The pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium.
We investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100β, and cortisol were measured during each data acquisition.
Data from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100β (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010).
In this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100β and cortisol in the diagnosis of sepsis-associated delirium are warranted.
Clinical monitoring of cerebral blood flow (CBF) autoregulation in patients undergoing liver transplantation may provide a means for optimizing blood pressure to reduce the risk of brain injury. The purpose of this pilot project is to test the feasibility of autoregulation monitoring with transcranial Doppler (TCD) and near infrared spectroscopy (NIRS) in patients undergoing liver transplantation and to assess changes that may occur perioperatively.
We performed a prospective observational study in 9 consecutive patients undergoing orthotopic liver transplantation. Patients were monitored with TCD and NIRS. A continuous Pearson’s correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity and between MAP and NIRS data, rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Both Mx and COx were averaged and compared during the dissection phase, anhepatic phase, first 30 mins of reperfusion, and remaining reperfusion phase. Impaired autoregulation was defined as Mx ≥ 0.4.
Autoregulation was impaired in one patient during all phases of surgery, in two patients during the anhepatic phase, and in one patient during reperfusion. Impaired autoregulation was associated with a MELD score > 15 (p=0.015) and postoperative seizures or stroke (p<0.0001). Analysis of Mx categorized in 5-mmHg bins revealed that MAP at the lower limit of autoregulation (MAP when Mx increased to ≥ 0.4) ranged between 40 and 85 mmHg. Average Mx and average COx were significantly correlated (p=0.0029). The relationship between COx and Mx remained when only patients with bilirubin > 1.2 mg/dL were evaluated (p=0.0419). There was no correlation between COx and baseline bilirubin (p=0.2562) but MELD score and COx were correlated (p=0.0458). Average COx was higher for patients with a MELD score > 15 (p=0.073) and for patients with a neurologic complication than for patients without neurologic complications (p=0.0245).
These results suggest that autoregulation is impaired in patients undergoing liver transplantation, even in the absence of acute, fulminant liver failure. Identification of patients at risk for neurologic complications after surgery may allow for prompt neuroprotective interventions, including directed pressure management.
Impaired cerebral autoregulation may predispose patients to cerebral hypoperfusion during cardiopulmonary bypass (CPB). The purpose of this study was to identify risk factors for impaired autoregulation during coronary artery bypass graft, valve surgery with CPB, or both and to evaluate whether near-infrared spectroscopy (NIRS) autoregulation monitoring could be used to identify this condition.
Two hundred and thirty-four patients were monitored with transcranial Doppler and NIRS. A continuous, moving Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and cerebral blood flow (CBF) velocity, and between MAP and NIRS data, to generate the mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Functional autoregulation is indicated by an Mx and COx that approach zero (no correlation between CBF and MAP); impaired autoregulation is indicated by an Mx and COx approaching 1. Impaired autoregulation was defined as an Mx ≥0.40 at all MAPs during CPB.
Twenty per cent of patients demonstrated impaired autoregulation during CPB. Based on multivariate logistic regression analysis, time-averaged COx during CPB, male gender, , CBF velocity, and preoperative aspirin use were independently associated with impaired CBF autoregulation. Perioperative stroke occurred in six of 47 (12.8%) patients with impaired autoregulation compared with five of 187 (2.7%) patients with preserved autoregulation (P=0.011).
Impaired CBF autoregulation occurs in 20% of patients during CPB. Patients with impaired autoregulation are more likely than those with functional autoregulation to have perioperative stroke. Non-invasive monitoring autoregulation may provide an accurate means to predict impaired autoregulation.
Clinical trials registration. www.clinicaltrials.gov (NCT00769691).
cardiac surgery; cardiopulmonary bypass; cerebral autoregulation; stroke
To compare cerebral blood flow (CBF) autoregulation in patients undergoing continuous flow left ventricular assist device (LVAD) implantation with that in patients undergoing coronary artery bypass graft (CABG) surgery.
Prospective, observational, controlled study.
Academic medical center.
Fifteen patients undergoing LVAD insertion and 10 patients undergoing CABG surgery.
Measurements and Main Results
Cerebral autoregulation was monitored with transcranial Doppler and near-infrared spectroscopy (NIRS). A continuous, Pearson's correlation coefficient was calculated between mean arterial pressure (MAP) and CBF velocity, and between MAP and NIRS data rendering the variables mean velocity index (Mx) and cerebral oximetry index (COx), respectively. Mx and COx approach zero when autoregulation is intact (no correlation between CBF and MAP), but approach 1 when autoregulation is impaired. Mx was lower during and immediately after cardiopulmonary bypass (CPB) in the LVAD group than it was in the CABG surgery patients, indicating better preserved autoregulation. Based on COx monitoring, autoregulation tended to be better preserved in the LVAD group than in the CABG group immediately after surgery (p=0.0906). On postoperative day 1, COx was lower in LVAD patients than in CABG surgery patients, again indicating preserved CBF autoregulation (p=0.0410). Based on COx monitoring, 3 (30%) of the CABG patients had abnormal autoregulation (COx ≥ 0.3) on the first postoperative day but none of the LVAD patients had this abnormality (p=0.037).
