JOURNAL OF NEUROTRAUMA Volume 20, Number 1, 2003 © Mary Ann Liebert, Inc.
Noninvasive Cerebrovascular Autoregulation Assessment in Traumatic Brain Injury: Validation and Utility ERHARD W. LANG,1 JIM LAGOPOULOS,2 JANE GRIFFITH,1 KWOK YIP,1 YUGAN MUDALIAR,3 H. MAXIMILIAN MEHDORN,4 and NICHOLAS W.C. DORSCH1
ABSTRACT A moving correlation index (Mx-CPP) of cerebral perfusion pressure (CPP) and mean middle cerebral artery blood flow velocity (CBFV) allows continuous monitoring of dynamic cerebral autoregulation (CA) in patients with severe traumatic brain injury (TBI). In this study we validated MxCPP for TBI, examined its prognostic relevance, and assessed its relationship with arterial blood pressure (ABP), CPP, intracranial pressure (ICP), and CBFV. We tested whether using ABP instead of CPP for Mx calculation (Mx-ABP) produces similar results. Mx was calculated for each hemisphere in 37 TBI patients during the first 5 days of treatment. All patients received sedation and analgesia. CPP and bilateral CBFV were recorded, and GOS was estimated at discharge. Both Mx indices were calculated from 10,000 data points sampled at 57.4Hz. Mx-CPP . 0.3 indicates impaired CA; in these patients CPP had a significant positive correlation with CBFV, confirming failure of CA, while in those with Mx , 0.3, CPP was not correlated with CBFV, indicating intact CA. These findings were confirmed for Mx-ABP. We found a significant correlation between impaired CA, indicated by Mx-CPP and Mx-ABP, and poor outcome for TBI patients. ABP, CPP, ICP, and CBFV were not correlated with CA but it must be noted that our average CPP was considerably higher than in other studies. This study confirms the validity of this index to demonstrate CA preservation or failure in TBI. This index is also valid if ABP is used instead of CPP, which eliminates the need for invasive ICP measurements for CA assessment. An unfavorable outcome is associated with early CA failure. Further studies using the Mx-ABP will reveal whether CA improves along with patients’ clinical improvement. Key words: cerebral perfusion pressure; dynamic cerebral pressure autoregulation; intracranial pressure; severe traumatic brain injury; transcranial Doppler ultrasound
(ABP) or cerebral perfusion pressure (CPP). After traumatic brain injury (TBI) or subarachnoid hemorrhage, CA constitutes a major self defensive mechanism against secondary ischemic insults. CA represents CBF regulation based on slow pressure changes called “static au-
INTRODUCTION
C
(CA) is the brain’s intrinsic ability to maintain a stable environment in the face of changing arterial blood pressure EREBRAL PRESSURE AUTOREGULATION
Departments of 1Neurosurgery, 2Neurology, and 3Intensive Care, University of Sydney, Westmead Hospital, Sydney, Australia. 4 Department of Neurosurgery, Christian-Albrechts-Universität, Kiel, Germany.
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LANG ET AL. toregulation” (Strebel et al., 1995), and fast pressure changes called “dynamic autoregulation” (Czosnyka et al., 1996), both of which are mutually correlated in traumatic brain injury (TBI; Lang et al., 2002). Czosnyka and co-workers have introduced an index, the Mx, which allows grading of dynamic CA. The Mx is based on continuous analysis of slow, spontaneous fluctuations of cerebral perfusion pressure (CPP) and cerebral blood flow velocity (CBFV) measured by transcranial Doppler ultrasound (TCD; Czosnyka et al., 1996). Correlation has been reported between Mx and admission Glasgow Coma Scale (GCS), outcome, CPP, and intracranial pressure (ICP; Czosnyka et al., 2001). The advantage of this index over other CA assessment techniques is that it is calculated from spontaneous fluctuations and does not require external blood pressure manipulation, such as the carotid compression and release manoeuver (Giller, 1991), sudden head-tilt maneuvers (Heckmann et al., 1999), adjustment of ventilation patterns (Diehl et al., 1995), or leg-cuff deflation tests (Aaslid et al., 1989). In this study, we tested the validity of the Mx as an indicator of the stability of cerebral blood flow regulation. Because Mx calculation from CPP (Mx-CPP) requires invasive ICP measurements, which limits its utility for follow-up examinations after ICP monitor removal, we were interested to know whether calculating the Mx from mean arterial blood pressure (Mx-ABP) produces similar results. For both indices, the Mx-CPP and the Mx-ABP, we assessed their prognostic relevance, and their relationships with ABP, CPP, ICP, and CBFV.
