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.
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.
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
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.
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.
Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest.
Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n=8) or 2 days (n=8), or that had undergone sham surgery with 2 days of recovery (n=8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n=5) or sham surgery (n=5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter.
The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percent change in cerebrovascular resistance divided by the percent change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury.
In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA compared to laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.
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 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.
Patients undergoing aortic surgery with hypothermic circulatory arrest (HCA) may require prolonged rewarming, a maneuver associated with impaired cerebral blood flow (CBF) autoregulation. The purpose of this study was to determine the effects of HCA on CBF autoregulation with validated method based on near-infrared spectroscopy.
Regional cerebral oxygen saturation (rScO2) was monitored in 25 patients undergoing aortic reconstructive surgery. HCA was used in 13 patients. Autoregulation was measured continuously during surgery by calculating the linear correlation coefficient between lowfrequency changes in rScO2 and mean arterial pressure (MAP), generating the variable cerebral oximetry index (COx). When CBF autoregulation is functional, COx is near zero, as CBF and MAP are not correlated, but it approaches 1 when autoregulation is impaired (i.e., CBF is pressure passive). Based on prior studies, impaired autoregulation was defined as COx > 0.3.
COx did not differ between HCA and non-HCA groups before cardiopulmonary bypass or during the cooling phase of surgery, although the lower limit of autoregulation tended to be lower in patients before HCA (p=0.053). During patient rewarming, COx was lower in the HCA group (p=0.045) and abnormal COx was less frequent ( 31% vs 75%, p=0.047) compared with the non-HCA group.
During aortic reconstructive surgery, CBF autoregulation is preserved during the cooling phase of surgery in patients undergoing HCA. Perfusion maneuvers associated with HCA may be protective against impaired autoregulation during rewarming compared with the non-HCA group.
Aorta operations; cerebral autoregulation
Moyamoya syndrome carries a high risk of cerebral ischemia, and impaired cerebrovascular autoregulation may play a critical role. Autoregulation indices derived from near-infrared spectroscopy (NIRS) may clarify hemodynamic goals that conform to the limits of autoregulation.
The aims of this pilot study were to determine whether the NIRS-derived indices could identify blood pressure ranges that optimize autoregulation and whether autoregulatory function differs between anatomic sides in patients with unilateral vasculopathy.
Pediatric patients undergoing indirect surgical revascularization for moyamoya were enrolled sequentially. NIRS-derived autoregulation indices, the cerebral oximetry index (COx) and the hemoglobin volume index (HVx), were calculated intraoperatively and postoperatively to measure autoregulatory function. The 5-mmHg ranges of optimal mean arterial blood pressure (MAPOPT) with best autoregulation and the lower limit of autoregulation (LLA) were identified.
Of seven enrolled patients (aged 2–16 years), six had intraoperative and postoperative autoregulation monitoring and one had only intraoperative monitoring. Intraoperative MAPOPT was identified in six (86%) of seven patients with median values of 60–80 mmHg. Intraoperative LLA was identified in three (43%) patients at 55–65 mmHg. Postoperative MAPOPT was identified in six (100%) of six patients with median values of 70–90 mmHg. Patients with unilateral disease had higher intraoperative HVx (p=0.012) on the side with vasculopathy.
NIRS-derived indices may identify hemodynamic goals that optimize autoregulation in pediatric moyamoya.
Pediatric; neurosurgery; moyamoya; cerebrovascular; autoregulation
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.
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.
