European Journal of Cardiovascular Medicine

Muscle relaxation is an essential component of anaesthesia and critical care, facilitating tracheal intubation and optimal surgical conditions [1]. Among the non- depolarising agents, atracurium was used first for endotracheal intubation. But it is associated with side effects like flushing, erythema, bradycardia, bronchospasm, and dyspnoea resulting from histamine release. [2-3]Cis-atracurium is one of the 10[4] stereoisomers of atracurium, which is devoid of histamine release. Cis-atracurium is three to four times more potent than atracurium with better hemodynamic stability. [5]It was first approved for use in humans by the FDA in 1995. It is a benzo-isoquinoline neuromuscular blocker with an intermediate duration of action . [5] The dose of muscle relaxant usually recommended for facilitating tracheal intubation approximates at least 2 times the drug’s ED 95 [6] ED 95 is the amount of neuromuscular blocking drug required to reduce twitch height by 95%. The dose of a neuromuscular blocking drug required to produce an effect (e.g., 95% depression of twitch height, commonly expressed as ED95) is its potency. The ED      95 dose of cis- atracurium is estimated to be 0.05 mg/kg body weight. [7]However, two times the ED   95 dose of cis-atracurium does not provide satisfactory intubating conditions. [8] Higher doses of this drug may eliminate this problem, but may be associated with significant hemodynamic changes. It is safe in hepatic and renal impairment [9] and has a slower onset than atracurium, shortened by higher doses; ED₉₅ ≈0.05 mg/kg. [10] Effective intubation doses range from 0.1 to 0.2 mg/kg, but optimal dosing remains uncertain. [11]

In the study conducted by Shaikh et al [8], they examined cis-atracurium at different (2×ED95, 3×ED95, and 4×ED95) doses and found that higher doses improved the efficacy of tracheal intubation conditions, but they did not advocate the safe higher dose of this drug for endotracheal intubation. In another study by Aswani et al [11],it was found that the dose of 4 times ED 95 of cis-atracurium for tracheal intubation provided excellent intubating conditions with stable cardiovascular parameters. We found very few studies and limited literature evaluating the intubating condition 1 by using a high dose of cis-atracurium during endotracheal intubation. Hence, the present study was designed to evaluate and compare the onset time, duration of action, intubating conditions, and side effects of three different doses of cis- atracurium during tracheal intubation.

