Neuromuscular blocking characteristics of rocuronium bromide mixed with sodium bicarbonate

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1 International Journal of Advances in Health Sciences (IJHS) ISSN Vol 3, Issue 3, 2016, pp Research Article Neuromuscular blocking characteristics of rocuronium bromide mixed with sodium bicarbonate Bedi Jyoti, Mahotra KK and Mehta Nandita Department of Anaesthesiology and Intensive Care, Acharya Shri Chander College of Medical Sciences and Hospital, Sidhra, Jammu (J&K), India Corresponding Author: Dr. Jyoti Bedi, address: ABSTRACT: Intravenous rocuronium produces intense discomfort at the site of injection hence leading to limb movements. Strategies to reduce or prevent pain on injection, along with the effect of adjuvant on the onset and duration of action were studied. 80 ASA physical status I or II patients, aged years scheduled to undergo elective surgery with general anesthesia were enrolled for the study. Patients were randomly allocated into two groups to receive either rocuronium with 7.5% sodium bicarbonate or rocuronium with 0.9% isotonic saline. The patient s response to rocuronium injection was verified through neuromuscular monitoring at the adductor pollicis muscle using train-offour (TOF) response. The incidence of withdrawal movement after rocuronium administration was significantly lower in the sodium bicarbonate group along with shorter onset time and increased duration of action than the saline group. We concluded that the mixing of sodium bicarbonate with rocuronium reduces the pain on injection, enhances the potency, shortens the onset and prolongs the duration of action. Key words: Rocuronium, Pain, Withdrawal movement, Sodium bicarbonate, train-of-four (TOF) and General Anaesthesia. INTRODUCTION: Rocuronium was introduced to clinical practice in Rocuronium bromide is a monoquaternary aminosteroid with a quick onset time and an intermediate duration of action. It is currently one of the most commonly used neuromuscular blocking agent. 15 Rocuronium has an ED 95 of 0.3 mg kg -1 with an onset of action in minutes and duration of neuromuscular blockade lasting minutes. 8 However, even in unconscious patients during anesthetic induction, rocuronium causes withdrawal movement of the injected hand or arm, or generalized movements of the body after intravenous injection. The major disadvantage of rocuronium is the pain associated with its injection, and generalized movements of the body caused by injection pain may even lead to reflux of gastric contents and pulmonary aspiration. 16 Several methods have been reported for reducing pain on injection, including treatment with fentanyl, lidocaine, ondansetron, 8.4% sodium bicarbonate, 7.5% sodium bicarbonate, magnesium sulphate and alfentanil. 4,9,7,10,22,28 Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula NaHCO 3. It is found in dissolved form in bile, where it serves to neutralize the acidity of the hydrochloric acid produced by the stomach, and is excreted into the duodenum of the small intestine via the bile duct. It can be produced artificially by the Solvay process. After injection, intravenous sodium bicarbonate dissociates to provide sodium (Na + ) and bicarbonate (HCO3 - ) anions.

