Cardiac specific transcription factor Csx/Nkx2.5 regulates transient-outward K+ channel expression in pluripotent P19 cell-derived cardiomyocytes

We hypothesized that cerebral blood flow (CBF) regulation in the posterior circulation differs from that of the anterior circulation during a cold pressor test (CPT) and is accompanied by elevations in arterial blood pressure (ABP) and sympathetic nervous activity (SNA). To test this, dynamic cerebral autoregulation (dCA) in the middle and posterior cerebral arteries (MCA and PCA) were measured at three different conditions: control, early phase of the CPT, and the late phase of the CPT. The dCA was examined using a thigh cuff occlusion and release technique. The MCA and PCA blood velocities were unchanged at CPT compared with the control conditions despite an elevation in the ABP. The dCA in both the MCA and PCA remained unaltered at CPT. These findings suggest that CPT-induced elevations in the ABP and SNA did not cause changes in the CBF regulation in the posterior circulation compared with the anterior circulation.

     

Hemodynamic Effect of Cerebral Vasospasm in Humans: A Modeling Study

A mathematical model of cerebral hemodynamics during vasospasm is presented. The model divides arterial hemodynamics into two cerebral territories: with and without spasm. It also includes collateral circulation between the two territories, cerebral venous hemodynamics, cerebrospinal fluid circulation, intracranial pressure (ICP) and the craniospinal storage capacity. Moreover, the pial artery circulation in both territories is affected by cerebral blood flow (CBF) autoregulation mechanisms. In this work, a numerical value to model parameters was given assuming that vasospasm affects only a single middle cerebral artery (MCA). In a first stage, the model is used to simulate some clinical results reported in the literature, concerning the patterns of MCA velocity, CBF and pressure losses during vasospasm. The agreement with clinical data turns out fairly good. In a second stage, a sensitivity analysis on some model parameters is performed (severity of caliber reduction, longitudinal extension of the spasm, autoregulation gain, ICP, resistance of the collateral circulation, and mean systemic arterial pressure) to clarify their influence on hemodynamics in the spastic territory. The results suggest that the clinical impact of vasospasm depends on several concomitant factors, which should be simultaneously taken into account to reach a proper diagnosis. In particular, while a negative correlation between MCA velocity and cross sectional area can be found until CBF is well preserved, a positive correlation may occur when CBF starts to decrease significantly. This might induce false-negative results if vasospasm is assessed merely through velocity measurements performed by the transcranial Doppler technique. © 1999 Biomedical Engineering Society. PAC99: 8719Uv, 8719La, 8710+e     

Sympathetic nervous control of the cerebral circulation in sleep

Cerebral vessels are extensively innervated by sympathetic nerves arising from superior cervical ganglia, and these nerves might play a protective role during the large arterial pressure surges of active sleep (AS). We studied lambs (n=10) undergoing spontaneous sleep-wake cycles before and after bilateral removal of the superior cervical ganglia (SCGx, n=5) or sham ganglionectomy (n=5). Lambs were instrumented to record cerebral blood flow (CBF, flow probe on the superior sagittal sinus), carotid arterial pressure (P(ca)), intra-cranial pressure (P(ic)), cerebral perfusion pressure (Pcp=Pca-Pic) and cerebral vascular resistance (CVR). Prior to SCGx, CBF (mL min-1) was significantly higher in AS than in Quiet Sleep (QS) and Quiet Wakefulness (QW) (17+/-2, 13+/-3, and 14+/-3 respectively, mean+/-SD, P<0.05). Following SCGx, baseline CBF increased by 34, 31, and 29% respectively (P<0.05). CVR also decreased in all states by approximately 25% (P<0.05). During phasic AS, surges of Pca were associated with transient increases in Pcp, Pic and CBF. Following SCGx, peak CBF and Pic during surges became higher and more prolonged (P<0.05). Our study is the first to reveal that tonic sympathetic nerve activity (SNA) constricts the cerebral circulation and restrains baseline CBF in sleep. SNA is further incremented during arterial pressure surges of AS, limiting rises in CBF and Pic, possibly by opposing vascular distension as well as by constricting resistance vessels. Thus, SNA may protect cerebral microvessels from excessive distension during AS, when large arterial blood pressure surges are common.     

