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University Department of Anaesthesia and Intensive Care, Queen’s Medical Centre and City Hospital NHS Trust, Nottingham, United Kingdom
Address correspondence and reprint requests to Dr. R. P. Mahajan, University Department of Anaesthesia and Intensive Care, Queen’s Medical Centre, Nottingham, UK, NG7 2UH. Address e-mail to Ravi.Mahajan{at}nottingham.ac.uk
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Abstract |
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Implications: When compared with the established test of static autoregulation, thetransient hyperemic response test provides a valid method for assessing gradedimpairment in cerebral autoregulation.
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Introduction |
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Traditionally, cerebral autoregulation is assessed by measuring cerebral blood flow (CBF) during changes in cerebral perfusion pressure (or mean arterial pressure [MAP], assuming normal intracranial pressure) (6). CBF is first measured at a steady-state baseline MAP and then again after manipulation of MAP to other steady-state levels (6–8). Because CBF measurements are made after achieving steady-state MAP, this test is suggested to assess "static autoregulation" (7,8). Since the introduction of transcranial Doppler (TCD) ultrasound, CBF can be estimated by measuring red blood cell flow velocity (FV) in the middle cerebral artery (MCA) to assess static autoregulation (8).
Other methods that use TCD for the assessment of cerebral autoregulation have been described (8). The transient hyperemic response (THR) test involves measurement of changes in MCA FV during and after the release of a brief compression of the ipsilateral common carotid artery (9). If cerebral autoregulation is intact, the decrease in perfusion pressure in the MCA at the onset of compression would trigger vasodilatation in the distal vascular bed; this would transiently increase the CBF (and therefore MCA FV) after the release of compression (10). The THR test is reproducible and reliable (11,12). It also offers the advantages of avoiding the manipulation of systemic blood pressure, being simple to perform and allowing repeated measurements.
Although the THR test has been used as a surrogate measure of cerebral autoregulation, no previous studies have compared this test with the static autoregulation test. Therefore, in the strictest sense, the THR test has not been validated against traditional concepts of autoregulation. This study aimed to compare the THR test with the static autoregulation test during graded impairment of cerebral autoregulation induced by incremental concentrations of desflurane.
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Methods |
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All subjects were studied in the supine position, each with his or her head on one pillow. The study was performed in the anesthetic room before surgery. The left MCA was insonated with a 2-MHz TCD ultrasound probe (Scimed QVL120; Scimed, Bristol, UK). The standard criteria were used to identify the MCA FV trace (11,13). The probe was fixed in position by using a custom-made headband to maintain a constant angle of insonation during the study. A continuous recording of MCA FV was stored on digital audiotape for subsequent analysis. IV access was secured, and monitoring was initiated with electrocardiogram, noninvasive blood pressure measurement, and pulse oximetry. MAP was measured at 2-min intervals, and end-tidal carbon dioxide partial pressure (PETCO2) was measured continuously with a Capnomac Ultima monitor (Datex-Ohmeda, Helsinki, Finland), which was also used for all other end-tidal gas analysis.
Cerebral autoregulation was assessed with the THR test and the static autoregulation test. At least two THR tests were performed by using a 10-s compression of the ipsilateral common carotid artery. A period of 2 min was allowed between the tests. The static autoregulation test was then performed. The MCA FV was measured over a period of 2 min at baseline MAP and again after the MAP was increased to a second steady-state level, at least 15% above baseline. A phenylephrine infusion (20 µg/mL in saline IV) was used to increase MAP. All measurements were taken at steady state, which was defined as <10% fluctuation in MAP, heart rate, and PETCO2, 5 min before and during the measurements.
