Can interhemispheric desynchronization of cerebral blood flow anticipate upcoming vasospasm in aneurysmal subarachnoid haemorrhage patients?

BACKGROUND: Asymmetry of cerebral autoregulation (CA) was demonstrated in patients after aneurysmal subarachnoid haemorrhage (aSAH). A classical method for CA assessment requires simultaneous measurement of both arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). In this study, we have proposed a cerebral blood flow asymmetry index based only on CBFV and analysed its association with the occurrence of vasospasm after aSAH. NEW METHOD: The phase shifts (PS) between slow oscillations in left and right CBFV (side-to-side PS) and between ABP and CBFV (CBFV-ABP PS) were estimated using multichannel matching pursuit (MMP) and cross-spectral analysis. RESULTS: We retrospectively analysed data collected from 45 aSAH patients (26 with vasospasm). Data were analysed up to 7th day after aSAH unless the vasospasm was detected earlier. A progressive asymmetry, manifested by a gradual increase in side-to-side PS on consecutive days after aSAH, was observed in patients who developed vasospasm (Radj2 = 0.14, p = 0.009). In these patients, early side-to-side PS was more positive than in patients without vasospasm (2.8° ± 5.6° vs -1.7° ± 5.7°, p = 0.011). No such a difference was found in CBFV-ABP PS. Patients with positive side-to-side PS were more likely to develop vasospasm than patients with negative side-to-side PS (21/7 vs 5/12, p = 0.0047). COMPARISON WITH EXISTING METHOD: MMP, in contrast to the spectral approach, accounts for non-stationarity of analysed signals. MMP applied to the PS estimation reflects the cerebral blood flow asymmetry in aSAH better than the spectral analysis. CONCLUSIONS: Changes in side-to-side PS might be helpful to identify patients who are at risk of vasospasm

Association of transcranial Doppler blood flow velocity slow waves with delayed cerebral ischemia in patients suffering from subarachnoid hemorrhage: a retrospective study.

BACKGROUND: Cerebral vasospasm (VS) and delayed cerebral ischemia (DCI) constitute major complications following subarachnoid hemorrhage (SAH). A few studies have examined the relationship between different indices of cerebrovascular dynamics with the occurrence of VS. However, their potential association with the development of DCI remains elusive. In this study, we investigated the pattern of changes of different transcranial Doppler (TCD)-derived indices of cerebrovascular dynamics during vasospasm in patients suffering from subarachnoid hemorrhage, dichotomized by the presence of delayed cerebral ischemia. METHODS: A retrospective analysis was performed using recordings from 32 SAH patients, diagnosed with VS. Patients were divided in two groups, depending on development of DCI. Magnitude of slow waves (SWs) of cerebral blood flow velocity (CBFV) was measured. Cerebral autoregulation was estimated using the moving correlation coefficient Mxa. Cerebral arterial time constant (tau) was expressed as the product of resistance and compliance. Complexity of CBFV was estimated through measurement of sample entropy (SampEn). RESULTS: In the whole population (N = 32), magnitude of SWs of ipsilateral to VS side CBFV was higher during vasospasm (4.15 ± 1.55 vs before: 2.86 ± 1.21 cm/s, p < 0.001). Ipsilateral SWs of CBFV before VS had higher magnitude in DCI group (N = 19, p < 0.001) and were strongly predictive of DCI, with area under the curve (AUC) = 0.745 (p = 0.02). Vasospasm caused a non-significant shortening of ipsilateral values of tau and increase in SampEn in all patients related to pre-VS measurements, as well as an insignificant increase of Mxa in DCI related to non-DCI group (N = 13). CONCLUSIONS: In patients suffering from subarachnoid hemorrhage, TCD-detected VS was associated with higher ipsilateral CBFV SWs, related to pre-VS measurements. Higher CBFV SWs before VS were significantly predictive of delayed cerebral ischemia

Baroreflex sensitivity and heart rate variability are predictors of mortality in patients with aneurysmal subarachnoid haemorrhage.

