Application of Robotic Transcranial Doppler for Extended Duration Recording in Moderate/Severe Traumatic Brain Injury: First Experiences

Long duration application of transcranial Doppler (TCD) for recording of middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) has been fraught with difficulties.[1,2] Classically, TCD has been labor intensive, with limited ability to obtain uninterrupted recordings for extended periods. Furthermore, application of TCD within neurocritically ill for long durations has been limited given the complexity of care, regular bedside nursing care/patient manipulations, and presence of various other multi-modal monitoring devices. This is especially the case in traumatic brain injury (TBI) patients, with the adoption of extensive multi-modal monitoring. Within TBI, most TCD recordings, using standard widely available probes and holders, range from 30 minutes to 1-hour duration and are frequently interrupted due to shifting of the probe and signal loss.[3,4] Thus, we are typically left with a “snap-shot” recording with TCD examination, limiting our ability to extract valuable continuous variables, such as autoregulatory capacity.[3-5] Recent advances in robotics have le

Comparison of high versus low frequency cerebral physiology for cerebrovascular reactivity assessment in traumatic brain injury: a multi-center pilot study

Current accepted cerebrovascular reactivity indices suffer from the need of high frequency data capture and export for post-acquisition processing. The role for minute-by-minute data in cerebrovascular reactivity monitoring remains uncertain. The goal was to explore the statistical time-series relationships between intra-cranial pressure (ICP), mean arterial pressure (MAP) and pressure reactivity index (PRx) using both 10-s and minute data update frequency in TBI. Prospective data from 31 patients from 3 centers with moderate/severe TBI and high-frequency archived physiology were reviewed. Both 10-s by 10-s and minute-by-minute mean values were derived for ICP and MAP for each patient. Similarly, PRx was derived using 30 consecutive 10-s data points, updated every minute. While long-PRx (L-PRx) was derived via similar methodology using minute-by-minute data, with L-PRx derived using various window lengths (5, 10, 20, 30, 40, and 60 min; denoted L-PRx_5, etc.). Time-series autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) models were created to analyze the relationship of these parameters over time. ARIMA modelling, Granger causality testing and VARIMA impulse response function (IRF) plotting demonstrated that similar information is carried in minute mean ICP and MAP data, compared to 10-s mean slow-wave ICP and MAP data. Shorter window L-PRx variants, such as L-PRx_5, appear to have a similar ARIMA structure, have a linear association with PRx and display moderate-to-strong correlations (r ~ 0.700, p Peer reviewe

ICP versus Laser Doppler Cerebrovascular Reactivity Indices to Assess Brain Autoregulatory Capacity

Objective: To explore the relationship between various autoregulatory indices in order to determine which approximate small-vessel/microvascular autoregulatory capacity most accurately. Methods: Utilizing a retrospective cohort of traumatic brain injury (TBI) 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 betrween 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 were more closely associated with ICP derived PRx, PAx and RAC. This indicates that vascular derived indices of autoregulatory capacity (ie. TCD and LDF based) co-vary, with Sx/Sx_a being the exception. Whereas, indices of cerebrovascular reactivity derived from pulsatile CBV (ie. 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/microvascular cerebrovascular reactivity. Sx/Sx_a co-cluster/co-vary with ICP derived indices, as seen in our previous work.This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada – Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean’s Fellowship Fund. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150) MC is supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1790). JD is supported by a Woolf Fisher Scholarship (NZ)

Cerebrospinal Fluid and Microdialysis Cytokines in Severe Traumatic Brain Injury: A Scoping Systematic Review.

OBJECTIVE: To perform two scoping systematic reviews of the literature on cytokine measurement in: 1. cerebral microdialysis (CMD) and 2. cerebrospinal fluid (CSF) in severe traumatic brain injury (TBI) patients. METHODS: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Both were conducted in severe TBI (sTBI) patients only. DATA SOURCES: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. STUDY SELECTION: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. DATA EXTRACTION: Patient demographic and study data were extracted to tables. RESULTS: There were 19 studies identified describing the analysis of cytokines via CMD in 267 sTBI patients. Similarly, there were 32 studies identified describing the analysis of CSF cytokines in 1,363 sTBI patients. The two systematic reviews demonstrated: 1. limited literature available on CMD cytokine measurement in sTBI, with some preliminary data supporting feasibility of measurement and associations between cytokines and patient outcome. 2. Various CSF measured cytokines may be associated with patient outcome at 6-12 months, including interleukin (IL)-1b, IL-1ra, IL-6, IL-8, IL-10, and tumor necrosis factor 3. There is little to no literature in support of an association between CSF cytokines and neurophysiologic or tissue outcomes. CONCLUSION: The evaluation of CMD and CSF cytokines is an emerging area of the literature in sTBI. Further, large prospective multicenter studies on cytokines in CMD and CSF need to be conducted.This work was made possible through salary support through: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Traveling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean’s Fellowship Fund. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Center, an NIHR Senior Investigator Award to DM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150). ET has received funding support from Swedish Society of Medicine (Grant no. SLS-587221). AH is supported by an MRC Studentship for Neuro-inflammation following Human Traumatic Brain injury (G0802251)

