Lower Limit Of Cerebral Autoregulation Research Articles

Additional predictors of the lower limit of cerebral autoregulation during cardiac surgery.

The lower limit of autoregulation (LLA) of cerebral blood flow was previously shown to vary directly with the Ambulatory Arterial Stiffness Index (AASI) redefined as 1-regression slope of DBP-versus-SBP readings invasively measured from the radial artery before the bypass. We aimed expanding the predictive capacity of the LLA with AASI by combining it with additional predictors and provide new indications whether mean arterial pressure (MAP) is above/below the LLA. In 181 patients undergoing cardiac surgery, mean (SD) age 71 (8) years), we identified from the demographic, preoperative and intraoperative characteristics independent and statistically significant 'single predictors' of the LLA (including AASI). This was achieved using multivariate linear regression with a backward-elimination technique. The single predictors combined with 1-AASI generated new multiplicative and additive composite predictors of the LLA. Indicators for the MAP-to-LLA difference (DIF) were determined using DIF-versus-predictor plots. The odds ratio (OR) for the DIF sign (Outcome = 1 for DIF≤0) and predictor-minus-median sign (Exposure = 1 for Predictor  ≤ Median) were calculated using logistic regression. BMI, 1-AASI and systolic coefficient of variation were identified single predictors that correlated similarly with the LLA ( r  = -0.26 to -0.27, P  < 0.001). The multiplicative and additive composite predictors displayed higher correlation with LLA ( r  = -0.41 and r  = -0.43, respectively, P  < 0.001) and improved LLA estimation. The adjusted OR for the composite predictors was nearly twice that of the single predictors. The novel composite predictors may enhance the LLA estimation and the ability to maintain MAP in the cerebral autoregulatory range during cardiac surgery.

Quick Assessment of the Lower Limit of Cerebral Autoregulation Using Transcranial Doppler during Cardiopulmonary Bypass in Cardiac Surgery: A Feasibility Study

Background: During cardiac surgery, maintaining a mean arterial pressure (MAP) within the range of cerebral autoregulation (CA) may prevent postoperative morbidity. The lower limit of cerebral autoregulation (LLA) can be determined using the mean velocity index (Mx). The standard Mx is averaged over a ten second period (Mx10s) while using a two second averaging period (Mx2s) is faster and may record more rapid variations in LLA. The objective of this study is to compare a quick determination of LLA (qLLA) using Mx2s with the reference LLA (rLLA) using Mx10s. Methods: Single center, retrospective, observational study. Patients undergoing cardiac surgery with cardiopulmonary bypass. From January 2020 to April 2021, perioperative transcranial doppler measuring cerebral artery velocity was placed on cardiac surgery patients in order to correlate with continuous MAP values. Calculation of each patient’s Mx was manually determined after the surgery and qLLA and rLLA were then calculated using a threshold value of Mx &gt;0.4. Results: 55 patients were included. qLLA was found in 78% of the cases versus 47% for rLLA. Despite a –3 mmHg mean bias, limits of agreement were large [–19 mmHg (95% CI: –13; –25), and +13 mmHg (95% CI: +6; +19)]. There was an important interobserver variability (kappa rLLA = 0.46; 95% CI: 0.24–0.66; and Kappa qLLA = 0.36; 95% CI: 0.20–0.52). Conclusions: Calculation of qLLA is feasible. However, the large limits of agreement and significant interobserver variability prevent any clinical utility or interchangeability with rLLA.

Pro-Con Debate: The Clinical (Ir)relevance of the Lower Limit of Cerebral Autoregulation for Anesthesiologists.

In this Pro-Con commentary article, we discuss whether the lower limit of cerebral autoregulation is clinically relevant for anesthesiologists. The central question regarding this issue is whether mean arterial blood pressure below the lower limit of autoregulation is detrimental for the brain. The Pro side argues that continuous monitoring of cerebral autoregulation has revealed an association between going below the lower limit and mortality in the critically ill patient. Conversely, the Con side argues that cerebral autoregulation is only one of various defense mechanisms of the brain that protect against cerebral hypoperfusion, and that cerebral autoregulation may be more important to protect against intracranial hypertension.

Cerebral Autoregulation in Healthy Term Newborns: Brief Report

Cerebral autoregulation is a homeostatic process that maintains cerebral blood flow (CBF) across a range of mean arterial pressures (MAPs). Cerebral autoregulation can be impaired in pathologic systemic and neurological conditions and can lead to cerebral hypoperfusion or cerebral hyperperfusion from low and high MAPs, respectively. 1 Obrist W.D. Gennarelli T.A. Segawa H. Dolinskas C.A. Langfitt T.W. Relation of cerebral blood flow to neurological status and outcome in head-injured patients. J Neurosurg. 1979; 51: 292-300 Crossref PubMed Scopus (116) Google Scholar Little is known about the maturation of cerebral autoregulation after birth or whether there are sex differences in CBF at birth. One study of 16 term neonates without congenital heart disease tested autoregulation using cerebral oximeter monitoring with tilt testing and reported that cerebral autoregulation was intact between three and 10 days. 2 Tran N.N. Kumar S.R. Hodge F.S. Macey P.M. Cerebral autoregulation in neonates with and without congenital heart disease. Am J Crit Care. 2018; 27: 410-416https://doi.org/10.4037/ajcc2018672 Crossref PubMed Scopus (11) Google Scholar Sex differences in CBF have been observed in older ages. Similar to healthy adolescents aged 10 to 16 years and healthy adults, prepubertal girls between four and eight years have higher middle cerebral and basilar artery flow velocities than age-matched boys. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar ,4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar Studies report that both healthy boys and girls aged between four and 16 years have intact cerebral autoregulation and children aged two to six years have a lower limit of autoregulation (LLA) similar to adolescents and adults. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar , 4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar , 5 Vavilala M.S. Lee L.A. Lam A.M. The lower limit of cerebral autoregulation in children during sevoflurane anesthesia. J Neurosurg Anesthesiol. 2003; 15: 307-312 Crossref PubMed Scopus (78) Google Scholar This finding means that infants and young children have less cerebral autoregulatory reserve (difference between MAP and LLA) than older children. 5 Vavilala M.S. Lee L.A. Lam A.M. The lower limit of cerebral autoregulation in children during sevoflurane anesthesia. J Neurosurg Anesthesiol. 2003; 15: 307-312 Crossref PubMed Scopus (78) Google Scholar However, girls aged four to 16 years have higher normative autoregulatory indices of the basilar artery compared with age-matched boys and healthy boys aged four to 16 years have higher normative autoregulatory indices of the middle cerebral artery (MCA) compared with healthy girls; the reasons for these differences are not well understood. 3 Vavilala M.S. Kincaid M.S. Muangman S.L. Suz P. Rozet I. Lam A.M. Gender differences in cerebral blood flow velocity and autoregulation between the anterior and posterior circulations in healthy children. Pediatr Res. 2005; 58: 574-578 Crossref PubMed Scopus (92) Google Scholar ,4 Tontisirin N. Muangman S.L. Suz P. et al. Early childhood gender differences in anterior and posterior cerebral blood flow velocity and autoregulation. Pediatrics. 2007; 119: e610-e615 Crossref PubMed Scopus (62) Google Scholar In clinical practice, hypotension is commonly defined in relation to gestational age (GA), and hypotension is common in critically ill neonates. 6 Dilli D. Soylu H. Tekin N. Neonatal hemodynamics and management of hypotension in newborns. Turk Pediatri Ars. 2018; 53: S65-S75 Crossref PubMed Scopus (10) Google Scholar Obtaining normative data for female and male newborns is a requisite for further understanding CBF and cerebral autoregulation and optimizing cerebral perfusion in critically ill neonates. We explored CBF velocity and cerebral autoregulation of the anterior cerebral circulation among healthy term newborns.

Blood pressure target in neurosurgical patients: How high and how low should we go?

