Despite much attention in recent years, the mechanism of action of IV anesthetics is still incompletely understood, but it probably involves modulation of neurotransmitter release at synapses. In particular, IV anesthetics may enhance the inhibitory effects of the neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor (1). Neuronal L-type voltage-sensitive calcium channels (L-VSCC) are located on neuronal cell bodies and may be involved in the regulation of neurotransmitter release (2). The anesthetic potency of some common IV anesthetics is enhanced in electrophysiological studies by antagonists acting at L-VSCC (3,4) and, indeed, pentobarbitone and propofol inhibit L-VSCC (5,6), perhaps at the dihydropyridine binding site (7). Furthermore, calcium-dependent K+-evoked [3H]noradrenaline release from SH-SY5Y human neuroblastoma cells (which is predominantly mediated via L-VSCC) is inhibited by thiopental, propofol, and etomidate (8,9), suggesting that the L-VSCC may be a target site of IV anesthetics. Moreover, carbachol-evoked noradrenaline release is inhibited by thiopental but not by propofol, suggesting that thiopental also inhibits release of intracellular calcium from its stores and supporting the hypothesis that both agents act as calcium antagonists (8). This hypothesis has not been tested clinically.
Although L-VSCC antagonists, such as verapamil and nifedipine, are in common clinical use for conditions such as hypertension and ischemic heart disease, they penetrate the blood-brain barrier poorly. Therefore, they are unlikely to reach sufficient concentration within the central nervous system to have any relevant effect on clinical anesthesia. Nimodipine is also a substituted 1,4-dihydropyridine that is lipid soluble and crosses the blood-brain barrier (10). In animal studies at small doses, it has no affect on systemic blood pressure, but increases cerebral blood flow (CBF) by a vasodilator effect (10,11). Nimodipine’s established clinical role is to reduce the incidence of severe neurologic deficits caused by cerebral arterial spasm, when given orally to patients after a subarachnoid hemorrhage (12).
In a randomized, double-blinded, placebo-controlled, clinical study, we tested the hypothesis that premedication with oral nimodipine would reduce the induction dose of propofol anesthesia, independently of its effect on the cerebral circulation.
After institutional ethics committee approval and informed consent, 64 ASA physical status I or II patients, aged 18–60 yr, scheduled for elective knee arthroscopy or minor genitourinary procedures under general anesthesia, were enrolled into this randomized, double-blinded, placebo-controlled, clinical study. Patients were premedicated 1–2 h before the anticipated time of the induction of anesthesia. Exclusion criteria were: age outside the limits of 18–60 yr, pregnancy, treated hypertension, those receiving medications known to be active on the cardiovascular system or psychotropic or antihistaminergic medications which might have a confounding sedative effect, and those in ASA physical status III–V.
Patients received either nimodipine 60 mg or placebo in an identical, brown capsule, which was prepared in advance by our pharmacy department. Allocation of patients to the groups was performed at random, according to computer-generated numbers, which was also documented by the pharmacy department. Hence, both the patients and clinical investigators who enrolled them and collected the study data were blinded to their group allocation. The study period commenced with baseline recordings of hemodynamic data, CBF data, and time-averaged mean velocity and ended with repeat recordings of these variables 5 min after the induction of anesthesia.
In all patients, transcranial Doppler ultrasonography (TCD) was used to assess cerebral blood flow velocity (CBFV) to determine whether those receiving nimodipine had a greater CBFV after the induction of anesthesia than that of patients in the control group. All patients were studied in the supine position with their heads resting on a single pillow. The right middle cerebral artery (MCA) was insonated at a depth of 40–50 mm before and 5 min after the induction of anesthesia, by using the temporal window. A 2-MHz transcranial Doppler ultrasonography probe was used in pulsed wave mode. This system had a range gate facility and indicated bidirectional flow. Time-averaged mean velocity of blood flow in the MCA was derived from the shifts in frequency spectra of the Doppler signals and expressed as cm/sec. The probe was fixed in place by using a headband to maintain a constant angle of insonation, but we found that the necessary airway manipulation after the induction of anesthesia and placement of the laryngeal mask airway (LMA) often disrupted the signal quality. Hence, the signal was optimized by using the gain, power, and range controls and the position and angle of the probe. The sample width was set as narrow as possible (<0.5 cm), consistent with signal quality. By using this method, a quality signal was received over a narrow angle, and the section of the vessel insonated was well-defined and repeatable.
