Frederick A. Zeiler

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.

Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics: A systematic review

Background The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term “effective half-life” (t1/2) in order to describe the “fall” rate in serum. Materials and methods Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations. Results Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1–2 h) though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t1/2 of about 24–48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use. Conclusion Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.

A Unique Model for Ultrasound Assessment of Optic Nerve Sheath Diameter

BACKGROUND Ultrasonic assessment of optic nerve sheath diameter (ONSD) as a non-invasive measure of intracranial pressure (ICP) has been evaluated in the literature as a potential valid technique for rapid ICP estimation in the absence of invasive intracranial monitoring. The technique can be challenging to perform and little literature exists surrounding intra-operator variability. OBJECTIVES In this study we describe the creation of a novel model of ONSD to be utilized in ultrasound training of this technique. We demonstrate the realistic ultrasonographic images created utilizing this novel model. METHODS We designed ocular models composed of gelatin spheres and variable three dimensional printed cylinders, which simulate the globe of the eye and variable ONSDs respectively. These models were suspended in a gelatin background and ultrasound of the ONSD was conducted using standard techniques described in the literature. RESULTS This model produces clear and accurate representation of ONSD that closely mimics in vivo images. It is affordable and easy to produce in large quantities, portending its use in an educational environment. CONCLUSIONS Utilizing the standard linear array ultrasound probe for ONSD measurements in our model provided realistic images comparable to in vivo. This provides an affordable and exciting means to test intra- and inter- operator variability in a standardized environment. Knowing this, we can further apply this novel model of ONSD to ultrasound teaching and training courses with confidence in its ability and the techniques ability to produce consistent results.

The Cerebrovascular Response to Ketamine: A Systematic Review of the Animal and Human Literature.

Background: The aim of the study was to perform a systematic review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of ketamine in both animal and human subjects. Materials and Methods: We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2014. Two reviewers independently identified all manuscripts pertaining to the administration of ketamine in both human and animal subjects in which the impact on CBF/cerebral vasculature was recorded by means of functional magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, xenon computed tomography, transcranial Doppler velocities, arteriovenous difference in N2O method of CBF measurement, cerebral digital subtraction angiography, or any other objective means of CBF determination. Results: We identified 38 animal studies with various animal models studied. Overall there was a trend to a direct vasodilatory effect of ketamine on the cerebral vasculature, with a trend in most studies to an increase or regional CBF (rCBF) or global CBF. Twenty human studies were identified. The majority displayed an increase in rCBF and global CBF on imaging in patients without neurological illness. Conclusions: Animal models indicate an increase in global CBF and rCBF with ketamine administration, with a trend to vasodilation of medium-sized intracranial vessels through a calcium-dependent mechanism. Human studies display an Oxford 2b, Grading of Recommendation Assessment Development and Education C, level of evidence to support a trend to increased global CBF and rCBF with ketamine administration in both healthy volunteers and elective surgical patients without neurological illness.

A Unique Model for ONSD Part II: Inter/Intra-operator Variability.

OBJECTIVE To evauluate our novel ultrasound model for measurement of optic nerve sheath diameter (ONSD) and determine the intra- and inter-operator variability associated with this technique. METHODS We conducted ten measurements of ONSD per model amongst eight different models with a single experienced operator to examine intra-operator variability. Similarly, we had seven different operators measure the OSND twice in eight different models, in order to determine inter-operator variability analyzed with a three level linear statistical model. RESULTS For intra-operator variability, the intra-cluster correlation coefficients for the experienced and novice operators were 0.643 and 0.453 respectively. This displayed improvement in intra-operator variability with experience. The inter-cluster correlation coefficient was 0 for the group of novice operators, indicating negligible difference amongst multiple operators in measuring any given model of ONSD. A strong, statistically significant, linear relationship between the actual model disc size and the ultrasound ONSD measures was identified, implying the reliability of the images produced by our novel model. CONCLUSIONS Utilizing a novel model for ONSD ultrasonography, we have determined the intraoperator reliability of ONSD measurement to be moderate, with no appreciable difference amongst multiple operators. Improvement in measurement reliability has been demonstrated between expert and novice operators with our model, indicating the potential benefit of simulation platforms for teaching the technique of ONSD ultrasound.

