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Anesth Analg 2001;93:45-52
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Reduced Regional and Global Cerebral Blood Flow During Fenoldopam-Induced Hypotension in Volunteers

Richard C. Prielipp, MD, FCCM*, Michael H. Wall, MD*, Leanne Groban, MD*, Joseph R. Tobin, MD, FCCM*, Frederic H. Fahey, DSc{dagger}, Beth A. Harkness, MS{dagger}, David A. Stump, PhD*, Robert L. James, MS*, Mark A. Cannon, MD*, Judy Bennett, RN*, and John Butterworth, MD*

Departments of *Anesthesiology (Sections of Critical Care and Cardiothoracic Anesthesiology) and {dagger}Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence and reprint requests to Richard C. Prielipp, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. Address e-mail to prielipp{at}wfubmc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 APPENDIX
 References
 
Dopamine has a wide spectrum of receptor and pharmacologic actions that may affect cerebral blood flow (CBF). A new, selective dopamine-1 agonist, fenoldopam, is a potent systemic vasodilator with moderate {alpha}2-receptor affinity. However, the effects of fenoldopam on the cerebral circulation are undefined. We therefore hypothesized that infusion of fenoldopam would decrease mean arterial blood pressure (MAP) and might concurrently decrease CBF via vascular {alpha}2-adrenoreceptor activation in awake volunteers. We studied nine healthy normotensive subjects, using positron emission tomography to measure CBF in multiple cortical and subcortical regions of interest. In addition, bioimpedance cardiac output and middle cerebral artery blood flow velocity were determined during fenoldopam-induced hypotension. Three men and four women, aged 25–43 yr, completed the study. Fenoldopam infused at 1.3 ± 0.4 µg · kg-1 · min-1 (mean ± SD) reduced MAP 16% from baseline: from 94 (89–100) mm Hg (mean [95% confidence interval]) to 79 [74–85] mm Hg (P < 0.0001). During the fenoldopam infusion, both cardiac output (+39%), and heart rate (+45%) increased significantly, whereas global CBF decreased from baseline, 45.6 [35.6–58.5] mL · 100 g-1 · min-1, to 37.7 [33.9–42.0] mL · 100 g-1 · min-1 (P < 0.0001). Despite restoration of baseline MAP with a concurrent infusion of phenylephrine, global CBF remained decreased relative to baseline values at 37.9 [34.0–42.3] mL · 100 gm-1 · min-1 (P < 0.0001). Changes in middle cerebral artery velocity did not correlate with positron emission tomography-measured changes of CBF induced by fenoldopam, with or without concurrent phenylephrine.

Implications: In awake volunteers with (presumably) intact cerebral autoregulation,fenoldopam-induced hypotension significantly decreased global cerebral bloodflow (CBF). Clinicians should be aware of these pharmacodynamic effects whenchoosing a vasodilator to control blood pressure, especially in situationswhere control of CBF, cerebral blood volume, and intracranial pressure aretherapeutic priorities.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 APPENDIX
 References
 
Dopamine’s (DA’s) complex receptor and pharmacologic effects produce a spectrum of cerebrovascular actions. In vitro models usually demonstrate potent direct contractile effects of DA on major cerebral arteries, whereas drug infusion in awake sheep produces a dose-dependent increase in cerebral blood flow (CBF) (1). Indeed, at large doses, DA may produce cerebral hyperemia and increase intracranial pressure (1). These latter effects may parallel those of the traditional nitric oxide-mediated vasodilators, which may produce a phenomenon known as hyperemic intracranial hypertension (2).

