Cerebral pressure autoregulation is defined as the process by which the brain maintains constant cerebral blood flow (CBF). Autoregulation is accomplished through changes in cerebral vascular tone and is generally observed to persist between mean arterial pressure (MAP) values of approximately 50 and 150 mm Hg in normal adults (1). Patients with impaired cerebral autoregulation are at an increased risk of cerebral hyper- or hypoperfusion, leading to cerebral hyperemia or ischemia. Vasodilators are extensively used to control MAP in clinical settings. However, the drugs may directly affect not only systemic blood vessels, but also cerebral blood vessels. We hypothesized that vasodilators influence cerebral autoregulation by changing cerebral vascular tone.
The aim of this study was to examine the influence of nicardipine-, nitroglycerin-, and prostaglandin E1-induced hypotension at a MAP of 60–70 mm Hg on cerebral pressure autoregulation in adult patients during propofol-fentanyl anesthesia by using transcranial Doppler ultrasonography (TCD).
After institutional Ethics Committee approval and written informed consent were obtained, 45 adult patients (ASA physical status I or II) scheduled for elective extremity or lower-abdominal surgery were recruited. Patients with psychiatric drug administration, systemic or cerebral vascular disease, hypertension (systolic blood pressure >150 mm Hg, diastolic blood pressure >90 mm Hg, or both), age <20 yr, obesity (body mass index >35), cerebral tumor, or diabetes mellitus were excluded. These patients were randomly allocated, via the sample without replacement method, to the Nicardipine, Nitroglycerin, or Prostaglandin E1 group (n = 15 each). The study was performed with the patients in a supine position and was completed before surgery.
All patients were injected with atropine 0.5 mg and hydroxyzine 50 mg IM 1 h before transfer to the operating room. Before the induction of anesthesia, a lumbar epidural catheter was placed for intraoperative and postoperative analgesia in 30 of 45 patients. However, no drug was administered through the catheter before completion of this study. Anesthesia was induced with an IV bolus injection of fentanyl (2.0–3.5 μg/kg), propofol (2.0–2.5 mg/kg), and vecuronium bromide (0.1 mg/kg) and maintained with a continuous infusion of propofol (6.0–7.0 mg · kg−1 · h−1) and fentanyl (2.0–3.5 μg · kg−1 · h−1). Muscle relaxation was maintained with intermittent bolus injections of vecuronium bromide (2 mg/h). The trachea was intubated, and the lungs were mechanically ventilated with a mixture of 60% air and 40% oxygen. A radial artery catheter was inserted for measurements of MAP and blood gas tension. Routine monitoring included electrocardiogram, bladder temperature, percutaneous arterial oxygen saturation, and end-tidal CO2 tension (Petco2). Petco2 was maintained at 39–41 mm Hg. Bladder temperature during the study was maintained at 36.0°C–37.5°C by use of warmed IV fluids and a thermal blanket.
The M1 segment of the right middle cerebral artery (MCA) was insonated with a 2-mHz TCD transducer (MultidopT, software version TCD-7; DWL Electronische Systeme GmbH, Sipplingen, Germany) at a depth of 45–55 mm through the right temporal window according to standard procedures (2). The transducer was positioned with a custom-designed frame to keep the insonation angle constant during the study. Time-averaged mean blood flow velocity in the MCA (Vmca) was continuously measured by fine tuning of the Doppler gain so that the spectral envelope was as noise free as possible. Vmca and MAP were simultaneously displayed on the TCD monitor and recorded into digital videotape for subsequent analyses.
Hypotension was induced and maintained at a MAP of 60–70 mm Hg with continuous IV infusion of nicardipine, nitroglycerin, or prostaglandin E1. Cerebral pressure autoregulation was tested by slow continuous infusion of phenylephrine to induce an increase in MAP of approximately 20–30 mm Hg over approximately 5 min; the test was performed twice in each condition on each patient, and the results were averaged. The sequence of each condition was random for each patient. The interval between the two conditions was at least 15 min, and the interval between the two tests in each condition was at least 10 min. Paco2 was measured immediately before starting each test. During hypotension, the autoregulation test was not started until at least 5 min of steady state had been achieved at a constant infusion rate of all drugs. Steady-state was defined as unchanged Petco2 (within ±2 mm Hg) and unchanged MAP (within ±3 mm Hg). From the simultaneously recorded data of Vmca and MAP, ignoring the contribution of intracranial pressure to cerebral perfusion pressure, cerebral vascular resistance (CVR) could be simply calculated with the equation CVR = MAP/Vmca (3). In addition, the index of autoregulation (IOR) was defined and calculated by using the equation IOR = ΔCVR/ΔMAP, where ΔCVR = change in CVR and ΔMAP = change in MAP (3–8). Theoretically, with perfect cerebral autoregulation, the extent of increases or decreases in MAP equals changes in CVR, indicating an IOR of 1.0. In contrast, with abolished cerebral autoregulation, CVR does not change in response to MAP, indicating an IOR of 0. Thus, IOR has a value ranging from 0 to 1 (3–8).