tracranial mass lesions, mechanical ventilation, and control of intracranial pressure via a protocol previously described (Lang and Chesnut, 1994), consistent with the Guidelines for the Management of Severe Head Injury (Bullock et al., 1996). Blood pressure recordings were obtained with a radial artery fluid coupled system (pvb, Kirchseeon, Germany). Intracranial pressure (ICP) was measured with an intraparenchymal sensor (Spiegelberg Brain Pressure Monitor®, Hamburg, Germany; Camino V420® , San Diego, CA; or ICP Express® , Codman, Bracknell, U.K.), or with a ventriculostomy connected to a pressure transducer (pvb, Kirchseeon, Germany). Intraparenchymal ICP sensors were placed ipsilateral to the main site of injury, or in cases with diffuse injury or multiple contusions in the right frontal area; in case of contusions they were placed adjacent to but not in contused tissue, i.e. without pathological densities on CT. Bilateral middle cerebral artery blood flow velocities were recorded using transcranial Doppler ultrasound (Multi-Dop X2®, or Multi-Dop T® , DWL, Sipplingen, Germany), and the calculated mean flow velocity from both sides combined was used. All analog signals were recorded, averaged and stored digitally in the TCD unit. The need for informed consent was waived, because this was a non-invasive study using routinely monitored parameters without any external stimulation.
Methods The Mx indices were calculated as moving correlation coefficients between CPP and CBFV (Mx-CPP) and between ABP and CBFV (Mx-ABP) from 10,000 simultaneously recorded data points sampled at 57.4 Hz for each hemisphere in the 37 patients during the first 5 days of treatment. The Mx represents a mathematical approach to quantify the relationship of spontaneous fluctuations between CPP and CBFV and can be used as an index to express the stability of cerebral blood flow during CPP changes. Based on previous studies, negative values or values less than 0.3 indicate intact CA, whereby a increase in CPP should have no or little effect on CBFV, while positive values of .0.3 indicate failure of CA (Czosnyka et al., 1996; Lang et al., 2002). To test the validity of the MxCPP and Mx-ABP we examined the correlation between ABP or CPP and CBFV in patients with Mx , 0.3 and in patients with Mx . 0.3. We examined the prognostic relevance of impaired CA by comparing the Mx-CPP and Mx-ABP to the GOS at discharge. We assessed its relationship with ABP, CPP, ICP, and CBFV at the time of recording.
MATERIALS AND METHODS Patients There were seven female and 30 male patients with severe TBI, defined as a GCS of 8 or less after initial resuscitation or a deterioration to this level within the first 12 h of treatment. Their average age was 41 6 16 years. The Glasgow Outcome Score (GOS) was estimated at discharge (Jennett and Bond, 1975). The average admission GCS was 8.4 6 4.1. Further details are shown in Table 1. All patients received sedation and analgesia. All physiological parameters were closely observed; ventilator settings, pCO2 , and the levels of sedation and analgesia were maintained constant during the study. No additional ICP management agents (e.g., mannitol or barbiturates) were administered between 45 min prior to the study and its completion. Management included aggressive surgical and medical therapy with immediate evacuation of in-
