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Neuromuscular blocking agents

Influence of preoperative oral rehydration on arterial plasma rocuronium concentrations and neuromuscular blocking effects

A randomised controlled trial

Ishigaki, Sayaka; Ogura, Takahiro; Kanaya, Ayana; Miyake, Yu; Masui, Kenichi; Kazama, Tomiei

Author Information
European Journal of Anaesthesiology: January 2017 - Volume 34 - Issue 1 - p 16-21
doi: 10.1097/EJA.0000000000000526
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Abstract

Introduction

A short preoperative fasting period limits the decrease in the total body water1 and maintains renal blood flow.2 Further benefit is to be found in the administration of preoperative oral fluids, which compared with prolonged fasting, can significantly decrease the stroke volume variation (SVV), a predictor of fluid responsiveness,3,4 with no significant change in the cardiac output.5 A rapid infusion of fluid after preoperative fasting can also decrease the SVV.6 Collectively, these results suggest that preoperative oral rehydration maintains intravascular blood volume.

We have previously reported that preoperative rehydration significantly shortens the duration of neuromuscular blockade after the administration of a rocuronium bolus.7 Rocuronium is distributed throughout the extracellular fluid because of its low lipophilicity and high water solubility.8 Therefore, an increase in blood volume and distribution volume may decrease rocuronium concentrations in the plasma and at the target site.

The aim of the study was to evaluate the effects of preoperative rehydration on plasma rocuronium concentrations and the associated neuromuscular blocking effects.

Methods

The randomised, controlled, single-blind study was approved by the institutional ethics committee (Japan Self Defence Force Hospital Yokosuka, Kanagawa, Japan; registration number: 24–1) and registered with the UMIN Clinical Trials Registry (ref: UMIN000011981). All patients provided written informed consent before randomisation. Men aged 20 to 60 years with American Society of Anesthesiology physical status classes 1 and 2, who were scheduled for elective surgery at the Japan Self Defence Force Hospital Yokosuka between October 2013 and July 2014 were enrolled. The exclusion criteria were hepatic, renal or cardiovascular disorder; neuromuscular disease; history of allergy to rocuronium and/or a BMI of more than 30 kg m−2 , receiving medication known to influence neuromuscular function. Patients were randomly allocated before surgery to either the control or rehydration group. Block randomisation was performed according to a computer-generated schedule and concealed until the day before operation. The allocation ratio was 1 : 1 and block size was selected randomly from four or six.

Preoperative rehydration

The last meal was eaten the night before surgery. All were allowed to take clear fluids at their discretion until 6 h before anaesthesia, following which the control group was instructed to fast, whereas the rehydration group received 1500 ml of oral rehydration solution (ORS) (OS-1, Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan) up to 2 h before anaesthesia. Bicarbonate Ringer's solution was infused at 80 ml h−1 from 2 h before anaesthesia in both groups. Anaesthesia was induced in the afternoon for all patients.

Anaesthetic management

No premedication was used. Routine monitoring, including electrocardiography, noninvasive blood pressure measurement, pulse oximetry and electroencephalography were initiated following arrival at the operating room. Bicarbonate Ringer's solution was infused at 80 ml h−1 until the completion of neuromuscular monitoring and blood sampling; subsequently, the infusion rate was changed as needed. Propofol administration was initiated at a target plasma concentration of 4 μg ml−1 using a target-controlled infusion pump applying the Marsh model (Terufusion Syringe Pump TE-371 incorporating Diprifusor software, Terumo, Tokyo, Japan). The target concentration was temporarily increased if required. In addition, remifentanil was administered at a target plasma concentration of 6 ng ml−1 using simulation software (Tivatrainer version 8).9 Following no response to verbal command and cessation of spontaneous respiration, a laryngeal mask was placed. Mechanical ventilation was performed under the following settings: 100% oxygen; inspiratory pressure, 15 cmH2O; breathing rate, 10 breaths min−1 and inspiratory : expiratory ratio 1 : 2. A 22-G arterial catheter was inserted into the radial artery on the opposite side of the venous catheter. Once the cardiovascular system had stabilised, and before rocuronium administration, invasive blood pressure, heart rate and the output from the FloTrac-Vigileo (Version 4.0, Edwards Lifesciences, California, USA) system were recorded.