2 Bicarbonate anions can consume hydrogen ions (H + ) and thereby be converted to carbonic acid (H 2 CO 3 ), which can subsequently be converted to water (H 2 O) and carbon-dioxide (CO 2 ), latter of which is excreted by the lung. The mechanism of action involved is that the transmembrane diffusion of weakly basic drugs, like rocuronium, is commonly assessed from the degree of ionisation or the ratio of unionised/ionised forms. The more the unionized forms, implies a higher lipid solubility and hence, greater transmembrane diffusion of drug. Therefore, the drugs capable of bringing about a change in ph from 4.01 to an alkaline ph around 7.78, increase the amount of unionised rocuronium, and hence, increase the potency. Neuromuscular monitoring using train-of-four stimulus has been recommended in clinical practice because, it tests only neuromuscular function, is sensitive, provides information even if a control value is not obtained, is repeatable, simple to use and reliable data demonstrating its relationship with respiratory function is available. 1 In practice, train-of-four stimulation of the ulnar nerve, observation and recording of the force of contraction of the adductor pollicis muscle is the most common method of monitoring, both in the clinical and research settings. 5,26 The present double-blind, randomized study was undertaken to evaluate the neuromuscular blocking characteristics of rocuronium bromide when mixed with 7.5% sodium bicarbonate, with respect to pain on injection, onset of action and duration of action. MATERIALS AND METHODS: After obtaining approval from the institutional ethics committee and patients written informed consent, 80 ASA physical status I or II patients, aged years, scheduled to undergo elective surgery under general anesthesia were enrolled. Patients with ASA physical status III or greater, uncontrolled hypertension, coronary heart disease, neuromuscular disorders, pregnancy, anticipated difficult airway, body weight more than 20% of ideal body weight, on any drug known or suspected of interfering with neuromuscular dysfunction, in whom vocal cords were not completely visualized during laryngoscopy or in whom onset time was longer than 300 seconds, were not included in the study. Patients were randomly allocated into 2 groups (40 in each group) with the help of a computer generated table of random numbers to receive drug either from study solution containing 50mg rocuronium mixed with 7.5% sodium bicarbonate or from the study solution containing 50mg rocuronium mixed with 0.9% isotonic saline. All patients were premedicated with Tablet Alprazolam 0.25 mg on the night before surgery. After arrival in the pre-operative room, an intravenous catheter of 18G was secured to administer drugs and fluids. In the operation theater, standard monitoring was done with continuous ECG (lead II), SPO 2 (pulse oximetery) and non-invasive blood pressure (systolic, diastolic and mean) monitoring at regular intervals. In order to eliminate bias, the drug given to all the patients, whether study or control, was prepared by a single person not involved in handling of the patient included in the study. To prepare the study solution, 50 mg of rocuronium was taken in a 10 ml syringe, while 5 ml of 7.5 % sodium bicarbonate in another syringe. Then 1 ml sodium bicarbonate was gradually and slowly mixed with rocuronium. We diluted rocuronium with sodium bicarbonate in a 1:1 volume ratio to obtain a rocuronium concentration of 5 mg/ml study solution. Small CO 2 bubbles developed on mixing sodium bicarbonate with rocuronium. The solution thus formed, was used 30 minutes after mixing to allow the bubbles to settle and thus obtain a clear solution. The drug given to the control group (Group II) was prepared in the same manner, with the only difference that sodium bicarbonate was replaced by 0.9% isotonic saline. A standardized general anaesthetic technique was used for induction with Injection Ranitidine (50 mg I/v), Injection Ondansetron (0.1 mg kg -1 I/v), Injection Fentanyl (0.5 µg kg -1 I/v) and Injection Bedi Jyoti, et al. 201

3 Propofol (2.5 mg kg -1 I/v). The whole of the technique was supported with neuromuscular monitoring. The ulnar nerve was stimulated at the wrist to study the train-of-four (TOF) response at the adductor pollicis muscle. To stimulate the ulnar nerve, one electrode was placed on the radial side of flexor carpi ulnaris tendon about 1 cm proximal to the wrist skin crease. The other electrode was placed 3-4 cm proximal to the distal electrode. The nerve stimulation was carried out with square-wave supramaximal stimuli of 0.2 msec duration, delivered in a train-of-four (TOF) sequence at 30mA, using a peripheral nerve stimulator. After induction, baseline TOF monitoring was done and the reading noted before administering the induction dose of rocuronium. Depending upon the patient group, the patient was given his/her respective study solution, in a dosage of 0.6 mg kg -1 I/v, for intubation. Withdrawal limb movement in response to rocuronium