Critical Thresholds of ICP Derived Continuous Cerebrovascular Reactivity Indices for outcome prediction in Non-Craniectomized TBI Patients: PRx, PAx and RAC

The aim of the study was to compare intracranial pressure (ICP)-derived cerebrovascular reactivity indices in their ability to predict six-month outcome, and to determine/compare critical thresholds related to outcome for each index in adult noncraniectomized traumatic brain injury (TBI). Using a retrospective cohort of nondecompressive craniectomy (non-DC) patients with TBI, we performed univariate and multi-variate binary logistic regression outcome analysis of: pressure reactivity index (PRx), pulse amplitude index (PAx), and a newly described index (RAC) calculated as the regression coefficient between ICP waveform amplitude and cerebral perfusion pressure (CPP). Finally, we performed sequential chi-square threshold analysis for each index as it related to six-month binary outcomes. Outcome was assessed via dichotomized Glasgow Outcome Scores (GOS): (A) favorable (GOS 4 or 5) versus unfavorable (GOS 3 or less), (B) alive versus dead. There were 358 non-DC patients with TBI included in all aspects of the analysis. In an analysis of the entire recording period for all patients using univariate binary logistic regression, the areas under the curves (AUCs) for favorable versus unfavorable outcome were: PRx (0.573, p < 0.0001), PAx (0.606, p < 0.0001), and RAC (0.655, p < 0.0001). Similarly, the AUCs for alive versus dead outcome were: PRx (0.651, p < 0.0001), PAx (0.705, p < 0.0001), and RAC (0.722, p < 0.0001). RAC displayed superior AUC statistics compared with PRx and PAx, using both univariate and multi-variate regression. RAC displayed more stable critical thresholds related to six-month outcomes. Thresholds for both favorable versus unfavorable and alive versus dead outcomes for PRx, PAx, and RAC across the entire recording period were: +0.35 and +0.35, 0 and +0.25, -0.10 and -0.05, respectively. In non-DC patients with TBI, RAC appears to be superior to PRx and PAx in six-month outcome prediction, using both univariate and multi-variate logistic regression. Further, RAC displayed more stable critical thresholds associated with binary outcomes at six months. Further analysis of RAC in TBI is required.

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.

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.

Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury, Part I: A Scoping Review of Intermittent/Semi-Intermittent Methods.

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. JD is supported by a Woolf Fisher Scholarship (NZ). These studies were also 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)

The Use of Milrinone in Patients with Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage: A Systematic Review.

OBJECTIVE The purpose of this article is to provide a systematic review of the evidence supporting the use of milrinone for the management of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). DESIGN Primary outcomes were functional neurological status and the incidence of cerebral infarction. Search strategies adapted to the different databases were developed by a professional librarian. Medline, EMBASE, the Cochrane Library database, Web of Science, SCOPUS, BIOSIS, Global Health, Health Star, Open SIGLE, Google Scholar and the New York Academy of Medicine Gray Literature were searched as well as clinical trials databases and the proceedings of several scientific meetings. Quality of the evidence for these outcomes across studies was adjudicated using the GRADE Working Group criteria. RESULTS The search resulted in 284 citations after elimination of duplicates. Of those 9 conference proceedings and 15 studies met inclusion criteria and consisted of case reports, case series and two comparative studies: one non-randomized study with physiological outcomes only and a case series with historical controls. There was considerable variation in dosing and in co-interventions and no case control or randomized controlled studies were found. CONCLUSION There is currently only very low quality evidence to support the use of milrinone to improve important outcomes in patients with delayed cerebral ischemia secondary to subarachnoid hemorrhage. Further research is needed to clarify the value and risks of this medication in patients with SAH.