Cisatracurium besylate is an intermediate-acting, non-depolarizing neuromuscular blocking drug (NMBD). Cisatracurium besylate has a benzylisoquinolinium structure and is the 1R cis-1-prime R cis isomer of atracurium. As an NMBD, it has found use as an adjunct to general anesthesia, facilitating tracheal intubation and providing skeletal muscle relaxation during surgery. Cisatracurium besylate may also be used to provide skeletal muscle relaxation to facilitate mechanical ventilation in an intensive care unit setting but must be used with sedation. This activity reviews indications, mechanism of action, administration, contraindications, monitoring, and toxicity associated with Cisatracurium besylate and the role of the interprofessional team in caring for patients who have received cisatracurium. Cisatracurium undergoes organ-independent Hofmann elimination—a chemical process dependent on pH and temperature—to form the monoquaternary acrylate metabolite and laudanosine. Patients with hypothermia, which typically occurs in surgeries needing cardiopulmonary bypass and therapeutic hypothermia, may require a lower dose of cisatracurium.

Cisatracurium Besilate in Anaesthetic Practice

Cisatracurium besilate (besylate) is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. It is the R-cis,R′-cis isomer of atracurium besilate and is approximately 3-fold more potent than the mixture of isomers that constitute the parent drug. In clinical trials, Cisatracurium besylate has been used successfully to facilitate intubation (at 2 to 4× ED95) and as a muscle relaxant during surgery and in intensive care. Compared with vecuronium, cisatracurium besilate was associated with a significantly faster recovery after continuous infusion in patients in intensive care.The ED95for Cisatracurium besylate (dose required to produce 95% suppression of twitch response to nerve stimulation) in adults is 0.05 mg/kg during N2O/O2 opioid anaesthesia. Relative to atracurium besilate, Cisatracurium besylate has a lower propensity to cause histamine release, is more potent but has a slightly longer onset time at equipotent doses. It also offers a more predictable recovery profile than vecuronium after prolonged use in patients in intensive care. Thus, comparative data provide some indication of the potential of Cisatracurium besylate as an intermediate-duration neuromuscular blocking agent but further comparisons with other like agents are required to define precisely its relative merits.[1]

Cisatracurium besylate undergoes temperature and pH-dependent chemical (Hofmann) degradation. This is the main route by which the drug is broken down and accounts for 77% of its total clearance. Cisatracurium besilate degrades to form laudanosine and the corresponding monoquaternary acrylate (which in turn is broken down to a monoquaternary alcohol and then laudanosine). Although the liver and kidneys play only a small role in the excretion of Cisatracurium besylate, urinary and hepatic elimination pathways are important for the metabolites of laudanosine. For adult patients in intensive care, the mean infusion rate of cisatracurium besilate required to maintain adequate neuromuscular block ranged between 2.6 and 3.2 μg/kg/min. The mean time to 70% recovery of the ratio of the fourth to the first train-of-four response after an infusion duration of at least 12 hours was significantly faster in Cisatracurium besylate than vecuronium recipients (68 vs 387 minutes). According to an overview of all clinical data (n=946), events possibly related to cisatracurium besilate were bradycardia (0.4%), hypotension (0.2%), flushing (0.2%), bronchospasm (0.2%) and rash (0.1%).

Cisatracurium besylate rescues Mycobacterium Tuberculosis-infected macrophages

Mycobacterium tuberculosis can induce necrotic-dominant multiple modes of cell death in macrophages, which accelerates bacterium dissemination and expands tissue injury in host lungs. Mining drugs to counteract Mycobacterium tuberculosis-induced cell death would be beneficial to tuberculosis patients. Since the death mode of Mtb-infected cells directs the subsequent anti-infectious immune responses, dissecting the mechanism of Mtb infection induced-cell death in Mφ is expected to be beneficial for developing an effective therapeutic modality. Among the screened drugs, Cisatracurium besylate (CIS, C53H72N2O12·2C6H5O3S) showed the strongest protective effect by targeting necroptosis to significantly reduce the mortality of Mtb-infected Mφ. CIS is a potent non-depolarizing neuromuscular blocking drug (NMBD) and binds to cholinergic receptors at the motor endplate to antagonize the action of acetylcholine, resulting in a competitive neuromuscular blockade. The involvement of CIS in modulating immune responses has been reported but not related to its role during cell death, especially in Mtb infection.[2]

