The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use. Our intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient. We think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neuro-intensive care have been early pioneers and supporters of evidence-based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines.

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition

Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators

/pdf/traumatic-brain-injury-integrated-approaches-to-improve-29obvlh2iu.pdf

Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research

We conducted a multicenter, controlled trial in which 324 patients 13 years of age or older who had severe traumatic brain injury and were being treated in intensive care units (ICUs) in Bolivia or Ecuador were randomly assigned to one of two specific protocols: guidelines-based management in which a protocol for monitoring intraparenchymal intracranial pressure was used (pressure-monitoring group) or a protocol in which treatment was based on imaging and clinical examination (imaging– clinical examination group). The primary outcome was a composite of survival time, impaired consciousness, and functional status at 3 months and 6 months and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). Results There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging–clinical examination group; P = 0.49). Six-month mortality was 39% in the pressure-monitoring group and 41% in the imaging–clinical examination group (P = 0.60). The median length of stay in the ICU was similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging–clinical examination group; P = 0.25), although the number of days of brain-specific treatments (e.g., administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging–clinical examination group than in the pressure-monitor ing group (4.8 vs. 3.4, P = 0.002). The distribution of serious adverse events was similar in the two groups. Conclusions For patients with severe traumatic brain injury, care focused on maintaining monitored intracranial pressure at 20 mm Hg or less was not shown to be superior to care based on imaging and clinical examination. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01068522.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1207363

A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury

Objective. —To determine whether carotid endarterectomy provides protection against subsequent cerebral ischemia in men with ischemic symptoms in the distribution of significant (>50%) ipsilateral internal carotid artery stenosis. Design. —Prospective, randomized, multicenter trial. Setting. —Sixteen university-affiliated Veterans Affairs medical centers. Patients. —Men who presented within 120 days of onset of symptoms that were consistent with transient ischemic attacks, transient monocular blindness, or recent small completed strokes between July 1988 and February 1991. Among 5000 patients screened, 189 individuals were randomized with angiographic internal carotid artery stenosis greater than 50% ipsilateral to the presenting symptoms. Forty-eight eligible patients who refused entry were followed up outside of the trial. Outcome Measures. —Cerebral infarction or crescendo transient ischemic attacks in the vascular distribution of the original symptoms or death within 30 days of randomization. Intervention. —Carotid endarterectomy plus the best medical care (n = 91) vs the best medical care alone (n=98). Results. —At a mean follow-up of 11.9 months, there was a significant reduction in stroke or crescendo transient ischemic attacks in patients who received carotid endarterectomy (7.7%) compared with nonsurgical patients (19.4%), or an absolute risk reduction of 11.7% (P=.011). The benefit of surgery was more profound in patients with internal carotid artery stenosis greater than 70% (absolute risk reduction, 17.7%;P=.004). The benefit of surgery was apparent within 2 months after randomization, and only one stroke was noted in the surgical group beyond the 30-day perioperative period. Conclusions. —For a selected cohort of men with symptoms of cerebral or retinal ischemia in the distribution of a high-grade internal carotid artery stenosis, carotid endarterectomy can effectively reduce the risk of subsequent ipsilateral cerebral ischemia. The risk of cerebral ischemia in this subgroup of patients is considerably higher than previously estimated. (JAMA. 1991;266:3289-3294)

Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Commentary

Summary Almost two decades have elapsed since posterior reversible encephalopathy syndrome (PRES) was described in an influential case series. This usually reversible clinical syndrome is becoming increasingly recognised, in large part because of improved and more readily available brain imaging. Although the pathophysiological changes underlying PRES are not fully understood, endothelial dysfunction is a key factor. A diagnosis of PRES should be considered in the setting of acute neurological symptoms in patients with renal failure, blood pressure fluctuations, use of cytotoxic drugs, autoimmune disorders, or eclampsia. Characteristic radiographic findings include bilateral regions of subcortical vasogenic oedema that resolve within days or weeks. The presence of haemorrhage, restricted diffusion, contrast enhancement, and vasoconstriction are all compatible with a diagnosis. In most cases, PRES resolves spontaneously and patients show both clinical and radiological improvements. The range of symptoms that can comprise the syndrome might be broader than usually thought. In its mild form, this disorder might cause only one clinical symptom (headache or seizure) and radiographically might show few areas of vasogenic oedema or even normal brain imaging in some rare cases. In severe forms, PRES might cause substantial morbidity and even mortality, most often as a result of acute haemorrhage or massive posterior fossa oedema causing obstructive hydrocephalus or brainstem compression.

Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions

Patients with carotid atherosclerosis develop symptoms most commonly due to plaque progression or rupture. Many factors influence the risk of a lesion rupturing. The degree of stenosis as seen on digital subtraction angiography is no longer a sufficient means of stratifying patients’ risk and thus guiding therapy. The term “vulnerable plaque” is used to describe plaques that have a high risk of causing symptoms. Such plaques typically have active inflammation and a thin fibrous cap overlying a large lipid-rich, necrotic core, often with intraplaque hemorrhage. The endothelial surface of such plaques may be irregular, with endothelial ulceration or fibrous cap rupture. A plaque may be characterized as “vulnerable” based on morphology without necessarily causing a significant stenosis. Various means of depicting the characteristics of plaque vulnerability are available. The following chapter aims to describe the established, as well as some of the emerging noninvasive techniques used to image vulnerable carotid plaques. A brief description of novel agents, targeted to specific molecules involved in the atherogenic process, is presented. Furthermore, a comparison of the various techniques in the context of their ability to depict the many characteristics of high risk atherosclerotic lesions is made.

Noninvasive Targeting of Vulnerable Carotid Plaques for Therapeutic Interventions

Longitudinal Changes in Size of Conservatively Managed Flow-Related Aneurysms Associated with Brain Arteriovenous Malformations.

Carotid artery atherosclerosis is a major cause of stroke. It has been traditionally thought that luminal stenosis secondary to the presence of atherosclerotic plaques reduces blood flow along the carotid arteries, leading to cerebral ischaemia and infarction. However, recent advances have shown that atherosclerotic plaques which carry a high risk of developing complications, i.e. ‘vulnerable plaques’, display certain features which can be identified by various imaging techniques. Specifically, a variety of MRI sequences and modalities have been employed to recognise characteristics of fibrous cap, lipid-rich necrotic core, inflammation and biomechanical stress. They have been shown to be linked to the disease progression of atherosclerotic plaques, as well as the improvement following treatment. This chapter reviews the use of MRI in the investigation of carotid artery disease and the identification of vulnerable atherosclerotic plaques.

