A Precision Medicine Approach to Cerebral Edema and Intracranial Hypertension after Severe Traumatic Brain Injury: Quo Vadis?

Abstract

Purpose of Review Standard clinical protocols for treating cerebral edema and intracranial hypertension after severe TBI have remained remarkably similar over decades. Cerebral edema and intracranial hypertension are treated interchangeably when in fact intracranial pressure (ICP) is a proxy for cerebral edema but also other processes such as extent of mass lesions, hydrocephalus, or cerebral blood volume. A complex interplay of multiple molecular mechanisms results in cerebral edema after severe TBI, and these are not measured or targeted by current clinically available tools. Addressing these underpinnings may be key to preventing or treating cerebral edema and improving outcome after severe TBI. Recent Findings This review begins by outlining basic principles underlying the relationship between edema and ICP including the Monro-Kellie doctrine and concepts of intracranial compliance/elastance. There is a subsequent brief discussion of current guidelines for ICP monitoring/management. We then focus most of the review on an evolving precision medicine approach towards cerebral edema and intracranial hypertension after TBI. Personalization of invasive neuromonitoring parameters including ICP waveform analysis, pulse amplitude, pressure reactivity, and longitudinal trajectories are presented. This is followed by a discussion of cerebral edema subtypes (continuum of ionic/cytotoxic/vasogenic edema and progressive secondary hemorrhage). Mechanisms of potential molecular contributors to cerebral edema after TBI are reviewed. For each target, we present findings from preclinical models, and evaluate their clinical utility as biomarkers and therapeutic targets for cerebral edema reduction. This selection represents promising candidates with evidence from different research groups, overlap/inter-relatedness with other pathways, and clinical/translational potential. Summary We outline an evolving precision medicine and translational approach towards cerebral edema and intracranial hypertension after severe TBI.

CT‐Based Classification of Acute Cerebral Edema: Association with Intracranial Pressure and Outcome

“…Among the 31 patients with focal edema (grade 1-3), only 3 patients died, and 12 achieved a favorable outcome . Outcome of patients with TBI n = 14 Contusion (9) Subdural (9) Subarachnoid (12) Moderate 3Severe (11) Frontal (9) Temporal 7Parietal 3Yes ( 4none 2VA 1Clip (13) Coil 11None 29.0/2.0 3/0.5…”

“…In TBI, cerebral edema is a central cause of elevated ICP, relating to ICP via the Monroe-Kellie doctrine, autoregulation, and pressure-volume relationships; other factors also contribute, for example, primary injury and CSF obstruction. 11 Animal models can measure brain edema as water content 12 and BBB disruption using Evans blue dye extravasation. 13 In clinical studies, monitoring the extent of edema formation on CT scans can be used and for ICP management, this technique has been shown to be feasible as a guide for antiedematous therapy management.…”

“…Current treatments like hypertonic saline, mannitol, or decompressive craniectomy, while effective at reducing intracranial hypertension, have an unclear impact on outcome, highlighting the elusive but essential balance of adaptive versus pathologic swelling. 20 As more and more molecular components of edema formation such as aquaporin-4, glutamate, matrixmetalloproteinase-9, NKCC1, SUR1-TRPM4, or VEGF-A are recognized, 11 evaluating the effectiveness of targeted antiedematous therapies becomes increasingly important. For example, sulfonylurea receptor-1 levels have been shown to correlate with compression of ventricles, effacement of basilar cisterns or sulci, transfalcine herniation and loss of gray/white matter differentiation on CT scanning indicating presence or absence of edema.…”

Immunomodulatory Effect of Hypertonic Saline Solution in Traumatic Brain-Injured Patients and Intracranial Hypertension

“…Its efficacy has been demonstrated in reducing an elevated ICP after TBI or due to other causes including intracranial bleeding of spontaneous or traumatic etiology. 9,[18][19][20]22,23,29,[32][33][34][35][36] One of the main advantages of the HSS usage is the rapid reduction of the ICP with extended responsiveness greater than 2 hours without pressure rebound, which is related to improved neurologic outcomes. 23 Additionally, HSS has shown other rheological effects such as plasma expansion, improvement in microcirculatory blood flow, reperfusion injury protection, and recovery of CPP, among others.…”

Hydrogen exerts neuroprotection by activation of the miR‐21/PI3K/AKT/GSK‐3β pathway in an in vitro model of traumatic brain injury

“…It is well known that TBI causes progressive damage in brain tissue, such as blood‐brain barrier leakage, brain oedema and intracranial hypertension, which may partly be induced or promoted by oxidative stress, neuronal apoptosis and many other cellular/molecular dysfunctions . These pathological abnormalities at tissue, cellular or molecular levels eventually affect neurons, resulting in quantity reduction, structural change and subsequent neurological dysfunction .…”