Effects of tramadol via a µ-opioid receptor on pancreatic ductal adenocarcinoma in vitro and in vivo.

INTRODUCTION: Tramadol, a weak opioid anesthetic, is used for pain management in patients with cancer, but the effects of tramadol on cancer via µ-opioid receptor are still unknown. We assessed the effects of tramadol on pancreatic ductal adenocarcinoma using transgenic mice (LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ). METHODS: Six-week-old transgenic mice were orally administered 10 mg/kg/day tramadol (n=12), 10 mg/kg/day tramadol and 1 mg/kg/day naltrexone (n=9), or vehicle water (n=14) until the humane endpoint. Cancer-related pain and plasma cytokine levels were assessed by the mouse grimace scale and cytokine array, respectively. Tumor status was determined histopathologically. Tramadol's effects on proliferation and invasion in pancreatic ductal adenocarcinoma cell lines were studied in vitro. RESULTS: Tramadol with/without naltrexone improved mouse grimace scale scores while decreasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. Proliferative Ki-67 and cyclins decreased by tramadol, while local M1-like tumor-associated macrophages increased by tramadol, which was blocked by naltrexone. Meanwhile, tramadol with/without naltrexone reduced juxta-tumoral cancer-associated fibroblasts and M2-like tumor-associated macrophages. Tumor-associated neutrophils, natural killers, and cytotoxic T cells were not altered. Tramadol decreased the proliferative and invasive potentials of pancreatic ductal adenocarcinoma cell lines via decreasing cyclins/cyclin-dependent kinases, which was partially reversed by naltrexone. CONCLUSIONS: These findings imply that tramadol might be a useful anesthetic for pancreatic ductal adenocarcinoma: inhibiting the proliferation and invasion along with increasing antitumor M1-like tumor-associated macrophages via the µ-opioid receptor, while improving cancer-associated pain possibly through the antitumor effects with the decrease of inflammatory cytokines.

Influence of the Pringle maneuver during partial hepatectomy on the neuromuscular block induced by intermittent and continuous dosing of rocuronium.

PURPOSE: The Pringle maneuver (PM) is a common procedure in hepatectomy that is known to interrupt drug elimination. The purpose of this study was to examine the influence of PM on the duration of action of rocuronium administered by intermittent bolus dosing, the continuous rocuronium infusion dose required for maintenance of a moderate neuromuscular block, and changes in plasma concentrations of rocuronium. METHODS: Twenty-seven adult patients undergoing partial hepatectomy with PM were enrolled in this study. The duration of action of 0.2 mg/kg rocuronium boluses (DUR), and the continuous rocuronium infusion dose required for maintenance of the height of the first twitch of the train-of-four (T1) at 10-20% of the control value (%T1), respectively, were electromyographically monitored on the adductor digiti minimi muscle. The effects of PM on DUR, %T1, and the plasma concentration of rocuronium were measured. RESULTS: The DUR was significantly prolonged during PM [mean: 42.2 (SD: 8.0) min, P < 0.001] compared to baseline [29.7 (6.3) min]. It was prolonged even after completion of the PM [46.2 (10.5) min, P < 0.001]. The plasma concentration of rocuronium measured at every reappearance of T1 was comparable between before and during PM. %T1 [15.5 (5.6)%] was significantly depressed after the start of PM [6.5 (3.9)%, P < 0.001], with persistence of the depression even after completion of PM. However, there were no significant changes in the plasma concentration of rocuronium. CONCLUSIONS: Rocuronium-induced neuromuscular block is significantly augmented during PM. However, the augmentation is not associated with an increase in plasma rocuronium concentration.

Mirogabalin improves cancer-associated pain but increases the risk of malignancy in mice with pancreatic cancer.