Continuous time-domain monitoring of cerebral autoregulation in neurocritical care

Integration of various brain signals can be used to determine cerebral autoregulation in neurocritical care patients to guide clinical management and to predict outcome. In this review, we will discuss current methodology of multimodal brain monitoring focusing on secondary ‘reactivity indices’ derived from various brain signals which are based on a ‘moving correlation coefficient’. This algorithm was developed in order to analyze in a time dependent manner the degree of correlation between two factors within a time series where the number of paired observations is large. Of the various primary neuromonitoring sources which can be used to calculate reactivity indices, we will focus in this review on indices based on transcranial Doppler (TCD), intracranial pressure (ICP), brain tissue oxygenation (PbtO₂) and near infrared spectroscopy (NIRS). Furthermore, we will demonstrate how reactivity indices can show transient changes of cerebral autoregulation and can be used to optimize management of arterial blood pressure (ABP) and cerebral perfusion pressure (CPP).     

A mathematical model of the relationship between cerebral blood volume and intracranial pressure changes: The generation of plateau waves

The relationship between intracranial pressure (ICP), cerebral blood volume (CBV), cerebrospinal fluid dynamics, and the action of cerebral blood-flow (CBF) regulatory mechanisms is examined in this work with the help of an original mathematical model. In building the model, particular emphasis is placed on reproducing the mechanical properties of proximal cerebral arteries and small pial arterioles, and their active regulatory response to perfusion pressure and cerebral blood flow changes. The model allows experimental results on cerebral vessel dilatation and cerebral blood-flow regulation, following cerebral perfusion pressure decrease, to be satisfactorily reproduced. Moreover, the effect of cerebral blood volume changes—induced by autoregulatory adjustments — on the intracranial pressure time pattern can be examined at different levels of arterial hypotension. The results obtained with normal parameter values demonstrate that, at the lower lumits of autoregulation, when dilatation of small arterioles becomes maximal, the increase in cerebral blood volume can cause a significant, transient increase in intracranial pressure. This antagonism between intracranial pressure and autoregulatory adjustments can lead to instability of the intracranial system in pathological conditions. In particular, analysis of the linearized system “in the small” demonstrates that an impairment in cerebrospinal fluid (CSF) reabsorption, a decrease in intracranial compliance and a high-regulatory capacity of the cerebrovascular bed are all conditions which can lead the system equilibrium to become unstable (i.e., the real part of at least one eigenvalue to turn out positive). Accordingly, mathematical simulation “in the large,” in the above-mentioned conditions, exhibits intracranial pressure periodic fluctuations which closely resemble, in amplitude, duration, frequency and shape, the well-known Lundberg A-waves (or plateau waves).     

Non-linear multivariate modeling of cerebral hemodynamics with autoregressive Support Vector Machines

Cerebral blood flow (CBF) is normally controlled by myogenic and metabolic mechanisms that can be impaired in different cerebrovascular conditions. Modeling the influences of arterial blood pressure (ABP) and arterial CO(2) (PaCO(2)) on CBF is an essential step to shed light on regulatory mechanisms and extract clinically relevant parameters. Support Vector Machines (SVM) were used to model the influences of ABP and PaCO(2) on CBFV in two different conditions: baseline and during breathing of 5% CO(2) in air, in a group of 16 healthy subjects. Different model structures were considered, including innovative non-linear multivariate autoregressive (AR) models. Results showed that AR models are significantly superior to finite impulse response models and that non-linear models provide better performance for both structures. Correlation coefficients for multivariate AR non-linear models were 0.71 ± 0.11 at baseline, reaching 0.91 ± 0.06 during 5% CO(2). These results warrant further work to investigate the performance of autoregressive SVM in patients with cerebrovascular conditions.     

Vasomotion in the rat cerebral microcirculation recorded by laser-Doppler flowmetry.

