Neuromuscular-blocking drugs (NMBDs) are generally infused into a peripheral vein and then enter the central circulation, reaching their site of action through the bloodstream. Previously, several studies investigated the influence of transit time of NMBD from the peripheral injection site to the effect site on the drug onset. Harrison and Junius1 found that the latent onset time, defined as the time of the first depression in twitch height after NMBD administration, and the onset time of succinylcholine were closely correlated with the transit time. Iwasaki et al.2 reported that the administration of vecuronium into a pulmonary artery shortened the onset time by approximately 40 seconds than that after administration into a dorsal vein of the hand.
IV drug administration through a peripheral vein is typically followed by administration of a fluid bolus in many clinical practices. To treat paroxysmal supraventricular tachycardia, adenosine is administered through a peripheral vein and is followed by a 20-mL saline flush.3 Adenosine is metabolized by erythrocytes and vascular endothelial cells and has an extremely short half-life of <10 seconds; therefore, the 20-mL saline flush helps adenosine rapidly reach the heart. During dynamic contrast-enhanced computed tomography, a saline flush is typically administered to ensure high contrast4 and reduce the volume of contrast medium remaining in the peripheral vein.5 Accordingly, saline flush after rocuronium bolus administration may shorten the onset time of rocuronium.
The main objective of this study was to investigate the influence of a saline flush on the pharmacodynamic effect of rocuronium. We evaluated the effect of rocuronium by measuring the latent onset time,2 onset time, clinical duration, recovery index, and total recovery time in patients administered a saline bolus after rocuronium. We hypothesized that administering a 20-mL saline flush after a 10-mL rocuronium bolus reduced the latent onset time and onset time without influencing the recovery profile.
This randomized, controlled, single-blind study was approved by the institutional ethics committee (National Defense Medical College, Saitama, Japan, No. 781 and 1215) and is registered at the UMIN Clinical Trials Registry (ref: UMIN000005102). Patients with an ASA physical status I or II, aged 20 to 80 years, and scheduled for elective surgery at the National Defense Medical College were recruited. Patients with severe hepatic, renal, or cardiovascular disease, neuromuscular disease, a history of rocuronium allergy, body mass index >30 kg/m2, and those receiving medications known to influence neuromuscular function were excluded. Patients provided written informed consent and were then randomly allocated to either receive or not receive a 20-mL saline bolus immediately after rocuronium (ESLAX IV; MSD Co. Ltd., Tokyo, Japan) administration. The randomization sequence was stratified (20–64 years and 65–80 years of age, and male and female) and computer generated. Patients, but not investigators, were blinded to the allocation.
No premedication was administered to any patient. A 22- or 20-gauge catheter was inserted into a large forearm vein and connected to 2 3-way stopcocks (Fig. 1). The first 3-way stopcock was directly connected to the IV catheter and was used to administer rocuronium, and the second was directly connected to the first stopcock and used to administer the saline flush. Routine monitoring was initiated once patients arrived at the surgical suite including electrocardiography, noninvasive arterial blood pressure, pulse oximetry, capnography, and electroencephalography. The noninvasive blood pressure cuff was placed on the contralateral arm to neuromuscular monitoring. The arterial blood pressure was recorded immediately before rocuronium administration (described subsequently) and immediately after the first twitch (T1) of train-of-four (TOF) stimulation depressed to 0; the arterial blood pressure was not measured between these 2 events. Propofol was administered at 3 μg/mL of the target plasma concentration using a target-controlled infusion pump (Terufusion® TCI pump TE-371; Terumo Corporation, Tokyo, Japan); the target concentration was increased as needed. Remifentanil was simultaneously initiated at 0.3 μg/kg/min and decreased to 0.15 μg/kg/min after 1 minute. Once the patient was unresponsive to verbal commands and spontaneous respiration stopped, bag and mask ventilation was initiated to maintain an end-tidal carbon dioxide pressure of 32 to 40 mm Hg.
Neuromuscular Monitoring and Rocuronium Administration
Neuromuscular blockade was assessed by acceleromyography at the adductor pollicis muscle of the arm contralateral to the IV catheter. The ulnar nerve was stimulated at the wrist of the immobilized study arm using a TOF-Watch SX® monitor (MSD Co. Ltd.) according to the guidelines for Good Clinical Research Practice in pharmacodynamics studies.6 The transducer was placed on the volar aspect of the thumb using a hand adaptor (MSD Co. Ltd.), and contraction of the adductor pollicis muscle was measured. The temperature of the palm was maintained at >32°C and the rectal temperature at >35°C using warming blankets. After the patient became unresponsive to verbal commands, a 50-Hz tetanic stimulation was applied for 5 seconds. The acceleromyograph was calibrated for supramaximal TOF stimulation, after which TOF stimulation (4 pulses 0.2 ms in duration, 2-Hz frequency, and 15-s interval) was started. Once a T1 height variation of <5% was observed for >2 minutes, 0.6 mg/kg of rocuronium in 10 mL of normal saline was infused over 5 seconds (120 mL/min) through the first 3-way stopcock that was connected to the IV catheter. In this configuration, the remaining dead space containing the rocuronium bolus was <0.18 mL. Immediately after rocuronium administration, patients in the saline flush group were administered 20 mL of normal saline over 10 seconds (120 mL/min) using a 20-mL syringe connected to the second 3-way stopcock by hand. The total dead space for the saline flush was <0.22 mL. Acetate Ringer’s solution was infused at 300 mL/h (5 mL/min) through the 2 3-way stopcocks in both groups from the start of propofol administration until tracheal intubation. Neuromuscular monitoring was discontinued once the surgery was complete. Patients requiring additional rocuronium or a reversal drug for rocuronium were excluded from the analysis. All neuromuscular monitoring data were stored automatically on a laptop computer with TOF-Watch SX using TOF-Link® (MSD Co. Ltd.).
