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Objectives: Validated optimal cerebral perfusion pressure (CPP) treatment thresholds in children do not exist. To improve the intensive care unit (ICU) management of the paediatric traumatic brain injury (TBI) population, we are forming a new paediatric multi-centre collaboration to recruit standardised ICU data for running and reporting upon models for assessing autoregulation and optimal CCP (CPPopt)., Materials and Methods: We are adapting the adult BrainIT group's approach to develop a new Paediatric Brain Monitoring and Information Technology Group (KidsBrainIT), which will include a repository to store prospectively collected high-resolution physiological, clinical, and outcome data. In the first phase of this project there are 7 UK Paediatric Intensive Care Units, 1 Spanish, 1 Belgium, and 1 Romanian Centre interested in participating. In subsequent phases, we plan to open recruitment to other centres both within Europe, US and abroad. We are collaborating with the Leuven Group and plan to use their LAx (low-frequency autoregulation index), DATACAR (dynamic adaptive target of active cerebral autoregulation), CPPopt and visualisation methodologies. We also plan to use the continuous diffuse optical monitoring and tomography technology developed in Barcelona as an acute surrogate end-point for optimising brain perfusion. This technology allows non-invasive continuous monitoring of deep tissue perfusion and oxygenation in adults but its clinical application in infants and children with TBI has not been studied previously., Results: We report on the current status of setting up this new collaboration and also on pilot analyses in two centres which are the basis of our rationale for the need for a prospective validation study of CPPopt in children. Specifically, we demonstrated that CPPopt varied with time for each patient during their paediatric intensive care unit (PICU) stay, and the median overall CPPopt levels for children aged 2-6 years, 7-11 years and 12-16 years were 68.83, 68.09, and 72.17 mmHg respectively. Among survivors and patients with favourable outcome (GOS 4 and 5), there were significantly higher proportions with CPP monitoring time within CPPopt (p = 0.04 and p = 0.01 respectively)., Conclusions: There is a need and an interest in forming a multi-centre PICU collaboration for acquiring data and performing analyses for determining validated CPPopt thresholds in the paediatric TBI population. KidsBrainIT is being formed to meet that need.

Introduction: Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade the extracellular matrix and are found in a large amount of human tissues. Their main functions are to maintain the integrity of the extracellular matrix, to modulate the interaction of the cells during development, to contribute to tissue remodeling, to directly participate in angiogenesis and to facilitate cellular migration. Due to the importance of its maintaining extracellular matrix function, MMP expression is tightly regulated at transcriptional level, through proform activation and with the binding to tissular inhibitors. Despite this complex regulation system, MMP regulation can be altered, producing an overexpression of these proteolytic proteins that alter the tissular structure, possibly destroying the tissue, as observed in some neurologic pathologies such as multiple sclerosis, aneurism formation and cerebral ischemia. The role that MMP have in traumatic brain lesions is almost unknown and is derived mainly from in vivo and in vitro experimental studies, and only from three papers performed in humans. There are some experimental studies that relate the brain alterations produced after traumatic brain injury with an increase in the concentration of various MMP., Aim: To review the role of these proteases in human brain lesions, emphasizing on the function of these proteases in traumatic brain injury lesions and their possible therapeutic target., Development: A bibliographic search was performed on Medline database., Conclusions: Some MMP could be related to blood-brain barrier alteration and postraumatic edema formation, turning them into promising therapeutic targets.

Background: Brain contusions are inflammatory evolutive lesions that induce intracranial pressure increase and edema, contributing to neurological outcome. Matrix metalloproteinases (MMPs) 2 and 9 can degrade the majority of the extracellular matrix components, and are implicated in blood-brain barrier disruption and edema formation. The aim of this study was to investigate MMP-2 and MMP-9 profiles in human brain contusions using zymography., Methods: A prospective study was conducted in 20 traumatic brain injury patients where contusion brain tissue was resected. Brain tissues from lobectomies were used as controls. Brain homogenates were analysed by gelatin zymography and in situ zimography was performed to confirm results, on one control and one brain contusion tissue sample., Findings: MMP-2 and MMP-9 levels were higher in brain contusions when compared to controls. MMP-9 was high during the first 24 hours and at 48 to 96 hours, whereas MMP-2 was slightly high at 24 to 96 hours. In situ zymography confirmed gelatin zymography results. A relation between outcome and MMP-9 levels was found; MMP-9 levels were higher in patients with worst outcome., Conclusions: Our results indicate strong time-dependent gelatinase expression primarily from MMP-9, suggesting that the inflammatory response induced by focal lesions should be considered as a new therapeutic target.

