Anesth Analg 1999;89:1565
© 1999 International Anesthesia Research Society
GENERAL ARTICLES
The Ulinastatin-Induced Effect on Neuromuscular Block Caused by Vecuronium
Yuhji Saitoh, MD*,
Yoshitaka Fujii, MD , and
Tsutomu Oshima, MD
*Department of Anesthesiology, Toride Kyodo General Hospital, Ibaraki;
Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki; and
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu, Japan
Address correspondence and reprint requests to Yuhji Saitoh, MD, Department of Anesthesiology, Toride Kyodo General Hospital, 2-1-1, Hongo, Toride City, Ibaraki, 302-0022, Japan. Address e-mail to 69481654{at}people.or.jp
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Abstract
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We examined the effect of ulinastatin, a protease inhibitor purified from human urine, on neuromuscular block caused by vecuronium. Sixty adult patients were randomly divided into four groups of 15 patients each: ulinastatin-posttetanic count (U-PTC), ulinastatin-train-of-four (U-TOF), control-posttetanic count (C-PTC) or control-train-of-four (C-TOF) group. In the U-PTC and U-TOF groups, a bolus dose of ulinastatin 5000 U/kg was administered 2 min before the injection of vecuronium 0.1 mg/kg. In the C-PTC and C-TOF groups, normal saline was administered instead of ulinastatin. The onset of neuromuscular block in the U-PTC and U-TOF groups was significantly slower than in the C-PTC and C-TOF groups (250 ± 49 vs 214 ± 35 s, mean ± SD, P < 0.05). The time from the vecuronium injection to the return of PTC in the U-PTC group was significantly shorter than in the C-PTC group (11.0 ± 2.8 vs 17.6 ± 6.8 min, P < 0.05). Similarly, times to the returns of T1, T2, T3, and T4 (first, second, third, and fourth stimulation of TOF) in the U-TOF group were significantly shorter than in the C-TOF group (18.5 ± 5.0 vs 28.0 ± 9.1 min for T1, P < 0.05). PTC in the U-PTC group was significantly higher than in the C-PTC Group 10–30 min after the administration of vecuronium (P < 0.05). T1/control twitch height and TOF ratios in the U-TOF group were significantly higher than those in the C-TOF Group 30–70 min and 40–70 min after the administration of vecuronium, respectively (P < 0.05). Ulinastatin delays the onset of neuromuscular block and hastens its recovery caused by vecuronium.
Implications: Ulinastatin delays the onset of neuromuscular block and hastens its recovery caused by vecuronium. This is because ulinastatin may release acetylcholine at the neuromuscular junction and increase hepatic and/or renal clearance of vecuronium.
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Introduction
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Ulinastatin is a protease inhibitor purified from human urine. Furthermore, protease inhibitor homologs release acetylcholine (ACh) at the neuromuscular junction (1). We hypothesized that the increased release of ACh caused by ulinastatin would enhance muscular contraction and therefore weaken the degree of neuromuscular block. Moreover, ulinastatin increases blood flow in the liver (2) and urine volume (3). Vecuronium is eliminated mainly in the liver and partially in the kidney (4–7). Because ulinastatin may increase hepatic and/or renal clearance of vecuronium, recovery of vecuronium-induced neuromuscular block would be quickened. However, no previous studies have investigated the degree of neuromuscular block after the administration of ulinastatin. The present study was undertaken to determine the onset of neuromuscular block and recovery of posttetanic count (PTC) or train-of-four (TOF) response after the administration of ulinastatin in anesthetized patients receiving vecuronium.
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Methods
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Our local ethics committee approved the protocol of this study, and written, informed consent was obtained from each patient. Sixty adult patients, ASA physical status I or II, undergoing elective general anesthesia, were enrolled. The patients were randomly divided into four groups of 15 patients each: ulinastatin-PTC (U-PTC), ulinastatin-TOF (U-TOF), control-PTC (C-PTC), or control-TOF (C-TOF). No patient had neuromuscular, hepatic, renal, or cardiac disorders or was receiving any drugs known to affect neuromuscular transmission.
Premedication consisting of atropine 0.01 mg/kg and hydroxyzine 1.0 mg/kg was given IM 30 min before the induction of anesthesia. On arriving at the surgery room, two surface-stimulating electrodes were positioned over the ulnar nerve at the wrist. A force displacement transducer was attached to the thumb of the investigated arm.
