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Anesth Analg 2000;90:609-613
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Remifentanil on Cerebral Capacity in Awake Volunteers

Ingo H. Lorenz, MD*, Christian Kolbitsch, MD*, Christoph Hörmann, MD*, Michael Schocke, MD{dagger}, Fritz Zschiegner*, Stephan Felber, MD{dagger}, and Arnulf Benzer, MD*

Departments of *Anesthesia and Intensive Care Medicine and {dagger}Magnetic Resonance Imaging, University of Innsbruck, Austria

Address correspondence and reprint requests to Ingo H. Lorenz, MD, Department of Anesthesia and Intensive Care Medicine, The Leopold-Franzens University of Innsbruck, A-6020 Innsbruck, Anichstr. 35, Austria.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Remifentanil, a short-acting potent µ-opioid agonist proposed for intraoperative analgesia but also for postoperative pain therapy, has not been investigated with regard to the effects of the drug on cerebral capacity in awake humans. We assessed cerebral capacity noninvasively by means of phase-contrast magnetic resonance imaging measurement of systolic cerebrospinal fluid peak velocity in the aqueduct of Sylvius before and during infusion of remifentanil (0.1 µg · kg-1 · min-1 IV) in normocapnic humans. Remifentanil had no significant effect on systolic cerebrospinal fluid peak velocity as compared with baseline (mean ± SD): baseline, -4.3 ± 1.3 cm/s versus remifentanil (0.1 µg · kg-1 · min-1): -4.7 ± 1.0 cm/s. Small-dose remifentanil (0.1 µg · kg-1 · min-1) did not influence cerebral capacity in healthy, awake volunteers free of intracranial pathology.

Implications: Knowledge about the influence of remifentanil on cerebral capacity is crucial before routine use of the drug in neuroanesthesia. Thus, we assessed the influence of remifentanil on cerebral capacity noninvasively by means of phase-contrast magnetic resonance imaging measurement of systolic cerebrospinal fluid peak velocity in the aqueduct of Sylvius in humans.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Potent opioid analgesics are used for intraoperative and postoperative pain therapy, e.g., in patients with intracranial pathology. For various opioids, undesirable side effects, such as an increase in cerebral blood flow (CBF) (1), cerebrospinal fluid (CSF) pressure (2–4), cerebral blood volume (CBV) (5), and CBF velocity in the middle cerebral artery (6) have been shown in animals and in humans.

Cerebral capacity, which is determined by brain volume and CBV and CSF volume can be assessed noninvasively by phase-contrast magnetic resonance imaging (MRI) measurement of systolic CSF peak velocity (CSFVPeak) in the aqueduct of Sylvius (7). Therefore, any impairment of cerebral capacity should be easily and noninvasively detected by MRI scan.

Remifentanil, a short-acting potent µ-opioid agonist (8), has been recommended not only for intraoperative (9) analgesia but also for postoperative (10) pain therapy. Previous studies investigated only the influence of remifentanil on arbitrarily selected isolated aspects of cerebral capacity, such as CBF (11,12), CBF velocity in the middle cerebral artery (13), and intracranial pressure (ICP) (12). Studies on the effects of remifentanil on cerebral capacity itself, however, have not been conducted.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After we obtained the approval of the local university ethics committee and written, informed consent, 10 healthy awake male volunteers with no history of drug or alcohol abuse and no history of surgery in the preceding 6 mo, underwent physical examination and blood screening for opioids. After negative drug screening results, two consecutive MRI measurements of systolic CSFVPeak in the aqueduct of Sylvius were performed. Wearing a tightly fitting face mask, the volunteers normoventilated (ETCO2 = 40 mm Hg, fraction of inspired oxygen = 0.5) during baseline measurement and subsequent continuous infusion of remifentanil (0.1 µg · kg-1 · min-1). The continuous infusion rate for steady state (14) was preceded by a 25% increased infusion rate for a period of 5 min. After 10 min of remifentanil infusion, tests of thermal and tactile nociception, as well as of pupillary constriction, were repeated to verify opioid action before starting MRI measurement. The cumulative duration of remifentanil infusion was 45 to 60 min. The sequence of measurements, namely baseline measurement first and measurement during infusion of remifentanil second, was fixed.

The volunteers had been trained both by verbal instruction and by watching the capnographic trace of the monitor on the day before the MRI session. During the experiment, breathing at a constant ETCO2 (e.g., 40 mm Hg) was supported by voice command when necessary.

ETCO2, noninvasive mean blood pressure (MAP), and SpO2 were monitored (Compact; Datex-Ohmeda, Helsinki, Finland) during the investigative period.

