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Background: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty., Aim: To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities., Methods: A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants., Results: Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence., Conclusion: The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Background: The Full Outline of UnResponsivness (FOUR) score is a neurological assessment score. Its theoretical benefit over preexisting scores is its evaluation of brainstem reflexes and respiratory pattern which may allow better assessment of patients with severe neurologic impairment., Objective: Our goal was to perform a scoping systematic review on the available literature for FOUR score and outcome prediction in critically ill patients. The primary outcome of interest was patient global outcome, as assessed by any of: mortality, modified Rankin Score, Glasgow Outcome Score, or any other functional or neuropsychiatric outcome. Information on interobserver reliability was also extracted., Methods: MEDLINE and five other databases were searched. Inclusion criteria were: humans, adults, and children; prospective randomized controlled trial; prospective cohort, cohort/control, case series, prospective, and retrospective studies. Two reviewers independently screened the results. Full texts for citations passing this initial screen were obtained. Inclusion and exclusion criteria were applied to each article to obtain final articles for review. Results on adult populations are presented here. Data are reported following the preferred reporting items for systematic reviews and meta-analyses guidelines., Results: The initial search yielded 1709 citations. Of those used, 49 were based on adult and 6 on pediatric populations. All but 8 retrospective adult studies were performed prospectively. Patient categories included traumatic brain injury, intraventricular hemorrhage, intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke, general/combined neurology and neurosurgery, post-cardiac arrest, medicine/general critical illness, and patients in the emergency department. A total of 9092 adult patients were studied. Fourteen studies demonstrated good interobserver reliability of the FOUR score. Nine studies demonstrated prognostic value of the FOUR score in predicting mortality and functional outcomes. Thirty-two studies demonstrated equivalency or superiority of the FOUR score compared to Glasgow Coma Score in prediction of mortality and functional outcomes., Conclusions: The FOUR score has been shown to be a useful outcome predictor in many patients with depressed level of consciousness. It displays good inter-rater reliability among physicians and nurses.

Background: To explore the relationship between various autoregulatory indices in order to determine which approximate small vessel/microvascular (MV) autoregulatory capacity most accurately., Methods: Utilizing a retrospective cohort of traumatic brain injury patients (N = 41) with: transcranial Doppler (TCD), intracranial pressure (ICP) and cortical laser Doppler flowmetry (LDF), we calculated various continuous indices of autoregulation and cerebrovascular responsiveness: A. ICP derived [pressure reactivity index (PRx)-correlation between ICP and mean arterial pressure (MAP), PAx-correlation between pulse amplitude of ICP (AMP) and MAP, RAC-correlation between AMP and cerebral perfusion pressure (CPP)], B. TCD derived (Mx-correlation between mean flow velocity (FVm) and CPP, Mx_a-correlation between FVm and MAP, Sx-correlation between systolic flow velocity (FVs) and CPP, Sx_a-correlation between FVs and MAP, Dx-correlation between diastolic flow index (FVd) and CPP, Dx_a-correlation between FVd and MAP], and LDF derived (Lx-correlation between LDF cerebral blood flow [CBF] and CPP, Lx_a-correlation between LDF-CBF and MAP). We assessed the relationship between these indices via Pearson correlation, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC), and k-means cluster analysis (KMCA)., Results: LDF-based autoregulatory index (Lx) was most associated with TCD-based Mx/Mx_a and Dx/Dx_a across Pearson correlation, PCA, AHC, and KMCA. Lx was only remotely associated with ICP-based indices (PRx, PAx, RAC). TCD-based Sx/Sx_a was more closely associated with ICP-derived PRx, PAx and RAC. This indicates that vascular-derived indices of autoregulatory capacity (i.e., TCD and LDF based) covary, with Sx/Sx_a being the exception, whereas indices of cerebrovascular reactivity derived from pulsatile CBV (i.e., ICP indices) appear to not be closely related to those of vascular origin., Conclusions: Transcranial Doppler Mx is the most closely associated with LDF-based Lx/Lx_a. Both Sx/Sx-a and the ICP-derived indices appear to be dissociated with LDF-based cerebrovascular reactivity, leaving Mx/Mx-a as a better surrogate for the assessment of cortical small vessel/MV cerebrovascular reactivity. Sx/Sx_a cocluster/covary with ICP-derived indices, as seen in our previous work.