These data suggest that CBF autoregulation is preserved during and immediately after surgery in patients undergoing LVAD insertion.
Individualizing arterial blood pressure (ABP) targets during cardiopulmonary bypass (CPB) based on cerebral blood flow (CBF) autoregulation monitoring may provide a more effective means for preventing cerebral hypoperfusion than the current standard of care. Autoregulation can be monitored in real-time with transcranial Doppler (TCD). We have previously demonstrated that near infrared spectroscopy (NIRS) derived regional cerebral oxygen saturation (rScO2) provides a clinically suitable surrogate of CBF for autoregulation monitoring. The purpose of this study was to determine the accuracy of a stand-alone “plug-and-play” investigational system for autoregulation monitoring that uses a commercially available NIRS monitor with TCD methods.
TCD monitoring of middle cerebral artery CBF velocity and NIRS monitoring was performed in 70 patients during CPB. Indices of autoregulation were computed by both a personal computer-based system and an investigational prototype NIRS-based monitor. A moving linear correlation coefficient between slow waves of ABP and CBF velocity (mean velocity index, M×) and between ABP and rScO2 (cerebral oximetry index, CO×) were calculated. When CBF is autoregulated, there is no correlation between CBF and ABP; when CBF is dysregulated, M× and CO× approach 1 (i.e., CBF and ABP are correlated). Linear regression and bias analysis was performed between time-averaged values of M× and CO× derived from the personal computer-based system and from CO× measured with the prototype monitor. Values for M× and CO× were categorized in 5 mmHg bins of ABP for each patient. The lower limit of CBF autoregulation) was defined as the ABP where M× incrementally increased to ≥ 0.4.
There was correlation and good agreement between CO× derived from the prototype monitor and M× (r=0.510, 95% confidence interval [CI], 0.414 to 0.595, p<0.001; bias -0.07 ± 0.19). The correlation and bias between the personal computer-based CO× and CO× from the prototype NIRS monitor were r=0.957, 95% CI, 0.945 to 0.966, p<0.001 and 0.06±0.06, respectively. The average ABP at the lower limit of autoregulation was 63 ± 11 mmHg (95% prediction interval, 52 to 74 mmHg mmHg). While the mean ABP at the CO×-determined lower limit of autoregulation determined with the prototype monitor was statistically different from that determined by M× (59 ± 9 mmHg, 95% prediction interval, 50 to 68 mmHg, p=0.026), the difference is not likely clinically meaningful.
Monitoring CBF autoregulation with an investigational stand-alone NIRS monitor is correlated and in good agreement with TCD based methods. Availability of such a device would allow wide-spread autoregulation monitoring as a means of individualizing ABP targets during CPB.
Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis.
Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2.
30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035).
AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD.
clinicalTrials.gov ID NCT01029080
Mean arterial blood pressure (MAP) targets are empirically chosen during cardiopulmonary bypass (CPB). We have previously shown that near-infrared spectroscopy (NIRS) can be used clinically for monitoring cerebral blood flow autoregulation. The hypothesis of this study was that real-time autoregulation monitoring using NIRS-based methods is more accurate for delineating the MAP at the lower limit of autoregulation (LLA) during CPB than empiric determinations based on age, preoperative history, and preoperative blood pressure.
Two hundred thirty-two patients undergoing coronary artery bypass graft and/or valve surgery with CPB underwent transcranial Doppler monitoring of the middle cerebral arteries and NIRS monitoring. A continuous, moving Pearson's correlation coefficient was calculated between MAP and cerebral blood flow velocity, and between MAP and NIRS data to generate mean velocity index and cerebral oximeter index. When autoregulated, there is no correlation between cerebral blood flow and MAP (i.e., mean velocity and cerebral oximetry indices approach 0); when MAP is below the LLA, mean velocity and cerebral oximetry indices approach 1. The LLA was defined as the MAP where mean velocity index increased with declining MAP to ≥ 0.4. Linear regression was performed to assess the relation between preoperative systolic blood pressure, MAP, MAP in 10% decrements from baseline, and average cerebral oximetry index with MAP at the LLA.
The MAP at the LLA was 66 mmHg (95% prediction interval, 43 to 90 mmHg) for the 225 patients in which this limit was observed. There was no relationship between preoperative MAP and the LLA (p = 0.829) after adjusting for age, gender, prior stroke, diabetes, and hypertension, but a cerebral oximetry index value of >0.5 was associated with the LLA (p=0.022). The LLA could be identified with cerebral oximetry index in 219 (94.4%) patients. The mean difference in the LLA for mean velocity index versus cerebral oximetry index was −0.2±10.2 mmHg (95%CI, −1.5 to 1.2 mmHg). Preoperative systolic blood pressure was associated with a higher LLA (p=0.046) but only for those with systolic blood pressure ≤160 mmHg.
There is a wide range of MAP at the LLA in patients during CPB making estimating this target difficult. Real-time monitoring of autoregulation with cerebral oximetry index may provide a more rational means for individualizing MAP during CPB.