Cerebrovascular events contribute to ~40% of preeclampsia/eclampsia‐related deaths, and neurological symptoms are common among preeclamptic patients. We previously reported that placental ischemia, induced by reducing utero‐placental perfusion pressure, leads to impaired myogenic reactivity and cerebral edema in the pregnant rat. Whether the impaired myogenic reactivity is associated with altered cerebral blood flow (CBF) autoregulation and the edema is due to altered blood–brain barrier (BBB) permeability remains unclear. Therefore, we tested the hypothesis that placental ischemia leads to impaired CBF autoregulation and a disruption of the BBB. CBF autoregulation, measured in vivo by laser Doppler flowmetry, was significantly impaired in placental ischemic rats. Brain water content was increased in the anterior cerebrum of placental ischemic rats and BBB permeability, assayed using the Evans blue extravasation method, was increased in the anterior cerebrum. The expression of the tight junction proteins: claudin‐1 was increased in the posterior cerebrum, while zonula occludens‐1, and occludin, were not significantly altered in either the anterior or posterior cerebrum. These results are consistent with the hypothesis that placental ischemia mediates anterior cerebral edema through impaired CBF autoregulation and associated increased transmission of pressure to small vessels that increases BBB permeability leading to cerebral edema.
Preeclampsia is associated with an increased risk for developing encephalopathies. A prevailing theory is that impaired cerebral blood flow autoregulation contributes to this process. Whether placental ischemia, commonly thought to be a major underlying factor in the development of preeclampsia, can cause impaired cerebral blood flow autoregulation is not clear. In this study, placental ischemia is experimentally induced to test this directly. The results show that placental ischemia in the pregnant rat causes marked impairment of cerebral blood flow autoregulation.
AQP4; blood–brain barrier; CBF autoregulation; cerebrovascular abnormalities; edema; preeclampsia; pregnancy; tight junction proteins
Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during post-resuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy.
Prospective, balanced animal study.
Basic physiology laboratory at an academic institution.
Eighty-four neonatal swine.
Piglets underwent hypoxic-asphyhxic cardiac arrest or sham surgery and recovered for 2 hours with normothermia followed by 4 hours of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hours post-resuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared.
Measurements and Main Results
Laser-Doppler flux was lower in post-arrest animals compared to sham-operated controls during the 2-hour normothermic period after resuscitation. During the subsequent 4-hour recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and post-arrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, post-arrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to post-arrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension.
In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from non-invasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.
pediatrics; heart arrest; cerebrovascular circulation; ischemia; blood pressure; hypothermia
Cerebral autoregulation (CA) is an important vascular control mechanism responsible for relatively stable cerebral blood flow despite changes of systemic blood pressure (BP). Impaired CA may leave brain tissue unprotected against potentially harmful effects of BP fluctuations. It is generally accepted that CA is less effective or even inactive at frequencies >∼0.1 Hz. Without any physiological foundation, this concept is based on studies that quantified the coupling between BP and cerebral blood flow velocity (BFV) using transfer function analysis. This traditional analysis assumes stationary oscillations with constant amplitude and period, and may be unreliable or even invalid for analysis of nonstationary BP and BFV signals. In this study we propose a novel computational tool for CA assessment that is based on nonlinear dynamic theory without the assumption of stationary signals. Using this method, we studied BP and BFV recordings collected from 39 patients with chronic ischemic infarctions and 40 age-matched non-stroke subjects during baseline resting conditions. The active CA function in non-stroke subjects was associated with an advanced phase in BFV oscillations compared to BP oscillations at frequencies from ∼0.02 to 0.38 Hz. The phase shift was reduced in stroke patients even at > = 6 months after stroke, and the reduction was consistent at all tested frequencies and in both stroke and non-stroke hemispheres. These results provide strong evidence that CA may be active in a much wider frequency region than previously believed and that the altered multiscale CA in different vascular territories following stroke may have important clinical implications for post-stroke recovery. Moreover, the stroke effects on multiscale cerebral blood flow regulation could not be detected by transfer function analysis, suggesting that nonlinear approaches without the assumption of stationarity are more sensitive for the assessment of the coupling of nonstationary physiological signals.