Data were analyzed with a statistical software package (SPSS 10.0 for Windows, Base and Advanced Models 10.0; SPSS, Inc., Chicago, IL). Categorical data were compared by use of χ2 tests. Within- and between-group comparisons were made by using one-way analysis of variance for repeated measures and one-way analysis of variance, respectively. When significance was found, Fisher’s protected least significant difference test was used as a post hoc comparison procedure. Probability values <0.05 were considered to be significant.
Power analysis was made with a statistical software package (Sample Power 1.0 for Windows; SPSS, Inc.).
Of the 45 patients recruited, one patient each in the Nicardipine and the Nitroglycerin groups was excluded because of impaired cerebral autoregulation during baseline (the IOR was <0.6) (9). Thus, data were obtained from the remaining 43 patients (14 patients in the Nicardipine group, 14 in the Nitroglycerin group, and 15 in The Prostaglandin E1 group). The results are expressed as mean ± sd. During the study, percutaneous arterial oxygen saturation was maintained >99%, and Petco2 was maintained at 39–41 mm Hg.
The demographic and anesthetic data are given in Table 1. Except for sex distribution, there were no significant differences among the groups with respect to age, body weight and height, hemoglobin concentration, or anesthetic doses.
MAP during baseline and hypotension was similar among the three groups. The mean infusion rates of nicardipine, nitroglycerin, and prostaglandin E1 necessary for maintaining hypotension were 4.36 ± 1.76, 2.77 ± 0.99, and 0.11 ± 0.06 μg · kg−1 · min−1, respectively. The mean decreased MAP change from baseline was not different among the three groups (23.6% ± 8.6% for the Nicardipine group, 20.3% ± 8.6% for the Nitroglycerin group, and 21.2% ± 6.9% for the Prostaglandin E1 group).
Changes in physiologic variables during the autoregulation test are given in Table 2. Paco2 was maintained at 39–40 mm Hg during the study. Infusion of phenylephrine increased MAP by >20 mm Hg, and the increase in MAP was similar among the groups between baseline and hypotension. Phenylephrine caused a significant decrease in heart rate in all groups (P < 0.05). However, the decrease in heart rate was similar among the groups. During baseline, Vmca was relatively stable despite the increase in MAP in each group. During nitroglycerin- and prostaglandin E1-induced hypotension, the increase in MAP showed no significant effect on Vmca. In contrast, during nicardipine-induced hypotension, the increase in MAP increased Vmca significantly (P < 0.01). Figure 1 shows values of mean IOR during baseline and hypotension in each group. IOR during baseline was similar among the groups. During nitroglycerin- and prostaglandin E1-induced hypotension, IOR was not significantly different from baseline. In contrast, during nicardipine-induced hypotension, IOR was attenuated compared with baseline (P < 0.01).
We assessed the influence of drug-induced hypotension on CBF autoregulation by increasing MAP with phenylephrine in adult patients during propofol-fentanyl anesthesia. This study did not address changes in the width of the autoregulatory plateau because the changes induced in MAP were relatively moderate (approximately 20 mm Hg). According to Matta et al. (6), Matta and Stow (7), and Gupta et al. (8), a 15% change in IOR is clinically insignificant because the standard deviation of normal values of dynamic cerebral autoregulation is as much as 15%(9). Power analysis demonstrated that 14 patients in each group were sufficient to have a >90% chance of detecting a difference in means of 0.15 in IOR at the 5% level of significance. On this basis, we concluded that nicardipine, but not nitroglycerin or prostaglandin E1, attenuates cerebral pressure autoregulation.