Background and Purpose
Assessment of autoregulation in the time domain is a promising monitoring method for actively optimizating cerebral perfusion pressure (CPP) in critically ill patients. The ability to detect loss of autoregulatory vasoreactivity to spontaneous fluctuations in CPP was tested with a new time-domain method that used near-infrared spectroscopic measurements of tissue oxyhemoglobin saturation in an infant animal model.
Piglets were made progressively hypotensive over 4 to 5 hours by inflation of a balloon catheter in the inferior vena cava, and the breakpoint of autoregulation was determined using laser-Doppler flowmetry. The cerebral oximetry index (COx) was determined as a moving linear correlation coefficient between CPP and INVOS cerebral oximeter waveforms during 300-second periods. A laser-Doppler derived time-domain analysis of spontaneous autoregulation with the same parameters (LDx) was also determined.
An increase in the correlation coefficient between cerebral oximetry values and dynamic CPP fluctuations, indicative of a pressure-passive relationship, occurred when CPP was below the steady state autoregulatory breakpoint. This COx had 92% sensitivity (73% to 99%) and 63% specificity (48% to 76%) for detecting loss of autoregulation attributable to hypotension when COx was above a threshold of 0.36. The area under the receiver-operator characteristics curve for the COx was 0.89. COx correlated with LDx when values were sorted and averaged according to the CPP at which they were obtained (r=0.67).
The COx is sensitive for loss of autoregulation attributable to hypotension and is a promising monitoring tool for determining optimal CPP for patients with acute brain injury.
autoregulation; cerebral blood flow; hypotension; neonate; oxygenation; piglet
The cerebrovascular effects of nimodipine are still poorly understood even in the healthy condition; in particular, its effects on tissue oxygenation have never been investigated.
The aim of the present study was to investigate changes in cerebral oxygenation and blood volume upon oral administration of nimodipine (90 mg) in the healthy condition.
In eight subjects, changes in cerebral tissue oxygenation and blood volume were determined simultaneously with changes in blood velocity of the middle cerebral artery (VMCA) by using, respectively, near infrared spectroscopy (NIRS) and transcranial Doppler ultrasonography (TCD). The subjects also underwent non-invasive assessment of arterial blood pressure (ABP) and end-tidal CO2. TCD and NIRS CO2 reactivity indices were also extracted.
Nimodipine significantly reduced ABP (11±13%) and increased heart rate, as well as NIRS oxygenation (6.0±4.8%) and blood volume indices (9.4±10.1%), while VMCA was not significantly decreased (2.0±3.5%). Nimodipine slightly but significantly reduced the VMCA response to changes in pCO2 whereas the CO2 reactivity of NIRS parameters was improved.
The observed changes in cerebral tissue oxygenation and blood volume indicate nimodipine-induced cerebrovascular dilation and increased perfusion, while the effect on VMCA possibly results from dilation of the insonated artery. The present results cast doubt on the putative nimodipine-induced impairment of CO2 reactivity.
cerebral blood flow; hyperventilation; near infrared spectroscopy; nimodipine; rebreathing
To compare changes in cerebral autoregulation in response to controlled, lower body negative pressure‐induced hypotension in patients with carotid sinus syndrome (CSS) and case controls.
Prospective case controlled study.
Secondary and tertiary referral falls and syncope service.
17 consecutive patients with CSS and 11 asymptomatic controls.
Hypotension insufficient to cause syncope induced by lower body negative pressure (minimum 30 mm Hg fall in systolic blood pressure (SBP)) during concomitant transcranial Doppler ultrasonography.
Main outcome measures
Cerebral autoregulation (systolic, diastolic and mean middle cerebral arterial blood flow velocities and cerebrovascular resistance) with continuous end‐tidal carbon dioxide and haemodynamic monitoring.
Cerebral autoregulatory indices differed significantly between patients with CSS and controls. Systolic, diastolic and middle cerebral arterial blood flow velocities were, respectively, 9.2 m/s (95% confidence interval (CI) 2.9 to 15.4 m/s), 4.7 m/s (95% CI 1.5 to 7.9 m/s) and 6.9 m/s (95% CI 2.5 to 11.4 m/s) slower in patients with CSS. Cerebrovascular resistance was significantly greater in patients with CSS than in controls at SBP nadir and suction release; differences were 0.9 mm Hg/m/s (95% CI 0.0 to 1.7 mm Hg/m/s) and 0.8 mm Hg/m/s (95% CI 0.0 to 1.7 mm Hg/m/s), respectively. End‐tidal carbon dioxide and systemic haemodynamic variables were similar for patients and controls at baseline and during lower body negative pressure.