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AUTOREGULATION IN SEVERE HEAD INJURY TABLE 1. DEMOGRAPHIC DETAILS Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
OF THE
PATIENTS
GCS
Age (years)
Gender
GOS
Days in hospital
Recording day
Injury
4 12 11 6 14 10 14 14 11 11 10 7 4 10 7 4 14 13 6 12 6 9 9 3 3 12 3 13 13 3 5 6 15 5 5 3 3
46 61 28 71 63 22 46 44 53 18 54 44 17 28 78 20 36 59 39 47 63 42 35 49 43 58 47 21 40 26 23 43 30 49 22 24 44
M M M M M M M M M F M M M M F M M M F M M M M M M M M M M F F M F F M M M
4 5 5 1 5 5 4 5 3 5 3 5 2 4 1 2 5 4 1 3 1 3 3 3 2 5 1 5 4 5 4 5 5 3 2 3 1
28 42 32 42 32 17 40 36 27 37 46 20 25 21 16 51 29 16 14 16 7 26 20 17 46 23 4 8 47 20 29 31 13 42 35 33 5
4 4 5 0 1 1 2 5 4 2 4 5 1 3 1 4 3 2 2 1 1 3 1 3 2 2 1 1 3 3 1 2 0 3 3 1 1
EDH, contusion aSDH, contusion aSDH Contusion aSDH EDH Contusion Contusion Contusion, aSDH, iSDH Contusion, aSDH Contusion aSDH Brainstem contusion aSDH aSDH Contusion, aSDH, EDH EDH aSDH aSDH Contusion aSDH aSDH Contusion Contusion Contusion, aSDH, EDH Contusion, aSDH Contusion, aSDH Contusion aSDH, EDH aSDH Diffuse injury Contusion, aSDH Diffuse injury Contusion, aSDH aSDH aSDH aSDH
EDH, epidural hematoma; aSDH, acute convexity subdural hematoma; iSDH, acute interhemispheric subdural hematoma; GCS, Glasgow Coma Scale score on admission; GOS, Glasgow Outcome Scale score at discharge; recording day, day postinjury.
RESULTS
CA failure (Mx-ABP . 0.3). Shifting these six patients from one group and maintaining the same threshold (0.3) for Mx-ABP and Mx-CPP did not affect our statistics and overall results.
The mean values 6 standard deviations, and ranges for ABP, CPP, ICP [mmHg], and CBFV [cm/sec] were 93 6 28, 76 6 22, 17 6 15, and 69 6 29, respectively. The Mx-CPP ranged from 20.76 to 0.93 with a median of 0.05. The Mx-ABP ranged from 20.38 to 0.93 with a median of 0.35. Based on Mx-CPP 14 of 37 patients (38%) had CA failure (MxCPP . 0.3). Based on the same threshold for Mx-ABP 20 of 37 patients (54%) had
Validation Mx-CPP . 0.3 indicates CA failure; in these patients CPP had a significant positive correlation with CBFV (R 5 0.73, p , 0.01, Pearson’s correlation; R 5 0.63,
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LANG ET AL. p , 0.05, Spearman’s correlation). In patients with MxCPP , 0.3 (intact CA), CPP had no influence on CBFV, indicating intact CA (R 5 0.35, not significant, Pearson’s correlation; R 5 0.22, not significant, Spearman’s correlation). These findings were confirmed for the Mx-ABP. In patients with Mx-ABP . 0.3 (CA failure), ABP had a significant positive correlation with CBFV (R 5 0.72, p , 0.01, Pearson’s correlation; R 5 0.56, p , 0.01, Spearman’s correlation; Fig. 1a). In patients with MxABP , 0.3, ABP had no influence on CBFV, indicating intact CA (R 5 0.41, not significant, Pearson’s correlation; R 5 0.24, not significant, Spearman’s correlation; Fig. 1b).
Prognostic Relevance The Mx-ABP was significantly correlated with outcome (R 5 20.42, p , 0.05, Spearman’s correlation; Fig. 2a). This was confirmed for the Mx-CPP (R 5 20.56, p , 0.01, Spearman’s correlation; Fig. 2b).
FIG. 2. (a) Statistically significant correlation between the Mx-ABP and the five-point Glasgow Outcome Scale (GOS). (b) Statistically significant correlation between the Mx-CPP and GOS.
Correlation with CPP, ICP, and CBFV ABP, CPP, ICP, and CBFV were not correlated with Mx-CPP or Mx-ABP. There was no difference in these parameters between patients with lost and intact CA.