The cerebral autoregulation is considered to be dynamic rather than static as it was originally thought. The revised lower limit of cerebral autoregulation, narrower range of autoregulation in neurosurgical patients and data from randomized conttrolled trials and large retospective anlaysis required the revision of blood pressure(BP) targets in neurosurgical patients.

Neurocognitive, Quality of Life, and Behavioral Outcomes for Patients With Covert Stroke After Cardiac Surgery: Exploratory Analysis of Data From a Prospectively Randomized Trial.

Asymptomatic brain ischemic injury detected with diffusion-weighted magnetic resonance imaging (DWI) is reported in more than one-half of patients after cardiac surgery. There are conflicting findings on whether DWI-detected covert stroke is associated with neurocognitive dysfunction after surgery, and it is unclear whether such ischemic injury affects quality of life or behavioral outcomes. The purpose of this study was to perform exploratory analysis on whether covert stroke after cardiac surgery is associated with delayed neurocognitive recovery 1 month after surgery, impaired quality of life, anxiety, or depression. Analysis of data collected in a prospectively randomized study in patients undergoing cardiac surgery testing whether basing mean arterial pressure (MAP) targets during cardiopulmonary bypass to be above the lower limit of cerebral autoregulation versus usual practices reduces the frequency of adverse neurological outcomes. A neuropsychological testing battery was administered before surgery and then 1 month later. Patients underwent brain magnetic resonance imaging (MRI) between postoperative days 3 and 5. The primary outcome was DWI-detected ischemic lesion; the primary end point was change from baseline in domain-specific neurocognitive Z scores 1 month after surgery. Secondary outcomes included a composite indicator of delayed neurocognitive recovery, quality of life measures, state and trait anxiety, and Beck Depression Inventory scores. Of the 164 patients with postoperative MRI data, clinical stroke occurred in 10 patients. Of the remaining 154 patients, 85 (55.2%) had a covert stroke. There were no statistically significant differences for patients with or without covert stroke in the change from baseline in Z scores in any of the cognitive domains tested adjusted for sex, baseline cognitive score, and randomization treatment arm. The frequency of delayed neurocognitive recovery (no covert stroke, 15.1%; covert stroke, 17.6%; P = .392), self-reported quality of life measurements, anxiety rating, or depression scores were not different between those with or without DWI ischemic injury. More than one-half of patients undergoing cardiac surgery demonstrated covert stroke. In this exploratory analysis, covert stroke was not found to be significantly associated with neurocognitive dysfunction 1 month after surgery; evidence of impaired quality of life, anxiety, or depression, albeit a type II error, cannot be excluded.

The Regional Cerebral Oxygen Saturation Effect of Inotropes/Vasopressors Administered to Treat Intraoperative Hypotension: A Bayesian Network Meta-analysis.

One of the main concerns of intraoperative hypotension is adequacy of cerebral perfusion, as cerebral blood flow decreases passively when mean arterial pressure falls below the lower limit of cerebral autoregulation. Treatment of intraoperative hypotension includes administration of drugs, such as inotropes and vasopressors, which have different pharmacological effects on cerebral hemodynamics; there is no consensus on the preferred drug to use. We performed a network meta-analysis (NMA) to pool and analyze data comparing the effect on cerebral oxygen saturation (ScO2) measured by cerebral oximetry of various inotropes/vasopressors used to treat intraoperative hypotension. We searched randomized control trials in Embase, Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that enrolled adult patients undergoing surgery under general/spinal anesthesia that compared at least 2 inotropes/vasopressors to treat hypotension. We reviewed 51 full-text manuscripts and included 9 randomized controlled trials in our study. The primary outcome was change in ScO2. Our results showed the likelihood that dopamine, ephedrine, and norepinephrine had the lowest probability of decreasing ScO2. The suggested rank order to maintain ScO2, from higher to lower, was dopamine <ephedrine <norepinephrine <phenylephrine. Drugs in the lower rank order, like phenylephrine, produce higher reductions in ScO2. Compared with dopamine, the mean difference (95% credible interval) of ScO2 reduction was: ephedrine -3.19 (-15.74, 8.82), norepinephrine -4.44 (-18.23, 9.63) and phenylephrine -6.93 (-18.31, 4.47). The results of our NMA suggest that dopamine and ephedrine are more likely to preserve ScO2, followed by norepinephrine. Compared with the other inotropes/vasopressors, phenylephrine decreased ScO2. Because of the inherent imprecision of direct/indirect comparisons, the rank orders are possibilities, not absolute ranks. Therefore the results of this NMA should be interpreted with caution.

Is a Mean Arterial Pressure Less Than 65 mm Hg an Appropriate Indicator of the Quality of Anesthesia Care?

