Equipotent Dose and Cost Comparison of Atracurium and Rocuronium in Propofol-Anaesthetized Pigs

1. Introduction

Neuromuscular blocking agents (NMBAs) play a crucial role in the framework of a comprehensive anesthetic plan. Their addition at induction of anesthesia has been reported to ease endotracheal intubation in both human [1,2] and pigs [3,4]. Moreover, they are essential in achieving adequate muscle relaxation during specific operations, allowing surgeons to perform procedures with greater precision and ease, significantly reducing the risk of muscle-related issues and improving surgical outcomes [5,6,7,8]. Particularly in the domain of biomedical research, the use of non-depolarizing NMBAs is commonplace during surgical procedures in pigs. A review of research studies conducted between 2012 and 2014 revealed that NMBAs were administered in approximately 20% of the cases [6]. Unfortunately, there is limited information available on the species-specific dosing of NMBAs for pigs, and those reported are often extrapolated from other species. To date, few studies have reported effective doses for atracurium and rocuronium in pigs. For experimental subjects, intravenous doses of atracurium ranging from 0.4 to 2.5 mg/kg [9,10,11] and rocuronium from 0.5 to 5 mg/kg have been documented [12,13,14,15]. However, no formal guidelines have yet been established for their use in this species. Both drugs are classified as non-depolarizing neuromuscular blocking agents (NMBAs) and are well-documented in porcine medical research [9,10,13,14,16]. While they exhibit comparable pharmacodynamic profiles, metabolic pathways differ and may influence the choice between them. Atracurium undergoes organ-independent metabolism via Hoffmann elimination, ensuring consistent clearance even in cases of renal or hepatic impairment or during prolonged administration. In contrast, rocuronium is primarily metabolized by the liver, with a minor portion excreted renally [10,12,16]. Despite these differences, pharmacokinetic considerations are rarely of practical relevance, and current literature does not favor the use of one agent over the other. Another consideration that may influence drug selection is the cost required to maintain comparable neuromuscular relaxation. This study aims to evaluate the cost-effectiveness of atracurium and rocuronium within the Swiss healthcare system in laboratory swine undergoing propofol anesthesia at equipotent infusion rates.

2. Materials and Methods

This study was conducted in accordance with the Committee for Animal Experiments of the Canton of Bern, Switzerland (Cantonal no. BE65/2023). Each pig underwent a single experimental trial, at the end of which euthanasia was performed (pentobarbital; 150 mg kg-1 intravenous (IV)). Data collection presented here was performed concomitantly to another study objective on the evaluation of propofol-induced modulation of the electroencephalographic activity. Therefore, variations in the propofol administration rate by target-controlled infusion was performed during the study. The present investigation was designed as a prospective, blinded, randomized, crossover trial. Sample size analysis revealed that at least 11 pigs needed to be included to significantly detect a relevant difference in cost between the two groups (paired Wilcoxon signed rank test, α=0.05, β=0.8, effect size=1, difference=10%, standard deviation=10%, GPower v3.1.9.7, Germany).

3. Results

Table 1. Main characteristics of the enrolled population.

Pigs Name	Group	Body mass (kg)	Sex	Age (weeks)
F	A	42.1	F	12
G	R	46.8	F	13
H	R	45.2	F	12.5
I	A	28	M	10.5
J	R	47.8	M	13.5
K	A	28.9	F	10.5
L	A	23.9	M	9
M	A	29	M	10.5
N	R	33.4	M	11.5
O	R	30.6	F	11
P	A	28.5	F	10.5
Q	R	28.9	F	10.5

* A: Atracurium group; R. Rocuronium group; M: male; F: female

Table 1. Main characteristics of the enrolled population.