ABSTRACT: Mirogabalin, a selective voltage-gated calcium channel α2δ ligand, improves peripheral neuropathic pain; however, its effects on patients with cancers including pancreatic ductal adenocarcinoma (PDAC) remain unknown. We analyzed the effects of mirogabalin on a KPPC ( LSL-KrasG12D/+; Trp53flox/flox; Pdx-1cre/+ ) mouse model of PDAC. Six-week-old KPPC mice received oral mirogabalin (10 mg/kg/day) (n = 10) or vehicle water (n = 14) until the humane end point. Cancer-associated pain was evaluated using the scores of hunching and mouse grimace scale (MGS). Tumor status and plasma cytokine levels were determined using histopathological analysis and cytokine array, respectively. The effects of mirogabalin on the proliferative ability of PDAC cell lines were determined. The scores of the hunching and MGS improved after mirogabalin administration with a decrease in the plasma levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interferon-γ. Although no significant difference in the survival rate was observed, mirogabalin significantly increased pancreatic tumor size and proliferative index of Ki-67 and cyclins. Local arginase-1 + M2-like tumor-associated macrophages and CD31 + tumor blood vessels increased after mirogabalin administration. By contrast, the number of α-smooth muscle actin + cancer-associated fibroblasts, desmoplastic stroma, and CD8 + T cells decreased. Local myeloperoxidase + tumor-associated neutrophils and CD45R + B cells were unaltered. Mirogabalin enhanced the proliferative ability of PDAC cell lines with the upregulation of cyclins and cyclin-dependent kinases; however, it inhibited the potential of pancreatic stellate cells in vitro. Therefore, our results suggest that mirogabalin improves cancer-associated pain but enhances the proliferative potential of PDAC in vitro and in vivo.

A comparison between the adductor pollicis muscle and the abductor digiti minimi muscle using electromyography AF-201P in rocuronium-induced neuromuscular block: a prospective comparative study.

BACKGROUND: The AF-201P, a new electromyography (EMG)-based neuromuscular monitor has been developed recently. The aim of this clinical study was to compare two ulnar nerve innervated muscles: the adductor pollicis (AP) muscle and the abductor digiti minimi (ADM) muscle during the recovery from rocuronium-induced neuromuscular block by using EMG AF-201P. METHODS: Twenty patients undergoing surgery with general anesthesia were enrolled in the study. During total intravenous general anesthesia, train-of-four (TOF) and post-tetanic counts (PTC) responses following 0.9 mg/kg rocuronium administration were concurrently monitored at the AP and the ADM muscles with EMG AF-201P on the opposite arms. At the end of the surgery, sugammadex 2 mg/kg was administered when TOF counts of 2 (TOFC2) was observed at both muscles. The primary outcome of the study was time from administration of rocuronium to first appearance of PTC response (first PTC). The secondary outcomes of the study were time from administration of rocuronium to TOF count of 1 (TOFC1), time from first PTC to TOFC1 (PTC-TOF time), time to TOFC2, and time from administration of sugammadex to TOF ratio ≥ 0.9. Agreement between the two muscles was assessed using the Bland-Altman analysis. Data are expressed as mean ± standard deviation. RESULTS: Nineteen patients were included in the analysis. Time to first PTC was significantly faster at the ADM muscle than the AP muscle (24.4 ± 11.4 min vs 32.4 ± 13.1 min, p = 0.006). PTC-TOF time was significantly longer with the ADM muscle than the AP muscle (19.4 ± 7.3 min vs 12.4 ± 10.6 min, p = 0.019). There were no significant differences in time to TOFC2 and sugammadex-facilitated recovery between the two muscles. Bland-Altman analyses showed acceptable ranges of bias and limits of agreement of the two muscles. CONCLUSIONS: The ADM muscle showed a good agreement with the AP muscle during rocuronium-induced neuromuscular block but faster recovery of PTC response when using EMG. TRIAL REGISTRATION: UMIN-CTR (Registration No. UMIN000044904 ). Registered 19 July 2021 -Retrospectively registered, https://center6.umin.ac.jp/cgi-bin/ctr_e/ctr_view.cgi?recptno=R000051290 .

Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma.

BACKGROUND: Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-KrasG12D/+;Trp53flox/flox;Pdx-1cre/+ transgenic mice with pancreatic ductal adenocarcinoma. METHODS: Six-week-old transgenic mice were administered midazolam 30 mg kg-1 day-1 p.o. (n=13); midazolam 30 mg kg-1 day-1 with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg-1 day-1 i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines. RESULTS: Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase+ tumour-associated neutrophils, arginase-1+ M2-like tumour-associated macrophages, and CD11b+Ly-6G+ polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro. CONCLUSIONS: These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.

A Comparison Between the Adductor Pollicis Muscle Using TOF-Watch SX and the Abductor Digiti Minimi Muscle Using TetraGraph in Rocuronium-Induced Neuromuscular Block: A Prospective Observational Study.

