European Journal of Cardiovascular Medicine

Muscle relaxation is a fundamental component of general anaesthesia and critical care, essential for facilitating successful endotracheal intubation and ensuring optimal surgical conditions [1]. Historically, atracurium was the primary non-depolarising neuromuscular blocking agent utilised for this purpose. However, its clinical utility is frequently limited by adverse effects—such as flushing, erythema, bradycardia, bronchospasm, and dyspnoea—triggered by systemic histamine release [2-3].

Cis-atracurium, one of the ten stereoisomers of atracurium, was developed to eliminate these histamine-mediated side effects [4]. Approved by the FDA in 1995, cis-atracurium is an intermediate-acting benzylisoquinolinium neuromuscular blocker that exhibits three to four times the potency of atracurium alongside superior hemodynamic stability [5].

In clinical practice, the standard recommended dose of a muscle relaxant to facilitate tracheal intubation is typically at least twice its effective dose 95 (2 × ED₅₀) [6]. The ED₅₀ represents the drug potency required to reduce twitch height by 95%, which for cis-atracurium is estimated at 0.05 mg/kg body weight [7]. However, a standard 2 × ED₅₀ dose of cis-atracurium often fails to provide satisfactory intubating conditions [8]. While escalating the dose can overcome this limitation and accelerate the drug's characteristically slow onset, higher doses raise concerns regarding potential hemodynamic instability [9,10]. Notably, the drug remains safe for use in patients with renal and hepatic impairment due to its organ-independent metabolism [9].

While effective intubation doses are reported to range from 0.1 to 0.2 mg/kg, the optimal dosing regimen remains a subject of debate [11]. Shaikh et al. evaluated cis-atracurium at 2 × ED₅₀, 3 × ED₅₀, and 4 × ED₅₀ doses; they noted that higher doses significantly improved tracheal intubation quality but stopped short of advocating a specific, safe higher-dose threshold [8]. Conversely, Aswani et al. demonstrated that a dose of 4 × ED₅₀ provided excellent intubating conditions while maintaining completely stable cardiovascular parameters [11].Given the paucity of literature and clinical trials evaluating high-dose cis-atracurium regimens, the ideal strategy for optimizing intubation remains unestablished. Therefore, this study was designed to evaluate and compare the onset time, duration of action, intubating conditions, and side-effect profiles of three distinct doses of cis-atracurium during endotracheal 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.

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: n = [2 × (Zα + Zβ)² × σ²] / d², where n is the sample size per group, Zα is the standard normal deviation for the significance level (1.96 for α = 0.05), Zβ is the standard normal deviation for statistical power (0.84 for 80% power), σ is the pooled standard deviation (7.30), and d is the expected mean difference (8.94).

Sample Size Calculation

The sample size was calculated using an α error of 5% (Zα = 1.96) and a power of 80% (Zβ = 0.84).

Mean of Group A (2 × ED95): 27.23 minutes

Mean of Group B (4 × ED95): 36.17 minutes

Standard deviation (SD) of Group A: 6.97 minutes

Standard deviation (SD) of Group B: 7.62 minutes

Based on these values, the minimum required sample size was determined 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 and Blinding

A computer‑generated randomisation sequence was prepared using GraphPad (GraphPad.com) by an independent observer. Forty‑five participants were randomly allocated into three groups. Allocation details were secured in sequentially numbered, sealed, opaque envelopes. Both the investigator and participants were blinded to group assignments, ensuring a double‑blind study design.

Inclusion Criteria

Patients meeting the following criteria were included:

·        American Society of Anaesthesiologists (ASA) physical status I or II

·        Age between 18 and 60 years, either sex

·        Mallampati score grade 1 or 2

·        Provided informed written consent

Exclusion Criteria

Patients were excluded if they had:

·        Known allergy to the study drug

·        Anticipated difficult intubation

·        Pregnancy or lactation

·        Medications known to interact with neuromuscular blocking agents

·        Neuromuscular disorders

·        Bronchial asthma

·        Psychiatric illness requiring medication

Group Allocation

Participants were randomly assigned into three groups (n = 15 each):

·        Group A: Received injection cisatracurium 0.2 mg/kg (4 × ED95) diluted to 10 ml with normal saline (NS).

·        Group B: Received injection cisatracurium 0.3 mg/kg (6 × ED95) diluted to 10 ml with NS.

Group C: Received injection cisatracurium 0.4 mg/kg (8 × ED95) diluted to 10 ml with NS.

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 2 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

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

Table 2. Demographic profile between the groups

Notes:  * 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 3. Comparison of the Onset of Action Between Groups

Note: One‑way ANOVA with Bonferroni post hoc test

Table 4. Comparison of Duration of Action Between Groups (N = 45)

Note: 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 hemodynamic profile and minimal histamine release.

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 et al [8] also showed that cisatracurium in a dose of 0.2 mg/kg and 0.3 mg/kg 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] reported that 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 conditions remained optimal with varying doses of cisatracurium [17].

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 cisatracurium lead to a faster onset due to increased receptor occupancy and a prolonged duration owing to sustained neuromuscular blockade [18].

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 cisatracurium 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 cisatracurium. 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 cisatracurium 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] concluded that higher doses of cisatracurium (4 × ED95 and 6 × ED95) resulted in a faster onset and longer duration of action than both atracurium and the lower cisatracurium dose (2 × ED95). Notably, the 6 × ED95 dose of cisatracurium 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 intubation was significantly shorter with increasing doses. A study by Parpucu ÜM [21] 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 cisatracurium 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 cisatracurium has minimal cardiovascular effects compared to other neuromuscular blockers like atracurium, which is known to cause histamine‑induced hypotension [24]. This stability makes cisatracurium 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 cisatracurium 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 parameters were 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 cisatracurium 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 cisatracurium. 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 cisatracurium doses.

The sample size was small, so rare side effects might not have been seen, and it was conducted in only one hospital, so the results may not apply to all patients. Since no patient had severe side effects, they were 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 duration 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 of 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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