Fenoldopam is a new, rapid-acting vasodilator indicated for in-hospital, short-term management of severe hypertension when rapid, but quickly reversible, reduction of blood pressure is indicated (3–6). Many physicians also infuse this selective DA-1 agonist in fixed doses during major cardiac or vascular operations in an attempt to optimize renal blood flow and preserve renal function (7,8). Fenoldopam has a unique pharmacodynamic profile compared with DA because of its high affinity for the DA-1 receptor, moderate affinity for {alpha}2 adrenoreceptors (though it is devoid of known sedative effects), and lack of affinity for DA-2, {alpha}1, or ß adrenoreceptors. However, unlike DA, the effects of fenoldopam on the cerebral circulation are largely unknown. Animal studies demonstrate that most DA-1 receptors are localized on postjunctional cerebral vessels, with equal density in the medial smooth muscle layer of small, medium, and large arteries (9). Although in vitro application of fenoldopam dilates mesenteric, renal, coronary, and cerebral vascular beds (10), in vivo infusion of fenoldopam increased CBF in rabbits with experimental heart failure but had no effect on CBF in control animals (11). It is important to note that {alpha}2-adrenergic receptors are also found on both large and small cerebral vessels and appear to mediate cerebral vasoconstriction and decrease CBF (12–14). These effects appear to be both anesthetic- and species-dependent (13,15,16). Currently, there are no data regarding the effects of fenoldopam on human cerebral vasculature or CBF. We therefore tested the hypothesis that doses of fenoldopam that decrease mean arterial blood pressure (MAP) via the DA-1 receptor might simultaneously decrease global and regional CBF via activation of the {alpha}2 receptor in healthy, awake, normotensive volunteers.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 APPENDIX
 References
 
After IRB approval, nine normotensive human subjects gave written informed consent to participate in this open-label, pharmacodynamic study. All volunteers were between 18 and 50 yr old, no more than 150% of their ideal body weight, and classified as ASA physical status I or II. Subjects were excluded if they manifested any of the following: migraine headaches requiring medical therapy, cerebrovascular disease, stroke, previous intracranial aneurysm, hemorrhage, traumatic brain injury requiring hospitalization within the previous 6 mo, stage I or higher hypertension (as defined by the Joint National Commission VI) (17), glaucoma, known allergy to fenoldopam or metabisulfites, or pregnancy. Subjects were also excluded if they were currently taking antihypertensive medication.

Subjects were studied sequentially without randomization. All volunteers underwent placement of the following catheters, with local 1% lidocaine anesthesia: 1) an 18-gauge IV catheter in the antecubital vein of their left arm, dedicated for H215O injections during dynamic positron emission tomography (PET) scans; 2) a 20-gauge IV catheter in the left forearm for the administration of the vasoactive medications—fenoldopam and phenylephrine; and 3) a 20-gauge intraarterial catheter in the right radial artery for continuous arterial blood pressure monitoring and for blood sampling after H215O injections. Additional monitoring included standard oscillometric blood pressure determination (DINAMAP®; TW Medical, Cedar Park, TX) at 10-min intervals, cardiac output (CO) measurement via thoracic bioimpedance (CIC-1000; Sorba, Milwaukee, WI), lead II electrocardiogram, and peripheral digital pulse oximetry. Lastly, a NicoletPioneer transcranial Doppler (TCD) probe (Nicolet, Golden, CO) was positioned (directed through the temporal region of the skull) by an experienced technician to intermittently measure flow velocity in the left middle cerebral artery (MCA) via a 2-MHz pulsed Doppler signal. TCD estimated flow velocity (cm/s) at each of the pertinent hemodynamic time points.

Subjects were studied in the supine position on the PET scan gantry after two sequential 15-min periods of stabilization and monitoring. Hemodynamic profiles were determined at the end of study intervals, and each profile included the determination of the following:

Heart rate (HR), systolic and diastolic blood pressure, and MAP.
Noninvasive impedance CO estimation.
Dynamic PET scans for global and regional CBF measurement.
MCA blood flow velocities.
Oxygen saturation.
Infusion rates of vasoactive medications.

During the study period, HR and CO were collected at intervals by using the CIC-1000. The CIC-1000 is a Food and Drug Administration-approved, fully automated, real-time, noninvasive CO monitor (based on the technology of impedance cardiography) that has been fully tested and validated (18). Compared with Fick, Doppler, and thermodilution determinations of CO, bioimpedance technology provides acceptable estimates of CO, especially in healthy patients or volunteers. The system uses R wave triggering and ensemble averaging (which improves the signal to noise ratio by reducing respiratory and motion artifacts). Impedance electrodes are placed on the forehead, at the base of the neck, at the left midaxillary line at the level of the xiphoid, and at the crest of the left hip. A phonograph microphone was placed over the left second parasternal region to assist with determination of the left ventricular ejection time. The system generates a 50-kHz, 500-µA signal, which is applied to the outer two electrodes, and impedance wave forms are continuously recorded and ensemble-averaged over 10-s intervals across the inner two electrodes. Stroke volume was determined by a computer algorithm that is based on the equation of Kubicek et al. (19). CO was then calculated as the product of stroke volume and mean HR (bpm) during the10-s interval.

