Jon Sen

Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage

Cerebral vasospasm is a recognised but poorly understood complication for many patients who have aneurysmal subarachnoid haemorrhage and can lead to delayed ischaemic neurological deficit (stroke). Morbidity and mortality rates for vasospasm are high despite improvements in management. Since the middle of the 1970s, much has been written about the treatment of cerebral vasospasm. Hypervolaemia, hypertension, and haemodilution (triple-H) therapy in an intensive-care setting has been shown in some studies to improve outcome and is an accepted means of treatment, although a randomised controlled trial has never been undertaken. In this review, the rationale for this approach will be discussed, alongside new thoughts and future prospects for the management of this complex disorder.

Metabolic failure precedes intracranial pressure rises in traumatic brain injury: a microdialysis study

SummaryBackground: Cerebral microdialysis (MD) is able to detect markers of tissue damage and cerebral ischaemia and can be used to monitor the biochemical changes subsequent to head injury. In this prospective, observational study we analysed the correlation between microdialysis markers of metabolic impairment and intracranial pressure (ICP) and investigated whether changes in biomarker concentration precede rises in ICP.Methods: MD and ICP monitoring was carried out in twenty-five patients with severe TBI in Neurointensive care. MD samples were analysed hourly for lactate:pyruvate (LP) ratio, glutamate and glycerol. Abnormal values of microdialysis variables in presence of normal ICP were used to calculate the risk of intracranial hypertension developing within the next 3 h.Findings: An LP ratio >25 and glycerol >100 µmol/L, but not glutamate >12 µmol/L, were associated with significantly higher risk of imminent intracranial hypertension (odds ratio: 9.8, CI 5.8–16.1; 2.2, CI 1.6–3.8; 1.7, CI 0.6–3, respectively). An abnormal LP ratio could predict an ICP rise above normal levels in 89% of cases, whereas glycerol and glutamate had a poorer predictive value.Conclusions: Changes in the compound concentrations in microdialysate are a useful tool to describe molecular events triggered by TBI. These changes can occur before the onset of intracranial hypertension, suggesting that biochemical impairment can be present before low cerebral perfusion pressure is detectable. This early warning could be exploited to expand the window for therapeutic intervention.

IS ASPECT RATIO A RELIABLE PREDICTOR OF INTRACRANIAL ANEURYSM RUPTURE

OBJECTIVE:This study was undertaken to assess the reliability of the aspect ratio (AR) (i.e., aneurysm depth to aneurysm neck) in predicting aneurysm rupture. It has been shown that the AR is a key factor in predicting intraaneurysmal blood flow and aneurysm rupture. METHODS:Seventy-five patients with subarachnoid hemorrhage and multiple aneurysms were studied. The sizes of the aneurysms and their ARs were determined by examining the angiographic films. By comparing the difference between ruptured and unruptured aneurysms in the same individual, each patient in effect served as his or her own control. Each ruptured aneurysm was confirmed during surgery. RESULTS:There were 75 ruptured and 107 unruptured aneurysms. The mean AR was 2.70 for ruptured aneurysms, compared with 1.8 for unruptured aneurysms. This difference between the ARs was statistically significant (P < 0.001). The difference in aneurysm sizes in the two groups also was significant (P < 0.001). CONCLUSION:AR on its own is as reliable a variable as the size of the aneurysm for predicting aneurysm rupture.

Extracellular N-acetylaspartate depletion in traumatic brain injury

N‐Acetylaspartate (NAA) is almost exclusively localized in neurons in the adult brain and is present in high concentration in the CNS. It can be measured by proton magnetic resonance spectroscopy and is seen as a marker of neuronal damage and death. NMR spectroscopy and animal models have shown NAA depletion to occur in various types of chronic and acute brain injury. We investigated 19 patients with traumatic brain injury (TBI). Microdialysis was utilized to recover NAA, lactate, pyruvate, glycerol and glutamate, at 12‐h intervals. These markers were correlated with survival and a 6‐month Glasgow Outcome Score. Eleven patients died and eight survived. A linear mixed model analysis showed a significant effect of outcome and of the interaction between time of injury and outcome on NAA levels (p = 0.009 and p = 0.004, respectively). Overall, extracellular NAA was 34% lower in non‐survivors. A significant non‐recoverable fall was observed in this group from day 4 onwards, with a concomitant rise in lactate–pyruvate ratio and glycerol. These results suggest that mitochondrial dysfunction is a significant contributor to poor outcome following TBI and propose extracellular NAA as a potential marker for monitoring interventions aimed at preserving mitochondrial function.

