Impaired Cerebral Blood Flow Autoregulation Research Articles

Monitoring of Cerebral Blood Flow Autoregulation after Cardiac Arrest.

Background: Cardiac arrest remains one of the leading causes of death. After successful resuscitation of patients in cardiac arrest, post-cardiac arrest syndrome develops, part of it being an impaired cerebral blood flow autoregulation. Monitoring cerebral blood flow autoregulation after cardiac arrest is important for optimizing patient care and prognosticating patients' survival, yet remains a challenge. There are still gaps in clinical implications and everyday use. In this article, we present a systematic review of studies with different methods of monitoring cerebral blood flow autoregulation after non-traumatic cardiac arrest. Methods: A comprehensive literature search was performed from 1 June 2024 to 27 June 2024 by using multiple databases: PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials. Inclusion criteria were studies with an included description of the measurement of cerebral blood flow autoregulation in adult patients after non-traumatic cardiac arrest. Results: A total of 16 studies met inclusion criteria. Our data show that the most used methods in the reviewed studies were near-infrared spectroscopy and transcranial Doppler. The most used mathematical methods for calculating cerebral autoregulation were cerebral oximetry index, tissue oxygenation reactivity index, and mean flow index. Conclusions: The use of various monitoring and mathematical methods for calculating cerebral blood flow autoregulation poses a challenge for standardization, validation, and daily use in clinical practice. In the future studies, focus should be considered on clinical validation and transitioning autoregulation monitoring techniques to everyday clinical practice, which could improve the survival outcomes of patients after cardiac arrest.

The impact of collateral therapeutics on stroke hemodynamics in normotensive and hypertensive rats: a step toward translation.

Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy. We compared the efficacy of two different collateral therapeutics during transient middle cerebral artery occlusion (tMCAO) in normotensive and hypertensive rats. The change in collateral and core perfusion was measured using dual laser Doppler in response to either a pressor agent (phenylephrine, 10 mg/kg iv or vehicle) or a collateral vasodilator (TM5441, 5 mg/kg iv or vehicle) given 30 min into tMCAO in male Wistar and spontaneously hypertensive rats (SHRs). Pressor therapy increased collateral flow in the Wistar rats but was ineffective in the SHRs. The increase in collateral flow in the Wistar rats was associated with impaired cerebral blood flow autoregulation (CBFAR) that was intact in the SHRs. TM5441 caused a decrease in collateral perfusion in the Wistar rats and a modest increase in the SHRs. The pressor therapy reduced early infarction in both groups but increased edema in the SHRs, whereas TM5441 did not have any beneficial effects in either group. Thus, the pressor therapy was superior to a collateral vasodilator in increasing collateral flow and improving outcomes in the Wistar rats, likely due to pial collaterals that were pressure passive; the lack of CBF response in the SHRs to pressor therapy was likely due to intact CBFAR that limited perfusion. While TM5441 modestly increased CBF in the SHRs but not in the Wistar rats, it did not have a beneficial effect on stroke outcomes. These results suggest that collateral therapies may need to be selected for certain comorbidities.

AT1-AA Infusion during Pregnancy Impairs CBF Autoregulation Postpartum.

Preeclampsia (PE), new-onset hypertension during pregnancy alongside organ dysfunction, is a leading cause of morbidity and mortality for the mother and fetus. PE women have activated B cells that produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA impairs cerebral blood flow (CBF) autoregulation during pregnancy. Although AT1-AA often remains elevated up to 8 years postpartum, AT1-AA's effect on CBF autoregulation postpartum is unknown. This study examined whether elevated AT1-AA during pregnancy impairs CBF autoregulation postpartum and if this was augmented by infusion of AT1-AA postpartum. AT1-AA was infused into 12-week-old timed-pregnant Sprague Dawley rats beginning on gestational day 14. Uterine artery resistance index (UARI) was measured on gestational day 18 as a measure of endothelial dysfunction associated with PE. Dams were allowed to deliver. One group was given a second infusion of AT1-AA (50% perinatal dose mimicking levels observed in postpartum PE women) at 9 weeks postpartum. After postpartum week 10, mean arterial pressure (MAP) was measured in conscious rats and CBF autoregulation was measured by laser Doppler flowmetry. AT1-AA during pregnancy increased UARI (P<0.05). AT1-AA during pregnancy did not affect MAP postpartum but did impair CBF autoregulation postpartum. Infusion of AT1-AA postpartum significantly elevated blood pressure (P<0.01) but did not further impair CBF autoregulation. This study demonstrates that circulating AT1-AA during pregnancy causes impairment of CBF autoregulation well into the postpartum period indicating that elevated AT1-AA leads to long-term cerebrovascular consequences. Targeting AT1-AA may prevent cerebrovascular effects associated with PE during pregnancy and postpartum.