BACKGROUND: The commonly used acceleromyography (AMG)-based neuromuscular monitor TOF-Watch SX is no longer manufactured. Recently, a new portable electromyography (EMG)-based neuromuscular monitor TetraGraph was introduced in clinical anesthesia. The aim of the study was to compare the responses obtained simultaneously from the abductor digiti minimi (ADM) muscle with TetraGraph and the adductor pollicis (AP) muscle with TOF-Watch SX during rocuronium-induced neuromuscular block. METHODS: Patients undergoing orthopedic surgery with general anesthesia were enrolled in this prospective, observational study. During total intravenous general anesthesia, train-of-four (TOF) responses following 0.9-mg·kg -1 rocuronium administration were monitored at the AP muscle with TOF-Watch SX and the ADM muscle with TetraGraph on the opposite arms. Sugammadex 2 mg·kg -1 was administered when both devices showed TOF counts (TOFCs) = 2. The primary outcome was time from rocuronium administration to first appearance of posttetanic count (PTC) response (first PTC). The secondary outcomes were baseline TOF ratios (TOFRs), onset time, time to first reappearance of TOFC = 1 (time to TOFC1), time to first reappearance of TOFC = 2 (time to TOFC2), and time from sugammadex administration to TOFR ≥0.9 with TetraGraph or to normalized TOFR ≥0.9 with TOF-Watch SX (recovery time). We used paired t test and Wilcoxon signed-rank test to analyze parametric and nonparametric data, respectively. P <.05 defined statistical significance. RESULTS: A total of 20 patients were analyzed. The baseline TOFRs were significantly higher with TOF-Watch SX than with TetraGraph (105 [96-110] vs 100 [98-101]; P = .0002). The time to first PTC (minutes) (31.7 ± 9.6 vs 41.1 ± 12.3; P < .001), time to TOFC1 (minutes) (48.0 ± 12.7 vs 58.8 ± 19.2; P < .001), time to TOFC2 (minutes) (56.2 ± 15.7 vs 74.2 ± 23.7; P < .001), and recovery time (seconds) (61.5 [32-148] vs 75.5 [94-102]); P = .043) were significantly faster with TOF-Watch SX than with TetraGraph. There were no significant differences in onset time. CONCLUSIONS: TOF-Watch SX overestimated recovery from rocuronium-induced neuromuscular block compared with TetraGraph.

Extravascular leakage of induction doses of rocuronium: four cases in which both depth of neuromuscular block and plasma concentration of rocuronium were assessed.

The duration of action of extravasated rocuronium varies depending on the patient's comorbidities. In patients who receive high doses of non-depolarizing neuromuscular blocking agents subcutaneously, anesthesiologists should be aware of unexpected prolongation of the progress and recovery of neuromuscular block. In such cases, the depth and recovery of neuromuscular block should be objectively monitored to avoid residual neuromuscular block and recurarization.

Plasma rocuronium concentration in cell salvage blood following cardiac surgery: a case series.

PURPOSE: The aim of the study was to evaluate the plasma rocuronium concentration in autologous blood transfusion obtained from the cell salvage (CS) system following cardiac surgery with cardiopulmonary bypass (CPB). METHODS: This prospective observational study was conducted in a university teaching hospital from July to November 2020. Patients undergoing general anesthesia for cardiac surgery with CPB were enrolled in the study. After separation from CPB, residual blood remaining in the extracorporeal system was collected as the control sample. The second sample (CS blood) was collected from the autologous blood transfusion obtained after completion of the CS system with Cell Saver® Elite®. Hematocrit values of both samples were also examined. RESULTS: Ten subjects (aged 57-86 years) were enrolled in this study. Plasma rocuronium concentrations (ng/ml) were significantly lower in the CS blood (94.0 ± 77.5) compared to the control (2950 ± 812.2) (p = 0.002). Hematocrit values (%) were significantly higher in the CS blood (75.2 ± 11.3) compared to the control (40.2 ± 10.2) (p = 0.002). CONCLUSION: Autologous blood transfusion obtained from CS system following cardiac surgery with CPB, only retained a small amount of plasma rocuronium concentration, therefore, the risk of autologous blood transfusion contributing to clinically relevant residual neuromuscular blockade postoperatively should be considered to be low. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network under registration number UMIN000040877 (registration date; June 24, 2020).

