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Anesth Analg 2003;97:480-483 © 2003 International Anesthesia Research Society
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Abstract |
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The onset time of neuromuscular blocking drugs is partially determined by circulatory factors, including muscle blood flow and cardiac output. We thus tested the hypothesis that a bolus of ephedrine accelerates the onset of vecuronium neuromuscular block by increasing cardiac output. A prospective, randomized study was conducted in 53 patients scheduled for elective surgery. After the induction of anesthesia, the ulnar nerve was stimulated supramaximally every 10 s, and the evoked twitch response of the adductor pollicis was recorded with accelerometry. Patients were maintained under anesthesia with continuous infusion of propofol for 10 min and then randomly assigned to ephedrine 210 µg/kg (n = 27) or an equivalent volume of saline (n = 26). The test solution was given 1 min before the administration of 0.1 mg/kg of vecuronium. Cardiac output was monitored with impedance cardiography. Ephedrine, but not saline, increased cardiac index (17%; P = 0.003). Nonetheless, the onset of 90% neuromuscular block was virtually identical in the patients given ephedrine (183 ± 41 s) and saline (181 ± 47 s). There was no correlation between cardiac index and onset of the blockade. We conclude that the onset of the vecuronium-induced neuromuscular block is primarily determined by factors other than cardiac output. The combination of ephedrine and vecuronium thus cannot be substituted for rapid-acting nondepolarizing muscle relaxants.
IMPLICATIONS: Ephedrine increased cardiac index but failed to speed onset of neuromuscular block with vecuronium. We conclude that ephedrine administration does not shorten the onset time of vecuronium.
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Introduction |
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The onset of neuromuscular blockade usually determines the period from anesthetic induction to tracheal intubation, a stage of anesthesia during which the patient is exposed to the risk of hypoxia and pulmonary aspiration. Various strategies have been developed to shorten the onset time of muscle relaxation, including increasing the dose and priming (1,2). However, these alternatives often provoke a long duration of muscle paralysis or muscle weakness before the induction of anesthesia.
The onset time of neuromuscular blocking drugs is partially determined by circulatory factors, including muscle blood flow and cardiac output (3,4). We tested the hypothesis that by increasing cardiac output, a bolus of ephedrine accelerates the onset of the nondepolarizing neuromuscular blocker vecuronium. We chose to test vecuronium because the drug itself has virtually no cardiovascular effects (5). Cardiac output was chosen as the critical circulatory factor because cardiac output modulates the transport of any neuromuscular blocker to skeletal muscle.
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Methods |
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With approval of the Human Research Committee at the Tokyo Women’s Medical University and informed consent, we studied 53 ASA physical status I or II patients, aged 20–65 yr, who were scheduled for elective surgery with general anesthesia. Exclusion criteria included the presence of cardiovascular or neuromuscular diseases, any medications known to affect neuromuscular function, obesity (exceeding 130% of optimal body weight), hepatic or renal disorders, increased risk of pulmonary aspiration, and anticipated airway difficulties.
Thirty minutes before the induction of anesthesia, patients were given hydroxyzine (50 mg IM). Anesthesia was induced with 2 µg/kg of fentanyl given through an indwelling cannula on the dorsum of the hand, followed 1 min later by 1.5 mg/kg of propofol administered over 10 s. Anesthesia was subsequently maintained with a propofol infusion at a rate of 8 mg · kg-1 · h-1.
The patients were randomly assigned to receive 210 µg/kg of ephedrine (n = 27) or an equivalent volume of saline (n = 26). Randomization was based on computer-generated codes that were maintained in sequentially numbered opaque envelopes. The test solutions were given IV 10 min after the initial dose of propofol. An IV bolus of 0.1 mg/kg of vecuronium was given 1 min later and followed by a 5-mL saline flush. During the study period, patients were ventilated manually via a face mask to maintain end-tidal PCO2 between 30 and 40 mm Hg.
The usual monitors were used. The cardiac index was measured with an impedance cardiograph device (Physio Flow PF-03; Manatec Biomedical, Macheren, France). The cardiac index was expressed as a moving average of 20 heartbeats; we recorded the last value before the administration of ephedrine and the last value before the administration of vecuronium.
Neuromuscular block was monitored starting immediately after the induction of anesthesia by using accelerometry (TOF Guard). The ulnar nerve of the arm contralateral to the IV cannula was stimulated supramaximally through surface electrodes with a single square-wave pulse of 0.2 ms in duration; pulses were repeated at 10-s intervals. The duration of control stimulation was standardized to 11 min (i.e., from bolus administration of propofol to just before the administration of vecuronium).