Cerebral autoregulation is altered in patients with CSS. This difference may have aetiological implications in the differential presentation with falls and drop attacks rather than syncope.
ageing; carotid arteries; cerebral autoregulation; cerebrovascular circulation; syncope
Analysis of cerebral autoregulation by measuring spontaneous oscillations in the low frequency spectrum of cerebral cortical vessels might be a useful tool for assessing risk and investigating different treatment strategies in carotid artery disease and stroke. Near infrared spectroscopy (NIRS) is a non-invasive optical method to investigate regional changes in oxygenated (oxyHb) and deoxygenated hemoglobin (deoxyHb) in the outermost layers of the cerebral cortex. In the present study we examined oxyHb low frequency oscillations, believed to reflect cortical cerebral autoregulation, in 16 patients with both symptomatic carotid occlusive disease and cerebral hypoperfusion in comparison to healthy controls. Each hemisphere was examined with two NIRS channels using a 3 cm source detector distance. Arterial blood pressure (ABP) was measured via a finger plethysmograph. Using transfer function analysis ABP-oxyHb phase shift and gain as well as inter-hemispheric phase shift and amplitude ratio were assessed. We found that inter-hemispheric amplitude ratio was significantly altered in hypoperfusion patients compared to healthy controls (P = 0.010), because of relatively lower amplitude on the hypoperfusion side. The inter-hemispheric phase shift showed a trend (P = 0.061) toward increased phase shift in hypoperfusion patients compared to controls. We found no statistical difference between hemispheres in hypoperfusion patients for phase shift or gain values. There were no differences between the hypoperfusion side and controls for phase shift or gain values. These preliminary results suggest an impairment of autoregulation in hypoperfusion patients at the cortical level detected by NIRS.
cerebral autoregulation; low frequency oscillations; hypoperfusion; stroke; carotid artery disease; Doppler; near infrared spectroscopy
To determine whether mean arterial blood pressure (MAP) excursions below the lower limit of cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB) are associated with acute kidney injury (AKI) after surgery.
Tertiary care medical center.
Four hundred ten patients undergoing cardiac surgery with CPB.
Prospective observational study.
Measurements and Main Results
Autoregulation was monitored during CPB by calculating a continuous, moving Pearson’s correlation coefficient between MAP and processed near-infrared spectroscopy signals to generate the variable cerebral oximetry index (COx). When MAP is below the lower limit of autoregulation, COx approaches 1, because CBF is pressure passive. An identifiable lower limit of autoregulation was ascertained in 348 patients. Based on the RIFLE criteria, AKI developed within 7 days of surgery in 121 (34.8%) of these patients. Although the average MAP during CPB did not differ, the MAP at the limit of autoregulation and the duration and degree to which MAP was below the autoregulation threshold (mmHg × min/hr of CPB) were both higher in patients with AKI than in those without AKI. Excursions of MAP below the lower limit of autoregulation (relative risk, 1.02, 95% confidence interval, 1.01 to 1.03, p<0.0001) and diabetes (relative risk, 1.78, 95% confidence interval, 1.27 to 2.50, p=0.001) were independently associated with for AKI.
Excursions of MAP below the limit of autoregulation and not absolute MAP are independently associated with for AKI. Monitoring COx may provide a novel method for precisely guiding MAP targets during CPB.
Cerebral autoregulation; blood pressure; cardiac surgery; acute kidney injury
By mapping the dynamics of brain reorganization, functional magnetic resonance imaging MRI (fMRI) has allowed for significant progress in understanding cerebral plasticity phenomena after a stroke. However, cerebro-vascular diseases can affect blood oxygen level dependent (BOLD) signal. Cerebral autoregulation is a primary function of cerebral hemodynamics, which allows to maintain a relatively constant blood flow despite changes in arterial blood pressure and perfusion pressure. Cerebral autoregulation is reported to become less effective in the early phases post-stroke.
This study investigated whether any impairment of cerebral hemodynamics that occurs during the acute and the subacute phases of ischemic stroke is related to changes in BOLD response.
We enrolled six aphasic patients affected by acute stroke. All patients underwent a Transcranial Doppler to assess cerebral autoregulation (Mx index) and fMRI to evaluate the amplitude and the peak latency (time to peak-TTP) of BOLD response in the acute (i.e., within four days of stroke occurrence) and the subacute (i.e., between five and twelve days after stroke onset) stroke phases.
As patients advanced from the acute to subacute stroke phase, the affected hemisphere presented a BOLD TTP increase (p = 0.04) and a deterioration of cerebral autoregulation (Mx index increase, p = 0.046). A similar but not significant trend was observed also in the unaffected hemisphere. When the two hemispheres were grouped together, BOLD TTP delay was significantly related to worsening cerebral autoregulation (Mx index increase) (Spearman's rho = 0.734; p = 0.01).
The hemodynamic response function subtending BOLD signal may present a delay in peak latency that arises as patients advance from the acute to the subacute stroke phase. This delay is related to the deterioration of cerebral hemodynamics. These findings suggest that remodeling the fMRI hemodynamic response function in the different phases of stroke may optimize the detection of BOLD signal changes.
A variety of near-infrared spectroscopy devices can be used to make noninvasive measurements of cerebral tissue oxygen saturation (ScO2). The ScO2 measured by the NIRO 300 spectrometer (Hamamatsu Photonics, Japan) is called the cerebral tissue oxygenation index (TOI) and is an assessment of the balance between cerebral oxygen delivery and utilization. We designed this study to investigate the effect of systemic and intracranial physiological changes on TOI.
