Wessex Neurological Centre (RJN, JDP, SP, JLM, AHJL), Southampton General Hospital, Southampton, England; Institute of Electronics Fundamentals (MC), Warsaw University of Technology, Warsaw, and Department of Neurosurgery (WM), Academy of Medicine, Warsaw, Poland; and Academic Neurosurgical Unit (MC, JDP), Addenbrooke's Hospital, Cambridge, England Neurosurgery 31; 705-710, 1992 ABSTRACT: THE DYNAMIC RELATIONSHIPS among mean flow velocity, its pulsatile amplitude (FVa), cortical cerebral blood flow (CBF), and cerebral perfusion pressure (CPP) were studied in normal rabbits and rabbits with subarachnoid hemorrhage using 8-MHz pulsed transcranial Doppler ultrasound and hydrogen clearance under conditions of systemic hypotension and intracranial hypertension. A two-slope relationship was observed between FVa and CPP with a break point that correlated closely with the lower limit of CBF autoregulation in each animal. Below this CPP break point, FVa varied directly with CPP, and above the break point FVa varied inversely with CPP. In this experimental model, an inverse correlation between FVa and CPP indicates intact CBF autoregulation, whereas loss of that correlation implies exhaustion of autoregulatory reserve. Simultaneous recording and computation of FVa, CPP, and the correlation coefficient between FVa and CPP may be a means of monitoring CBF autoregulation in clinical practice. KEY WORDS: Blood flow velocity; Cerebral autoregulation; Cerebral blood flow; Cerebral perfusion pressure Anoninvasive method for continuously monitoring cortical cerebral blood flow (CBF) autoregulatory reserve would refine neurological intensive care aimed at the prevention of secondary ischemic damage from raised intracranial pressure or systemic hypotension. A pulse wave with a fundamental frequency equal to the heart rate is characteristic of transcranial Doppler (TCD) flow velocity recordings from the basal cerebral arteries (1). The amplitude of the pulse wave (FVa) reflects pulsatile changes in regional CBF and is affected by the amplitude of the systemic
MATERIALS AND METHODS Preparation The study was performed in nine New Zealand White rabbits (3.2-3.9 kg) of both sexes and was approved under the UK Animals (Scientific Procedures) Act of 1986. The animals were divided into three experimental groups: 1) normal animals with intracranial hypertension (n = 3); 2) normal animals with trimetaphan-induced hypotension (n = 3); and 3) hypertensive SAH animals with trimetaphan-induced hypotension (n = 3). Renovascular hypertension was established in Group 3 animals by encapsulation of one kidney in a cellophane membrane 3 weeks after performing a contralateral nephrectomy (13). Three months later, experimental SAH was induced by two intracisternal injections of autologous venous blood, and the animals were then studied on Day 6 after the first SAH. Experimental procedure General anesthesia was induced with intravenous alphaxalone/alphadalone, 3 mg/kg (Saffan, Glaxovet, UK) and maintained by controlled ventilation with 1 to 3% halothane in 1:1 nitrous oxide in oxygen via a tracheostomy. Muscle relaxation was obtained by continuous infusion of pancuronium, 0.5 mg/kg/hr. Both femoral arteries and femoral veins were cannulated. Arterial blood pressure (ABP) was continuously monitored (Hewlett-Packard 78342A transducer and monitor, Hewlett Packard, Boeblingen, Germany). Arterial blood gas analysis was performed frequently (Corning 168 pH/Blood gas analyzer), and the ventilation was adjusted to maintain the blood gases within the following limits: PaCO2, 36 to 43 mm Hg; PaO2, 115 to 140 mm Hg; pH, 7.25 to 7.35. Core temperature was maintained
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AUTHOR(S): Nelson, R. J., M.A., F.R.C.S.; Czosnyka, M., Ph.D.; Pickard, J. D., M.Chir., F.R.C.S.; Maksymowicz, W., M.D.; Perry, S., J. L. Martin, F.R.C.S.; Lovick, A. H. J., Ph.D.