Measurements of systolic CSFVPeak in the aqueduct of Sylvius were performed on a 1.5Tesla whole-body scanner (Magnetom VISION®; Siemens, Erlangen, Germany) by using a standard circular polarized head coil. A two-dimensional gradient echo sequence (2D-FISP) (repetition time = 100 ms, echo time = 12ms, {alpha} = 10°, acquisition matrix: 256 x 512, field of view 160 mm) with flow velocity encoding in slice-select direction was used. For this high-resolution axial technique, which is sensitive to through-plan flow, the maximal detectable flow velocity was 20 cm/s. Electrocardiography triggering was used for prospective gating of the acquisition. The disadvantage of prospective gating, however, is that acquisition is stopped within about 200 ms of the next R wave for accurate detection of the next trigger. Thus, the diastolic phase is not evaluated (15). Cardiac gating produced a series of phase-contrast images in different cardiac phases. From these phase-contrast images, a blinded investigator measured the CSFVPeak in the aqueduct of Sylvius using region of interest measurements.

Data were presented as mean ± SD. The Student’s t-test for paired samples was used for data analysis. A P < 0.05 was considered statistically significant. The statistical computer package SPSS® Professional Statistics (SPSS, Chicago, IL) 8.0.0 for Windows (95) run on a Compaq® Deskpro EP Series 6350/6.4 (Houston, TX) was used for statistical analysis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All volunteers (n = 10; age: 25 ± 3 yr; weight: 76 ± 6 kg; height: 181 ± 6 cm) completed the study without complication.

Remifentanil (0.1 µg · kg-1 · min-1) had no influence on cerebral capacity, as indicated by unchanged systolic CSFVPeak in the aqueduct of Sylvius (baseline: -4.3 (± 1.3) cm/s versus remifentanil: -4.7 (± 1.0) cm/s) (Table 1) (Figures 1 and 2).


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  		Table 1. Systolic CSFVPeak and Systemic Values P <= 0.05
 


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  		Figure 1. Systolic cerebrospinal fluid peak velocity tracing during baseline measurement. The vertical scale is given in cm/s and the horizontal scale in ms. The negative deflections represent craniocaudal systolic cerebrospinal fluid flow in the aqueduct of Sylvius.

 


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  		Figure 2. Systolic cerebrospinal fluid peak velocity tracing during infusion of remifentanil (0.1 µg · kg-1 · min-1). The vertical scale is given in cm/s and the horizontal scale in ms. The negative deflections represent craniocaudal systolic cerebrospinal fluid flow in the aqueduct of Sylvius.

 
Heart rate, MAP, SpO2 and ETCO2 remained unchanged during the infusion of remifentanil (Table 1).

Tests of thermal and tactile nociception, as well as of pupillary constriction after 10 min of remifentanil infusion, confirmed the opioid action of this dose of remifentanil (0.1 µg · kg-1 · min-1) as compared with baseline (Table 2).


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  		Table 2. Results of Tests of Thermal and Tactile Nociception and Pupillary Constriction During Baseline, 10 min After Start of Remifentanil Infusion and 10 min After Stop of Remifentanil Infusion (0.1 µg · kg-1 · min-1)
 
Opioid side-effects observed are summarized (Table 3).


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  		Table 3. Summarizes Observed Opioid Side Effects, Maximal Effect is Given During Remifentanil Infusion
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our results show that small-dose remifentanil (0.1 µg · kg-1 · min-1) does not influence cerebral capacity in awake volunteers, as indicated by unchanged systolic CSFVPeak in the aqueduct of Sylvius.

In clinical practice, impairment of cerebral capacity may be induced not only by pathological states (e.g., brain tumor, brain edema, hydrocephalus), but also by drug-induced vasodilatation [i.e., inhaled anesthetics (16,17)]. Such vasodilatory effects have also been found after the administration of opioids, thus causing increased ICP (1,18). In contrast to invasive lumbar, or even cranial, monitoring of ICP for assessment of cerebral capacity, measurement of systolic CSFVPeak in the aqueduct of Sylvius allows noninvasive assessment (7).

In the adult, the rigid skull establishes the cranial vault as an essentially fixed volume. Any change in one of the anatomical compartments therein (brain tissue, CBV, or CSF volume) requires compensatory changes in one or more of the other compartments. Under physiological conditions, an increase in CBV, i.e., during cardiac systole, is swiftly compensated by venous egress and caudally directed CSF displacement (19). In contrast to such a short compensation of increased CBV by pulse synchronous to-and-fro movement of CSF volume, a longer-lasting increase in volume causes a new equilibrium among the three volumes harbored in the cranium. This mechanism for maintaining intracranial volume homeostasis, which prevents an increase in ICP under physiological conditions, has been described as "cerebral capacity" (20).

