive measures, including oxygenation, hydration, vasopressors, inotropics, antiarrhythmics and anticonvulsants. If the patient does not respond to supportive measures, lipid infusion should be considered, starting at a dose of 1.5ml/kg-1 at 20% and repeating this every 3–5 min up to a total dose of 8ml/kg-1.<a class="elsevierStyleCrossRef" href="#bib0330">16</a>Clinical applicationRandomised studies, meta-analyses and systematic reviews support the use of iv lidocaine and its clinical application.<a class="elsevierStyleCrossRef" href="#bib0325">15</a> Intravenous lidocaine infusion (bolus of 1.5mg/kg-1 followed by 1.5–3mg/kg-1/h-1) is indicated in videolaparoscopic abdominal surgery, such as colectomy,<a class="elsevierStyleCrossRef" href="#bib0335">17</a> cholecystectomy,<a class="elsevierStyleCrossRef" href="#bib0340">18</a> gastrectomy,<a class="elsevierStyleCrossRef" href="#bib0345">19</a> appendectomy,<a class="elsevierStyleCrossRef" href="#bib0350">20</a> and bariatric surgery.<a class="elsevierStyleCrossRef" href="#bib0355">21</a> In these procedures, lidocaine has been shown to reduce pain measured on a visual analogue scale, reduce opioid requirements and the incidence of ileus within the first 24 postoperative hours. In bariatric surgery, obese patients and those with obstructive sleep apnoea syndrome are the group most likely to develop respiratory depression, so iv lidocaine is indicated in these cases.<a class="elsevierStyleCrossRef" href="#bib0360">22</a> In open abdominal surgery<a class="elsevierStyleCrossRef" href="#bib0365">23</a> and colorectal surgery,<a class="elsevierStyleCrossRefs" href="#bib0370">24,25</a> lidocaine exhibits the same properties as in videolaparoscopic surgery, and shortens hospital stay. Intravenous lidocaine can be used in fast-track surgery protocols, specifically, the enhanced recovery after surgery (ERAS) protocol, and also in patients in whom neuraxial blockade is contraindicated.<a class="elsevierStyleCrossRef" href="#bib0320">14</a> Lidocaine can be continued for 24h after surgery at a reduced dose of 1.33mg/kg-1h-1.<a class="elsevierStyleCrossRef" href="#bib0335">17</a> Computer simulations based on 3-compartment models support its use during prolonged infusion.<a class="elsevierStyleCrossRef" href="#bib0320">14</a>Intravenous lidocaine perfusion (bolus of 1.5mg/kg-1 followed by 2mg/kg-1/h-1) is indicated in urological procedures, such a as laparoscopic nephrectomy<a class="elsevierStyleCrossRef" href="#bib0380">26</a> and laparoscopic nephrectomy prostatectomy,<a class="elsevierStyleCrossRef" href="#bib0385">27</a> and also in chest surgery,<a class="elsevierStyleCrossRef" href="#bib0390">28</a> where it has been shown to alleviate pain measured on a visual analogue scale and reduce the need for opioids.In different types of day surgery procedures, such general surgery, endocrine, breast, gynaecological, urological, plastic and otorhinolaryngology surgery,<a class="elsevierStyleCrossRefs" href="#bib0395">29,30</a> iv lidocaine was found to alleviate pain and reduce opioid requirements, but had no effect on the incidence of postoperative nausea and vomiting. Evidence suggests that good analgesia and fewer opioid requirements can shorten hospital stay.In radical mastectomy to treat breast cancer, iv lidocaine reduced the area of hyperalgesia when compared to placebo, but did not improve pain management.<a class="elsevierStyleCrossRef" href="#bib0405">31</a>There is no evidence that lidocaine improves pain management in radical hysterectomy,<a class="elsevierStyleCrossRef" href="#bib0410">32</a> cosmetic breast surgery,<a class="elsevierStyleCrossRef" href="#bib0415">33</a> or hip replacement.<a class="elsevierStyleCrossRef" href="#bib0420">34</a> The failure of pain management in these procedures could be related to differences in dosage and perfusion times, and also to differences in the variables analysed.New fields of researchChronic postoperative painThe chronification of acute postoperative pain is a poorly understood, multifactorial process that has sparked growing interest in recent years.<a class="elsevierStyleCrossRef" href="#bib0425">35</a> Many patients experience chronic pain after certain surgical procedures, such as thoracotomy, mastectomy or limb amputation. Recent studies have shown that opioid-induced hyperalgesia (OIH) can progress to chronic POP through complex central and/or peripheral mechanisms that alter the sensitisation of the pain stimulus. The opioids identified as potentially causing OIH in animal models and human volunteers are remifentanil, fentanyl, morphine, and diamorphine.<a class="elsevierStyleCrossRef" href="#bib0430">36</a> The main factor associated with this phenomenon is the cumulative dose administered, particularly the effect site concentration. Similarly, Salengros et al. found that the area of allodynia around the wound measured using von Frey filaments at 24, 48 and 72 h was greater in the high dose remifentanil group (0.14–0.26µg/kg-1/min-1). Finally, in the high-dose remifentanil group the number of patients with chronic pain assessed using the DN4 questionnaire for neuropathic pain was significantly higher at 1, 3, 6 and 9 months after surgery.<a class="elsevierStyleCrossRef" href="#bib0435">37</a> Grigoras et al.<a class="elsevierStyleCrossRef" href="#bib0405">31</a>, meanwhile, showed that iv lidocaine perfusion reduced the area of hyperalgesia compared with placebo in patients undergoing mastectomy for breast cancer. In another study, Terkawi et al.