arterial pressure wave (2), regional cerebrovascular resistance (CVR), the elastance of the capillary bed (9) , and the basal cerebral arteries (8). At low mean cerebral perfusion pressures (CPP), FVa is also influenced by the relationship between systolic and diastolic CPP and the critical closing pressure of the capillary bed (4,6). The myogenic autoregulation of CBF is partly mediated by changes in the transmural pressure of cerebral arterioles (13). As CPP falls, the resistance arterioles respond to the decrease in transmural pressure by a reduction in vasomotor tone (11,12) . The resulting fall in CVR maintains CBF. The concomitant increase in cerebral blood volume and change in vascular elastance alter the Doppler waveform and FVa (9). Because CVR is calculated as the mean CPP divided by CBF and CBF is proportional to the FVm, if the cross-sectional area of the insonated artery remains constant (10), a Doppler estimate of CVR (CVRe) is given by the ratio CPPm/FVm. We propose that continuous monitoring of the relationships among FVm, FVa, and CPP will provide valuable information regarding CBF autoregulation. We have tested the hypothesis in normal rabbits (autoregulating) and rabbits with subarachnoid hemorrhage (SAH) (nonautoregulating). Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Neurosurgery 1992-98 October 1992, Volume 31, Number 4 705 Experimental Aspects of Cerebrospinal Hemodynamics: The Relationship between Blood Flow Velocity Waveform and Cerebral Autoregulation Experimental Study
Statistical methods The break point of the FVa/CPP relationship of each animal was determined from the midpoint of the CPP range where there was a statistically significant (P < 0.05) change in the floating correlation coefficient RFVa/CPP (based on 15 sequential data points) from below -0.3 to above +0.3. The lower limit of CBF autoregulation, defined as the CPP below which there was a statistically significant (P < 0.05) reduction in CBF by analysis of variance with Duncan's multiple range test, was compared with the FVa/CPP break point using simple linear regression. RESULTS Plots of CBF, FVm, FVa, CVR, and CVRe against CPP or ABP for individual animals from Groups 1, 2, and 3 are shown in Figure 1, A, B, and C, respectively. In the animals with intact autoregulation (Fig. 1, A and B) a sharp break point in FVa was observed at 28 and 35 mm Hg, respectively, and this break point occurred just below the CPP or ABP at which FVm and CBF began to fall. CVR and CVRe decreased above the break point and increased below the FVa break point. In the Group 3 animals with severely disordered autoregulation (Fig. 1C), the FVa break point was shifted upward to an ABP of about 100 mm Hg. In these animals, FVm and CBF fell in direct proportion to the reduction in ABP. CVRe and CVR did not change until ABP had fallen below 100 mm Hg (the FVa break point), when they both rose. In normal animals, there was a close correlation between CBF and FVm and between CVR and CVRe during changes in CPP/ABP (r > 0.96). Figure 2 shows the linear correlation (r = 0.94; P < 0.01) between the autoregulatory break points estimated using the TCD method (break point of FVa) and the CBF autoregulatory thresholds determined from the
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Signal analysis The ICP, amplitude, and FV signals were individually amplified and processed before being fed via an analog-to-digital converter (DT2814) to an IBM-compatible computer with a purpose-designed multi-signal physiological monitoring and analysis program (5). Based on a special short-term spectral analysis algorithm, the program provides for the calculation of averages, maxima, minima, amplitudes, and frequency of power in selected frequency band widths. A total of 10 final parameters may be computed on-line and stored for subsequent display and statistical analysis. In this study, the parameters were: heart rate, ABP, ICP, FV, their amplitudes (ABPa, ICPa, FVa, respectively), mean CPP, and floating correlation coefficient between FVa and CPP (RFVa/CPP). The Doppler signal was processed using a mean/maximum frequency processor (Pedof, Vingmed, Norway); the mean frequency signal was analyzed.
Experimental protocol The animals were allowed to stabilize for at least 1 hour after the completion of surgery and then maintained under light anesthesia. Continuous monitoring of ABP, ICP, and FV was started and three control CBF measurements were made. In Group 1 animals, mock CSF (millimolar composition: Na+, 151; K+, 3; Ca++, 1.5; Mg++, 1; Cl-, 135; HCO3-, 20; PO4-, 0.2; glucose, 4.4; buffered to pH 7.35-7.4 at 38°C) was infused (Harvard Syringe Infusion Pump 22) via the subarachnoid catheter at rates increasing from 0.01 to 1 ml/min. CPP was reduced by ∼10 mm Hg for each increase in the infusion rate, and CBF was measured again at the end of each steady-state period. When conditions allowed, additional measurements of CBF were made for smaller reductions in CPP below 40 mm Hg. In Group 2 and 3 animals, mean ABP was reduced in 10 mm Hg decrements by infusion of a 2.5% weight/volume solution trimetaphan camsylate (Arfonad) in normal saline infused at rates of 0.5 to 5 mg/min. Fine control of mean ABP at each pressure level was obtained by removal or addition of up to 5 ml of heparinized arterial blood.
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between 38.5 and 39.5°C by a thermostatically controlled warming blanket (Harvard Apparatus, South Natick, MA). The animals were then placed prone in the sphinx position and supported in a purpose-built head frame with three-point skull fixation (10). The pin sites and all surgical incisions were infiltrated with 0.5% bupivicaine. A midline sagittal incision was made and a 6-mm posterior frontal burr hole was created at the bregma using a saline-cooled, high-speed dental drill. An 8MHz pulsed ultrasound probe (EME, Uberlingen, Germany) with a 5-mm sample volume range-gated to a depth of 22 mm was placed over the burr hole and separated from the intact dura by ultrasound contact gel. The probe was directed at an angle of 10 to 15 degrees caudal to the canthomeatal line in the sagittal plane and adjusted to obtain Doppler spectra from the distal basilar artery at the lowest signal gain, before being clamped in position. Four 2-mm burr holes were placed around the central Doppler burr hole. A fiber optic pressure transducer (Camino 110-4 catheter, Camino Laboratories, San Diego, CA) was inserted intraparenchymally via the right frontal burr hole to a depth of 5 mm using a micromanipulator and secured in position with a fast-setting polycarboxylate cement (Poly-F Plus, Dentsply Ltd, UK). Three 0.25-mm diameter sharpened platinum wire electrodes were similarly inserted into the cerebral cortex to a depth of 1.5 mm via the remaining left frontal and parietal burr holes for the determination of focal cortical CBF using the hydrogen clearance method (10). A silver/silver chloride reference electrode was placed subcutaneously in the back. In Group 1 animals, a drill laminectomy was performed at the level of the first sacral lamina, and the sacral dural sac was identified and opened. A 0.3-mm-diameter polyethylene catheter was introduced into the subarachnoid space and advanced to the level of the cervicothoracic junction. The laminectomy was sealed with polycarboxylate cement and the soft tissues closed.