injection was noted. Neuromuscular monitoring was done every 10 seconds, till we obtained the absence of all the four twitch responses out of the TOF sequence. Thereafter, we proceeded with endotracheal intubation. During maintenance, anaesthesia was maintained using varying concentration of halothane with N 2 O and O 2 in a ratio of 66 % : 33%, with intermittent boluses of same group rocuronium in a dose 1/5th of the loading dose, based on neuromuscular monitoring which was repeated every 5 minutes and the maintenance dose of relaxant was given when T2 response was recorded out of the TOF sequence. Injection Diclofenac sodium (1.5 mg kg -1 ), was also given intravenously in infusion, intra-operatively during maintenance. At the end of surgery, residual neuromuscular blockade was reversed with 0.06 mg kg -1 neostigmine and 0.01 mg kg -1 glycopyrrolate, only when a TOF count of 3 or more was recorded and then we proceeded with extubation. At the end of the study, all the data so collected was compiled and analyzed statistically using Students Independent T-test, when the means of two groups were compared and Pearson Chi- Square test to compare non-parametric data. RESULTS: Each group consisted of 40 patients and there were no significant differences in the characteristics of patients receiving rocuronium mixed with 0.9% isotonic saline or 7.5% sodium bicarbonate. No precipitants or colour changes were observed after rocuronium was mixed with 0.9% isotonic saline or 7.5% sodium bicarbonate. No erythema or any change of the skin surrounding the point of injection or the arm was observed. The overall incidence of withdrawal movement after rocuronium administration was significantly different in both groups, 7.5% in Group I vs 35% in Group II (P = 0.003), with group I showing definite reduction in pain caused by rocuronium injection. The onset time of rocuronium in the bicarbonate group was significantly shorter than that in the saline group, with a mean time of 96 seconds in Group I vs seconds in Group II (P = 0.000). There was not much variation in heart rate, systolic, diastolic and mean arterial pressure when monitored at various intervals after intubation as compared to baseline values (P > 0.05). In our study, we found that addition of 7.5% sodium bicarbonate had enhanced the potency and prolonged the duration of action of rocuronium. It was seen that both Group I and Group II had similar average duration of surgery per case ( minutes in Group I vs minutes in Group II), and the number of maximum top-ups repeated during the maintenance of the cases confirmed that the requirement of top-ups decreased with bicarbonate group (maximum count of six top-ups needed in just 1 case ; 2.5%; in Group I vs 3 cases ; 7.5% ; in Group II). Also no top-ups were required in 16 cases in Group I as compared to only 4 cases in Group II (40% in Group I vs 10% in Group II, P = 0.007). DISCUSSION: Bedi Jyoti, et al. 202

4 The principal finding of our study was that rocuronium mixed with 7.5% sodium bicarbonate is more potent than rocuronium alone. We demonstrated that addition of sodium bicarbonate resulted in decreased pain response to rocuronium injection, shortened onset time and increased the duration of action. Rocuronium is an isotonic solution with a ph of Pain on injection has been associated with solutions with a ph of 4 or less. 11 Consequently, it has been suggested that the injection pain produced by rocuronium is related to its low ph. 3,14 Pain associated with the administration of rocuronium is not only common, but distressing for patients, and the incidence of withdrawal movement associated with rocuronium injection has been reported in % of patients. 2,4,24,25 With this background, this study was conceptualized to evaluate the neuromuscular blocking properties of rocuronium bromide on addition of 7.5% sodium bicarbonate, in terms of effect on pain on injection, onset of action and duration of action, and the whole of the technique was supported with neuromuscular monitoring at the adductor pollicis muscle via ulnar nerve stimulation. In our study, we chose to use adductor pollicis muscle, because of the easy accessibility and visualization of the hand. Circulatory factors determine the distribution of neuromuscular blocking agents from the site of injection to different muscles, which consequently may affect the onset of neuromuscular block. Many factors including depth of anaesthesia, determine adequate intubating conditions. Therefore, same anaesthetic induction and maintenance techniques were used in both the groups. The baseline values of mean heart rate in both the groups were comparable with no statistically significant difference among them (p > 0.05). The results were almost similar to a study conducted in 2009, with the difference that the heart rate increased significantly in their rocuronium group after injection as compared to the baseline value. 