In the present study, changes in frequency and amplitude of the rhythmic variations (vasomotion) in blood flow in the intact cerebral circulation of the rat were investigated using laser-Doppler flowmetry (LDF) during stepwise decrease in mean arterial blood pressure (MABP) and hyper- and hypocapnia. Experiments were performed on 12 adult Sprague-Dawley rats of either sex, anesthetized with alpha-chloralose. The rat's head was fixed on a stereotaxic frame and a small hole was made in the parietal bone but the dura and a thin inner bone layer were kept intact. The microvascular blood flow of the parietal cortex on the right or on both sides was continuously recorded by the laser-Doppler flowmeter (Periflux PF2B, Perimed, Stockholm, Sweden). The cerebral circulation of the rat exhibited vasomotion in control conditions with a frequency of 8-10 cycles per minute (cpm) and an amplitude of 5-10% of the cerebral blood flow (CBF). No significant changes in CBF could be detected when the MABP was above 60 mmHg, but it decreased significantly when MABP was reduced below 50 mmHg. However, during stepwise pressure reduction the vasomotion frequency decreased progressively while its amplitude showed a reversed U-shaped curve with a peak at 60-80 mmHg. During hypercapnia, the rhythmical oscillations showed a decrease in both frequency and amplitude, whereas during hypocapnia their frequency did not change but their amplitude increased. These results support the hypothesis that the vasomotion frequency might be dependent of the wall tension and cellular pH while its amplitude could be related to decreased tissue oxygenation.     

Vasomotion in the rat cerebral microcirculation recorded by laser-Doppler flowmetry

In the present study, changes in frequency and amplitude of the rhythmic variations (vasomotion) in blood flow in the intact cerebral circulation of the rat were investigated using laser-Doppler flowmetry (LDF) during stepwise decrease in mean arterial blood pressure (MABP) and hyper-and hypocapnia. Experiments were performed on 12 adult Sprague-Dawley rats of either sex, anaesthetized with α-chloralose. The rat's head was fixed on a stereotaxic frame and a small hole was made in the parietal bone but the dura and a thin inner bone layer were kept intact. The microvascular blood flow of the parietal cortex on the right or on both sides was continuously recorded by the laser-Doppler flowmeter (Periflux PF2B, Perimed, Stockholm, Sweden). The cerebral circulation of the rat exhibited vasomotion in control conditions with a frequency of 8–10 cycles per minute (cpm) and an amplitude of 5–10% of the cerebral blood flow (CBF). No significant changes in CBF could be detected when the MABP was above 60 mmHg, but it decreased significantly when MABP was reduced below 50 mmHg. However, during stepwise pressure reduction the vasomotion frequency decreased progressively while its amplitude showed a reversed U-shaped curve with a peak at 60–80 mmHg. During hypercapnia, the rhythmical oscillations showed a decrease in both frequency and amplitude, whereas during hypocapnia their frequency did not change but their amplitude increased. These results support the hypothesis that the vasomotion frequency might be dependent of the wall tension and cellular pH while its amplitude could be related to decreased tissue oxygenation.     

A new method for processing of continuous intracranial pressure signals

This paper describes a new method for processing of continuous pressure signals. Continuous intracranial pressure (ICP) signals were sampled at 100 Hz, converted into digital data and processed during 6s time windows. According to a new algorithm, cardiac beat-induced single ICP waves were identified; pressure waves caused by noise in the signal were rejected for further analysis. The amplitude and latency values of the accepted single ICP waves were determined. For accepted 6s time windows, the mean ICP wave was computed as mean ICP wave amplitude and mean ICP wave latency. Mean ICP for every time window was computed according to current practice as sum of pressure levels divided by number of samples. The mean ICP wave parameters provide information about the single ICP waves that is not given by mean ICP. The method has been implemented in software to be used during online ICP monitoring, revealing mean ICP wave amplitude, mean ICP wave latency and mean ICP as numerical values every 6s. The values are presented in trend plots. Verification of correct single ICP wave identification can be done during online ICP monitoring. The clinical significance of the method was illustrated in four patients by observations that mean wave amplitudes corresponded better to the acute clinical state than the mean ICP; mean wave amplitudes could be elevated despite a normal mean ICP. In one patient with ICP and arterial blood pressure (ABP) signals monitored simultaneously with identical time reference, there was a weak correlation between mean ICP and ABP wave amplitudes. It is tentatively suggested that the mean ICP wave parameters are related to intracranial pressure-volume compensatory reserve capacity (compliance).     

Hypothermia related changes in electrocortical activity at stepwise increase of intracranial pressure in piglets.