Sedation [measured by one investigator, DJB, using the Ramsay scale (13)], heart rate, and noninvasive mean blood pressure (MBP) were measured on arrival in the induction room. Baseline MBP was taken as the mean of two successive readings at 3-min intervals in the induction room. Heart rate and MBP measurements were repeated at 2-min intervals until the end of the study. After placement of routine monitors, (electrocardiogram, noninvasive blood pressure, and pulse oximetry) and assessment of all baseline measurements, the induction of anesthesia was commenced. All patients held a 100-mL bag of normal saline in their dominant hand and flexed their elbow to 90°. Propofol 1% (mixed with lidocaine 1%, ratio 10:1) was administered by an infusion pump. At the commencement of the propofol infusion, all patients began breathing 100% oxygen through a face mask via a Bain circuit. The end-point of the induction was deemed to have occurred when the patient’s forearm, holding the bag of saline, fell by his or her side. The infusion was stopped at this point and the total dose of propofol infused noted. Patients then breathed 2% isoflurane in a 50% mixture of nitrous oxide-oxygen at 8 L/min for 2–3 min, after which a LMA was positioned. Further boluses of propofol 0.5 mg/kg were given as required. No other drug was given during the study. End-tidal carbon dioxide values were recorded 5 min after the induction of anesthesia.
Previous studies with other effective premedications found a 15% reduction in dose of propofol and a requirement for 2.5 mg/kg as an approximate induction dose for unpremedicated patients, who have not concurrently received an opioid such as fentanyl (14).
Therefore, to obtain a reduction of 0.35 mg/kg in induction dose, approximately 32 patients would be required in each group to achieve a Type I error = 0.05 and a Type II error = 0.2 (power 80%). Student’s unpaired t-test was used for comparison between the groups for continuous data (age, weight, mean arterial pressure [MAP]). Nonparametric between-group data comparisons were undertaken with the Mann-Whitney U-test.(time-averaged mean velocity, time to induction, dose of propofol). A χ2 analysis of a 2 × 2 contingency table was used to evaluate differences in the sex ratio between the groups. P < 0.05 was taken as indicating statistical significance .
Four patients were lost to follow up. One patient from each group was discontinued because of technical problems with the TCD probe and difficulty obtaining a satisfactory MCA blood flow velocity (Vmca) signal. One patient from each group was lost after premedication because the anticipated time interval to the induction of anesthesia exceeded 2 h. These patients were not included in the data analysis; hence, data from 30 patients in each group are reported. Demographic data, sex distribution, self-reported weekly alcohol consumption and interval between premedication and the induction of anesthesia are shown in Table 1. There was no difference in the degree of sedation of patients, as measured by the Ramsay scale (13), on arrival in the induction room (1.2 ± 0.4 vs 1.3 ± 0.5, mean ± SD in the nimodipine and control groups, respectively).
A significant reduction in preinduction MAP occurred when compared with 5 min after the induction in both groups (P < 0.01), but there were no significant differences in MAP or heart rate between the groups at any time (Table 2). There were no significant differences in TCD ultrasonography within or between the groups at any time (Table 3).
The weight-adjusted induction dose of propofol (i.e., the total amount of propofol given at induction, in mg, divided by the patient’s weight in kg) was 2.19 mg/kg (95% confidence interval: 1.97–2.42) in the nimodipine group, compared with 2.16 mgkg−1 (95% confidence interval: 1.98–2.34) in the control group, P = 0.8, Figure 1. Thirteen patients in the nimodipine group compared with 11 in the control group required additional boluses of propofol for successful LMA insertion (P = 0.5).
We found no difference in the induction dose of propofol required in healthy adults whether they had received or not received premedication with oral nimodipine 60 mg one to two hours previously. This raises the possibility that the dose was insufficient or that the nimodipine was not pharmacologically active at the time of the study. However, a clinically significant reduction in neurologic deficit after subarachnoid hemorrhage was demonstrated in a previous study with 0.7 mg/kg initially, decreasing to 0.35 mg/kg for subsequent doses. This produced plasma and cerebrospinal fluid levels of nimodipine of 9.9 ± 4.9 and 0.77 ± 0.34 ng/mL, respectively (12). We did not titrate our dose to patient weight, but the mean weight in both groups was approximately 80 kg. Therefore, if our patients were to receive 0.7 mg/kg, a mean dose of 56 mg would have been required. We thus gave our patients nimodipine 60 mg, a slightly larger dose than that sufficient to produce a clinical effect in the study by Allen et al. (12). We felt that measuring plasma and serum levels was superfluous, given this previous experience of nimodipine at these doses. For the same reason we avoided a dose-response study, as our principal objective was to investigate whether clinically relevant doses of nimodipine would have an impact on the induction of general anesthesia.
