Why labor epidural causes fever and why Lidocaine burns on injection ? Role of TRPV 1 receptor in hyperthermia .Possible explanation of mechanism of hyperthermia during labor epidural and burning sensation on injection of local anesthetics.
Dr I. Kozlov
Anesthesia Department, Wyckoff Heights Medical Center, Brooklyn NY, USA
The mechanisms of epidural-associated fever remain incompletely understood(1).We propose that action of local anesthetic on TPRV 1 vanillioid receptor can explain this effect and explain mechanism of burning sensation on local anesthetic injected subcutaneously or intramuscular. Role of TRPV1 receptor was not discussed previously in Obstetric Anesthesia literature.Based on available data , we propose that Local Anesthetics work as agonist / antagonist on TPRV1 receptors. Antagonist action may cause hyperthermia through modifying thermoregulation(4), agonist action may cause hyperthermia thru release of IL-6 and other mediators of inflammation(5-11,17,18). Agonist action may explain burning sensation on injection of Local Anesthetics.Burning sensation can be diminished by increasing pH of Local Anesthetic solution, because vanillin receptors are stimulated by acidification through lower pH (19,20)
Keywords:Labor epidural, hyperthermia, fever, vanilloid receptor, TPRV 1, lidocaine, local anesthetics,neurogenic inflammation,
Mechanisms proposed in literature;
Significant research advances were made in the last 18 months around the topic of epidural-related fever, but major gaps in knowledge persist especially with understanding the precise mechanism. The most pressing area of research is the development of well tolerated and effective prophylactic interventions to prevent maternal and fetal exposure to hyperthermia and inflammation.
Overall, 18.5% of women had a temperature more than 100.4°F develop during labor. However, only 4.5% ) of women in this low-risk population had microbiologic-proven chorioamnionitis. Whereas women with epidural were far more likely to have intrapartum fever develop, 22.7% with epidural compared with 6.0% no epidural , the use of epidural analgesia was not associated with infection. (15)
Elevation in maternal body temperature can be seen in a subset of laboring women in as little as 1 hour after administration of epidural analgesia. However, it is estimated that intrapartum temperature elevation usually begins 4 to 6 hours after epidural placement and rises at a rate of 0.08 to 0.14°C per hour. Although this rise in temperature is considered idiopathic, researchers have proposed several mechanisms that might explain the phenomenon. These include an inflammatory response, oxidative stress, an alteration in sympathetic stimulation and thermoregulatory mechanisms, and subclinical chorioamnionitis.
Recent research has focused on the inflammation and oxidative stress seen in women who develop intrapartum fever. Earlier work revealed that levels of interleukin-6 (IL-6), a proinflammatory cytokine, are elevated in women who receive epidural analgesia and become febrile.A longer duration of epidural infusion is associated with higher levels of IL-6, whereas this elevation is not seen with longer duration of labor without epidural. This suggests that the epidural itself induces an inflammatory response; the response is not a physiologic process of labor. Similar findings with additional proinflammatory mediators and reactive oxygen species seem to support this theory.
Epidural analgesia also appears to affect the body’s thermoregulatory mechanisms. That epidurals cause an increase in shivering has been well-documented, but epidural analgesia also seems to be associated with a decrease in heat dissipation via sweating and hyperventilation, most likely due to a blockade of sympathetic stimulation. . However, because epidurals have been reliably shown to diminish thermoregulatory capacity, it is probable that these factors contribute to the development of the associated fever.
Finally, there remains the possibility that a subclinical chorioamnionitis might underlie a subset of maternal intrapartum fevers. Women may be more likely to request an epidural if they are experiencing symptoms of subclinical chorioamnionitis, such as uterine tenderness.
Role of TRPV1 receptor was not mentioned in Obstetric Anesthesia literature known to us.
Action of Local Anesthetics on TRPV 1 Receptor .
C fibers are found in the nerves of the somatic sensory system. They are afferent fibers, conveying input signals from the periphery to the central nervous system.
C fibres are unmyelinated unlike most other fibers in the nervous system.