OBJECT: We aimed to investigate the link between the autonomic nervous system (ANS) impairment, assessed using baroreflex sensitivity (BRS) and heart rate variability (HRV) indices, and mortality after aneurysmal subarachnoid haemorrhage (aSAH). METHODS: A total of 57 patients (56 ± 18 years) diagnosed with aSAH were retrospectively enrolled in the study, where 25% of patients died in the hospital. BRS was calculated using a modified cross-correlation method. Time- and frequency-domain HRV indices were calculated from a time-series of systolic peak intervals of arterial blood pressure signals. Additionally, cerebral autoregulation (CA) was assessed using the mean velocity index (Mxa), where Mxa > 0 indicates impaired CA. RESULTS: Both BRS and HRV indices were lower in non-survivors than in survivors. The patients with disturbed BRS and HRV had more extensive haemorrhage in the H-H scale (p = .040) and were more likely to die (p = .013) when compared to patients with the intact ANS. The logistic regression model for mortality included: the APACHE II score (p = .002; OR 0.794) and the normalised high frequency power of the HRV (p < <.001; OR 0.636). A positive relationship was found between the Mxa and BRS (R = 0.48, p = .003), which suggests that increasing BRS is moderately strongly associated with worsening CA. CONCLUSION: Our results indicated that lower values of HRV indices and BRS correlate with mortality and that there is a link between cerebral dysautoregulation and the analysed estimates of the ANS in aSAH patients

Robotic Semi-Automated Transcranial Doppler Assessment of Cerebrovascular Autoregulation in Post-Concussion Syndrome: Methodological Considerations.

Post-concussion syndrome (PCS) refers to a constellation of physical, cognitive, and emotional symptoms after traumatic brain injury (TBI). Despite its incidence and impact, the underlying mechanisms of PCS are unclear. We hypothesized that impaired cerebral autoregulation (CA) is a contributor. In this article, we present our protocol for non-invasively assessing CA in patients with TBI and PCS in a real-world clinical setting. A prospective, observational study was integrated into outpatient clinics at a tertiary neurosurgical center. Data points included: demographics, symptom profile (Post-Concussion Symptom Scale [PCSS]) and neuropsychological assessment (Cambridge Neuropsychological Test Automated-Battery [CANTAB]). Cerebrovascular metrics (nMxa co-efficient and the transient hyperaemic-response ratio [THRR]) were collected using transcranial Doppler (TCD), finger plethysmography, and bespoke software (ICM+). Twelve participants were initially recruited but 2 were excluded after unsuccessful insonation of the middle cerebral artery (MCA); 10 participants (5 patients with TBI, 5 healthy controls) were included in the analysis (median age 26.5 years, male to female ratio: 7:3). Median PCSS scores were 6/126 for the TBI patient sub-groups. Median CANTAB percentiles were 78 (healthy controls) and 25 (TBI). nMxa was calculated for 90% of included patients, whereas THRR was calculated for 50%. Median study time was 127.5 min and feedback (n = 6) highlighted the perceived acceptability of the study. This pilot study has demonstrated a reproducible assessment of PCS and CA metrics (non-invasively) in a real-world setting. This protocol is feasible and is acceptable to participants. By scaling this methodology, we hope to test whether CA changes are correlated with symptomatic PCS in patients post-TBI

Exactly solvable Richardson–Gaudin models and their applications

3 pages, 1 table, 1 figure.--PACS nrs.: 21.60.Cs, 21.60.Fw, 02.30.Ik.--Arxiv pre-print available at: http://arxiv.org/abs/math-ph/0609022v1We first show that the quantum pairing problem can be mapped exactly on to a classical electrostatic problem in two dimensions and then use this analogy to obtain a pictorial representation of how superconductivity arises in a finite fermionic system. Specific application to the nuclei 114−116Sn suggests some new insight into the evolution of pairing correlations in a quantum system with few active particles. We also summarize other recent work on exactly solvable pairing models, including their applications in a wide variety of strongly correlated quantum systems.The work reported herein was supported in part by the US National Science Foundation under grant no PHY-0140036 and in part by the Spanish DGI under grant no BFM2003-05316-C02-02.Peer reviewe

Comparison of frequency and time domain methods of assessment of cerebral autoregulation in traumatic brain injury.

The impulse response (IR)-based autoregulation index (ARI) allows for continuous monitoring of cerebral autoregulation using spontaneous fluctuations of arterial blood pressure (ABP) and cerebral flow velocity (FV). We compared three methods of autoregulation assessment in 288 traumatic brain injury (TBI) patients managed in the Neurocritical Care Unit: (1) IR-based ARI; (2) transfer function (TF) phase, gain, and coherence; and (3) mean flow index (Mx). Autoregulation index was calculated using the TF estimation (Welch method) and classified according to the original Tiecks' model. Mx was calculated as a correlation coefficient between 10-second averages of ABP and FV using a moving 300-second data window. Transfer function phase, gain, and coherence were extracted in the very low frequency (VLF, 0 to 0.05 Hz) and low frequency (LF, 0.05 to 0.15 Hz) bandwidths. We studied the relationship between these parameters and also compared them with patients' Glasgow outcome score. The calculations were performed using both cerebral perfusion pressure (CPP; suffix 'c') as input and ABP (suffix 'a'). The result showed a significant relationship between ARI and Mx when using either ABP (r=-0.38, P<0.001) or CPP (r=-0.404, P<0.001) as input. Transfer function phase and coherence_a were significantly correlated with ARI_a and ARI_c (P<0.05). Only ARI_a, ARI_c, Mx_a, Mx_c, and phase_c were significantly correlated with patients' outcome, with Mx_c showing the strongest association.This is the accepted manuscript. The final version's available from Nature Publishing at http://dx.doi/10.1038/jcbfm.2014.192

Relationship Between Baroreflex and Cerebral Autoregulation in Patients With Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage.