Impact of impaired cerebral blood flow autoregulation on cognitive impairment.

Although the causes of cognitive impairment are multifactorial, emerging evidence indicates that cerebrovascular dysfunction plays an essential role in dementia. One of the most critical aspects of cerebrovascular dysfunction is autoregulation of cerebral blood flow (CBF), mainly mediated by the myogenic response, which is often impaired in dementia individuals with comorbidities, such as diabetes and hypertension. However, many unsolved questions remain. How do cerebrovascular networks coordinately modulate CBF autoregulation in health and disease? Does poor CBF autoregulation have an impact on cognitive impairment, and what are the underlying mechanisms? This review summarizes the cerebral vascular structure and myogenic (a three-phase model), metabolic (O2, CO2, adenosine, and H+), and endothelial (shear stress) factors in the regulation of CBF; and the consequences of CBF dysautoregulation. Other factors contributing to cerebrovascular dysfunction, such as impaired functional hyperemia and capillary abnormalities, are included as well. Moreover, this review highlights recent studies from our lab in terms of novel mechanisms involved in CBF autoregulation and addresses a hypothesis that there is a three-line of defense for CBF autoregulation in the cerebral vasculature.

Risk of overestimating loss of cerebral autoregulation-author's reply.

Editor—We read with great interest the correspondence from Claudia Niño and colleagues about our paper ‘Impact of impaired cerebral blood flow autoregulation on electroencephalogram signals in adults undergoing propofol anaesthesia: a pilot study’.1 Their main concern is that the number of patients with impaired cerebral autoregulation (CA) may have been overestimated. They point to a possible difference in prevalence of comorbidities between the preserved CA group (CA+, mean flow index, Mxa <0.3) and the impaired CA group (CA−, Mxa ≥0.3).

Regional impairment of deep gray matter perfusion in neonates with congenital heart disease revealed by arterial spin labeling MRI.

The present study examined deep gray matter perfusion in neonates with congenital heart disease (CHD) with arterial spin labeling magnetic resonance imaging preoperatively. We found that neonates with cyanotic CHD showed lower right thalamus compared with controls and lower right basal ganglia perfusion compared with acyanotic CHD. When the CHD group was assessed as a whole, it showed slightly decreased left thalamus perfusion compared with controls. The results suggest that cardiac physiology plays a crucial part in changes in regional cerebral perfusion. Perfusion with arterial spin labeling may be a useful marker of high risk for impaired cerebral blood flow auto-regulation and cerebral hypoperfusion in neonates with CHD.

Sex differences in cerebrovascular dysfunction and hypertension in offspring of hypertensive pregnant rats