Duloxetine improves cancer-associated pain in a mouse model of pancreatic cancer through stimulation of noradrenaline pathway and its antitumor effects.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. Patients with inoperative PDAC require effective chemotherapy and pain control to increase their quality of life. We investigated whether duloxetine, a serotonin-noradrenaline reuptake inhibitor, improves quality of life in a KPPC (LSL-Kras;Trp53;Pdx1-cre) mouse model of PDAC. Six-week-old KPPC mice were orally administered 4 mg/kg/d duloxetine (n = 12); 4 mg/kg/d duloxetine with 0.15 mg/kg/d atipamezole, a synthetic α2 adrenergic receptor antagonist (n = 9); or vehicle water (n = 11). Body weight and food intake were measured daily, and cancer pain was evaluated by the hunching score and mouse grimace scale. At the endpoint, the tumor status, angiogenesis, and immunoinflammatory condition were analyzed. The pain level using the hunching and mouse grimace scale scores improved by duloxetine in KPPC mice (P < 0.01), whereas the scores that had been reduced by duloxetine were elevated by administration of atipamezole. Kaplan-Meier analysis demonstrated that duloxetine-treated mice had significantly prolonged survival (P < 0.05) with delayed appetite loss, cachexia, and body weight loss. Duloxetine inhibited the proliferation of PDAC cells and cancer-associated fibroblasts in vivo with a shift into an antitumor immunoinflammatory condition and the corresponding plasma cytokine levels. The migrative/invasive potentials of PDAC were inhibited by duloxetine in vitro. Meanwhile, atipamezole did not inhibit the antitumor effects of duloxetine in vitro and in vivo. Therefore, our results indicate that duloxetine mainly improves cancer-associated pain by enhancement of the noradrenergic pathway rather than the serotonergic pathway, whereas duloxetine modulates antitumor effects on PDAC without involvement of the noradrenergic pathway.

Potency estimation of sugammadex for the reversal of moderate rocuronium-induced neuromuscular block: a non-randomized dose-response study.

PURPOSE: There is no report investigating the precise potency of sugammadex for antagonizing various intensities of rocuronium-induced neuromuscular block. The aim of this study was to evaluate the ED95 of reversibility of sugammadex and reveal the safety factor of 2 mg/kg of sugammadex for moderate rocuronium-induced neuromuscular block. METHODS: Fifteen patients were enrolled in this study. After induction of anesthesia, we recorded the adductor pollicis muscle response to ulnar nerve stimulation using acceleromyography. All patients received 0.6 mg/kg rocuronium. When the first twitch (T1) of the train-of-four (TOF) response reappeared, rocuronium infusion was commenced to maintain T1 at 10% of the control. After the surgery was completed and infusion of rocuronium was stopped, patients were given sugammadex by a cumulative dose technique. The effective doses of sugammadex that led to recovery of the amplitude of T1 and the TOF ratio by 95% (ED95) were calculated from the regression lines of least-squares regression analysis. RESULTS: The mean ED95 of sugammadex for recovery of T1 and the TOF ratio from rocuronium-induced moderate neuromuscular block was 1.34 (0.24) and 1.14 (0.24) mg/kg, respectively. CONCLUSIONS: The ED95 of sugammadex for the recovery of T1 was significantly greater than that for the TOF ratio. However, a sugammadex dose of 2 mg/kg is equivalent to about 1.5 times the ED95 of sugammadex for reversal of moderate rocuronium-induced block, indicating its safety margin.

Efficiency of the TOF-Cuff™ for the evaluation of rocuronium-induced neuromuscular block and its reversal with sugammadex: a comparative study vs. acceleromyography.