Drug Administration and Monitoring of Neuromuscular Block
In the U-PTC and U-TOF groups, before the induction of anesthesia, a bolus dose of ulinastatin 5000 U/kg was administered IV. This method of the administration of ulinastatin was comparable to those in previous studies (3,8,9). In the C-PTC and C-TOF groups, 0.1 mL/kg of normal saline was given instead of ulinastatin. Immediately after the injection of ulinastatin or normal saline, propofol 2 mg/kg was administered IV. In each group, after the loss of eyelash reflex was confirmed, TOF stimuli were given at 50 mA every 12 s using an electrical nerve stimulator (Myotest DBS; Biometer International, Odense, Denmark). For TOF stimulation, four single-twitch stimuli consisting of 0.2-ms duration square waves were applied at 2 Hz. Mechanical twitch responses of the adduction of the thumb were measured using a neuromuscular transmission analyzer (Myograph 2000; Biometer International). Twitch height of the T1 (the first response in TOF) was regarded as the control. Once the control had been recorded, vecuronium 0.1 mg/kg was administered IV to facilitate tracheal intubation. The time interval from the administration of ulinastatin or normal saline to that of vecuronium was 2 min. After the vecuronium injection, the disappearance of the T1 response was regarded as the onset of neuromuscular block. The time to the onset of neuromuscular block measured in the U-PTC and U-TOF groups was compared with that in the C-PTC and C-TOF groups. After the administration of vecuronium, in the U-PTC and C-PTC groups, PTC was measured every 5 min at 50 mA. For PTC, a 50-Hz tetanic stimulation was delivered at 50 mA for 5 s, and after a pause of 3 s, 20 single-twitch stimuli of 0.2-ms duration square waves were given every 1 s at 50 mA. The number of detectable muscular contractions in response to the stimuli was regarded as PTC. The times from the vecuronium injection to the return of PTC1 (only one response to the 20 single-twitch stimuli delivered after the tetanic stimulation could be elicited) were compared between the U-PTC and C-PTC groups. In addition, in the U-PTC and C-PTC groups, time courses of recovery of PTC were compared. In U-TOF and C-TOF groups, TOF stimuli were applied every 12 s at 50 mA. The times from the vecuronium injection to the return of T1, T2, T3, and T4 (the first, second, third, and fourth response in TOF) were compared between the two groups. Also, T1/control and TOF ratios were recorded every 10 min and were compared between the U-TOF and C-TOF groups.
Maintenance of Anesthesia
In each group, anesthesia was maintained with nitrous oxide 66%, oxygen 33%, and 0.5% end-tidal isoflurane. Additionally, a bolus dose of fentanyl 2 µg/kg was administered IV. When the patients demonstrated systolic hypertension (systolic arterial pressure > 150 mm Hg) or tachycardia (heart rate > 100 bpm), a bolus dose of fentanyl 2 µg/kg was again administered IV. Ventilation was controlled sufficiently to maintain normocapnia (PETCO2 32–38 mm Hg). The concentrations of anesthetics and PETCO2 were measured by using a multiple gas monitor (Capnomac Ultima; Datex Inc., Helsinki, Finland). The peripheral temperature over the adductor pollicis muscle was monitored by using a surface skin thermometer.
All results were expressed as number or mean ± SD. Patient data were compared among the four groups using analysis of variance and Scheffe multiple comparison. The time to the onset of neuromuscular block in the U-PTC and U-TOF groups was compared with that in the C-PTC and C-TOF groups by using the unpaired t-test. The times to the return of PTC1 between the U-PTC and C-TOF groups were compared by using the unpaired t-test. Similarly, times to the return of T1, T2, T3, or T4 were compared between the U-TOF and C-TOF groups by using the unpaired t-test. The comparison of recoveries of PTC between the U-PTC and C-PTC groups was made by using the Kruskal-Wallis test followed by the Mann-Whitney U-test with Bonferroni’s adjustment. The recoveries of T1/control or TOF ratio were compared between the U-TOF and C-TOF groups by using analysis of variance followed by the unpaired t-test with Bonferroni’s adjustment. A P value < 0.05 was considered to be statistically significant. Statistical analyses were performed with a statistical package (SYSTAT 8.0; SPSS Inc., Chicago, IL) on a personal computer.
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Results
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Patient data were comparable among the four groups (Table 1).
The time to the onset of neuromuscular block measured in the U-PTC and U-TOF groups was significantly longer than that in the C-PTC and C-TOF groups (250 ± 49 vs 214 ± 35 s, P < 0.05).
The time from the vecuronium injection to the return of PTC1 in the U-PTC group was significantly shorter than in the C-PTC groups (P < 0.05). Also, times to the returns of T1, T2, T3, and T4 in the U-TOF group were significantly shorter than those in the C-TOF group (P < 0.05) (Table 2).
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Table 2. Times from the Administration of Vecuronium 0.1 mg/kg to the Returns of PTC1 in the U-PTC and C-PTC Groups, and Those of T1, T2, T3, and T4 in the U-TOF and C-TOF Groups
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PTC in the U-PTC group was significantly higher than in the C-PTC groups 10–30 min after the administration of vecuronium (P < 0.05) (Figure 1). The T1/control and TOF ratios in the U-TOF group were significantly higher than in the C-TOF Group 30–70 min and 40–70 min after the administration of vecuronium, respectively (P < 0.05) (Figures 2 and 3).
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Figure 1. Recoveries of PTC in the U-PTC (•) and C-PTC ( )) groups. PTC = posttetanic count. U = ulinastatin, C = control, PTC = posttetanic count. *P < 0.05 between the groups.
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Figure 2. Recoveries of T1/control in the U-TOF (•) and C-TOF ()) groups. U = ulinastatin, C = control, TOF = train-of-four. *P < 0.05 between the two groups.