Hemodynamic changes in the presence of impaired autoregulation In the Group 3 animals with impaired autoregulation (Fig. 1C), CBF and FVm fall pressurepassively as CPP is reduced. There is no "active" increase in FVa because of the loss of normal myogenic autoregulation. A transitional phase is not identifiable and at mean ABPs just above 100 mm Hg the FVa falls and CVR rises in a manner similar to Phase 3 described above. The behavior of FVa and CVR may be interpreted as an effect of early closing of vasospastic arterioles with abnormal vessel characteristics and high mural tension (14).
ACKNOWLEDGMENTS We are grateful to the British Council for sponsoring Drs. Czosnyka and Maksymowicz and EME, Urbelingen, Germany for their continued support of fundamental research into the application of transcranial Doppler. Received, November 22, 1991. Accepted, April 17, 1992. Reprint requests: R. J. Nelson, M.A., F.R.C.S., Consultant Neurosurgeon, Department of Neurosurgery, Frenchay Hospital, Bristol, BS16 1LE, England. REFERENCES: (1-14) 1.
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Aaslid R, Markwalder TM, Nornes H: Noninvasive transcranial Doppler recording of flow velocity in basal cerebral arteries. J Neurosurg 57:769-774, 1982. Aaslid R, Lundar T, Lindegaard K-F, Nornes H: Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial Doppler recordings, in Miller JD, Teasdale GM, Rowan JO, Galbraith SL, Mendelow AD (eds): Intracranial Pressure. Berlin, Springer-
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DISCUSSION Hemodynamic changes in the presence of intact autoregulation This study describes the dynamic relationships among FVm, FVa, CBF, and CPP. In both the intracranial hypertension and systemic hypotension experimental Groups 1 and 2 with intact autoregulation, the changes in CBF, FVm, and FVa were identical, suggesting that the observed phenomena depend on CPP. Our results confirm those of other studies (3,10) demonstrating a close correlation between the FVm and CBF of normal animals during changes in CPP. We have defined three hemodynamic phases based on these experimental observations and theoretical modeling of the cerebral circulation (Fig. 3). Phase 1 is the phase of intact autoregulation, which represents the classical "autoregulatory plateau" (7). Above the lower limit of autoregulation, falls in CPP are matched by a reduction in CVR and CVRe such that CBF and FVm remain stable. The associated changes in arteriolar tone and elastance result in a gradual increase in FVa. Phase 2 is the transitional phase. At CPPs below ∼50 to 60 mm Hg, CBF and FVm start to fall gradually. This point is difficult to define statistically in individual animals, but is easily observed experimentally. During this phase, CPP in diastole is close to or below the critical closing pressure of the capillaries (6) so that the fall in FV in diastole is greater and FVa increases further. Despite the falling CBF and FVm, some arteriolar dilatation may still be taking place until the end of this phase is reached, when CVR and CVRe reach their minimum values (11) . Phase 3 is the phase of exhausted autoregulation. This phase is characterized by a rapid fall in CBF and FVm, a sharp decrease in FVa, and an increase in both CVR and CVRe. The functional increase in CVR is probably due to an increase in the period of arteriolar collapse during each cardiac cycle rather than increased venous resistance (3), because the same phenomenon is observed in both the intracranial hypertension and systemic hypotension groups. The sharp break point in FVa reflects the rapid fall in systolic FV as systolic CPP approaches the critical closing pressure and functional CVR rises.
Clinical applications We have demonstrated a two-slope relationship between FVa and CPP in the presence of intact autoregulation with a break point that correlates closely with the lower limit of CBF autoregulation. Continuous monitoring of the inverse correlation between FVa and CPP (RFVa/CPP) during spontaneous or therapeutically induced changes in the CPP of the patient in intensive care may allow the clinician to determine whether cerebral autoregulation is intact and to warn of the impending exhaustion of autoregulatory reserve. On the other hand, the demonstration of a pressure-passive direct relationship between FVa and CPP may indicate impairment of autoregulation and abnormal vasomotor responses even at CPPs where other measures suggest that CBF is adequate. This methodology is shown in Figure 4, where the time course of ABP and RFVa/ABP of a Group 2 animal are plotted throughout Phases 2 and 3. As ABP falls below 60 mm Hg and the transitional phase is entered, RFVa/ABP becomes strongly negative, approaching -0.7. At the autoregulatory threshold (35 mm Hg), there is abrupt reversal in RFVa/ABP, which changes polarity and becomes strongly positive. This point, which defines the beginning of the phase of exhausted autoregulation, is easily determined statistically. These studies have been performed under carefully controlled conditions to exclude the many factors disturbing the relationship between CBF and FVm (10) . Attempts to assess absolute changes in CBF circulation using TCD may be an unreachable goal of noninvasive monitoring. We suggest that an analysis of the pulsatile hemodynamics of the cerebrospinal space may be more realistic and clinically useful.
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hydrogen clearance method for all nine experimental animals.
4.
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7.
8. 9.
10.
11.