BACKGROUNDOffspring from preeclamptic women have a greater risk of hypertension and cerebrovascular dysfunction later in life. One of the major contributors of cerebrovascular dysfunction is impaired cerebral blood flow (CBF) autoregulation. In the USA, 1 in 25 pregnancies are preeclamptic. Preeclampsia, as defined as new‐onset hypertension during pregnancy, is an inflammatory condition characterized by elevated interleukin 17 (IL‐17), mitochondrial reactive oxygen species (mtROS), mitochondrial dysfunction (mt‐Dys), and intrauterine growth restriction (IUGR). Preliminary work from our laboratory demonstrates that offspring from preeclamptic rats have sex differences. Males have hypertension and a greater impairment of CBF autoregulation, while females have no change in blood pressure with impaired CBF autoregulation. The exact mechanisms for the sex differences in cerebrovascular dysfunction and hypertension is unknown and is the focus of this study. We hypothesize that changes in cerebral mt‐Dys, cerebral mtROS, and circulating IL‐17 contributes to the sex differences in hypertension and cerebrovascular dysfunction in male and female offspring from preeclamptic rats.METHODSIn this study, we compared male and female offspring from normal pregnant and preeclamptic Sprague Dawley rats. All offspring were divided into controls (CON) and IUGR by sex. Hypertensive male and non‐hypertensive female offspring’s with impaired CBF autoregulation were examined at 17 weeks of age for changes in cerebral mitochondrial electron transport chain (ETC) protein complexes, cerebral manganese superoxide dismutase (MnSOD), and circulating IL‐17.RESULTSFemale CON (151±5% IU/Protein/male CON) and IUGR (149±8 %IU/Protein/male CON) offspring have increased MnSOD compared to CON (100±7 %IU/Protein/male CON) and IUGR (122±4 %IU/Protein/male CON) males (p&lt;0.05). No changes in female ETC protein complexes between IUGR and CON. Male IUGR have a decrease in complex II (71±5 vs. 100±8 %IU/Protein/male CON, p&lt;0.05) and V (57±2 vs. 100±10 %IU/Protein/male CON, p&lt;0.05) ETC proteins, and elevated IL‐17 (944±370 vs. 412±115 pg/mL, ns) compared to CON males.CONCLUSIONMale IUGR offspring have mt‐Dys and elevated IL‐17, which may contribute to hypertension and a greater impairment in CBF autoregulation. Female IUGR offspring may be protected due to an increase in mitochondrial antioxidants. In summary, studying the dimorphic sex differences in the mechanisms of hypertension and cerebrovascular dysfunction in offspring of preeclamptic women, may improve the offspring’s risk of hypertension, cardiovascular disease, stroke, and cognitive dysfunction later in life.

Contribution of cerebral microvascular mechanisms to age-related cognitive impairment and dementia.

Cognitive impairment and dementia are significant health burdens worldwide. Aging, hypertension, and diabetes are the primary risk factors for Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD). There are no effective treatments for AD/ADRD to date. An emerging body of evidence indicates that cerebral vascular dysfunction and hypoperfusion precedes the development of other AD pathological phenotypes and cognitive impairment. However, vascular contribution to dementia is not currently well understood. This commentary highlights the emerging concepts and mechanisms underlying the microvascular contribution to AD/ADRD, including hypotheses targeting the anterograde and retrograde cerebral vascular pathways, as well as the cerebral capillaries and the venous system. We also briefly discuss vascular endothelial dysfunction, oxidative stress, inflammation, and cellular senescence that may contribute to impaired cerebral blood flow autoregulation, neurovascular uncoupling, and dysfunction of cerebral capillaries and the venous system.

Impact of impaired cerebral blood flow autoregulation on electroencephalogram signals in adults undergoing propofol anaesthesia: a pilot study.

Cerebral autoregulation actively maintains cerebral blood flow over a range of MAPs. During general anaesthesia, this mechanism may not compensate for reductions in MAP leading to brain hypoperfusion. Cerebral autoregulation can be assessed using the mean flow index derived from Doppler measurements of average blood velocity in the middle cerebral artery, but this is impractical for routine monitoring within the operating room. Here, we investigate the possibility of using the EEG as a proxy measure for a loss of cerebral autoregulation, determined by the mean flow index. Thirty-six patients (57.5 [44.25; 66.5] yr; 38.9% women, non-emergency neuroradiology surgery) anaesthetised using propofol were prospectively studied. Continuous recordings of MAP, average blood velocity in the middle cerebral artery, EEG, and regional cerebral oxygen saturation were made. Poor cerebral autoregulation was defined as a mean flow index greater than 0.3. Eighteen patients had preserved cerebral autoregulation, and 18 had altered cerebral autoregulation. The two groups had similar ages, MAPs, and average blood velocities in the middle cerebral artery. Patients with altered cerebral autoregulation exhibited a significantly slower alpha peak frequency (9.4 [9.0, 9.9] Hz vs 10.5 [10.1, 10.9] Hz, P<0.001), which persisted after adjusting for age, norepinephrine infusion rate, and ASA class (odds ratio=0.038 [confidence interval, 0.004, 0.409]; P=0.007). In this pilot study, we found that loss of cerebral autoregulation was associated with a slower alpha peak frequency, independent of age. This work suggests that impaired cerebral autoregulation could be monitored in the operating room using the existing EEG setup. NCT03769142.

Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats.

Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40-100mmHg in young DM rats but was reduced at 140-180mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30-60mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and long-term memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly DM.

The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats

BackgroundPlacental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure.MethodsPlacental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry.ResultsPlacental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content.ConclusionsThese results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.

Abstract TP168: Impairment of Cerebral Blood Flow Autoregulation in Patients With Acute Cerebral Infarction Recovered Within 7-10 Days After Onset

InIntroduction: Cerebral blood flow (CBF) autoregulation is impaired after acute cerebral infarction (AIS). Although previous studies revealed that changes in cerebral oxygenation occurred when head-of-bed raised from flat to head-up position within 72hr after onset, chronological changes of this phenomenon had never been evaluated. Hypothesis: We hypothesized that the impairment of CBF autoregulation improved within 7-10 days after onset of AIS. We aimed to evaluated the chronological changes in oxygenated- (ΔHbO 2 ), deoxygenated- (ΔHb) and total-hemoglobin (ΔtHb) concentration in response to passive sitting between &lt;72hr and 7-10 days after onset of AIS. Method: We repeatedly measured forehead ΔHbO2, ΔHb and ΔtHb in response to raise the head-of-bed to 30 degrees from spine within 72hr (1 st measurement) and 7-10 days (2 nd measurement) after onset of AIS by using time-resolved near-infrared spectroscopy. Difference in the ΔHbO2, ΔHb and ΔtHb values between two measurements were compared. We also evaluated Spearman Rank Correlation Coefficient of those values between affected and unaffected side in each measurement. Results: A total of 37 participants (mean age, 70.4±12.5 years; 13 females) with a first AIS hospitalization in the Seirei Mikatahara General Hospital, Hamamatsu, Japan, were enrolled. No significant differences of ΔHbO 2, ΔHb or ΔtHb in either affected or unaffected side were observed between two measurements. The ΔHbO 2, ΔHb or ΔtHb of the affected side did not correlate with those in the unaffected side at the first measurement (ΔHbO 2 ; r=0.197, p=0.282, ΔHb; r=0.065, p=0.695. and ΔtHb; r=0.193, p=0.245, respectively). Interestingly, the correlation coefficients of the ΔHbO 2, ΔHb and ΔtHb between affected and unaffected side at the 2 nd measurement were statistically significant (ΔHbO 2 ; r=0.420, p=0.011, ΔHb; r=0.398, p=0.017. and ΔtHb; r=0.490, p=0.003, respectively). Conclusion: Although cerebral oxygenation changes in relation to posture change did not correlate between affected or unaffected side within 72hr after onset, this difference was improved in 7-10 days after onset. Our result suggested that the impairment of CBF autoregulation improved, at least partially, within 7-10 days after onset of AIS.

Cerebral Small Vessel, But Not Large Vessel Disease, Is Associated With Impaired Cerebral Autoregulation During Cardiopulmonary Bypass: A Retrospective Cohort Study.

Impaired cerebral blood flow (CBF) autoregulation during cardiopulmonary bypass (CPB) is associated with stroke and other adverse outcomes. Large and small arterial stenosis is prevalent in patients undergoing cardiac surgery. We hypothesize that large and/or small vessel cerebral arterial disease is associated with impaired cerebral autoregulation during CPB. A retrospective cohort analysis of data from 346 patients undergoing cardiac surgery with CPB enrolled in an ongoing prospectively randomized clinical trial of autoregulation monitoring were evaluated. The study protocol included preoperative transcranial Doppler (TCD) evaluation of major cerebral artery flow velocity by a trained vascular technician and brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. Brain MRI images were evaluated for chronic white matter hyperintensities (WMHI) by a vascular neurologist blinded to autoregulation data. "Large vessel" cerebral vascular disease was defined by the presence of characteristic TCD changes associated with stenosis of the major cerebral arteries. "Small vessel" cerebral vascular disease was defined based on accepted scoring methods of WMHI. All patients had continuous TCD-based autoregulation monitoring during surgery. Impaired autoregulation occurred in 32.4% (112/346) of patients. Preoperative TCD demonstrated moderate-severe large vessel stenosis in 67 (25.2%) of 266 patients with complete data. In adjusted analysis, female sex (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P = .014) and higher average temperature during CPB (OR, 1.23; 95% CI, 1.02-1.475; P = .029), but not moderate-severe large cerebral arterial stenosis (P = .406), were associated with impaired autoregulation during CPB. Of the 119 patients with available brain MRI data, 42 (35.3%) demonstrated WMHI. The presence of small vessel cerebral vascular disease was associated with impaired CBF autoregulation (OR, 3.25; 95% CI, 1.21-8.71; P = .019) after adjustment for age, history of peripheral vascular disease, preoperative hemoglobin level, and preoperative treatment with calcium channel blocking drugs. These data confirm that impaired CBF autoregulation is prevalent during CPB predisposing affected patients to brain hypoperfusion or hyperperfusion with low or high blood pressure, respectively. Small vessel, but not large vessel, cerebral vascular disease, male sex, and higher average body temperature during CPB appear to be associated with impaired autoregulation.