The latent onset time was defined as the time from the start of rocuronium administration until the first occurrence of T1 depression of TOF ≥5% (Fig. 2). The onset time was defined as the time from the start of rocuronium administration until first occurrence of T1 depression ≥95%. The recovery indices (Fig. 2) were recorded as follows: the time from the start of rocuronium administration until the T1 of the TOF recovered to 25% of the final T1 value (clinical duration); the time for recovery of T1 from 25% to 75% of the final T1 value (recovery index); and the time from the start of rocuronium administration until TOF ratio recovered to 0.9 (total recovery time). All of the recorded T1 values were normalized to the final T1 value.
The sample size calculation was performed based on a power of 0.9 and an α of 0.05; 20 patients per group were required to detect a 30-second difference in the onset time, which was considered clinically relevant. Data were expressed as the mean ± SD or the median (5th–95th percentile range). Data were analyzed using the unpaired Student t test, Mann-Whitney U test with Hodges–Lehmann method, and repeated measured 2-way analysis of variance with Sidak multiple comparison test. The Hodges–Lehmann method was used to estimate the median of the difference between the groups with a 95.2% confidence interval (CI). Prism 6.03 (GraphPad Software, La Jolla, CA) and JMP 10.0.2 (SAS Institute Inc., Cary, NC) were used for statistical analysis.
We recruited 63 patients from May 2010 to August 2014 and included 48 patients in the analysis. Fifteen patients were excluded from data analysis because of artifacts on neuromuscular monitoring (n = 4), unstable recovery of T1 to <80% or >120% of the baseline T1 (n = 9), and a TOF value <0.9 at the end of surgery (n = 2; they were administered sugammadex). Additional rocuronium was not required in any patient.
There were no significant differences in the age, sex, weight, height, or body mass index between groups (Table 1). No episodes of hemodynamic instability or adverse events occurred in any patient during the study. Heart rate and mean arterial blood pressure immediately before rocuronium administration and immediately after the T1 of TOF stimulation were similar between groups (Table 2).
The time course of T1 height is shown in Figure 3. Saline flush significantly depressed T1 height at 30, 45, and 60 seconds after rocuronium administration by 17% (95% CI, 5%–28%, P < 0.001), 24% (13%–35%, P < 0.001), and 14% (3%–25%, P = 0.005), respectively. The measured latent onset time and onset time were significantly shorter in the saline flush group than in the control group by 15 seconds (95.2% CI, 0–15; P = 0.007) and 15 seconds (0–30; P = 0.017), respectively (Table 3). The measured latent onset time and onset time using box-and-whisker plots are shown in Figure 4. In all patients, the T1 height decreased to 0 after rocuronium administration.
The recovery indices are shown in Table 3 and Figure 4. Saline flush significantly prolonged the clinical duration by 4.8 minutes (95.2% CI, 0.3–9.3, P = 0.031), the recovery index by 2.3 minutes (0.5–4.5, P = 0.018), and the total recovery time by 8.8 minutes (0.0–17.5, P = 0.047).
We found that a 20-mL saline flush immediately after a rocuronium bolus (0.6 mg in 10 mL) shortened the measured latent onset time and onset time by 15 seconds each. Furthermore, saline flush administration prolonged the clinical duration, recovery index, and total recovery time of rocuronium contrary to our hypothesis.
The onset time was significantly decreased by a 20-mL saline flush. Circulation factors such as cardiac output, circulation time to muscle, and muscle perfusion are factors that clearly modify the clinical effect of NMBD.7 Because saline flush significantly shortens latent onset time, rocuronium may be rapidly transported from the peripheral vein into the central vein. One mechanism explaining the short onset time in the saline flush group may have been the decreased transit time from the peripheral injection site to the muscle. Harrison and Junius1 reported that the transit time (from the right to left wrist) of indocyanine green was 31.1 ± 7.2 seconds, the time from succinylcholine infusion to the first depression of twitch height (latent onset time) was 40.5 ± 17.5 seconds, and the onset time of succinylcholine was 80.9 ± 24.0 seconds when 5 mL of each drug was followed by a 5-mL saline flush. In this study, the correlation between the transit time and latent onset time (R = 0.91) and between the transit time and onset time (R = 0.89) was highly significant. Accordingly, saline flush may also decrease the onset time of other drugs. In contrast to our results, a previous study showed the injection rate of rocuronium when administered through a running fluid infusion decreased the time from start of rocuronium administration to 50% but not 90% depression of T1.8 The influence of the administration scheme on the circulation time may underlie this discrepancy in results. The difference in the rocuronium infusion rate does not change the transit time, whereas saline flush decreases the transit time of rocuronium. It is unlikely that a 20-mL saline flush itself changes cardiac output and muscle perfusion. Because the 20-mL saline flush also pushed propofol and remifentanil from the peripheral vein of the upper extremity, these drugs might have reduced cardiac output, resulting in the longer transit time in the saline flush group. However, the hemodynamic variables immediately before the rocuronium bolus and after the T1 height was depressed to 0 were similar between groups (Table 2).