Adductor pollicis contractions were measured with a piezoelectric accelerometer fastened to the thumb. The arm used for neuromuscular monitoring was gently heated with forced air to maintain ulnar skin temperature at more than 32.5°C (6). Ulnar skin temperature was monitored with a thermometer attached to a neuromuscular monitoring device. Neuromuscular data were recorded on a memory card, and a computer printout was obtained by using TOF Guard Reader software. The times from the end of the vecuronium bolus to 10%, 50%, 90%, and maximum block were recorded.
Our primary outcome was the time that elapsed between vecuronium administration and a 90% neuromuscular block. Unpaired Student’s t-tests were used for statistical comparisons between the two groups of demographic data and the times to 10%, 50%, 90%, and maximum neuromuscular blockade. The heart rate, systolic blood pressure, and cardiac index before and after the administration of ephedrine or saline were compared by using paired Student’s t-tests in each group.
Correlation analysis was used to evaluate potential relationships between the cardiac index and the time to 90% block. Statistical analysis was performed with StatView Version 5.0 and Sample Power 2.0. Values are expressed as mean (SD) unless otherwise stated; P < 0.05 was considered statistically significant.
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Results |
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The demographic data and ulnar skin temperatures were similar in the patients given ephedrine and saline (Table 1). Ephedrine 210 µg/kg did not cause clinically unacceptable tachycardia (heart rate exceeding 100 bpm) or hypertension (systolic blood pressure exceeding 170 mm Hg) in any patient. Arrhythmias were uncommon during the study period. Before administration of the test solution, the cardiac index was 3.0 ± 0.6 L · m-2 · min-1 in the ephedrine group and 3.0 ± 0.8 L · m-2 · min-1 in the saline group (Table 2). Ephedrine increased the cardiac index by 0.5 L · m-2 · min-1 (17% of the preephedrine value; P = 0.003). In contrast, saline administration did not change the cardiac index (P = 0.71).
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Times to the onset of 10%, 50%, 90%, and maximum neuromuscular block did not differ significantly in the two treatment groups (Table 3). The study had a 70% power for detecting a 17% (i.e., 31-s) difference in the time to a 90% block level at an
level of 0.05. The magnitude of cardiac index did not correlate with the time to 90% block (Fig. 1).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The circulation time to the target organ and its blood flow partly determine the onset time of the neuromuscular block. For example, onset time is faster when a neuromuscular blocking drug is injected directly into the pulmonary artery rather than into a peripheral vein (7). Similarly, neuromuscular block is especially rapid in highly perfused muscles (8). Both circulation time and blood flow depend on cardiac output, a variable confirmed to be a primary determinant of the onset time of the neuromuscular blocker succinylcholine (3). Ephedrine increases blood pressure and heart rate while also increasing leg blood flow and leg muscle oxygen consumption (9). Similarly, IV ephedrine increases cardiac output with a decrease in total peripheral and forearm vascular resistance (10). These findings thus indicate that the increased cardiac output caused by ephedrine is accompanied by increases in the muscle blood flow of the extremities.
We chose to give ephedrine at a dose of 210 µg/kg because this dose increases cardiac output substantially and largely prevents the hypotensive response to anesthetic induction with propofol (11). We did not test a larger dose because it could have caused an unacceptable increase in blood pressure (12). For example, 300 µg/kg of ephedrine added to propofol and alfentanil induction causes a considerable increase in systolic blood pressure even before intubation. Conversely, we did not choose a small dose of ephedrine because a dose of 70 µg/kg only slightly increases heart rate and blood pressure (13).
The precision of cardiac output measurements by the Physio Flow PF-03 was validated by Charloux et al. (14): the coefficients of repeatability were 0.94 L/min for the Physio Flow PF-03 and 0.96 L/min for the direct Fick method. The correlation coefficient of cardiac output values measured simultaneously by the Physio Flow PF-03 and the direct Fick method was 0.89 (P < 0.001). For neuromuscular monitoring, a single-twitch stimulation with a 10-second interval was used to avoid faster onset secondary to the increased blood flow resulting from the higher stimulus frequency.
Although cardiac index at the time of the administration of vecuronium was 17% larger in patients given ephedrine, we did not identify any significant differences in the time of onset between the groups or any correlations between the cardiac index and onset variables. Audibert and Donati (15) showed that inflation of a tourniquet during the onset of neuromuscular block slowed the onset of block with rocuronium, but not with mivacurium or vecuronium. They reported that the onset time of drugs with rapid onset, such as rocuronium, chiefly depends on the circulation time to muscle, whereas the process of redistribution of drug from an extrajunctional to a junctional area is a more important determinant for the onset of action of vecuronium and mivacurium. As might thus be expected, ephedrine decreases the onset time of block from rocuronium (13,16,17).