Fifteen healthy volunteers were studied during isocapneic hyperoxia and hypoxemia, and normoxic hypercapnea and hypocapnea. Absolute cerebral TOI and changes in oxy- and deoxy-hemoglobin concentrations were measured using a NIRO 300. Changes in arterial oxygen saturation (SaO2), end-tidal carbon dioxide tension (EtCO2), heart rate, mean arterial blood pressure (MBP) and middle cerebral artery blood flow velocity (Vmca) were also measured during these physiological challenges. Changes in cerebral blood volume (CBV) were subsequently calculated from changes in total cerebral hemoglobin concentration.
Baseline TOI was 67.3% with an interquartile range (IQR) of 65.2% - 71.9%. Hypoxemia was associated with a median decrease in TOI of 7.1% (IQR -9.1% to -5.4%) from baseline (p<0.0001) and hyperoxia with a median increase of 2.3% (IQR 2.0% to 2.5%) (p<0.0001). Hypocapnea caused a reduction in TOI of 2.1% (IQR -3.3% to -1.3%) from baseline (p<0.0001) and hypercapnea an increase of 2.6% (IQR 1.4% to 3.7%) (p<0.0001). Changes in SaO2 (p<0.0001), EtCO2 (p<0.0001), CBV (p=0.0003) and MBP (p=0.03) were significant variables affecting TOI. Changes in Vmca (p=0.7) and heart rate (p=0.2) were not significant factors.
TOI is an easy-to-monitor variable that provides real-time, multi-site and noninvasive assessment of the balance between cerebral oxygen delivery and utilization. However, TOI is a complex variable that is affected by SaO2 and EtCO2, and, to a lesser extent, by MBP and CBV. Clinicians need to be aware of the systemic and cerebral physiological changes that can affect TOI in order to interpret changes in this variable during clinical monitoring.
The effects of an acute cryogenic injury on cerebral flow (CBF) and cerebral vascular reactivity were studied in 12 anaesthetised, ventilated baboons. Autoregulation, defined in this study as intact with a greater than 20% change in cerebrovascular resistance in response to a change in cerebral perfusion pressure, was tested before the lesion by arterial hypotension. Intact autoregulation was found in half the animals, but all animals showed an increase in CBF with hypercarbia. The cryogenic lesion was followed by a marked rise in intracranial pressure, and a fall in CBF which was only partly related to the status of autoregulation beforehand. After injury, arterial hypertension caused an increase in cerebrovascular resistance of more than 20% in half the animals. This response was not related to the presence of autoregulation before the lesion, and was accompanied by a greater impairment of the cerebrovascular response to carbon dioxide, more severe brain oedema, and lower cerebral oxygen consumption, than in the remaining baboons which had a pressure passive response to arterial hypertension. This study confirms that the failure of CBF to increase with arterial hypertension may indicate severe brain damage rather than intact physiological autoregulation.
Background: It has been suggested that a moving correlation index between mean arterial blood pressure and intracranial pressure, called PRx, can be used to monitor and quantify cerebral vasomotor reactivity in patients with head injury.
Objectives: To validate this index and study its relation with cerebral blood flow velocity and cerebral autoregulation; and to identify variables associated with impairment or preservation of cerebral vasomotor reactivity.
Methods: The PRx was validated in a prospective study of 40 head injured patients. A PRx value of less than 0.3 indicates intact cerebral vasomotor reactivity, and a value of more than 0.3, impaired reactivity. Arterial blood pressure, intracranial pressure, mean cerebral perfusion pressure, and cerebral blood flow velocity, measured bilaterally with transcranial Doppler ultrasound, were recorded. Dynamic cerebrovascular autoregulation was measured using a moving correlation coefficient between arterial blood pressure and cerebral blood flow velocity, the Mx, for each cerebral hemisphere. All variables were compared in patients with intact and impaired cerebral vasomotor reactivity.
Results: No correlation between arterial blood pressure or cerebral perfusion pressure and cerebral blood flow velocity was seen in 19 patients with intact cerebral vasomotor reactivity. In contrast, the correlation between these variables was significant in 21 patients with impaired cerebral vasomotor reactivity, whose cerebral autoregulation was reduced. There was no correlation with intracranial pressure, arterial blood pressure, cerebral perfusion pressure, or interhemispheric cerebral autoregulation differences, but the values for these indices were largely within normal limits.
Conclusions: The PRx is valid for monitoring and quantifying cerebral vasomotor reactivity in patients with head injury. This intracranial pressure based index reflects changes in cerebral blood flow and cerebral autoregulatory capacity, suggesting a close link between blood flow and intracranial pressure in head injured patients. This explains why increases in arterial blood pressure and cerebral perfusion pressure may be useful for reducing intracranial pressure in selected head injured patients (those with intact cerebral vasomotor reactivity).
