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Frontiers in veterinary science2022; 9; 984108; doi: 10.3389/fvets.2022.984108

Clinical effects and pharmacokinetics of nebulized lidocaine in healthy horses.

Abstract: Nebulized lidocaine appears promising as a novel corticosteroid-sparing therapeutic for equine asthma, but its safety and pharmacokinetic behavior have yet to be confirmed. Unassigned: To describe the effect of nebulized lidocaine on upper airway sensitivity, lung mechanics, and lower respiratory cellular response of healthy horses, as well as delivery of lidocaine to lower airways, and its subsequent absorption, clearance, and duration of detectability. Unassigned: Six healthy university- and client-owned horses with normal physical examination and serum amyloid A, and no history of respiratory disease within 6 months. Unassigned: Prospective, descriptive study evaluating the immediate effects of 1 mg/kg 4% preservative-free lidocaine following nebulization with the Flexineb®. Prior to and following nebulization, horses were assessed using upper airway endoscopy, bronchoalveolar lavage, and pulmonary function testing with esophageal balloon/pneumotachography and histamine bronchoprovocation. Additionally, blood and urine were collected at predetermined times following single-dose intravenous and nebulized lidocaine administration for pharmacokinetic analysis. Unassigned: Upper airway sensitivity was unchanged following lidocaine nebulization, and no laryngospasm or excessive salivation was noted. Lidocaine nebulization (1 mg/kg) resulted in a mean epithelial lining fluid concentration of 9.63 ± 5.05 μg/mL, and a bioavailability of 29.7 ± 7.76%. Lidocaine concentrations were higher in epithelial lining fluid than in systemic circulation (Cmax 149.23 ± 78.74 μg/L, CELF:Cmaxplasma 64.4, range 26.5-136.8). Serum and urine lidocaine levels remained detectable for 24 and 48 h, respectively, following nebulization of a single dose. Baseline spirometry, lung resistance and dynamic compliance, remained normal following lidocaine nebulization, with resistance decreasing post-nebulization. Compared to the pre-nebulization group, two additional horses were hyperresponsive following lidocaine nebulization. There was a significant increase in mean airway responsiveness post-lidocaine nebulization, based on lung resistance, but not dynamic compliance. One horse had BAL cytology consistent with airway inflammation both before and after lidocaine treatment. Unassigned: Nebulized lidocaine was not associated with adverse effects on upper airway sensitivity or BAL cytology. While baseline lung resistance was unchanged, increased airway reactivity to histamine bronchoprovocation in the absence of clinical signs was seen in some horses following nebulization. Further research is necessary to evaluate drug delivery, adverse events, and efficacy in asthmatic horses.
Publication Date: 2022-09-15 PubMed ID: 36187809PubMed Central: PMC9521615DOI: 10.3389/fvets.2022.984108Google Scholar: Lookup
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  • Journal Article

Summary

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This research article studies the effects and pharmacokinetics of nebulized lidocaine in healthy horses. The study aims to establish its potential as a novel, steroid-sparing therapy for equine asthma and to understand its safety and pharmacokinetics.

Research Design and Methodology

  • The study was a prospective, descriptive one involving six healthy university- and client-owned horses that had no history of respiratory disease within the past six months.
  • The horses were administered 1 mg/kg of 4% preservative-free lidocaine through nebulization using the Flexineb device.
  • Prior to and after the nebulization, the horses underwent various examinations including upper airway endoscopy, bronchoalveolar lavage (BAL), and pulmonary function testing with esophageal balloon/pneumotachography and histamine bronchoprovocation.
  • For pharmacokinetic analysis, blood and urine samples were collected at predetermined times following single-dose intravenous and nebulized lidocaine administration.

Results and Findings

  • Nebulized lidocaine did not change upper airway sensitivity and it was not associated with laryngospasm or excessive salivation.
  • Lidocaine nebulization resulted in a mean epithelial lining fluid concentration of 9.63 ± 5.05 μg/mL, with a bioavailability of 29.7 ± 7.76%.
  • Lidocaine concentrations were higher in the epithelial lining fluid than in the systemic circulation, hinting at local delivery and absorption of the drug.
  • After nebulization, detectable levels of serum and urine lidocaine were present for 24 and 48 hours respectively.
  • Lung resistance and dynamic compliance remained normal following lidocaine nebulization, with resistance actually decreasing post-nebulization. However, airway responsiveness to histamine bronchoprovocation increased in some horses after nebulization.
  • One horse showed signs of airway inflammation both before and after lidocaine treatment, as assessed by BAL cytology.