Introduction: Common consequences following aneurysmal subarachnoid hemorrhage (aSAH) are cerebral vasospasm (CV), impaired cerebral autoregulation (CA), and disturbance in the autonomic nervous system, as indicated by lower baroreflex sensitivity (BRS). The compensatory interaction between BRS and CA has been shown in healthy volunteers and stable pathological conditions such as carotid atherosclerosis. The aim of this study was to investigate whether the inverse correlation between BRS and CA would be lost in patients after aSAH during vasospasm. A secondary objective was to analyze the time-trend of BRS after aSAH. Materials and Methods: Retrospective analysis of prospectively collected data was performed at the Neuro-Critical Care Unit of Addenbrooke's Hospital (Cambridge, UK) between June 2010 and January 2012. The cerebral blood flow velocity (CBFV) was measured in the middle cerebral artery using transcranial Doppler ultrasonography (TCD). The arterial blood pressure (ABP) was monitored invasively through an arterial line. CA was quantified by the correlation coefficient (Mxa) between slow oscillations in ABP and CBFV. BRS was calculated using the sequential cross-correlation method using the ABP signal. Results: A total of 73 patients with aSAH were included. The age [median (lower-upper quartile)] was 58 (50-67). WFNS scale was 2 (1-4) and the modified Fisher scale was 3 (1-3). In the total group, 31 patients (42%) had a CV and 42 (58%) had no CV. ABP and CBFV were higher in patients with CV during vasospasm compared to patients without CV (p = 0.001 and p < 0.001). There was no significant correlation between Mxa and BRS in patients with CV, neither during nor before vasospasm. In patients without CV, a significant, although moderate correlation was found between BRS and Mxa (rS = 0.31; p = 0.040), with higher BRS being associated with worse CA. Multiple linear regression analysis showed a significant worsening of BRS after aSAH in patients with CV (R p = -0.42; p < 0.001). Conclusions: Inverse compensatory correlation between BRS and CA was lost in patients who developed CV after aSAH, both before and during vasospasm. The impact of these findings on the prognosis of aSAH should be investigated in larger studies

Baroreflex Impairment After Subarachnoid Hemorrhage Is Associated With Unfavorable Outcome.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) is characterized by important changes in the autonomic nervous system with potentially adverse consequences. The baroreflex has a key role in regulating the autonomic nervous system. Its role in SAH outcome is not known. The purpose of this study was to evaluate the association between the baroreflex and the functional 3-month outcome in SAH. METHODS: The study used a prospective database of 101 patients hospitalized for SAH. We excluded patients receiving β-blockers or noradrenaline. Baroreflex sensitivity (BRS) was measured using the cross-correlation method. A good outcome was defined by a Glasgow Outcome Scale score at 4 or 5 at 3 months. RESULTS: Forty-eight patients were included. Median age was 58 years old (36-76 years); women/men: 34/14. The World Federation of Neurosurgery clinical severity score on admission was 1 or 2 for 73% of patients. In the univariate analysis, BRS (P=0.007), sedation (P=0.001), World Federation of Neurosurgery score (P=0.001), Glasgow score (P=0.002), Fisher score (P=0.022), and heart rate (P=0.037) were associated with outcome. The area under the receiver operating characteristic curve for the model with BRS as a single predictor was estimated at 0.835. For each unit increase in BRS, the odds for a good outcome were predicted to increase by 31%. Area under the receiver operating characteristic curve for heart rate alone was 0.670. In the multivariate analysis, BRS (odds ratio, 1.312; 95% confidence interval, 1.048-1.818; P=0.018) and World Federation of Neurosurgery (odds ratio, 0.382; 95% confidence interval, 0.171-0.706; P=0.001) were significantly associated with outcome. Area under the receiver operating characteristic curve was estimated at 0.900. CONCLUSIONS: In SAH, early BRS was associated with 3-month outcome. This conclusion requires confirmation on a larger number of patients in a multicentre study

Cerebral vasospasm affects arterial critical closing pressure.