Cerebral autoregulation is an important mechanism that regulates blood supply to brain tissue to match metabolic demands during daily activities. Impaired cerebral autoregulation increases the dependence of cerebral blood flow on systemic blood pressure, and is associated with fatal outcomes in patients after brain injury and acute ischemic stroke. Reliable and noninvasive assessment of cerebral autoregulation is still a major challenge in medical diagnostics and clinic studies, mainly because blood pressure and flow are intrinsically nonstationary (possessing complex oscillations/fluctuations with varying amplitude and frequency) while traditional methods for assessment of the pressure-flow dependence assume stationary signals. We propose a new computational technique that is based on nonlinear theories without the assumption of stationary signals. This technique allows us to detect the degradation of cerebral autoregulation in patients with mild ischemic stroke even at >6 months after the insult. The degradation was present in both stroke and non-stroke sides and was accompanied by an altered pressure-flow interaction over a wide range of frequencies from 0.02–0.38 Hz. Our results challenges the traditionally accepted functional region of autoregulation (<∼0.1 Hz). The observed long-term influences of stroke highlight the importance of reliable monitoring of cerebral blood flow regulation for the management and daily care of stroke patients.
Understanding changes in cerebral oxygenation, haemodynamics and metabolism holds the key to individualised, optimised therapy after acute brain injury. Near-infrared spectroscopy (NIRS) offers the potential for non-invasive, continuous bedside measurement of surrogates for these processes. Interest has grown in applying this technique to interpret cerebrovascular pressure reactivity (CVPR), a surrogate of the brain’s ability to autoregulate blood flow. We describe a physiological model-based approach to NIRS interpretation which predicts autoregulatory efficiency from a model parameter k_aut. Data from three critically brain-injured patients exhibiting a change in CVPR were investigated. An optimal value for k_aut was determined to minimise the difference between measured and simulated outputs. Optimal values for k_aut appropriately tracked changes in CVPR under most circumstances. Further development of this technique could be used to track CVPR providing targets for individualised management of patients with altered vascular reactivity, minimising secondary neurological insults.
Cerebral blood flow (CBF) increases and dynamic cerebral autoregulation is impaired by acute hypoxia. We hypothesized that progressive hypocapnia with restoration of arterial oxygen content after altitude acclimatization would normalize CBF and dynamic cerebral autoregulation. To test this hypothesis, dynamic cerebral autoregulation was examined by spectral and transfer function analyses between arterial pressure and CBF velocity variabilities in 11 healthy members of the Danish High-Altitude Research Expedition during normoxia and acute hypoxia (10.5% O2) at sea level, and after acclimatization (for over 1 month at 5,260 m at Chacaltaya, Bolivia). Arterial pressure and CBF velocity in the middle cerebral artery (transcranial Doppler), were recorded on a beat-by-beat basis. Steady-state CBF velocity increased during acute hypoxia, but normalized after acclimatization with partial restoration of SaO2 (acute, 78%±2% chronic, 89%±1%) and progression of hypocapnia (end-tidal carbon dioxide: acute, 34±2 mm Hg; chronic, 21±1 mm Hg). Coherence (0.40±0.05 Units at normoxia) and transfer function gain (0.77±0.13 cm/s per mm Hg at normoxia) increased, and phase (0.86±0.15 radians at normoxia) decreased significantly in the very-low-frequency range during acute hypoxia (gain, 141%±24% coherence, 136%±29% phase, −25%±22%), which persisted after acclimatization (gain, 136%±36% coherence, 131%±50% phase, −42%±13%), together indicating impaired dynamic cerebral autoregulation in this frequency range. The similarity between both acute and chronic conditions suggests that dynamic cerebral autoregulation is impaired by hypoxia even after successful acclimatization to an extreme high altitude.
acclimatization; dynamic cerebral autoregulation; high altitude
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
While the decrease in blood carbon dioxide (CO2) secondary to hyperventilation is generally accepted to play a major role in the decrease of cerebral tissue oxygen saturation (SctO2), it remains unclear if the associated systemic hemodynamic changes are also accountable.
