The Effect of Ephedrine on the Onset Time of Rocuronium

The time from loss of consciousness to tracheal intubation is a period during which the patient is at risk of hypoxia and pulmonary aspiration. The length of this period is usually determined by the establishment of neuromuscular blockade, so it is usually desirable to use a muscle relaxant with a short onset time. The onset time is partly determined by the speed with which these drugs reach the neuromuscular junction, a factor that appears to be proportional to cardiac output and muscle blood flow [1]. Since ephedrine can increase these variables [2,3], our hypothesis was that it could reduce the onset time of muscle relaxants. The aim of this study was to evaluate the effects of a single dose of ephedrine, given at the moment of induction, on the onset time of rocuronium and on blood pressure and heart rate evolution during the induction sequence. Methods The protocol was approved by our ethics committee. After obtaining informed consent, we studied 60 ASA physical status I-II patients, aged 20-50 yr, scheduled for elective surgery under general anesthesia. Exclusion criteria included any cardiovascular or neuromuscular disease, intake of drugs known to interact with the neuromuscular junction or ephedrine, increased risk of pulmonary aspiration, and anticipated airway difficulties. Midazolam 7.5 mg per os was used 60-90 min before the induction of anesthesia in 10 patients in each group; the remainder did not receive premedication. Usual monitoring was used, and the cuff for pressure measurement was placed around the calf. Anesthesia was induced through an intravenous (iv) line, at maximum gravity flow of lactated Ringer's solution, with fentanyl 3 micro g/kg followed 4 min later by thiopental 4 mg/kg in 15 s. Patients were randomly assigned to receive in 5 s either ephedrine 70 micro g/kg diluted up to 5 mL with saline (Group 1, n = 30) or 5 mL of saline (Group II, n = 30) 30 s before thiopental. After loss of the eyelid reflex and confirmation that ventilation via a facemask was possible, rocuronium 0.6 mg/kg was administered in 5 s. When maximum neuromuscular blockade was achieved, an additional dose of thiopental 2 mg/kg was given, and tracheal intubation was performed. Only oxygen was given between fentanyl administration and tracheal intubation, and anesthesia was then continued with isoflurane 1%-2% and N2 O 50% in O2. Neuromuscular blockade monitoring was started 2 min after the administration of fentanyl, on the arm contralateral to the iv line using the evoked compound electromyogram of the adductor pollicis to a train-of-four stimuli at 10-s intervals (NMT Monitor 221; Datex Instrumentarium Corp, Helsinski, Finland). Onset time was defined as the time from the end of injection of rocuronium to maximum depression of electromyographic response. Heart rate and arterial pressure were measured preoperatively (baseline), immediately before the administration of each of the drugs used in the induction sequence, and prior to and 1, 3, and 5 min after tracheal intubation. The presence of arrhythmias on the electrocardiograph ECG monitor was noted. The recording of the onset time of rocuronium and hemodynamic variables was performed by investigators blinded to the study drug. Statistical comparisons were made with an unpaired two-tailed Student's t-test for demographic data, Mann-Whitney u-test for the onset time of rocuronium, and two-way repeated measures analysis of variance for hemodynamic variables. A P value less than 0.05 was considered significant. Values are mean +/- SD unless otherwise stated. Results No differences in demographic data were found between both groups (Table 1). The onset time of rocuronium was 72 +/- 19 s (95% confidence interval [CI 95%] 65-80 s) in the group receiving ephedrine versus 98 +/- 31 (CI 95% 86-109 s) in the group receiving placebo (P = 0.0006). In addition, the SD in Group I was significantly smaller than that in Group II (P < 0.01 with the F test). Complete twitch abolition was observed in 26 patients in each group; in the remaining 8, more than 95% twitch depression was achieved. The hemodynamic profile was similar in both groups (Figure 1 and Figure 2), and no patient presented arrhythmias during the study period.Table 1: General DataFigure 1: Systolic and diastolic arterial pressures (mm Hg) in both groups. Preop = preoperative, OR = at the operating room before fentanyl, drug = before ephedrine or placebo, T = before thiopental, R = before rocuronium, Int = before intubation, 1, 3, and 5 = minutes after intubation. No differences were found between the groups.Figure 2: Heart rate (bpm) in both groups. Preop = preoperative, OR = at the operating room before fentanyl, drug = before ephedrine or placebo, T = before thiopental, R = before rocuronium, Int = before intubation, 1, 3, and 5 = minutes after intubation. No significant differences were found.Discussion The main finding of this study is that a small dose of ephedrine administered at the moment of induction reduced the onset time of rocuronium by 26% without significant adverse effects in this group of patients. The fast and reliable onset time of succinylcholine is the gold standard against which all other muscle relaxants are compared, but some side effects preclude its use in all patients [4]. This has led to a long-standing interest in decreasing the onset time of nondepolarizing neuromuscular blocking drugs, resulting in the development of faster drugs [5] and new techniques of administration, such as the use of a priming dose before the