Cerebrovascular reactivity to changes in PaCO2 is preserved during remifentanil infusion (21). To eliminate PaCO2-mediated increases in cerebral hemodynamics with consequent changes in cerebral capacity, normocapnia was controlled in our volunteers by continuous monitoring of ETCO2 (22,23). In spontaneous breathing, nonintubated volunteers, Hoffmann et al. (24) found a good correlation between PaCO2 and ETCO2.

Effects of opioids, especially nonPaCO2-mediated ones, on CBF and ICP were reviewed by Artru (25) and Schregel et al. (26). Depending on study design, species differences, methods of measurement, but also background medication and anesthesia, sufentanil, alfentanil, and fentanyl increased, decreased, or had no influence on CBF and/or ICP (26).

Doses of alfentanil equipotent to the dose of remifentanil in the present study, but also 10 to 100 times larger doses of fentanyl and sufentanil, showed a tendency to increase ICP as a consequence of a drug-induced decrease in MAP (25) only in patients with intact autoregulation (26). In contrast, in the case of disturbed, or even abolished, autoregulation, an opioid-mediated decrease in MAP did not further increase an already elevated ICP by autoregulatory vasodilatation (27,28).

Alfentanil (29), fentanyl (28), sufentanil (30), but also remifentanil (31) have been shown to leave cerebral autoregulation intact. In the light of intact autoregulation and the fact that in our study remifentanil did not decrease MAP, autoregulatory cerebral vasodilatation with subsequent increase in CBV during infusion of remifentanil appears unlikely. This assumption is well supported by our finding that remifentanil does not influence cerebral capacity, which demonstrates that the overall effect of small-dose remifentanil on cerebrovascular hemodynamics is well compensated in healthy volunteers.

Drug-induced disturbance of the equilibrium between CSF formation and reabsorption may alter CSF volume, whereby the duration of opioid administration, and thus a longer-lasting influence on the production/reabsorption balance, determines the development of CSF volume. Artru et al. (32) showed, in the dog, that, after 90 minutes, smaller doses of sufentanil, alfentanil, and fentanyl reduced resistance to reabsorption of CSF.

Data on the influence of remifentanil on CSF formation and reabsorption in humans during the first 30 to 60 minutes of drug administration are not available. Very recent studies in rabbits, however, found that remifentanil had no significant influence on CSF formation rate or resistance to reabsorption of CSF (A. A. Artru and Y. Momota, written communication, 1999). Thus, the net effect of remifentanil on CSF volume is negligible, which is in accordance with our finding that remifentanil does not impair cerebral capacity in humans.

Methodological inaccuracies, however, may influence measurements of systolic CSFVPeak in the aqueduct of Sylvius because of the small size of this structure (normal 2–3 mm) (33). Inaccuracies between 5% (34) and 7.5% (35) have been described for flow measurements, but control systolic CSFVPeak values (-4.3 ± 1.3 cm/s) in our study were in accordance with previously reported data (-2.0 cm/s to -5.2 cm/s) (15,36). Another possible source of methodological inaccuracy is the variance of the aqueductal CSF wave form amplitude, which can be assumed from previous studies on the variance of the CSF wave form amplitude at the C2-3 disk level in healthy subjects (19). However, the sensitivity of the method to detect changes in systolic CSFVPeak during clinically relevant, continuous positive airway pressure breathing was shown previously (7). Therefore, a clinically relevant impact of remifentanil on systolic CSFVPeak, e.g., comparable to that of continuous positive airway pressure breathing, should be reliably detected.

The opioid action of the chosen dose of remifentanil (0.1 µg · kg-1 · min-1) was confirmed in our volunteers by tests of thermal and tactile nociception, as well as of pupillary constriction (Table 2). In a recent study, the extremely short-lived pharmacodynamic effects of remifentanil were called into question, as psychomotor effects were still apparent one hour after the infusion was discontinued (37). Thus, to avoid carry-over effects and to keep the time between the two measurements as short as possible, a fixed sequence of measurements, namely baseline measurement first and measurement during infusion of remifentanil second, was chosen, despite a possible effect of this study design on our results.

In conclusion, using a noninvasive MRI method, we found that small-dose remifentanil (0.1 µg · kg-1 · min-1) does not influence cerebral capacity in awake volunteers, when normocapnia and normotension are present during short-term administration of the drug.


   Acknowledgments
 
The authors are greatly indebted to those volunteers at Innsbruck University Hospital whose participation made this study possible.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 18, 1999.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press