Twenty-six patients (American Society of Anesthesiologists I–II) undergoing nonneurosurgical procedures were anesthetized with either propofol-remifentanil (n = 13) or sevoflurane (n = 13). During a stable intraoperative period, ventilation was adjusted stepwise from hypoventilation to hyper-ventilation to achieve a progressive change in end-tidal CO2 (ETCO2) from 55 to 25 mmHg. Minute ventilation, SctO2, ETCO2, mean arterial pressure (MAP), and cardiac output (CO) were recorded.
Hyperventilation led to a SctO2 decrease from 78 ± 4% to 69 ± 5% (Δ = −9 ± 4%, P < 0.001) in the propofol-remifentanil group and from 81 ± 5% to 71 ± 7% (Δ = −10 ± 3%, P < 0.001) in the sevoflurane group. The decreases in SctO2 were not statistically different between these two groups (P = 0.5). SctO2 correlated significantly with ETCO2 in both groups (P < 0.001). SctO2 also correlated significantly with MAP (P < 0.001) and CO (P < 0.001) during propofol-remifentanil, but not sevoflurane (P = 0.4 and 0.5), anesthesia.
The main mechanism responsible for the hyperventilation-induced decrease in SctO2 is hypocapnia during both propofol-remifentanil and sevoflurane anesthesia. Hyperventilation-associated increase in MAP and decrease in CO during propofol-remifentanil, but not sevoflurane, anesthesia may also contribute to the decrease in SctO2 but to a much smaller degree.
Background: Continuous monitoring of dynamic cerebral autoregulation, using a moving correlation index of cerebral perfusion pressure and mean middle cerebral artery flow velocity, may be useful in patients with severe traumatic brain injury to guide treatment, and has been shown to be of prognostic value.
Objective: To compare an index of dynamic cerebral autoregulation (Mx) with an index of static cerebral autoregulation (sRoR).
Methods: Mx was validated in a prospective comparative study against sRoR, using 83 testing sessions in 17 patients with traumatic brain injury. sRoR and Mx were calculated simultaneously during pharmacologically induced blood pressure variations.
Results: Mx was significantly correlated with sRoR (R = -0.78, p < 0.05). Nine patients were found to have failure of cerebral autoregulation, with an sRoR value < 50%. If an Mx value of 0.3 was used as the cut off point for failure of cerebral autoregulation, this index had 100% sensitivity and 90% specificity for demonstrating failure of autoregulation compared with the sRoR. An increase in cerebral blood flow velocity correlated significantly with Mx (R = 0.73, p < 0.05) but not with cerebral perfusion pressure (R = 0.41).
Conclusions: Dynamic and static cerebral autoregulation are significantly correlated in traumatic brain injury. Cerebral autoregulation can be monitored continuously, graded, and reliably assessed using a moving correlation analysis of cerebral perfusion pressure and cerebral blood flow velocity (Mx). The Mx index can be used to monitor cerebral blood flow regulation. It is useful in traumatic brain injury because it does not require any external stimulus.
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
The purpose of this study was to examine the effects of hyperventilation or hyperoxia on cerebral hemodynamic parameters over time in patients with severe traumatic brain injury (TBI). We prospectively studied 186 patients with severe TBI. CO2 and O2 reactivity tests were conducted twice a day on days 1–5 and once daily on days 6–10 after injury. During hyperventilation there was a significant decrease in intracranial pressure (ICP), mean arterial pressure (MAP), jugular venous oxygen saturation (Sjvo2), brain tissue Po2 (Pbto2), and flow velocity (FV). During hyperoxia there was an increase in Sjvo2 and Pbto2, and a small but consistent decrease in ICP, end-tidal carbon dioxide (etco2), partial arterial carbon dioxide pressure (Paco2), and FV. Brain tissue oxygen reactivity during the first 12 h after injury averaged 19.7 ± 3.0%, and slowly decreased over the next 7 days. The autoregulatory index (ARI; normal = 5.3 ± 1.3) averaged 2.2 ± 1.5 on day 1 post-injury, and gradually improved over the 10 days of monitoring. The ARI significantly improved during hyperoxia, by an average of 0.4 ± 1.8 on the left, and by 0.5 ± 1.8 on the right. However, the change in ARI with hyperoxia was much smaller than that observed with hyperventilation. Hyperventilation increased ARI by an average of 1.3 ± 1.9 on the left, and 1.5 ± 2.0 on the right. Pressure autoregulation, as assessed by dynamic testing, was impaired in these head-injured patients. Acute hyperoxia significantly improved pressure autoregulation, although the effect was smaller than that induced by hyperventilation. The very small change in Paco2 induced by hyperoxia does not appear to explain this finding. Rather, the vasoconstriction induced by acute hyperoxia may allow the cerebral vessels to respond better to transient hypotension. Further studies are needed to define the clinical significance of these observations.
