Top

Trials

Published in:

Open Access 01-12-2022 | Pharmacodynamics | Study protocol

The effect of obstructive jaundice on the sensitivity of intravenous anesthetic of remimazolam: study protocol for a controlled multicenter trial

Authors: Wen Liu, Bin Yang, Jun-Wei Ji, Hua Yang, Hong-Hao Song, Hai-Bo Qiu, Jin-Chao Song

Published in: Trials | Issue 1/2022

Abstract

Background

It is well known that obstructive jaundice could affect the pharmacodynamics of some anesthetics, and the sensitivity of some anesthetics would increase among icteric patients. Remimazolam is a new ultra-short-acting intravenous benzodiazepine sedative/anesthetic, which is a high-selective and affinity ligand for the benzodiazepine site on the GABAA receptor. However, no study has reported the pharmacodynamics of remimazolam in patients with obstructive jaundice. We hypothesize that obstructive jaundice affects the pharmacodynamics of remimazolam, and the sensitivity of remimazolam increases among icteric patients.

Methods/design

The study will be performed as a prospective, controlled, multicenter trial. The study design is a comparison of remimazolam requirements to reach a bispectral index of 50 in patients with obstructive jaundice versus non-jaundiced patients with chronic cholecystitisor intrahepatic bile duct stones. Remimazolam was infused at 6 mg/kg/h until this endpoint was reached.

Discussion

Remimazolam could be suitable for anesthesia of patients with obstructive jaundice, because remimazolam is not biotransformed in the liver. Hyperbilirubinemia has been well-described to have toxic effects on the brain, which causes the increasing of sensitivity to some anesthetics, such as desflurane, isoflurane, and etomidate. Furthermore, remimazolam and etomidate have the same mechanism of action when exerting an anesthetic effect. We aim to demonstrate that obstructive jaundice affects the pharmacodynamics of remimazolam, and the dose of remimazolam when administered to patients with obstructive jaundice should be modified.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100043585. Registered on 23 February 2021

Brandoni A, Villar SR, Picena JC, Anzai N, Endou H, Torres AM. Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction. Hepatology. 2006;43(5):1092–100. https://doi.org/10.1002/hep.21142.CrossRefPubMed

Green J, Better OS. Systemic hypotension and renal failure in obstructive jaundice-mechanistic and therapeutic aspects. J Am Soc Nephrol. 1995;5(11):1853–71. https://doi.org/10.1681/ASN.V5111853.CrossRefPubMed

Kimmings AN, van Deventer SJ, Obertop H, Rauws EA, Gouma DJ. Inflammatory and immunologic effects of obstructive jaundice: pathogenesis and treatment. J Am Coll Surg. 1995;181(6):567–81.PubMed

Keam SJ. Remimazolam: first approval. Drugs. 2020;80(6):625–33. https://doi.org/10.1007/s40265-020-01299-8.CrossRefPubMed

Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, et al. CNS 7056: a novel ultra-short-acting benzodiazepine. Anesthesiology. 2007;107(1):60–6. https://doi.org/10.1097/01.anes.0000267503.85085.c0.CrossRefPubMed

Wiltshire HR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesth Analg. 2012;115(2):284–96. https://doi.org/10.1213/ANE.0b013e318241f68a.CrossRefPubMed

Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012;115(2):274–83. https://doi.org/10.1213/ANE.0b013e31823f0c28.CrossRefPubMed

Song JC, Sun YM, Zhang MZ, Yang LQ, Tao TZ, Yu WF. The etomidate requirement is decreased in patients with obstructive jaundice. Anesth Analg. 2011;113(5):1028–32. https://doi.org/10.1213/ANE.0b013e31822dac4a.CrossRefPubMed

Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346(jan08 15):e7586. https://doi.org/10.1136/bmj.e7586.CrossRefPubMedPubMedCentral

10.

Mochida S, Ogata I, Hirata K, Ohta Y, Yamada S, Fujiwara K. Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats. Gastroenterology. 1990;99(3):771–7. https://doi.org/10.1016/0016-5085(90)90967-6.CrossRefPubMed

11.

Song JC, Gao H, Qiu HB, Chen QB, Cai MH, Zhang MZ, et al. The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: a clinical trial. PLoS One. 2018;13(11):e0207427. https://doi.org/10.1371/journal.pone.0207427.CrossRefPubMedPubMedCentral

12.