<a class="elsevierStyleCrossRef" href="#bib0440">38</a> found that iv lidocaine perfusion reduced the incidence of chronic postmastectomy pain (12%) compared with placebo (30%), showing a preventive effect on the development of hyperalgesia. Some authors have speculated that the use of pharmacological strategies aimed at reducing the intensity of POP and opioid requirements could prevent progression to OIH. Opioid-sparing anaesthesia and opioid-free anaesthesia techniques are designed to avoid or minimise the development of OIH while blocking nociceptive stimuli. Backan et al.<a class="elsevierStyleCrossRef" href="#bib0445">39</a> using opioid-free anaesthesia with propofol, dexmedetomidine and lidocaine, achieved good POP control and lower analgesic and antiemetic consumption. However, post-anaesthesia recovery was slower in this group, and new, well-designed prospective studies are needed to support the use of this anaesthetic technique.Postoperative cognitive dysfunctionPostoperative cognitive dysfunction (PCD) is defined as moderate to severe impairment of intellectual capacity caused by poorly resolved neuroinflammatory response. Growing evidence from experimental in vitro models, cell cultures, and animal models point to an interaction between surgery and anaesthesia.<a class="elsevierStyleCrossRef" href="#bib0450">40</a> Exposure to inhalational agents can activate lytic enzymes called caspases, increase the synthesis and accumulation of ß-amyloid protein, and induce hyperphosphorylation of tau proteins, all of which are cellular responses consistent with the neuropathogenesis of Alzheimer's disease.<a class="elsevierStyleCrossRef" href="#bib0455">41</a> There is widespread consensus on the need to develop strategies that avoid or limit possible neuronal damage.<a class="elsevierStyleCrossRef" href="#bib0460">42</a> Perfusion of iv lidocaine reduces requirements of volatile agents such as sevoflurane<a class="elsevierStyleCrossRefs" href="#bib0335">17,43</a> and desflurane,<a class="elsevierStyleCrossRef" href="#bib0370">24</a> and thus reduces the time- and dose-dependent effects of these drugs. A study in laparoscopic cholecystectomy found that administration of iv lidocaine (bolus of 1mg/kg-1 followed by 2mg/kg-1/h-1) reduced by 19% the inspired fraction of sevoflurane needed to maintain adequate haemodynamic stability.<a class="elsevierStyleCrossRef" href="#bib0465">43</a> In coronary bypass surgery, Wang et al. showed that the use of iv lidocaine reduced incidence of PCD compared with placebo (18.6% vs 40%; p=0.028).<a class="elsevierStyleCrossRef" href="#bib0470">44</a> In addition to avoiding exposure to volatile agents, animal studies in lidocaine have shown that the drug has neuroprotective properties. Perfusion of lidocaine reduced the incidence of cognitive dysfunction in rat models exposed to isoflurane. Pain is also a risk factor for the development of PCD. Some authors hypothesise that iv lidocaine infusions can reduce the risk of PCD, possibly due to its neuroprotective effects, opioid-sparing properties, and impact on pain reduction.<a class="elsevierStyleCrossRef" href="#bib0475">45</a>Cancer recurrenceRecent evidence has shown that lidocaine and other local anaesthetics may decrease the progression and recurrence of cancer through its indirect and direct effect on tumour cells. The indirect effects stem from inhibition of the neuroendocrine stress response to surgery and to a reduction in the requirements of volatile anaesthetics and opioids.<a class="elsevierStyleCrossRefs" href="#bib0315">13,46</a> The direct effects are mediated by specific molecular actions on cancer cells. Tumour cells are known to express VGSC in a wide variety of carcinomas, including breast, cervix, colon, lung (small cell, non-small cell and mesothelioma), skin, ovarian and prostate cancer. In vitro, VGSC activity has been shown to enhance metastatic cell behaviours, such as lateral motility and invasion. This induces tumour cells to become “electrically excitable”, becoming hyperactive and aggressive. This is known as CELEX (for cellular excitability), and is a novel hypothesis of metastatic progression.<a class="elsevierStyleCrossRef" href="#bib0485">47</a> In this regard, Fraser et al. suggest that intra- and postoperative local anaesthetics may reduce the ability of tumour cells to metastasise by blocking VGSC and thus inhibiting their motility and invasiveness. This, in turn, could reduce the ability of the cancer cells to escape from the perioperative area and metastasise, which would increase patient survival and improve quality of life. Aside from VGSC blockage, local anaesthetics have been shown to exhibit antiproliferative properties. In vitro studies have shown that exposure to lidocaine inhibits Src protein tyrosine kinase activation in neoplastic cells, a protein involved in proliferation, migration, invasiveness and tumour metastasis.<a class="elsevierStyleCrossRefs" href="#bib0480">46,48</a> In tumour cells, lidocaine and other local anaesthetics have also been shown to inhibit the expression of intercellular adhesion molecules, which are synthesised de novo during the process of metastasis. In a recent study in cultures of breast tumour cells, Chang et al. found that lidocaine has apoptosis-inducing properties.<a class="elsevierStyleCrossRef" href="#bib0495">49</a> With respect to clinical practice, retrospective studies with regional anaesthesia suggest that local anaesthetics might protect against tumour recurrence.