PURPOSE: The aim of this study was to compare TOF-Cuff™ (TOF-C) and TOF-Watch™ (TOF-W) data following rocuronium-induced neuromuscular block and its reversal with sugammadex. METHODS: Twenty elderly patients aged 68-82 years scheduled for surgery under general anesthesia were enrolled in this study. After induction of anesthesia, neuromuscular block resulting from administration of 0.6 mg/kg rocuronium was concurrently evaluated using TOF-C and TOF-W. The onset of neuromuscular block and duration until the first twitch response following post-tetanic count (PTC) and 2 Hz train-of-four (TOF) stimulation reappeared were evaluated. When the response to the TOF stimulus was detected with both monitors, additional doses of rocuronium were administered to maintain the neuromuscular block. After surgery, 2 mg/kg sugammadex was administered when 1-2 TOF twitches were observed with the TOF-W and the time required for facilitated recovery to a TOF ratio of > 0.9 was assessed. RESULTS: Regression analyses revealed no statistically significant differences in the mean [SD] onset of rocuronium-induced neuromuscular block [127.8 (27.2) s, 123.5 (30.5) s], time to recovery of the first PTC twitch [23.9 (8.0) min, 25.4 (8.6) min], time to recovery of the first twitch with TOF stimulation [37.2 (8.8) min, 38.9 (11.1) min] and time to adequate reversal with sugammadex [139.2 (30.6) s, 151.8 (31.5) s] between TOF-C and TOF-W, respectively. Bland-Altman analyses also showed acceptable ranges of the biases and limits of agreement between the two methods. CONCLUSIONS: TOF-C may be clinically applicable for the evaluation of both the depth of neuromuscular block and restoration of neuromuscular function.

Effects of cardiac output on the onset of rocuronium-induced neuromuscular block in elderly patients.

PURPOSE: The aim of this study was to elucidate the relationship between the onset of rocuronium-induced neuromuscular block and arterial pressure-based cardiac output (CO) in elderly patients. METHODS: Forty elderly patients aged 65-83 years were enrolled in this study. After induction of anesthesia, contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation were acceleromyographically evaluated and 1 mg/kg rocuronium was administered following CO measurement. The correlation between onset of rocuronium action and CO was analyzed. RESULTS: The mean [SD] CO reduced after induction of anesthesia from 5.1 [1.8] L/min to 3.8 [1.1] L/min. The onset time of rocuronium-induced neuromuscular block was 110.3 [23.9] s (range 60-165). There was a statistically significant inverse correlation between the onset time of rocuronium and CO [onset time (s) = - 13.2·CO + 159.7, R2 = 0.376]. CONCLUSIONS: In the elderly, CO influences the onset of action of rocuronium.

Onset of rocuronium-induced neuromuscular block evaluated subjectively and accerelomyographically at the masseter muscle.

PURPOSE: The main aim of this study was to compare the onset times of rocuronium evaluated subjectively and by acceleromyography at the masseter muscle (MM). METHODS: Forty female patients were sequentially enrolled in this study. In the first 20 patients, neuromuscular block was evaluated subjectively. After induction of anesthesia with fentanyl and propofol, both the left masseter and ulnar nerves were stimulated in 2-Hz train-of-four (TOF) mode using peripheral nerve stimulators. Contractions of the MM were felt with an anesthesiologist's left hand holding an anesthesia facemask; those of the adductor pollicis (APM) were visually observed. All the patients received a bolus of rocuronium, 0.6 mg/kg. Onset times after rocuronium were defined as the duration until the contractions became impalpable at the MM or invisible at the APM. At the time contraction of the MM had not been felt, intubating conditions were assessed. In the next 20 patients, contractions of the MM and the APM were concurrently quantified using acceleromyography after induction of anesthesia and laryngeal mask insertion. Following 0.6 mg/kg rocuronium, onset of the action was recorded. RESULTS: Onset of the action of rocuronium at the MM evaluated subjectively [mean (SD), 70.3 (17.7) s] was similar to that monitored acceleromyographically [73.3 (27.6) s, P > 0.05], and significantly shorter than that at the APM acceleromyographically [111.0 (34.8) s, P = 0.016]. Intubating conditions of 20 patients were graded either excellent or good. CONCLUSION: Subjective evaluation of contractions of the MM by an anesthesiologist's hand may be reliable to determine faster timing for safe tracheal intubation.

Monitoring masseter muscle evoked responses enables faster tracheal intubation.