13 This increase in heart rate, however, was not seen in rocuronium-sodium bicarbonate group in their study. There was not much variation in systolic, diastolic and mean arterial pressure when monitored at various intervals after intubation as compared to the baseline values (p > 0.05). The results of our study are comparable to the above mentioned study, which showed almost similar results with the mean arterial pressure decreasing significantly in the rocuronium-sodium bicarbonate group, which could be due to the different concentration (8.4%) of sodium bicarbonate used in their study. We used 7.5% sodium bicarbonate instead. 13 As already stated, an important observation of our study was decreased incidence of painful response to intravenous rocuronium injection. The etiology of the discomfort caused by the intravenous administration of rocuronium is unknown. Peripheral veins are known to be innervated with polymodal nociceptors that mediate pain response to the injection of certain anaesthetic agents. Rocuronium is supplied as an isotonic solution, and the isotonicity is obtained with sodium chloride, and a ph of 4 by adding acetic acid or sodium hydroxide. The relatively low ph of the rocuronium solution may be a possible cause, as Klement and Arndt have shown that the injection of acidic solutions with a ph of 4 or less causes pain on injection, which increases linearly with a lower ph. 11 However, the authors noted that after injection of acidic solutions, perivenous oedema developed immediately and was followed by thrombophlebitis for upto 3 weeks, which was not the case in this study. A study conducted by Chiarella and colleagues demonstrated that the pain associated with administration of a 10 mg dose of rocuronium bromide can be almost eliminated by combining it with sodium bicarbonate 8.4% in a 1:2 volume ratio. 4 They also compared sodium bicarbonate with fentanyl 100 µg, lidocaine 2% and normal saline, to conclude that none was as effective as the 18.4 times reduction accomplished by sodium bicarbonate. Compared with the previous study, the occurrence of withdrawal movement was significantly reduced in bicarbonate group of our Bedi Jyoti, et al. 203

5 study also, which received rocuronium bromide diluted with sodium bicarbonate 7.5% in a 1:1 volume ratio. The incidence of withdrawal movement was 7.5% in Group I or bicarbonate group as against 35% in Group II or saline group (P = 0.003), thus, showing a definite reduction in pain caused by rocuronium injection in our study. Young Hee Shin and colleagues showed that the combination of manual slow injection and simple dilution of rocuronium, was effective in decreasing the incidence of withdrawal movement followed by rocuronium injection in paediatric patients. 30 They concluded that manual slow injection of diluted rocuronium significantly reduced the incidence of withdrawal movement, and therefore recommended their method as a daily usable technique of rocuronium injection for reducing withdrawal movement in paediatric patients because of its simplicity and availability. However, in our study, not only did we take a population above 18 years of age, and our control group involved use of 0.9% normal saline, but also, the speed of giving rocuronium injection was not time-bound or being assessed with a device. This makes us unable to comment on the effect of sodium bicarbonate on pain caused by intravenous rocuronium in the paediatric population or the effect of injection speed on the elicited pain response. Age and gender play important roles in rocuronium induced withdrawal movements. 18,19,20,21 The overall incidence of rocuronium-induced pain was lower in older patients aged over 65 years compared with that in the young patients aged between years in the placebo group. 21 Gender difference in severity and incidence of rocuronium-induced pain also exists in adults. 18 A previous study by Mencke and colleagues has suggested that females reported more frequent and severe pain responses than males. Also, females are considered to be 20-25% more sensitive to rocuronium than males. They demonstrated slower onset by 26% and shorter clinical duration by 35% in men. 20 Mencke et al. studied not only the gender difference to pain perception with intravenous rocuronium, but also concluded that when rocuronium is used as a precurarization agent, an analgesic pretreatment, like opoids, should be considered, especially in female patients. 19 Xue et al. showed that the doseresponse curve of rocuronium in men was shifted to the right, indicating a decrease in the sensitivity to rocuronium-induced neuromuscular block versus the women. However, in our study, we used the most usual dose of rocuronium (2 x ED mg kg -1 ) that is larger than the doses used in the above mentioned studies, and still, no such age or gender difference appeared evident. 