According to the clinical dosage of Cisatracurium besylate, dose conversion is carried out according to the equivalent dose ratio converted from the body surface area between humans and animals, and the dose administered to mice is about 12.3 times that of humans. The clinical dose of CIS is 0.15 mg/kg; thus, the intravenous injection dose of mice was converted to 1.845 mg/kg. The protective effects of CIS through suppressing necroptosis were supposed to maintain the viability and anti-Mtb activity of Mφ and in turn promote immune responses against Mtb infection, which prompted us to explore whether CIS could inhibit intracellular Mtb survival. As expected, CIS inhibited the intracellular H37Rv replication in BMDM in a dose-dependent manner. Enhancing necroptosis by FK866 could slightly promote Mtb survival, which was also significantly suppressed by CIS. Cisatracurium besylate was identified to be highly protective for the viability of macrophages during Mycobacterium tuberculosis infection via inhibiting necroptosis. Cisatracurium besylate prevented RIPK3 to be associated with the executive molecule MLKL for forming the necroptotic complex, resulting in the inhibition of MLKL phosphorylation and pore formation on cell membrane.

Pharmacokinetics and Pharmacodynamics of Cisatracurium Besylate in Children.

Previous pediatric studies have examined cisatracurium pharmacology during nitrous oxide (N2O)-narcotic anesthesia and during halothane anesthesia but not during propofol anesthesia. de Ruiter and Crawford performed a dose-response study of Cisatracurium besylate in children aged 3 to 10 yr using N2O-narcotic anesthesia to determine effective dose and infusion requirements. They found an ED50 25% larger than that reported by Meretoja et al., although similar to values in adults undergoing a N2O-narcotic technique. It is unclear whether this difference is merely the result of methodological factors. However, there have been no PK or PK/PD studies conducted for cisatracurium in children. The objective of the present study was therefore to characterize the concentration-effect relation of Cisatracurium besylate in children during N2O/O2/propofol anesthesia. Three-milliliter blood samples were drawn from the dedicated IV cannula and placed into chilled vacutainer tubes containing EDTA for the baseline sample and heparin for all others. Eight venous samples were drawn for each patient: at baseline (blank) and at 2, 5, 10, 30, 60, 90, and 120 min after Cisatracurium besylate administration. The blood was immediately transferred into chilled microcentrifuge tubes for a 45-s centrifugation at 14,000 rpm. [3]

The relation between plasma concentration and effect for Cisatracurium besylate has not been characterized in children. Because propofol, with or without opioids, is a commonly used drug in pediatric anesthesia for both induction and maintenance, it is important to obtain PK/PD data of Cisatracurium besylate during this type of anesthesia. In our patients, the recovery index from 25% to 75% of baseline twitch height (11 ± 4 min) was virtually identical to that reported in the abovementioned studies. This observation suggests that although the biological half-life of cisatracurium was not measured in other studies, it may not differ significantly among treatment groups. Moreover, spontaneous recovery rate seems independent of initial dosage and duration of infusion or the number of maintenance doses of Cisatracurium besylate administered. In one case report, a 7-kg infant received an overdose of 0.86 mg/kg and nevertheless obtained a recovery index between 10 and 15 min.

References

[1]Bryson, H M, and D Faulds. “Cisatracurium besilate. A review of its pharmacology and clinical potential in anaesthetic practice.” Drugs vol. 53,5 (1997): 848-66. doi:10.2165/00003495-199753050-00012

[2]Wen, Qian et al. “Cisatracurium besylate rescues Mycobacterium Tuberculosis-infected macrophages from necroptosis and enhances the bactericidal effect of isoniazid.” International immunopharmacology vol. 120 (2023): 110291. doi:10.1016/j.intimp.2023.110291

[3]Imbeault, Karynn et al. “Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children during N2O/O2/propofol anesthesia.” Anesthesia and analgesia vol. 102,3 (2006): 738-43. doi:10.1213/01.ane.0000195342.29133.ce