Anesth Analg 2003;97:572-576
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
The Effects of Large-Dose Propofol on Cerebrovascular Pressure Autoregulation in Head-Injured Patients
Luzius A. Steiner, MD DEAA*,
,
Andrew J. Johnston, FRCA,
Doris A. Chatfield, BA
,
Marek Czosnyka, PhD DSc*,
Martin R. Coleman, PhD,
Jonathan P. Coles, FRCA,
Arun K. Gupta, FRCA,
John D. Pickard, MChir FRCS, FMedSci*, and
David K. Menon, MD PhD, FRCP, FRCA, FMedSci
*Academic Neurosurgery,
University Department of Anaesthesia, and
Wolfson Brain Imaging Centre, Addenbrooke’s Hospital, Cambridge, United Kingdom
Address correspondence and reprint requests to Luzius A. Steiner, MD, DEAA, Academic Neurosurgery, Box 167, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. Address e-mail to las30{at}cam.ac.uk
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Abstract
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In healthy individuals, cerebrovascular pressure autoregulation is preserved or even improved when propofol is infused. We examined the effect of an increase in propofol plasma concentration on pressure autoregulation in 10 head-injured patients. Using target-controlled infusions, the static rate of autoregulation was determined at a moderate (2.3 ± 0.4 µg/mL) and a large (4.3 ± 0.04 µg/mL) plasma target concentration of propofol. Using norepinephrine to control cerebral perfusion pressure, transcranial Doppler measurements from the middle cerebral artery were made at a cerebral perfusion pressure of 70 and 85 mm Hg at each propofol concentration. Middle cerebral artery flow velocities at the large propofol concentration were significantly lower than at the moderate concentration, without any concurrent increase in arterio-jugular difference in oxygen content, a finding compatible with maintained flow-metabolism coupling. Despite this, static rate of autoregulation decreased significantly from 54% ± 36% to 28% ± 35% (P = 0.029). Our data suggest that after head injury, the cerebrovascular effects of propofol are different from those observed in healthy individuals. We propose that large doses of propofol should be used cautiously in head-injured patients, because there is the potential to increase the injured brain’s vulnerability to secondary insults.
IMPLICATIONS: Propofol is used for sedation and control of intracranial pressure in head-injured patients. In contrast to previous data from healthy individuals, we show a deterioration of cerebrovascular pressure autoregulation with fast propofol infusion rates after head injury. Large propofol doses may increase the injured brain’s vulnerability to secondary insults.
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Introduction
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Propofol is frequently used for sedation and control of increased intracranial pressure (ICP) in head-injured patients (1). The literature suggests that in healthy individuals propofol improves cerebrovascular pressure autoregulation (2), i.e., the brain’s ability to keep cerebral blood flow (CBF) relatively constant despite changes in cerebral perfusion pressure (CPP). Propofol has also been shown to restore impaired pressure autoregulation in patients during cardiopulmonary bypass (3). Even large doses of this drug, leading to a burst-suppression pattern on the electroencephalogram (EEG), do not lead to a deterioration of pressure autoregulation (4). This is possibly explained by the cerebral vasoconstrictor effect of this drug, because vasoconstrictors are generally expected to increase vascular smooth muscle tone and therefore to improve pressure autoregulation (5).
After head injury, pressure autoregulation is an important prognostic factor with a strong association between dysautoregulation and impaired outcome (6–8). This may be because intact pressure autoregulation is a powerful mechanism that protects the injured brain against secondary physiological insults related to unstable perfusion pressure. Consequently, interventions that improve pressure autoregulation may provide benefit in this patient population. This study was designed to test the hypothesis that increasing the dose of propofol improves pressure autoregulation in head-injured patients initially sedated with a moderate dose of this drug.