Recent experimental studies have demonstrated that mild hypothermia can be effective in the control of intracranial hypertension. However, investigations to analyze the effects of hypothermia on changes in brain oxygen metabolism and electrocortical activity caused by increased intracranial pressure (ICP) are lacking. We examined the effects of mild hypothermia on electrocorticogram (ECoG) in combination with measurement of regional cerebral blood flow (CBF) and estimation of brain oxygen metabolism during stepwise increase of ICP. For this purpose thirteen female piglets (14 days old, 4-5 kg b.w.) were anaesthetized and mechanically ventilated. An epidural balloon was gradually inflated in order to increase ICP to 25 mmHg, 35 mmHg and 45 mmHg every 30 minutes at adjusted mean arterial blood pressures (MAP). This procedure resulted in gradual cerebral perfusion pressure (CPP) reduction of about 70%, 50%, and 30% of baseline [baseline CPP: normothermia (NT) 80+/-3 mmHg; hypothermia (HT) 84+/-3 mmHg]. Control animals were maintained in a normothermic state (38.6+/-0.2 degrees C). HT animals were surface cooled and maintained at 31.9+/-0.1 degrees C. ECoG, regional CBF, cerebral oxygen delivery (cDO2) and the cerebral metabolic rate of oxygen (CMRO2) were estimated during the normothermic period, after hypothermic stabilization, and after the gradual CPP reductions. The baseline ECoG showed the typical delta-dominated frequency pattern for isoflurane anaesthesia. At the hypothermic level, a frequency shift was seen from delta activity towards the higher frequencies (theta- and alpha activity) and the total spectral power was significantly reduced (56+/-17% from baseline, p < 0.05). the cortical CBF decreased markedly to 67+/-10% (p < 0.05), whereas the medulla oblongata blood flow increased slightly. During controlled increase of ICP by regional mass expansion from epidural balloon inflation, we found at mild and moderate stages of ICP increase (25 and 35 mmHg) only minimal changes in the ECoG in hypothermic animals compared to the hypothermic baseline, whereas the ECoG in normothermic animals showed a marked decrease in frequency, amplitude and total spectral power. We conclude that mild hypothermia produces an arousal-like ECoG activity with marked frequency shift to alpha activity and a change from high to low voltage activity. Furthermore, the hypothermic brain showed a preserved neuronal function at moderate stages of ICP. Obviously, hypothermia improves the functional tolerance of the brain to impaired oxygen supply.     

Dynamic cerebral autoregulation assessment using an ARX model: comparative study using step response and phase shift analysis

Middle cerebral arterial blood velocity (MCAv) response to spontaneous and manipulated changes of arterial blood pressure (ABP) was studied in eight subjects using a linear autoregressive with exogenous input (ARX) model. ABP and MCAv were measured non-invasively by photoplethysmograph and transcranial Doppler ultrasound, respectively. Data were recorded at rest (spontaneous changes in ABP) and during thigh cuff (step-wise changes) and lower body negative pressure (sinusoidal changes of 1/12 Hz) tests in both normocapnia and hypercapnia (5% CO2). Since autoregulation is modulated by CO2, respiratory CO2 was simultaneously monitored to allow comparison of cerebral autoregulation status with different CO2 levels. ABP and MCAv were fitted by ARX models and dynamic cerebral autoregulation was estimated by analysing both the step responses and phase shift at the 1/12 Hz of the corresponding ARX models. The ARX model consistently modelled the phase lead of MCAv to ABP and it showed that the phase shift at 1/12 Hz of ARX model is consistent with the real phase shift of the data (p=0.59). Strong linear relationships between pCO2 and gradient of the step response (r=-0.58, p<0.0001) and between pCO2 and phase shift (r=-0.76, p<0.0001) were observed, which suggests that cerebral autoregulation can be assessed by step response or phase shift analysis of the ARX model fitted to ABP and MCAv data with spontaneous changes.     

Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450 enzymes

This short review summarizes the potential role of cytochrome P450 (P450) in regulating blood flow in the brain tissue and in the skeletal muscle. We provide data showing that pressure-induced myogenic activity in the brain is largely responsible for autoregulation of CBF. This myogenic response to pressure is maintained, in part, by 20-HETE formation in arterial muscle cells through a P450 omega-hydroxylase coded for by a P450 4A cDNA. Autoregulation of CBF is a hallmark of the cerebral circulation and provides adequate nutritive blood flow despite large fluctuations in arterial pressure. Given the importance of oxidative metabolism in the brain, support of neuronal activity is mediated by functional hyperaemia to active neurones providing adequate delivery of oxidative substrate. We provide data demonstrating that this functional hyperaemia in the brain is regulated by astrocytes which sense neural activity and release dilator metabolites which shunt blood flow to active neurones. One of the metabolites released by astrocytes in this regard are epoxygenated products of arachidonic acid (AA) formed by P450 enzymes. These AA metabolites of P450 enzymes are epoxyeicosatrienoic acid (EETs). One of these P450 enzymes is coded by a 2C11 cDNA present in astrocytes. Furthermore, astrocytes are capable of inducing capillary angiogenesis which appears to be mediated, in part, by P450-derived EETs.     