Conclusion

  • The study concludes that nebulized lidocaine did not have adverse effects on upper airway sensitivity or BAL cytology.
  • However, there was an increase in airway reactivity to histamine bronchoprovocation in some horses following nebulization, even though clinical signs of inflammation were not apparent.
  • With these findings, the researchers suggest that further research is needed to evaluate drug delivery, potential adverse events, and the efficacy of nebulized lidocaine in asthmatic horses.

Cite This Article

APA
Minuto J, Bedenice D, Ceresia M, Zaghloul I, Böhlke M, Mazan MR. (2022). Clinical effects and pharmacokinetics of nebulized lidocaine in healthy horses. Front Vet Sci, 9, 984108. https://doi.org/10.3389/fvets.2022.984108

Publication

ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 984108

Researcher Affiliations

Minuto, Jillian
  • Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, United States.
Bedenice, Daniela
  • Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, United States.
Ceresia, Michelle
  • Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, United States.
  • Department of Pharmacy Practice, School of Pharmacy, MCPHS University, Boston, MA, United States.
Zaghloul, Iman
  • Department of Pharmaceutical Sciences, School of Pharmacy, MCPHS University, Boston, MA, United States.
Böhlke, Mark
  • Department of Pharmaceutical Sciences, School of Pharmacy, MCPHS University, Boston, MA, United States.
Mazan, Melissa R
  • Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, United States.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 59 references
  1. . Uniform Classification Guidelines for Foreign Substances and Recommended Penalties Model Rule. V.14.3. (2020).
  2. Hermanns H, Hollmann MW, Stevens MF, Lirk P, Brandenburger T, Piegeler T. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review. Br J Anaesth (2019) 123:335–49.
    doi: 10.1016/j.bja.2019.06.014pubmed: 31303268google scholar: lookup
  3. Viner M. Comparison of serum amyloid a in horses with infectious and noninfectious respiratory diseases. JEVS (2017) 2017:11–3.
  4. Talbot S, Abdulnour RE, Burkett PR, Lee S, Cronin SJ, Pascal MA. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron (2015) 87:341–54.
  5. Nafe LA, Guntur VP, Dodam JR, Lee-Fowler TM, Cohn LA, Reinero CR. Nebulized lidocaine blunts airway hyper-responsiveness in experimental feline asthma. J Feline Med Surg (2013) 15:712–6.
    doi: 10.1177/1098612X13476705pmc: PMC11191712pubmed: 23392613google scholar: lookup
  6. Mahalingam-Dhingra A, Mazan MR, Bedenice D, Ceresia M, Minuto J, Deveney EF. A CONSORT-guided, randomized, double-blind, controlled pilot clinical trial of inhaled lidocaine for the treatment of equine asthma. Can J Vet Res (2022) 86:116–24.
    pmc: PMC8978287pubmed: 35388235
  7. Abdulqawi R, Satia I, Kanemitsu Y, Khalid S, Holt K, Dockry R. A randomized controlled trial to assess the effect of lidocaine administered via throat spray and nebulization in patients with refractory chronic cough. J Allergy Clin Immunol Pract (2021) 9:1640–7.
    doi: 10.1016/j.jaip.2020.11.037pubmed: 33259976google scholar: lookup
  8. Carvalho KIM, Coutinho DS, Joca HC, Miranda AS, Cruz JDS, Silva ET. Anti-bronchospasmodic effect of JME-173, a novel mexiletine analog endowed with highly attenuated anesthetic activity. Front Pharmacol (2020) 11:1159.
    doi: 10.3389/fphar.2020.01159pmc: PMC7438868pubmed: 32903732google scholar: lookup
  9. Lim KG, Rank MA, Hahn PY, Keogh KA, Morgenthaler TI, Olson EJ. Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series. Chest (2013) 143:1060–5.
    doi: 10.1378/chest.12-1533pubmed: 23238692google scholar: lookup
  10. Ohnishi T, Kita H, Mayeno AN, Okada S, Sur S, Broide DH. Lidocaine in bronchoalveolar lavage fluid (BALF) is an inhibitor of eosinophil-active cytokines. Clin Exp Immunol (1996) 104:325–31.