<a class="elsevierStyleCrossRef" href="#bib0500">50</a> However, more recent investigations found no differences in survival when compared to patients who did not receive local anaesthetics. These discrepancies could be due to the different routes of administration and plasma concentration of local anaesthetics, and also to differences in the behaviour to the tumours studied.ConclusionsEvidence supports the use of iv lidocaine perfusion in a wide variety of procedures, due to its analgesic, anti-inflammatory and anti-hyperalgesia action. Pharmacokinetic studies have shown the most effective concentration need to achieve the desired effect, and lidocaine toxicity is rare. The advantages of lidocaine include its efficacy and effectiveness in abdominal surgery and outpatient surgery procedures, and it is also used in different fast track surgery protocols. The latest studies analyse its potential to prevent the development of chronic POP by minimising the appearance of opioid-induced hyperalgesia, and it can be used as an opioid-sparing analgesic technique. Opioid-sparing anaesthesia has been extensively researched, but prospective studies are needed to show that it improves anaesthetic outcomes compared to standard opioid-based techniques. Some authors hypothesise that iv lidocaine infusion can reduce the risk of PCD in elderly patients, potentially due to its neuroprotective effects, opioid sparing properties and impact on pain reduction. Retrospective and preliminary in vitro studies indicate that lidocaine inhibits tumour cell proliferation by blocking VGSC and other molecular targets. Although these findings are encouraging, further research in animals and humans is needed to develop clinical indications. Intravenous lidocaine perfusion could be indicated in a context of multimodal analgesia due to its capacity to modulate the inflammatory response produced by surgical stress, and it is considered essential in today's perioperative practice.FundingNo funding.Conflicts of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1024765" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec982666" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1024764" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec982665" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Mechanisms of action" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Pharmacokinetics and toxicity" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical application" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "New fields of research" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Chronic postoperative pain" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Postoperative cognitive dysfunction" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Cancer recurrence" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0050" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 12 => array:2 [ "identificador" => "xack346140" "titulo" => "Acknowledgement" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-10-02" "fechaAceptado" => "2018-01-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec982666" "palabras" => array:5 [ 0 => "Intravenous lidocaine" 1 => "Opioid free anaesthesia" 2 => "Opioid-induced hyperalgesia" 3 => "Post-operative cognitive dysfunction" 4 => "Cancer recurrence" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec982665" "palabras" => array:5 [ 0 => "Lidocaína intravenosa" 1 => "Anestesia libre de opioides" 2 => "Hiperalgesia inducida por opioides" 3 => "Disfunción cognitiva posoperatoria" 4 => "Recurrencia de cáncer" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Systemic lidocaine used in continuous infusion during the peri-operative period has analgesic, anti-hyperalgesic, as well as anti-inflammatory properties. This makes it capable of reducing the use of opioids and inhalational anaesthetics, and the early return of bowel function, and patient hospital stay. The aim of this narrative review was to highlight the pharmacology and indications for clinical application, along with new and interesting research areas. The clinical applications of peri-operative lidocaine infusion have been reviewed in several recent systematic reviews and meta-analyses in patients undergoing open and laparoscopic abdominal procedures, ambulatory procedures, and other types of surgery. Peri-operative lidocaine infusion may be a useful analgesic adjunct in enhanced recovery protocols. Potential benefits of intravenous lidocaine in chronic post-surgical pain, post-operative cognitive dysfunction, and cancer recurrence are under investigation. Due to its immunomodulation properties over surgical stress, current evidence suggests that intravenous lidocaine could be used in the context of multimodal analgesia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La perfusión perioperatoria de lidocaína intravenosa tiene propiedades analgésicas, antihiperalgésicas y antiinflamatorias, disminuyendo el consumo de opioides y agentes volátiles, brindando una rápida recuperación de la función intestinal y alta hospitalaria. Esta revisión narrativa tiene como objetivo exponer su farmacología e indicaciones para su aplicación en la clínica anestésica. Recientes revisiones sistemáticas y metaanálisis confirman su empleo en cirugía abdominal videolaparoscópica y abierta, como también en otros tipos de cirugía, destacándose su uso en protocolos de pronta recuperación. Potenciales beneficios en dolor crónico posoperatorio, disfunción cognitiva posoperatoria y recurrencia de cáncer están siendo investigados. La evidencia actual avala su administración en el contexto de analgesia multimodal debido a sus propiedades inmunomoduladoras sobre el estrés quirúrgico, considerándose un fármaco necesario en la clínica perioperatoria moderna." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "?" "nota" => "Please cite this article as: Soto G, Naranjo González M, Calero F. Perfusión de lidocaína intravenosa. Rev Esp Anestesiol Reanim. 2018;65:269–274." ] 1 => array:2 [ "etiqueta" => "??" "nota" => "This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program. 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Intravenous lidocaine infusion

Perfusión de lidocaína intravenosa

G. Sotoa,?

Corresponding author

dr.germansoto@gmail.com

Corresponding author.