12. 13.
14.
COMMENTS This is a well written, succinct manuscript that demonstrates that transcranial Doppler techniques can be utilized by the state of autoregulation in both experimental and clinical conditions. While the authors deal with normal rabbits and rabbits with
subarachnoid hemorrhage, similar results have been reported at recent meetings by Aaslid and his colleagues in humans with head injury. In these experiments, fluctuations in the blood pressure were used along with recording of the intracranial pressure to predict autoregulatory abnormalities. The model here of the hypertensive rabbit with subarachnoid hemorrhage is ingenious and makes two major points: 1) the curve is shifted upward with impaired autoregulation, and 2) as the authors conclude, one can interpret this as evidence of early closing of vasospastic arterioles, indicating that the vessels have abnormal mural tension. The authors' caution is particularly meritorious. The use of pulsatile techniques should not be seen as a method to absolutely assess cerebral blood flow and its changes under a variety of conditions, but rather as a means of telling us in relative terms about the cerebrovascular compartment and potentially other compartments within the brain under varying conditions. In summary, this is a well written and carefully crafted manuscript that reports some interesting findings with implications both for further laboratory research and for clinical care. Coupled with the observations of Miller, in Edinburgh, regarding changes in oxygen saturation associated with critical changes in cerebral perfusion pressure and the work of Aaslid and his group, in particular, this further advances our understanding of cerebral autoregulatory reserve. Lawrence F. Marshall San Diego, California It has been known for at least 25 years (1) that the pulse waveform in a vessel is affected not only by the generator (the heart), but also by the condition of the vascular bed fed by the vessel. This paper by Nelson et al. demonstrates that the condition of the cerebral vascular bed can be evaluated using transcranial Doppler ultrasound. In animals with normal cerebrovascular autoregulation, pulsatile flow velocity (FVa) gradually increases as cerebral perfusion pressure decreases, until the cerebral perfusion pressure is so low as to not be able to maintain blood flow. This results in a break point in the FVa curve. This is not surprising, because the cerebrospinal fluid pulse wave increases with increasing intracranial pressure (ICP) (decreasing cerebral perfusion pressure) (2). In contrast, when autoregulation is lost, FVa is high and simply falls passively with decreasing blood pressure and cerebral blood flow. Note that the cerebrovascular resistance in Figure 1C is lowest at the highest blood pressure. This suggests to me that the non-autoregulating cerebrovascular bed, including the arterioles, is dilated and acting passively to the blood pressure. I do not think that the arterioles are vasospastic as suggested by the authors. This paper would have had more impact had the authors also plotted mean and pulsatile ICP. I suspect that FVa and pulsatile ICP are closely related.
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Verlag, 1985, vol 6, pp 226-229. Barzo P, Doczi T, Csete K, Buza Z, Bodosi M: Measurements of regional cerebral blood flow and blood flow velocity in experimental intracranial hypertension: Infusion via cisterna magna in rabbits, Neurosurgery 28:821-25, 1991. Burton AC: On the physical equilibrium of small blood vessels. Am J Physiol 164:319329, 1951. Czosnyka M, Laniewski P, Darwaj P: Software for neurosurgery intensive care, in Hoff JT, Betz AL (eds): Intracranial Pressure. Berlin, Springer-Verlag, 1988, vol 7, pp 84-87. Dewey RC, Pieper HP, Hunt WE: Experimental cerebral hemodynamics. Vasomotor tone, critical closing pressure, and vascular resistance. J Neurosurg 41:597-606, 1974. Fitch W, Ferguson CC, Sengupta D, Garibi J, Harper AM: Autoregulation of cerebral blood flow during controlled hypotension in baboons. J Neurol Neurosurg Psychiatry 39:1014-1022, 1976. Giller CA, Hodges K, Batjer HH: Transcranial Doppler pulsatility in vasodilatation and stenosis. J Neurosurg 72:901-7, 1990. Giulioni M, Ursino M, Alvisi C: Correlations among intracranial pulsatility, intracranial hemodynamics, and transcranial Doppler waveform: literature review and hypothesis for future studies. Neurosurgery 22:807-812, 1988. Nelson RJ, Perry S, Hames TK, Pickard JD: Transcranial Doppler ultrasound studies of cerebral autoregulation and subarachnoid haemorrhage in the rabbit. J Neurosurg 73:601-610, 1990. MacKenzie ET, Farrar JK, Fitch W, Graham DI, Gregory PC, Harper AM: Effects of hemorrhagic hypotension on the cerebral circulation: I. Cerebral blood flow and pial arteriolar caliber. Stroke 10:711-8, 1979. Paulson OB, Strandgaard S, Edvinsson L: Cerebral autoregulation. Cereb Brain Metab Rev 2:161-192, 1990. Portnoy HD, Chopp MC, Branch C: Hydraulic model of myogenic autoregulation and the cerebrovascular bed: The effects of altering systemic arterial pressure. Neurosurgery 13:482-498, 1983. Young AR, Richards HK, Pickard JD: Contractile activity of cerebral arteries from normal and renal hypertensive rabbits. J Cereb Blood Flow Metab 7[Suppl 1]:612, 1987.