cerebral autoregulation; hyperoxia; hyperventilation; traumatic brain injury
Traumatic brain injury (TBI) causes an early reduction of cerebral blood flow (CBF). The purpose was to study cerebrovascular endothelial function by examining the reactivity of cerebral vessels to L-arginine.
Fifty-one patients with severe TBI were prospectively studied by measuring cerebral hemodynamics before and after the administration of L-arginine, 300 mg/kg at 12 hrs and at 48 hrs after injury. These hemodynamic measurements, using transcranial Doppler techniques, included internal carotid flow volume as an estimate of hemispheric cerebral blood flow, flow velocity in intracranial vessels, CO2 reactivity, and dynamic pressure autoregulation using thigh cuff deflation and carotid compression methods. Changes in the hemodynamics with L-arginine administration were analyzed using a general linear mixed model.
L-arginine produced no change in mean arterial pressure, intracranial pressure, or brain oxygenation. Overall, L-arginine induced an 11.3% increase in internal carotid artery flow volume (p= .0190). This increase was larger at 48 hrs than at 12 hrs (p= .0045), and tended to be larger in the less injured hemisphere at both time periods. The response of flow velocity in the intracranial vessels was similar, but smaller differences with administration of L-arginine were observed. There was a significant improvement in CO2 reactivity with L-arginine, but no change in dynamic pressure autoregulation.
The low response of the cerebral vessels to L-arginine at 12 hrs post-injury with improvement at 48hrs suggests that dysfunction of cerebrovascular endothelium plays a role in the reduced CBF observed after TBI.
cerebral autoregulation; endothelial dysfunction; L-arginine; nitric oxide; traumatic brain injury
The detection of increased cerebral oxygenation secondary to cerebral hyperaemia, induced by hypercapnia has been studied in anaesthetised patients using a near infrared, reflectance mode, cerebral oxygenation monitor (Invos 3100 Somanetics, Troy, Michigan, USA). Two studies were performed, with and without a pneumatic scalp tourniquet, to distinguish between extracranial and intracranial changes in tissue oxygenation. In the control study a mean increase in end tidal CO2 of 23.1 mm Hg was accompanied by a mean increase in middle cerebral artery flow velocity of 116%. Regional cerebral oxygen saturation (rSO2) measured transcutaneously in the frontal distribution of the middle cerebral artery increased significantly from 70.5% to 74.6% (p = 0.001). During the second study with a scalp tourniquet inflated to maintain the extracranial tissues in a state of stable ischaemia a mean increase in end tidal CO2 of 22.3 mm Hg was accompanied by a mean increase in middle cerebral artery flow velocity of 121%. The change in rSO2 from 62.6% to 64.5% was not significant (p = 0.085). There was no correlation between the change in middle cerebral artery flow velocity and rSO2 in the control or scalp ischaemia group. This study shows that the Invos 3100 monitor is sensitive to tissue oxygenation but does not reliably detect changes in cerebral oxygenation as a result of profound cerebral hyperaemia. The contribution of extracerebral tissue to the attenuation of near infrared light and the lack of spatial resolution remain major problems to be overcome before this or other near infrared spectroscopy instruments can be introduced into clinical practice.