administration of the intubating dose [6-8], increments in the dose [9-11], and the combination of drugs [12-14]. While these alternatives can reduce the onset time of these drugs, some can also lead to adverse effects, such as the development of muscle weakness, difficulty in breathing, loss of the protective reflexes of the airway, and even pulmonary aspiration before the induction of anesthesia [15,16], or an increased duration of neuromuscular blockade [9-11]. The rate of onset of neuromuscular blockade in any one individual depends only on the rate at which a pharmacologically effective concentration is achieved in the biophase, in this case, the neuromuscular junctional cleft. This rate, in turn, is influenced by several factors, such as the potency of the drug, the dose administered, and the cardiovascular status, including cardiac output and muscle blood flow [1,17-19]. The influence of cardiovascular factors on the onset time of neuromuscular blockade has not been completely defined. We are not aware of studies showing the influence of cardiac output, although, arguably, age-related variability in the onset time of muscle relaxants could be related to differences in cardiac output in the different age groups [1]. Moreover, a close, linear relation between the circulation time and onset time of succinylcholine has been found in humans [17]. Regarding muscle blood flow, the onset time of gallamine was found to be directly related to it in an experimental model in dogs [18], and the faster onset of blockade in the diaphragm compared with the adductor pollicis might also be related to the larger blood flow to the former [1]. Etomidate induction, when compared with propofol and thiopental in humans, was associated with a shorter onset time of vecuronium, which could be due to the lesser hemodynamic depression produced by etomidate than the other two induction drugs [20]. In this context, an increase in cardiac output and muscle blood flow at the moment of the administration of a muscle relaxant could lead to a reduction in its onset time. Ephedrine can produce an increase in these two variables [2,3] and in doses of 70, 140, 210, and 260 micro g/kg, has been effective in the prevention of hypotension after an induction dose of propofol [21,22]. Although cardiac output and systemic vascular resistance were not measured in these studies, it is possible that an increase in cardiac output is in part responsible for this effect. We decided to use the smallest dose (i.e., 70 micro g/kg) to minimize the possibility of adverse effects. Rocuronium was chosen since it is the nondepolarizing neuromuscular blocking drug in clinical use with the fastest onset time [5]. We found that ephedrine reduced the onset time of rocuronium by almost 30 seconds, a fact that we believe is clinically relevant, especially when this was accomplished with a low dose of ephedrine without important adverse effects, at least in relatively healthy patients. A question that remains to be answered is whether this effect of ephedrine is still present when the dose of rocuronium is increased (e.g., 3 times the 95% effective dose) or when a different muscle relaxant (e.g., mivacurium) is used. Although we expected to find significant differences in the hemodynamic profile of both groups after the injection of ephedrine, which suggests a difference in cardiac output (e.g., higher heart rate or blood pressure in the group receiving ephedrine), this was not the case. Although systolic pressure in the two measurements after thiopental decreased by 10% in controls compared with measurements before thiopental and was unchanged in the group given ephedrine, this difference was not statistically significant. Interestingly, this coincided with the period when the influence of cardiovascular factors on the onset time of neuromuscular blockade is expected to be most important. Since cardiac output and muscle blood flow were not measured, we can only speculate as to whether these variables were increased by the ephedrine, and that this is the mechanism for the observed reduction of the onset time. In addition, the possibility of a direct effect of ephedrine at the neuromuscular junction cannot be ruled out. Although we did not find adverse effects after the administration of ephedrine-such as tachycardia, hypertension, and arrhythmias-it must be considered that in a sample of 30 patients having an incidence of adverse effects equal to zero, the upper limit of the 95% confidence interval is estimated in 10% [23]. Also, their incidence might be higher in patients with cardiovascular disease or with a different induction technique [21]. Finally, one additional effect of ephedrine was observed. This is the reduction of the variability in the onset time of rocuronium, a fact that has been regarded as one of the disadvantages of this drug (and the other nondepolarizing neuromuscular blocking drugs) when compared with succinylcholine. In studies comparing the onset times of both drugs, the SD deviation ranged from 30 to 76 seconds for rocuronium versus 6 to 21 seconds for succinylcholine [11,13,24,25]. In this study, the administration of ephedrine resulted in a variability of the onset time of rocuronium within the range reported for succinylcholine. In conclusion, ephedrine reduced the onset time of rocuronium without significant adverse effects in a group of relatively healthy patients. This combination can be valuable when succinylcholine is contraindicated and the shortest possible time from loss of consciousness to tracheal intubation is desirable.