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Harold D. Portnoy Bloomfield Hills, Michigan REFERENCES: (1,2)
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O'Rourke MF, Taylor MG: Vascular impedance of the femoral bed. Circ Res 18:126-139, 1966. Portnoy HD, Chopp M, Branch C, Shannon M: Cerebrospinal fluid pulse waveform as an indicator of cerebral autoregulation. J Neurosurg 56:666-678, 1982.
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1.
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Figure 1. The relationships among FVm, FVa, CBF, CVR, Doppler estimate of CVRe, and either mean CPP or mean ABP. A, Group 1 animal (intracranial hypertension); B, Group 2 animal (systemic hypotension); C, Group 3 animal (SAH systemic hypotension).
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Figure 3. Computer-generated representation of the relationships among FVm, FVa, CVR, and CPP in the normal cerebral circulation. The phases of intact autoregulation, transition, and exhausted autoregulation are demonstrated (see "Discussion").
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Figure 2. The correlation between the ABP (CPP in Group 1) corresponding to the FVa break point determined using TCD and the CBF autoregulatory threshold determined by hydrogen clearance (r = 0.94, P < 0.01, n = 9). *, Group 3 animals.
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Figure 4. Experimental monitoring of autoregulatory reserve by continuous recording of ABP and RFVa/ABP in a Group 2 animal (see "Discussion").
MATERIALS AND METHODS Preparation The study was performed in nine New Zealand White rabbits (3.2-3.9 kg) of both sexes and was approved under the UK Animals (Scientific Procedures) Act of 1986. The animals were divided into three experimental groups: 1) normal animals with intracranial hypertension (n = 3); 2) normal animals with trimetaphan-induced hypotension (n = 3); and 3) hypertensive SAH animals with trimetaphan-induced hypotension (n = 3). Renovascular hypertension was established in Group 3 animals by encapsulation of one kidney in a cellophane membrane 3 weeks after performing a contralateral nephrectomy (13). Three months later, experimental SAH was induced by two intracisternal injections of autologous venous blood, and the animals were then studied on Day 6 after the first SAH. Experimental procedure General anesthesia was induced with intravenous alphaxalone/alphadalone, 3 mg/kg (Saffan, Glaxovet, UK) and maintained by controlled ventilation with 1 to 3% halothane in 1:1 nitrous oxide in oxygen via a tracheostomy. Muscle relaxation was obtained by continuous infusion of pancuronium, 0.5 mg/kg/hr. Both femoral arteries and femoral veins were cannulated. Arterial blood pressure (ABP) was continuously monitored (Hewlett-Packard 78342A transducer and monitor, Hewlett Packard, Boeblingen, Germany). Arterial blood gas analysis was performed frequently (Corning 168 pH/Blood gas analyzer), and the ventilation was adjusted to maintain the blood gases within the following limits: PaCO2, 36 to 43 mm Hg; PaO2, 115 to 140 mm Hg; pH, 7.25 to 7.35. Core temperature was maintained
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AUTHOR(S): Nelson, R. J., M.A., F.R.C.S.; Czosnyka, M., Ph.D.; Pickard, J. D., M.Chir., F.R.C.S.; Maksymowicz, W., M.D.; Perry, S., J. L. Martin, F.R.C.S.; Lovick, A. H. J., Ph.D.
arterial pressure wave (2), regional cerebrovascular resistance (CVR), the elastance of the capillary bed (9) , and the basal cerebral arteries (8). At low mean cerebral perfusion pressures (CPP), FVa is also influenced by the relationship between systolic and diastolic CPP and the critical closing pressure of the capillary bed (4,6). The myogenic autoregulation of CBF is partly mediated by changes in the transmural pressure of cerebral arterioles (13). As CPP falls, the resistance arterioles respond to the decrease in transmural pressure by a reduction in vasomotor tone (11,12) . The resulting fall in CVR maintains CBF. The concomitant increase in cerebral blood volume and change in vascular elastance alter the Doppler waveform and FVa (9). Because CVR is calculated as the mean CPP divided by CBF and CBF is proportional to the FVm, if the cross-sectional area of the insonated artery remains constant (10), a Doppler estimate of CVR (CVRe) is given by the ratio CPPm/FVm. We propose that continuous monitoring of the relationships among FVm, FVa, and CPP will provide valuable information regarding CBF autoregulation. We have tested the hypothesis in normal rabbits (autoregulating) and rabbits with subarachnoid hemorrhage (SAH) (nonautoregulating). Redistribution of this article permitted only in accordance with the publisher’s copyright provisions.