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Methods
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The local research ethics committee approved this study and written informed consent was obtained from the next of kin of all patients. All patients with severe traumatic brain injury (initial Glasgow coma score [GCS] 
8) or moderate traumatic brain injury (initial GCS 12) with secondary deterioration to a GCS 8 necessitating intensive-care treatment, sedation with propofol and fentanyl, and artificial ventilation were eligible for inclusion. Exclusion criteria were prior sedation with benzodiazepines or barbiturates, a history of cardiovascular disease, and an insufficient temporal window for acquisition of transcranial Doppler (TCD) signals. Patients were treated according to a protocol aiming to keep CPP >70 mm Hg and ICP <20 mm Hg (9). Mean arterial blood pressure was monitored invasively from the radial artery (Edwards Lifesciences, Irvine, CA). ICP was monitored using intraparenchymal sensors (Codman MicroSensors ICP Transducer; Codman & Shurtleff, Raynham, MA). Mean blood flow velocity (FVm) from both middle cerebral arteries was measured using TCD with 2 2-MHz probes and a "Lam" head rack (10) (Multi Dop X4; DWL Elektronische Systeme, Sipplingen, Ger-many). The middle cerebral artery was identified using standard criteria and the position of the probes was not changed during the study. All patients had continuous EEG cortical function monitoring (bandpass 0.1–70 Hz) during the study.
Before the study, all patients were sedated with IV propofol (Diprivan® 2%, AstraZeneca UK Ltd., London, UK) using conventional infusion pumps as an aid to control intracranial hypertension as part of the routine management protocol on the unit. Starting at least 4 h before the study, the infusion pumps were exchanged and patients received propofol using a target-controlled infusion pump (Master TCI UK; Fresenius Vial S. A., Grenoble, France), incorporating DiprifusorTM software. All target concentrations during this time were stable and in the range of 2 µg/mL, corresponding to infusion rates of approximately 3–4 mg · kg-1 · h-1. This dose range is within the range specified in the treatment algorithm of our unit. This target concentration was then used as the baseline concentration for the first part of the study. For the second half of the protocol, a propofol plasma target concentration 2 µg/mL greater than the baseline target concentration was used, corresponding to infusion rates of approximately 6–8 mg · kg-1 · h-1. Any reductions in blood pressure that occurred when the propofol dose was increased were treated primarily with IV colloids but IV norepinephrine was used if this was not sufficient. The static rate of autoregulation (SROR) was determined at baseline and at the larger propofol target concentration from FVm and CPP data using a standard formula (11):
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For measurements of SROR, CPP was adjusted to approximately 70 and 85 mm Hg at each propofol concentration using norepinephrine. At least 20 min was allowed for the propofol concentration to reach the new target concentration before measurements for the second part of the protocol were begun. Using the DiprifusorTM software, this time span is sufficient to ensure that not only the blood but also the brain concentration has equilibrated with the new dose (12). Arterial blood gases were checked at regular intervals and PaCO2 was kept stable by adjusting the ventilator settings as necessary. If a jugular bulb catheter was in situ, then paired jugular bulb and arterial samples were taken immediately before increasing the propofol dose and at least 30 min after the new target concentration had been reached at the same CPP level as the first samples had been taken. These samples were used to calculate arterial-jugular oxygen difference (AVDO2). At each CPP level, CPP and TCD data were acquired and averaged over a 20-min period. TCD has limited spatial resolution, and after head injury, pressure autoregulation may be disturbed in areas of the brain not apparently affected by the injury (13), and computed tomography scans underestimate the extent of dysautoregulation after head injury (14). Furthermore, the propofol dose and CPP experienced by both hemispheres are identical in individual patients, and formal statistical advice suggested that it was unsafe to treat the closely correlated data from two hemispheres in an individual patient as independent data points. We therefore decided to adopt a conservative approach and averaged TCD data from both hemispheres. Patient temperature was kept constant throughout the study.
Data were recorded continuously as averaged 6-s values using the analog output of the monitors, analog-digital conversion, and waveform time integration (7), and stored on a computer for off-line data analysis. Statistical analysis was performed using SPSS for Windows 10.1 (SPSS Inc., Chicago, IL) and paired t-tests. All data are presented as mean ± SD unless otherwise stated.
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Results
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Ten patients were investigated (7 men, 3 women, aged 35 ± 12 yr). Median admission GCS was 7 (range, 3–9). The pattern of injury was classified as evacuated mass lesion in eight patients and as diffuse injury II in two patients (15). Five patients had large bilateral lesions on computed tomography scan. In 7 of the patients, a craniectomy had been performed for evacuation of a subdural hematoma (n = 6) or a large hemorrhagic contusion (n = 1). In 2 of the 5 patients who had predominantly unilateral pathology, ICP monitors were sited in the injured hemisphere. Studies were performed 2.7 ± 1.1 days after injury.