See Article, p 946 Physician anesthesiologists have understood for more than a century the importance of blood pressure management during anesthesia.1 There has been divergent opinion during the ensuing decades, however, on what blood pressure constitutes “hypotension” with no clear consensus.2 Implementation of electronic health records has allowed for analysis of large hemodynamic data sets linked to patient outcomes. Multiple investigators have hence evaluated various blood pressure cut-offs in relationship to organ injury finding an association between a mean arterial pressure (MAP) <65 mm Hg and acute kidney injury, myocardial infarction, and mortality in selected populations of adults undergoing noncardiac surgery.3–5 The results of these retrospective analysis supports the hypothesis that hypotension might represent a potentially modifiable risk factor for poor patient outcome after noncardiac surgery and thus an indicator of clinician skill. These findings have fostered consideration of a MAP <65 mm Hg for ≥15 minutes as an internal quality improvement measure by the Anesthesia Quality Institute (measure ID IIM025) and as a future qualified clinical data registry (QCDR) measure for the Center for Medicare & Medicaid Services Merit-Based Incentive Payment System (MIPS) program (measure ID EPREOP31). The study by Sessler et al6 in this issue of Anesthesia & Analgesia has important implications on interpreting whether a MAP <65 mm Hg is indeed a suitable measure of intraoperative quality of care. Their study involved analysis of electronic anesthesia records collected during a 10-year period at a single institution from 25,702 adult patients undergoing general anesthesia for noncardiac surgery lasting at least 1 hour. Blood pressure was monitored either directly with an arterial catheter (35% of cases) or with oscillometry. Whether less frequent measurement of blood pressure with the latter method rather than continuous monitoring confounds the relationship between MAP <65 mm Hg and adverse outcomes is not clear. Certainly, the different frequency of recording blood pressure could influence the promptness of intervention, as well as the potential for unrecognized hypotension when measurements occur at 5 or more-minute intervals. Regardless, in their investigation Sessler et al6 limited the analysis to anesthetics administered by a certified registered nurse anesthetist (CRNA) medically directed by an anesthesiologist. Since medical direction by an anesthesiologist is a prevalent model of anesthetic care in the United States, it is a reasonable approach to focus on the provider most likely to immediately intervene for hypotension. Analysis was restricted to cases where a single CRNA was present for 80% of the case and it only considered CRNAs who logged >200 cases during the study period. The study’s analysis was based on 110,391 hours of anesthesia and 99 CRNAs whom provided on average (mean ± standard deviation [SD]) 260 ± 124 cases lasting 4.3 ± 1.8 hours. Using various statistical approaches the authors had 4 basic aims. First, they attempted to develop a multivariate model to predict hypotension based on preoperative patient characteristics and medical history but excluded the provider as a variable. Second, they calculated the observed versus predicted amount of MAP <65 mm Hg for each case and then summarize excess hypotension as the difference between these 2 variables. Third, they determined the amount of MAP <65 mm Hg on a case basis associated with complications. For this, they used a composite complication end-point consisting of myocardial injury (troponin ≥0.03 ng/mL), stroke, acute kidney injury, infections, readmission to their facilities, or death. Their final goal was to assess the range of minutes and excess MAP <65 mm Hg for each CRNA and whether this was associated with the composite complication end-point. The authors found that MAP <65 mm Hg was common with nearly 70% of cases having at least 1 minute of MAP <65 mm Hg. The average minutes of MAP <65 mm Hg was (mean ± SD) 13 ± 23 minutes with a median (interquartile range) of 4 (0, 15) minutes. Regarding their first aim, they were unable to accurately predict hypotension based on preoperative data. Introducing CRNA into the modeling as a random effect suggested that inter-CRNA minutes of MAP <65 mm Hg represented a small portion of the variance in predicting this end-point. In other words, minutes of MAP <65 mm Hg is not a strong performance indicator between CRNAs medically directed by an anesthesiologist. Both actual and excess minutes of MAP <65 mm Hg were associated with the adjusted risk of the composite complication outcome confirming the findings of other studies.3–5 Each 10 minutes of MAP <65 mm Hg was associated with a 3.8% higher odds of a major complication (95% confidence interval [CI], 2.1-5.6; P < .0001). Cases in the highest quartile of excess minutes of MAP <65 mm Hg (>24 minutes above predicted) had approximately a 31% higher odds for complications compared to patients without hypotension (odds ratio, 1.31, 95% CI, 1.16-1.47; P < .0001). Patients in the third quartile (10–24 minutes) of excess hypotension had an odds ratio of 1.27 (95% CI, 1.12-1.44; P = .0002) for a complication compared with no hypotension. Nonetheless, there was no association in confounder-adjusted models for an individual CRNA’s average amount of excess MAP <65 mm Hg and complications as a continuous exposure (P = .09) or as quintiles (P = .30). These results were confirmed in sensitivity analysis. They conclude that while MAP <65 mm Hg is associated with complications, the average amount of blood pressure below this cutoff varied only slightly between CRNAs and it was insufficient to account for differences in complications. The authors appropriately temper their conclusions as representing analysis from a single, tertiary medical center making generalizability of the results untested. The results, though, raise questions about whether a MAP <65 mm Hg during anesthesia for noncardiac surgery is an appropriate quality indicator. The support for this measure is derived from retrospective data analysis and represents an association but not a causal relationship with acute kidney injury, myocardial infarction, or mortality.3–5 Notably, a recent investigation that included intra- and postoperative hemodynamic data suggests that hypotension after, rather than during surgery is a stronger predictor of myocardial injury.7 Support for avoiding hypotension during noncardiac surgery as a strategy for improving outcomes comes from the 9-center Intraoperative Norepinephrine to Control Arterial Pressure (INPRESS) study.8 In that study, high-risk patients (n = 298) undergoing noncardiac surgery under general anesthesia were randomized to maintain systolic blood pressure within 10% of a reference values versus standard practice of maintaining >80 mm Hg or 40% of a reference value. Patients in the intervention arm had a lower frequency of the composite outcome of systemic inflammatory response syndrome and dysfunction of at least 1 organ system by day 7 after surgery compared with the standard care arm (38.1% vs 51.7%; P = .02). That study did not specifically address the risks and benefits of maintaining MAP >65 mm Hg. Blood pressure data reported every 30 minutes as supplemental data from that study suggests that the median MAP, even in the standard care group, may have been >65 mm Hg. Rather than an empiric MAP cutoff derived from population-based data, our group has advocated for an individualized approach for defining hypotension based on bed-side monitoring of cerebral blood flow autoregulation.9 Interestingly, we have found is that the median MAP at the lower limit of cerebral blood flow autoregulation during cardiopulmonary bypass is 66 mm Hg and during shoulder surgery in the lateral decubitus position 65 mm Hg. What is striking, though, is the breadth of the CIs at this cutoff: 43–90 mm Hg during cardiac surgery and 55–75 mm Hg during noncardiac surgery. Thus, a MAP <65 mm Hg for defining hypotension may be sufficient for ensuring cerebral autoregulation for the “average patient” but it may be too high or too low for others. Moreover, experimentally, kidneys have a higher blood pressure cutoff for autoregulation than the brain, and perfusion is also dependent on cardiac output.10 In that laboratory investigation, when MAP was at the lower limit of cerebral blood flow autoregulation, renal blood flow was 75% of baseline. One could argue in favor of the quality measure of MAP <65 mm Hg if there is no harm with the treatment needed to meet this goal. Data from the INPRESS study and our own experience suggests that a higher dose of vasoconstrictive drugs do not lead to a higher frequency of complications.8,11 The potential harms of an empiric MAP target of 65 mm Hg is that it may represent hypotension in individuals whose lower limit of cerebral autoregulation is higher. Further, we have found that the cumulative magnitude and duration that MAP is above the upper limit of cerebral autoregulation is associated with delirium.12 Thus, simply keeping every patient’s MAP “high” could potentially have unintended consequences. The study by Sessler et al6 should prompt debate on the appropriateness of a MAP <65 mm Hg for >15 minutes as an indicator of the quality of anesthesia care during noncardiac surgery (Table). A MAP <65 mm Hg may or may not be a modifiable risk factor for adverse events. Conversely, it may simply be an epiphenomenon identifying patients at high risk for complications regardless of blood pressure management during the anesthetic. If true, a MAP <65 mm Hg for ≥15 minutes may simply identify an anesthesiologist caring for more complex and “sicker” patients. The inclusion of a quality measure based on evidence obtained only from retrospective database analysis is reminiscent of our specialty’s travails with a strategy of administration of β-adrenergic receptor blocking drugs to reduce perioperative myocardial infarction after noncardiac surgery. This practice was subsequently refuted as causing more deaths and strokes in an adequately powered prospective randomized, placebo controlled study.13 In the absence of evidence from such appropriately designed studies, judging anesthesia provider clinical performance based on associations derived from retrospective data base analysis will likely remain imprecise. Further, with a care team model of anesthesiologist medical direction of CRNAs, this measure will more likely reflect performance of the team and not necessarily an individual physician. The challenges of developing anesthesiologist-specific quality dashboards is underscored by investigations of large databases of patients undergoing cardiac surgery. Those investigations have emphasized that major postoperative complications and mortality are more dependent on patient, surgeon, and institutional characteristics than individual anesthesiologist.14,15 Those observations further confound using such outcomes for judging anesthesiologist quality of perioperative care. Table. - Arguments For and Against a MAP <65 mm Hg for ≥15 min as Quality Indicator for Individual Anesthesiologist Pro • Retrospective database analysis from a limited number of tertiary care centers have linked this MAP cutoff with organ injury and mortality. • Objective data are easily collected from electronic anesthesia records. • Data linked to individual provider easily transferred to quality reporting platforms. Con • Validation using data from a wide variety of medical practices representing academic and private groups of varying sizes from across the United States and containing adequate numbers of women and underrepresented minorities is lacking. • Insufficient evidence that prospectively maintaining MAP above this threshold reduces complications and mortality. • When applied to care provided by anesthesiologist medical direction of CRNAs, the metric reflects results of the anesthesia team model more than individual anesthesiologist. • Metric may identify anesthesiologist caring for higher risk and “sicker” patients, thus potentially discouraging care of such patients to improve externally monitored quality of care. • Fails to consider the impact of postoperative hemodynamic events or other complications on the risk for acute kidney injury, myocardial infarction, and mortality. • Single threshold for defining hypotension based on population averages fails to precisely identify what MAP for an individual patient compromises organ perfusion. Abbreviations: CRNA, certified registered nurse anesthetist; MAP, mean arterial pressure. DISCLOSURES Name: Eric Kamenetsky, MD. Contribution: This author helped with the concepts, literature review, and writing of this article. Conflicts of Interest: None. Name: Charles W. Hogue, MD, FAHA. Contribution: This author helped with the concepts of this study and writing of the article. Conflicts of Interest: C. W. Hogue has served as a consultant and provided lectures for Medtronic, Inc (Boulder, CO) and Edwards Lifescience (Irvine, CA). He serves on a data safety and monitoring committee for Merck, Inc (Kenilworth, NJ). This manuscript was handled by: Richard C. Prielipp, MD.