Neurosurgery 1992-98 October 1992, Volume 31, Number 4 705 Experimental Aspects of Cerebrospinal Hemodynamics: The Relationship between Blood Flow Velocity Waveform and Cerebral Autoregulation Experimental Study
Statistical methods The break point of the FVa/CPP relationship of each animal was determined from the midpoint of the CPP range where there was a statistically significant (P < 0.05) change in the floating correlation coefficient RFVa/CPP (based on 15 sequential data points) from below -0.3 to above +0.3. The lower limit of CBF autoregulation, defined as the CPP below which there was a statistically significant (P < 0.05) reduction in CBF by analysis of variance with Duncan's multiple range test, was compared with the FVa/CPP break point using simple linear regression. RESULTS Plots of CBF, FVm, FVa, CVR, and CVRe against CPP or ABP for individual animals from Groups 1, 2, and 3 are shown in Figure 1, A, B, and C, respectively. In the animals with intact autoregulation (Fig. 1, A and B) a sharp break point in FVa was observed at 28 and 35 mm Hg, respectively, and this break point occurred just below the CPP or ABP at which FVm and CBF began to fall. CVR and CVRe decreased above the break point and increased below the FVa break point. In the Group 3 animals with severely disordered autoregulation (Fig. 1C), the FVa break point was shifted upward to an ABP of about 100 mm Hg. In these animals, FVm and CBF fell in direct proportion to the reduction in ABP. CVRe and CVR did not change until ABP had fallen below 100 mm Hg (the FVa break point), when they both rose. In normal animals, there was a close correlation between CBF and FVm and between CVR and CVRe during changes in CPP/ABP (r > 0.96). Figure 2 shows the linear correlation (r = 0.94; P < 0.01) between the autoregulatory break points estimated using the TCD method (break point of FVa) and the CBF autoregulatory thresholds determined from the
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Signal analysis The ICP, amplitude, and FV signals were individually amplified and processed before being fed via an analog-to-digital converter (DT2814) to an IBM-compatible computer with a purpose-designed multi-signal physiological monitoring and analysis program (5). Based on a special short-term spectral analysis algorithm, the program provides for the calculation of averages, maxima, minima, amplitudes, and frequency of power in selected frequency band widths. A total of 10 final parameters may be computed on-line and stored for subsequent display and statistical analysis. In this study, the parameters were: heart rate, ABP, ICP, FV, their amplitudes (ABPa, ICPa, FVa, respectively), mean CPP, and floating correlation coefficient between FVa and CPP (RFVa/CPP). The Doppler signal was processed using a mean/maximum frequency processor (Pedof, Vingmed, Norway); the mean frequency signal was analyzed.
Experimental protocol The animals were allowed to stabilize for at least 1 hour after the completion of surgery and then maintained under light anesthesia. Continuous monitoring of ABP, ICP, and FV was started and three control CBF measurements were made. In Group 1 animals, mock CSF (millimolar composition: Na+, 151; K+, 3; Ca++, 1.5; Mg++, 1; Cl-, 135; HCO3-, 20; PO4-, 0.2; glucose, 4.4; buffered to pH 7.35-7.4 at 38°C) was infused (Harvard Syringe Infusion Pump 22) via the subarachnoid catheter at rates increasing from 0.01 to 1 ml/min. CPP was reduced by ∼10 mm Hg for each increase in the infusion rate, and CBF was measured again at the end of each steady-state period. When conditions allowed, additional measurements of CBF were made for smaller reductions in CPP below 40 mm Hg. In Group 2 and 3 animals, mean ABP was reduced in 10 mm Hg decrements by infusion of a 2.5% weight/volume solution trimetaphan camsylate (Arfonad) in normal saline infused at rates of 0.5 to 5 mg/min. Fine control of mean ABP at each pressure level was obtained by removal or addition of up to 5 ml of heparinized arterial blood.
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between 38.5 and 39.5°C by a thermostatically controlled warming blanket (Harvard Apparatus, South Natick, MA). The animals were then placed prone in the sphinx position and supported in a purpose-built head frame with three-point skull fixation (10). The pin sites and all surgical incisions were infiltrated with 0.5% bupivicaine. A midline sagittal incision was made and a 6-mm posterior frontal burr hole was created at the bregma using a saline-cooled, high-speed dental drill. An 8MHz pulsed ultrasound probe (EME, Uberlingen, Germany) with a 5-mm sample volume range-gated to a depth of 22 mm was placed over the burr hole and separated from the intact dura by ultrasound contact gel. The probe was directed at an angle of 10 to 15 degrees caudal to the canthomeatal line in the sagittal plane and adjusted to obtain Doppler spectra from the distal basilar artery at the lowest signal gain, before being clamped in position. Four 2-mm burr holes were placed around the central Doppler burr hole. A fiber optic pressure transducer (Camino 110-4 catheter, Camino Laboratories, San Diego, CA) was inserted intraparenchymally via the right frontal burr hole to a depth of 5 mm using a micromanipulator and secured in position with a fast-setting polycarboxylate cement (Poly-F Plus, Dentsply Ltd, UK). Three 0.25-mm diameter sharpened platinum wire electrodes were similarly inserted into the cerebral cortex to a depth of 1.5 mm via the remaining left frontal and parietal burr holes for the determination of focal cortical CBF using the hydrogen clearance method (10). A silver/silver chloride reference electrode was placed subcutaneously in the back. In Group 1 animals, a drill laminectomy was performed at the level of the first sacral lamina, and the sacral dural sac was identified and opened. A 0.3-mm-diameter polyethylene catheter was introduced into the subarachnoid space and advanced to the level of the cervicothoracic junction. The laminectomy was sealed with polycarboxylate cement and the soft tissues closed.
Hemodynamic changes in the presence of impaired autoregulation In the Group 3 animals with impaired autoregulation (Fig. 1C), CBF and FVm fall pressurepassively as CPP is reduced. There is no "active" increase in FVa because of the loss of normal myogenic autoregulation. A transitional phase is not identifiable and at mean ABPs just above 100 mm Hg the FVa falls and CVR rises in a manner similar to Phase 3 described above. The behavior of FVa and CVR may be interpreted as an effect of early closing of vasospastic arterioles with abnormal vessel characteristics and high mural tension (14).
