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Anesth Analg 2000;91:642-646
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Nicardipine on Dynamic Cerebral Autoregulation in Patients Anesthetized with Propofol and Fentanyl

Hiroshi Endoh, MD, PhD*, Tadayuki Honda, MD, PhD*, Noboru Komura, MD{dagger}, Chieko Shibue, MD{dagger}, Ippei Watanabe, MD{dagger}, and Koki Shimoji, MD, PhD, FRCA{dagger}

Departments of *Emergency and Critical Care Medicine and {dagger}Anesthesiology, Niigata University School of Medicine, Niigata, Japan

Address correspondence and reprint requests to Hiroshi Endoh, MD, PhD, Department of Emergency and Critical Care Medicine, Niigata University School of Medicine, 1-757 Asahimachi, Niigata 951-8122, Japan. Address e-mail to endoh{at}med.niigata-u.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated the effects of nicardipine on dynamic cerebral pressure autoregulation in 13 normal adult patients undergoing gynecologic or orthopedic surgery. Anesthesia was induced and maintained with propofol and fentanyl. Hypotension to a mean arterial pressure of 60–65 mm Hg was induced and maintained with a continuous infusion of nicardipine. Time-averaged mean blood flow velocity in the right middle cerebral artery was measured continuously by using transcranial Doppler ultrasonography. The cerebral autoregulatory responses were activated by releasing thigh cuffs. The actual blood flow velocity in the right middle cerebral artery response to acute change in mean arterial pressure was fitted to 1 of 10 computer-generated curves to determine the dynamic rate of cerebral autoregulation (dRoR), and the best fitting curve was used. The autoregulation test was repeated until two values of dRoR were obtained at baseline and during induced hypotension. Nicardipine significantly reduced dRoR values of 13.1% ± 3.6%/s at baseline to 8.3% ± 2.6%/s during hypotension (P < 0.01). During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients.

Implications: During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Cerebral pressure autoregulation is defined as the ability to maintain a constant cerebral blood flow during variations in mean arterial pressure (MAP) within the range of 50 to 150 mm Hg; this regulation is accomplished through changes in cerebral vasomotor tone (1,2). Patients with impaired cerebral autoregulation are at a much greater risk of cerebral hyper- or hypoperfusion. Vasodilators directly affect not only systemic blood vessels but also cerebral blood vessels. Thus, we reasoned that vasodilators may also influence cerebral autoregulatory response by changing vasomotor tone. Nicardipine is a short-acting dihydropyridine calcium channel antagonist that has been used extensively for hemodynamic control during and after surgery (3). However, no attempts have been made to study the effects of the drug on human cerebral autoregulation.

Dynamic cerebral autoregulation is a fast cerebral autoregulatory response that is completed within 5 to 8 s after an acute change in arterial pressure. Cerebral autoregulation is clinically evaluated using transcranial Doppler ultrasonography (TCD) to measure the dynamic rate of autoregulation (dRoR) (4).

In this study, we evaluated the effects of nicardipine-induced hypotension to a MAP of 60 to 65 mm Hg on dynamic cerebral autoregulation in normal adult patients anesthetized with propofol and fentanyl.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
After obtaining institutional ethics committee approval and written informed consent, we enrolled 20 adult patients (ASA physical status I or II) scheduled for elective gynecologic or orthopedic surgery. Patients with cerebrovascular disease, hypertension (systolic blood pressure >150 mm Hg or diastolic blood pressure >90 mm Hg), or diabetes mellitus were excluded. No patients were premedicated, and the study was completed before surgery.

Anesthesia was induced with an IV bolus injection of fentanyl (2–3.5 µg/kg), propofol (2–2.5 mg/kg), and vecuronium bromide (0.1 mg/kg) and maintained with a continuous infusion of propofol (6–7 mg · kg-1 · h-1) and fentanyl (2–3.5 µg · kg-1 · h-1). Muscle relaxation was maintained with intermittent bolus injections of vecuronium bromide. The trachea was intubated, and the lungs were mechanically ventilated with a mixture of 60% air and 40% oxygen to normocapnia. Monitoring included a radial artery catheter for measurements of MAP and blood gas tensions, electrocardiography, bladder temperature, arterial oxygen saturation, and end-tidal CO2 tension (PETCO2). Body temperature during the study was maintained at 36° to 37.5°C by using a thermal blanket. In addition, the M1 segment of the right middle cerebral artery was insonated with a 2-MHz TCD probe (Multidop T; DWL Electronische Systeme, Sipplingen, Germany) at a depth of 45 to 55 mm through the right temporal window according to standard procedures (5). The TCD continuously measured the time-averaged mean red blood cell flow velocity in the middle cerebral artery (Vmca). The probe was positioned with a custom-designed frame to keep the insonation angle constant during the study. Vmca and MAP were displayed simultaneously on the TCD monitor and recorded onto digital videotape for subsequent analysis.