Relationship between endothelial function and vascular stiffness on lower limit of cerebral autoregulation in patients undergoing cardiovascular surgery.

Hemodynamic management based on cerebral autoregulation range is a possible strategy for preserving major organ perfusion during cardiovascular surgery. The purpose of this study was to evaluate the relation of vascular properties with lower limit of cerebral autoregulation (LLA). LLA was monitored in 66 patients undergoing cardiovascular surgery using near-infrared spectroscopy. To determine the clinical importance of LLA monitoring, association of blood pressure excursions below LLA and acute kidney injury (AKI) was evaluated. Flow-mediated dilation (FMD) and pulse wave velocity (PWV) were measured for the evaluation of endothelial function and aortic stiffness. Variables associated with LLA were evaluated. Excluding patients on hemodialysis, there were 15 patients (25.9%) who developed AKI. Blood pressure excursions below LLA were higher in patients who developed AKI (4.55mmHg×hr vs. 1.23mmHg×hr, P=.017). In the univariate analysis, prevalence of ischemic heart disease (No IHD: 53±13.0mmHg vs. IHD: 60.0±13.6mmHg, P=.056) and FMD (r=-0.42, 95% CI -0.61 to -0.19, P<.001) were associated with LLA before cardiopulmonary bypass (CPB). During CPB, calcium channel blocker (No Ca blocker: 42±10.6mmHg vs. Ca blocker: 49±14.3mmHg, P=.033), diabetes (no DM: 44±13.2mmHg vs. DM: 55±10.0mmHg, P=.024), FMD (r=-0.32, 95% CI -0.55 to -0.05, P=.021), and PWV (r=0.28, 95% CI 0.012 to 0.513, P=.041) were associated with LLA. Multivariate analysis showed that FMD was correlated with LLA before CPB (r=-2.19, 95% CI -3.621 to -0.755, P=.003), while PWV was correlated with LLA during CPB (r=0.01, 95% CI 0.001-0.019, P = .023). Endothelial function and aortic stiffness may be important factors in determining LLA at different phases in cardiovascular surgery.

P.16 Expanding on the Observed Correlation between the Ambulatory Arterial Stiffness Index and the Lower Limit of Cerebral Autoregulation during Cardiac Surgery

BackgroundThe lower limit of cerebral autoregulation (LLA) refers to the mean blood pressure (BP) below which cerebral blood flow becomes pressure-dependent, resulting, among others, in an increased stroke risk. The LLA measured during cardiac surgery, correlates with the vascular measure Ambulatory Arterial Stiffness Index (AASI) determined from intraoperative continuous radial BP before cardiopulmonary bypass [1]. Using these data we investigated added factors that may enhance this correlation.Design and methodThe study population included 167 patients undergoing cardiac surgery (age 71 ± 8 years, 68% males) with good-quality BP records. The AASI. Additionally tested predictors were body-mass index (BMI), the coefficient of variation (SD/mean) of the systolic BP (SBP_CV), the composite variables BMI*(1-AASI), and its linear combination with SBP_CV. The odds ratio (OR) was determined by applying logistic regression to dichotomized predictors (by medians) and LLA- (by selected thresholds) adjusted to age, sex, diabetes mellitus, heart rate and preoperative diastolic BP.ResultsThe Table shows that the LLA of individuals correlated significantly with each of the (continuous) predictors, and the adjusted OR increased for the composite predictors (dichotomized), while showing insensitivity to adjustors. The ORs reached a maximum for a LLA threshold of 55 mmHg.ConclusionThe newly-defined composite predictors that increased the likelihood of predicting a LLA higher than 55 mmHg enhances our knowledge regarding the cerebral vasculature and autoregulation, and BP variability determinants of LLA under anesthesia.TableUnivariate regressionAdjusted ORPredictorr (p-value)Mean [95% CI] (p-value)AASI0.27 (0.0004)2.41 [1.16–5.00] (0.02)BMI−0.26 (0.0007)3.77 [1.78–8.00] (0.0005)SBP_CV−0.29 (0.0002)3.50 [1.71–7.16] (0.0006)BMI*(1-AASI)−0.35 (0.000005)4.51 [2.16–9.40] (0.00006)80*SBP_CV + BMI*(1-AASI)−0.44 (<0.000001)8.20 [3.67–18.3] (<0.000001)

Effect of Targeting Mean Arterial Pressure During Cardiopulmonary Bypass by Monitoring Cerebral Autoregulation on Postsurgical Delirium Among Older Patients

Delirium occurs in up to 52% of patients after cardiac surgery and may result from changes in cerebral perfusion. Using intraoperative cerebral autoregulation monitoring to individualize and optimize cerebral perfusion may be a useful strategy to reduce the incidence of delirium after cardiac surgery. To determine whether targeting mean arterial pressure during cardiopulmonary bypass (CPB) using cerebral autoregulation monitoring reduces the incidence of delirium compared with usual care. This randomized clinical trial nested within a larger trial enrolled patients older than 55 years who underwent nonemergency cardiac surgery at a single US academic medical center between October 11, 2012, and May 10, 2016, and had a high risk for neurologic complications. Patients, physicians, and outcome assessors were masked to the assigned intervention. A total of 2764 patients were screened, and 199 were eligible for analysis in this study. In the intervention group, the patient's lower limit of cerebral autoregulation was identified during surgery before CPB. On CPB, the patient's mean arterial pressure was targeted to be greater than that patient's lower limit of autoregulation. In the control group, mean arterial pressure targets were determined according to institutional practice. The main outcome was any incidence of delirium on postoperative days 1 through 4, as adjudicated by a consensus expert panel. Among the 199 participants in this study, mean (SD) age was 70.3 (7.5) years and 150 (75.4%) were male. One hundred sixty-two (81.4%) were white, 26 (13.1%) were black, and 11 (5.5%) were of other race. Of 103 patients randomized to usual care, 94 were analyzed, and of 102 patients randomized to the intervention 105 were analyzed. Excluding 5 patients with coma, delirium occurred in 48 of the 91 patients (53%) in the usual care group compared with 39 of the 103 patients (38%) in the intervention group (P = .04). The odds of delirium were reduced by 45% in patients randomized to the autoregulation group (odds ratio, 0.55; 95% CI, 0.31-0.97; P = .04). The results of this study suggest that optimizing mean arterial pressure to be greater than the individual patient's lower limit of cerebral autoregulation during CPB may reduce the incidence of delirium after cardiac surgery, but further study is needed. ClinicalTrials.gov identifier: NCT00981474.

Determining the Upper and Lower Limits of Cerebral Autoregulation With Cerebral Oximetry Autoregulation Curves: A Case Series.

Critical care guidelines recommend a single target value for mean arterial blood pressure in critically ill patients. However, growing evidence regarding cerebral autoregulation challenges this concept and supports individualizing mean arterial blood pressure targets to prevent brain and kidney hypo- or hyperperfusion. Regional cerebral oxygen saturation derived from near-infrared spectroscopy is an acceptable surrogate for cerebral blood flow and has been validated to measure cerebral autoregulation. This study suggests a novel mechanism to construct autoregulation curves based on near-infrared spectroscopy-measured cerebral oximetry. Case-series study. Neurocritical care unit in a tertiary medical center. Patients with acute neurologic injury and Glasgow coma scale score less than or equal to 8. Autoregulation curves were plotted using the fractional-polynomial model in Stata after multimodal continuous monitoring of regional cerebral oxygen saturation and mean arterial blood pressure. Individualized autoregulation curves of seven patients exhibited varying upper and lower limits of autoregulation and provided useful clinical information on the autoregulation trend (curves moving to the right or left during the acute coma period). The median lower and upper limits of autoregulation were 86.5 mm Hg (interquartile range, 74-93.5) and 93.5 mm Hg (interquartile range, 83-99), respectively. This case-series study showed feasibility of delineating real trends of the cerebral autoregulation plateau and direct visualization of the cerebral autoregulation curve after at least 24 hours of recording without manipulation of mean arterial blood pressure by external stimuli. The integration of multimodal monitoring at the bedside with cerebral oximetry provides a noninvasive method to delineate daily individual cerebral autoregulation curves.