ACKNOWLEDGMENTS We are grateful to the British Council for sponsoring Drs. Czosnyka and Maksymowicz and EME, Urbelingen, Germany for their continued support of fundamental research into the application of transcranial Doppler. Received, November 22, 1991. Accepted, April 17, 1992. Reprint requests: R. J. Nelson, M.A., F.R.C.S., Consultant Neurosurgeon, Department of Neurosurgery, Frenchay Hospital, Bristol, BS16 1LE, England. REFERENCES: (1-14) 1.
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Aaslid R, Markwalder TM, Nornes H: Noninvasive transcranial Doppler recording of flow velocity in basal cerebral arteries. J Neurosurg 57:769-774, 1982. Aaslid R, Lundar T, Lindegaard K-F, Nornes H: Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial Doppler recordings, in Miller JD, Teasdale GM, Rowan JO, Galbraith SL, Mendelow AD (eds): Intracranial Pressure. Berlin, Springer-
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DISCUSSION Hemodynamic changes in the presence of intact autoregulation This study describes the dynamic relationships among FVm, FVa, CBF, and CPP. In both the intracranial hypertension and systemic hypotension experimental Groups 1 and 2 with intact autoregulation, the changes in CBF, FVm, and FVa were identical, suggesting that the observed phenomena depend on CPP. Our results confirm those of other studies (3,10) demonstrating a close correlation between the FVm and CBF of normal animals during changes in CPP. We have defined three hemodynamic phases based on these experimental observations and theoretical modeling of the cerebral circulation (Fig. 3). Phase 1 is the phase of intact autoregulation, which represents the classical "autoregulatory plateau" (7). Above the lower limit of autoregulation, falls in CPP are matched by a reduction in CVR and CVRe such that CBF and FVm remain stable. The associated changes in arteriolar tone and elastance result in a gradual increase in FVa. Phase 2 is the transitional phase. At CPPs below ∼50 to 60 mm Hg, CBF and FVm start to fall gradually. This point is difficult to define statistically in individual animals, but is easily observed experimentally. During this phase, CPP in diastole is close to or below the critical closing pressure of the capillaries (6) so that the fall in FV in diastole is greater and FVa increases further. Despite the falling CBF and FVm, some arteriolar dilatation may still be taking place until the end of this phase is reached, when CVR and CVRe reach their minimum values (11) . Phase 3 is the phase of exhausted autoregulation. This phase is characterized by a rapid fall in CBF and FVm, a sharp decrease in FVa, and an increase in both CVR and CVRe. The functional increase in CVR is probably due to an increase in the period of arteriolar collapse during each cardiac cycle rather than increased venous resistance (3), because the same phenomenon is observed in both the intracranial hypertension and systemic hypotension groups. The sharp break point in FVa reflects the rapid fall in systolic FV as systolic CPP approaches the critical closing pressure and functional CVR rises.
Clinical applications We have demonstrated a two-slope relationship between FVa and CPP in the presence of intact autoregulation with a break point that correlates closely with the lower limit of CBF autoregulation. Continuous monitoring of the inverse correlation between FVa and CPP (RFVa/CPP) during spontaneous or therapeutically induced changes in the CPP of the patient in intensive care may allow the clinician to determine whether cerebral autoregulation is intact and to warn of the impending exhaustion of autoregulatory reserve. On the other hand, the demonstration of a pressure-passive direct relationship between FVa and CPP may indicate impairment of autoregulation and abnormal vasomotor responses even at CPPs where other measures suggest that CBF is adequate. This methodology is shown in Figure 4, where the time course of ABP and RFVa/ABP of a Group 2 animal are plotted throughout Phases 2 and 3. As ABP falls below 60 mm Hg and the transitional phase is entered, RFVa/ABP becomes strongly negative, approaching -0.7. At the autoregulatory threshold (35 mm Hg), there is abrupt reversal in RFVa/ABP, which changes polarity and becomes strongly positive. This point, which defines the beginning of the phase of exhausted autoregulation, is easily determined statistically. These studies have been performed under carefully controlled conditions to exclude the many factors disturbing the relationship between CBF and FVm (10) . Attempts to assess absolute changes in CBF circulation using TCD may be an unreachable goal of noninvasive monitoring. We suggest that an analysis of the pulsatile hemodynamics of the cerebrospinal space may be more realistic and clinically useful.
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hydrogen clearance method for all nine experimental animals.