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Figure 3. Recoveries of TOF ratio in the U-TOF (•) and C-TOF ()) groups. U = ulinastatin, C = control, TOF = train-of-four. *P < 0.05 between the two groups.
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After the administration of ulinastatin or normal saline, no patient demonstrated severe hypertension (systolic arterial pressure > 200 mm Hg) or hypotension (systolic arterial pressure < 80 mm Hg), severe tachycardia (heart rate > 120 bpm), bradycardia (heart rate < 50 bpm), or arrhythmia.
In no patient did the peripheral temperature over the adductor pollicis muscle decrease to <32°C.
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Discussion
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This study shows that a bolus administration of ulinastatin delays the onset of vecuronium-induced neuromuscular block. After the administration of ulinastatin, the times to the return of PTC1, T1, T2, T3, and T4 are shortened. The recoveries of PTC, T1/control, and TOF ratios are also accelerated.
Protease inhibitor homolog facilitates the release of ACh in response to motor nerve stimulation (1). We presume that, because the ACh release increased after the administration of ulinastatin, skeletal muscles became resistant to vecuronium. Therefore, it might not be surprising that the onset of neuromuscular block was delayed and that the recovery of neuromuscular block was accelerated after the administration of ulinastatin.
In this study, the time interval from the administration of ulinastatin to that of vecuronium was as short as 2 min. However, ulinastatin given 2 min before the vecuronium injection delayed the onset of neuromuscular block significantly. Sugiki et al. (10) reported that the distribution half-life of protease inhibitor was 3.9 min. Ohnishi et al. (11) showed that a protease-inhibitor-induced cardiovascular effect could be observed 20 min after the administration of a protease inhibitor in rats. Although no previous studies have examined the onset of the ulinastatin-induced effect on neuromuscular transmission, we conclude that the ulinastatin-induced effect on the skeletal muscles may become apparent within 2 min after a bolus administration of ulinastatin.
Vecuronium is eliminated mainly in the liver (4–7). Upton et al. (4) reported that more than 40% of the dose of vecuronium was recovered in the bile of rats. Bencini et al. (5) showed that, in cats, after the administration of vecuronium, 70% of the dose of vecuronium was recovered: 40% in the bile, 15% in the liver, and 15% in the kidney. Lebrault et al. (6) demonstrated a 44% increase in the elimination half-life of vecuronium and a 100% increase in the duration of the recovery rate of neuromuscular block in patients with liver cirrhosis receiving vecuronium when compared with rates measured in healthy patients. Because ulinastatin increases blood flow in the liver (2), the hepatic elimination of vecuronium would be promoted after the administration of ulinastatin.
Vecuronium is partially excreted in the urine (4–7). Vecuronium 8% (4) or 15% (5) given IV is recovered in the kidney in rats. Because ulinastatin increases urine volume (3), vecuronium would be eliminated rapidly in the kidney after the ulinastatin injection.
We showed that if ulinastatin was given just before induction of anesthesia, PTC, T1/control, and TOF ratios were significantly higher than those measured without the administration of ulinastatin 10–30 min, 30–70 min, and 40–70 min after administration of vecuronium, respectively. It has been reported that, in humans, the plasma half-life of ulinastatin is 33 min (12). The relatively short half-life of ulinastatin may relate to the present result that the ulinastatin-induced potentiating effect on muscular contraction lasted, at most, 70 min.
In the U-PTC and U-TOF groups, the control twitch height was recorded after the administration of ulinastatin. However, it has been shown that some protease-inhibitor homologs, i.e., dendrotoxin, toxin I, or toxin K, increase muscular contraction in the nerve-muscle preparation (1). Therefore, in the U-PTC and U-TOF groups, the control twitch height might have been enhanced as compared with that in the C-PTC and C-TOF groups.
Chauvin et al. (13) reported that, at the adductor pollicis muscle, mean times from an administration of vecuronium 0.1 mg/kg to the recoveries of T1/control of 0.25 and 0.50 were 41 and 50 min, respectively. However, this study revealed that in the control group, times to the recoveries of T1/control of 0.25 and 0.50 were as long as 45 and 70 min, respectively. In a previous study (12), no inhaled anesthetic was used. In contrast, in this study, 0.5% end-tidal isoflurane was used to maintain general anesthesia. Isoflurane enhances the duration of neuromuscular block (14). We presume that, because anesthesia was maintained with isoflurane, the recovery of neuromuscular block would be delayed.
No previous studies examined ulinastatin-induced changes in arterial pressure or heart rate in humans. However, Ohnishi et al. (11) demonstrated that ulinastatin attenuated a decrease in arterial pressure caused by hemorrhagic shock in mice. They also showed that ulinastatin did not significantly alter heart rate after hemorrhagic shock. In this study, no severe change in arterial pressure or heart rate was observed after the administration of ulinastatin. Presumably, ulinastatin-induced changes in arterial pressure or heart rate may be trivial.
In conclusion, ulinastatin delays the onset of neuromuscular block caused by vecuronium and hastens the recovery of neuromuscular block in anesthetized patients. This is probably because ulinastatin increases the release of ACh, blood flow in the liver, and urine volume.
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References
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Accepted for publication August 31, 1999.
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Abstract
Introduction