Before the induction of anesthesia, patients were sedated with a target-controlled infusion of IV propofol to reach a calculated target blood concentration of 1 µg/mL, which was continued throughout the study. Baseline measurements of cerebral autoregulation were made while patients were sedated. Anesthesia was induced by increasing the calculated target blood concentration of IV propofol to 8 µg/mL. In addition, fentanyl 1 µg/kg IV and vecuronium 0.1 mg/kg IV were given. The trachea was intubated, and ventilation of the lungs was controlled to maintain PETCO2 at preinduction levels. The propofol infusion rate was reduced to background levels of 1 µg/mL immediately after intubation, and further measurements of cerebral autoregulation resumed only when calculated concentrations reached <2 µg/mL, usually within 10–15 min after the induction of anesthesia. Anesthesia was maintained with desflurane in 50% oxygen and nitrous oxide. Phenylephrine was used to maintain MAP at the preinduction baseline level. After at least 10 min of equilibration at end-tidal desflurane concentrations of 0.5 minimum alveolar anesthetic concentration (MAC) (3.6%) and then 1.5 MAC (10.8%), cerebral autoregulation was reassessed with both the THR tests and the static autoregulation test.
The methods of processing TCD data have been described previously (12). The THR tests were accepted only if they met strict criteria. These were sudden and maximal decrease in the MCA FV at the onset of compression, no flow transients (associated with inertia or volume compliance) after the release of compression (14), and no change in the power of the reflected Doppler signal during the test.
For analysis, three wave forms were chosen: F1, the wave form immediately preceding the compression; F2, that immediately after the compression; and F3, that immediately after the release of compression. The time-averaged mean of the outer envelope of the FV wave form was used in all calculations. Two indices of cerebral autoregulation were derived—the THR ratio (THRR) and the strength of autoregulation (SA), calculated as follows R09:
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and
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where P2 is the estimated pressure in the MCA at the onset of compression and is derived with the formula P2 = (MAP x F2)/F1 or the value of 60 mm Hg (the assumed lower limit of autoregulation), whichever is the greater (11,12,15).
Under normal physiologic conditions the mean (SD) values for THRR and SA are 1.35 (0.09) and 0.93 (0.06), respectively (16). A change of 1.5 SD, similar to that produced by a 7.5 mm Hg change in PETCO2 (12), was considered significant. The magnitude of decrease in MCA FV during compression, the compression ratio (CR), was calculated from the following formula:
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Static autoregulation was assessed with a previously described index called the static rate of regulation (sROR). This was calculated as the following:
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where 
CVR is the change in cerebrovascular resistance (CVR), as calculated by CVR = MAP/MCA FV, and MAP is the change in MAP (17). The average of 20 MCA FV wave forms recorded during each steady-state level of MAP was used for analysis. In theory, sROR can range from 0% to 100%; a value >60% indicates normal autoregulation, and a value <40% indicates significantly impaired autoregulation (8).
The mathematical averages of THRR, SA, and CR derived from the two THR tests, at each stage of study, were taken for statistical analysis. The changes in sROR, THRR, SA, MAP, and PETCO2 were analyzed with analysis of variance for repeated measures, and P < 0.05 was considered significant. Pearson’s correlation test was used to correlate SA and sROR and also THRR and sROR, and P < 0.05 was considered significant. The sensitivity of THRR or SA to detect impairment in cerebral autoregulation was calculated with this formula: sensitivity = true-positive tests/(true-positive tests + false-negative tests).
A change in THRR or SA in the same direction as sROR was considered a true-positive test, whereas no change or a change in the opposite direction was considered a false-negative test. The specificity of the THR test could not be calculated because the experiment was not designed to detect false-positive tests.
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Results |
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Baseline PETCO2 ranged from 28.5 to 40.5 mm Hg, but it changed by <3 mm Hg in each individual patient throughout the study. In every patient phenylephrine was used for manipulation of MAP, both to maintain preinduction baseline MAP during anesthesia and to increase MAP to the second steady-state level for the static autoregulation test. The total amount of phenylephrine used for each patient varied between 1.8 and 8 mg.
Four THR tests were rejected at the time of the study for not fulfilling the criteria described in Methods, and these THR tests were then repeated. Preinduction values of all the autoregulatory indices were within the normal limits (Tables 1 and 2). For the assessment of static autoregulation, the increase in MAP achieved was similar at three stages of the study (Table 1). The sROR showed a graded impairment in cerebral autoregulation with incremental concentrations of desflurane (P < 0.001) (Table 1, Fig. 1). Both autoregulatory indices of the THR tests, THRR and SA, also decreased in a graded manner with incremental concentrations of desflurane (P < 0.001) (Table 2, Figs. 1 and 2). The changes in sROR were reflected by the changes in THRR or SA (Figs. 1 and 2). Every decrease in sROR in each subject was detected by a decrease in THRR or SA; this resulted in 100% sensitivity with which the THR test was able to detect graded impairment of cerebral autoregulation. A correlation was found between sROR and THRR (r = 0.68; P < 0.001) and between sROR and SA (r = 0.73; P < 0.001) (Fig. 3).