C fibers are considered polymodal because they can respond to thermal, mechanical, and chemical stimuli(1). C fibers respond to all kinds of physiological changes in the body. For example, they can respond to hypoxia, hypoglycemia, hypo-osmolarity, the presence of muscle metabolic products, and even light or sensitive touch. C fiber receptors include:
▪C fiber nociceptors
▪responsible for the second, burning pain
▪C fiber warming specific receptors
▪responsible for warmth
The vanilloid receptor (VR-1, TRPV1) is a receptor that is found on the free nerve endings of both C and Aδ fibers that responds to elevated levels of heat (>43°C) and the chemical capsaicin. Capsaicin activates C fibers by opening a ligand-gated ion channel and causing an action potential to occur. Because this receptor responds to both capsaicin and heat, chili peppers are sensed as hot. VR-1 is also able to respond to extracellular acidification and can integrate simultaneous exposure to all three sensory stimuli. VR1 is essential for the inflammatory sensitization to noxious thermal stimuli.The transient receptor potential (TRP) family comprises a diverse group of cation channels that regulate a variety of intracellular signaling pathways. The TRPV1 (vanilloid 1) channel is best known for its role in nociception and sensory transmission. First studied in the dorsal root ganglia as the receptor for capsaicin, TRPV1 is now recog- nized to have a broader distribution and function within the central nervous system (CNS)(8). TRPV1 regulates vasomotor tone and metabolic heat production(4).Blocking this receptor elicits marked hyperthermia in humans(4).
Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na(+) channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. It was demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 (12).Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve.These data identify TRPV1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 in LA-induced neurotoxicity(12). Stimulation of TRPV1 stimulates microglial production of IL-6 , other cytokines, IL-8, Kinin B1 (5,6,7,8,9,10) involved in inflammation process.Lidocaine produces a short-lasting nonselective sensory and motor block in keeping with its nonselective sodium channel blocker action. However, lidocaine also acts as an agonist for the TRPV1 receptor. (13)
Based on available literature , we propose that Local Anesthetics work as agonist / antagonist on TPRV1 receptors. Antagonist action may cause hyperthermia through modifying thermoregulation(4), agonist action may cause hyperthermia thru release of IL-6 and other mediators of inflammation(5-11,17,18). Agonist action may explain burning sensation on injection of Local Anesthetics.Burning sensation can be diminished by increasing pH of Local Anesthetic solution, because vanillin receptors are stimulated by acidification through lower pH (19,20). We hope that this review will bring more attention of our colleagues in Obstetric anesthesia to role of TRPV1 receptor, missing link between labor epidural and hyperthermia.
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Labor epidural analgesia and maternal fever.
Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA. firstname.lastname@example.org
2) Curr Opin Anaesthesiol. 2012 Jun;25(3):292-9.
Epidural analgesia and maternal fever: a clinical and research update.
Division of Maternal Fetal Medicine, Department of Obstetrics/Gynecology, Medical University of South Carolina, Charleston, USA.
3) .J Midwifery Womens Health. 2012 Jan-Feb;57(1):82-5. doi: 10.1111/j.1542-2011.2011.00105.x.
Epidural Fever and its implications for mothers and neonates: taking the heat.
Shatken S, Greenough K, McPherson C.
Columbia University, New York, NY, USA
4) .Pain. 2008 May;136(1-2):202-10. Epub 2008 Mar 11.
Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.
Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G.
Department of Neuroscience, MS 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. email@example.com
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Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure.
Sappington RM, Calkins DJ.
Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0654, USA.
6) Contribution of TRPV1 to Microglia-Derived IL-6 and NFκB Translocation with Elevated Hydrostatic Pressure
.Rebecca M. Sappington and David J. Calkins
.From the Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
7) Vanilloid Receptor-1 Regulates Neurogenic Inflammation in Colon and Protects Mice from Colon Cancer
.Amaya G. Vinuesa1, Rocío Sancho2, Carmen García-Limones1, Axel Behrens2, Peter ten Dijke3, Marco A. Calzado1, and Eduardo Muñoz1
.Authors’ Affiliations: 1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain; 2Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, Lincoln’s Inn Fields Laboratories, London, United Kingdom; and 3Department of Molecular and Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
Eduardo Muñoz, Departamento de Biología Celular, Fisiología e Inmunología. Facultad de Medicina Universidad de Córdoba, C/María, Virgen y Madre s/n. 14004, Córdoba, Spain. Phone: 34-957-218267; Fax: 34-957-218266; E-mail: firstname.lastname@example.org
8) Am J Neurodegener Dis 2012;1(1):xxx-xxx
TRPV1: a stress response protein in the central nervous system
Karen W Ho, Nicholas J Ward, David J Calkins
The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN 37205, USA.