Objective: We introduced 'compensatory-reserve-weighted intracranial pressure (ICP),' named 'weightedICP' for brevity, as a variable that may better describe changes leading to mortality after traumatic brain injury (TBI) over the standard mean ICP., Methods: ICP was monitored prospectively in over 1023 sedated and ventilated patients. The RAP coefficient (R-correlation, A-amplitude, and P-pressure) was calculated as the running correlation coefficient between slow changes in the pulse amplitude of ICP and the mean ICP. RAP has a value of 0 on the linear part of the pressure-volume curve and a value of + 1 on the ascending exponential part. Then, RAP decreases towards zero or even becomes negative when ICP increases further-a phenomenon thought to be related to the critical closing of cerebral vessels. In this study, we investigated a derived variable called weightedICP, calculated as ICP*(1 - RAP)., Results: Mortality after TBI was associated with both elevated ICP and weightedICP. Analysis of variance showed higher values of test statistics for weightedICP (K = 93) than for ICP (K = 64) in outcome categorization. Additionally, receiver operator curve analysis indicated greater area under the curve for weightedICP (0.71) than for ICP (0.67) with respect to associated mortality; however, the difference was not statistically significant (p = 0.12). The best threshold (maximizing sensitivity and specificity) was 19.5 mm Hg for mean ICP, and 8 mm Hg for weightedICP. Mortality rate expressed as a function of mean ICP and weightedICP showed an ascending profile in both cases., Conclusion: The proposed variable shows a significant association with mortality following head injury. It is sensitive to both the rising absolute ICP and to the critical deterioration of pressure-volume compensation.

Background: Existing scoring systems for aneurysmal subarachnoid hemorrhage (SAH) patients fail to accurately predict patient outcome. Our goal was to prospectively study the Full Outline of UnResponsiveness (FOUR) score as applied to newly admitted aneurysmal SAH patients., Methods: All adult patients presenting to Health Sciences Center in Winnipeg from January 2013 to July 2015 (2.5 year period) with aneurysmal SAH were prospectively enrolled in this study. All patients were followed up to 6 months. FOUR score was calculated upon admission, with repeat calculation at 7 and 14 days. The primary outcomes were: mortality, as well as dichotomized 1- and 6-month Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) values., Results: Sixty-four patients were included, with a mean age of 54.2 years (range 26-85 years). The mean FOUR score upon admission pre- and post-external ventricular drain (EVD) was 10.3 (range 0-16) and 11.1 (range 3-16), respectively. There was a statistically significant association between pre-EVD FOUR score (total, eye, respiratory and motor sub-scores) with mortality, 1-month GOS, and 6-month GOS/mRS (p < 0.05 in all). The day 7 total, eye, respiratory, and motor FOUR scores were associated with mortality, 1-month GOS/mRS, and 6-month GOS/mRS (p < 0.05 in all). The day 14 total, eye, respiratory, and motor FOUR scores were associated with 6-month GOS (p < 0.05 in all). The day 7 cumulative FOUR score was associated with the development of clinical vasospasm (p < 0.05)., Conclusions: The FOUR score at admission and day 7 post-SAH is associated with mortality, 1-month GOS/mRS, and 6-month GOS/mRS. The FOUR score at day 14 post-SAH is associated with 6-month GOS. The brainstem sub-score was not associated with 1- or 6-month primary outcomes.

Our goal was to perform a systematic review of the literature on the use of tromethamine (THAM) and its effects on intracranial pressure (ICP) in patients with neurological illness. All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to February 2014), reference lists of relevant articles, and gray literature were searched. Two reviewers independently identified all manuscripts pertaining to the administration of THAM in human patients that recorded effects on ICP. Secondary outcomes of effect on cerebral perfusion pressure, mean arterial pressure, patient outcome, and adverse effects were recorded. Two reviewers independently extracted data including population characteristics and treatment characteristics. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total 2,268 citations. Twelve articles, 9 manuscripts, and 3 meeting proceedings were considered for the review with all utilizing THAM while documenting ICP in neurosurgical patients. All studies were prospective. Across all studies, there were a total of 488 patients studied, with 263 receiving THAM and 225 serving as controls in a variety of heterogeneous studies. All but one study documented a decrease in ICP with THAM administration, with both bolus and continuous infusions. One study documented a reduction in cerebral perfusion pressure. No significant renal dysfunction, hepatocellular injury, or hypoglycemia were reported. Three prospective randomized control trials displayed trends to improved outcome in severe traumatic brain injury (TBI) patients with THAM administration. There currently exists Oxford level 2b, GRADE B evidence to support that THAM reduces ICP in the TBI and malignant ischemic infarct population, with minimal side effects. The literature suggests THAM may be useful for ICP reduction in certain cases, though the safety of the compound in these circumstances is still unclear. Further prospective study is warranted.

