Introduction
Because of its unmatched rapid onset and short of action, succinylcholine (SUC) is widely used for endotracheal intubation. It is common practice to subsequently administer a nondepolarizing neuromuscular blocking agent to maintain paralysis for longer procedures. Previous studies of the effects of SUC on the neuromuscular effects of subsequently administered nondepolarizing neuromuscular agents, including rocuronium (ROC), have produced conflicting results1, 2,3,4,5. However, detailed effects of SUC on the potency of subsequently administered ROC have not been studied previously. The current study was designed to compare the dose-response relationship of ROC with or without prior administered of an intubating SUC in 48 healthy patients anesthetized with nitrous oxide-oxygen, fentanyl and thiopental.
Materials and Methods
After institutional ethics committee approval and written informed consent, 48 healthy, ASA physical status I and II adult patients, scheduled for elective general surgery with general anesthesia were included in this study. All patients were Chinese of the Han race. Patients were excluded if they had known cardiac, pulmonary, renal, hepatic, neurological, psychiatric, muscular or endocrine disorders; if they were females of childbearing potential; or if they had recently been exposed (72 hr) to medications known to interfere with neuromuscular transmission. Those patients with a body weight more than 10% above the ideal were also excluded. Ideal body weight (IBW) was defined for males as 110 lb±5 lb/inch above 5 foot height; for females IBW was defined as 100 lb±5 lb/inch above 5 foot height.6 All patients were randomly assigned via computer generation equally to either the rocuronium treatment group (R) or succinylcholine-rocuronium treatment group (SR). In R group (n=24), ROC was given after induction of anesthesia. In the SR group (n=24), patients were intubated after 1.5mg/kg of SUC and ROC was given 5 minutes after the complete recovery of neuromuscular blockade from SUC. Patients were further randomly divided into 4 subgroups to receive 150, 200, 250 or 300 μg/kg of ROC respectively in both groups. After an overnight fast, patients were premedicated with diazepam 0.2 mg/kg, meperidine 1 mg/kg, and atropine 0.01 mg/kg intramuscularly 1 hour before induction of anesthesia. Anesthesia was induced with intravenous (IV) diazepam 0.1 to 0.2 mg/kg, thiopental 4 to 6 mg/kg, and fentanyl 2 to 4 μg/kg. General anesthesia was maintained with nitrous oxide/oxygen 70%/30, and further increments of thiopental 2 mg/kg or fentanyl 2 μg/kg were administered as needed. No volatile anesthetics were used. The ventilation was ensured manually via mask until tracheal intubation was performed at the moment of maximal twitch height depression and end-tidal carbon dioxide (PETCO2) was maintained between 33 to 42 mmHg. Non-invasive blood pressure, electrocardiogram (ECG) and hemoglobin oxygen saturation (SpO2) were monitored. Inspired and end-tidal concentrations of O2, CO2, and N2O were measured. Skin temperature over the thenar muscles was maintained above 32°C throughout the study period by wrapping the arm in cotton.
After induction of anesthesia, the baseline measurements of neuromuscular function were assessed by accelerometry using a TOF Guard® accelerometer (Organon Teknika NV, Belgium) 7. The TOF Guard® electrodes, temperature thermistor-sensor and accelerometric transducer were positioned on the patient’s arm prior to induction of anesthesia, and the arm was carefully secured to the operating table armboard during the study period in order to obviate inadvertent movements which may produce artifactual readings. The ulnar nerve was stimulated at the wrist in train-of-four (TOF) mode through surface electrodes. Supramaximal square wave impulses of 0.2-ms duration at 2 Hz were administered every 12 seconds. The first twitch response (Th) of the TOF stimulus was used as the variable for pharmacodynamic measurements. Five minutes were allowed to stabilize the response to TOF stimulation before administering ROC. When the maximum effect of ROC was reached, the study was terminated and the anesthesia continued as appropriate for surgery. The dose-response relationships of ROC were determined using a single dose-response technique according to the method. ROC was injected as an IV bolus in less than 5 seconds into a rapidly running IV infusion. The mean of ten Th responses immediately preceding the administration of neuromuscular blocking drug became the control value with which all subsequent Th responses were compared. The dose-response relationship was examined by least squares linear regression of the logarithm of each dose against a probit transformation of the percent depression of Th response relative to the control respectively. Because probit 0 and probit 1 do not exist, 0% and 100% Th depression were plotted as effects of 0.5% and 99.5% used in the analysis. The doses required for 50%, 90%, and 95% of Th depression (ED50, ED90, and ED95) were calculated from the regression line, respectively. The regression lines were tested to determine whether they deviated from parallelism. If they did not, ED50, ED90, and ED95 values were compared between groups. Parallelism was tested using one-way analysis of variance8. A Chi-square test was used to compare male/female distribution between the two groups. An analysis of covariance was used to compare the dose-response curves of the two groups. The comparisons of demographic data and dose-response data between the two groups were made using the unpaired Student’s t-test. Data are expressed as means ± SD. Results of test were considered to be statistically significant for two-tailed p-value < 0.05.