A prospective, double-blind, randomised controlled trial was conducted in the Department of Anaesthesiology, Regional Institute of Medical Sciences (RIMS), Imphal, from April 2023 to March 2025. Forty-five patients undergoing elective surgery under general anaesthesia with endotracheal intubation were enrolled after obtaining Institutional Ethics Committee approval and written informed consent. Sample size calculation: The sample size was determined based on the study by Shaikh SA et al. [8], in which the mean duration of action of cis-atracurium at 2 × ED95 and 4 × ED95 doses was 27.23 ± 6.97 minutes and 36.17 ± 7.62 minutes, respectively. The sample size was calculated using the following formula: Where: (α error at 5%) = 1.96 (Power of 80%) = 0.84 = 27.23 min (mean of Group A, 2 × ED95) = 36.17 min (mean of Group B, 4 × ED95) = 6.97 min (SD of Group A) = 7.62 min (SD of Group B) By applying an α value of 0.05 and a β power of 0.8, the minimum required sample size was calculated to be 11 participants per group. To account for a possible 5% dropout, the final sample size was increased to 15 participants in each group. Randomisation: A computer-generated randomisation sequence was prepared using GraphPad (GraphPad.com) by an independent observer. Forty-five participants were randomly allocated into three groups. The allocation details for each participant were secured in sequentially numbered, sealed, opaque envelopes. Both the investigator and the participants were blinded to group assignments to ensure a double-blind study design. Inclusion criteria: Patients meeting the following criteria were included in the study: 1. American Society of Anaesthesiologists (ASA) I or II 2. Age 18 to 60 years of either sex 3. Mallampati scores grade 1 or 2 4. Informed written consent Exclusion criteria: Patients were excluded if they had a known allergy to the study drug, an anticipated difficult intubation, were pregnant or lactating, were receiving medications known to interact with neuromuscular blocking agents, had neuromuscular disorders, bronchial asthma, or psychiatric illness requiring medication. Group allocation: Participants were randomly assigned, using computer-generated randomisation, into three groups of 15 patients each: ● Group A (n = 15): Received injection cisatracurium 0.2 mg/kg (4 × ED95) diluted to 10 ml with normal saline (NS). ●Group B (n = 15): Received injection cisatracurium 0.3 mg/kg (6 ×ED95) diluted to 10 ml with NS. ●Group C (n = 15): Received injection cisatracurium 0.4 mg/kg (8 × ED95) diluted to 10 ml with NS. Fig. 1: Consort flow diagram for allocation of groups Procedure: All patients were reassured through a thorough explanation of the procedure, and preoperative assessments were completed one day before surgery. A good rapport was established with each participant, and written informed consent was obtained. Patients were instructed to take oral Ranitidine 300 mg and Alprazolam 0.5 mg with a sip of water at 10:00 p.m. the night before surgery and to remain nil per oral (NPO) for at least six hours before the operation. On arrival in the operating room, intravenous access was secured using an 18-gauge cannula in the forearm, and Normal Saline (NS) infusion was initiated. A multiparameter monitor was applied to record heart rate, systolic and diastolic blood pressure, ECG, SpO₂, and train-of-four (TOF) responses for neuromuscular monitoring. The adductor pollicis muscle of either hand was used for TOF monitoring. Electrodes were applied to the volar side of the wrist. The distal electrode was placed 1 cm proximal to the point where the proximal flexion crease of the wrist traverses the radial side of the tendon extending towards the flexor carpi ulnaris muscle, and the proximal electrode was placed 3 cm proximal to the distal electrode. Patients were premedicated with glycopyrrolate 4 mcg/kg, ondansetron 0.1mg/kg, injection pantoprazole 40mg intravenously 5 to 10 minutes before induction of anaesthesia. Patients were then preoxygenated with 100% oxygen for three minutes. A uniform anaesthetic technique was used for all participants. General anaesthesia was induced with intravenous fentanyl 2 µg/kg and propofol 42 mg/kg until loss of the eyelash reflex. Bag-mask ventilation was maintained using a mixture of 35% oxygen, 65% nitrous oxide, and 1% sevoflurane. Study procedure: Injection cisatracurium (Cisatra, Themis India) was prepared as a standardised solution of 10 ml and administered intravenously at the dose corresponding to the patient’s allocated group by an anaesthesiologist not involved in the study. Baseline train-of-four (TOF) monitoring was performed before drug administration. Ninety seconds after injection, TOF was recorded every 30 seconds using a TOF-Watch (Organon Pvt. Ltd.) until the response reached a count of zero. Once the TOF count reached zero, laryngoscopy and endotracheal intubation were performed using a Macintosh blade No. 3 by an experienced anaesthesiologist who was also blinded to the drug allocation. The airway was secured with an appropriately sized cuffed Protex endotracheal tube, fixed after confirming equal bilateral air entry by chest auscultation and end-tidal carbon dioxide monitoring. The onset time of cisatracurium and the intubation conditions were assessed using the intubation scoring system described by Cooper R et al. [12]. Table 1: Intubation score Scor Jaw relaxation (laryngoscopy) Vocal cords Response to Intubation e 0 Poor (impossible) Closed Severe coughing or bucking 1 Minimal (difficult) Closing Mild coughing 2 Moderate (fair) Moving Slight diaphragmatic movement 3 Good (easy) Open None The post-intubation vital parameters were recorded at 3-minute, 5-minute, and thereafter for every 5-minute intervals till 50 minutes to assess the intubation response. Anaesthesia was maintained with a balanced technique with N2O/O2 in a ratio of 65:35 with systemic analgesics and trace sevoflurane. Any signs of histamine release, like skin colour changes, were graded as flush (if redness > 120 sec), erythema, or wheals. Data was entered and analysed in IBM SPSS Statistics version 26.0 for Windows [Armonk, NY: IBM Corp; 2020]. Continuous variables are summarised as mean and standard deviation or median and interquartile range, depending on the type of distribution. Categorical variables are expressed as frequency and percentages. Chi squared test, student t-test, and ANOVA test were used. A P-value of <0.05 was taken as statistically significant. Ethical issues: Ethical approval was obtained from the Research Ethics Board, RIMS, Imphal (A/206/ REB Comm(SP)/RIMS/2015/975/06/2023) dated 30/09/2023 before the commencement of the study and registered to Clinical Trial Registry of India (CTRI No- CTRI/2024/03/064130). Written informed consent was taken from all the participants. The data was placed under lock and key and was not disclosed to anyone, except for the investigator and the co-investigator.