Partial loss of Ca2+‐Activated K+ channel (KCa) in Rat Cerebral Arterial Muscle in Insulin‐dependent diabetes mellitus

Cerebral arteries depolarize and constrict upon pressurization. This is one of the intrinsic mechanisms underlying autoregulation of cerebral blood flow (CBF). The Ca2+‐activated K+ channel (KCa) channel in arterial muscle is an important target through which cerebral arterial response to changes in endogenous or environmental stimulatory factors are sensed. The level of open state probability (NPo) of KCa channels determines the degree of myogenic tone and cytosolic Ca2+ concentration. In the present study we report impaired pressure‐dependent constriction of cerebral arteries and diminished density and NPo of KCa channel currents associated with reduced expression of KCa channel α‐ and β‐subunit proteins in cerebral arteries of genetically insulin‐dependent diabetic rats. In this study we also found that the expression of the CYP 4A ω‐hydroxylase protein and the production of 20‐HETE was significantly increased in the type 1 diabetic cerebral arteries compared to that in the non‐diabetic cerebral arteries. The observed changes in KCa channel function and expression of CYP 4A ω‐hydroxylase and production level of 20‐HETE could represent an important pathologic mechanisms that could underlie abnormalities in cerebral arterial reactivity in insulin‐dependent diabetes mellitus. It is concluded that the diminished KCa channel function, increased production of 20‐HETE and altered pressure‐dependent cerebral arterial constriction in insulin‐dependent diabetes mellitus may lead to impaired autoregulation of CBF that could contribute to increased risk of stroke in this disease condition.Support or Funding InformationNIH RO1 HL0338833This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Non-linear models for the detection of impaired cerebral blood flow autoregulation.

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model’s derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired.

Associations Between Impaired Cerebral Blood Flow Autoregulation, Cerebral Oxygenation, and Biomarkers of Brain Injury and Postoperative Cognitive Dysfunction in Elderly Patients After Major Noncardiac Surgery.

Increasing evidence links postoperative cognitive dysfunction (POCD) to surgery and anesthesia. POCD is recognized as an important neuropsychological adverse outcome in surgical patients, particularly the elderly. This prospective cohort study aimed to investigate whether POCD is associated with impaired intraoperative cerebral autoregulation and oxygenation, and increased levels of biomarkers of brain injury. Study subjects were patients ≥65 years of age scheduled for major noncardiac surgery. Cognitive function was assessed before and 1 week after surgery. POCD was diagnosed if a decline of >1 standard deviation of z-scores was present in ≥2 variables of the test battery. The incidence of POCD 1 week after surgery was modeled as a multivariable function of the index of autoregulation (MxA) and tissue oxygenation index (TOI), adjusting for baseline neuropsychological assessment battery (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery [CERAD-NAB]) total score and the maximum C-reactive protein (CRP) concentration. The biomarkers of brain injury neuron-specific enolase and S100β protein, age, and level of education were included in secondary multivariable logistic regression analyses. Of the 82 patients who completed the study, 38 (46%) presented with POCD 1 week after surgery. In the multivariable regression analysis, higher intraoperative MxA (odds ratio [OR; 95% confidence interval (CI)], 1.39 [1.01-1.90] for an increase of 0.1 units, P = .08 after Bonferroni adjustment), signifying less effective autoregulation, was not associated with higher odds of POCD. The univariable logistic regression model for MxA yielded an association with POCD (OR [95% CI], 1.44 [1.06-1.95], P = .020). Tissue oxygenation index (1.12 [0.41-3.01] for an increase of 10%, P = 1.0 after Bonferroni adjustment) and baseline CERAD-NAB total score (0.80 [0.45-1.42] for an increase of 10 points, P = .45) did not affect the odds of POCD. POCD was associated with elevated CRP on postoperative day 2 (median [interquartile range]; 175 [81-294] vs 112 [62-142] mg/L, P = .033); however, the maximum CRP value (OR [95% CI], 1.35 [0.97-1.87] for a 2-fold increase, P = .07) had no distinct effect on POCD. Impairment of intraoperative cerebral blood flow autoregulation is not predictive of early POCD in elderly patients, although secondary analyses indicate that an association probably exists.