The effect of cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (SAH) on critical closing pressure (CrCP) has not been fully delineated. Using cerebral impedance methodology, we sought to assess the behavior of CrCP during CVS. As CrCP expresses the sum of intracranial pressure (ICP) and vascular wall tension, we also explored its role in reflecting changes in vascular tone occurring in small vessels distal to spasm. This retrospective analysis was performed using recordings from 52 patients, diagnosed with CVS through transcranial Doppler measurements. Critical closing pressure was calculated noninvasively using arterial blood pressure and blood flow velocity. Outcome was assessed at both discharge and 3 months after ictus with the Glasgow Outcome Scale. The onset of CVS caused significant decreases in CrCP (P=0.025), without any observed significant changes in ICP (P=0.134). Vasospasm induced asymmetry, with CrCP ipsilateral to CVS becoming significantly lower than contralateral (P=0.025). Unfavorable outcomes were associated with a significantly lower CrCP after the onset of CVS (discharge: P=0.014; 3 months after SAH: P=0.020). Critical closing pressure is reduced in the presence of CVS in both temporal and spatial assessments. As ICP remained unchanged during CVS, reduced CrCP most probably reflects a lower wall tension in dilated small vessels distal to spasm.GVV is supported by an A.G. Leventis Foundation Scholarship, and a Charter Studentship from St Edmund’s College, Cambridge. AGK is supported by a Royal College of Surgeons of England Research Fellowship, a National Institute for Health Research (NIHR) Academic Clinical Fellowship, and a Raymond and Beverly Sackler Studentship. JD is supported by a Woolf Fisher Trust scholarship. PJH is supported by an NIHR Research Professorship, the NIHR Cambridge Biomedical Research Centre and has been appointed as the Surgical Specialty Lead for Neurosurgery, Royal College of Surgeons of England Clinical Research Initiative. JDP and MC are supported by the NIHR Cambridge Biomedical Research Centre and JDP by NIHR Senior Investigator Award. The prospective study16 on which this retrospective analysis was based, was supported by the National Institute of Health Research, Biomedical Research Centre (Neuroscience Theme). MC was supported by NIHR Cambridge Biomedical Research Centre.This is the accepted manuscript. The final published version is available from Nature Publishing at http://www.nature.com/jcbfm/journal/vaop/ncurrent/full/jcbfm2014198a.html

Systemic, local, and imaging biomarkers of brain injury: more needed, and better use of those already established?

Much progress has been made over the past two decades in the treatment of severe acute brain injury, including traumatic brain injury and subarachnoid hemorrhage, resulting in a higher proportion of patients surviving with better outcomes. This has arisen from a combination of factors. These include improvements in procedures at the scene (pre-hospital) and in the hospital emergency department, advances in neuromonitoring in the intensive care unit, both continuously at the bedside and intermittently in scans, evolution and refinement of protocol-driven therapy for better management of patients, and advances in surgical procedures and rehabilitation. Nevertheless, many patients still experience varying degrees of long-term disabilities post-injury with consequent demands on carers and resources, and there is room for improvement. Biomarkers are a key aspect of neuromonitoring. A broad definition of a biomarker is any observable feature that can be used to inform on the state of the patient, e.g., a molecular species, a feature on a scan, or a monitoring characteristic, e.g., cerebrovascular pressure reactivity index. Biomarkers are usually quantitative measures, which can be utilized in diagnosis and monitoring of response to treatment. They are thus crucial to the development of therapies and may be utilized as surrogate endpoints in Phase II clinical trials. To date, there is no specific drug treatment for acute brain injury, and many seemingly promising agents emerging from pre-clinical animal models have failed in clinical trials. Large Phase III studies of clinical outcomes are costly, consuming time and resources. It is therefore important that adequate Phase II clinical studies with informative surrogate endpoints are performed employing appropriate biomarkers. In this article, we review some of the available systemic, local, and imaging biomarkers and technologies relevant in acute brain injury patients, and highlight gaps in the current state of knowledge.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: Keri Linda H. Carpenter – NIHR BRC Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); Ibrahim Jalloh – MRC (Grant no. G1002277 ID 98489) and NIHR BRC Cambridge; Adel Helmy – MRC/Royal College of Surgeons of England Clinical Research Training Fellowship (Grant no. G0802251) and Raymond and Beverly Sackler Fellowship; Virginia F. J. Newcombe–Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship; Richard J. Shannon–NIHR BRC (Neuroscience Theme; Brain Injury and Repair Theme); Angelos G. Kolias–Royal College of Surgeons of England Research Fellowship, NIHR Academic Clinical Fellowship, and a Raymond and Beverly Sackler Studentship; David Krishna Menon–NIHR Senior Investigator Award; Peter J. Hutchinson – NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fneur.2015.00026/full#h13