Because of the importance of hypoxic/ischemic phenomena in head-injured patients, brain monitoring in these patients should be complemented by systems providing information on cerebral blood flow and metabolism. Indirect estimations of cerebral blood flow have been obtained from blood extracted from the jugular bulb, as a special bedside application of the Fick's principle to the brain. In the last few years, the use of jugular oximetry techniques has become routine in centers treating head-injured and other neurocritical patients such as those presenting subarachnoid hemorrhage or malignant middle cerebral artery infarction. The experience acquired in the use of these techniques, as well as the introduction of new neuromonitoring systems, have deepened our understanding of the information gained and have enabled more precise definition of their indications and limitations. This review describes the basic concepts underlying the use of jugular oximetry techniques in the neurocritical patient. We also explain the reasons why several variables derived from jugular blood such as arterio-jugular differences of lactate (AVDL) or the lactate-oxygen index (LOI) do not provide accurate information on brain metabolism.

Objective: The aim of this study was to characterize regional cerebral blood flow in patients with Adult Hydrocephalus Syndrome (AHS) and to evaluate the changes in brain perfusion after surgical derivation treatment., Patients and Methods: 20 patients with AHS (age: 72 +/- 14, 12 men) were studied before and six months after surgery. All patients underwent a brain perfusion SPECT (99mTc-HMPAO) prior to surgery and at 6 months post-surgery. Semi-quantitative analysis was done for brain uptake: 0=Normal, 1=Mild, 2=Moderate, 3= Severe, 4=No uptake. The severity of ventricular dilatation was assessed by classifying the intensity and extension of subcortical defects: 0=Normal, 1=Mild, 2=Moderate, 3=Severe. The scores of the pre- and post-surgical studies were compared using the Student-t test., Results: A global reduction of brain uptake was observed (mean score 12.85), mainly in frontal, parietal and temporal lobes, with a significant improvement in post surgical studies (mean score 6, p<0,001). After surgery, 16 (80%) of the 20 patients improved brain uptake. In relationship to subcortical uptake, 5 patients showed mild defects, 9 moderate defects and 6 patients presented severe uptake reduction. In post-surgical studies 15 (75%) patients improved almost one degree in the subcortical score and 65% of the patients showed a normal or mild subcortical uptake reduction., Conclusions: Brain perfusion SPECT is useful in patients with AHS, detecting brain perfusion defects and evaluating cerebral blood flow improvement after shunt operation.

The aim of our study was to perform and in-depth analysis of several episodes of regional brain hypoxia detected by monitoring brain partial pressure of oxygen (PtiO2) in which simultaneous measurements of cerebral oxygen extraction fraction (O2EF) suggested a normally perfused or even a hyperemic brain. To gain deeper insight into these episodes, we used the model of tissue hypoxia described by Siggaard-Andersen. In 244 simultaneous measurements, 31 episodes (12.7%) of brain hypoxia (PtiO2 < or = 15 mmHg) were detected simultaneously with an O2EF within the normal range or below the lowest normal percentile. Using Siggaard-Andersen methodology, we classified 6 episodes (19%) as high-affinity hypoxia and 25 (81%) as shunt hypoxia or dysperfusion hypoxia. Siggaard-Andersen's comprehensive classification of tissue hypoxia can be used as an integrative model to build coherent algorithms for diagnosing and managing neurocritical patients that are at risk of brain hypoxia due to either intracranial or extracranial conditions.

Normal pressure hydrocephalus, or adult chronic hydrocephalus, is a relatively unknown entity. Classically, this disease is characterized by progressive dementia, gait disturbance, and urinary incontinence. Despite an increase in the prevalence of this type of dementia due to longer life expectancy, its diagnosis and treatment remain controversial. Recent studies have reported that the percentage of patients who show clinical improvement after shunting is still low and that the complication rate is excessively high. However, our experience and that of other authors indicates that the percentage of improvement after shunting can be greater than 80% and the complication rate can be low if a strict diagnostic protocol is applied and if the most appropriate valve is selected, based on the hydrodynamic characteristics of the shunt. The aim of this review is to provide an update of the clinical features, diagnosis and treatment of adult chronic hydrocephalus. We also discuss the diagnostic and treatment protocols applied in our centre in patients with suspected adult chronic hydrocephalus.

Objectives: To establish whether surgery can improve the neuropsychological functioning of young adult patients with spina bifida and apparent clinically arrested hydrocephalus showing abnormal intracranial pressure., Methods: Twenty three young adults with spina bifida and assumed arrested hydrocephalus (diagnosed as active or compensated by continuous intracranial pressure monitoring) underwent surgery. All patients received neuropsychological examination before surgery and 6 months later. Neuropsychological assessment included tests of verbal and visual memory, visuospatial functions, speed of mental processing, and frontal lobe functions., Results: Shunt placement in this subgroup of patients improves neuropsychological functioning, especially in verbal and visual memory and attention and cognitive flexibility., Conclusions: Young adults with spina bifida and suspected non-functioning shunt or non-shunted ventriculomegaly should be carefully monitored to identify those who could benefit from shunting.