Cerebral Blood Flow Autoregulation in Sepsis for the Intensivist: Why Its Monitoring May Be the Future of Individualized Care.

Cerebral blood flow (CBF) autoregulation maintains consistent blood flow across a range of blood pressures (BPs). Sepsis is a common cause of systemic hypotension and cerebral dysfunction. Guidelines for BP management in sepsis are based on historical concepts of CBF autoregulation that have now evolved with the availability of more precise technology for its measurement. In this article, we provide a narrative review of methods of monitoring CBF autoregulation, the cerebral effects of sepsis, and the current knowledge of CBF autoregulation in sepsis. Current guidelines for BP management in sepsis are based on a goal of maintaining mean arterial pressure (MAP) above the lower limit of CBF autoregulation. Bedside tools are now available to monitor CBF autoregulation continuously. These data reveal that individual BP goals determined from CBF autoregulation monitoring are more variable than previously expected. In patients undergoing cardiac surgery with cardiopulmonary bypass, for example, the lower limit of autoregulation varied between a MAP of 40 to 90 mm Hg. Studies of CBF autoregulation in sepsis suggest patients frequently manifest impaired CBF autoregulation, possibly a result of BP below the lower limit of autoregulation, particularly in early sepsis or with sepsis-associated encephalopathy. This suggests that the present consensus guidelines for BP management in sepsis may expose some patients to both cerebral hypoperfusion and cerebral hyperperfusion, potentially resulting in damage to brain parenchyma. The future use of novel techniques to study and clinically monitor CBF autoregulation could provide insight into the cerebral pathophysiology of sepsis and offer more precise treatments that may improve functional and cognitive outcomes for survivors of sepsis.

Abstract P243: A New Type 2 Diabetic Rat Model That is Associated with Cognitive Impairment in Aging

Alzheimer’s disease (AD) is an incurable neurodegenerative disease and the most common form of dementia, and AD and type II diabetes (DM II) are two of the most common diseases of aging. Numerous studies demonstrate DM II with increased risk for dementia, however, the mechanisms linking DM II and AD have not been fully elucidated. There is increasing evidence suggesting that cerebral vascular dysfunction plays an important role in the development of AD. T2DN rat is a DM II rat model that exhibits diabetic nephropathy. The present study examines whether aged T2DN rat is associated with cognitive impairment, and whether autoregulation of cerebral blood flow (CBF) is impaired that contributes to AD. The levels of glucose (422 ± 32 vs. 94 ± 3 mg/dL) and glycated hemoglobin (HbA 1c , 11.5 ± 0.2 vs. 4.3 ± 0.1%) were higher in 12-18 months old T2DN than in age matched SD control rats. CBF rose by 137 ± 15% and 36 ± 5%, respectively, in T2DN and SD rats when MAP was increased from 100 to 180 mmHg. Aged T2DN rats exhibited BBB leakage and “AD” like cerebral vascular remodeling. The expression of Amyloid β 42 (Aβ 4 2 ), p-tau (S416), GFAP and IL-1 beta were significantly higher in the brains of T2DN vs. SD rats. T2DN rats also exhibited learning and memory dysfunction as the short term (2-hour; T2DN 96 ± 12 vs. SD 13 ± 3 seconds) and long term (24-hour; T2DN 105 ± 15 vs. SD 8 ± 2 seconds) latency of escape were longer in an eight-arm water maze test, and spent less time in the target arm 48 hours after training (T2DN 3.4 ± 2.6 vs. SD 45.0 ± 1.7%). These findings indicate that T2DN is a new type II diabetic rat model. Elderly T2DN rat is associated with an impaired autoregulation of CBF, glial activation and inflammation which may contribute to the development of cognitive impairment and AD.