, M. Naranjo Gonzálezb, F. Caleroa

a Médico Anestesiólogo, Hospital Escuela Eva Perón, Granadero Baigorria, Argentina

b Médica Anestesióloga, Clínica de Mérida, Mérida, Mexico

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        "titulo" => "Perfusi&#243;n de lidoca&#237;na intravenosa"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Postoperative pain &#40;POP&#41; is a nociceptive stimulus produced by surgery-induced tissue damage&#44; and results in emotional and cognitive experiences&#46; Good pain management reduces morbidity&#44; improves surgical outcomes&#44; and reduces hospital costs&#46; However&#44; estimates suggest that more than 50&#37; of patients undergoing surgical procedures experience moderate to severe pain&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">1</span></a> Persistence of the painful stimulus can even change the plasticity of the nervous system&#44; leading to chronic pain&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">2</span></a> Inter-individual differences in pain thresholds and the use of inappropriate drugs are among the causes of POP&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Although opioids are frequently used in pain therapy&#44; they can cause adverse effects&#44; such as respiratory depression&#44; postoperative nausea and vomiting&#44; ileus&#44; urinary retention&#44; hyperalgesia and immune changes&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">3</span></a> Intravenous &#40;iv&#41; perfusion of lidocaine&#44; a drug whose analgesic&#44; antihyperalgesic and anti-inflammatory properties modulate the inflammatory response produced by surgical stress&#44; is an alternative to opioids in pain management&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">4</span></a> Some studies have shown that lidocaine decreases POP and the need for opioids and volatile agents&#44; and rapidly restores intestinal function&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a> The antihyperalgesic action of lidocaine reduces allodynia by acting on spinal cord neurons&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">6</span></a> The anti-inflammatory action of the drug&#44; which inhibits cytokine release and polymorphonuclear activation&#44; has been demonstrated <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">7</span></a> The aim of this review is to describe the pharmacology of lidocaine&#44; its indications for use in anaesthesia practice&#44; and its effect on new fields of study&#44; including chronic POP&#44; postoperative cognitive dysfunction &#40;PCD&#41; and cancer recurrence&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Mechanisms of action</span><p id="par0015" class="elsevierStylePara elsevierViewall">Lidocaine is an amide-type local anaesthetic that acts by blocking voltage-gated sodium channels &#40;VGSC&#41; in neuronal tissues&#44; thus interrupting synaptic transmission&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">8</span></a> VGSCs are composed of an a subunit &#40;Nav1&#46;5&#44; 260<span class="elsevierStyleHsp" style=""></span>kDa&#41; and 1 or more &#223; subunits &#40;Nav&#223;1&#46;1&#44; Nav&#223;1&#46;1 a&#44; Nav&#223;3&#46;1&#59; 33&#8211;36<span class="elsevierStyleHsp" style=""></span>kDa&#41;&#46; The a subunit is an integral heteromultimeric protein complex consisting of 4 homologous domains &#40;D1&#8211;D4&#41;&#44; each of which contains 6 a-helix transmembrane segments &#40;S1&#8211;S6&#41;&#46; The C- and N-terminus ends and P loops that bind the domains are intracytoplasmic&#46; The S5&#8211;S6 segments and the P loop of each domain form the channel pore that penetrates the membrane&#46; In mammals&#44; VGSCs have 9 different a unit isotypes &#40;Nav1&#46;1 to 1&#46;9&#41;&#44; some of which are associated with neuropathic pain &#40;Nav1&#46;3&#44; 1&#46;7&#44; 1&#46;8 and 1&#46;9&#41; and others with inflammatory pain &#40;Nav1&#46;7&#44; 1&#46;8 and 1&#46;9&#41;&#46; Lidocaine passes through the neuron membrane and is converted to its non-ionised form by the effect of pH&#46; It binds to the S6 portion of domain 4 of the a subunit inside the sodium channel&#46; The affinity of lidocaine for VGSCs varies according to the status of the channel&#44; being high when the channel is open and low when it is closed&#46; Therefore&#44; the greater the neural discharge&#44; the greater the number of ionised lidocaine molecules entering the site of action&#44; thus increasing the analgesic capacity of the drug&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">9</span></a> The analgesic effect of intravenous administration is the result of increased acetylcholine levels in the cerebrospinal fluid&#44; which cause downward inhibition&#44; inhibition of glycine receptors&#44; and increase the release of endogenous opioids&#46; When lidocaine reaches the spinal cord&#44; it reduces the post-synaptic depolarisation mediated by N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate and neurokinin receptors&#44; thus modifying the pain response&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">10</span></a> N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate blockade inhibits protein kinase C&#44; thus reducing hyperalgesia and postoperative opioid tolerance&#46; In animal models&#44; lidocaine acts during the early stages of systemic inflammatory response&#44; modulating the marginalisation&#44; adherence and diapedesis of polymorphonuclear cells towards the site of the lesion&#44; thus inhibiting the production of reactive oxygen species and the release of histamine&#46; This immunomodulatory effect of the drug is achieved by blocking G protein-coupled receptors&#44; since polymorphonuclear cells do not contain VGSCs&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">11</span></a> Through G protein-coupled receptors&#44; lidocaine inhibits inflammatory processes&#44; such as the sensitisation and lysosomal degradation of neutrophils&#44; the production of reactive oxygen species&#44; and the secretion of cytokines in both