The dynamic autoregulatory response was activated by a sudden deflation of a specially designed large cuff with a width of 31 cm (DWL Electronische Systeme). The cuff was placed around both thighs and had been inflated to 30 to 50 mm Hg above the systolic blood pressure for 3 to 5 min (4,6). A suitable stimulus was considered as a steep decrease of MAP of >10 mm Hg and duration of the decrease >10 s (6). The actual response curves of Vmca and MAP were stored in a computer. Dynamic autoregulatory responses were analyzed off-line to determine dRoR (6–8) by using the software program supplied with the TCD (TCD7). This software program generated a series of 10 hypothetical dRoR curves based on the actual changes in MAP. Each dRoR curve generated was compared with the actual Vmca response curve by calculating SEM between the two curves by linear regression analysis. The best fitting curve (i.e., lowest SEM) was used.

Hypotension was induced and maintained at a MAP of 60 to 65 mm Hg with a continuous infusion of nicardipine. During baseline and nicardipine-induced hypotension, autoregulation testing was not performed until MAP and the infusion rate of the drugs had been stabilized for at least 5 min. After PaCO2 was measured, the autoregulation test was repeated under both baseline and hypotensive conditions. Under each condition, two values for dRoR and all physiologic variables were measured. The values were averaged for subsequent analysis. The sequence of experimental conditions—baseline and hypotension—was random for each patient. The interval between the two conditions was at least 15 min.

All values were expressed as mean ± SD. All values were compared by using one-way analysis of variance for repeated measures. When significance was found, Fisher’s protected least significant difference test was used as a post hoc comparison procedure. A P value <0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Of the 20 patients recruited, 7 were excluded because of inadequate magnitude or duration of MAP decrease, or because their lowest MAP decreased below 50 mm Hg (out of the range of normal cerebral blood flow autoregulation) after the cuff deflation. Thus, 13 patients (10 men and 3 women, mean age 57 ± 11 yr, mean weight 58 ± 9 kg) were included. Mean infusion rates of propofol and fentanyl for maintenance of anesthesia were 175 ± 25 and 35 ± 17 µg · kg-1 · min-1, respectively. The mean infusion rate of nicardipine was 5.0 ± 1.5 µg · kg-1 · min-1. Arterial blood saturation was maintained at >98%, and PETCO2 was maintained at normocapnia throughout the study.

The changes in physiologic variables, dRoR, and SEM during the autoregulation test are summarized in Table 1. At baseline, mean MAP was maintained at 82 ± 10 mm Hg, which decreased after cuff deflation by 21 ± 6 mm Hg. During nicardipine-induced hypotension, mean MAP was maintained at 63 ± 3 mm Hg, which decreased after cuff deflation by 12 ± 2 mm Hg to an average of 52 mm Hg. However, this was still within the range of normal cerebral pressure autoregulation. Decreases in MAP after cuff deflation during hypotension were significantly smaller than at baseline (P < 0.01). Vmca and heart rate during hypotension significantly increased compared with baseline (P < 0.05). Decreases in Vmca after cuff deflation during hypotension were significantly smaller than at baseline (P < 0.05). PaCO2 was maintained at normocapnia and comparable between the two states. SEM, which was calculated by using liner regression analysis and considered to indicate a degree of fit between actual Vmca response and computer-generated curve, was comparable between the two states. The dRoR of each individual under the two conditions is depicted in Figure 1. The dRoR during hypotension decreased in nine patients, was unchanged in two patients, and increased in two patients. The mean value of dRoR for baseline and hypotension was 13.1% ± 3.6% and 8.3% ± 2.6%/s, respectively (Table 1 and Figure 1). Power analysis demonstrated that at an {alpha} level of 0.05 and a ß level of 0.8, the number of 13 patients rejects the null hypothesis with a power of 0.91. Based on this, we concluded that nicardipine significantly attenuated the dynamic autoregulation.


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  		Table 1. Changes in Physiologic Variables, dRoR, and SEM During Autoregulation Test
 


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  		Figure 1. Illustration of the change in the dynamic rate of autoregulation (dRoR) in each individual under baseline and hypotensive conditions. Triangles indicate means; error bars denote standard deviations. {dagger}{dagger} indicates significantly different from baseline (P < 0.01).

 
Representative recordings of the autoregulation test from two patients are shown in Figure 2.



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  		Figure 2. Representative recordings of autoregulation test from 56-yr-old male patient (A) and 45-yr-old male patient (B). The mean arterial pressure (MAP) is shown in the upper panels, and actual response of time-averaged mean red blood cell flow velocity in the middle cerebral artery (Vmca) and computer-generated curve (the dark line) are shown in the lower panels. The y axis represents MAP (mm Hg) in the upper panels, and Vmca (cm/s) in the lower panels. The x axis represents time in seconds. DRoR = dynamic rate of autoregulation (%/s); SEM = standard error of mean between actual Vmca response and computer-generated curve.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Several animal and human experiments have demonstrated that the mechanism of cerebral autoregulation is a complex process with several components operating at different rates (4,6–9). There is a fast dynamic response to changes in pressure pulsations followed by a slow static response restoring cerebral blood flow after the initial dynamic response has settled (4,6–9). Several methods have been developed to evaluate the fast autoregulatory response. One of these, the thigh cuff method of Aaslid et al. (4), mechanically generates an acute drop of MAP by releasing large thigh cuffs. The validity of this method has been supported by experimental evidence (6–8). At normocapnia, the normal value for dRoR in awake humans is reported to be 20.0% ± 3.0% per second (4). However, hypocapnia hyperregulates cerebral vasomotor tone and improves dynamic autoregulation, and vice versa (4).