The demographic profiles were comparable among the three groups and did not affect the study outcome, as shown in Table 2 :

*One-way ANOVA, +Fisher exact test

Table 3 shows that the mean onset of action was shorter among the patients in Group C. On post hoc analysis with Bonferroni correction, the onset of action was significantly shorter among the patients in Group C when compared to Group A  (p<0.001) and Group B (p=0.003); but there was no significant difference between Group A and Group B (p=0.240).

Table 2. Demographic profile between the groups

Table 3. Comparison of the onset of action between the groups

Mean                 SD

*One-way ANOVA with Bonferroni post hoc test

Table 4 shows that the mean duration of action was longer among the patients in  Group C, and it was found to be statistically significant (p<0.001). On post hoc analysis with Bonferroni correction, the mean duration of action was significantly longer among the patients in Group C when compared to Group A and Group B, and also between Group A and Group B.

Table 4. Comparison of duration of action between the groups (N=45)

Mean                               SD

*One-way ANOVA with Bonferroni post hoc test

The hemodynamic parameters (SBP, DBP, HR, Spo2) and side effects were comparable among the three groups at all observed time points, with no statistically significant differences.

The selection of an optimal neuromuscular blocking agent and its appropriate dosage is crucial for achieving safe and effective tracheal intubation, a fundamental component of anaesthesia and critical care. Cisatracurium, a widely used non-depolarising neuromuscular blocker, possesses favourable pharmacodynamic properties such as intermediate duration of action, minimal histamine release, and predictable recovery, making it suitable for various surgical and intensive care scenarios. However, the optimal dosing strategy that balances rapid onset, favourable intubating conditions, and minimal side effects continues to

be an area of clinical interest.

Hence, it became necessary to conduct a randomised controlled trial to compare the efficacy and safety of three different doses of cisatracurium for tracheal intubation, with a focus on onset time, intubation conditions, and hemodynamic stability. Understanding the relationship between dose and onset time is particularly important in scenarios requiring rapid sequence induction or in patients with comorbidities that may influence drug metabolism. Additionally, it will help in making informed decisions that might contribute to refining neuromuscular blockade strategies for airway management.

The demographic homogeneity between the three groups in terms of age, gender, body weight, ASA status, and modified Mallampati score (MPS) ensures that  differences in outcomes can be attributed to the drug doses rather than confounding factors. The predominant surgical indication was laparoscopic cholecystectomy, which constituted nearly 80% of cases. This aligns with previous studies where cisatracurium has been preferred in laparoscopic procedures due to its stable [13] hemodynamic profile and minimal histamine release.[12]

Our study found that intubating conditions according to the score by Cooper R et al were excellent across all groups, indicating that cisatracurium provides effective neuromuscular blockade for tracheal intubation regardless of the dose administered. This could be due to its intermediate onset time, reliable neuromuscular blockade  with minimal histamine release, and hemodynamic stability. A study by Shaikh SA etal        [8]also showed that cisatracurium in a dose of 0.2 mg kg-1 and 0.3 mg kg-18

provides good-to excellent intubating conditions within less than 3 minutes, which is consistent with our study. El-Kasaby AM et al [7], in their study, showed that the 6×ED95 dose of cisatracurium demonstrated a significantly higher proportion of patients achieving optimal intubating conditions compared to atracurium, which also supports our study. Another study by Ashwini A et al [14], a 4×ED95 dose of  cisatracurium offers superior intubation conditions and improved hemodynamic stability, which is consistent with our study.

It offers a smooth and predictable muscle relaxation, reducing the risk of airway complications. [15,16] Similar findings were observed in other studies, where intubation [17] conditions remained optimal with varying doses of cis-atracurium.

The results indicate that the mean onset of action was significantly shorter while the mean duration of action was significantly longer in Group C compared to Groups A and B (p<0.001). This dose-dependent response is consistent with prior literature, where higher doses of cis-atracurium lead to a faster onset due to increased receptor [18] occupancy and a prolonged duration owing to sustained neuromuscular blockade.