29 According to Fick s law, the rate of diffusion depends on the unbound concentration of solute, the partition co-efficient and the degree of ionisation. The transmembrane diffusion of weakly basic drugs is commonly assessed from the degree of ionisation or the ratio of unionised/ionised forms as calculated from the Henderson-Hesselbalch equation. The ratio of unionised/ionised weakly basic drugs has been previously shown to increase fold with a ph increase from 5 to Rocuronium is a weakly basic neuromuscular blocking drug. The mechanism for the enhanced potency of rocuronium is unclear, but we suspect that the change in ph from 4.01 to an alkaline ph around 7.78 by the addition of 7.5% sodium bicarbonate increases the amount of unionised rocuronium in the solution. As the unionised form is more lipidsoluble, a higher proportion of a weakly basic drug will be in the lipid-soluble form, at alkaline ph, thus, enhancing the potency of rocuronium when combined with sodium bicarbonate. In a previous study by Lee and colleagues, it was suggested that addition of 8.4% sodium bicarbonate resulted in a left-ward shift of the rocuronium dose-response curve, enhanced potency and more rapid onset along with a prolonged recovery. 12 In our study we also found that addition of 7.5% sodium bicarbonate gave us an improved potency with shorter onset time and prolonged duration. Here, we needed the absence of all the four twitch responses out of the train-of- Bedi Jyoti, et al. 204

6 four (TOF) sequence, before we could intubate the patient. The average duration of time of disappearance of TOF (seconds) was significantly shorter in case of bicarbonate group, as compared to the saline group (96.0 seconds vs seconds; p < 0.001), indicating the positive effect of addition of sodium bicarbonate in enhancing the potency and shortening the time of onset of action of rocuronium bromide. The results of our study, thus, were comparable to the study conducted by Lee HJ et al. 12 Han and colleagues, however, have shown that the onset time, duration of action and ED50 values of rocuronium determined by acceleromyography do not change when the ph of rocuronium approaches physiologic ph after the addition of 8.4% sodium bicarbonate. 7 The neutralized rocuronium only prevented injection pain. But it is known, that drug potency plays a major role in the onset time of a neuromuscular blocking agent. 6 A more potent drug is expected to have a quicker effect compared with the same dose of a less potent drug. This explains the rapid onset of action observed in our present study. The average duration of surgeries in both the groups were comparable (80.8 minutes vs 79.7 minutes; p = 0.891). Based on this, the minimum and maximum number of rocuronium top-ups required during the maintenance period were calculated and analysed statistically. It was noticed that sixteen out of forty patients in the bicarbonate group required no top-up after the induction dose intraoperatively, as compared to just four patients out of forty in the saline group. Similarly, a maximum of six top-ups were required throughout the study in both the groups, and only one patient in the bicarbonate group, as compared to three patients in the saline group required such high doses of rocuronium during maintenance phase. This confirmed that the addition of sodium bicarbonate to rocuronium bromide, not only fastens its onset of action, but also prolongs the duration of action significantly (p = 0.007). Here also our results were found to be comparable to the study conducted by Lee HJ et al. 12 There were a few limitations in this study. First, ph of diluted rocuronium was not measured. However, it was already suggested that ph 4- adjusted saline did not trigger the injection pain in previous studies. 2 Moreover, Tuncali et al. reported that the dilution of rocuronium with 0.9% normal saline did not change its ph and osmolality. Therefore, we believed that the ph of our diluted solution had little effect on the results of this study. 27 Second, we did not apply our technique to paediatric (<18 years) patients. Considering the low incidence (12 to 28%) of withdrawal movement related to rocuronium injection in adults as compared to children, the results may be different from our results in adults. 17,19 Third, the injection speed of rocuronium may be inconsistent because we did not use any device to assess it. CONCLUSION: We demonstrated that the addition of 7.5% sodium bicarbonate to rocuronium, not only alleviated injection pain, but also, increased the potency of rocuronium and prolonged its duration of action in comparison to rocuronium alone. Rocuronium should be avoided in awake patients (e.g. priming). We believe that the similarities of movements of the arm observed in the awake patient and after induction of anaesthesia, indicate that the movements observed in anaesthetized patients are the direct consequence of pain associated with the administration of rocuronium. In order to avoid this side-effect, it is important to inject rocuronium only when a deep stage of unconsciousness has been reached. REFERENCES: 1. Ali HH, Wilson RS The effect of d- tubocurarine; an indirectly elicited train-of-four muscle response and respiratory measurements in humans. British Journal of Anaesthesia. 47: Bedi Jyoti, et al. 205

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