macrophages and glial cells&#46; On the other hand&#44; it can also inhibit leukocyte adhesion and migration through the endothelium by inhibiting intercellular adhesion molecules&#44; altering the cytoskeleton&#44; or attenuating the release of chemotactic factors&#46; Lidocaine blocks the release of interleukin &#40;IL&#41; 1&#44; IL-1&#223;&#44; tumour necrosis factora and IL-8 in polymorphonuclear cells&#46; It also decreases circulating IL-6 and phospholipase A2 levels&#44; both of which are involved in the disruption of the blood-brain barrier&#44; inflammation and brain damage&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">12</span></a> Lidocaine also inhibits the production of thromboxane B2 by inhibiting platelet aggregation&#44; which reduces the risk of venous thrombosis&#46; Finally&#44; lidocaine has been shown to exhibit antioxidant properties by inhibiting the production of reactive oxygen species due to its interaction with phospholipid membranes and interference with mitochondrial radical formation&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pharmacokinetics and toxicity</span><p id="par0020" class="elsevierStylePara elsevierViewall">Standard dosage is an initial bolus of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span> followed by continuous perfusion of 0&#46;5&#8211;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#46; The most widely used and best described dosage is continuous perfusion of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a> When administered intravenously&#44; lidocaine is distributed in highly vascularised organs such as the kidney&#44; brain and heart&#44; and then to less vascularised organs&#46; Around 40&#37; of the dose is extracted temporarily by the lung&#44; where pH is lower than in plasma&#46; This reduces the risk of accidental toxicity in the early stages of iv administration&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">5</span></a> When lidocaine is administered in a 1 mg&#47;kg bolus followed by continuous infusion of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#44; plasma concentrations of approximately 2<span class="elsevierStyleHsp" style=""></span>&#181;g&#47;ml<span class="elsevierStyleSup">-1</span> are obtained&#46; Plasma concentrations of more than 5<span class="elsevierStyleHsp" style=""></span>&#181;g&#47;ml<span class="elsevierStyleSup">-1</span> are considered toxic&#46; These concentrations are sufficient to attenuate the sympathetic response and reduce pain and the need for inhalational agents and opioids&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">10</span></a> In pharmacokinetic simulations&#44; continuous perfusion with no initial bolus takes between 4 and 8 h to reach equilibrium&#44; with a context-sensitive half-life of 20&#8211;40 min when the infusion is completed&#46; Lidocaine is metabolised in the liver by the P-450 system&#46; The liver&#39;s monoethyl-glycine-xylidide and glycine-xylidide metabolites are less effective at blocking the sodium channel&#46; Monoethyl-glycine-xylidide has the same potential for causing antiarrhythmia and convulsions as lidocaine&#59; however&#44; it is rapidly metabolised to glycine-xylidide&#46; Glycine-xylidide is less active than lidocaine and its metabolite is metabolised and excreted in urine&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Adverse effects and toxicity are extremely rare in controlled infusions&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a> Circulating plasma concentrations of lidocaine are affected by dose and rate of perfusion&#44; acid-base status&#44; hypoalbuminemia&#44; and liver and kidney function&#46; Toxicity manifests with plasma concentrations of over 5<span class="elsevierStyleHsp" style=""></span>&#181;g&#47;ml<span class="elsevierStyleSup">-1</span>&#44; and affects the CNS and the cardiovascular system&#46; In awake patients&#44; toxicity manifests as numbness of the tongue&#44; metallic taste&#44; dizziness and tinnitus&#46; Convulsions progressing to coma appear with concentrations greater than 10<span class="elsevierStyleHsp" style=""></span>&#181;g&#47;ml<span class="elsevierStyleSup">-1</span>&#46; Cardiovascular symptoms in awake patients are rare due to the lower cardiotoxicity of lidocaine compared to bupivacaine&#44; and include QRS and PR interval prolongation&#44; bradycardia and hypotension&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a> Toxicity will require supportive measures&#44; including oxygenation&#44; hydration&#44; vasopressors&#44; inotropics&#44; antiarrhythmics and anticonvulsants&#46; If the patient does not respond to supportive measures&#44; lipid infusion should be considered&#44; starting at a dose of 1&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg<span class="elsevierStyleSup">-1</span> at 20&#37; and repeating this every 3&#8211;5 min up to a total dose of 8<span class="elsevierStyleHsp" style=""></span>ml&#47;kg<span class="elsevierStyleSup">-1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical application</span><p id="par0030" class="elsevierStylePara elsevierViewall">Randomised studies&#44; meta-analyses and systematic reviews support the use of iv lidocaine and its clinical application&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">15</span></a> Intravenous lidocaine infusion &#40;bolus of 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span> followed by 1&#46;5&#8211;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#41; is indicated in videolaparoscopic abdominal surgery&#44; such as colectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a> cholecystectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">18</span></a> gastrectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">19</span></a> appendectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">20</span></a> and bariatric surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">21</span></a> In these procedures&#44; lidocaine has been shown to reduce pain measured on a visual analogue scale&#44; reduce opioid