Oxygen-15 was produced with a Siemens/CTI RDS 112 11-MeV negative-ion (H-) cyclotron. The PET scans were acquired on a Siemens ECAT 951/31 scanner (Siemens Nuclear Medicine Group, Hoffman Estates, IL). The ECAT 951 provides 31 transaxial slices over a 10.4-cm axial field of view (3.3-mm center-to-center slice spacing), producing approximately 6.5 mm of spatial resolution in all three dimensions, and it has a system sensitivity of approximately 120 kcps · µCi-1 · cm3. The subject was placed in the scanner and positioned with the majority of the cortex included within the field of view. A laser system was used to mark the subject so that the same positioning could be maintained throughout the study.

Six H215O emission scans were acquired for each subject: two for baseline studies, two during the administration of fenoldopam, and two after the reversal of fenoldopam-induced hypotension with phenylephrine (see below). Approximately 50 mCi of H215O was delivered to the subject for each scan. Before each group of two emission scans, a 4-min transmission scan was acquired to be used for segmented photon attenuation compensation by using the approach described by Xu et al. (20). Each emission scan was acquired as a 9-min dynamic study (six 5-s frames, three 20-s frames, three 30-s frames, two 60-s frames, and two 120-s frames). The data were reconstructed by filtered backprojection by use of a Hanning filter with a 0.3 cycles per pixel cutoff frequency. Arterial blood sampling was performed with an automated sampler (240/3; OLE DICH Instruments, Hvidovre, Denmark) that drew the blood through a line past opposing bismuth germanate scintillation detectors that operate in coincidence. However, the sampled blood was not available for arterial gas tension measurements. The automated blood sampler was calibrated on each day before study. Quantitative transaxial images of regional CBF (in mL · min-1 · 100 g-1 of tissue) were generated from these data by using the method described by Koeppe et al. (21).

To analyze the PET scan data, we drew 14 predetermined spherical (1.5-cm-diameter) regions of interest (ROI). Eight of the ROI sampled cortical brain, two were located in the thalamus, two represented the caudate nucleus, and two sampled deep-brain white matter (see Appendix). For each region, the maximal pixel counts at each ROI were determined from paired measurements and used in the standard calculation of CBF by PET (20,21). We calculated global CBF for each patient as the sum of the maximum CBF from all 14 brain ROIs.

After baseline determinations were completed as above, a fenoldopam infusion was initiated at 0.2 µg · kg-1 · min-1. The infusion was increased every 5–10 min to define a dose that decreased MAP by 15%. This infusion rate was maintained constant for 10 min, and repeat hemodynamic, CBF, and cerebral flow velocity measurements were completed. Lastly, while the infusion of fenoldopam was kept constant, MAP was restored to baseline values by the concurrent infusion of phenylephrine (starting dose, 30 µg/min), which was adjusted every 2–4 min as needed. Final hemodynamic and CBF measurements were then completed. All vasoactive medications were terminated, and blood pressure and other vital signs were observed for an additional 15 min. A final set of hemodynamic measurements was then obtained before the removal of invasive catheters and noninvasive monitors. The subjects were then medically discharged home.

The effect of drug treatment on CBF was analyzed with mixed-effects analysis of variance (ANOVA) with random effects for the volunteers and fixed effects for ROI, treatment, and the interaction. Residual analysis showed CBF to best fit a log-normal model; thus, the analysis was performed with log-transformed CBF values. Because of log-transformation, geometric least-squares means, 95% confidence intervals, and difference ratios are reported. Bonferroni corrections were made for post hoc multiple comparisons only when the ANOVA’s main effect and interactions were not significant (with Fisher’s protected least-significant difference approach). The effects of treatment on global CBF, TCD velocity, HR, MAP, and CO were each analyzed with mixed-effects ANOVA, with fixed effects for treatments and random effects for the volunteers. Pearson’s correlation tested for linear and simple monotonic association, respectively, between TCD (as percentage of baseline) and CBF (as percentage of baseline). Lastly, because the values for the hemodynamic indices were stable between the first two baseline periods, these two time points were averaged for subsequent analyses. All statistical analyses were performed with SAS (version 8.0; SAS Institute, Inc., Cary, NC). P values <0.05 were considered significant, unless otherwise corrected for multiple comparisons.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 APPENDIX
 References
 