Relationship Between the Ambulatory Arterial Stiffness Index and the Lower Limit of Cerebral Autoregulation During Cardiac Surgery

BackgroundPulse pressure, the ambulatory arterial stiffness index (AASI), and the symmetric AASI are established predictors of adverse cardiovascular outcomes. However, little is known about their relationship to cerebral autoregulation. This study evaluated whether these markers of vascular properties relate to the lower limit of cerebral autoregulation (LLA).Methods and ResultsThe LLA was determined during cardiac surgery with transcranial Doppler ultrasonography in 181 patients. All other variables were calculated from continuous intraoperative readings obtained before cardiopulmonary bypass. The LLA varied directly with the AASI (β=3.12 per 0.1 change in AASI, P<0.001) and to a lesser extent the symmetric AASI (β=2.02 per 0.1 change in symmetric AASI, P≤0.022), while peripheral pulse pressure was not significantly related (β=0.0, P>0.99). Logistic regression revealed that the likelihood of LLA being >65 mm Hg increased by 50% (95% confidence interval, 11%–102%, P=0.008) for every 0.1 increase in the AASI. The AASI was able to predict a LLA above certain thresholds (area under the curve receiver operating characteristic for AASI predicting an LLA >65 mm Hg: 0.60; 95% confidence interval, 0.51%–0.68%, P=0.043). Incorporating additional variables improved the model's predictive ability (area under the curve for AASI predicting a LLA >65 mm Hg: 0.75; 95% confidence interval, 0.68–0.82, P=0.036).ConclusionsThese data indicate that the LLA is related to the mechanical properties of the vasculature as represented by the AASI. The AASI can be used to predict LLA threshold levels during cardiac surgery. It is now possible to link elevations in the LLA with an increased AASI as determined from readily accessible intraoperative variables.

Optimal blood pressure during cardiopulmonary bypass defined by cerebral autoregulation monitoring

ObjectivesWe sought to define the lower and upper limits of cerebral blood flow autoregulation and the optimal blood pressure during cardiopulmonary bypass. We further sought to identify variables predictive of these autoregulation end points. MethodsCerebral autoregulation was monitored continuously with transcranial Doppler in 614 patients during cardiopulmonary bypass enrolled in 3 investigations. A moving Pearson's correlation coefficient was calculated between cerebral blood flow velocity and mean arterial pressure to generate the variable mean velocity index. Optimal mean arterial pressure was defined as the mean arterial pressure with the lowest mean velocity index indicating the best autoregulation. The lower and upper limits of cerebral blood flow autoregulation were defined as the mean arterial pressure at which mean velocity index was increasingly pressure passive (ie, mean velocity index ≥0.4) with declining or increasing blood pressure, respectively. ResultsThe mean (± standard deviation) lower and upper limits of cerebral blood flow autoregulation, and optimal mean arterial pressure were 65 ± 12 mm Hg, 84 ± 11 mm Hg, and 78 ± 11 mm Hg, respectively, after adjusting for study enrollment. In 17% of patients, though, the lower limit of cerebral autoregulation was above this optimal mean arterial pressure, whereas in 29% of patients the upper limit of autoregulation was below the population optimal mean arterial pressure. Variables associated with optimal mean arterial pressure based on multivariate regression analysis were nonwhite race (increased 2.7 mm Hg; P = .034), diuretics use (decreased 1.9 mm Hg; P = .049), prior carotid endarterectomy (decreased 5.5 mm Hg; P = .019), and duration of cardiopulmonary bypass (decreased 1.28 per 60 minutes of cardiopulmonary bypass). The product of the duration and magnitude that mean arterial pressure during cardiopulmonary bypass was below the lower limit of cerebral autoregulation was associated with the risk for stroke (P = .02). ConclusionsReal-time monitoring of autoregulation may improve individualizing mean arterial pressure during cardiopulmonary bypass and improving patient outcomes.

Relationship between Hypotension and Cerebral Ischemia during Hemodialysis.

The relationship between BP and downstream ischemia during hemodialysis has not been characterized. We studied the dynamic relationship between BP, real-time symptoms, and cerebral oxygenation during hemodialysis, using continuous BP and cerebral oxygenation measurements prospectively gathered from 635 real-world hemodialysis sessions in 58 prevalent patients. We examined the relationship between BP and cerebral ischemia (relative drop in cerebral saturation >15%) and explored the lower limit of cerebral autoregulation at patient and population levels. Furthermore, we estimated intradialytic exposure to cerebral ischemia and hypotension for each patient, and entered these values into multivariate models predicting change in cognitive function. In all, 23.5% of hemodialysis sessions featured cerebral ischemia; 31.9% of these events were symptomatic. Episodes of hypotension were common, with mean arterial pressure falling by a median of 22 mmHg (interquartile range, 14.3-31.9 mmHg) and dropping below 60 mmHg in 24% of sessions. Every 10 mmHg drop from baseline in mean arterial pressure associated with a 3% increase in ischemic events (P<0.001), and the incidence of ischemic events rose rapidly below an absolute mean arterial pressure of 60 mmHg. Overall, however, BP poorly predicted downstream ischemia. The lower limit of cerebral autoregulation varied substantially (mean 74.1 mmHg, SD 17.6 mmHg). Intradialytic cerebral ischemia, but not hypotension, correlated with decreased executive cognitive function at 12 months (P=0.03). This pilot study demonstrates that intradialytic cerebral ischemia occurs frequently, is not easily predicted from BP, and may be clinically significant.

Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial.

BackgroundDebilitating brain injury occurs in 1.6–5 % of patients undergoing cardiac surgery with cardiopulmonary bypass. Diffusion-weighted magnetic resonance imaging studies have reported stroke-like lesions in up to 51 % of patients after cardiac surgery. The majority of the lesions seem to be caused by emboli, but inadequate blood flow caused by other mechanisms may increase ischaemia in the penumbra or cause watershed infarcts. During cardiopulmonary bypass, blood pressure can be below the lower limit of cerebral autoregulation. Although much debated, the constant blood flow provided by the cardiopulmonary bypass system is still considered by many as appropriate to avoid cerebral ischaemia despite the low blood pressure.Methods/designThe Perfusion Pressure Cerebral Infarct trial is a single-centre superiority trial with a blinded outcome assessment. The trial is randomising 210 patients with coronary vessel and/or valve disease and who are undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients are stratified by age and surgical procedure and are randomised 1:1 to either an increased mean arterial pressure (70–80 mmHg) or ‘usual practice’ (40–50 mmHg) during cardiopulmonary bypass.The cardiopulmonary bypass pump flow is fixed and set at 2.4 L/minute/m2 body surface area plus 10–20 % in both groups.The primary outcome measure is the volume of the new ischaemic cerebral lesions (in mL), expressed as the difference between a baseline, diffusion-weighted, magnetic resonance imaging scan and an equal scan conducted 3–6 days postoperatively. Secondary endpoints are the total number of new ischaemic cerebral lesions, postoperative cognitive dysfunction at discharge and 3 months postoperatively, diffuse cerebral injury evaluated by magnetic resonance spectroscopy and selected biochemical markers of cerebral injury.The sample size will enable us to detect a 50 % reduction in the primary outcome measure in the intervention compared to the control group at a significance level of 0.05 and with a power of 0.80.DiscussionThis is the first clinical randomised study to evaluate whether the mean arterial pressure level during cardiopulmonary bypass influences the development of brain injuries that are detected by diffusion-weighted magnetic resonance imaging.Trial registrationClinicalTrials.gov, NCT02185885. Registered on 7 July 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1373-6) contains supplementary material, which is available to authorized users.