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COMMENTS This is a well written, succinct manuscript that demonstrates that transcranial Doppler techniques can be utilized by the state of autoregulation in both experimental and clinical conditions. While the authors deal with normal rabbits and rabbits with
subarachnoid hemorrhage, similar results have been reported at recent meetings by Aaslid and his colleagues in humans with head injury. In these experiments, fluctuations in the blood pressure were used along with recording of the intracranial pressure to predict autoregulatory abnormalities. The model here of the hypertensive rabbit with subarachnoid hemorrhage is ingenious and makes two major points: 1) the curve is shifted upward with impaired autoregulation, and 2) as the authors conclude, one can interpret this as evidence of early closing of vasospastic arterioles, indicating that the vessels have abnormal mural tension. The authors' caution is particularly meritorious. The use of pulsatile techniques should not be seen as a method to absolutely assess cerebral blood flow and its changes under a variety of conditions, but rather as a means of telling us in relative terms about the cerebrovascular compartment and potentially other compartments within the brain under varying conditions. In summary, this is a well written and carefully crafted manuscript that reports some interesting findings with implications both for further laboratory research and for clinical care. Coupled with the observations of Miller, in Edinburgh, regarding changes in oxygen saturation associated with critical changes in cerebral perfusion pressure and the work of Aaslid and his group, in particular, this further advances our understanding of cerebral autoregulatory reserve. Lawrence F. Marshall San Diego, California It has been known for at least 25 years (1) that the pulse waveform in a vessel is affected not only by the generator (the heart), but also by the condition of the vascular bed fed by the vessel. This paper by Nelson et al. demonstrates that the condition of the cerebral vascular bed can be evaluated using transcranial Doppler ultrasound. In animals with normal cerebrovascular autoregulation, pulsatile flow velocity (FVa) gradually increases as cerebral perfusion pressure decreases, until the cerebral perfusion pressure is so low as to not be able to maintain blood flow. This results in a break point in the FVa curve. This is not surprising, because the cerebrospinal fluid pulse wave increases with increasing intracranial pressure (ICP) (decreasing cerebral perfusion pressure) (2). In contrast, when autoregulation is lost, FVa is high and simply falls passively with decreasing blood pressure and cerebral blood flow. Note that the cerebrovascular resistance in Figure 1C is lowest at the highest blood pressure. This suggests to me that the non-autoregulating cerebrovascular bed, including the arterioles, is dilated and acting passively to the blood pressure. I do not think that the arterioles are vasospastic as suggested by the authors. This paper would have had more impact had the authors also plotted mean and pulsatile ICP. I suspect that FVa and pulsatile ICP are closely related.
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Verlag, 1985, vol 6, pp 226-229. Barzo P, Doczi T, Csete K, Buza Z, Bodosi M: Measurements of regional cerebral blood flow and blood flow velocity in experimental intracranial hypertension: Infusion via cisterna magna in rabbits, Neurosurgery 28:821-25, 1991. Burton AC: On the physical equilibrium of small blood vessels. Am J Physiol 164:319329, 1951. Czosnyka M, Laniewski P, Darwaj P: Software for neurosurgery intensive care, in Hoff JT, Betz AL (eds): Intracranial Pressure. Berlin, Springer-Verlag, 1988, vol 7, pp 84-87. Dewey RC, Pieper HP, Hunt WE: Experimental cerebral hemodynamics. Vasomotor tone, critical closing pressure, and vascular resistance. J Neurosurg 41:597-606, 1974. Fitch W, Ferguson CC, Sengupta D, Garibi J, Harper AM: Autoregulation of cerebral blood flow during controlled hypotension in baboons. J Neurol Neurosurg Psychiatry 39:1014-1022, 1976. Giller CA, Hodges K, Batjer HH: Transcranial Doppler pulsatility in vasodilatation and stenosis. J Neurosurg 72:901-7, 1990. Giulioni M, Ursino M, Alvisi C: Correlations among intracranial pulsatility, intracranial hemodynamics, and transcranial Doppler waveform: literature review and hypothesis for future studies. Neurosurgery 22:807-812, 1988. Nelson RJ, Perry S, Hames TK, Pickard JD: Transcranial Doppler ultrasound studies of cerebral autoregulation and subarachnoid haemorrhage in the rabbit. J Neurosurg 73:601-610, 1990. MacKenzie ET, Farrar JK, Fitch W, Graham DI, Gregory PC, Harper AM: Effects of hemorrhagic hypotension on the cerebral circulation: I. Cerebral blood flow and pial arteriolar caliber. Stroke 10:711-8, 1979. Paulson OB, Strandgaard S, Edvinsson L: Cerebral autoregulation. Cereb Brain Metab Rev 2:161-192, 1990. Portnoy HD, Chopp MC, Branch C: Hydraulic model of myogenic autoregulation and the cerebrovascular bed: The effects of altering systemic arterial pressure. Neurosurgery 13:482-498, 1983. Young AR, Richards HK, Pickard JD: Contractile activity of cerebral arteries from normal and renal hypertensive rabbits. J Cereb Blood Flow Metab 7[Suppl 1]:612, 1987.
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Harold D. Portnoy Bloomfield Hills, Michigan REFERENCES: (1,2)
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Figure 1. The relationships among FVm, FVa, CBF, CVR, Doppler estimate of CVRe, and either mean CPP or mean ABP. A, Group 1 animal (intracranial hypertension); B, Group 2 animal (systemic hypotension); C, Group 3 animal (SAH systemic hypotension).
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Figure 3. Computer-generated representation of the relationships among FVm, FVa, CVR, and CPP in the normal cerebral circulation. The phases of intact autoregulation, transition, and exhausted autoregulation are demonstrated (see "Discussion").
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Figure 2. The correlation between the ABP (CPP in Group 1) corresponding to the FVa break point determined using TCD and the CBF autoregulatory threshold determined by hydrogen clearance (r = 0.94, P < 0.01, n = 9). *, Group 3 animals.
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Figure 4. Experimental monitoring of autoregulatory reserve by continuous recording of ABP and RFVa/ABP in a Group 2 animal (see "Discussion").