Background and Methods
Low frequency oscillations (LFO) of cerebral vessels are believed to reflect cerebral autoregulation. We investigated day-to-day and hemispheric variations in 0·1 Hz LFO with near infrared spectroscopy (NIRS) and transcranial Doppler (TCD) to determine phase shift and gain of oxygenated haemoglobin (oxy-Hb) and the velocity of the middle cerebral artery (Vmca) to the arterial blood pressure (ABP). The direct left–right phase shifts of oxyHb and Vmca were also assessed. We examined 44 healthy volunteers by simultaneous recordings of ABP, oxyHb and Vmca during spontaneous and paced breathing at 6 breaths per minute on two separate days.
The variation between hemispheres had a prediction interval (PI) of ±39° for ABP–oxyHb phase shift and ±69% for gain. ABP–Vmca showed ±57° PI phase shift and ±158% PI for gain. The variation from day to day showed ±61° PI for ABP–oxyHb phase shift and ±297% PI for gain. ABP–Vmca showed ±45° PI phase shift and ±166% PI for gain. We found a linear relation between phase shift of oxyHb and Vmca at paced breathing (P = 0·0005), but not at rest (P = 0·235).
Our results show that LFO phase shift ABP–oxyHb may be used as a robust measurement of differences in autoregulation between hemispheres and over time. In addition, we found a strong relation between oxyHb and Vmca during paced breathing. Gain showed too large variation for clinical use, as the SD was up to 100-fold of mean values.
Cerebral autoregulation; low frequency oscillations; near infrared spectroscopy; transcranial Doppler
Brain tissue partial oxygen pressure (PbtO2) and near-infrared spectroscopy (NIRS) are novel methods to evaluate cerebral oxygenation. We studied the response patterns of PbtO2, NIRS, and cerebral blood flow velocity (CBFV) to changes in arterial pressure (AP) and intracranial pressure (ICP).
Digital recordings of multimodal brain monitoring from 42 head-injured patients were retrospectively analysed. Response latencies and patterns of PbtO2, NIRS-derived parameters [tissue oxygenation index (TOI) and total haemoglobin index (THI)], and CBFV reactions to fluctuations of AP and ICP were studied.
One hundred and twenty-one events were identified. In reaction to alterations of AP, ICP reacted first [4.3 s; inter-quartile range (IQR) −4.9 to 22.0 s, followed by NIRS-derived parameters and CBFV (10.9 s; IQR: −5.9 to 39.6 s, 12.1 s; IQR: −3.0 to 49.1 s, 14.7 s; IQR: −8.8 to 52.3 s for THI, CBFV, and TOI, respectively), with PbtO2 reacting last (39.6 s; IQR: 16.4 to 66.0 s). The differences in reaction time between NIRS parameters and PbtO2 were significant (P<0.001). Similarly when reactions to ICP changes were analysed, NIRS parameters preceded PbtO2 (7.1 s; IQR: −8.8 to 195.0 s, 18.1 s; IQR: −20.6 to 80.7 s, 22.9 s; IQR: 11.0 to 53.0 s for THI, TOI, and PbtO2, respectively). Two main patterns of responses to AP changes were identified. With preserved cerebrovascular reactivity, TOI and PbtO2 followed the direction of AP. With impaired cerebrovascular reactivity, TOI and PbtO2 decreased while AP and ICP increased. In 77% of events, the direction of TOI changes was concordant with PbtO2.
NIRS and transcranial Doppler signals reacted first to AP and ICP changes. The reaction of PbtO2 is delayed. The results imply that the analysed modalities monitor different stages of cerebral oxygenation.
brain tissue partial oxygen pressure; cerebral haemodynamics; cerebral oxygenation; cerebrovascular reactivity; near-infrared spectroscopy; tissue haemoglobin index; tissue oxygenation index
To determine whether alterations in cerebral blood flow regulation are associated with slow gait speed and falls in community-dwelling elderly individuals.
The study sample consisted of 419 individuals from the MOBILIZE Boston Study (MBS) who had transcranial Doppler ultrasound measures of cerebral blood flow velocity. The MBS is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We measured beat-to-beat blood flow velocity in the middle cerebral artery in response to 1) changes in end-tidal CO2 (cerebral vasoreactivity) and 2) blood pressure changes during a sit-to-stand protocol (cerebral autoregulation). Gait speed was measured during a 4-meter walk. Falls were tracked by monthly calendars, and demographic and clinical characteristics were assessed at baseline.
A multivariate linear regression analysis showed that cerebral vasoreactivity was cross-sectionally related to gait speed (p = 0.039). Individuals in the lowest quintile of vasoreactivity had lower gait speeds as compared to those in the highest quintile (p = 0.047). In a negative binomial regression analysis adjusted for relevant covariates, the relationship between cerebral vasoreactivity and fall rate did not reach significance. However, when comparing individuals in the lowest to highest quintile of cerebral vasoreactivity, those in the lowest quintile had a higher fall rate (p = 0.029).
Impaired cerebral blood flow regulation, as measured by cerebral vasoreactivity to CO2, is associated with slow gait speed and may lead to the development of falls in elderly people.