One male subject was deleted from analysis because the infusion of fenoldopam (dose = 2.3 µg · kg-1 · min-1) did not decrease MAP; significant tachycardia and increased CO apparently compensated for the marked decrease in afterload. CBF data from a second subject were not available because of technical problems with the PET acquisition scans. The other seven subjects completed the protocol without problems and were included in the analyses. Thus, three men and four women, aged 25–43 yr, weighing 59–86 kg, completed the study, and their demographics are summarized in Table 1.


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  		Table 1. Demographic Variables of Seven Subjects Who Completed the Cerebral Blood Flow Protocol
 
The fenoldopam infusion (mean dose, 1.3 ± 0.4 µg · kg-1 · min-1) decreased MAP 16% from baseline, from 94 (89–100) (95% confidence interval) mm Hg to 79 (74–85) mm Hg (P < 0.0001). Both CO (+39%) and HR (+45%) increased significantly during the fenoldopam infusion (Table 2). Concomitant infusion of fenoldopam and phenylephrine (dose, 130 ± 70 µg/min) restored MAP to baseline values (94 [89–100] mm Hg), (P = 0.95), whereas both CO (P = 0.0007) and HR (P = 0.0125) remained increased. Fifteen minutes after the termination of the infusion of both vasoactive drugs, CO had returned to baseline (P = 0.99). However, because the plasma half-life of fenoldopam ({approx}5 min) is longer than that of phenylephrine, neither MAP (87 [82–93] mm Hg) nor HR (79 [71–87] bpm) had returned completely to baseline within 15 min (Table 2).


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  		Table 2. Main Effects of Treatment on Each of the Hemodynamic Variables, by Using Mixed-Effects Analysis of Variance
 
Overall, the mixed-effects model found the effects of both treatment and ROI highly significant (P < 0.0001). CBF decreased significantly from baseline (45.6 mL · 100 g-1 · min-1 [35.6–58.5]) during fenoldopam infusion (37.7 [33.9–42.0]) (P < 0.0001) and during the combined infusion of fenoldopam plus phenylephrine (37.9 [34.0–42.3]) (P < 0.0001) (Fig. 1, Table 3). However, there was no statistical difference in CBF during the two experimental conditions of fenoldopam and fenoldopam plus phenylephrine (P = 0.96). During fenoldopam infusion, CBF was decreased significantly in 10 of 14 ROIs (Table 3). The two ROIs representing deep white matter (ROIs 13 and 14) had decreased baseline regional blood flow and may have been less affected by fenoldopam. Although the phenylephrine infusion returned MAP to baseline, the effects of fenoldopam on CBF were not reversed either overall or in any of the 14 ROI during the concurrent phenylephrine infusion (Table 3).



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  		Figure 1. PET (positron emission tomography) scan images from a typical subject, where color intensity correlates with cerebral blood flow (CBF). The left column shows baseline images, whereas the middle column shows images taken during fenoldopam (FEN) infusion titrated to decrease mean arterial blood pressure by 15%. Visual inspection clearly shows the decrease in CBF (P < 0.0001). The right column is the final phase of the experiment, which combined infusion of both FEN and phenylephrine (PHE). CBF was still decreased compared with baseline. The top row displays axial images, the middle row shows coronal images, and the bottom row shows the sagittal planes. The circles with cross-hairs represent how predetermined regions of interest are targeted, whereby regional blood flow is determined.