Our goal was to perform a systematic review of the literature on the use of ketamine in traumatic brain injury (TBI) and its effects on intracranial pressure (ICP). All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to November 2013), reference lists of relevant articles, and gray literature were searched. Two reviewers independently identified all manuscripts pertaining to the administration of ketamine in human TBI patients that recorded effects on ICP. Secondary outcomes of effect on cerebral perfusion pressure, mean arterial pressure, patient outcome, and adverse effects were recorded. Two reviewers independently extracted data including population characteristics and treatment characteristics. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total 371 citations. Seven articles, six manuscripts and one meeting proceeding, were considered for the review with all utilizing ketamine, while documenting ICP in severe TBI patients. All studies were prospective studies. Five and two studies pertained to adults and pediatrics, respectively. Across all studies, of the 101 adult and 55 pediatric patients described, ICP did not increase in any of the studies during ketamine administration. Three studies reported a significant decrease in ICP with ketamine bolus. Cerebral perfusion pressure and mean blood pressure increased in two studies, leading to a decrease in vasopressors in one. No significant adverse events related to ketamine were recorded in any of the studies. Outcome data were poorly documented. There currently exists Oxford level 2b, GRADE C evidence to support that ketamine does not increase ICP in severe TBI patients that are sedated and ventilated, and in fact may lower it in selected cases.

Refractory status epilepticus (RSE) poses significant challenge, with a variety of novel therapeutics employed. Our goal was to evaluate the effectiveness of N-methyl D-aspartate (NMDA) receptor antagonists in the control of RSE. We performed a systematic review of all the literature, with all articles pulled from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to September 2013), reference lists of relevant articles, and gray literature. Two reviewers independently identified all manuscripts pertaining to the administration of NMDA receptor antagonists in humans for the purpose of controlling refractory seizures. Secondary outcome of adverse NMDA antagonist effects and patient outcome was assessed. Two reviewers independently extracted data including population characteristics, treatment characteristics, and outcomes. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Our search strategy produced a total of 759 citations. Twenty-three articles, 16 manuscripts, and seven meeting proceedings, were considered for the review with all utilizing ketamine for seizure control. Only three studies were prospective studies. Fifteen and nine studies pertained to adults and pediatrics, respectively. Across all studies, of the 110 adult patients described, ketamine was attributed to electroencephalogram seizure response in 56.5 %, with a 63.5 % response in the 52 pediatric patients described. Adverse events related to ketamine were rare. Outcomes were poorly documented in the majority of the studies. There currently exists Oxford level 4, GRADE C evidence to support the use of ketamine for refractory seizures in the adult and pediatric populations. Further prospective study of early ketamine administration is warranted.

Background: Medically refractory status epilepticus, without an identifiable cause, post elective aneurysm clipping is a rare event., Objective: To describe the two cases of refractory status epilepticus post elective aneurysm clipping, without an identifiable cause, and discuss the potential role for early consideration of ketamine., Methods: Retrospectively reviewed two patients at our institution who developed refractory status epilepticus post elective aneurysm clipping, without a defined cause., Results: Two patients who underwent elective aneurysm clipping developed medically refractory status epilepticus post-craniotomy. No structural, vascular, infectious, or metabolic cause was identified. Seizure control failed with multiple medications and intravenous sedatives over the period of weeks in both. Ketamine was instituted at 20 and 40 mg/kg/min in these patients. Within hours of starting ketamine, burst suppression was obtained in both. Medications were all tapered over the next month, and both the patients recovered to be cognitively normal, with mild residual morbidity secondary to critical care polyneuropathy., Conclusions: Refractory status epilepticus, in the absence of an identifiable etiology, in elective aneurysm clipping is a rare event. Consideration should be given for the early use of ketamine in refractory status epilepticus.