  11. Wallen N, Kita H, Weiler D, Gleich GJ. Glucocorticoids inhibit cytokine-mediated eosinophil survival. J Immunol (1991) 147:3490–5.
    pubmed: 1940348
  12. Okada S, Hagan JB, Kato M, Bankers-Fulbright JL, Hunt LW, Gleich GJ. Lidocaine and its analogues inhibit IL-5-mediated survival and activation of human eosinophils. J Immunol (1998) 160:4010–7.
    pubmed: 9558110
  13. Molassiotis A, Bryan G, Caress A, Bailey C, Smith J. Pharmacological and non-pharmacological interventions for cough in adults with respiratory and non-respiratory diseases: A systematic review of the literature. Respir Med (2010) 104:934–44.
    doi: 10.1016/j.rmed.2010.02.010pubmed: 20385478google scholar: lookup
  14. Slaton RM, Thomas RH, Mbathi JW. Evidence for therapeutic uses of nebulized lidocaine in the treatment of intractable cough and asthma. Ann Pharmacother (2013) 47:578–85.
    doi: 10.1345/aph.1R573pubmed: 23548650google scholar: lookup
  15. Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NH. Particle size matters: diagnostics and treatment of small airways involvement in asthma. Eur Respir J (2011) 37:532–40.
    doi: 10.1183/09031936.00204109pubmed: 20595155google scholar: lookup
  16. . 4% Lidocaine Hydrochloride Injection. Lake Forest, IL; Hospira, Inc. (2021).
  17. Nannarone S, Cenani A, Gialletti R, Pepe M. Clinical comparison of two regimens of lidocaine infusion in horses undergoing laparotomy for colic. Vet Anaesth Analg (2015) 42:150–6.
    doi: 10.1111/vaa.12192pubmed: 24986751google scholar: lookup
  18. Chinn WM, Zavala DC, Ambre J. Plasma levels of lidocaine following nebulized aerosol administration. Chest (1977) 71:346–8.
    doi: 10.1378/chest.71.3.346pubmed: 319962google scholar: lookup
  19. Manneveau G, Lecallard J, Thorin C, Pamela H, Tessier C. Comparison of morphological changes and tactile sensitivity of the pharynx and larynx between four standing sedative and analgesic protocols in eight adult healthy horses. Vet Anaesth Analg (2018) 45:477–86.
    doi: 10.1016/j.vaa.2018.02.011pubmed: 29903423google scholar: lookup
  20. Gerber V, Straub R, Marti E, Hauptman J, Herholz C, King M. Endoscopic scoring of mucus quantity and quality: observer and horse variance and relationship to inflammation, mucus viscoelasticity and volume. Equine Vet J (2004) 36:576–82.
    doi: 10.2746/0425164044864525pubmed: 15581321google scholar: lookup
  21. Rennard SI, Basset G, Lecossier D, O'Donnell KM, Pinkston P, Martin PG. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol (1985) 60:532–8.
    doi: 10.1152/jappl.1986.60.2.532pubmed: 3512509google scholar: lookup
  22. Pocino K, Minucci A, Manieri R, Conti G, De Luca D, Capoluongo ED. Description of an automated method for urea nitrogen determination in bronchoalveolar lavage fluid (BALF) of neonates and infants. J Lab Autom (2015) 20:636–41.
    doi: 10.1177/2211068214567147pubmed: 25586999google scholar: lookup
  23. Mazan MR, Hoffman AM, Manjerovic N. Comparison of forced oscillation with the conventional method for histamine bronchoprovocation testing in horses. Am J Vet Res (1999) 60:174–80.
    pubmed: 10048547
  24. Hoffman AM, Mazan MR, Ellenberg S. Association between bronchoalveolar lavage cytologic features and airway reactivity in horses with a history of exercise intolerance. Am J Vet Res (1998) 59:176–81.
    pubmed: 9492932
  25. Dhanani JA, Diab S, Chaudhary J, Cohen J, Parker SL, Wallis SC. Lung pharmacokinetics of tobramycin by intravenous and nebulized dosing in a mechanically ventilated healthy ovine model. Anesthesiology (2019) 131:344–55.
    doi: 10.1097/ALN.0000000000002752pubmed: 31107274google scholar: lookup
  26. Almasry IO, Tschaubrunn CM. Antiarrhythmic electrophysiology and pharmacotherapy. In Jeremias A, Brown DL, editors. Cardiac Intensive Care. 2 ed. W.B. Saunders; (2010).