The proper functioning of cerebral autoregulation depends primarily on cerebral vascular tone (1). Fully constricted or dilated cerebral blood vessels cannot respond to further alterations of MAP by changing cerebral vascular tone (1,10), which results in impaired or abolished cerebral autoregulation. Thus, the results of this study indicate that nitroglycerin and prostaglandin E1 affect the cerebral vascular tone less than does nicardipine. Indeed, several animal studies have suggested that nitroglycerin and prostaglandin E1 did not significantly influence CBF. Hamaguchi et al. (11) showed that nitroglycerin did not significantly change CBF and cerebral oxygen consumption in enflurane-anesthetized canines. Similarly, Koyama et al. (12) reported that prostaglandin E1 at a dose-decreasing MAP did not significantly affect regional CBF in young rabbits. Furthermore, several human studies showed the presence of cerebral vascular carbon dioxide reactivity during nitroglycerin- (13,14) or prostaglandin E1-induced hypotension (13,14), indicating preserved cerebral vascular tone.
It is generally accepted that arterioles <400 μm in diameter are the main component of vascular resistance and are responsible for cerebral autoregulation (15,16). It was reported that nicardipine predominately dilated such cerebral arterioles controlling cerebral vascular tone (12,17). Abe et al. (18) reported that nicardipine increased local CBF during cerebral aneurysm surgery for subarachnoid hemorrhage. Additionally, we recently studied a fast cerebral autoregulatory response after a stepwise change in MAP introduced by releasing bilateral thigh cuffs and reported that nicardipine attenuates this response in propofol- and fentanyl-anesthetized patients (19). Thus, nicardipine-induced impairment of cerebral autoregulation is probably attributed to its potent vasodilating effect on the cerebral arteriole.
There are some limitations and methodological considerations for the use of TCD for quantitative mea-surements of CBF. An assumption of constant diameter of the insonated vessel is primarily required to interpret relative changes in blood flow velocity as relative changes in CBF. However, vasodilators may dilate the diameter of the MCA. Dahl et al. (20) showed that sublingual administration of 1 mg of nitroglycerin dilated the diameter of the MCA by 15%, as evidenced by a reduction in Vmca without a concurrent change in regional CBF in single-proton emission tomography. In addition, the effects of nicardipine and prostaglandin E1 on the diameter of the MCA have not been adequately studied. Therefore, cerebral autoregulation cannot be simply evaluated by comparing Vmca before and after the infusion of vasodilators. The methods used in this study examined cerebral autoregulation by increasing MAP with phenylephrine. In addition, it is conceivable that the diameter remained constant during autoregulation testing because each test was started after MAP, Petco2, and the infusion rate of all drugs had stabilized for at least five minutes, validating the comparison of IOR between baseline and drug-induced hypotension.
On the other hand, phenylephrine might change the diameter of the MCA. However, phenylephrine is generally considered to have no important influence on human intracerebral hemodynamics (21) and has been used to study cerebral autoregulation in numerous human studies (3,5–9,22).
Anesthetics possibly change cerebral vascular tone and may influence cerebral autoregulation. Propofol, used as a background anesthetic in this study, induces a hyperregulatory condition of cerebral autoregulation and improves cerebral autoregulation (23). A preliminary study by Matta et al. 1 suggested that a constant infusion of propofol at a rate of 200 μg · kg−1 · min−1 significantly improved cerebral autoregulation in patients with severe head injury. Ederberg et al. (24) also reported that propofol at a serum concentration of 9 μg/mL improved slightly impaired cerebral autoregulation during hypothermic cardiopulmonary bypass. The mechanism by which propofol improves cerebral autoregulation is presumably caused by its vasoconstrictive properties on cerebral arterioles (21). It is therefore likely that propofol counteracts the vasodilating action of the drug on cerebral arterioles, resulting in these findings. However, propofol and these drugs are simultaneously used in routine anesthetic practice. Thus, our findings are clinically relevant.
In conclusion, in normal adult patients during propofol-fentanyl anesthesia, both nitroglycerin and prostaglandin E1 preserved cerebral pressure autoregulation. In contrast, nicardipine significantly impaired autoregulation, probably because of its potent dilating effects on cerebral arterioles. Therefore, caution should be taken when using nicardipine in the clinical setting. Extrapolation of these data to patients with intracranial pathology or patients who are anesthetized with other anesthetics requires further study.
1 Matta BF, Risdall J, Menon D, Czosnyka M. Propofol improves autoregulation after head injury: a preliminary report [abstract]. Anesthesiology 1997;87:A181.
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© 2002 International Anesthesia Research Society
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