Pigs Name	Group	Body mass (kg)	Sex	Age (weeks)
F	A	42.1	F	12
G	R	46.8	F	13
H	R	45.2	F	12.5
I	A	28	M	10.5
J	R	47.8	M	13.5
K	A	28.9	F	10.5
L	A	23.9	M	9
M	A	29	M	10.5
N	R	33.4	M	11.5
O	R	30.6	F	11
P	A	28.5	F	10.5
Q	R	28.9	F	10.5

* A: Atracurium group; R. Rocuronium group; M: male; F: female

All pigs were included in the study leading to a total of six pigs per group, weighing 39.3 [31.3-46.4] and 28.7 [28.1-28.9] kg and aged 12 [11.1-12.9] and 10.5 [10.5-10.5] weeks in groups R and A, respectively. The stimulation intensity required to elicit an appropriate movement was between 35 and 50 mA in all pigs. The median predicted plasma concentration of propofol required for intubation was 22.0 [20.3-22.8] μg /mL and 19.7 [14.5-21.5] μg /mL in group R and A, respectively. During Phase 2, body temperature was 38.9 [38.8-38.9] °C and 38.7 [38.4-38.9] °C, end-tidal CO2 partial pressure was 43 [41-44] mmHg and 44 [42-44] ± 2 mmHg, and mean arterial pressure was 90 [86-93] mmHg for 11[11-13] CV%, and 73 [68-88] mmHg for 17[15-18] CV% (p = 0.1797), for group R and A, respectively. All pigs from group R required a single bolus of rocuronium (1 [1-1]), totaling 2 [2-2] mg/kg as induction dose in Phase 1. In contrast, animals receiving atracurium required 8 [6-9] boluses to reach the induction dose of 2.3 [1.8-2.6] mg/kg. The price of an IV bolus at the induction dose was 0.208 [0.208-0.208] CHF/kg for group R, and 1.122 [0.878-1.366] CHF/kg for group A (p= 0.002725). In Phase 2, the final infusion rate of rocuronium administered was 4.5 [4.4-4.5] mg/kg/h, while that of atracurium was 2.7 [2.5-2.8] mg/kg/h.

4. Discussion

This study reports that the dose of atracurium needed to induce muscle relaxation is slightly higher than that of rocuronium, while the maintenance infusion rate was about 40% lower for atracurium than for rocuronium. Overall, administration of atracurium leads to significantly higher costs for both initial bolus and maintenance when targeting a similar muscle relaxation. The present study reports that rocuronium may be markedly less expensive than atracurium to achieve appropriate muscle relaxation in Switzerland. Under the conditions presented here (the per-gram price of rocuronium being 21% that of atracurium), the cost of atracurium was 5.4 times higher than rocuronium for the initial bolus, and 2.8 times higher for maintenance infusion. This difference will vary with the purchase cost of the drugs (per gram). According to the dose equivalence obtained in the present study, atracurium would need to cost no more than 87% or 166% of rocuronium's price (per gram) to be equally expensive during initial bolus and maintenance infusion, respectively. The atracurium dose observed herein to reach deep muscular relaxation was 2.3 mg/kg for the initial dose, followed by 2.7 mg/kg/h. Previous information on the use of atracurium in pigs is scarce but seems in agreement with this result. Doses of 0.6 mg/kg or less were previously found inappropriate and only a mild blockade was achieved [17]. According to Shorten et al. (1993) [11], a dose of 1.15 mg/kg allowed near-complete suppression of T1 (ED95% that was represented by 1150 ± 270 µg/kg of atracurium) in juvenile pigs (age range seven to nine weeks), indicating profound relaxation. In other publications, doses of 2 mg/kg and above were required to elicit deep neuromuscular blockade [18,19]. It is noteworthy that pigs seem to require significantly higher doses of atracurium than other domestic animal species [20]. Regarding the use of rocuronium in pigs, an apparent result of the present study is that a similar or lower bolus dose is necessary compared to atracurium to induce neuro-muscular relaxation, while a significant higher dose is required for infusion maintenance. In previous studies, doses of rocuronium below 1 mg/kg were mostly judged inappropriate or insufficient [4,21,22,23].Doses between 1 and 2 mg/kg proved sufficient to elicit moderate relaxation including T1 depression of the TOF count for short durations [13,15,24,25]. Doses above 3 mg/kg induced prolonged deep muscle relaxation [26,27,28]. These observations are in agreement with the present study where 2 mg/kg provided marked relaxation. Regarding infusion rate, the current work reports that achieving optimal muscular blockade with a TOF count of 3 or lower required nearly double the maintenance amount (mg/kg/h) of rocuronium compared to atracurium. This is consistent with a previous study in juvenile animals where a dose of 2.5 mg/kg/h of rocuronium proved insufficient to elicit muscle relaxation, while 5 mg/kg/h was satisfactory [14]. An interesting finding of the current analysis is the number of boluses required to achieve muscle relaxation. The objective was to find the appropriate dose to induce a deep muscle relaxation as targeted by a TOF count of 3. Therefore, a slightly lower dose than expected was administered for both drugs to allow for titrating it up without requiring too many boluses. However, the strategy was suboptimal for both drugs. For rocuronium, deep relaxation was achieved at the first dose of 2 mg/kg in all pigs, suggesting that a lower dose would have been sufficient. For atracurium, the first dose of 1 mg/kg was never sufficient and at least 6 additional boluses (0.2 mg/kg increments) were necessary in all pigs to reach the targeted effect, suggesting that a higher initial dose would have been more appropriate. The high number of boluses prolonged the time between the first and the last administrations, potentially leading to a loss of effect from the initial doses. This suggests that a slightly lower total dose of atracurium may have been sufficient. For both groups, body temperature and end-tidal CO2 demonstrated stability within normal ranges during Phase 2. This is of importance as these variables (i.e. perianesthetic hypothermia or respiratory acidosis) have been reported to potentially influence the efficacy of neuromuscular blocking agents [29]. A significant difference was observed for the mean arterial pressure (MAP), with group R recording higher values (90 mmHg) compared to group A (73 mmHg). While more recently developed NMBAs are expected to exhibit mild to no cardiovascular effects, histamine release or sympathomimetic activity (i.e. affinity for cardiac muscarinic receptors) have been described and may vary across patients and situations [26]. However, the present study was not structured to answer this question, and no conclusion can be drawn.