 

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  		Table 3. Geometric Least Square Means (geolsm) of Cerebral Blood Flow (mL · 100 g-1 · min-1) with 95% Confidence Interval by Each Region of Interest
 
Baseline MCA flow velocity was 53 (40–66) cm/s. Although both fenoldopam and fenoldopam plus phenylephrine decreased CBF significantly, as described above, there was no treatment effect of these drugs detected by TCD velocities (P = 0.76) (Table 4). Adjusting the TCD for CO by including it in the ANOVA as a covariate still failed to find any treatment effect of fenoldopam or fenoldopam plus phenylephrine on TCD velocity. We further examined the correlation of changes in CBF (by PET methodology with H215O injections) and changes in TCD velocities under these experimental conditions. TCD was poorly associated with changes in cortical CBF. During fenoldopam infusion, no cortical ROI showed a statistically significant positive correlation to TCD. Indeed, during concomitant fenoldopam plus phenylephrine infusions, there were no positive correlations detected, but several negative correlations were identified (ROIs 5, 8, 9, and 11).


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  		Table 4. Mean Transcranial Doppler Velocities (cm/s) of the Left Middle Cerebral Artery at Baseline and After Each Treatment Condition
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
APPENDIX
 References
 
Fenoldopam is a rapid-acting vasodilator with high affinity for DA-1 receptors and moderate affinity for {alpha}2 adrenoreceptors, but no significant activity at DA-2, {alpha}1-, or ß-adrenergic receptors. Because an application of DA-receptor agonists generally mediates vasodilation of mesenteric, renal, cerebral, and coronary vas- cular smooth muscle in experimental animal preparations (10) and humans, fenoldopam is an effective antihypertensive drug (3–6). However, we found doses of fenoldopam that decreased system blood pressure by 16% and also decreased cortical, caudate, and thalamic CBF. This is the first study to define the CBF effects of fenoldopam in humans, and we believe that these findings are consistent with our hypothesis that activation of the {alpha}2 receptors by fenoldopam produces cerebral vasoconstriction. It appears that fenoldopam is a novel antihypertensive drug that vasodilates systemic vasculature but vasoconstricts cerebral vessels and reduces CBF in select cortical regions (or induces this effect indirectly).

Although the infusion of DA generally increases CBF in intact animals (1), the role of DA-agonists within the cerebral microcirculation is complex. Cortical blood vessels are innervated by axons containing norepinephrine (12,13), acetylcholine, serotonin, and neuropeptide receptors (22). New evidence from both light and electron-microscopic immunocytochemistry and autoradiographic labeling shows that dopaminergic axons also innervate intraparenchymal cerebral microvessels (9,23). The distribution of these dopaminergic receptors varies, with vascular innervation density being greatest in the frontal, sensorimotor, and entorhinal cortices. Many of these DA terminals are closely approximated to the microvessels within the cortex, and accumulating evidence suggests that they play a key role in the local regulation of microvascular flow (23,24). Indeed, DA applied directly to isolated cerebral arteries in situ invariably produces vasoconstriction, and this response likely represents direct adrenergic and serotoninergic receptor activation (24). Thus, theoretically, a DA-1 agonist such as fenoldopam might exert vasoconstrictor activity at the local or microcirculatory level.

In addition, however, it appears that our observation that fenoldopam decreased cortical, caudate, and thalamic CBF in humans is explained by {alpha}2-adrenergic receptor-induced vasoconstriction in these areas, consistent with the known distribution and activity of {alpha}2-adrenergic receptors in the cerebral vasculature (12–16,22,24,25). Indeed, direct {alpha}2-receptor vasoconstriction best explains the effects of another {alpha}2-agonist, dexmedetomidine, which decreases CBF in a dose-dependent manner (26). The final phase of our protocol infused fenoldopam concomitant with phenylephrine (a selective {alpha}1-agonist), titrated to restore MAP back to baseline in each volunteer. Although phenylephrine administration increased systemic arterial blood pressure, CBF did not change from that observed with fenoldopam alone. Thus, it appears the {alpha}2-adrenergic influences induced by fenoldopam predominated over {alpha}1-stimulation in regulation and control of the cerebral circulation in these volunteers. This is consistent with previous evidence highlighting the paucity of direct effects by {alpha}1-agonists on cerebral vessels (27).