Arterial pressure above the upper cerebral autoregulation limit during cardiopulmonary bypass is associated with postoperative delirium

Mean arterial pressure (MAP) below the lower limit of cerebral autoregulation during cardiopulmonary bypass (CPB) is associated with complications after cardiac surgery. However, simply raising empiric MAP targets during CPB might result in MAP above the upper limit of autoregulation (ULA), causing cerebral hyperperfusion in some patients and predisposing them to cerebral dysfunction after surgery. We hypothesized that MAP above an ULA during CPB is associated with postoperative delirium. Autoregulation during CPB was monitored continuously in 491 patients with the cerebral oximetry index (COx) in this prospective observational study. COx represents Pearson's correlation coefficient between low-frequency changes in regional cerebral oxygen saturation (measured with near-infrared spectroscopy) and MAP. Delirium was defined throughout the postoperative hospitalization based on clinical detection with prospectively defined methods. Delirium was observed in 45 (9.2%) patients. Mechanical ventilation for >48 h [odds ratio (OR), 3.94; 95% confidence interval (CI), 1.72-9.03], preoperative antidepressant use (OR, 3.0; 95% CI, 1.29-6.96), prior stroke (OR, 2.79; 95% CI, 1.12-6.96), congestive heart failure (OR, 2.68; 95% CI, 1.28-5.62), the product of the magnitude and duration of MAP above an ULA (mm Hg h; OR, 1.09; 95% CI, 1.03-1.15), and age (per year of age; OR, 1.01; 95% CI, 1.01-1.07) were independently associated with postoperative delirium. Excursions of MAP above the upper limit of cerebral autoregulation during CPB are associated with risk for delirium. Optimizing MAP during CPB to remain within the cerebral autoregulation range might reduce risk of delirium. clinicaltrials.gov NCT00769691 and NCT00981474.

The Acute Effects of Hemorrhagic Shock on Cerebral Blood Flow, Brain Tissue Oxygen Tension, and Spreading Depolarization following Penetrating Ballistic-Like Brain Injury

Traumatic brain injury (TBI) often occurs in conjunction with additional trauma, resulting in secondary complications, such as hypotension as a result of blood loss. This study investigated the combined effects of penetrating ballistic-like brain injury (PBBI) and hemorrhagic shock (HS) on physiological parameters, including acute changes in regional cerebral blood flow (rCBF), brain tissue oxygen tension (P(bt)O₂), and cortical spreading depolarizations (CSDs). All recordings were initiated before injury (PBBI/HS/both) and maintained for 2.5 h. Results showed that PBBI alone and combined PBBI and HS produced a sustained impairment of ipsilateral rCBF that decreased by 70% from baseline (p<0.05). Significant and sustained reductions in P(bt)O₂ (50% baseline; p<0.05) were also observed in the injured hemisphere of the animals subjected to both PBBI and HS (PBBI+HS). In contrast, PBBI alone produced smaller, more transient reductions in P(bt)O₂ levels. The lower limit of cerebral autoregulation was significantly higher in the PBBI+HS group (p<0.05, compared to HS alone). Critically, combined injury resulted in twice the number of spontaneous CSDs as in PBBI alone (p<0.05). It also lowered the propagation speed of CSD and the threshold of CSD occurrence [induced CSD at higher mean arterial pressure (MAP)]. However, rCBF and P(bt)O₂ were not responsive to the depolarizations. Our data suggest that PBBI together with HS causes persistent impairment of CBF and brain tissue oxygen tension, increasing the probability of CSDs that likely contribute to secondary neuropathology and compromise neurological recovery.

Impact of sevoflurane anesthesia on cerebral blood flow in children younger than 2 years

To assess the impact of sevoflurane and anesthesia-induced hypotension on cerebral blood flow (CBF) in children younger than 2 years. Inhalational induction with sevoflurane is the most commonly used technique in young children. However, the effect of sevoflurane on cerebral perfusion has been only studied in adults and children older than 1 year. The purpose of this study is to assess the impact of sevoflurane anesthesia on CBF in neonates and infants, using transcranial Doppler (TCD) sonography. Children younger than 2 years, ASA I or II, for abdominal or orthopedic surgery were included. Induction of anesthesia was started by sevoflurane 6% and maintained with an expired fraction of sevoflurane 3%. Mechanical ventilation was controlled to maintain an end tidal CO(2) around 39 mmHg. CBF was assessed by measuring the velocities (systolic velocity SVmca, diastolic velocity DVmca and mean velocity MVmca) in the proximal segment of the middle cerebral artery (mca) in children awake and then 15 min after induction. Mean arterial pressure (MAP) variation was noted. One hundred and thirteen children were included. We observed a significant decrease in MAP (-30%). DVmca decreased and pulsatility index increased significantly after induction. Subgroup analysis according to age showed that in infants older than 6 months, despite a significant reduction in MAP, there was no change in CBF velocity (CBFV) as measured by TCD sonography, until MAP dropped below 40% of baseline. In infants younger than 6 months, a significant decrease in MAP was observed which was associated with a significant variation in CBFV. In this population, when CBFV start to decrease, MAP under sevoflurane anesthesia was 38 mmHg or -20% from baseline value. Our results are in favor of a reduction in CBF after induction with sevoflurane in children younger than 6 months. This population is more sensitive to MAP decrease than older children because of a lower limit of cerebral autoregulation, and this limit may be 38 mmHg with sevoflurane anesthesia.