MR Imaging of Vulnerable Carotid Atherosclerotic Plaques

Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. 828 www.ccmjournal.org May 2018 • Volume 46 • Number 5 Early brain injury (EBI) and delayed cerebral ischemia (DCI) have increasingly become the focus of attention in the management of aneurysmal subarachnoid hemorrhage (SAH) (1). Although clearly spectacular when it occurs, vasospasm can be held responsible for only a part of delayed ischemic complications. Clinically, patients with significant narrowing of large cerebral arteries and lack of clear symptoms of ischemia or vice versa can be seen. Indeed, whereas vasospasm can be picked up in nearly two thirds of patients, DCI occurs in less than a third (2). PET and CT perfusion studies show that the brain after SAH may be perfused as heterogeneously as seen after traumatic brain injury—with regions of ischemia and hyperemia that do not always match the vascular territory of the vessel harboring the aneurysm nor the spastic vessel (3). Numerous pathophysiologic mechanisms have been proposed to explain the phenomenon of DCI, loss of cerebral autoregulation, but also inflammatory reactions, necrosis/apoptosis, or cortical spreading depression. Loss of cerebral autoregulation in the early phase after ictus has been implicated in a number of studies and has been shown to be independently associated with DCI, delayed infarcts, as well as outcomes (2, 4–8). Failure of autoregulation following SAH fits well with the dual insult theory proposed by Harper and Glass (9), which states that two hemodynamic insults (e.g., vascular spasm and hypotension with preserved autoregulation or vascular spasm and autoregulatory failure) are needed to induce ischemia. With many patients after SAH, particularly poor grade, being treated on ICUs and hypotension exceedingly rare, dysautoregulation may significantly contribute to cerebral ischemia even in the context of normotension. Gaash et al (10), in their article published in this issue of Critical Care Medicine, present a study looking at two known autoregulatory indices: the pressure reactivity index (PRx) and the brain tissue Po 2 (P bt o 2 )–derived autoregulation index (ORx) and their relationship with DCI as well as outcome. PRx has not been previously studied in this context. Although the authors demonstrate a clear association of early abnormal PRx with DCI and outcome, they fail to reproduce the results of Jaeger et al (4, 5), who demonstrated the same relationship with ORx. The authors detected two distinct peaks of autoregulatory failure: one early, only visible in the DCI group and another delayed, visible in both groups of patients. Without more detailed physiologic studies, it cannot be determined with certainty, but the early peak can be related to the broadly understood EBI occurring after SAH, whereas the second peak seems to overlap with the typical time window of vasospasm. Indeed, as the authors point out the first peak of autoregulatory disturbance may simply be related to the severity of injury sustained from the ictus, similarly to what has been described after head injury (11). If true, this would be a very important indicator of the severity of injury, above that of the clinically determined World Federation of Neurosurgical Societies grade (which in the current form is a very crude measure, albeit used in decision-making, particularly with respect to timing of endovascular or surgical intervention). It is well recognized that the treatment outcomes for poor grade patients with SAH are suboptimal with significant vulnerability to vessels occlusion (balloon or catheter) when treated endovascularly or temporary clipping when treated surgically. Therefore, knowledge about the status of autoregulation could be important in the critical care management of patients with SAH and estimating the risk of DCI and outcome as suggested by the authors, but also it could play a role in choosing the best timing for intervention and reducing treatment-related ischemic complications. Although the study by Gaash et al (10) is well reported, it is worth mentioning that DCI is extremely difficult to diagnose in comatose patients, which are the subjects of their article. The classical definitions related to clinical deterioration do not apply due to the inability to reliably assess patients (12). Therefore, surrogates, such as perfusion deficits or spasm seen on angiography, are typically used missing the previously mentioned heterogeneity of DCI. Second, monitoring of PRx when external ventricular (EVD) drainage is open also raises methodologic question, as open EVD decreases slope of pressurevolume curve, potentially disrupting a link between slow waves in blood pressure and intracranial pressure (ICP). Despite its limitations, the study by Gaash et al (10) provides further evidence on the utility of monitoring autoregulation after SAH. However, before widely adopted in the treatment of SAH, more work needs to be done in order to elucidate the best methodologies. While PRx and ORx are appealing due to their continuous nature, relative ease of use (once patient has ICP and/ or P bt o 2 probes inserted, no further interventions are needed), it remains to be determined whether indices using measurements of blood flow, such as transcranial Doppler blood flow velocities, near-infrared spectroscopy, or thermal dilution cerebral blood flow measurements fare better. Furthermore, invasive monitoring is only available in a small subset of patients who present in coma, *See also p. 774.

Growing Evidence: Dysautoregulation May Trigger Ischemic Deficit After Subarachnoid Hemorrhage.

OBJECTIVE
Flow-diverting devices have been used successfully for the treatment of complex intracranial vascular injuries in adults, but the role of these devices in treating iatrogenic and traumatic intracranial vascular injuries in children remains unclear. The authors present their experience using the Pipeline embolization device (PED) for treating intracranial pseudoaneurysms in children.


METHODS
This single-center retrospective cohort study included pediatric patients with traumatic and iatrogenic injuries to the intracranial vasculature that were treated with the PED between 2015 and 2021. Demographic data, indications for treatment, the number and sizes of PEDs used, follow-up imaging, and clinical outcomes were analyzed.


RESULTS
Six patients with a median age of 12 years (range 7-16 years) underwent PED placement to treat intracranial pseudoaneurysms. There were 3 patients with hemorrhagic presentation, 2 with ischemia, and 1 in whom a growing pseudoaneurysm was found on angiography. Injured vessels included the anterior cerebral artery (n = 2), the supraclinoid internal carotid artery (ICA, n = 2), the cavernous ICA (n = 1), and the distal cervical ICA (n = 1). All 6 pseudoaneurysms were successfully treated with PED deployment. One patient required re-treatment with a second PED within a week because of concern for a growing pseudoaneurysm. One patient experienced parent vessel occlusion without neurological sequelae.


CONCLUSIONS
Use of the PED is feasible for the management of iatrogenic and traumatic pseudoaneurysms of the intracranial vasculature in children, even in the setting of hemorrhagic presentation.

Karol P. Budohoski

Papers

Noninvasive Targeting of Vulnerable Carotid Plaques for Therapeutic Interventions

Longitudinal Changes in Size of Conservatively Managed Flow-Related Aneurysms Associated with Brain Arteriovenous Malformations.

MR Imaging of Vulnerable Carotid Atherosclerotic Plaques

Growing Evidence: Dysautoregulation May Trigger Ischemic Deficit After Subarachnoid Hemorrhage.

Initial experience with Pipeline embolization of intracranial pseudoaneurysms in pediatric patients.