requirements and the incidence of ileus within the first 24 postoperative hours&#46; In bariatric surgery&#44; obese patients and those with obstructive sleep apnoea syndrome are the group most likely to develop respiratory depression&#44; so iv lidocaine is indicated in these cases&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">22</span></a> In open abdominal surgery<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">23</span></a> and colorectal surgery&#44;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">24&#44;25</span></a> lidocaine exhibits the same properties as in videolaparoscopic surgery&#44; and shortens hospital stay&#46; Intravenous lidocaine can be used in fast-track surgery protocols&#44; specifically&#44; the enhanced recovery after surgery &#40;ERAS&#41; protocol&#44; and also in patients in whom neuraxial blockade is contraindicated&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a> Lidocaine can be continued for 24<span class="elsevierStyleHsp" style=""></span>h after surgery at a reduced dose of 1&#46;33<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span><span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleSup">-1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">17</span></a> Computer simulations based on 3-compartment models support its use during prolonged infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">14</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Intravenous lidocaine perfusion &#40;bolus of 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span> followed by 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#41; is indicated in urological procedures&#44; such a as laparoscopic nephrectomy<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">26</span></a> and laparoscopic nephrectomy prostatectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">27</span></a> and also in chest surgery&#44;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">28</span></a> where it has been shown to alleviate pain measured on a visual analogue scale and reduce the need for opioids&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In different types of day surgery procedures&#44; such general surgery&#44; endocrine&#44; breast&#44; gynaecological&#44; urological&#44; plastic and otorhinolaryngology surgery&#44;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">29&#44;30</span></a> iv lidocaine was found to alleviate pain and reduce opioid requirements&#44; but had no effect on the incidence of postoperative nausea and vomiting&#46; Evidence suggests that good analgesia and fewer opioid requirements can shorten hospital stay&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">In radical mastectomy to treat breast cancer&#44; iv lidocaine reduced the area of hyperalgesia when compared to placebo&#44; but did not improve pain management&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">There is no evidence that lidocaine improves pain management in radical hysterectomy&#44;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">32</span></a> cosmetic breast surgery&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">33</span></a> or hip replacement&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">34</span></a> The failure of pain management in these procedures could be related to differences in dosage and perfusion times&#44; and also to differences in the variables analysed&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">New fields of research</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chronic postoperative pain</span><p id="par0055" class="elsevierStylePara elsevierViewall">The chronification of acute postoperative pain is a poorly understood&#44; multifactorial process that has sparked growing interest in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">35</span></a> Many patients experience chronic pain after certain surgical procedures&#44; such as thoracotomy&#44; mastectomy or limb amputation&#46; Recent studies have shown that opioid-induced hyperalgesia &#40;OIH&#41; can progress to chronic POP through complex central and&#47;or peripheral mechanisms that alter the sensitisation of the pain stimulus&#46; The opioids identified as potentially causing OIH in animal models and human volunteers are remifentanil&#44; fentanyl&#44; morphine&#44; and diamorphine&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">36</span></a> The main factor associated with this phenomenon is the cumulative dose administered&#44; particularly the effect site concentration&#46; Similarly&#44; Salengros et al&#46; found that the area of allodynia around the wound measured using von Frey filaments at 24&#44; 48 and 72 h was greater in the high dose remifentanil group &#40;0&#46;14&#8211;0&#46;26<span class="elsevierStyleHsp" style=""></span>&#181;g&#47;kg<span class="elsevierStyleSup">-1</span>&#47;min<span class="elsevierStyleSup">-1</span>&#41;&#46; Finally&#44; in the high-dose remifentanil group the number of patients with chronic pain assessed using the DN4 questionnaire for neuropathic pain was significantly higher at 1&#44; 3&#44; 6 and 9 months after surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">37</span></a> Grigoras et al&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">31</span></a>&#44; meanwhile&#44; showed that iv lidocaine perfusion reduced the area of hyperalgesia compared with placebo in patients undergoing mastectomy for breast cancer&#46; In another study&#44; Terkawi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">38</span></a> found that iv lidocaine perfusion reduced the incidence of chronic postmastectomy pain &#40;12&#37;&#41; compared with placebo &#40;30&#37;&#41;&#44; showing a preventive effect on the development of hyperalgesia&#46; Some authors have speculated that the use of pharmacological strategies aimed at reducing the intensity of POP and opioid requirements could prevent progression to OIH&#46; Opioid-sparing anaesthesia and opioid-free anaesthesia techniques are designed to avoid or minimise the development of