Adel Helmy

The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production.

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1β, platelet derived growth factor (PDGF)-AA, MIP1β, RANTES; day 2: IL1 receptor antagonist (ra). IL6, granulocyte-colony stimulating factor (G-CSF), chemokine CXC motif ligand 10 (IP10); days 4 to 5: IL12p70, IL10. Brain extracellular fluid concentrations were significantly higher than plasma concentrations for 19 cytokines: basic fibroblast growth factor (FGF2), G-CSF, IL1α, IL1 β, IL1ra, IL3, IL6, IL8, IL10, IL12p40, IL12p70, IP10, monocyte chemotactic protein (MCP)1, MCP3, MIP1α, MIP1β, PDGF-AA, transforming growth factor (TGF)α and vascular endothelial growth factor. No clear arterio-jugular venous gradients were apparent. These data provide evidence for the cerebral production of these cytokines and show a stereotyped temporal pattern after TBI.

Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury.

There is an increasing recognition that following traumatic brain injury, a cascade of inflammatory mediators is produced, and contributes to the pathological consequences of central nervous system injury. This review summarises the key literature from pre-clinical models that underlies our understanding of innate inflammation following traumatic brain injury before focussing on the growing evidence from human studies. In addition, the underlying molecular mediators responsible for blood brain barrier dysfunction have been discussed. In particular, we have highlighted the different sampling methodologies available and the difficulties in interpreting human data of this sort. Ultimately, understanding the innate inflammatory response to traumatic brain injury may provide a therapeutic avenue in the treatment of central nervous system disease.

Impairment of Cerebral Autoregulation Predicts Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: A Prospective Observational Study

Background and Purpose— Delayed cerebral ischemia (DCI) is a recognized contributor to unfavorable outcome after subarachnoid hemorrhage (SAH). Recent data challenge the concept of vasospasm as the sole cause of ischemia and suggest a multifactorial process with dysfunctional cerebral autoregulation as a component. We tested the hypothesis that early autoregulatory failure, detected using near-infrared spectroscopy–based index, TOxa and transcranial Doppler–based index, Sxa, can predict DCI. Methods— In this prospective observational study we enrolled consecutive patients with aneurysmal SAH that occurred <5 days from admission. The primary end point was the occurrence of DCI within 21 days of ictus. The predictive value of autoregulatory disturbances detected in the first 5 days was assessed using univarate proportional hazards model and a multivariate model. Results— Ninety-eight patients were included. Univariate analysis demonstrated increased odds of developing DCI when early autoregulation failure was detected (odds ratio [OR], 7.46; 95% confidence interval [CI], 3.03–18.40 and OR, 4.52; 95% CI, 1.84–11.07 for Sxa and TOxa, respectively) but not TCD-vasospasm (OR, 1.36; 95% CI, 0.56–3.33). In a multivariate model Sxa and TOxa remained independent predictors of DCI (OR, 12.66; 95% CI, 2.97–54.07 and OR, 5.34; 95% CI, 1.25–22.84 for Sxa and TOxa, respectively). Conclusions— Disturbed autoregulation in the first 5 days after SAH significantly increases the risk of DCI. Autoregulatory disturbances can be detected using near-infrared spectroscopy and transcranial Doppler technologies.

Noninvasive Monitoring of Cerebrovascular Reactivity with Near Infrared Spectroscopy in Head-Injured Patients

Monitoring of cerebrovascular pressure reactivity (PRx) has diagnostic and prognostic value in head-injured patients, but requires invasive monitoring of intracranial pressure (ICP). Near infrared spectroscopy (NIRS) is a noninvasive method that is suitable for continuous detection of cerebral blood volume changes. We compared a NIRS-based index of cerebrovascular reactivity, called total hemoglobin reactivity (THx), against standard measurements of PRx in a prospective observational study. Forty patients with closed-head injury were monitored daily with arterial blood pressure (ABP), ICP, and a NIRS-based total hemoglobin index. PRx and THx were calculated as the moving correlation coefficients using 5-min time windows between 10-sec averaged values of ICP and ABP, and total hemoglobin index and ABP, respectively. A total of 120 recordings were performed between the median first (IQR 0.75-2) and fourth (IQR 2-6) day after head injury, giving a total duration of 1760 hours. PRx and THx demonstrated a significant association across averaged individual recordings (r = 0.49, p < 0.0001), and across patients (r = 0.56, p = 0.0002). Assessment of optimal cerebral perfusion pressure (CPP) and ABP using THx was possible in about 50% of recordings, and showed a significant agreement with the optimal CPP and ABP assessed with PRx. THx may be of diagnostic value to optimize therapy oriented toward restoration and continuity of cerebrovascular reactivity, especially in patients for whom direct ICP monitoring is not feasible.