  27. Oon Z, Ha CB, Sicinski M. Nebulized lidocaine in the treatment of refractory postoperative laryngospasm: a case report. A A Pract (2019) 13:20–2.
    doi: 10.1213/XAA.0000000000000974pubmed: 30730310google scholar: lookup
  28. Labedzki L, Scavone JM, Ochs HR, Greenblatt DJ. Reduced systemic absorption of intrabronchial lidocaine by high-frequency nebulization. J Clin Pharmacol (1990) 30:795–7.
  29. Westermann CM, Laan TT, van Nieuwstadt RA, Bull S, Fink-Gremmels J. Effects of antitussive agents administered before bronchoalveolar lavage in horses. Am J Vet Res (2005) 66:1420–4.
    doi: 10.2460/ajvr.2005.66.1420pubmed: 16173487google scholar: lookup
  30. Enright PL, McNally JF, Souhrada JF. Effect of lidocaine on the ventilatory and airway responses to exercise in asthmatics. Am Rev Respir Dis (1980) 122:823–8.
    pubmed: 7458056
  31. Kim JS, Kim DH, Joe HB, Oh CK, Kim JY. Effect of tracheal lidocaine on intubating conditions during propofol-remifentanil target-controlled infusion without neuromuscular blockade in day-case anesthesia. Korean J Anesthesiol (2013) 65:425–30.
    doi: 10.4097/kjae.2013.65.5.425pmc: PMC3866338pubmed: 24363845google scholar: lookup
  32. Jones TL, Boyer K, Chapman K, Craigen B, da Cunha A, Hofmeister EH. Evaluation of the time to desensitization of the larynx of cats following topical lidocaine application. J Feline Med Surg (2021) 23:563–7.
    doi: 10.1177/1098612X20967886pmc: PMC10741298pubmed: 33112192google scholar: lookup
  33. Gerber V, Lindberg A, Berney C, Robinson NE. Airway mucus in recurrent airway obstruction–short-term response to environmental challenge. J Vet Intern Med (2004) 18:92–7.
  34. McKane SA, Rose RJ. Radiographic determination of the location of a blindly passed bronchoalveolar lavage catheter. EVE (1993) 5:329–32.
  35. McKenzie HC 3rd, Murray MJ. Concentrations of gentamicin in serum and bronchial lavage fluid after once-daily aerosol administration to horses for seven days. Am J Vet Res (2004) 65:173–8.
    doi: 10.2460/ajvr.2004.65.173pubmed: 14974574google scholar: lookup
  36. Milligan M, Kukanich B, Beard W, Waxman S. The disposition of lidocaine during a 12-hour intravenous infusion to postoperative horses. J Vet Pharmacol Ther (2006) 29:495–9.
  37. DeToledo JC. Lidocaine and seizures. Ther Drug Monit (2000) 22:320–2.
  38. Meyer GA, Lin HC, Hanson RR, Hayes TL. Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horse. Equine Vet J (2001) 33:434–7.
    doi: 10.2746/042516401776254871pubmed: 11558736google scholar: lookup
  39. Trim CM, Hanson RR. Effects of xylazine on renal function and plasma glucose in ponies. Vet Rec (1986) 118:65–7.
    doi: 10.1136/vr.118.3.65pubmed: 3952942google scholar: lookup
  40. de Wasseige S, Picotte K, Lavoie JP. Nebulized dexamethasone sodium phosphate in the treatment of horses with severe asthma. J Vet Intern Med (2021) 35:1604–11.
    doi: 10.1111/jvim.16113pmc: PMC8162592pubmed: 33817859google scholar: lookup
  41. Isohanni MH, Neuvonen PJ, Olkkola KT. Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine. Pharmacol Toxicol (1999) 84:143–6.
  42. Soma LR, You Y, Robinson MA, Boston RC. Pharmacokinetics of intravenous, subcutaneous, and topical administration of lidocaine hydrochloride and metabolites 3-hydroxylidocaine, monoethylglycinexylidide, and 4-hydroxylidocaine in horse. J Vet Pharmacol Ther (2018) 41:825–37.
    doi: 10.1111/jvp.12695pubmed: 30028024google scholar: lookup
  43. Stephens RH, Benjamin AR, Walters DV. Volume and protein concentration of epithelial lining liquid in perfused in situ postnatal sheep lungs. J Appl Physiol (1985) 80:1911–20.
    doi: 10.1152/jappl.1996.80.6.1911pubmed: 8806894google scholar: lookup