The propofol target concentration at baseline was 2.3 ± 0.4 µg/mL, and 4.3 ± 0.4 µg/mL at the higher level. PaCO2 was similar at both levels of propofol (35 ± 3 versus 35 ± 3 mm Hg, P = 0.2). The increase in the propofol target-concentration attenuated cortical electrical activity in all patients, and in all but one patient, an EEG burst-suppression pattern was observed at the larger target concentration of propofol. In nine patients, data for calculation of AVDO2 were available. AVDO2 decreased slightly in 7 of the patients; however, the difference did not reach statistical significance (2.62 ± 1.20 versus 2.48 ± 1.23 mL/dL; P = 0.1) suggesting that flow-metabolism coupling was not significantly affected by the increase in propofol target concentration. The CPP range over which SROR was tested was comparable at both propofol levels and increasing the propofol concentrations resulted in the expected significant decrease in FVm. The vaso-constriction-induced reduction in cerebral blood volume is reflected by reductions in ICP but these reductions did not reach statistical significance (Table 1). The fact that FVm increased more, with the increase in CPP, at the larger propofol target concentration than at the smaller propofol target concentration can be interpreted as an indicator of dysautoregulation. Calculation of SROR confirmed this, showing a deterioration of SROR in eight patients and an improvement of SROR in two patients (Fig. 1). Overall, SROR decreased from 54% ± 36% to 28% ± 35% (P = 0.029).
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Figure 1. Static rate of autoregulation at a moderate and a large dose of propofol. Individual data from 10 patients are presented. The hexagon and error bars represent mean ± SD.
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Discussion
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In the majority of this small group of patients with traumatic brain injury, we have documented a deterioration of cerebrovascular pressure autoregulation after an increase in propofol infusion rates. This finding was unexpected and contrasts with data from healthy individuals and patients without brain injury. In normal brains, an increase in vascular resistance, induced for example through hyperventilation or drugs, is expected to lead to an improvement in pressure autoregulation, because this improves the vessel’s capacity to dilate in response to a decrease in perfusion pressure (5). Although the larger dose of propofol increased vascular resistance as expected, this increase in resistance did not translate into an improvement of pressure autoregulation in this group of patients. There are no data that address the question of how much pressure autoregulation must deteriorate before there is an impact on outcome and we cannot comment on the relevance of the observed reduction of SROR in respect to outcome. Using AVDO2 as a marker of flow-metabolism coupling, our data suggest that, in contrast to pressure autoregulation, flow-metabolism coupling was unaffected by the increase in propofol target concentration in this group of patients.
Interestingly, in the data reported by Harrison et al. (2), 2 of 10 volunteers showed a deterioration of pressure autoregulation during the infusion of propofol as compared with baseline. The reason for this remains unclear. In head-injured patients, the effective range of pressure autoregulation is frequently shifted toward larger CPP values and the CPP range is smaller than in healthy individuals (16). In the setting of our study, a decrease in SROR can be interpreted in three different ways: 1) as a drug-induced increase in the slope of the autoregulatory plateau, 2) as a shift of the lower limit of pressure autoregulation toward a higher CPP, with the FVm measurement made at the lower CPP level now lying below the autoregulatory plateau, 3) or as a downward shift of the upper limit of pressure autoregulation, with the FVm measurement made at the higher CPP level now situated above the autoregulatory plateau. Our method, based on a single moderate increase in CPP for the calculation of SROR, does not allow us to identify which of these three possible mechanisms is causing the deterioration in pressure autoregulation.
Is there a fundamental difference in the cerebrovascular response to propofol in head-injured patients compared with normal volunteers that could explain our results? Our data do not allow exploration of the mechanisms responsible for the deterioration of SROR. However, there is animal work showing that vascular dysfunction after fluid percussion injury is associated with dysfunction of adenosine triphosphate-sensitive potassium channels (17). Propofol has been shown to inhibit adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells (18). One could therefore speculate that in the setting of an underlying disturbance of potassium channel function, propofol could lead to a deterioration of cerebrovascular pressure autoregulation.