Ischemic Brain Injury After Intracerebral Hemorrhage

HomeStrokeVol. 43, No. 8Ischemic Brain Injury After Intracerebral Hemorrhage Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBIschemic Brain Injury After Intracerebral HemorrhageA Critical Review Shyam Prabhakaran, MD, MS and Andrew M. Naidech, MD, MSPH Shyam PrabhakaranShyam Prabhakaran From Department of Neurology, Northwestern University-Feinberg School of Medicine, Chicago, IL. Search for more papers by this author and Andrew M. NaidechAndrew M. Naidech From Department of Neurology, Northwestern University-Feinberg School of Medicine, Chicago, IL. Search for more papers by this author Originally published19 Jul 2012https://doi.org/10.1161/STROKEAHA.112.655910Stroke. 2012;43:2258–2263Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionIntracerebral hemorrhage (ICH) is the second most common cause of stroke and accounts for 8% to 15% of strokes in Western societies with an estimated incidence of 10 to 25 per 100 000 persons.1–3 Despite advances in the field of stroke and neurocritical care,4 the 30-day mortality has not changed significantly over the past 20 years.3 Indeed, ICH has the highest rates of dependence or death among stroke types and proven treatments are lacking.Clinical trials aimed at limiting hemorrhage growth, procoagulant agents for hemostasis,5 and surgical evacuation6 have not translated into improved clinical outcomes. Antihypertensive therapy for the purpose of reducing hematoma growth has been a mainstay of acute management. Guidelines recommend maintaining mean arterial pressure <130 mm Hg during the acute phase7; however, controversies exist given the lack of randomized clinical trial data and uncertainties about the rapidity and target level of blood pressure (BP)-lowering. Recent Phase 2 clinical trials evaluating acute BP control have shown promise in reducing hematoma expansion with an adequate safety profile and Phase 3 trials are underway.8,9Besides hematoma growth, other pathophysiological processes occur in the setting of ICH and may serve as potential therapeutic targets. In the acute period after ICH, a rapid rise in intracranial pressure (ICP) from an expanding hematoma may reduce cerebral perfusion pressure. In this setting, interventions aimed at BP-lowering and hemostasis may theoretically induce thrombosis or exacerbate brain ischemia, particularly in patients with pre-existing cerebrovascular disease. A recent publication suggests that aggressive BP-lowering may actually cause acute brain ischemia and worsen outcomes after ICH.10In this review, we outline the data on secondary acute ischemic injury after ICH, review the prevalence of remote ischemic lesions and risk factors associated with their occurrence, explore potential mechanisms and clinical impact of these lesions, and discuss future directions in this arena of research.Prevalence of Secondary Ischemic Injury After ICHAfter arteriolar rupture and parenchymal hemorrhage in the brain, a combination of local compression, cytotoxic injury, inflammation, and surrounding edema ensues. Imaging studies in patients with ICH have demonstrated these effects at varying stages of hemorrhage and within and surrounding the hematoma bed. Although there is restricted diffusion within the hematoma during the first 2 weeks,11 an effect of increased viscosity and suspectibility effects from blood breakdown products, much more attention has been paid to the potential for ischemia in the surrounding tissue.That aggressive BP-lowering might promote cerebral ischemia adjacent to the hematoma has been cited as a potential hazard of aggressive antihypertensive therapy; however, imaging studies using single-photon emission CT, positron emission tomography, and CT and MR single-photon emission computed tomography and perfusion studies12–18 have failed to show any significant rim of perihematomal ischemia. There appears to be decreased cerebral blood flow in the perihematomal region but it is accompanied by a decreased cerebral metabolic rate of oxygen and lowered, not elevated, oxygen extraction fraction.16,18 Thus, the data suggest that perihematomal hypoperfusion in ICH is a consequence of hypometabolism, which may be mediated by toxic effects from the hematoma itself.19 Other studies, however, using single-photon emission computed tomography20 and jugular venous oxygen tension21 have observed reduced hemispheric cerebral blood flow and impaired cerebral autoregulation in the setting of aggressive BP-lowering. It is also known that complex phasic variations in cerebral blood flow and metabolism may exist after ICH such that very aggressive BP-lowering or persistent modest lowering in the later periods of metabolic normalization may lead to cerebral ischemia both in the perihematomal and distant brain regions.22Diffusion-weighted imaging (DWI) offers greater spatial resolution (1–2 mm) than single-photon emission CT, positron emission tomography, or CT-based techniques (5–10 mm); can detect very small foci of acute neuronal injury; and is a sensitive marker of acute brain ischemia.23 The occurrence of DWI lesions, remote from the primary site of injury and delayed from the ictus, has been described in other types of brain injury including ischemic stroke,24 transient ischemic attack,25 and subarachnoid hemorrhage.26 Its recent application in ICH suggests that remote ischemic lesions are found in approximately 25% of patients.10,27–31 The lesions are typically subcortical, often multiple or bilateral, and very small (Figure 1). Additionally, they were noted in 27% of patients on subacute or delayed imaging at 30 days, of which 83% were incident lesions not present on the initial scan.30 These composite data suggest that a “stroke-prone” state may exist after either hemorrhagic or ischemic stroke, may be provoked by several factors, and may last weeks to months.Download figureDownload PowerPointFigure 1. Example of DWI lesions after ICH. DWI indicates diffusion-weighted imaging; ICH, intracerebral hemorrhage.Mechanisms and PathophysiologyMechanisms of secondary ischemic injury after ICH are uncertain. However, based on the recent publications,10,27–31 several potential factors have been consistently associated with acute ischemic lesions. These include BP-lowering, markers of microvasculopathy, and ICP elevation (Table). We theorize that these mechanisms interact in complex ways (Figure 2). Acting on a background-enhanced thrombotic milieu (“stroke-prone” state) after ICH, vulnerable patients with pre-existing cerebral microangiopathy due to atherosclerotic risk factors and/or cerebral amyloid angiopathy (CAA) may have lower thresholds for brain ischemia. In such patients, elevations of ICP, failure of autoregulation, and aggressive early BP-lowering could provoke acute brain ischemia.Table. Summary of Recent Publications on DWI Lesions After ICHKimberly et al29Prabhakaran et al31Gregoire et al27Garg et al10Menon et al30Kang et al28Sample size 78 (87% ICH) 118 (100% ICH) 114 (100% ICH) 95 (100% ICH) 138 (100% ICH) 97 (100% ICH)DesignRetrospective case–controlRetrospectiveMulticenter case–controlProspectiveProspectiveProspectiveTiming of MRIMedian, 4 dMedian, 1 dMedian, 7 dMedian, 2 dMedian, 2 d and 35 dMedian, 3 dAge, y78.259.670.764.159.859.1RaceWhite?Nonwhite 67%White?Nonwhite 62%Nonwhite 73%AsianICH cause100% CAA70% HTN34% CAA62% HTN62% HTN83% HTNPrevalence of DWI lesion15%23%13%41%Acute: 35%27%1 mo: 27%AssociationsTotal MBsPrior strokeCAA etiologyBP-loweringAcute: BP-loweringLeukoaraiosisCraniotomyLobar MBsIVHMBs >2BP-loweringLeukoaraiosisICH volumeHTN etiologyTotal MBs1 mo: prior strokeBaseline MBBaseline DWIDWI indicates diffusion weighted imaging; ICH, intracerebral hemorrhage; MB, microbleeds; CAA, cerebral amyloid angiopathy; HTN, hypertension; BP, blood pressure; IVH, intraventricular hemorrhage.Download figureDownload PowerPointFigure 2. A multihit hypothesis for development of brain ischemia after intracerebral hemorrhage.BP-LoweringThree studies10,30,31 have independently suggested a relationship between degree of BP-lowering and DWI lesions, whereas 2 have not found an association.27,28 In the positive studies, change in BP, in absolute and relative terms, correlated with presence of DWI lesions. This relationship may be heightened in the first few hours after BP treatment (Figure 3).Download figureDownload PowerPointFigure 3. Systolic blood pressure on the y-axis among those with DWI (red) and without DWI lesions (blue) with time in hours from presentation on the x-axis. DWI indicates diffusion-weighted imaging.Cerebral blood flow is regulated across a wide range of mean arterial pressure or cerebral perfusion pressure in the normal state. Cerebral autoregulation is right-shifted in chronic hypertension and may be lost in the setting of acute brain injury such that cerebral blood flow responds linearly to cerebral perfusion pressure.32 Aggressive BP reductions beyond the lower limits of cerebral autoregulation, therefore, have the potential of inducing cerebral ischemia. Elevated ICP and use of vasoactive substances with the potential of exacerbating ICP may further compromise cerebral perfusion pressure in patients with ICH.Cerebral MicroangiopathyFive of the studies consistently reported an association with either microhemorrhage burden on gradient-echo imaging or white matter hyperintensity burden on fluid-attenuated inversion recovery sequences.27–30 A history of stroke was associated with DWI lesions in another study.31 As markers of chronic cerebral vasculopathy, these factors may identify those with significant pre-existing cerebrovascular disease and who are more prone to ischemic injury after ICH.Ischemic stroke and ICH share many risk factors and pathological substrates. The characteristic locations of hypertensive ICH include the basal ganglia, thalamus, pons, and cerebellum, many of which are common sites for lacunar ischemic infarction. They also share many vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, and