Therapeutic Hypothermia in Children and Adults with Severe Traumatic Brain Injury.

Great expectations have been raised about neuroprotection of therapeutic hypothermia in patients with traumatic brain injury (TBI) by analogy with its effects after heart arrest, neonatal asphyxia, and drowning in cold water. The aim of this study is to review our present knowledge of the effect of therapeutic hypothermia on outcome in children and adults with severe TBI. A literature search for relevant articles in English published from year 2000 up to December 2013 found 19 studies. No signs of improvement in outcome from hypothermia were seen in the five pediatric studies. Varied results were reported in 14 studies on adult patients, 2 of which reported a tendency of higher mortality and worse neurological outcome, 4 reported lower mortality, and 9 reported favorable neurological outcome with hypothermia. The quality of several trials was low. The best-performed randomized studies showed no improvement in outcome by hypothermia-some even indicated worse outcome. TBI patients may suffer from hypothermia-induced pulmonary and coagulation side effects, from side effects of vasopressors when re-establishing the hypothermia-induced lowered blood pressure, and from a rebound increase in intracranial pressure (ICP) during and after rewarming. The difference between body temperature and temperature set by the biological thermostat may cause stress-induced worsening of the circulation and oxygenation in injured areas of the brain. These mechanisms may counteract neuroprotective effects of therapeutic hypothermia. We conclude that we still lack scientific support as a first-tier therapy for the use of therapeutic hypothermia in TBI patients for both adults and children, but it may still be an option as a second-tier therapy for refractory intracranial hypertension

The G protein-coupled oestrogen receptor 1 agonist G-1 disrupts endothelial cell microtubule structure in a receptor-independent manner.

The G protein-coupled oestrogen receptor GPER1, also known as GPR30, has been implicated in oestrogen signalling, but the physiological importance of GPER1 is not fully understood. The GPER1 agonist G-1 has become an important tool to assess GPER1-mediated cellular effects. Here, we report that this substance, besides acting via GPER1, affects the microtubule network in endothelial cells. Treatment with G-1 (3 μM) for 24 h reduced DNA synthesis by about 60 % in mouse microvascular endothelial bEnd.3 cells. Treatment with 3 μM G-1 prevented outgrowth of primary endothelial cells from mouse aortic explants embedded in Matrigel. Treatment with G-1 (0.3-3 μM) for 24 h disrupted bEnd.3 cell and HUVEC microtubule structure in a concentration-dependent manner as assessed by laser-scanning confocal immunofluorescence microscopy. G-1-induced (3 μM) disruption of microtubule was observed also after acute (3 and 6 h) treatment and in the presence of the protein synthesis inhibitor cycloheximide. Disruption of microtubules by 3 μM G-1 was observed in aortic smooth muscle cells obtained from both GPER1 knockout and wild-type mice, suggesting that G-1 influences microtubules through a mechanism independent of GPER1. G-1 dose dependently (10-50 μM) stimulated microtubule assembly in vitro. On the other hand, microtubules appeared normal in the presence of 10-50 μM G-1 as determined by electron microscopy. We suggest that G-1-promoted endothelial cell anti-proliferation is due in part to alteration of microtubule organization through a mechanism independent of GPER1. This G-1-promoted mechanism may be used to block unwanted endothelial cell proliferation and angiogenesis such as that observed in, e.g. cancer

The "Lund Concept" for the treatment of severe head trauma - physiological principles and clinical application.

The Lund Concept is an approach to the treatment of severe brain trauma that is mainly based on hypotheses originating from basic physiological principles regarding brain volume and cerebral perfusion regulation. Its main attributes have found support in experimental and clinical studies. This review explains the principles of the Lund Concept and is intended to serve as the current guide for its clinical application. The therapy has two main goals: (1) to reduce or prevent an increase in ICP (ICP-targeted goal) and (2) to improve perfusion and oxygenation around contusions (perfusion-targeted goal). The Lund therapy considers the consequences of a disrupted blood-brain barrier for development of brain oedema and the specific consequences of a rigid dura/cranium for general cerebral haemodynamics. It calls attention to the importance of improving perfusion and oxygenation of the injured areas of the brain. This is achieved by normal blood oxygenation, by maintaining normovolaemia with normal haematocrit and plasma protein concentrations, and by antagonizing vasoconstriction through reduction of catecholamine concentration in plasma and sympathetic discharge (minimizing stress and by refraining from vasoconstrictors and active cooling). The therapeutic measures mean normalization of all essential haemodynamic parameters (blood pressure, plasma oncotic pressure, plasma and erythrocyte volumes, PaO2, PaCO2) the use of enteral nutrition, and avoidance of overnutrition. To date, clinical outcome studies using the Lund Concept have shown favourable results

Mechanisms behind postspinal headache and brain stem compression following lumbar dural puncture - a physiological approach.