DISCUSSION This study shows that a moving correlation index between CPP or ABP and CBFV, measured by TCD, is able to distinguish between lost and intact dynamic CA, with a threshold of 0.3. A low Mx indicates that CBFV is independent of pressure, a state known as the “plateau phase” of cerebral blood flow (Larsen et al., 1994; McHenry et al., 1974). A high Mx indicates a linear relationship, where CBFV is purely dependent on perfusion pressure. The “Mx” monitoring protocol allows continuous CA monitoring, while other tests only offer intermittent “snapshot” monitoring. It was pointed out that autoregu-
FIG. 1. (a) Statistically significant correlation between arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) in patients with CA failure, indicated by MxABP . 0.3. (b) No significant correlation in patients with intact CA, indicated by MxABP , 0.3.
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AUTOREGULATION IN SEVERE HEAD INJURY latory disturbance precedes autoregulatory failure (Lewis et al., 2001). Continuous Mx monitoring in TBI patients thus has the potential to identify disturbances of CA before failure, that is, in time to allow therapeutic intervention.
0.41, p , 0.0002), and that CA was severely disturbed during the first 2 days in patients who died (Czosnyka et al., 1996). Further evidence to support the prognostic value of CA failure is provided in a study of 31 comatose head-injured patients in whom CA was assessed by measuring CPP and cortical CBF, measured with LDF (Lam et al., 1997). In their study nine of 11 patients with persistent loss of autoregulation died; transient loss of dynamic CA “did not always indicate poor outcome, provided the impaired autoregulation responded to treatment.” Steiger et al. (1994) reported that disturbed vasoreactivities, particularly during the first days, were common and did not necessarily predict an unfavorable outcome in TBI patients. Because we only measured during the first 5 days of treatment we cannot comment on how persistent or transient CA loss has affected outcome in our patients. It is noteworthy, however, that similar findings were obtained in a study of patients with aneurysmal subarachnoid hemorrhage, wherein early and persistent loss of dynamic CA was strongly correlated with an unfavorable outcome while transient and late loss of dynamic CA was not (Lang et al., 2001). We also wish to stress that middle cerebral artery flow velocity is not a very accurate estimate of global CBF and does not reflect the heterogeneity of cerebral hemodynamics after severe brain injury. These factors probably contribute to variations of Mx-ABP and Mx-CPP in patients with favorable outcomes.
Invasive and Noninvasive Monitoring The principle of dynamic CA testing and grading from moving correlations between flow and pressure is also applied when cortical cerebral blood flow is measured with invasive laser Doppler flowmetry (LDF) in both animal and human studies. It is noteworthy that CPP and ABP are used as pressure parameters (Engelborghs et al., 2000; Lam et al., 1997; Prat et al., 1997). In previous publications Czosnyka and co-workers have used the MxCPP which requires invasive ICP measurements for CPP calculations, although cerebral blood flow is assessed non-invasively with TCD (Czosnyka et al., 1996, Czosnyka et al., 2001). Invasive LDF and CPP measurements are largely restricted to the intensive care situation, limiting the ability to study dynamic CA after removal of ICP and LDF probes. Little if any is known about dynamic CA during recovery and rehabilitation. Further studies using a “non-invasive index” such as the Mx-ABP are needed to study this interesting topic. In this study we have shown that calculating Mx from ABP, which can be obtained non-invasively at a high resolution with devices such as the Finapress or Colin monitor (Ling et al., 1995; Lipsitz et al., 2000), and non-invasive TCD data (CBFV) produces similar results to those obtained by using CPP, validated against its physiological model. Czosnyka et al. have stressed the importance of using CPP rather than ABP for CA assessment, because the relationship between ABP and CPP depends on the ICP response to blood pressure fluctuations, which is itself related to the autoregulatory capacity (Lang and Chesnut, 2000). Our present findings suggest that this problem may not be significant, possibly because blood pressure fluctuations are usually small and ICP rather stable over the time periods studied. It would certainly be an important issue for indices which require large blood pressure decreases to stimulate the autoregulatory response and therefore risk causing a marked ICP rise, for example, the thigh cuff release test (Aaslid et al., 1989; Junger et al., 1997; Schnittger et al., 1997).