Received April 15, 2012; accepted April 21, 2012; Epub April 22, 2012; published May 30, 2012
9) NF-κB feedback control of JNK1 activation modulates TRPV1-induced increases in IL-6 and IL-8 release by human corneal epithelial cells
Z. Wang,1 Y. Yang,1 H. Yang,1 J.E. Capó-Aponte,1,2 S.D. Tachado,4 J.M. Wolosin,3 P.S. Reinach1
1Department of Biological Sciences, State University of New York, State College of Optometry, New York, NY; 2Visual Sciences Branch, U.S. Army Aeromedical Research Laboratory, Fort Rucker, AL; 3Department of Ophthalmology and the Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY; 4Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
Correspondence to: Dr. Peter S. Reinach, Department of Biological Sciences, State University of New York, State College of Optometry, New York, NY, 10036; Phone: (212) 938-5785; FAX: (212) 938-5794; email: email@example.com
10) Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia
Sébastien Talbot1†, Jenny P Dias1†, Karim Lahjouji1, Maurício R Bogo2,3, Maria M Campos4,5, Pierrette Gaudreau6 and Réjean Couture1*
Corresponding author: Réjean Couture firstname.lastname@example.org
† Equal contributors
Journal of Neuroinflammation 2012, 9:16 doi:10.1186/1742-2094-9-16
11) Calcium-dependent and independent mechanisms of capsaicin receptor (TRPV1)-mediated cytokine production and cell death in human bronchial epithelial cells†
.Christopher A. Reilly1,*, Mark E. Johansen1, Diane L. Lanza1, Jeewoo Lee2, Ju-Ok Lim2, Garold S. Yost1
Article first published online: 19 SEP 2005
12) The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons
Andreas Leffler1, Michael J. Fischer2, Dietlinde Rehner1, Stephanie Kienel1, Katrin Kistner2, Susanne K. Sauer2, Narender R. Gavva3, Peter W. Reeh2 and Carla Nau1
1Department of Anesthesiology and
2Department of Physiology and Pathophysiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
3Department of Neuroscience, Amgen Inc., Thousand Oaks, California, USA.
Address correspondence to: Carla Nau, Depart
13) Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.
Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson DP, Herbert T, Wang CF, Kim D, Chung G, Mitani AA, Wang GK, Bean BP, Woolf CJ.
Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
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Maternal and cord serum cytokine changes with continuous and intermittent labor epidural analgesia: a randomized study.
Mantha VR, Vallejo MC, Ramesh V, Jones BL, Ramanathan S.
Department of Anesthesiology, Magee-Womens Hospital of UPMC, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Riley LE, Celi AC, Onderdonk AB, Roberts DJ, Johnson LC, Tsen LC, Leffert L, Pian-Smith MC, Heffner LJ, Haas ST, Lieberman ES.
Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and Massachusetts General Hospital, Boston, Massachusetts 02114, USA. email@example.com
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.Narender R. Gavva1, Anthony W. Bannon1, Sekhar Surapaneni2, David N. Hovland Jr3, Sonya G. Lehto1, Anu Gore4, Todd Juan5, Hong Deng1, Bora Han3, Lana Klionsky1, Rongzhen Kuang1, April Le1, Rami Tamir1, Jue Wang1, Brad Youngblood1, Dawn Zhu1, Mark H. Norman6, Ella Magal1, James J. S. Treanor1, and Jean-Claude Louis1
.Departments of 1Neuroscience,
.2Pharmacokinetics and Drug Metabolism,
.5Protein Sciences, and
.6Chemistry Research and Discovery, Amgen, Thousand Oaks, California 91320-1799
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Leffler A, Fischer MJ, Rehner D, Kienel S, Kistner K, Sauer SK, Gavva NR, Reeh PW, Nau C.
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
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Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C.
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
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Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.