PURPOSE: The aim of this study was to investigate whether monitoring neuromuscular block at the masseter muscle (MM) would allow faster tracheal intubation when compared with that at the adductor pollicis muscle (APM). METHODS: Twenty female patients undergoing gynecological surgery were enrolled into this study. Immediately after inducing anesthesia with fentanyl and propofol, both the left masseter and ulnar nerves were stimulated in a 2 Hz train-of-four (TOF) mode using peripheral nerve stimulators. Contractions of the MM were felt with the anesthesiologist's left hand lifting the patient's jaw and holding an anesthesia facemask, while those of the APM were visually observed. Immediately after the contracting responses of the muscles were confirmed, all of the patients received an iv bolus of vecuronium 0.1 mg kg(-1). Onset times after vecuronium were defined as the duration until the contractions became impalpable at the MM or invisible at the APM. When the contraction of the MM could no longer be felt, the conditions for laryngoscopy and tracheal intubation were assessed. RESULTS: Onset time evaluated tactually at the MM (mean +/- SD, 108.4 +/- 27.7 s) was significantly shorter than that evaluated visually at the APM (181.2 +/- 32.1 s, P < 0.0001). The intubating conditions for all patients were graded as either excellent or good. CONCLUSION: Tactual evaluation of muscle paralysis of the MM during induction of anesthesia is clinically useful since it leads to faster tracheal intubation.

[Investigations into neostigmine-induced inhibition of neuromuscular transmission].

BACKGROUND: Fade of the muscle contraction evoked by indirect tetanic nerve stimulation shows residual neuromuscular block. Anticholinesterases can reverse the partial block; however, they may also inhibit normal neuromuscular transmission and can cause fading responses by misuse of these drugs. The aim of this study is to investigate how neostigmine acts on normal neuromuscular function. METHODS: In cats, we observed a series of 8 consecutive muscular compound action potentials (mCAPs; M1-8) of the gastrocnemius muscle evoked by repetitive sciatic nerve stimulation at 100 Hz and calculated the M8/M1 amplitude ratio as an index of fading phenomenon. Neostigmine 0.05 mg x kg(-1) repetitively every 5 minutes before neuromuscular blocking agent had been administered, or after the complete recovery from vecuronium-induced block had been obtained. RESULTS: Neostigmine caused dose-dependent fade in the mCAPs. The mean doses (SD) of neostigmine for depressing M8/M1 ratio to 50% of baseline were 0.087 (0.029) mg x kg(-1) before use of neuromuscular blocking agent and 0.161 (0.070) mg x kg(-1) after the recovery from neuromuscular block. The fading responses induced by neostigmine were paradoxically reversed by small doses of vecuronium. CONCLUSIONS: Therapeutic doses of neostigmine administered during normal neuromuscular function cause fade of the repetitive muscle contractions. Neuromuscular monitoring should be used before the reversal with neostigmine.

Duration of vecuronium-induced neuromuscular block can be predicted by change of skin temperature over the thenar muscles.

PURPOSE: The purpose of this study was to clarify the relationship between skin temperature over the thenar muscles and the duration of action of vecuronium measured acceleromyographically at the thumb in anesthetized patients. METHODS: In 15 patients undergoing elective open abdominal surgery under propofol, fentanyl, and nitrous oxide anesthesia, train-of-four (TOF) stimuli were delivered over the ulnar nerve at 2 Hz every 15 s, and the degree of neuromuscular block was measured acceleromyographically at the thumb. Each patient received an intubating dose of vecuronium 0.1 mg x kg(-1), followed by maintenance doses of 0.02 mg x kg(-1) administered repeatedly whenever the first twitch of TOF responses had recovered to 25% of control. The interval between maintenance doses was defined as the clinical duration (DUR25). The median values of skin temperature (ST) over the ipsilateral thenar muscles and esophageal temperature (ET) were recorded during the action of the first and all subsequent maintenance doses. The relationships between change in temperature and change in DUR25 were analyzed. RESULTS: Whereas ET showed only minor changes (median, -0.3 degrees C), ST fluctuated markedly between +0.9 degrees and -6.3 degrees C (median, -1.4 degrees C). Increase and decrease were also seen in a series of DUR25s, as expected from the changes in ST. The median values of DUR25 produced by the first and last maintenance vecuronium doses were 21.5 and 32.3 min, respectively. A negative linear correlation was found between the change in DUR25 and that in ST, demonstrating that DUR25 increased by 20% of baseline with each 1 degrees C decrease in ST. CONCLUSION: Our results show that peripheral ST decreases considerably during open abdominal surgery without reduction in core temperature, and the decrease contributes to the potentiation of neuromuscular block in the periphery during propofol, fentanyl, and nitrous oxide anesthesia.