  44. Fronius M, Clauss WG, Althaus M. Why do we have to move fluid to be able to breathe?. Front Physiol (2012) 3:146.
    doi: 10.3389/fphys.2012.00146pmc: PMC3357553pubmed: 22661953google scholar: lookup
  45. Cha ML, Costa LR. Inhalation therapy in horses. Vet Clin North Am Equine Pract (2017) 33:29–46.
    doi: 10.1016/j.cveq.2016.11.007pubmed: 28325181google scholar: lookup
  46. Gizurarson S. Anatomical and histological factors affecting intranasal drug and vaccine delivery. Curr Drug Deliv (2012) 9:566–82.
    doi: 10.2174/156720112803529828pmc: PMC3480721pubmed: 22788696google scholar: lookup
  47. Bahar S, Bolat D, Dayan MO, Paksoy Y. Two- and three-dimensional anatomy of paranasal sinuses in Arabian foals. J Vet Med Sci (2014) 76:37–44.
    doi: 10.1292/jvms.13-0172pmc: PMC3979937pubmed: 24004969google scholar: lookup
  48. Mazan MR, Lascola K, Bruns SJ, Hoffman AM. Use of a novel one-nostril mask-spacer device to evaluate airway hyperresponsiveness (AHR) in horses after chronic administration of albuterol. Can J Vet Res (2014) 78:214–20.
    pmc: PMC4068413pubmed: 24982553
  49. McAlpine LG, Thomson NC. Lidocaine-induced bronchoconstriction in asthmatic patients. Relation to histamine airway responsiveness and effect of preservative. Chest (1989) 96:1012–5.
    doi: 10.1378/chest.96.5.1012pubmed: 2805828google scholar: lookup
  50. Groeben H, Grosswendt T, Silvanus MT, Pavlakovic G, Peters J. Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: a comparison of lidocaine, ropivacaine, and dyclonine. Anesthesiology (2001) 94:423–8.
  51. Groeben H, Silvanus MT, Beste M, Peters J. Both intravenous and inhaled lidocaine attenuate reflex bronchoconstriction but at different plasma concentrations. Am J Respir Crit Care Med (1999) 159:530–5.
    doi: 10.1164/ajrccm.159.2.9806102pubmed: 9927369google scholar: lookup
  52. Groeben H, Silvanus MT, Beste M, Peters J. Lidocaine inhalation for local anaesthesia and attenuation of bronchial hyper-reactivity with least airway irritation. Effect of three different dose regimens. Eur J Anaesthesiol (2000) 17:672–9.
  53. Miller WC, Awe R. Effect of nebulized lidocaine on reactive airways. Am Rev Respir Dis (1975) 111:739–41.
    pubmed: 1137242
  54. Groeben H, Silvanus MT, Beste M, Peters J. Combined lidocaine and salbutamol inhalation for airway anesthesia markedly protects against reflex bronchoconstriction. Chest (2000) 118:509–15.
    doi: 10.1378/chest.118.2.509pubmed: 10936148google scholar: lookup
  55. Muraki M, Iwanaga T, Haraguchi R, Kubo H, Tohda Y. Continued inhalation of lidocaine suppresses antigen-induced airway hyperreactivity and airway inflammation in ovalbumin-sensitized guinea pigs. Int Immunopharmacol (2008) 8:725–31.
    doi: 10.1016/j.intimp.2008.01.021pubmed: 18387515google scholar: lookup
  56. Baser Y, deShazo RD, Barkman HW Jr., Nordberg J. Lidocaine effects on immunocompetent cells. Implications for studies of cells obtained by bronchoalveolar lavage. Chest (1982) 82:323–8.
    doi: 10.1378/chest.82.3.323pubmed: 6980778google scholar: lookup
  57. Lopez Sanchez CM, Kogan C, Gold JR, Sellon DC, Bayly WM. Relationship between tracheobronchoscopic score and bronchoalveolar lavage red blood cell numbers in the diagnosis of exercise-induced pulmonary hemorrhage in horses. J Vet Intern Med (2020) 34:322–9.
    doi: 10.1111/jvim.15676pmc: PMC6979084pubmed: 31880352google scholar: lookup
  58. Perkins GA, Goodman LB, Dubovi EJ, Kim SG, Osterrieder N. Detection of equine herpesvirus-1 in nasal swabs of horses by quantitative real-time PCR. J Vet Intern Med (2008) 22:1234–8.
  59. Tee SY, Dart AJ, MacDonald MH, Perkins NR, Horadagoda N, Jeffcott LB. Effects of collecting serial tracheal aspirate and bronchoalveolar lavage samples on the cytological findings of subsequent fluid samples in healthy Standardbred horses. Aust Vet J (2012) 90:247–51.