Another concern is whether the timing of the oral dose of nimodipine 60 mg, one to two hours before the induction of anesthesia with propofol was too early, resulting in the pharmacological activity of nimodipine being dissipated before the induction took place. However, the evidence of previous pharmacological studies strongly suggests that because nimodipine is rapidly absorbed after oral ingestion (within 30 minutes), its peak pharmacodynamic activity on the cerebral circulation should, in fact, occur within one to two hours and continue for up to four hours (10,11,15). Despite this, our TCD ultrasound measurements of Vmca before the induction of anesthesia did not show any significant increase in patients receiving nimodipine compared with those receiving controls. Whether the TCD was insensitive to detect a change in MCA flow velocity with this dose of nimodipine is unclear because we did not document TCD measurements before nimodipine premedication.
Nimodipine specifically dilates cerebral vessels in experimental and human studies. Single oral doses, 40–80 mg, and an IV infusion, given to 12 healthy humans, increased CBF as measured by radiolabeled xenon and arteriovenous oxygen difference and other techniques (10–12,15) The present study, in anesthetized subjects, did not detect any significant change in CBF by using a TCD ultrasound technique. There are few reports in the literature regarding the effect of nimodipine on CBF during anesthesia administration. In a rabbit model, animals anesthetized with chloralose had increased CBF in the presence of nimodipine (11), but an infusion of nimodipine given to patients undergoing cardiac surgery found no differences in CBF compared with a placebo group (16).
Anesthetics themselves also influence CBF. Propofol reduces it, independently of whether nitrous oxide is present(17). This contrasts with the use of sevoflurane, in which transient hyperemic response ratio (an index of autoregulation) is preserved during anesthesia, but not when nitrous oxide is added to a small sevoflurane concentration (18). However, autoregulation, i.e., the ability of the cerebral circulation to adjust blood flow within a range MAP of 50–170 mm Hg, is better preserved during the administration of propofol than isoflurane or desflurane anesthesia (19). Use of vasoconstrictors phenylephrine and noradrenaline increased blood flow velocity in isoflurane-anesthetized patients, but not in those receiving propofol, suggesting that, in anesthetized patients, vasoconstrictors do not directly affect CBF (20).
We detected no significant change in Vmca five minutes after induction of anesthesia, in either nimodipine or placebo patients. This observation may reflect the interactive effects of the initial propofol bolus and the subsequent inhaled isoflurane-nitrous oxide anesthesia on CBF. Alternatively, it is possible that TCD measurements taken at a later time after induction would have yielded similar results to these other studies, where a period of 30 minutes of stabilization after induction of anesthesia was allowed (19,20). Our objective in observing TCD measurements was to investigate qualitatively whether nimodipine premedication altered CBF compared with controls, which would have been relevant in the event that nimodipine had reduced the propofol dose at induction: such a reduction could have been due to greater cerebral redistribution of cardiac output or an intrinsic anesthetic effect.
There are certain limitations to the use of TCD measurements to assess CBF. TCD ultrasonography does not provide absolute measures of CBFV, but rather gives an assessment of acute changes in CBF (21). It is based on the assumption that Vmca is proportional to CBF, but this is invalid if the cross-sectional area changes. However, observations of the MCA during craniotomy indicate that its diameter changes minimally across a range of MAP values, even under anesthesia (22), supporting both the claim that velocity is proportional to flow and our finding of minimal change in Vmca.
Many premedication drugs, which affect the induction dose of IV anesthetics or MAC of volatile anesthetics, cause some degree of sedation and anxiolysis (14,23,24). Our assessment of sedation on the Ramsay scale (13) indicated a comparably high degree of alertness and lack of sedation in both groups, which is consistent with the observation in human studies that alertness and attention actually increased four hours after nimodipine ingestion, which was attributed to increased frontal lobe CBF around that time (15). Unfortunately, we did not attempt to measure anesthetic depth, which would have been possible with bispectral analysis. However, our aim was to investigate whether the experimental evidence that IV anesthetics may target L-VSCC was applicable to the clinical situation, rather than to evaluate nimodipine as a premedication per se.
In conclusion, we have found that premedication with oral nimodipine 60 mg one to two hours preoperatively, does not reduce the dose of propofol required for the induction of anesthesia in healthy adults, casting doubt on the hypothesis that propofol has an anesthetic action at L-VSCC. The discrepancy between laboratory studies suggesting a role for L-VSCC in anesthesia and our negative findings may be a result of the fact that animal models have used relatively larger doses of the calcium antagonists than would be feasible in humans. Hence, the observed in vitro effect in L-VSCC may reflect a “spill-over” from their effect on other subtypes of Ca2+ channels, particularly the N- and P- subtypes (25). The imminent development of a specific N-type voltage sensitive calcium channel antagonist such as ziconotide, which has analgesic properties, may stimulate further investigation of a possible role for this subtype of voltage sensitive calcium channel in the mechanism of general anesthesia.
1. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367:607–14.
2. Spedding M, Lepagnol J. Pharmacology of sodium and calcium channel modulation in neurons: implications for neuroprotection. Biochem Soc Trans 1995; 23:633–6.
3. Dolin SJ, Little HJ. Augmentation by calcium channel antagonists of general anaesthetic potency in mice. Br J Pharm 1988; 88:909–14.
4. Horvath G, Szikszay M, Benedik G. Calcium channels are involved in the hypnotic-anaesthetic action of dexmedetomidine in rats. Anesth Analg 1992; 74:884–8.
5. Gross RA, Macdonald RL. Differential actions of pentobarbitone on calcium current component of mouse sensory neurons in culture. J Physiol (Lond) 1988; 405:187–203.
6. Olcese R, Usai C, Maestrone E, Nobile M. The general anaesthetic propofol inhibits transmembrane calcium current in chick sensory neurons. Anesth Analg 1994; 78:955–60.
7. Hirota K, Lambert DG. IV anaesthetic agents inhibit dihydropyridine binding to L-type voltage sensitive Ca2+
channels in rat cerebrocortical membranes. Br J Anaesth 1996; 77:248–53.
8. Lambert DG, Willets JM, Atcheson R, et al. Effects of propofol and thiopentone on potassium- and carbachol-evoked [3
H] noradrenaline release and increased [Ca2+
from SH-SY5Y human neuroblastoma cells. Biochem Pharmacol 1996; 51:1613–21.
9. Sikand KS, Hirota K, Smith G, Lambert DG. Etomidate inhibits [3
H]noradrenaline release from SH-SY5Y human neuroblastoma cells. Neurosci Lett 1997; 236:87–90.
10. Wadworth AN, McTavish D. Nimodipine. Drugs Ageing 1992; 2:262–86.
11. Haws CW, Gourley JK, Heistad DD. Effects of nimodipine on cerebral blood flow. J Pharmacol Exp Therap 1983; 225:24–8.
12. Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm: a controlled trial of nimodipine in patients with subarachnoid hemorrhage. New Engl J Med 1983; 308:619–24.
13. Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974; 2:656–9.
14. Turtle MJ, Cullen P, Prys-Roberts C, et al. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. II. Patients premedicated with lorazepam. Br J Anaesth 1987; 59:283–7.
15. Savage IT, James IM. The effect of nimodipine on the cerebral circulation in normal volunteer subjects. In: Nimodipine: pharmacological and clinical properties. Munich: Proc 1st Int Nimotop®
Symposium, 1984: 177–83.
16. Forsman M, Tubylewicz-Olsnes B, Semb G, Steen PA. Effects of nimodipine on cerebral blood flow and neuropsychological outcome after cardiac surgery. Br J Anaesth 1990; 65:514–20.
17. Engl C, Lam AM, Mayberg TS, et al. The influence of propofol with and without nitrous oxide on cerebral blood flow velocity and CO2 reactivity in humans. Anesthesiology 1992; 77:872–9.
18. Bedforth NM, Girling KJ, Harrison JM, Mahajan RP. The effects of sevoflurane and nitrous oxide on middle cerebral artery blood flow velocity and transient hyperemic response. Anesth Analg 1999; 89:170–4.
19. Strebel S, Lam AM, Matta B, et al. Dynamic and static cerebral autoregulation during isoflurane, desflurane and propofol anesthesia. Anesthesiology 1995; 83:66–76.
20. Strebel SP, Kindler C, Bissonnette B, et al. the impact of systemic vasoconstrictors on the cerebral circulation of anesthetized patients. Anesthesiology 1998; 89:67–72.
21. Guglielminotti J, Descraques C, Petitmarie S, et al. Effects of premedication on dose requirements for propofol: comparison of clonidine and hydroxyzine. Br J Anaesth 1998; 80:733–6.
22. Spelina KR, Coates DP, Monk CR, et al. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. I. Patients premedicated with morphine sulphate. Br J Anaesth 1986; 58:1080–4.
23. Bishop CC, Powell S, Rutt D, Browse NL. Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study. Stroke 1986; 17:913–5.
24. Giller CA, Bowman G, Dyer H, et al. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery 1993; 32:737–41.
© 2000 International Anesthesia Research Society
25. Hirota K, Lambert DG. Voltage sensitive calcium channels and anaesthesia. Br J Anaesth 1996; 76:344–6.