Neuromuscular monitoring and rocuronium administration

Neuromuscular blockade was assessed by measuring the response to ulnar nerve stimulation with TOF-Watch SX (Organon Ltd, Dublin, Ireland) according to the guidelines for good clinical research practice in pharmacodynamic studies.10 The transducer was placed on the volar aspect of the thumb using a hand adaptor (MSD Co. Ltd., Tokyo, Japan) and contraction of the adductor pollicis muscle was measured. The temperature of the palm was maintained at more than 32°C, whereas the rectal temperature was maintained at more than 35°C using warming blankets. Following measurement of haemodynamic variables, the ventilator was set up again to maintain an end-tidal carbon dioxide pressure of 32 to 40 mmHg. A 50-Hz tetanic stimulation was applied for 5 s and the acceleromyograph was calibrated. Then, 0.1-Hz single-twitch stimuli were initiated. After a twitch height variation of less than 5% was observed for longer than 2 min, 0.6 mg kg−1 rocuronium (Eslax, MSD Co. Ltd., Tokyo, Japan) diluted to 10 ml with isotonic saline was infused over 5 s, followed by flushing with 2 ml of saline. After the twitch height decreased to 0, the trachea was intubated. Neuromuscular monitoring was discontinued when more than three consecutive twitches were detected after administration of rocuronium and at this point surgery began. Anaesthesiologists and patients were not blinded to preoperative intake.

Sample acquisition, handling, processing and drug assay

Blood samples were collected through a radial artery catheter before, and 60, 90, 120 s and 30 min after rocuronium administration. These blood samples were centrifuged and the plasma was transferred to polyethylene tubes and maintained at −30°C until assay. Plasma rocuronium concentrations were measured using HPLC and an electrochemical detector (Coulochem III Electrochemical Detector, Thermo Fisher Scientific, Waltham, MA, USA). HPLC shows a linear relationship between the drug concentration and peak height in a range of 0.020 to 100 μg ml−1. The correlation coefficients were more than 0.999. The accuracy (precision) of 0.020 and 100 μg ml−1 rocuronium were −11% (coefficient of variation, 16%) and 2.1% (co-efficient of variation, 2.1%), respectively. The limit of quantitation for the assay was 20 ng ml−1. The measurer was blinded until the end of the study.

Study outcomes

Primary outcomes were the arterial plasma rocuronium concentrations at 60, 90 and 120 s and 30 min after administration. The following neuromuscular indices were determined and compared as secondary outcomes: lag time, the interval between rocuronium administration and the beginning of depression of twitch height; onset time, the interval between rocuronium administration and 95% depression of twitch height and twitch re-appearance time, the interval between rocuronium administration and spontaneous re-appearance of the first twitch.

Statistics

The sample size for measurement of arterial plasma concentrations was calculated using data from the first five patients in the control group. The mean ± SD plasma concentration at 90 s after rocuronium administration was 10.9 ± 1.9 μg ml−1. We considered a 25% decrease to be relevant and found that nine patients were required in each group, with α = 0.05 and a power of 0.80. The sample size for assessment of neuromuscular blocking effects was calculated using data from a previously published study where the mean ± SD onset time with 0.1-Hz single-twitch stimuli was 93 ± 25 s.11 We considered a 25% prolongation to be clinically relevant. To obtain statistically significant results with α = 0.05 and a power of 0.80, we found that we required 20 patients in each group. Neuromuscular data were presented in part in our previous study.7

All data are expressed as mean ± SD, unless stated otherwise. A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed with unpaired Student's t-tests and Mann–Whitney U tests using Prism 5.04 (GraphPad Software, La Jolla, California, USA) and JMP 10.0.2 (SAS Institute Inc., Cary, North Carolina, USA) software.

Results

We enrolled 46 patients from October 2013 to July 2014 and allocated 24 for plasma rocuronium levels and 40 for neuromuscular assessments in the analysis. Two patients in each group were excluded from the data analysis because of calibration errors during neuromuscular monitoring, one in the control group because of a mistake in the preoperative fluid infusion rate, and one in the rehydration group because of an error in ventilation settings during neuromuscular monitoring (Fig. 1). There were no significant differences in patient characteristics between the two groups (Table 1). Adverse events because of dehydration such as hypotension (mean arterial pressure <50 mmHg) or tachycardia (heart rate >100 beats min−1) were not observed.

Fig. 1
Fig. 1:
CONSORT study flowchart.
Table 1
Table 1:
Patient characteristics

The haemodynamic status before rocuronium administration is shown in Table 2. SVV was significantly smaller in the rehydration group, than in the control group (P = 0.039), whereas the cardiac output was similar between groups.

Table 2
Table 2:
Haemodynamic status

Mean arterial plasma rocuronium concentrations in the control and rehydration groups were 13.7 ± 4.0 and 10.1 ± 2.9 μg ml−1 (P = 0.021) at 60 s, 9.5 ± 2.2 and 6.7 ± 1.8 μg ml−1 (P = 0.0028) at 90 s, 8.1 ± 1.8 and 6.2 ± 1.9 μg ml−1 (P = 0.015) at 120 s and 1.1 ± 0.5 and 0.8 ± 0.4 μg ml−1 (P = 0.16) at 30 min (Fig. 2), respectively. Thus, mean arterial plasma rocuronium concentrations are significantly reduced in the first 2 minutes after administration in the rehydration group.

Fig. 2
Fig. 2:
Plasma rocuronium concentrations at 60, 90, and 120 s and 30 min after administration. The data are expressed as mean ± SD. Grey lines, control group; black lines, rehydration group.