Background: The cause of postspinal headache and its specific characteristics are unknown, and whether lumbar dural puncture (LP) triggers brain-stem compression in patients with brain oedema is still controversial. Methods: Hydrostatic effects of distal opening of the dural sac towards the atmosphere are described and applied to the normal brain and the brain with disrupted BBB. Analogue analyses from previous results using an isolated skeletal muscle enclosed in a rigid shell were applied to the brain in an attempt to simulate and verify the haemodynamic effects of distal opening of the spinal canal. Results: The theoretical considerations and the experimental results are compatible with the hypothesis that hydrostatic effects of distal opening of the fluid-filled spinal canal may obliterate the normal subdural venous collapse after a change from the horizontal to vertical position, which may be compatible with postural postspinal headache as occurring close to pain-sensitive meningeal regions. The hydrostatic forces may also initiate transcapillary filtration and aggravate oedema when permeability is increased, which may cause a narrower situation in the brain stem region, perhaps aggravated by venous stasis and a Cushing reflex-induced increase in blood pressure. An magnetic resonance imaging (MRI) picture illustrates how this scenario may separate the subdural space into an upper high- and a lower low-pressure cavity, pressing the brain downwards with sagging of the brain. A life-threatening positive feedback situation for brain-stem compression may develop. Conclusion: The present study strongly suggests that postspinal headache and brain-stem compression and other LP-related effects are predictable following LP, without involving CSF leakage, and can be explained by hydrostatic effects triggered by distal opening of the normally closed dural space to the atmosphere

PRO: The "Lund Concept" for Treatment of Patients With Severe Traumatic Brain Injury.

Two different main concepts for the treatment of severe traumatic brain injury have been established during the last 15 years, namely the more conventional concept recommended in well-established guidelines (eg, the US Guideline, European Guideline, Addelbrook's Guideline from Cambridge) on the one hand, and the Lund concept from the University Hospital of Lund, Sweden on the other. Owing to the lack of well-controlled randomized outcome studies comparing these 2 main therapeutic approaches, we cannot conclude that one is better than the other. This study is the PRO part in a PRO-CON debate on the Lund concept in the present journal. Although the Lund concept is based on a physiology-oriented approach dealing with hemodynamic principles of brain volume and brain perfusion regulation, traditional treatments are primarily based on a meta-analytic approach from clinical studies. High cerebral perfusion pressure has been an essential goal in the conventional treatments (the cerebral perfusion pressure-guided approach), even though it has been modified in a recent update of US guidelines. The Lund concept has instead concentrated on management of brain edema and intracranial pressure, simultaneously with improvement of cerebral perfusion and oxygenation (the intracranial pressure and perfusion-guided approach). Although conventional guidelines are restricted to clinical data from meta-analytic surveys, the physiological approach of the Lund therapy finds support in both experimental and clinical studies. It offers a wider base and can also give recommendations regarding fluid therapy, lung protection, optimal hemoglobin concentration, temperature control, the use of decompressive craniotomy, and ventricular drainage. This study puts forward arguments in support of the Lund therapy

Isolated Brain Trauma in Cats Triggers Rapid Onset of Hypovolemia

Background: Hemodynamic instability responsive to fluid resuscitation is common after a traumatic brain injury (TBI), also in the absence of systemic hemorrhage. The present study tests if an isolated severe TBI induces a decrease in plasma volume (PV). Methods: The study was performed in three groups of anesthetized and tracheostomized male cats (n = 21). In one group (n = 8), the cats were prepared with a cranial borehole (10 mm i.d) used to expose the brain to a fluid percussion brain injury (FPI) (1.90–2.20 bar), and two smaller cranial boreholes (4 mm i.d) for insertion of an intracranial pressure (ICP) and a microdialysis catheter. To differentiate the effect of FPI from that of the surgical preparation, a sham group was exposed to the same surgical preparation but no FPI trauma (n = 8). A control group had no brain trauma and no surgical preparation (n = 5). PV was determined by a 125I-albumin dilution technique. PV, electrolytes, pH, BE (base excess), hematocrit (Hct), PaO2, and PaCO2 were measured at baseline and after 3 h. Mean arterial pressure (MAP) was measured continuously. ICP was measured in the FPI and the sham group. Results: In the FPI group, PV decreased by 11.2 mL/kg from 31.7 mL/kg (p < 0.01) with a simultaneous increase in Hct and decrease in pH. In the sham group, PV decreased by 5.7 mL/kg from 32.7 mL/kg (p < 0.01). The control group showed no PV reduction. Conclusions: The results support that an isolated severe head trauma triggers a significant and rapid reduction in PV, most likely due to vascular leak