Results
The two groups of patients were comparable with respect to demographic data (Table 1). All patients had stable hemodynamics and were normothermic throughout the observation.
The slope and intercept of the dose-response curve of ROC is not significantly different between the two groups. The dose-response curve of ROC, when given after an intubating dose of SUC, was shifted to the left in a parallel fashion and the neuromuscular blocking potency of ROC after SUC was significantly higher than potency of ROC given without SUC (Figure 1). Mean ED50, ED90, and ED95 of the two groups are given in Table 2. There were significant differences in ED50, ED90, and ED95 between the two groups. The dose-response curves for ROC showed a 1.22 potentiation factor for ED50 and 1.16 for ED95, caused by the previous administration of SUC.
Discussion
The goals of this study were to study the effect of SUC on the dose-response relationship of subsequently administered ROC in healthy patients. This study shows that the administration of SUC will potentiate the neuromuscular blocking effects of subsequently administered ROC. Previous reports have yielded conflicting results1, 2,3,4,5; however in this study we used the strict exclusion criteria and controlled for the factors known to interfere with neuromuscular block. There was no significant difference between the two groups in the distribution of gender, age, height, and weight, and all study patients were Chinese of the Han race. The study drugs had the same batch number. The output variable, percent of twitch depression, was measured using the same neuromuscular function monitor in all the patients. All of the anesthetics were given by the same anesthesiologist and comparable anesthetic equipment and drugs were used in all the cases. During the study, PETCO2 was kept in the normal range and volatile inhaled anesthetics were avoided because the potentiation of neuromuscular block.
Because neuromuscular blockade has a quantal response to the drug concentration, pharmacodynamic studies are suitably described by a linear log dose-probit dose-response relationship. The cumulative-dose technique becomes questional when studying intermediate duration muscle relaxants like ROC because significant recovery may start to take place in the interval between incremental doses9, 10. We used the single-dose technique rather than the cumulative-dose technique to study pharmacodynamics of Roc. Construction of dose-response curves showed ROC, when given after an intubating dose of SUC, to be approximately 1.16 times more potent than without SUC for doses producing 95%, and 1.22 time more potent for producing 50% depression of twitch response.
The interaction of SUC with nondepolarizing muscle relaxants is complex, depending on whether SUC is administered before or after the nondepolarizing muscle relaxants. SUC is commonly given to facilitate intubation of trachea followed by a nondepolarizing relaxant. The prior administration of an intubating dose of SUC has been shown to reduce the subsequent requirement for a pancuronium, atracurium, vecuronium and rocuronium nondepolarizing neuromuscular block 1,2,3,4. However, some authors found no effect of a previous dose of SUC on pancuronium, vecuronium neuromuscular block11, 12,13. There have been few studies of the use of prior SUC and ROC. Similar to our finding, Dubois et al found that SUC given prior to ROC decreased onset time and increased duration of ROC3. However, Muir et al found no effect of prior treatment with SUC on the dose response of ROC in anesthetized cats14.
Succinylcholine has the fastest onset of any muscle relaxant in use. It is therefore the drug of choice when the airway has to be secured without delay. It is common practice to continue to subsequently administer a nondepolarizing neuromuscular blocking agent to maintain paralysis, and therefore the potential for interactions between SUC and nondepolarizing agents need to be considered. Although it is recommended to await recovery from the SUC before administer a second relaxant, this second agent is commonly given before complete recovery from SUC. In the current study we waited 5 minutes after complete recovery of neuromuscular blockade from SUC as indicated by the acceleromyographic response of the adductor pollicis muscle. Despite this delay, we found that the dose-response curves for ROC are potentiated by a factor 1.22 for ED50 and 1 and1.16 for ED95.The mechanisms responsible for the potentiating effect of SUC on nondepolarizing agents are not clear. They include the reduction of the clearance of nondepolarizing agents in the plasma, alteration of sensitivity on the end–plate and alteration of acetylcholine receptors due to interaction between SUC and non-depolarizing agents1, 2, 15,16,17. It has been shown that SUC-induced phase II block may potentiate and prolong the neuromuscular blockade of subsequently administered nondepolarizing neuromuscular blocking agents18. In this study ROC was given 5 minutes after the complete recovery of neuromuscular blockade from SUC, eliminating the possibility a phase of II block.
When considering the use of a nondepolarizing neuromuscular blocking agent for continuation of the neuromuscular blockade after an intubating dose of SUC, the dose of nondepolarizing neuromuscular blocking agent should be slightly smaller and it is better to monitoring of neuromuscular function when subsequently administering a nondepolarizing neuromuscular blocking agent.
In conclusion, we have shown that SUC shifts the dose-response curve of ROC to the left, potentiates the neuromuscular blockade of subsequently administered ROC by 15%. A prior dose of SUC allows the use of a slightly smaller dose of ROC for continuation of the block.
Acknowledgement The authors thank Stephen A. Stayer, M.D. in the department of anesthesiology and pediatrics, Texas Children's Hospital, for his help preparing in this article.
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