Substance p antagonists as a novel intervention for brain edema and raised intracranial pressure

Authors: Gabrielian L, Helps SC, Thornton E, Turner RJ, Leonard AV, Vink R.

Increased intracranial pressure (ICP) following acute brain injury requires the accumulation of additional water in the intracranial vault. One source of such water is the vasculature, although the mechanisms associated with control of blood-brain barrier permeability are unclear. We have recently shown that acute brain injury, such as neurotrauma and stroke, results in perivascular accumulation of the neuropeptide, substance P. This accumulation is associated with increased blood-brain barrier permeability and formation of vasogenic edema. Administration of a substance P antagonist targeting the tachykinin NK1 receptor profoundly reduced the increased blood-brain barrier permeability and edema formation, and in small animal models of acute brain injury, improved functional outcome. In a large, ovine model of experimental traumatic brain injury, trauma resulted in a significant increase in ICP. Administration of an NK1 antagonist caused a profound reduction in post--traumatic ICP, with levels returning to normal within 4 h of drug administration. Substance P NK1 antagonists offer a novel therapeutic approach to the treatment of acute brain injury.

Review and recommendations on management of refractory raised intracranial pressure in aneurysmal subarachnoid hemorrhage

Authors: Mak CH, Lu YY, Wong GK.

Intracranial hypertension is commonly encountered in poor-grade aneurysmal subarachnoid hemorrhage patients. Refractory raised intracranial pressure is associated with poor prognosis. The management of raised intracranial pressure is commonly referenced to experiences in traumatic brain injury. However, pathophysiologically, aneurysmal subarachnoid hemorrhage is different from traumatic brain injury. Currently, there is a paucity of consensus on the management of refractory raised intracranial pressure in spontaneous subarachnoid hemorrhage. We discuss in this paper the role of hyperosmolar agents, hypothermia, barbiturates, and decompressive craniectomy in managing raised intracranial pressure refractory to first-line treatment, in which preliminary data supported the use of hypertonic saline and secondary decompressive craniectomy. Future clinical trials should be carried out to delineate better their roles in management of raised intracranial pressure in aneurysmal subarachnoid hemorrhage patients.

National Variability in Intracranial Pressure Monitoring and Craniotomy for Children with Moderate to Severe Traumatic Brain Injury

Authors: Van Cleve W, Kernic MA, Ellenbogen RG, Wang J, Zatzick DF, Bell MJ, Wainwright MS, Groner JI, Mink RB, Giza CC, Boyle LN, Mitchell PH, Rivara FP, Vavilala MS; for the PEGASUS (Pediatric Guideline Adherence and Outcomes) Project.

BACKGROUND: Traumatic brain injury (TBI) is a significant cause of mortality and disability in children. Intracranial pressure monitoring (ICPM) and craniotomy/craniectomy (CRANI) may affect outcomes. Sources of variability in the use of these interventions remain incompletely understood.

OBJECTIVE: To analyze sources of variability in the use of ICPM and CRANI.

METHODS: Retrospective cross-sectional study of patients with moderate/severe pediatric TBI using data submitted to the American College of Surgeons National Trauma Databank.

RESULTS: We analyzed data from 7,140 children at 156 US hospitals during 7 continuous years. 27.4% of children had ICPM, while 11.7% had a CRANI. Infants had lower rates of ICPM and CRANI than older children. A lower rate of ICPM was observed among children hospitalized at combined pediatric/adult trauma centers than children treated at adult-only trauma centers (RR 0.80, 95% CI 0.66 - 0.97). For ICPM and CRANI, 18.5% and 11.6%, respectively, of residual model variance was explained by between-hospital variation in care delivery, but almost no correlation was observed between within-hospital tendency towards performing these procedures.

CONCLUSION: Infants received less ICPM than older children, and children hospitalized at pediatric trauma centers received less ICPM than children at adult-only trauma centers. In addition, significant between-hospital variability existed in the delivery of ICPM and CRANI to children with moderate-severe TBI.

Pressure is only part of the story in traumatic brain injured patients; focal cerebral blood flow goes to zero in some patients with adequate cerebral perfusion pressure

Authors: Chovanes G, Richards RM.