Ma Z, Zhang Y, Huet PM, Lee SS. Differential effects of jaundice and cirrhosis on beta-adrenoceptor signaling in three rat models of cirrhotic cardiomyopathy. J Hepatol. 1999;30(3):485–91. https://doi.org/10.1016/S0168-8278(99)80109-3.CrossRefPubMed

13.

Lumlertgul D, Boonyaprapa S, Bunnachak D, Thanachaikun N, Praisontarangkul OA, Phornphutkul K, et al. The jaundiced heart: evidence of blunted response to positive inotropic stimulation. Ren Fail. 1991;13(1):15–22. https://doi.org/10.3109/08860229109022141.CrossRefPubMed

14.

Ljubuncic P, Said O, Ehrlich Y, Meddings JB, Shaffer EA, Bomzon A. On the in vitro vasoactivity of bile acids. Br J Pharmacol. 2000;131(3):387–98. https://doi.org/10.1038/sj.bjp.0703554.CrossRefPubMedPubMedCentral

15.

Padillo J, Puente J, Gómez M, Dios F, Naranjo A, Vallejo JA, et al. Improved cardiac function in patients with obstructive jaundice after internal biliary drainage: hemodynamic and hormonal assessment. Ann Surg. 2001;234(5):652–6. https://doi.org/10.1097/00000658-200111000-00010.CrossRefPubMedPubMedCentral

16.

Schüttler J, Eisenried A, Lerch M, Fechner J, Jeleazcov C, Ihmsen H. Pharmacokinetics and pharmacodynamics of remimazolam (CNS 7056) after continuous infusion in healthy male volunteers: Part I. Pharmacokinetics and clinical pharmacodynamics. Anesthesiology. 2020;132(4):636–51. https://doi.org/10.1097/ALN.0000000000003103.CrossRefPubMed

17.

Sheng XY, Liang Y, Yang XY, Li LE, Ye X, Zhao X, et al. Safety, pharmacokinetic and pharmacodynamic properties of single ascending dose and continuous infusion of remimazolam besylate in healthy Chinese volunteers. Eur J Clin Pharmacol. 2020;76(3):383–91. https://doi.org/10.1007/s00228-019-02800-3.CrossRefPubMed

18.

Doi M, Hirata N, Suzuki T, Morisaki H, Morimatsu H, Sakamoto A. Safety and efficacy of remimazolam in induction and maintenance of general anesthesia in high-risk surgical patients (ASA Class III): results of a multicenter, randomized, double-blind, parallel-group comparative trial. J Anesth. 2020;34(4):491–501. https://doi.org/10.1007/s00540-020-02776-w.CrossRefPubMed

19.

Furukawa Y. Histological changes in the brain due to experimental obstructive jaundice. Nihon Geka Gakkai Zasshi. 1991;92(1):37–45.PubMed

20.

Brito MA, Brites D, Butterfield DA. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes. Brain Res. 2004;1026(1):33–43. https://doi.org/10.1016/j.brainres.2004.07.063.CrossRefPubMed

21.

Haustein MD, Read DJ, Steinert JR, Pilati N, Dinsdale D, Forsythe ID. Acute hyperbilirubinaemia induces presynaptic neurodegeneration at a central glutamatergic synapse. J Physiol. 2010;588(Pt 23):4683–93. https://doi.org/10.1113/jphysiol.2010.199778.CrossRefPubMedPubMedCentral

22.

Silva RF, Rodrigues CM, Brites D. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res. 2002;51(4):535–41. https://doi.org/10.1203/00006450-200204000-00022.CrossRefPubMed

23.

Silva R, Mata LR, Gulbenkian S, Brito MA, Tiribelli C, Brites D. Inhibition of glutamate uptake by unconjugated bilirubin in cultured cortical rat astrocytes: role of concentration and pH. Biochem Biophys Res Commun. 1999;265(1):67–72. https://doi.org/10.1006/bbrc.1999.1646.CrossRefPubMed

24.

Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med. 1995;123(3):161–7. https://doi.org/10.7326/0003-4819-123-3-199508010-00001.CrossRefPubMed

25.

Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology. 1995;108(5):1582–8. https://doi.org/10.1016/0016-5085(95)90709-2.CrossRefPubMed

26.

