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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