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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 

Email: ilyako2000@yahoo.com

ABSTRACT 

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.[1] They are afferent fibers, conveying input signals from the periphery to the central nervous system.[2]

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.[7] C fiber receptors include:

C fiber nociceptors

responsible for the second, burning pain

C fiber warming specific receptors

responsible for warmth

Vanilloid Receptor

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.[1] Capsaicin activates C fibers by opening a ligand-gated ion channel and causing an action potential to occur.[1] Because this receptor responds to both capsaicin and heat, chili peppers are sensed as hot.[1] VR-1 is also able to respond to extracellular acidification and can integrate simultaneous exposure to all three sensory stimuli.[1] 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)

Summary

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.

REFERENCES

1)  Anesth Analg. 2010 Dec;111(6):1467-75. Epub 2010 Sep 22.

Labor epidural analgesia and maternal fever.

Segal S.

Source

Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts, USA. bssegal@zeus.bwh.harvard.edu

 j

2)  Curr Opin Anaesthesiol. 2012 Jun;25(3):292-9.

Epidural analgesia and maternal fever: a clinical and research update.

Goetzl L.

Source

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.

Source

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.

Source

Department of Neuroscience, MS 29-2-B, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. ngavva@amgen.com

5)   Invest Ophthalmol Vis Sci. 2008 Jul;49(7):3004-17. Epub 2008 Mar 24.

Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure.

Sappington RM, Calkins DJ.

Source

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

+

Author Affiliations

.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

+

Author Affiliations

.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

.Corresponding Author:
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: fi1muble@uco.es

8)    Am J Neurodegener Dis 2012;1(1):xxx-xxx

www.AJND.us /ISSN:2165-591X/AJND1204002

Review Article

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: preinach@sunyopt.edu

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 rejean.couture@umontreal.ca

† Equal contributors

Author Affiliations

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

DOI: 10.1002/jbt.20084

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.

Source

Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.

14)    ScientificWorldJournal. 2012;2012:607938. Epub 2012 May 1.

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.

Source

Department of Anesthesiology, Magee-Womens Hospital of UPMC, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

15)   Obstet Gynecol. 2011 Mar;117(3):588-95.

Association of epidural-related fever and noninfectious inflammation in term labor.

Riley LE, Celi AC, Onderdonk AB, Roberts DJ, Johnson LC, Tsen LC, Leffert L, Pian-Smith MC, Heffner LJ, Haas ST, Lieberman ES.

Source

Department of Obstetrics and Gynecology, Brigham and Women’s Hospital and Massachusetts General Hospital, Boston, Massachusetts 02114, USA. lriley@partners.org

16) The Vanilloid Receptor TRPV1 Is Tonically Activated In Vivo and Involved in Body Temperature Regulation

.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

+

Author Affiliations

.Departments of 1Neuroscience,

.2Pharmacokinetics and Drug Metabolism,

.3Toxicology,

.4Pharmaceutics,

.5Protein Sciences, and

.6Chemistry Research and Discovery, Amgen, Thousand Oaks, California 91320-1799

17)  J Clin Invest. 2008 Feb;118(2):763-76.

The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons.

Leffler A, Fischer MJ, Rehner D, Kienel S, Kistner K, Sauer SK, Gavva NR, Reeh PW, Nau C.

Source

Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.

18)   Mol Pain. 2011 Aug 23;7:62.

Activation of TRPA1 by membrane permeable local anesthetics.

Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C.

Source

Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.

19)  Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc.. ISBN 0-87893-725-0.

20)  Int J Radiat Oncol Biol Phys. 1992;23(3):585-91.

Reduction of pain and local complications when buffered lidocaine solution is used as a local anesthetic in conjunction with hyperthermia treatments: results of a randomized trial.

Barnett TA, Kapp DS.

Source

Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.

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