The recovery phase of rocuronium was prolonged in patients administered a saline flush in this study (Fig. 4). If a saline flush simply shortens the transit time from the forearm vein into the central vein, the recovery phase would not change. Behrendt et al.9 found that administration of a saline flush after contrast material infusion resulted in a higher attenuation value in the ascending and descending aorta. This result indicated that a saline flush increased the peak plasma concentration of the contrast material. Weiss et al.10 reported that the increment of cardiac output decreased the variance of the systemic transit time of indocyanine green. Because both the increment of cardiac output and the saline flush would increase the velocity of drug transportation in a peripheral vein, saline flush may also influence the variance of transit time. Therefore, saline flush not only appeared to shorten the drug transit time to the central circulation, but also may have increased the peak rocuronium concentration and may have decreased the variance in transit time distribution at the effect site. A higher peak plasma concentration at the effect site can prolong the recovery phase.
Subsequent administration of a 20-mL saline flush can be used to shorten the onset time of NMBD in anesthesia practice. Another study investigated the latent onset time, and onset time after 0.1 mg/kg vecuronium was administered into the dorsal vein of the hand followed by a 20-mL saline flush with arm elevation using TOF stimulation every 15 seconds.11 Saline flush and arm elevation shortened the latent onset time by 20 seconds from 68 seconds and the onset time by 24 seconds from 128 seconds. One reason for the smaller difference between the groups in this study may be the faster onset time of rocuronium than vecuronium. Iwasaki et al.2 reported that the administration of vecuronium through a pulmonary artery catheter into the right atrium shortened the latent onset time by 11 seconds compared with 82 seconds when vecuronium was administered into the dorsal vein of the hand. Drug administration followed by a 20-mL saline flush may be comparable with drug administration into the right atrium.
The estimated difference in the latent onset time between the groups was −15 seconds, whereas the median latent onset time of both groups was identical. Although there seems to have been a discrepancy, these results are consistent. Figure 4 shows that the medians of both groups were identical in the box-and-whisker plots, but the distribution of the latent onset time differed between groups. The difference between T1 heights at 30, 45, and 60 seconds after the rocuronium bolus also supports the difference in latent onset time and onset time between groups. Neuromuscular monitoring using 0.1-Hz single twitch stimulation at a shorter interval may resolve the discrepancy. We used TOF stimulation to measure all typical recovery indices, including the total recovery index estimated using the TOF ratio. The guidelines for Good Clinical Research Practice in pharmacodynamic studies of neuromuscular-blocking agents6 recommend a 10-second interval for 0.1-Hz single twitch stimulation and a ≥12-second interval for TOF stimulation. TOF SX allows a ≥15-second interval for TOF stimulation. The monitoring interval was 1 of the study limitations.
This study also has other limitations. The ideal volume of saline flush for decreasing the onset time is unclear. Yamaguchi et al.12 investigated the required volume of saline flush that allows efficient use of contrast medium for dynamic computed tomography. By comparing the time courses of measured and simulated computed tomography values in the aorta, they estimated that the volume of the vein segment including the antecubital and subclavian veins was 18 mL. Although we administered rocuronium and saline into a forearm vein, the total infused fluid volume of 30 mL (10 mL of rocuronium solution and 20 mL of flushed saline) was enough to change the pharmacodynamic indices of rocuronium, including the onset time. Another limitation is that this study only evaluated the pharmacodynamic effect. Further study is needed to clarify the influence of rocuronium concentration. The bore size of the catheter may also influence the latent onset time and onset time because a smaller bore catheter may result in high-speed spouting of the rocuronium solution. This is an additional potential study limitation.
In conclusion, a 20-mL saline flush immediately after administering a rocuronium bolus of 0.6 mg/kg in 10 mL of normal saline shortened the latent onset time and onset time and prolonged the recovery phase of rocuronium. This study was performed in an experimental setting under stable anesthesia with neuromuscular monitoring implemented at the adductor pollicis. Therefore, onset time may not decrease with a 20-mL saline flush when administering neuromuscular blockade during a hemodynamically unstable state such as anesthetic induction or at a different muscle.
Name: Sayaka Ishigaki, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Sayaka Ishigaki has seen the original study data, reviewed the data analysis, and approved the final manuscript.
Name: Kenichi Masui, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write and compose the manuscript.
Attestation: Kenichi Masui has seen the original study data, reviewed the data analysis, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Tomiei Kazama, MD, PhD.
Contribution: This author helped conduct the study and compose the manuscript.
Attestation: Tomiei Kazama has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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