We demonstrated that nicardipine significantly attenuates fast dynamic autoregulation. The proper functioning of cerebral autoregulation primarily depends on intact cerebral vasomotor tone (4,10). Fully dilated or constricted cerebral blood vessels cannot respond to further alterations of MAP by changing the cerebral vascular resistance (10). Although a distinct anatomic site responsible for cerebral vascular resistance has not been fully identified, it is generally accepted that arterioles of less than 400 µm in diameter are the main component of vascular resistance and are responsible for cerebral autoregulation (11,12). Several studies have indicated that nicardipine predominately dilates cerebral arterioles controlling vascular resistance (13,14). Furthermore, the fact that nicardipine is used clinically for the treatment of cerebral vasospasm after subarachnoid hemorrhage (15) also supports the above finding. Thus, the disruption of dynamic autoregulation we observed may be mainly attributed to impaired cerebral vasomotor tone secondary to the arteriolar dilating effects of nicardipine. However, some studies have found that vasomotor tone is maintained during nicardipine-induced hypotension (16,17). Kawaguchi et al. (16) demonstrated that the cerebrovascular CO2 responsiveness, measured as changes in Vmca, remained intact during nicardipine-induced hypotension. This finding is completely contradicted by our data. One possible reason for this discrepancy may be the different levels of PaCO2 maintained in the two studies. In their study, the cerebrovascular CO2 reactivity was evaluated during hypocapnia (PaCO2 ranged from 33.8 to 28.6 mm Hg). In contrast, our study was performed during normocapnia. Certainly, human study has suggested that hypocapnic alkalosis counteracts the action of nicardipine on cerebral blood vessels (18).

There are some limitations and methodological considerations for the use of TCD for quantitative measurements of cerebral blood flow. An assumption of constant diameter of the insonated vessel is required to interpret relative changes in blood flow velocity as relative changes in cerebral blood flow (19). Some vasodilators may change the diameter of the M1 segment. Indeed, Dahl et al. (20) reported that sublingual administration of nitroglycerin dilates the M1 segment by approximately 15%, as shown by a reduction in Vmca without a concurrent change in regional cerebral blood flow measured by single photon emission computed tomography. The overall effects of nicardipine on the diameter of the M1 segment have not been studied adequately and therefore a simple comparison of Vmca from baseline may lead to a misleading interpretation. However, because each autoregulation test was not performed until MAP and the infusion rate of the drugs had been stabilized for at least five minutes, it is likely that the diameter remained constant throughout the test. However, CO2-rich venous blood returning to the systemic circulation from the legs after cuff deflation may influence vasomotor tone. Data collection for the dRoR had been completed within the first 10 seconds after deflation, and therefore was still before CO2 was transported from the legs to the brain (approximately 15 seconds) (4). In addition, PETCO2 remained stable during the test, suggesting that effects of CO2-rich leg blood on cerebral vasomotor tone were minimal.

It is well known that some anesthetics influence cerebral autoregulation by changing the cerebral vasomotor tone. Propofol, used as a basal anesthesia in this study, has been reported to improve dynamic or static cerebral autoregulation. A preliminary study by Matta et al. (21) indicated that a constant infusion of propofol at a rate of 200 µg · kg-1 · min-1 significantly improved static cerebral autoregulation in patients with severe head injury. Ederberg et al. (22) also reported that propofol at a serum concentration of 9 µg/mL improved slightly impaired static cerebral autoregulation during hypothermic cardiopulmonary bypass. Additionally, Harrison et al. (23) examined the effects of propofol at a serum concentration of 6.7 µg/mL on transient hyperemic response and found that propofol significantly improved dynamic autoregulation. The mechanisms by which propofol improves cerebral autoregulation are generally attributed to either its direct vasoconstrictive properties (24) or its indirect vasoconstrictive action secondary to depressive effects on cerebral metabolism with normal cerebral flow metabolism coupling (25). Therefore, it is possible that in this study propofol counteracted the effects of nicardipine on cerebral vasculature. In other words, it is likely that the cerebral autoregulatory response might be more prominently impaired or abolished when using other anesthetics.

In conclusion, we observed that nicardipine attenuated cerebral dynamic autoregulation at the lowest range of normal cerebral pressure autoregulation in normal subjects under propofol and fentanyl anesthesia. This finding may provide useful information when using nicardipine in clinical settings. However, further studies are needed to clarify the effects of the drug at a higher MAP or in patients with impaired cerebral autoregulation.


   Acknowledgments
 
We thank the operating room nursing staff at the Niigata City General Hospital for their help in making this study possible. We thank Jennifer Macke for assistance in preparing the text.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 26, 2000.




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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