Cushing's mechanism maintains cerebral perfusion pressure in experimental subarachnoid haemorrhage

Mortality following subarachnoid haemorrhage (SAH) is high, especially within the first 48 h. Poor outcome is predicted by high intracranial pressure which causes diminished cerebral perfusion pressure unless a compensatory increase in mean arterial blood pressure occurs. Therefore blood pressure elevation can be protective following subarachnoid haemorrhage despite the potential for rebleeding. This study investigated blood pressure responses to SAH and the impact on cerebral perfusion pressure and outcome, as demonstrated by two experimental models. Various blood pressure responses were demonstrated, both at the ictus and within the following 5 h. Elevated MABP at the ictus and at 2 h following experimental SAH was associated with maintenance of CPP in the presence of raised ICP. Poor outcome (arrest of the cerebral circulation) was predicted by failure of MABP to increase significantly above sham levels within 2 h of SAH. Rat SAH provides relatively inexpensive models to investigate physiological mechanisms that maintain cerebral perfusion in the presence of intracranial hypertension.     

Estimating normal and pathological dynamic responses in cerebral blood flow velocity to step changes in end-tidal pCO2

The regulation of cerebral blood flow (CBF) following changes in arterial blood pressure (ABP) and end-tidal pCO₂ (EtCO₂) are of clinical interest in assessing cerebrovascular reserve capacity. Linear finite-impulse-response modelling is applied to ABP, EtCO₂ and CBF velocity (CBFV, from transcranial Doppler measurements), which allows the CBFV response to ideal step changes in EtCO₂ to be estimated from clinical data showing more sluggish, and additional random variations. The confounding effects of ABP changes provoked by hypercapnia on the CBFV are also corrected for. Data from 56 patients suffering from stenosis of the carotid arteries (with normal or diminished cerebrovascular reactivity to EtCO₂ changes—CVR_{CO 2} were analysed. The results show the expected significant differences (p<0.05) between EtCO₂ steps up and down, the significant contribution from ABP variation, and also differences in the dynamic responses of patients with reduced CVR_{CO 2} (p<0.01 after 10 s). For the latter the CBFV response appears exhausted after about 15s, whereas for normals CBFV continues to increase. While dispersion of individual step responses remains large, the method gives encouraging results for the non-invasive study of compromised haemodynamics in different patient groups.     

Model-based noninvasive estimation of intracranial pressure from cerebral blood flow velocity and arterial pressure

Intracranial pressure (ICP) is affected in many neurological conditions. Clinical measurement of pressure on the brain currently requires placing a probe in the cerebrospinal fluid compartment, the brain tissue, or other intracranial space. This invasiveness limits the measurement to critically ill patients. Because ICP is also clinically important in conditions ranging from brain tumors and hydrocephalus to concussions, noninvasive determination of ICP would be desirable. Our model-based approach to continuous estimation and tracking of ICP uses routinely obtainable time-synchronized, noninvasive (or minimally invasive) measurements of peripheral arterial blood pressure and blood flow velocity in the middle cerebral artery (MCA), both at intra-heartbeat resolution. A physiological model of cerebrovascular dynamics provides mathematical constraints that relate the measured waveforms to ICP. Our algorithm produces patient-specific ICP estimates with no calibration or training. Using 35 hours of data from 37 patients with traumatic brain injury, we generated ICP estimates on 2665 nonoverlapping 60-beat data windows. Referenced against concurrently recorded invasive parenchymal ICP that varied over 100 millimeters of mercury (mmHg) across all records, our estimates achieved a mean error (bias) of 1.6 mmHg and SD of error (SDE) of 7.6 mmHg. For the 1673 data windows over 22 hours in which blood flow velocity recordings were available from both the left and the right MCA, averaging the resulting bilateral ICP estimates reduced the bias to 1.5 mmHg and SDE to 5.9 mmHg. This accuracy is already comparable to that of some invasive ICP measurement methods in current clinical use.     