Consensus statement from the 2014 International Microdialysis Forum

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Microdialysis of Cytokines: Methodological Considerations, Scanning Electron Microscopy, and Determination of Relative Recovery

Cerebral microdialysis is a monitoring technique with expanding clinical and research utility following traumatic brain injury. This studys aim was to determine the relative recovery for 12 cytokines using both crystalloid (CNS perfusion fluid) and colloid (CNS perfusion fluid supplemented with 3.5% human serum albumin) perfusate. Six CMA71 microdialysis catheters (nominal molecular weight cut-off 100 kDa) were perfused in vitro with either crystalloid or colloid and the relative recovery (%) determined for the cytokines as follows (crystalloid/colloid perfusate): IL-1alpha (50.6/48), IL-1beta (34.6/38.4), IL-1ra (21.9/38.4), IL-2 (17.1/52.8), IL-4 (26/56.7), IL-6 (9.8/25.5), IL-8 (47.7/73.4), IL-10 (2.9/8.7), IL-17 (14.4/43.7), TNF-alpha (4.4/31.2), MIP-1alpha (31.8/55.6), and MIP-1beta (31.9/50.1). The colloid perfusate significantly improved relative recovery for nine of these cytokines ( p < 0.05), but not for IL-1alpha, IL-1beta, and IL-8. Relative recovery was related to apparent molecular weight of cytokine and to isoelectric point (pI), a surrogate marker of hydrophilicity. The mean fluid recovery for crystalloid and colloid perfusate was 92% and 145%, respectively. Scanning electron microscopy was utilized to investigate the ultrastructure of microdialysis membranes: (1) 20-kDa membrane, (2) 100-kDa membrane, and (3) ex vivo 100-kDa membrane. The 100-kDa membranes possessed multiple large cavities and the catheter examined after use in human brain clearly demonstrated cellular debris within the pores of the membrane. While colloid perfusate improves relative recovery, it causes a net influx of fluid into the microdialysis catheter, potentially dehydrating the extracellular space. This study is the first to systematically determine relative recovery in vitro for a wide range of cytokines. The two forms of perfusion fluid require direct comparison in vivo.

Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rh I Lira-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.

Principal Component Analysis of the Cytokine and Chemokine Response to Human Traumatic Brain Injury

There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI). This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR) of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study.

The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage

Cerebral vasospasm has traditionally been regarded as an important cause of delayed cerebral ischaemia (DCI) which occurs after aneurysmal subarachnoid haemorrhage, and often leads to cerebral infarction and poor neurological outcome. However, data from recent studies argue against a pure focus on vasospasm as the cause of delayed ischaemic complications. Findings that marked reduction in the incidence of vasospasm does not translate to a reduction in DCI, or better outcomes has intensified research into other possible mechanisms which may promote ischaemic complications. Early brain injury and cell death, blood-brain barrier disruption and initiation of an inflammatory cascade, microvascular spasm, microthrombosis, cortical spreading depolarisations and failure of cerebral autoregulation, have all been implicated in the pathophysiology of DCI. This review summarises the current knowledge about the mechanisms underlying the development of DCI. Furthermore, it aims to describe and categorise the known pharmacological treatment options with respect to the presumed mechanism of action and its role in DCI.

Traumatic brain injury in adults

Traumatic brain injury (TBI) remains a major public health problem. This review aims to present the principles upon which modern TBI management should be based. The early management phase aims to achieve haemodynamic stability, limit secondary insults (eg hypotension, hypoxia), obtain accurate neurological assessment and appropriately select patients for further investigation. Since 2003, the mainstay of risk stratification in the UK emergency departments has been a system of triage based on clinical assessment, which then dictates the need for a CT scan of the head. For patients with acute subdural or extradural haematomas, time from clinical deterioration to operation should be kept to a minimum, as it can affect their outcome. In addition, it is increasingly recognised that patients with severe and moderate TBI should be managed in neuroscience centres, regardless of the need for neurosurgical intervention. The monitoring and treatment of raised intracranial pressure is paramount for maintaining cerebral blood supply and oxygen delivery in patients with severe TBI. Decompressive craniectomy and therapeutic hypothermia are the subject of ongoing international multi-centre randomised trials. TBI is associated with a number of complications, some of which require specialist referral. Patients with post-concussion syndrome can be helped by supportive management in the context of a multi-disciplinary neurotrauma clinic and by patient support groups. Specialist neurorehabilitation after TBI is important for improving outcome.