Cerebrospinal fluid and microdialysis cytokines in aneurysmal subarachnoid hemorrhage: A scoping systematic review

Objective: To perform two scoping systematic reviews of the literature on cytokine measurement in cerebral microdialysis (CMD) and cerebrospinal fluid (CSF) in aneurysmal subarachnoid hemorrhage (SAH) patients, aiming to summarize the evidence relating cytokine levels to pathophysiology, disease progression, and outcome. Methods: Two separate systematic reviews were conducted: one for CMD cytokines and the second for CSF cytokines. Data sources: Articles from MEDLINE, BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to October 2016), reference lists of relevant articles, and gray literature were searched. Study selection: Two reviewers independently identified all manuscripts utilizing predefined inclusion/exclusion criteria. A two-tier filter of references was conducted. Data extraction: Patient demographic and study data were extracted to tables. Results: There were 9 studies identified describing the analysis of cytokines via CMD in 246 aneurysmal SAH patients. Similarly, 20 studies were identified describing the analysis of CSF cytokines in 630 patients. The two scoping systematic reviews demonstrated the following: (1) limited literature available on CMD cytokine measurement in aneurysmal SAH with some preliminary data supporting feasibility of measurement and potential association between interleukin (IL)-6 and patient outcome. (2) Various CSF measured cytokines may be associated with patient outcome at 3-6 months, including IL-1ra, IL-6, IL-8, and tumor necrosis factor-alpha. (3) There is a small literature body supporting an association between acute/subacute CSF transforming growth factor levels and the development of chronic hydrocephalus at 2-3 months. Conclusion: The evaluation of CMD and CSF cytokines is an emerging area of the literature in aneurysmal SAH. Further large prospective multicenter studies on cytokines in CMD and CSF need to be conducted.This work was made possible through salary support through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Travelling Fellowship in Surgery, the University of Manitoba Clinician Investigator Program, R. Samuel McLaughlin Research and Education Award, the Manitoba Medical Service Foundation, and the University of Manitoba Faculty of Medicine Dean’s Fellowship Fund. ET has received funding support from Swedish Society of Medicine (grant no. SLS-587221). AH receives support from the Medical Research Council (MRC) (Studentship for Neuro-inflammation following Human Traumatic Brain Injury - G0802251), Cambridge Biomedical Research Centre, and Royal College of Surgeons of England. These studies were supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, an NIHR Senior Investigator Award to DKM, and an NIHR Research Professorship to PH. Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; grant agreement no. 602150). PH receives support from the National Institute of Health Research, Cambridge Biomedical Research Centre

Cerebral autoregulation monitoring in acute traumatic brain injury: what’s the evidence?

