Effects Of Temperature On Pharmacodynamics Of Rocuronium

Objective: To investigate effects of hypothermia and hyperthermia on the time-course in vivo and potency in vitro of rocuronium, by controlling of temperature continuously and preciously, and illustrate mechanism of the influences of temperature on rocuronium's actionMethods: This study was composed of two parts1. 50 male Wistar rats weighting 250～350g were randomly divided into 5 groups (n=10, in each). H group:38～40℃, N group:36～38℃, L₁ group:34～36℃, L₂ group:32～34℃,L₃ group:30～32℃. Animals were anaesthetized by intraperitoneally injection with 20% chloral hydrate(10mg/kg). After the rat lost consciousness, it was fixed on the operation table(room temperature is 18～20℃). Temperature probe was lubricated with paraffin oil and inserted into anal 5～8㎝. Homeothermic blanket was adjusted to maintain the body temperature of rats to the target level, according to the temperature monitoring. 2-lead surface ECG was monitored. After tracheotomy ,animal ventilator was set with tidal volume of 10 ml / kg, respiratory rate of 50 ⁶0 beats / min, respiratory ratio (I: E) of 1: 1.5 and oxygen flow of 0.5 L / min, to maintain PaCO2 at 35⁴5 mmHg. Femoral vein was isolated and cannulated for administration of rocuronium. Force transducer was connected to the tibialis anterior muscle and two needle electrodes of stimulator were inserted to the distal and proximal of tibial nerve,respectively. Tibial nerves were stimulated with 2Hz, 3～5 V,train-of-four(TOF) stimuli. The first twitch response in TOF stimulation (T1) was observed. After T1 block was kept constant at 100% for 10min, rocuronium 0.6mg/kg was administrated. Time was recorded and mechanical ventilation was given. Clinical duration (from injection to 25% T1 recovery), recovery index (from 25 to 75% T1 recovery) (RI), and total duration (from injection to 90% T1 recovery) were recorded. All statistical analyses were performed using the SPSS11.5 program package. Data were expressed as the mean±SD. One-way ANOVA was used to compare the differences between groups each other. P<0.05 was considered statistically significant2. 50 male Wistar rats weighting 250～350g were randomly divided into 5 groups(n=10 each group). H group:38～40℃, N group:36～38℃, L₁ group:34～36℃, L₂ group : 32～34℃, L₃ group : 30～32℃. Rats were sacrificed and phrenic nerve-hemidiaphragm preparations were made. Each preparation was mounted in an individual organ bath containing 50ml Kreb's oxygened solution with 95% oxygen-5% carbon dioxide gas mixture. The diaphragm was pretensioned to 4 g, and 0.1 Hz supramaximal square wave pulses were delivered to the phrenic nerve by a nerve stimulator. Twitch heights were measured and recorded via a precalibrated force displacement transducer. After a 30-minute stabilization period, rocuronium 50μg was added to the 50 mL Kreb's solution, to obtain an initial concentration of 1μg/ml. Subsequently, 25-μg increments of rocuronium were added after a stable response to each dose (more than 10 minutes of equal height twitches were recorded) until more than 95% inhibition of twitch response was achieved. Statistical analyses were performed using 2 models, logistic nonlinear regression and probit regression. A cumulative concentration–response curve of rocuronium was fitted for each animal. The observed data were logistic and probit transformed to calculate the estimates of effective concentrations for 5% (EC5), 50% (EC50), 90% (EC90), and 95% (EC95) twitch depression. Statistical differences in mean point estimates of EC5, EC50, EC90, and EC95 between groups were compared using ANOVA. P<0.05 was considered to statistically significantResults:1 There was no significant difference in body temperature before anesthesia between groups each other2 Clinical duration: N group was 8.0±2.2min,H group was 5.0±1.3min ,L₁ group was 8.5±1.6min,L₂ group was 10.5±2.2min,L₃ group was 13.5±2.2min. Compared with N group, H group was significantly shorter (P<0.01), L₁ group was not significantly longer, L₂ group was significantly longer (P<0.01), L₃ group was significantly longer (P<0.01). Compared with L₁ group, L₂ group was significantly longer (P<0.05), L₃ group was significantly longer (P<0.01). Compared with L₂ group, L₃ group was significantly longer (P<0.01). RI: N group was 5.0±1.2 min, H group was 4.5±1.0min , L₁ group was 5.3±1.7min , L₂ group was 5.9±1.7min,L₃ group was 6.9±0.6min. Compared with N group, H group was not significantly shorter, L₁ group and L₂ group was not significantly longer, L₃ group was significantly longer (P<0.01). Compared with L₁ group, L₃ group was significantly longer (P<0.01), L₂ group was not significantly longer. Compared with L₂ group, L₃ group was not significantly longer. Total duration : N group was 16.0±2.4min,H group was 10.4±3.0min ,L₁ group was 17.3±3.7min,L₂ group was 19.4±3.4min,L₃ group was 24.6±1.9min. Compared with N group, H group was significantly shorter (P<0.01), L₁ group was not significantly longer, L₂ group was significantly longer (P<0.05), L₃ group was significantly longer (P<0.01). Compared with L₁ group, L₂ group was not significantly longer, L₃ group was significantly longer (P<0.01). Compared with L₂ group, L₃ group was significantly longer (P<0.01)3 Compared with EC5 (3.8±0.8μg/ml), EC50 (5.5±0.7μg/ml), EC90(7.2±0.7μg/ml) and EC95(7.9±0.7μg/ml) of N group, EC5 ( 4.4±0.5μg/ml ) , EC50 ( 6.2±0.4μg/ml ) , EC90(8.1±0.6μg/ml) and EC95(8.8±0.6μg/ml) of H group were significantly increased (P<0.05 or <0.01). Compared with N group, EC5(3.4±0.5μg/ml), EC50(5.1±0.6μg/ml), EC90 (6.8±0.7μg/ml) and EC95(7.4±0.7μg/ml) of L₁ group is not significantly different; EC5 ( 3.0±0.4μg/ml ) , EC₅₀( 4.6±0.4μg/ml ) , EC₉₀ ( 6.4±0.4μg/ml ) and EC₉₅(7.0±0.4μg/ml)of L₂ group were significantly decreased (P<0.01); EC₅(2.5±0.4μg/ml), EC₅₀(4.0±0.5μg/ml), EC90(5.7±0.6μg/ml)and EC95(6.4±0.7μg/ml)of L₃ group were significantly decreased (P<0.01). Compared with L₁ group, all the indices of L₂ group were not significantly different, the indices of L₃ group were significantly decreased (P<0.01). Compared with L₂ group, all the indices of L₃ group were significantly deceased (P<0.01). The 2 statistical analyses probit regression (linear) and logistic (nonlinear) led to similar results. Hypothermia resulted in a shift to left of rocuronium concentration-response curve, while hyperthermia resulted in a shift to left of rocuronium concentration-response curveConclusion: Clinical duration, RI, and total duration were prolonged in hypothermia and shortened in hyperthermia. In vitro, potency of rocuronium was increased in hypothermia and decreased in hyperthermia. Thus, to obtain the same level of neuromuscular blocking, the dosage of rocuronium should be decreased in hypothermia; the dosage of rocuronium should be increased in hyperthermia...