Extracellular fluid S100B in the injured brain: a future surrogate marker of acute brain injury?

SummaryThe authors describe the measurement of S100B protein in brain extracellular fluid (ECF) of patients with acute brain injury (traumatic brain injury and subarachnoid haemorrhage) using the technique of microdialysis. To our knowledge, this is the first report of S100B measurement in the human brain. Acute Brain Injury (ABI) is a leading cause of death and disability and the need for a practical and sensitive biochemical marker for monitoring these patients is urgent. The calcium binding astrocyte protein, S100B, may be a candidate for this role. Previous serum studies have shown S100B to be a sensitive predictor of mortality and rise in intracranial pressure in ABI, but it has never before been measured directly within the brain. The ECF reflects the local biochemistry of the brain parenchyma, and the use of intracerebral microdialysis opens up the possibility of studying many novel surrogate markers of injury in the laboratory, in addition to the conventional markers it measures at the bedside (lactate, pyruvate, glucose, and glycerol). In this preliminary report of two cases, the authors demonstrate the quantification of S100B in ECF microdialysate, and investigate whether changes in hourly S100B profile can be related to secondary brain injury. It is shown that extracellular concentrations of S100B change markedly in response to secondary brain injury. Further investigation is required to determine whether extracellular S100B measurement in ABI could assist in patient management.

Free phenytoin concentration measurement in brain extracellular fluid: a pilot study

This article investigates the relationship between brain extracellular fluid free phenytoin concentration and plasma free phenytoin concentration in adults with acute brain injury. Daily cerebral microdialysate free phenytoin concentration was measured in eight adults with acute brain injury and compared with simultaneous measurement of plasma free phenytoin concentration. The group data revealed no significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.34, p = 0.41). However, in two patients, with a sufficient number of samples for intra-individual analysis, there was a significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.92, p < 0.001 and r = 0.88, p < 0.01). In vitro microdialysis relative recovery for phenytoin was 2.1%. In the context of acute brain injury, measurement of free plasma phenytoin concentration may not provide an accurate reflection of regional brain extracellular fluid free phenytoin concentration and may have limitations with respect to achieving reproducible brain extracellular fluid free phenytoin concentrations. This has implications for dosing regimens relying on plasma phenytoin levels.

A proteomic investigation into mechanisms underpinning corticosteroid effects on neural stem cells

Abstract Corticosteroids (CSs) are widely used clinically, for example in pediatric respiratory distress syndrome, and immunosuppression to prevent rejection of stem cell transplant populations in neural cell therapy. However, such treatment can be associated with adverse effects such as impaired neurogenesis and myelination, and increased risk of cerebral palsy. There is increasing evidence that CSs can adversely influence key biological properties of neural stem cells (NSCs) but the molecular mechanisms underpinning such effects are largely unknown. This is an important issue to address given the key roles NSCs play during brain development and as transplant cells for regenerative neurology. Here, we describe the use of label‐free quantitative proteomics in conjunction with histological analyses to study CS effects on NSCs at the cellular and molecular levels, following treatment with methylprednisolone (MPRED). Immunocytochemical staining showed that both parent NSCs and newly generated daughter cells expressed the glucocorticoid receptor, with nuclear localisation of the receptor induced by MPRED treatment. MPRED markedly decreased NSC proliferation and neuronal differentiation while accelerating the maturation of oligodendrocytes, without concomitant effects on cell viability and apoptosis. Parallel proteomic analysis revealed that MPRED induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. Our findings support the hypothesis that some neurological deficits associated with CS use may be mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects. HighlightsTreatment of NSCs with a widely used clinical corticosteroid showed that proliferation of neural stem cells was reduced.Genesis of neurons and axonal length were reduced, while oligodendrocyte maturation was increased after corticosteroid treatment.Proteomic analysis shows corticosteroids induced downregulation of GAP‐43 and MMP‐16 with upregulation of CYP51A1.

Nimodipine for subarachnoid haemorrhage: the end of the road or better trials?

Traumatic subarachnoid haemorrhage is a common finding in all degrees of severity of head injury and is an independent predictor of poor outcome. However, to what extent the presence of subarachnoid blood contributes to secondary deterioration or whether this is simply an epiphenomenon of the injury is unclear. In patients with aneurysmal subarachnoid haemorrhage nimodipine is widely used for the prevention and treatment of cerebral vasospasm, a major contributor to morbidity and mortality in this disorder. Although the main effect of nimodipine is thought to be relaxation of the smooth muscle of the cerebral vasculature mediated by its Ca2+ antagonistic action, other mechanisms have been invoked, including possible antioxidant activity