OIH while blocking nociceptive stimuli&#46; Backan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">39</span></a> using opioid-free anaesthesia with propofol&#44; dexmedetomidine and lidocaine&#44; achieved good POP control and lower analgesic and antiemetic consumption&#46; However&#44; post-anaesthesia recovery was slower in this group&#44; and new&#44; well-designed prospective studies are needed to support the use of this anaesthetic technique&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Postoperative cognitive dysfunction</span><p id="par0060" class="elsevierStylePara elsevierViewall">Postoperative cognitive dysfunction &#40;PCD&#41; is defined as moderate to severe impairment of intellectual capacity caused by poorly resolved neuroinflammatory response&#46; Growing evidence from experimental <span class="elsevierStyleItalic">in vitro</span> models&#44; cell cultures&#44; and animal models point to an interaction between surgery and anaesthesia&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">40</span></a> Exposure to inhalational agents can activate lytic enzymes called caspases&#44; increase the synthesis and accumulation of &#223;-amyloid protein&#44; and induce hyperphosphorylation of tau proteins&#44; all of which are cellular responses consistent with the neuropathogenesis of Alzheimer&#39;s disease&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">41</span></a> There is widespread consensus on the need to develop strategies that avoid or limit possible neuronal damage&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">42</span></a> Perfusion of iv lidocaine reduces requirements of volatile agents such as sevoflurane<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">17&#44;43</span></a> and desflurane&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">24</span></a> and thus reduces the time- and dose-dependent effects of these drugs&#46; A study in laparoscopic cholecystectomy found that administration of iv lidocaine &#40;bolus of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span> followed by 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg<span class="elsevierStyleSup">-1</span>&#47;h<span class="elsevierStyleSup">-1</span>&#41; reduced by 19&#37; the inspired fraction of sevoflurane needed to maintain adequate haemodynamic stability&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">43</span></a> In coronary bypass surgery&#44; Wang et al&#46; showed that the use of iv lidocaine reduced incidence of PCD compared with placebo &#40;18&#46;6&#37; vs 40&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">44</span></a> In addition to avoiding exposure to volatile agents&#44; animal studies in lidocaine have shown that the drug has neuroprotective properties&#46; Perfusion of lidocaine reduced the incidence of cognitive dysfunction in rat models exposed to isoflurane&#46; Pain is also a risk factor for the development of PCD&#46; Some authors hypothesise that iv lidocaine infusions can reduce the risk of PCD&#44; possibly due to its neuroprotective effects&#44; opioid-sparing properties&#44; and impact on pain reduction&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Cancer recurrence</span><p id="par0065" class="elsevierStylePara elsevierViewall">Recent evidence has shown that lidocaine and other local anaesthetics may decrease the progression and recurrence of cancer through its indirect and direct effect on tumour cells&#46; The indirect effects stem from inhibition of the neuroendocrine stress response to surgery and to a reduction in the requirements of volatile anaesthetics and opioids&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">13&#44;46</span></a> The direct effects are mediated by specific molecular actions on cancer cells&#46; Tumour cells are known to express VGSC in a wide variety of carcinomas&#44; including breast&#44; cervix&#44; colon&#44; lung &#40;small cell&#44; non-small cell and mesothelioma&#41;&#44; skin&#44; ovarian and prostate cancer&#46; In vitro&#44; VGSC activity has been shown to enhance metastatic cell behaviours&#44; such as lateral motility and invasion&#46; This induces tumour cells to become &#8220;electrically excitable&#8221;&#44; becoming hyperactive and aggressive&#46; This is known as CELEX &#40;for cellular excitability&#41;&#44; and is a novel hypothesis of metastatic progression&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">47</span></a> In this regard&#44; Fraser et al&#46; suggest that intra- and postoperative local anaesthetics may reduce the ability of tumour cells to metastasise by blocking VGSC and thus inhibiting their motility and invasiveness&#46; This&#44; in turn&#44; could reduce the ability of the cancer cells to escape from the perioperative area and metastasise&#44; which would increase patient survival and improve quality of life&#46; Aside from VGSC blockage&#44; local anaesthetics have been shown to exhibit antiproliferative properties&#46; <span class="elsevierStyleItalic">In vitro</span> studies have shown that exposure to lidocaine inhibits Src protein tyrosine kinase activation in neoplastic cells&#44; a protein involved in proliferation&#44; migration&#44; invasiveness and tumour metastasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0480"><span class="elsevierStyleSup">46&#44;48</span></a> In tumour cells&#44; lidocaine and other local anaesthetics have also been shown to inhibit the expression of intercellular adhesion molecules&#44; which are synthesised <span class="elsevierStyleItalic">de novo</span> during the process of metastasis&#46; In a recent study in cultures of breast tumour cells&#44; Chang et al&#46; found that lidocaine has apoptosis-inducing properties&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">49</span></a> With respect to clinical practice&#44; retrospective studies with regional anaesthesia suggest that local anaesthetics might protect against tumour recurrence&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">50</span></a> However&#44; more recent investigations found no differences