Regional cerebral blood volume response to hypocapnia using susceptibility contrast MRI

We used steady-state susceptibility contrast MRI to evaluate the regional cerebral blood volume (rCBV) response to hypocapnia in anesthetised rats. The rCBV was determined in the dorsoparietal neocortex, the corpus striatum, the cerebellum, as well as blood volume in extracerebral tissue (group 1). In addition, we used laser-Doppler flow (LDF) measurements in the left dorsoparietal neocortex (group 2), to correlate changes in CBV and in cerebral blood flow. Baseline values, expressed as a percentage of blood volume in each voxel, were higher in the brain regions than in extracerebral tissue. Hypocapnia (P(a)CO(2) approximately 25 mmHg) resulted in a significant decrease in CBV in the cerebellum (-17 +/- 9%), in the corpus striatum (-15 +/- 6%) and in the neocortex (-12 +/- 7%), compared to the normocapnic CBV values (group 1). These changes were in good agreement with the values obtained using alternative techniques. No significant changes in blood volume were found in extracerebral tissue. The CBV changes were reversed during the recovery period. In the left dorsoparietal neocortex, the reduction in LDF (group 2) induced by hypocapnia (-21 +/- 8%) was in accordance with the values predicted by the Poiseuille's law. We conclude that rCBV changes during CO(2) manipulation can be accurately measured by susceptibility contrast MRI. Copyright -Copyright 2000 John Wiley & Sons, Ltd. Abbreviations used: ANOVA analysis of variance CBF cerebral blood flow CBV cerebral blood volume CPMG Carr-Purcell-Meiboom-Gill FiO(2) fractional inspired oxygen ICP intracranial pressure LDF laser-Doppler flow MABP mean arterial blood pressure MRI magnetic resonance imaging MTT mean transit time PaCO(2) arterial partial pressure of carbon dioxide PaO(2) arterial partial pressure of oxygen PET positron emission tomography rCBV regional cerebral blood volume SPECT single-photon emission computed tomography     

Intracranial pressure dynamics: changes of bandwidth as an indicator of cerebrovascular tension

The transmission bandwidth (BW) of arterial blood pressure (ABP) to intracranial pressure (ICP) was examined as a means of bedside monitoring of the state of cerebrovascular tension. Changes of BW of a black box identification model, relative arteriolar resistance and intracranial compliance were obtained from a piglet model equipped with a cranial window during induction of asphyxia, hypercapnia, and hypoxia. Changes of black box BW values and simulated changes of BW produced by a physiologically based lump parameter model of ICP dynamics are used to evaluate the hypothesis that during active cerebrovascular tension, changes of BW are inversely related to cerebral perfusion pressure (CPP), and during passive cerebrovascular tension, changes of BW are not inversely related to changes of CPP. Induction of asphyxia (n = 3) produced BW changes of the black box model that were simulated as an active cerebrovascular tension phase during decreasing CPP followed by a passive tension phase. Reventilation after prolonged asphyxia produced significant increases of BW that were simulated by a passive tension. Hypercapnic (n = 6) and hypoxic (n = 6) challenges produced: (1) significant changes of BW that were matched with simulations of the lumped parameter model for active tension; and (2) relationships between values of BW and relative average cerebral arteriolar resistance and intracranial compliance were inverse and correlated to a regression function of approximately x(-1). Changes of BW of the black box model and the simulations of the lumped parameter model support the feasibility of the stated hypothesis. As such, the evaluation of changes of BW of the black box model with respect to changes of CPP may be a useful method for monitoring the state of cerebrovascular tension.     