Correlation with ABP, CPP, ICP, and CBFV At first sight of our results we were surprised not to find a correlation of ABP, CPP, ICP, and CBFV with dynamic CA in TBI. The fact that CA is, apart from higher central nervous system regulation, controlled by intrinsic vascular mechanisms was first shown by Symon et al. (1971). The fact that low CPP is at least partly responsible for CA impairment was shown in a study by Wallis et al., who demonstrated that isolated human cerebral resistance arteries spontaneously contract when exposed to raised intravascular pressure and concluded that a pressure-induced myogenic response may contribute to CA of blood flow (Wallis et al., 1996). The Cambridge group reported that if CPP fell below 55 mm Hg, CA became exhausted (Czosnyka et al., 1994); later they reported that the Mx-CPP correlated with CPP (R 5 0.34, p , 0.002) and with ICP (R 5 0.46, p , 0.0001) (Czosnyka et al., 1996). In a more recent study they reported that “CA was disturbed in the presence of intracranial hypertension (ICP $ 25 mm Hg) and when mean ABP was too low (ABP # 75 mm Hg) or too high (ABP $ 125 mm Hg)” (Czosnyka et al., 2001). Al-
Prognostic Value Our data confirm that dynamic CA disturbances during the first 5 days after TBI are associated with an unfavorable outcome. This observation is supported by previous work from the Cambridge group, who reported that the Mx correlated with outcome after head injury (r 5 73
LANG ET AL. though their average Mx-CPP is similar to ours, indicating comparable recording conditions, our average CPP of 76 mm Hg was about 15 mm Hg higher than their average of 60 mm Hg (Czosnyka et al., 1996); only two of 37 patients in our series had a CPP below 55 mm Hg. This difference, which is probably due to a CPP-oriented therapy in our patients, may be the reason for this discrepancy. It is also possible that their low CPP may be due to higher ICPs at comparable ABPs; further comparison is not possible because ICP values were not provided in their paper (Czosnyka et al., 1996). Only five of 37 patients in our series had a mean CBFV above 100 cm/sec, which is considered a low threshold for cerebral vasospasm, and in only two patients was it over 120 cm/sec (Ringelstein, 1989). Overall, it appears that cerebral vasospasm does not occur often in TBI, and we could not find a study addressing the issue of vasospasm and its effects on CA in TBI.
reveal whether CA improves along with patients’ recovery.
ACKNOWLEDGMENTS We wish to thank sincerely the nursing staff of the intensive care unit at Westmead Hospital and the neurosurgical intensive care unit in Kiel for their support and cooperation in this investigation. This study was in part supported by the Westmead Charitable Trust No. HREC2001/3/4.8(1185), Westmead, NSW, Australia, and in part by grant no. La 916 2/1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany.
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Limitations and Outlook There are three issues which may confound our data and its interpretation. (1) Our recordings were obtained within the first five days after injury and it would be interesting to learn more about temporal profiles of CA. The only study, to our knowledge, in which this issue has ever formally addressed was in Czosnyka’s paper, in which it is stated that “autoregulation was disturbed for the first 2 days and after day 6, but only in patients with fatal outcomes” (Czosnyka et al., 1996). Our study does not offer the opportunity to address this question. (2) The issue of hemispheric CA asymmetry deserves further investigation. (3) The effects of age on cerebrovascular autoregulation in adults has only recently been a matter of investigation and deserves further investigation after traumatic brain injury although it has been reported that dynamic CA is unaffected by aging in healthy adults (Carey et al., 2000).
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CONCLUSION This study shows that CA can be continuously monitored, graded and reliably assessed using the moving correlation analysis of slow CBFV waves and ABP called Mx-ABP, which does not require any external stimuli and can be obtained non-invasively, eliminating the need for invasive CPP measurements for CA assessment. This study confirms the validity of this index to demonstrate CA preservation or failure in TBI. An unfavorable outcome is associated with early CA failure. ABP, CPP, ICP, and CBFV were not correlated with CA but it must be noted that our average CPP was considerably higher than in other studies. Further studies using the Mx-ABP will
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Address reprint requests to: Erhard W. Lang, M.D. Department of Neurosurgery CD Wing, Level 5 University of Sydney Westmead Hospital Sydney, NSW 2145, Australia
LIPSITZ, L.A., MUKAI, S., HAMNER, J., et al. (2000). Dynamic regulation of middle cerebral artery blood
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