in survival when compared to patients who did not receive local anaesthetics&#46; These discrepancies could be due to the different routes of administration and plasma concentration of local anaesthetics&#44; and also to differences in the behaviour to the tumours studied&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusions</span><p id="par0070" class="elsevierStylePara elsevierViewall">Evidence supports the use of iv lidocaine perfusion in a wide variety of procedures&#44; due to its analgesic&#44; anti-inflammatory and anti-hyperalgesia action&#46; Pharmacokinetic studies have shown the most effective concentration need to achieve the desired effect&#44; and lidocaine toxicity is rare&#46; The advantages of lidocaine include its efficacy and effectiveness in abdominal surgery and outpatient surgery procedures&#44; and it is also used in different fast track surgery protocols&#46; The latest studies analyse its potential to prevent the development of chronic POP by minimising the appearance of opioid-induced hyperalgesia&#44; and it can be used as an opioid-sparing analgesic technique&#46; Opioid-sparing anaesthesia has been extensively researched&#44; but prospective studies are needed to show that it improves anaesthetic outcomes compared to standard opioid-based techniques&#46; Some authors hypothesise that iv lidocaine infusion can reduce the risk of PCD in elderly patients&#44; potentially due to its neuroprotective effects&#44; opioid sparing properties and impact on pain reduction&#46; Retrospective and preliminary <span class="elsevierStyleItalic">in vitro</span> studies indicate that lidocaine inhibits tumour cell proliferation by blocking VGSC and other molecular targets&#46; Although these findings are encouraging&#44; further research in animals and humans is needed to develop clinical indications&#46; Intravenous lidocaine perfusion could be indicated in a context of multimodal analgesia due to its capacity to modulate the inflammatory response produced by surgical stress&#44; and it is considered essential in today&#39;s perioperative practice&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Funding</span><p id="par0075" class="elsevierStylePara elsevierViewall">No funding&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Postoperative cognitive dysfunction"
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            1 => "Opioid free anaesthesia"
            2 => "Opioid-induced hyperalgesia"
            3 => "Post-operative cognitive dysfunction"
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            0 => "Lidoca&#237;na intravenosa"
            1 => "Anestesia libre de opioides"
            2 => "Hiperalgesia inducida por opioides"
            3 => "Disfunci&#243;n cognitiva posoperatoria"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Systemic lidocaine used in continuous infusion during the peri-operative period has analgesic&#44; anti-hyperalgesic&#44; as well as anti-inflammatory properties&#46; This makes it capable of reducing the use of opioids and inhalational anaesthetics&#44; and the early return of bowel function&#44; and patient hospital stay&#46; The aim of this narrative review was to highlight the pharmacology and indications for clinical application&#44; along with new and interesting research areas&#46; The clinical applications of peri-operative lidocaine infusion have been reviewed in several recent systematic reviews and meta-analyses in patients undergoing open and laparoscopic abdominal procedures&#44; ambulatory procedures&#44; and other types of surgery&#46; Peri-operative lidocaine infusion may be a useful analgesic adjunct in enhanced recovery protocols&#46; Potential benefits of intravenous lidocaine in chronic post-surgical pain&#44; post-operative cognitive dysfunction&#44; and cancer recurrence are under investigation&#46; Due to its immunomodulation properties over surgical stress&#44; current evidence suggests that intravenous lidocaine could be used in the context of multimodal analgesia&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La perfusi&#243;n perioperatoria de lidoca&#237;na intravenosa tiene propiedades analg&#233;sicas&#44; antihiperalg&#233;sicas y antiinflamatorias&#44; disminuyendo el consumo de opioides y agentes vol&#225;tiles&#44; brindando una r&#225;pida recuperaci&#243;n de la funci&#243;n intestinal y alta hospitalaria&#46; Esta revisi&#243;n narrativa tiene como objetivo exponer su farmacolog&#237;a e indicaciones para su aplicaci&#243;n en la cl&#237;nica anest&#233;sica&#46; Recientes revisiones sistem&#225;ticas y metaan&#225;lisis confirman su empleo en cirug&#237;a abdominal videolaparosc&#243;pica y abierta&#44; como tambi&#233;n en otros tipos de cirug&#237;a&#44; destac&#225;ndose su uso en protocolos de pronta recuperaci&#243;n&#46; Potenciales beneficios en dolor cr&#243;nico posoperatorio&#44; disfunci&#243;n cognitiva posoperatoria y recurrencia de c&#225;ncer est&#225;n siendo investigados&#46; La evidencia actual avala su administraci&#243;n en el contexto de analgesia multimodal debido a sus propiedades inmunomoduladoras sobre el estr&#233;s quir&#250;rgico&#44; consider&#225;ndose un f&#225;rmaco necesario en la cl&#237;nica perioperatoria moderna&#46;</p></span>"
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        "etiqueta" => "&#63;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Soto G&#44; Naranjo Gonz&#225;lez M&#44; Calero F&#46; Perfusi&#243;n de lidoca&#237;na intravenosa&#46; Rev Esp Anestesiol Reanim&#46; 2018&#59;65&#58;269&#8211;274&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This article is part of the Anaesthesiology and Resuscitation Continuing Medical Education Program&#46; An evaluation of the questions on this article can be made through the Internet by accessing the Education Section of the following web page&#58; <a class="elsevierStyleInterRef" target="_blank" id="intr0010" href="http://www.elsevier.es/redar">www&#46;elsevier&#46;es&#47;redar</a></p>"
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