Ondansetron-related hemorrhagic posterior reversible encephalopathy syndrome (PRES) following gastric bypass.

BackgroundPosterior reversible encephalopathy syndrome (PRES) is a clinical-radiographic syndrome formally recognized in 1996, which describes specific changes noted on neuroimaging thought to be related to impaired cerebral blood flow autoregulation and endothelial dysfunction. We report a case of PRES in the setting of increased ingestion of ondansetron; complicated by hemorrhagic transformation and refractory intracranial hypertension. We hypothesize an association of 5-HT3 antagonism and PRES.FindingsThis is a case study report; with review of previously published literature through PubMed search. We describe the case of a 25 year old man following bariatric surgery who increased his ingestion of ondansetron, taking up to 40 tablets/day due to excessive nausea and vomiting. The patient was hospitalized for progressively more severe headache of 1 week’s duration. Computed tomography (CT) revealed bilateral cerebral edema in the parietal and occipital lobes in the setting of elevated blood pressure (BP). Three days into his admission, following improvement in his BP with oral anti-hypertensive but continued use of the ondansetron, the patient developed near complete blindness. CT head imaging revealed progression of the posterior cerebral edema and intraparenchymal hemorrhage. He was admitted to our ICU and despite supportive treatment, his neurological examination worsened while CT head imaging findings remained stable. Invasive multimodality monitoring revealed elevated intracranial pressure. The patient was aggressively treated and after a prolonged hospitalization and rehabilitation course, made a significant recovery.ConclusionThis case highlights a very rare potential neurological complication of ondansetron, a commonly used medication. We hypothesize an underlying association between PRES and 5-HT3 antagonism, via the latter’s potential role in endothelial dysfunction. Prompt recognition and treatment of PRES is essential, in order to prevent secondary cerebral injury and the associated potentially grave consequences.

Abstract 127: Agonistic Autoantibodies to Angiotensin II Type I Receptor Contributes Partly to Placental Ischemia-induced Cerebrovascular Abnormalities

Placental ischemia, a characteristic feature of preeclampsia, leads to impaired cerebral blood flow (CBF) autoregulation, cerebral edema, and increased blood-brain barrier (BBB) permeability; however, the placental factors that contribute to these cerebral abnormalities are not clear. Agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are increased in preeclamptic patients as well as in a rat model of preeclampsia induced by placental ischemia. In this study, we tested the hypothesis that AT1-AA mediates placental ischemia-induced cerebrovascular abnormalities. To determine whether the AT1-AA contributes to impaired CBF autoregulation, we infused purified rat AT1-AA into normal pregnant rats from gestational day (GD) 12 to 19 via mini-osmotic pumps and measured CBF using laser Doppler flowmetry on GD 19. Autoregulatory index increased from 0.7 to 1.0±0.2 in the AT1-AA infused group over the range of 120 to 160 mmHg compared to pregnant controls (0.3 to 0.5±0.1 over the same range of pressures, p&lt;0.05) suggesting impaired CBF autoregulation. However, AT1-AA infusion did not affect brain water content at baseline blood pressures (104±2 mmHg in normal pregnant rats vs. 113±2 mmHg in AT1-AA infused rats, p&lt;0.01). To determine the role of endogenous AT1-AA in mediating placental ischemia-induced cerebrovascular abnormalities, losartan (5 mg/kg/day), an AT1 receptor antagonist, was administered in the drinking water from GD 14 to 19. Losartan reduced anterior brain water content from 79.6±0.2% in placental ischemic rats to 79.2±0.1% (compared to 79.1±0.1% in normal pregnant untreated rats) and BBB permeability from 0.06±0.01 in placental ischemic rats to 0.03±0.03 (compared to 0.03±0.004 in normal pregnant untreated rats). These results indicate that impaired CBF autoregulation in response to placental ischemia is due, at least in part, to increases in circulating AT1-AA. While AT1-AA infusion, by itself, did not alter brain water content at baseline blood pressures, the beneficial effects of losartan in placental ischemic rats suggests that the renin-angiotensin system may interact with other placental factors to promote cerebral vascular changes common to preeclampsia.