= angiotensin converting enzyme inhibitors;
= activities of daily living;
= arterial pressure monitoring;
= blood flow velocity;
= Center for Epidemiologic Studies Depression Scale;
= cerebrovascular resistance;
= heart rate;
= Hopkins Verbal Learning Test–Revised;
= l-NG-monomethyl arginine;
= MOBILIZE Boston Study;
= middle cerebral artery;
= Short Physical Performance Battery;
= signal abnormalities in cerebral white matter.
The capacity of the brain to regulate its blood flow in order to meet metabolic demands and to compensate for acute and chronic changes in cerebral perfusion pressure (cerebral autoregulation) is an essential protecting mechanism against cerebral ischemia.
We reviewed existing data on methods of assessing cerebral blood flow and autoregulation.
Cerebral autoregulation is mechanistically complex and depends on myogenic, neuronal, endothelial, and metabolic factors. There are numerous methods of estimating cerebrovascular reserve (CVR) non-invasively including Positive Emission Tomography (gold standard), Transcranial Doppler ultrasound, dynamic contrast-enhanced perfusion Magnetic Resonance Imaging, Single-Photon Emission Computed Tomography and Xenon Computed Tomography. Since each of these techniques has its advantages and disadvantages, selection of a specific method for CVR testing depends on availability, acquired experience in interpreting the study, required precision, and cost. Cerebral autoregulation may be impaired in patients with symptomatic or asymptomatic carotid stenosis or occlusion and is associated with a higher risk of stroke or transient ischemic attack (TIA) ipsilateral to the carotid artery disease.
Assessment of CVR can help stratify patients based on their risk of stroke or TIA and select patients who may benefit from revascularization therapies. Cerebral vasoreactivity testing may be useful to evaluate cerebral autoregulation after revascularization procedures as a surrogate endpoint of vascular events related to hypoperfusion or hyperperfusion.
Regional cerebral blood flow; autoregulation; cerebral ischemia; cerebral blood volume; cerebral perfusion pressure
Background and Purpose
Clinical application of continuous autoregulation monitoring would benefit from a comparison of curves generated by online monitoring with standard autoregulation curves in animal models. We characterized the accuracy of 3 continuous monitors of autoregulation in a piglet model of hypotension.
Piglets 5 to10 days old with intracranial pressure (ICP) at naïve or elevated (20 mm Hg) levels had gradual arterial hypotension induced by a balloon catheter in the inferior vena cava. Elevated ICP was maintained by a continuous infusion of artificial cerebrospinal fluid. Three indices of autoregulation were simultaneously and continuously calculated. A moving, linear Pearson's coefficient between spontaneous slow waves of cerebral perfusion pressure and slow waves of laser-Doppler flux or cortical oxygenation rendered the laser-Doppler index and cerebral-oximetry index, respectively. Similar correlation between slow waves of arterial blood pressure and ICP rendered the pressure-reactivity index. The lower limit of autoregulation was determined directly for each animal by plotting laser-Doppler cortical red blood cell flux as a function of cerebral perfusion pressure. Receiver-operator characteristics were determined for the 3 indices.
The areas under the receiver-operator characteristics curves for discriminating the individual lower limit of autoregulation at low and high ICP were 0.89 and 0.85 for the laser-Doppler index, 0.89 and 0.84 for the cerebral-oximetry index, and 0.79 and 0.79 for the pressure-reactivity index. The pressure-reactivity index performed equally well at low and high ICPs.
Continuous monitoring of autoregulation by spontaneous slow waves of cerebral perfusion pressure can accurately detect loss of autoregulation due to hypotension in piglets by all 3 modalities.
autoregulation; cerebral blood flow; hypotension; neonates; oxygenation; piglets
Transcranial Doppler (TCD) ultrasound provides rapid, noninvasive, real-time measures of cerebrovascular function. TCD can be used to measure flow velocity in the basal arteries of the brain to assess relative changes in flow, diagnose focal vascular stenosis, or to detect embolic signals within these arteries. TCD can also be used to assess the physiologic health of a particular vascular territory by measuring blood flow responses to changes in blood pressure (cerebral autoregulation), changes in end-tidal CO2 (cerebral vasoreactivity), or cognitive and motor activation (neurovascular coupling or functional hyperemia). TCD has established utility in the clinical diagnosis of a number of cerebrovascular disorders such as acute ischemic stroke, vasospasm, subarachnoid hemorrhage, sickle cell disease, as well as other conditions such as brain death. Clinical indication and research applications for this mode of imaging continue to expand. In this review, the authors summarize the basic principles and clinical utility of TCD and provide an overview of a few TCD research applications.
transcranial Doppler; cerebral blood flow; ultrasound; cerebrovascular diseases
Background and purpose
Our objective was to investigate the associations between polymorphisms in representative genes of the renin angiotensin system with measures of cerebral blood flow regulation in older adults.