The speed of onset of a neuromuscular blocker is influenced by factors such as the rate of delivery of the drug to the neuromuscular junction, receptor affinity, and plasma clearance. [19]Laryngeal adductors were found to be more resistant to the action of cis-atracurium than the adductor pollicis (AP) muscles. Our results demonstrated that the onset of neuromuscular blockade (NMB) was rapid in the AP muscle at a higher dose of cis-atracurium. A high dose is predictive of a rapid onset of the effect and vice versa. For the aforementioned reasons, we speculated that a high dose of cis-atracurium provides the rapid onset of action in our study. This observation, that the higher dose leads to faster onset and prolonged duration of action, has been supported by various other studies. For instance, in a study by Shaikh SA et al [8], Group C (0.3 mg/kg) demonstrated a significantly faster onset of action and longer duration of action compared to Groups A (0.1 mg/kg) and Group B (0.2 mg/kg). Even a study by El-Kasaby AM et al [7], in their study, had concluded that higher doses of cis-atracurium (4×ED95 and 6×ED95) resulted in a faster onset and longer duration of action than both atracurium and the lower cis-atracurium dose (2×ED95). Notably, the 6×ED95 dose of cis-atracurium demonstrated a significantly higher proportion of patients achieving optimal intubating conditions compared to atracurium. Also, to support our evidence is a study by Amini S et al [20], in which the time to achieve complete neuromuscular blockade (TOF=0) for endotracheal [21] intubation was significantly shorter with increasing doses.

A study by Parpucu ÜM also concluded that patients with higher doses of NMBAs demonstrated significantly superior intubation quality compared to the lower dose. A study by Sengul N et al [22], also supported our study findings concerning the onset and duration of blockade. In  contrast, a study by Teymourian H et al [23] had shown that the onset of complete  neuromuscular blockade, defined by a Train-of-Four (TOF) count of zero, was comparable between the modified dose group and the high-dose group.

It is also noteworthy to mention that there was no significant difference in onset time between Groups A and B, but Group B exhibited a significantly longer duration of action compared to Group A. This suggests that at lower doses, the pharmacokinetic properties of cis-atracurium exhibit a plateau effect, whereas higher doses enhance  the duration of neuromuscular blockade. Hemodynamic parameters remained stable across all groups, with no significant differences over time. However, there was a transient decrease followed by a rise in these parameters within each group. This transient hypotensive effect is likely due to the initial vasodilatory response seen with neuromuscular blocking agents, which is counteracted by compensatory mechanisms such as sympathetic activation. [2] Prior research supports the observation that cis-atracurium has minimal cardiovascular effects compared to

other neuromuscular blockers like atracurium, which is known to cause histamine-  induced hypotension. [24] This stability makes cis-atracurium particularly advantageous in patients with cardiovascular comorbidities. Several other studies have supported this observation about hemodynamic stability. The hemodynamic stability concerning our study results has been observed across various studies. A study by Shaikh SA et al [8], showed that the patients in the group who received a higher dose of cis-atracurium exhibited superior hemodynamic stability, maintaining a more stable heart rate post-intubation compared to the other groups. Even a study by Amini S et al [20] reported that hemodynamic was stable across the groups without any significant difference with different doses. A study by Paul A et al [25], also supported our study findings in which no significant differences were noted between  the groups regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), or mean arterial pressure (MAP). Higher doses of cis-atracurium yielded stable hemodynamic parameters and no clinically evident signs of histamine release, in a study by Kant S et al [26]. None of the patients in the study experienced any adverse

effects, which aligns with the well-documented safety profile of cis-atracurium. The lack of histamine release and absence of autonomic side effects have been consistently reported in the literature, making it a preferred agent in patients with reactive airway disease or cardiovascular instability.

Strengths and limitations

The study was randomised, reducing selection bias and ensuring fair comparison between cis-atracurium doses. The sample size was small, so rare side effects might not have been seen, and it was done in only one hospital, so the results may not apply to all patients. Since no patient had severe side effects, and thereby not included in the data for statistical analysis. Future research on a multicentric level focusing on optimising dosing strategies to balance efficacy and recovery time with follow-up for a longer time

would add robustness to the study findings.

The findings of this study suggest that while all three doses provide excellent intubation conditions, the highest dose (Cisatra 0.4mg/kg (8 x ED 95) offers a significantly faster onset and prolonged duration of action. The stability in hemodynamic parameters further supports the safe use o cisatracurium in various patient populations. Future research on a multicentric level focusing on optimizing dosing strategies to balance efficacy and recovery time with follow-up for a longer time would add robustness to the study findings.

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