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Discussion |
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This study assessed the validity of the indices of autoregulation derived from the THR test when compared with an established method of evaluating static autoregulation. Desflurane, an anesthetic known to impair cerebral autoregulation, was used in increments to induce graded impairment in cerebral autoregulation (17). We have shown that the indices from both the THR test and the static autoregulation test follow the same trends, with a significant stepwise decrease from preinduction values to the values at 0.5 MAC and then at 1.5 MAC desflurane.
There are theoretical concerns with comparing the THR test with the static autoregulation test. The principle behind the THR test is to physically produce a transient decrease in perfusion pressure in the MCA territory, whereas the static autoregulation test relies on pharmacologic manipulation of MAP and a global increase in cerebral perfusion pressure. Theoretically the two tests assess slightly different aspects of cerebral autoregulation, which in itself is a complex phenomenon (8). Static tests assess the gradient of the autoregulatory plateau, whereas the THR test assesses both the gradient and the width of the autoregulatory plateau (12,15). In theory, both THRR and SA may be altered significantly if the limits of autoregulation change, even if the gradient of the plateau remains unaltered. Direct comparison of both SA with sROR and THRR with sROR demonstrated significant linear correlation, indicating that results from the two tests were comparable despite these theoretical concerns.
The effects of desflurane have been assessed by Strebel et al. (17). They compared sROR with the dynamic rate of regulation from the thigh-cuff deflation method of assessment of cerebral autoregulation during the administration of desflurane with 70% nitrous oxide in oxygen with a 3 µg/kg fentanyl infusion. Values for sROR at 0.5 MAC of desflurane and at 1.5 MAC of desflurane were comparable to the values obtained in this study, although we used 50% nitrous oxide in oxygen and a propofol infusion at 1 µg/mL with the administration of desflurane. We continued the propofol infusion throughout the study because in the preliminary trials of the feasibility of this study, we found that the coadministration of small quantities of propofol attenuated the desflurane-induced swings in MAP.
No previous studies have compared the THR test with the test of static autoregulation. Smielewski et al. (11) compared the THR test, by using THRR as the index of autoregulation, with the thigh-cuff method to assess dynamic autoregulation. The thigh-cuff method essentially assesses the speed of autoregulation. Smielewski et al. (11) found a significant correlation between the dynamic rate of regulation and THRR (r = 0.86). However, they regard THRR to be a qualitative indicator of autoregulation, with a value <1.09 indicating poor autoregulation. This is because, in the THR test, the magnitude of decrease in MCA FV at the onset of compression or CR, which serves as the stimulus to autoregulation, is not taken into consideration when calculating the THRR. Cavill et al. (21) have shown that CR has a strong influence on the value of THRR. In theory, changes in MAP can also influence THRR (12,15). Therefore, changes in THRR can be taken to indicate quantitative changes in cerebral autoregulation only if CR and MAP remain unchanged.
Mathematically, SA is the THRR normalized for the estimated change in MCA blood pressure (to the point of the lower limit for autoregulation) at the onset of compression (12). Therefore, changes in MAP or CR should not affect the value of SA. A previous study has shown that SA has better reproducibility as compared with THRR (12). This may explain the slightly higher correlation between SA and sROR than that between THRR and sROR in this study. The theoretical range of SA has been suggested to lie between 0.7 and 1.0; SA = 1.0 is ideal, whereas a value <0.80 would suggest poor autoregulation (12,15). Similarly sROR can range between 0% and 100%, with a value <40% suggesting poor autoregulation (8). In this study, all the indices of autoregulation, THRR, SA, and sROR showed that cerebral autoregulation was normal at preinduction, poor at 1.5 MAC desflurane, and between normal and poor at 0.5 MAC desflurane. Any further quantitative comparison between the indices of two tests, in our opinion, would be inappropriate. This is because, at this stage, it is unclear whether the ranges of different indices of autoregulation from different tests are linearly related to the degree of impairment in autoregulation.