INTRODUCTION: The pathophysiology of traumatic brain injury (TBI) is still not clearly understood. Recently, a decompressive craniectomy trial (1) and a trial of intracranial pressure (ICP) treatment with ICP monitoring vs no monitoring (2) failed to support the concept that increases in ICP are exclusively responsible for TBI mortality and morbidity. To analyze the role ICP, cerebral perfusion pressure (CPP = BP-ICP), and cerebral blood flow (CBF) play in head injury, we monitored brain injured patients' ICP, blood pressure (BP), CPP, and focal cerebral blood flow (fCBF), recording the real-time data for computer analysis.
METHODS: 20 patients with severe brain injury were monitored with recordings of ICP, BP, CPP, and fCBF every minute. 17 patients had severe closed TBI, 1 gunshot wound, and 2 intracerebral hemorrhages. 13 patients lived (GCS 3-9, average 5), 7 died (GCS 3-7, average 5). Of the 7 patients who died, 5 had technically adequate recordings before and as death supervened. Graphs were prepared of time vs CPP, ICP and fCBF and reviewed for the time course of fCBF deterioration vs CPP elevation. If CPP obviously and substantially decreased before fCBF decreased, that was termed a pressure death. However, if CPP stayed adequate and fCBF still decreased to zero, that was termed a non-pressure death.
RESULTS: Three patients had a pressure death (Fig 1), and 2 patients had a non-pressure death (Fig 2).
CONCLUSION: This may be the first real-time documentation of non-CPP dependent brain death as expressed by fCBF. There are pathological processes in the injured brain that do not directly involve increases in ICP and decreases in CPP. Heretofore clinical treatment efforts in brain injury have focused on ICP: other mechanisms are also extant and should be further investigated so as to more successfully treat brain injury.

Mathematical Modelling of Near-Infrared Spectroscopy Signals and Intracranial Pressure in Brain-Injured Patients

Authors: Highton D, Panovska-Griffiths J, Smith M, Elwell CE.

Raised intracranial pressure (ICP) is a key concern following acute brain injury as it may be associated with cerebral hypoperfusion and poor outcome. In this research we describe a mathematical physiological model designed to interpret cerebral physiology from neuromonitoring: ICP, near-infrared spectroscopy and transcranial Doppler flow velocity. This aims to characterise the complex dynamics of cerebral compliance, cerebral blood volume, cerebral blood flow and their regulation in individual patients. Analysis of data from six brain-injured patients produces cohesive predictions of cerebral biomechanics suggesting reduced cerebral compliance, reduced volume compensation and impaired blood flow autoregulation. Patient-specific physiological modelling has the potential to predict the key biomechanical and haemodynamic changes following brain injury in individual patients, and might be used to inform individualised treatment strategies.

Association between visual parameters and neuroimaging features of idiopathic intracranial hypertension

Authors: Padhye LV, Van Stavern GP, Sharma A, Viets R, Huecker JB, Gordon MO.

BACKGROUND/AIMS: Papilledema refers to optic disc swelling resulting from high intracranial pressure (ICP). The precise mechanism by which papilledema occurs remains uncertain. Although orbital neuroimaging features associated with papilledema are well-described, it is unclear whether these findings correlate with visual function. Idiopathic Intracranial Hypertension (IIH) is a condition in which the intracranial pressure is elevated with no obvious cause, causing papilledema and visual loss. The utility of papilledema and IIH neuroimaging findings as a surrogate marker for visual loss, or a predictor of visual loss, is understudied. This retrospective cross-sectional review aims to correlate parameters of visual function with orbital magnetic resonance imaging (MRI) findings.
METHODS: Patients meeting criteria for IIH who had received orbital imaging within 4weeks of examination were included. Visual parameters of papilledema grade, visual field mean deviation, and visual acuity were correlated with neuroimaging features, including optic nerve thickness, and optic nerve sheath thickness, among others. All MRI scans were reviewed by a neuroradiologist blinded to clinical status. Spearman rank correlations and t-tests were generated with SAS (v9.2).
RESULTS: Thirty five patients were included. No significant relationships were found between the main visual parameters of papilledema grade and visual field mean deviation, and MRI findings.
CONCLUSIONS: We found no significant correlation between visual parameters and imaging features of papilledema. This might indicate that MRI features may provide insight into the structural changes that occur in papilledema, but may not be helpful when making clinical management decisions for patients with IIH in particular, and papilledema in general.

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