Several limitations of this study should be acknowledged. First, the placement of the electrodes for the TOF assessment was not exactly similar to previous literature but adapted to experimental constraints. In prior porcine studies, ulnar nerve stimulation typically involves electrodes positioned on the palmar side of the forearm [11,14]. In the present study, however, the sling used to support the pig partially obstructed this configuration. As a pragmatic adaptation, electrodes were placed laterally, guided by visible muscle activation. While the amplitude of the neuromuscular responses may vary with electrode positioning relative to the targeted nerve, a clear and reproducible response was verified in each subject priori to data collection. All comparisons between groups were conducted under standardized conditions to minimize bias. Nevertheless, the impact of electrode placement variations on TOF results in pigs remains understudied and warrants further investigation. A second limitation is the absence of pre-experimental calibration of the TOF-Watch® device. Although manufacturer guidelines recommend calibration to account for individual variability in movement response gain, this step was omitted. To mitigate potential bias, according to guidelines published for reporting studies on the use of NMBAs [30], a standardized protocol was implemented: a fixed 2-Hz TOF stimulation for 1.5 seconds with a 12-second minimum latency, consistent current intensity, and unchanged stimulation duration throughout experiments. Stimulation intensity was initially adjusted to elicit a robust response in each animal (in particular to avoid excessive muscular response), and TOF counts were validated by visual observation during NMBA administration. Despite these measures, the lack of formal calibration may introduce unquantified variability. Finally, the small sample size limits the generalizability of the findings. While the study provides preliminary insights into NMBA cost-effectiveness in swine, larger cohorts are needed to confirm these results and explore interindividual variability.

5. Conclusions

The results of this study demonstrate that rocuronium may offer a financial advantage over atracurium in inducing muscle relaxation in pigs. The final infusion rate of rocuronium (4.5 mg/kg/h) was higher than that of atracurium (2.7 mg/kg/h), but the unit cost for the infusion was significantly lower for rocuronium compared to atracurium.