Could our results be a consequence of our methods? First, despite being widely used, the SROR has never been formally validated against a true measurement of pressure autoregulation based on CBF measurements in head-injured patients. Moreover, in contrast to our data, some of the earlier studies examining the effects of propofol on pressure autoregulation have used dynamic rather than static measurements to quantify pressure autoregulation (2). However, TCD seems to be a reasonably reliable tool to quantify changes in CBF in head-injured patients (19) and dynamic and static measurements of pressure autoregulation have been shown to correlate significantly even when pressure autoregulation is impaired (20,21). To further investigate the issue of dynamic versus static autoregulation, we have calculated an index of dynamic autoregulation in nine of the study patients. This index (Mx) is based on analysis of the FVm response to slow spontaneous waves in CPP and is calculated continuously as the linear correlation coefficient between consecutive values for CPP and FVm. Values 0 represent intact pressure autoregulation whereas values >0 represent disturbed pressure autoregulation (7). Supporting the concept that dynamic and static autoregulation are closely related, we have found a significant deterioration of Mx at the larger propofol target concentration (Mx = 0.03 ± 0.19 at the smaller propofol target-concentration versus 0.18 ± 0.19 at the larger target concentration; P = 0.028).
The most obvious factor that could have influenced our results is the use of norepinephrine to control CPP. Norepinephrine does not directly affect CBF in patients without intracranial pathology (11). Yet, if there is disruption of the blood-brain barrier, norepinephrine will lead to an increase in cerebral metabolism and blood flow (22). Such an increase in CBF, which could partly be masked by the vasoconstrictor effect of propofol, could result in an erroneously small value for SROR. Despite our efforts to use colloids to compensate for the peripheral vasodilatation after the increase of the propofol target concentration, in some patients more norepinephrine was necessary to reach the same CPP than at the smaller propofol target concentration. However, the necessary increases in infusion rates were small (<0.01 µg · kg-1 · min-1). We cannot completely exclude an effect of norepinephrine on pressure autoregulation but the combination of an overall reduction in CBF as indicated by the decrease in TCD flow velocity, no significant change in AVDO2, and the changes observed on the EEG do not support the concept of a large norepinephrine-induced increase in cerebral metabolism. However, comparison of SROR in head-injured patients demands tight control of CPP to test pressure autoregulation on the same part of the autoregulatory curve. This is not possible without vasoactive drugs, and typically 
agonists such as norepinephrine are used for this purpose. Although it would have been possible to use angiotensin, the cerebrovascular effects of this drug are poorly documented and its use would not reflect clinical reality.
The larger target concentration of propofol that we used is within the range of doses that are clinically used. However, after the observation of cardiac failure associated with long-term propofol infusion, not only in children but also in adults, it has been suggested that propofol infusions exceeding 5 mg · kg-1 · h-1 should not be used for long-term sedation in head-injured patients (23). Nevertheless, in view of the continuing debate about the potential of moderate hyperventilation to cause cerebral ischemia (24,25), metabolic suppression using propofol could still be an attractive, albeit less potent (1) alternative, to control high ICP. However, our data suggest that this may increase the brain’s vulnerability to perfusion pressure-related secondary insults. Further studies are needed to investigate whether there is an individual optimal dose of propofol in regard to cerebrovascular pressure autoregulation after head injury and what the mechanisms behind the deterioration of pressure autoregulation are.
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Acknowledgments
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LAS is supported by a Myron B. Laver Grant (Department of Anaesthesia, University of Basel, Switzerland), a grant from the Margarete und Walter Lichtenstein-Stiftung (Basel, Switzerland), by the Swiss National Science Foundation, and is recipient of an Overseas Research Student Award (Committee of Vice-Chancellors and Principals of the Universities of the United Kingdom). AJJ is recipient of a grant from Codman. JPC is funded by a Wellcome Research Training Fellowship and by a Beverley and Raymond Sackler Studentship Award. This work was further supported by the MRC Acute Brain Injury Programme Grant G9439390 ID 56833.
We thank Dr. Raymond Salvador, Wolfson Brain Imaging Centre, University of Cambridge, for statistical advice.
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Footnotes
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MC is on leave from the Warsaw University of Technology, Poland.
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References
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Accepted for publication March 20, 2003.
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Abstract
Introduction