Cerebrovascular transmural pressure and autoregulation

The cerebral blood flow (CBF) response to changes in perfusion pressure mediated through decreases in arterial pressure, increases in cerebrospinal fluid (CSF) pressure and increases in jugular venous pressure was studied in anesthetized dogs. A preparation was developed in which each of the three relevant pressures could be controlled and manipulated independently of each other. In this preparation, the superior vena cava and femoral vein were cannulated and drained into a reservoir. Blood was pumped from the reservoir into the right atrium. With this system, mean arterial pressure and jugular venous pressure could be independently controlled. CSF pressure (measured in the lateral ventricle) could be manipulated via a cisternal puncture. Total and regional CBF responses to alterations in perfusion pressure were studied with the radiolabelled microsphere technique. Each hemisphere was sectioned into 13 regions: spinal cord, cerebellum, medulla, pons, midbrain, diencephalon, caudate, hippocampus, parahippocampal gyrus, and occipital, temporal, parietal and frontal lobes. Despite 30 mm Hg reductions in arterial pressure or increases in jugular venous pressure or CSF pressure, little change in CBF was observed provided the perfusion pressure (arterial pressure minus jugular venous pressure or CSF pressure depending on which pressure was of greater magnitude) was greater than the lower limit for cerebral autoregulation (approximately 60 mm Hg). However, when the perfusion pressure was reduced by any of the three different methods to levels less than 60 mm Hg (average of 48 mm Hg), a comparable reduction (25–35%) in both total and regional CBF was obtained. Thus comparable changes in the perfusion pressure gradient established by decreasing arterial pressure, increasing jugular venous pressure and increasing CSF pressure resulted in similar total and regional blood flow responses. Independent alterations of arterial and CSF pressures, and jugular venous pressure produce opposite changes in vascular transmural pressure yet result in similar CBF responses. These results show that cerebral autoregulation is a function of the perfusion pressure gradient and cannot be accounted for predominantly by myogenic mechanisms.     

Sympathetic Withdrawal Augments Cerebral Blood Flow During Acute Hypercapnia in Sleeping Lambs

Study Objectives:

Cerebral sympathetic activity constricts cerebral vessels and limits increases in cerebral blood flow (CBF), particularly in conditions such as hypercapnia which powerfully dilate cerebral vessels. As hypercapnia is common in sleep, especially in sleep disordered breathing, we tested the hypothesis that sympathetic innervation to the cerebral circulation attenuates the CBF increase that accompanies increases in PaCO₂ in sleep, particularly in REM sleep when CBF is high.

Design:

Newborn lambs (n = 5) were instrumented to record CBF, arterial pressure (AP) intracranial pressure (ICP), and sleep-wake state (quiet wakefulness (QW), NREM, and REM sleep). Cerebral vascular resistance was calculated as CVR = [AP-ICP]/CBF. Lambs were subjected to 60-sec tests of hypercapnia (FiCO₂ = 0.08) during spontaneous sleep-wake states before (intact) and after sympathectomy (bilateral superior cervical ganglionectomy).

Results:

During hypercapnia in intact animals, CBF increased and CVR decreased in all sleep-wake states, with the greatest changes occurring in REM (CBF 39.3% ± 6.1%, CVR −26.9% ± 3.6%, P < 0.05). After sympathectomy, CBF increases (26.5% ± 3.6%) and CVR decreases (−21.8% ± 2.1%) during REM were less (P < 0.05). However the maximal CBF (27.8 ± 4.2 mL/min) and minimum CVR (1.8 ± 0.3 mm Hg/ min/mL) reached during hypercapnia were similar to intact values.

Conclusion:

Hypercapnia increases CBF in sleep and wakefulness, with the increase being greatest in REM. Sympathectomy increases baseline CBF, but decreases the response to hypercapnia. These findings suggest that cerebral sympathetic nerve activity is normally withdrawn during hypercapnia in REM sleep, augmenting the CBF response.

Citation:

Cassaglia PA; Griffiths RI; Walker AM. Sympathetic withdrawal augments cerebral blood flow during acute hypercapnia in sleeping lambs. SLEEP 2008;31(12):1729–1734.     

Hemodynamic changes in the posterior cerebral circulation triggered by insufficient sympathetic innervation – Cause of primary intracerebral hemorrhage?

Primary intracerebral hemorrhage (ICH) is caused by hypertensive disease of small penetrating blood vessels in the basal ganglia, brain stem and cerebellum. Those regions are supplied by arteries of the so-called posterior brain circulation with insufficient sympathetic innervation. We propose the following hypothesis: due to insufficient sympathetic innervation hemodynamic changes occur in the vascular bed of the posterior brain circulation serving as a key factor for arterial rupture. If autoregulation is insufficient to maintain normal cerebral blood flow, in abrupt rise in the blood pressure, the amount of blood is rising causing higher static pressure, and according to Laplace's law higher pressure and larger radius leads to higher wall tension and subsequent rupture of arterial wall previously weakened by prolonged hypertension.