Cerebral autoregulation is conceptualized as a vascular self-regulatory mechanism within the brain. Controlled by elusive relationships between various biophysical processes, it functions to protect the brain against potential damages caused by sudden changes in cerebral perfusion pressures and flow. Following events such as traumatic brain injuries (TBI), autoregulation may be compromised, potentially leading to an unfavorable outcome. In spite of its complexity, autoregulation has been able to be quantified non-invasively within the neuro-critical care setting with the aid of transcranial Doppler. This information is interpreted particularly through calculated derived indices based on commonly-monitored input signals such as arterial blood pressure and intracranial pressure (i.e. Pressure reactivity index (PRx), mean flow index (Mx), etc.). For example, PRx values that trend towards positive numbers are correlated with unfavorable outcome. These predictors are primarily surrogate markers of cerebral hemodynamic activity, although suggesting robust correlations between these indices and patient outcome. This review of the literature seeks to explain the methodology behind the calculations of various measures of autoregulation in adult patients suffering from traumatic brain injuries, and how they can interact with one another to both create larger effects on patient outcome and general outcome prediction models. Insight into the driving forces behind cerebral autoregulation is imperative for guiding both clinical decision-making and global treatment protocols for neuro-critically ill patients. The evidence that autoregulation-oriented therapy may improve outcome after TBI is still oscillating around Level III.Joseph Donnelly is supported by the Woolf Fisher Trust (New Zealand). The funder had no influence over the contents of this manuscript. Frederick A. Zeiler has obtained financial support from: The Royal College of Surgerons of Canada, Harry S. Morton Traveling Fellowship in Surgery, University of Manitoba - McLaughlin Fellowship in Medicine, University of Manitoba - Dean’s Fellowship, the Manitoba Medical Services Foundation (MMSF) and the University of Manitoba Clinican Investigator Program. Eric P. Thelin has obtained financial support from the Swedish Society of Medicine. The funder had no influence over the contents of this manuscript. Both Peter Smielewski and Marek Czosnyka receive licensing fees from ICM+ software (Cambridge Enterprises, Ltd.)

Monitoring the Neuroinflammatory Response Following Acute Brain injury

Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are major contributors to morbidity and mortality. Following the initial insult, patients may deteriorate due to secondary brain damage. The underlying molecular and cellular cascades incorporate components of the innate immune system. There are different approaches to assess and monitor cerebral inflammation in the neuro intensive care unit. The aim of this narrative review is to describe techniques to monitor inflammatory activity in patients with TBI and SAH in the acute setting. The analysis of pro- and anti-inflammatory cytokines in compartments of the central nervous system (CNS), including the cerebrospinal fluid and the extracellular fluid, represent the most common approaches to monitor surrogate markers of cerebral inflammatory activity. Each of these compartments has a distinct biology that reflects local processes and the cross-talk between systemic and CNS inflammation. Cytokines have been correlated to outcomes as well as ongoing, secondary injury progression. Alongside the dynamic, focal assay of humoral mediators, imaging, through positron emission tomography, can provide a global in vivo measurement of inflammatory cell activity, which reveals long-lasting processes following the initial injury. Compared to the innate immune system activated acutely after brain injury, the adaptive immune system is likely to play a greater role in the chronic phase as evidenced by T-cell-mediated autoreactivity toward brain-specific proteins. The most difficult aspect of assessing neuroinflammation is to determine whether the processes monitored are harmful or beneficial to the brain as accumulating data indicate a dual role for these inflammatory cascades following injury. In summary, the inflammatory component of the complex injury cascade following brain injury may be monitored using different modalities. Using a multimodal monitoring approach can potentially aid in the development of therapeutics targeting different aspects of the inflammatory cascade and improve the outcome following TBI and SAH

Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study

Magnitude of intracranial pressure (ICP) elevations and their duration have been associated with worse outcomes in patients with traumatic brain injuries (TBI), however published thresholds for injury vary and uncertainty about these levels has received relatively little attention. In this study, we have analyzed high-resolution ICP monitoring data in 227 adult patients in the CENTER-TBI dataset. Our aim was to identify thresholds of ICP intensity and duration associated with worse outcome, and to evaluate the uncertainty in any such thresholds. We present ICP intensity and duration plots to visualize the relationship between ICP events and outcome. We also introduced a novel bootstrap technique to evaluate uncertainty of the equipoise line. We found that an intensity threshold of 18 +/- 4 mmHg (2 standard deviations) was associated with worse outcomes in this cohort. In contrast, the uncertainty in what duration is associated with harm was larger, and safe durations were found to be population dependent. The pressure and time dose (PTD) was also calculated as area under the curve above thresholds of ICP. A relationship between PTD and mortality could be established, as well as for unfavourable outcome. This relationship remained valid for mortality but not unfavourable outcome after adjusting for IMPACT core variables and maximum therapy intensity level. Importantly, during periods of impaired autoregulation (defined as pressure reactivity index (PRx)>0.3) ICP events were associated with worse outcomes for nearly all durations and ICP levels in this cohort and there was a stronger relationship between outcome and PTD. Whilst caution should be exercised in ascribing causation in observational analyses, these results suggest intracranial hypertension is poorly tolerated in the presence of impaired autoregulation. ICP level guidelines may need to be revised in the future taking into account cerebrovascular autoregulation status considered jointly with ICP levels