Participants in this analysis were white subjects (n=335) in the MOBILIZE Boston study, an observational study of community-dwelling elders who underwent transcranial Doppler while sitting and standing and during hypercapnea and hypocapnea. Autoregulation phenotype was the change in cerebrovascular resistance from sit to stand. Vasoreactivity (VR) phenotype was the slope of the change in cerebrovascular conductance vs change in end-tidal CO2. Total of 33 tagged single nucleotide polymorphisms (SNP) were selected in the angiotensinogen gene (AGT), the angiotensin converting enzyme (ACE) gene and the angiotensin receptor gene (AGTR). Regression analyses adjusted for age, gender, body mass index, mean arterial blood pressure, stroke and use of antihypertensives were conducted for each SNP and outcome. Bonferroni corrections were used to adjust p-values for multiple testing.
In the AGT gene, only the rs699 SNP was associated with VR after Bonferroni correction (p=0.00028). Homozygous carriers of the CC genotype of this SNP had lower VR compared to the CT or TT genotypes. There were no significant associations with autoregulation measures. None of the SNP’s in the other genes was associated with our phenotypes.
This analysis suggests that the AGT gene may be involved in vasoreactivity independent of blood pressure. Larger studies are needed to confirm the role of this gene in cerebrovascular health and aging.
Angiotensin; cerebral blood flow; vasoreactivity
Dynamic cerebral autoregulation after intracerebral hemorrhage (ICH) remains poorly understood. We performed a case-control study to compare dynamic autoregulation between ICH patients and healthy controls.
Twenty-one patients (66 ± 15 years) with early (< 72 hours) lobar or basal ganglia ICH were prospectively studied and compared to twenty-three age-matched controls (65 ± 9 years). Continuous measures of mean flow velocity (MFV) in the middle cerebral artery and mean arterial blood pressure (MAP) were obtained over 5 min. Cerebrovascular resistance index (CVRi) was calculated as the ratio of MAP to MFV. Dynamic cerebral autoregulation was assessed using transfer function analysis of spontaneous MAP and MFV oscillations in the low (0.03-0.15 Hz) and high (0.15-0.5 Hz) frequency ranges.
The ICH group demonstrated higher CVRi compared to controls (ipsilateral: 1.91 ± 1.01 mmHg·s·cm-1, p = 0.04; contralateral: 2.01 ± 1.24 mmHg·s·cm-1, p = 0.04; vs. control: 1.42 ± 0.45 mmHg·s·cm-1). The ICH group had higher gains than controls in the low (ipsilateral: 1.33 ± 0.58%/mmHg, p = 0.0005; contralateral: 1.47 ± 0.98%/mmHg, p = 0.004; vs. control: 0.82 ± 0.30%/mmHg) and high (ipsilateral: 2.11 ± 1.31%/mmHg, p < 0.0001; contralateral: 2.14 ± 1.49%/mmHg, p < 0.0001; vs. control: 0.66 ± 0.26%/mmHg) frequency ranges. The ICH group also had higher coherence in the contralateral hemisphere than the control (ICH contralateral: 0.53 ± 0.38, p = 0.02; vs. control: 0.38 ± 0.15) in the high frequency range.
Patients with ICH had higher gains in a wide range of frequency ranges compared to controls. These findings suggest that dynamic cerebral autoregulation may be less effective in the early days after ICH. Further study is needed to determine the relationship between hematoma size and severity of autoregulation impairment.
Cerebral autoregulation; Intracerebral hemorrhage; TCD Ultrasound
Despite widespread use in sick infants, it is still debated whether vasopressor-inotropes have direct cerebral effects that might affect neurological outcome. We aimed to test direct cerebrovascular effects of three commonly used vasopressor-inotropes (adrenaline, dopamine and noradrenaline) by comparing the responses to those of nonpharmacologically induced increases in blood pressure. We also searched for reasons for a mismatch between the response in perfusion and oxygenation.
Twenty-four piglets had long and short infusions of the three vasopressor-inotropes titrated to raise mean arterial blood pressure (MAP) 10 mmHg in random order. Nonpharmacological increases in MAP were induced by inflation of a balloon in the descending aorta. We measured cerebral oxygenation (near-infrared spectroscopy), perfusion (laser-Doppler), oxygen consumption (co-oximetry of arterial and superior sagittal sinus blood), and microvascular heterogeneity (side stream dark field video microscopy).
Vasopressor-inotropes increased cerebral oxygenation significantly less (p≤0.01) compared to non-pharmacological MAP increases, whereas perfusion was similar. Furthermore, cerebral total hemoglobin concentration increased significantly less during vasopressor-inotrope infusions (p = 0.001). These physiologic responses were identical between the three vasopressor-inotropes (p>0.05). Furthermore, they induced a mild, although insignificant increase in cerebral metabolism and microvascular heterogeneity (p>0.05). Removal of the scalp tissue did not influence the mismatch (p>0.05).
We demonstrated a moderate vasopressor-inotrope induced mismatch between cerebral perfusion and oxygenation. Scalp removal did not affect this mismatch, why vasopressor-inotropes appear to have direct cerebral actions. The statistically nonsignificant increases in cerebral metabolism and/or microvascular heterogeneity may explain the mismatch. Alternatively, it may simply reflect a vasopressor-inotrope-induced decrease in the arterial-to-venous volume ratio as detected by near-infrared spectroscopy.