Complete neuromuscular blockade was achieved in all patients. The neuromuscular indices are shown in Table 3. The onset time was significantly prolonged in the rehydration group, 92.0 ± 35.8 s, compared with that in the control group, 69.5 ± 14.7 s; P = 0.01, whereas the twitch re-appearance time was significantly shortened in the former group, 25.3 ± 4.9 min, compared with that in the latter group, 30.4 ± 7.1 min; P = 0.004.

Table 3
Table 3:
Time course of action of rocuronium

Discussion

In our study, we have evaluated the effects of preoperative oral rehydration on arterial plasma rocuronium concentrations and neuromuscular blocking effects. The preoperative intake of 1500 ml of ORS lowered arterial plasma rocuronium concentrations during the first 2 min after the administration of a bolus of 0.6 mg kg−1. Evidence that preoperative oral rehydration prevents dehydration is available from measurements of the amount of body water using multifrequency impedance.1 In our study, the SVV, which reflects the intravascular blood volume,12 was significantly smaller in the rehydration group indicating that the lower plasma rocuronium concentrations were caused by dilution of blood volume. Similarly, an increase in drug concentrations because of hypovolaemia can be achieved by the acute withdrawal of blood.13–19 Benowitz et al.17 attributed increased drug concentrations to decreases in both initial and steady-state volumes of distribution and elimination clearance. Krejcie et al.19 investigated the disposition of extracellular fluid marker (inulin) in a modified blood volume and found that the central volume and total clearance were significantly decreased in mildly hypovolaemic conditions. Thus, it can be inferred that preoperative oral rehydration increases distribution volume and clearance in contrast to phlebotomy. The fact that rocuronium is mostly distributed within extracellular fluid clarifies the blood dilution effect. Furthermore, the major routes of rocuronium elimination are urinary and biliary excretion.20 Itou et al.2 reported that preoperative oral rehydration increases renal blood flow but there are no studies of the relationship between rehydration and hepatic blood flow. However, Klein et al.21 reported that hepatic blood flow, which was estimated using the indocyanine green clearance method, was significantly higher in patients receiving a preoperative infusion of Ringer's solution compared with no infusion. Therefore, oral rehydration may accelerate the elimination of rocuronium.

We also found that the intake of ORS prolonged the onset time and shortened the twitch re-appearance time. The movement of rocuronium to the target site occurs according to the concentration gradient between blood and interstitial spaces. Lower plasma concentrations result in a smaller concentration gradient and a smaller number of transiting rocuronium molecules, and a reduced concentration at the target site, prolonging the onset time and shortening the recovery time in our study.

Our results are similar to those reported in a study on neuromuscular blockade with smaller doses of rocuronium.22,23 When 0.6 and 0.9 mg kg−1 of rocuronium were compared, the lag time did not differ, at 37 ± 12 s and 33 ± 14 s, respectively, whereas the onset time was shortened with 0.9 mg kg−1 193 ± 47 s and 118 ± 23 s (P < 0.01) and the duration of clinical effect was prolonged at 21 ± 4 min and 34 ± 11 min (P < 0.01).23 Thus, clinicians should consider a higher dose for patients who receive preoperative rehydration, although the neuromuscular effects of other doses of rocuronium were not investigated in our study.

The time course of neuromuscular blocking effects is modified by muscle perfusion, a factor of cardiac output and muscle blood flow.24 Cardiac output was comparable between the two groups in our study and we did not measure the muscle blood flow. However, if the muscle blood flow increases with preoperative rehydration, the onset time would be expected to shorten in the rehydration group.

The study has several limitations. First, a detailed pharmacokinetic analysis was unavailable because of the sparse blood sampling. Although, we have shown the influence of preoperative rehydration on plasma rocuronium concentrations, further investigation is needed. The rate of dilution caused by oral rehydration is unclear because there are no data on haemoglobin concentrations or haematocrit before and after oral rehydration. Second, we did not have data on time to complete recovery of neuromuscular block. We evaluated twitch re-appearance time, which is the initial phase of recovery. Third, this study was performed in an experimental setting under stable anaesthesia with neuromuscular monitoring implemented at the adductor pollicis muscle. Our results for onset time may not be valid when rocuronium is administered in a haemodynamically unstable setting, such as induction of anaesthesia.

In conclusion, preoperative oral rehydration leads to lower plasma rocuronium concentrations in the early phase, prolongs the onset time and shortens the duration of neuromuscular effects. Clinicians should consider a higher dose or earlier additional administration for patients who receive preoperative rehydration.

Acknowledgements relating to this article

Assistance with the study: the authors would like to thank Editage (www.editage.jp) for English language editing.

Financial support and sponsorship: the work was supported by the Department of Anesthesiology, National Defence Medical College, Saitama, Japan.

Conflicts of interest: none.

Presentation: the study was presented in part as a poster presentation at the International Anesthesia Research Society Annual Meeting, 21–24 March 2015, Hawaii, USA.

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