Our results are also relatively consistent with a study by Iwasaki et al. (18), which demonstrated only a weak correlation between vecuronium onset time and cardiac index over a threefold range of cardiac indexes in prebypass cardiac patients. Gill and Scott (19) showed that the onset time of neuromuscular block with vecuronium is inversely related to mean arterial blood pressure in patients anesthetized with etomidate, thiopental, or propofol. In that case, although blood pressure was 30% greater in the etomidate group than in the thiopental group, the accompanying decrease of 50 seconds in the onset time of vecuronium may not have been clinically important. Furthermore, it seems likely that potentiation of the neuromuscular blocking activity of a nondepolarizing neuromuscular blocking drug by etomidate per se, rather than changes in hemodynamics, decreased the onset of vecuronium (20).
The limitation of our study was that vecuronium was administered after 11 minutes of stable propofol anesthesia to standardize the duration of control ulnar nerve stimulation. Hemodynamic conditions at the administration of vecuronium in our study were depressed. Therefore, our results might not be applicable in the typical clinical situation, in which vecuronium is given just after propofol administration at induction, when blood pressure and cardiac index are substantially higher than during our study condition. In addition, the effect of ephedrine could be different if it were given at induction with propofol.
In summary, ephedrine increased cardiac index and caused a considerable increase in blood pressure. However, ephedrine failed to accelerate the onset time of vecuronium neuromuscular block. The combination of ephedrine and vecuronium thus cannot be substituted for rapid-acting nondepolarizing muscle relaxants.
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Acknowledgments |
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Supported by National Institutes of Health Grant GM 58273 (Bethesda, MD) and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).
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Footnotes |
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None of the authors has any financial interest in this research.
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References |
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- Foldes F. Rapid tracheal intubation with non-depolarizing neuromuscular blocking drugs: the priming principle. Br J Anaesth 1984; 56: 663.
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[Abstract/Free Full Text] - Robertson EN, Booij LHDJ, Fragen RJ, Crul JF. Clinical comparison of atracurium and vecuronium (ORG NC 45). Br J Anaesth 1983; 55: 125–9.
[Abstract/Free Full Text] - Eriksson LI, Lennmarken C, Jensen E, Vilby-Morgensen J. Twitch tension and train-of-four ratio during prolonged neuromuscular monitoring at different peripheral temperatures. Acta Anaesthesiol Scand 1991; 35: 247–52.[Web of Science][Medline]
- Iwasaki H, Igarashi M, Kawana S, Namiki A. Accelerated onset of vecuronium neuromuscular block with pulmonary arterial administration. Can J Anaesth 1994; 41: 1178–80.[Web of Science][Medline]
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- Astrup A, Bulow J, Madsen J, Christensen NJ. Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man. Am J Physiol 1985; 248: E507–15.
- Cohn JN. Comparative cardiovascular effects of tyramine, ephedrine, and norepinephrine. Circ Res 1965; 16: 174–82.
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[Abstract/Free Full Text] - Charloux A, Lonsdorfer-Wolf E, Richard R, et al. A new impedance cardiograph device for the non-invasive evaluation of cardiac output at rest and during exercise: comparison with the "direct" Fick method. Eur J Appl Physiol 2000; 82: 313–20.[Web of Science][Medline]
- Audibert G, Donati F. The onset of rocuronium, but not of vecuronium or mivacurium, is modified by tourniquet inflation. Anesth Analg 1996; 82: 848–53.[Abstract]
- Kovac AL, Salerno D, Elliott C. Does pre-treatment with ephedrine affect the onset of neuromuscular block with rocuronium [abstract]? Anesthesiology 2002; 97: A994.
- Munoz HR, Gonzalez AG, Dagnino JA, et al. The effect of ephedrine on the onset time of rocuronium. Anesth Analg 1997; 85: 437–40.[Web of Science][Medline]
- Iwasaki H, Igarashi M, Yamauchi M, Namiki A. The effect of cardiac output on the onset of neuromuscular block by vecuronium. Anaesthesia 1995; 50: 361–2.[Web of Science][Medline]
- Gill RS, Scott RP. Etomidate shortens the onset time of neuromuscular block. Br J Anaesth 1992; 69: 444–6.
[Abstract/Free Full Text] - Booij LH, Crul JF. The comparative influence of gamma-hydroxy butyric acid, althesin and etomidate on the neuromuscular blocking potency of pancuronium in man. Acta Anaesthesiol Belg 1979; 30: 219–23.[Medline]
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