smoking.33 It is well established that these risk factors lead to distinct pathologies affecting arterioles (typically perforators) including fibrinoid changes, lipohyalinosis, necrosis, and microaneurysm formation. These changes can predispose them to occlusion and/or rupture.34 Further evidence of the link between ischemic stroke and ICH is drawn from the observations that patients surviving ICH have comparable risks for subsequent ischemic and hemorrhagic stroke.35,36In contrast to hypertensive vasculopathy, which affects the deep and subcortical arterioles, CAA affects small superficial and leptomeningeal arterioles. Beta-amyloid protein deposition in these vessel walls leads to degenerative changes that predispose them to vessel fragility and rupture.37 Just as hypertensive vasculopathy can manifest as ICH, ischemic infarction, leukoaraiosis, and vascular dementia, patients harboring CAA pathology can have multiple cerebrovascular presentations including ICH, vasculitis and ischemic stroke, leukoencephalopathy, and dementia.38 Indeed, white matter disease is increased and cerebral blood flow responses are impaired in patients with CAA compared with control subjects.39,40Thus, a chronic microangiopathy, either due to hypertension or CAA, may pre-exist in many patients with ICH. These underlying disease processes may place such patients at risk for both ischemic and hemorrhagic stroke. Vascular biological substrates may also play critical roles in determining the response to hemodynamic alternations after ICH and precipitate secondary ischemic injury. For instance, pre-existing microvascular flow impairment may be exacerbated by aggressive BP-lowering and/or thrombotic activation after ICH and result in small ischemic infarcts.Further support of an underlying microangiopathy in both hemorrhagic and ischemic stroke comes from a recent report of subclinical incident microhemorrhage occurrence (unrelated to hemorrhagic transformation) after acute ischemic stroke. In a serial brain MRI study of 237 patients with ischemic stroke, 12.7% of patients developed new microhemorrhages within days of the initial scan.41 A common microvascular disarray might underlie both hemorrhagic and ischemic stroke and promote a “stroke-prone state” after any acute cerebrovascular insult.24 These may be mediated by endothelial dysfunction, active inflammation, and breakdown of the blood–brain barrier in ICH.42 We, therefore, speculate that hypertensive and CAA-mediated changes in the microvasculature lead to hemorrhagic or ischemic stroke in isolation in most patients but can occur in rapid sequence or simultaneously in some patients.Other Mechanisms and Provoking FactorsAs noted, ICP elevation in moderate- or large-volume hemorrhages or those associated with intraventricular hemorrhage and hydrocephalus may lower the threshold for ischemia in the setting of relatively modest but rapid BP-lowering. Volume of ICH and intraventricular extension, probably as surrogate markers of ICP, have been associated with DWI lesions.30,31 Alternatively, many patients with ICH with vascular risk factors may ingest antithrombotic agents and harbor large-artery stenosis or cardiac sources of embolism at baseline. Thus, ischemic stroke may simply be occurring in high-risk patients in the setting of antiplatelet therapy withdrawal.43Another possibility is that frank hemorrhagic transformation of an embolic ischemic stroke may be misdiagnosed as spontaneous ICH with remote DWI lesions providing evidence of embolism. This would unlikely explain such a large proportion of patients with this finding, however. Other unlikely mechanisms include local vascular compression due to the mass effect from the hematoma. A small percentage of patients also undergo craniotomy, during which low BPs, anesthetic agents, manipulation of arteries, and thrombotic activation with surgery may promote ischemia. Vasospasm, which is common after subarachnoid hemorrhage, is not known to occur after spontaneous ICH in the absence of an unusual amount of subarachnoid blood or a reversible vasculopathy that may present with ischemic and hemorrhagic stroke (ie, Call-Fleming or reversible cerebral vasoconstriction syndrome). Finally, given the delayed incident lesions at 1 month, there may be a period of thrombotic or inflammatory activation that leads to subclinical and clinical events soon after ICH, like in other acute brain injury states. In animal models of subarachnoid hemorrhage44 and traumatic brain injury,45 platelets have been shown to aggregate and cause mircrovascular occlusion due to an inflammatory prothrombotic environment.Impact on Long-Term OutcomesGiven the data on the prevalence of ischemic lesions after ICH, the next logical question is: do they matter? Silent brain infarcts are frequently observed on brain imaging of elderly individuals, serve as markers for the extent or severity of cerebrovascular disease, and predict subsequent risk of stroke and vascular dementia.46–48 Early subclinical DWI lesions after acute ischemic stroke also increase the subsequent risk of recurrent ischemic stroke, transient ischemic attack, and vascular death.49 Silent infarcts may also interact with the index infarct volume and worsen the degree of motor impairment in patients with stroke.50Two longitudinal studies have evaluated the influence of DWI lesions on subsequent functional outcomes after ICH. At 3 months, those with DWI lesions were 5-fold more likely to have poor functional outcomes (defined as modified Rankin Scale score 4–6 indicating dependence or death) adjusting for known predictors (age, initial stroke severity, and ICH score).10 Another single-center study evaluated outcomes at 1 year and noted that those with DWI lesions were >6-fold more likely to have poor outcomes at follow-up than those without, independent of stroke severity.51 A third prospective study of 97 patients with ICH followed for median 42 months demonstrated that DWI lesions significantly increased risks of ischemic stroke and combined ischemic stroke, ICH, and vascular death.28The mechanisms by which small ischemic lesions worsen outcome after ICH are uncertain. These may reduce neuroplasticity and retard restorative ipsi- and contralesional synaptic networks. Some lesions may be strategically symptomatic but only become recognized after the initial clinical presentation, influenced mostly by the hematoma itself, recedes in the subacute period. Lastly, DWI lesions in ICH may simply be markers for “frail” patients who are destined for poor recovery and elevated risk of recurrent stroke.Implications for Current PracticeThese studies cumulatively support (1) a considerable (approximately 25%) prevalence of DWI lesions; (2) a strong correlation with BP-lowering; and (3) a negative impact of DWI lesions on functional outcomes after ICH. Thus, it may be time to reconsider our approach to this disease and to re-evaluate ongoing clinical trials aimed at BP-lowering after ICH. Aggressive BP-lowering has become standard practice at many centers at the time the pivotal clinical trials to determine its clinical impact are still underway; a more refined approach with careful titration of antihypertensive therapy and using individualized targets may be necessary. Randomized clinical trials of BP-lowering should incorporate MRI to evaluate for secondary ischemic lesions and assess their influence on functional outcomes. We postulate that DWI lesions may modify the effect of BP-lowering on functional outcomes after ICH such that it may be hazardous in those with DWI lesions and beneficial in those without.Future DirectionsGiven these potential implications and yet many open questions, it is imperative that research in this area continue. First, imaging techniques including perfusion and functional imaging may help quantify the hemodynamic effects of acute BP-lowering after ICH and evaluate the impact of “silent” lesions on functional recovery. Second, serial MRI studies are needed to define the timing of ischemic lesions because subacute infarcts may be amenable to prevention. Third, detailed outcomes assessments are currently lacking but would provide insights into subtle cognitive or quality-of-life effects not appreciated by crude outcome measures such as the Rankin Scale. Fourth, pilot studies should assess the prevalence of DWI lesions at different target BP levels and the safety of ischemic stroke prevention strategies such as aspirin and statin therapy after ICH.New targets for therapeutic intervention in ICH are sorely needed. Current guidelines for BP reduction and hemostatic therapy to limit hematoma growth at the possible expense of cerebral hypoperfusion and arterial thrombosis, respectively, may be doing more harm than good. If an active biological link between hemorrhagic and ischemic brain disease exists and imaging-based techniques can identify those at risk for either or both conditions, then the relative value of secondary prevention strategies such as lipid-lowering, long-term BP control, glycemic regulation, and antithrombotic agents gains even greater importance for individualized application in vulnerable patients. Early use of antiplatelet and statin therapies to prevent secondary neuronal injury during a proinflammatory, “stroke-prone” period even at the expense of hemorrhage growth or recurrent hemorrhage may be more beneficial than currently believed. Furthermore, risk factors such as carotid artery stenosis, atrial fibrillation, and underlying hypercoagulable states may need to be considered in the diagnostic evaluation of ICH. In summary, the emerging data on secondary brain ischemia after ICH may offer a novel therapeutic target for this deadly disease.Source of FundingSupported by American Heart Association Midwest Affiliate Grant 11CRP7520073 (S.P.).DisclosuresNone.FootnotesCorrespondence to Shyam Prabhakaran, MD, MS, 710 N Lakeshore Drive, Suite 1417, Chicago, IL 60611. E-mail shyam.[email protected]edu