One of the limitations in our study is the use of noninvasive blood pressure monitoring with the potential for variation in MAP between the readings that were taken at 2-min intervals during the static autoregulation test. We defined steady state when the changes in successive MAP measurements, heart rate, and PETCO2 were <10% from the baseline. Because we strictly adhered to these criteria, it is unlikely that a significant change in MAP occurred while we recorded MCA FV during steady state.
The use of TCD to measure MCA FV as an estimate of CBF is valid only if there is no change in the diameter of the vessel being assessed. Matta and Lam1 suggest that desflurane does not appreciably alter the diameter of the MCA. Also, other investigators have shown that MCA diameter does not change when autoregulation tests are performed that involve stepwise changes in arterial pressure (14,22,23). We did not note any change in the power of the reflected TCD signal during the study period, indicating that changes in MCA diameter, if any, were insignificant.
The measurement of PETCO2 may not correspond to the arterial partial pressure of CO2 (PaCO2), which influences cerebral autoregulation (11–13). The patients in this study were all healthy, ASA grade I or II, in whom PETCO2 would have approximated PaCO2. However, it is possible that the gradient may have altered during the study. Because the individual variations in PETCO2 from the baseline during each test were not significant and each subject was his/her own control, we believe that the differences in the gradient between PETCO2 and PaCO2 would have affected each of the indices equally.
We allowed a period of 10 minutes to ensure adequate equilibration of desflurane at 0.5 MAC and then at 1.5 MAC. Because the blood-brain partition coefficient for desflurane is 1.3, it has an equilibration time constant of 2.6 (partition coefficient x 100/CBF, where CBF is 50 mL/100 g brain tissue per minute) (24,25). Thus, in all our patients, we waited for at least three times the length of the time constant, allowing >95% equilibration.
We did not randomize the sequence of receiving 0.5 MAC or 1.5 MAC desflurane because our primary object was not to test the effects of different concentrations of desflurane on cerebral autoregulation per se, but rather to assess whether changes in cerebral autoregulation as assessed by the static autoregulation test were reflected in changes assessed by the THR test. We also did not randomize the sequence of the two tests. The order of the tests (i.e., the THR test before the static autoregulation test) was selected to minimize the total time taken for the study, because restabilizing the MAP to the preinduction baseline level after manipulating it for the static autoregulation test can be time-consuming. Because both the tests were performed under exactly the same experimental conditions after allowing >95% equilibration with desflurane, it is unlikely that changing the order of tests would have had a significant effect on the results of this study.
In conclusion, we have shown that the THR test is a valid method of assessing graded impairment in cerebral autoregulation when compared with the assessment by the established test of static autoregulation in patients with no intracranial pathology.
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Acknowledgments |
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Footnotes |
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The transient hyperemic response (THR) test has been used to assess cerebral autoregulation in anesthesia and intensive care. To date it has not been compared with the static autoregulation test for assessing graded changes in cerebral autoregulation. We compared the two tests during propofol, desflurane, and nitrous oxide anesthesia. Seven subjects were studied. For the THR test, changes in the middle cerebral artery blood flow velocity were assessed during and after a 10-s compression of the ipsilateral common carotid artery. Two indices of autoregulation—THR ratio (THRR) and strength of autoregulation (SA)—were calculated. For the test of static autoregulation, changes in the middle cerebral artery flow velocity after a phenylephrine-induced increase in mean arterial pressure were assessed, and the static rate of regulation (sROR) was calculated. The tests were performed before induction and after equilibration at 0.5 minimum alveolar anesthetic concentration (MAC) and then at 1.5 MAC of desflurane. THRR, SA, and sROR decreased significantly (P < 0.001) at 0.5 MAC and then at 1.5 MAC desflurane. Changes in THRR and SA reflected the changes in sROR with a sensitivity of 100%.
1Matta BF, Lam AM. Isoflurane and desflurane do not dilate the middle cerebral artery appreciably. [abstract]. Br J Anaesth 1995;74:486P. 
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