PET emission scans of bolus H215O injections are accurate, quantitative, three-dimensional measurements of regional CBF from both superficial and deep structures under normal and pathologic conditions (28,29). Indeed, PET is currently the most accurate and versatile tracer method to measure in vivo physiologic variables in human brain (30). The technique is sufficiently sensitive to determine CBF even in very young infants. Advantages of PET include high resolution at normal blood flows and the ability to measure blood flow differences between brain structures (28). One limitation is that CBF in small areas of low reactivity surrounded by areas of high radioactivity are difficult to measure accurately. Our ROIs were selected to minimize this effect. Thus, we believe that PET is the best current technology for measuring regional CBF in humans.

By contrast, evidence both supports (31) and refutes (32) the use of TCD as a measure of CBF in humans. The most important limitation of TCD is its inability to measure flow per se. Only velocity can be measured; flow is inferred. A valid TCD determination requires that the diameter of the MCA and the measurement angle of the Doppler signal remain constant. A change in TCD velocity may represent a change in vessel diameter and not a change in CBF itself. For instance, increased MCA TCD velocity does not correlate with increased CBF (measured by xenon techniques) after subarachnoid hemorrhage (33). Doppler measurements also assume that blood flow in the basal arteries of the brain is directly related to cortical CBF (32). However, we are aware of no evidence that prospectively supports this assumption, and we know of some that disputes it (32). Our data would suggest that (at least during infusion of fenoldopam and perhaps other vasoactive medications in awake humans) TCD lacks sufficient sensitivity to be a surrogate for direct CBF measurements.

Several limitations of this study are evident. First, we were studying young, healthy, normotensive volunteers, and it is unclear if the same findings will be seen in hypertensive patients, older patients, anesthetized patients, patients with traumatic brain injury, or patients with other intracranial alterations of cerebral autoregulation. Indeed, in patients without normal cerebral autoregulation, one would expect an increase in CBF as systemic blood flow increases. Studying young, healthy, robust individuals required rapid titration of fairly large fenoldopam doses (indeed, one subject’s blood pressure never decreased despite receiving the maximal infusion rate of fenoldopam recommended in the package insert: 1.6 µg · kg-1 · min-1). Thus, we were unable to determine whether there was a dose-dependent effect of fenoldopam on CBF. Also, we did not determine fenoldopam pharmacokinetics, and, therefore, we cannot comment on what blood or effect-site concentrations were produced by our fenoldopam infusion protocol. We did not determine arterial PaCO2 tension during the study. Fenoldopam-induced changes in pulmonary blood flow and physiologic dead-space might alter PaCO2 in some subjects and thereby affect CBF. We also need to acknowledge that our global CBF is based on the sum of the multiple, preidentified ROIs. Indeed, we have no certain way of knowing what vascular changes may be occurring anywhere other than where we sampled. Furthermore, at the end of the protocol, after all drug infusions were terminated, we would have liked to determine CBF again to confirm its return to baseline. However, the number of H215O water injections were at the upper limit of body irradiation allowed by our IRB protocol. Lastly, but perhaps most important, is the question of whether the fenoldopam-induced decrease in CBF altered cerebral metabolic activity; that is, was there a significant affect on cerebral oxygen consumption? We did not measure this variable. Some preliminary animal data suggest that the decrease in CBF associated with {alpha}2-agonists (such as dexmedetomidine) is not metabolically mediated and that the cerebral metabolic rate of oxygen is maintained constant (15).

In summary, fenoldopam is a unique DA-agonist vasodilator with rapid onset and short duration of action that produces dose-dependent systemic vasodilation and increases renal plasma flow and CO. In addition, we found that fenoldopam decreases both regional and global CBF, probably as a consequence of its {alpha}2-agonist activity. Clinicians should be aware of these important pharmacodynamic effects when choosing a vasodilator, especially in situations in which control of CBF, cerebral blood volume, and control of intracranial pressure are priorities.


   APPENDIX
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 APPENDIX
References
 
Go


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  		Table 5. Appendix. Number system representing predetermined brain ROI standardized for calculation of PET regional CBF.
 


   Acknowledgments
 
Supported, in part, by an unrestricted educational grant from Neurex, Menlo Park, California.


   Footnotes
 
Presented in part at the International Anesthesia Research Society 74th Clinical and Scientific Congress, Honolulu, HI, March 10–14, 2000.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 APPENDIX
 References
 

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Accepted for publication February 27, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press