Jones EA, Yurdaydin C. Is fatigue associated with cholestasis mediated by altered central neurotransmission? Hepatology. 1997;25(2):492–4. https://doi.org/10.1002/hep.510250239.CrossRefPubMed

27.

Swain MG, Maric M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology. 1997;25(2):291–4. https://doi.org/10.1002/hep.510250206.CrossRefPubMed

28.

Burak KW, Le T, Swain MG. Increased midbrain 5-HT1A receptor number and responsiveness in cholestatic rats. Brain Res. 2001;892(2):376–9. https://doi.org/10.1016/S0006-8993(00)03058-4.CrossRefPubMed

29.

Song JG, Cao YF, Yang LQ, Yu WF, Li Q, Song JC, et al. Awakening concentration of desflurane is decreased in patients with obstructive jaundice. Anesthesiology. 2005;102(3):562–5. https://doi.org/10.1097/00000542-200503000-00014.CrossRefPubMed

30.

Yang LQ, Song JC, Irwin MG, Song JG, Sun YM, Yu WF. A clinical prospective comparison of anesthetics sensitivity and hemodynamic effect among patients with or without obstructive jaundice. Acta Anaesthesiol Scand. 2010;54(7):871–7. https://doi.org/10.1111/j.1399-6576.2010.02222.x.CrossRefPubMed

31.

Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ. The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci U S A. 1997;94(20):11031–6. https://doi.org/10.1073/pnas.94.20.11031.CrossRefPubMedPubMedCentral

32.

Desai R, Ruesch D, Forman SA. Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity. Anesthesiology. 2009;111(4):774–84. https://doi.org/10.1097/ALN.0b013e3181b55fae.CrossRefPubMed

33.

Martin LJ, Oh GH, Orser BA. Etomidate targets alpha5 gamma-aminobutyric acid subtype A receptors to regulate synaptic plasticity and memory blockade. Anesthesiology. 2009;111(5):1025–35. https://doi.org/10.1097/ALN.0b013e3181bbc961.CrossRefPubMed

34.

Shi HB, Kakazu Y, Shibata S, Matsumoto N, Nakagawa T, Komune S. Bilirubin potentiates inhibitory synaptic transmission in lateral superior olive neurons of the rat. Neurosci Res. 2006;55(2):161–70. https://doi.org/10.1016/j.neures.2006.02.015.CrossRefPubMed

35.

Li CY, Shi HB, Wang J, Ye HB, Song NY, Yin SK. Bilirubin facilitates depolarizing GABA/glycinergic synaptic transmission in the ventral cochlear nucleus of rats. Eur J Pharmacol. 2011;660(2-3):310–7. https://doi.org/10.1016/j.ejphar.2011.03.017.CrossRefPubMed

Title: The effect of obstructive jaundice on the sensitivity of intravenous anesthetic of remimazolam: study protocol for a controlled multicenter trial
Authors: Wen Liu
Bin Yang
Jun-Wei Ji
Hua Yang
Hong-Hao Song
Hai-Bo Qiu
Jin-Chao Song
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Pharmacodynamics
Anesthetics
Etomidate
Anesthetics
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-021-05987-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The effect of obstructive jaundice on the sensitivity of intravenous anesthetic of remimazolam: study protocol for a controlled multicenter trial

Abstract

Background

Methods/design

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods/design

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2022

Effect of time restricted feeding on anthropometric measures, eating behavior, stress, and brain-derived neurotrophic factor (BDNF) and lipopolysaccharide-binding protein (LBP) levels in women with overweight/obesity and food addiction: a study protocol for a randomized clinical trial

PATHWEIGH, pragmatic weight management in adult patients in primary care in Colorado, USA: study protocol for a stepped wedge cluster randomized trial

Online Parent Training for The Initial Management of ADHD referrals (OPTIMA): the protocol for a randomised controlled trial of a digital parenting intervention implemented to support parents and children on a treatment waitlist

Study protocol for ACTIVE study: safety and feasibility evaluation of external ventricular drainage with ACTIVE fluid exchange in intraventricular hemorrhage—a phase 2, multi-center, randomized controlled trial

Impact of telelactation services on breastfeeding outcomes among Black and Latinx parents: protocol for the Tele-MILC randomized controlled trial

How do we know a treatment is good enough? A survey of non-inferiority trials