The adequate management of cerebral perfusion pressure (CPP) continues to be a controversial issue in head-injured patients. The purpose of our study was to test two hypotheses. The first was that in patients with a CPP below 70 mm Hg, oxygen delivery is compromised and that therefore signs of tissue hypoxia would be reflected in low PtiO2 measurements. The second hypothesis was that manipulating mean arterial blood pressure to increase CPP improves oxygen delivery, particularly in patients with a CPP below 70 mm Hg. Twenty-five moderately or severely head-injured patients were included in the study. In all of them PtiO2 was monitored in the non-injured hemisphere using the Licox system (GMS, Kiel-Mielkendorf, Germany). Arterial hypertension was induced with phenylephrine 29 times. To quantify the effect of increasing mean arterial blood pressure (MABP) on oxygen delivery to the brain, the PtiO2-BP index was calculated (PtiO2-BP index = delta PtiO2/delta MABP). In 16 tests (55%) baseline CPP was above or equal to 70 mm Hg and in the remaining 13 (45%) it was below 70 mm Hg. Mean increase in MABP after phenylephrine was 23.7 +/- 10.2 mm Hg. Mean PtiO2 was 29.5 +/- 14.7 mm Hg in patients with a basal CPP of below 70 mm Hg and 28.9 +/- 10.6 mm Hg in patients in the high CPP group. These differences being not statistically significant. The PtiO2-BP index was 0.29 +/- 0.23 in patients with a basal CPP of below 70 mm Hg and in patients with a CPP of above 70 mm Hg this index was 0.16 +/- 0.11 Hg. These differences were not statistically significant (Student's t-test, P = 0.09). In our study a low PtiO2 was not observed in patients with marginally low CPPs (48-70 mm Hg) and readings below 15 mm Hg were observed in cases with both normal or supranormal CPPs. We conclude that episodes of low PtiO2 could not be predicted on the basis of CPP alone. On the other hand, raising CPP did not increase oxygen availability in the majority of cases, even if the CPP was markedly improved.

False autoregulation has been described as an alteration of autoregulation in which the apparent maintenance of a constant cerebral blood flow (CBF) when increasing cerebral perfusion pressure (CPP) is due to an increase in brain tissue pressure. The objective of our study was to investigate how often false autoregulation occurred in patients with a severe head injury. In forty-six patients with a moderate or severe head injury autoregulation was studied using arteriojugular differences of oxygen (AVDO2) to estimate changes in CBF after inducing arterial hypertension with phenylephrine. Changes in mean arterial blood pressure (MABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP) and AVDO2 were calculated before and after inducing hypertension. Ninety-five episodes of provoked hypertension were studied in 46 patients. In 28 tests (29.5%) a constant or even reduced CBF was detected simultaneously with a median increase in parenchymal ICP of 8.5 mm Hg (false autoregulation). In this group the median of the induced increase in MABP was 20.6 mm Hg with a median increase in CPP of 11.5 mm Hg. From our data we can conclude that false autoregulation is frequently found in patients after a severe head injury. Increasing MABP to obtain a better CPP in these patients is not beneficial because CBF is not modified or may even be reduced.

The present study was undertaken to elucidate the status of autoregulation and CO2-reactivity soon after injury in patients with a post-traumatic diffuse bilateral brain swelling. A prospective study was carried out in 31 consecutively admitted patients with a severe head injury and a Diffuse Brain Injury type III, following the definition stated by the Traumatic Coma Data Bank classification. To evaluate CO2-reactivity, AVDO2 was measured before and after ventilator manipulations. Assuming a constant CMRO2 during the test, changes in 1/AVDO2 reflect changes in CBF. Patients with changes in estimated CBF below or equal to 1% were included in the impaired/abolished CO2-reactivity group. To test autoregulation, hypertension was induced using phenylephrine. Arterial and jugular blood samples were taken to calculate AVDO2 before and after a steady state of MABP was obtained. Cerebrovascular response to CO2 was globally preserved in all but two cases (6.5%). In contrast, autoregulation was globally preserved in 10 (32.3%) and impaired/abolished in 21 cases (67.7%). Our data do not support the premise that increasing cerebral perfusion pressure by inducing arterial hypertension is beneficial in those patients with a diffuse brain swelling in whom autoregulation is impaired or abolished. Clinical implications for treatment are discussed.

Autoregulation and CO2-reactivity can be impaired independently of each other in many brain insults, the so-called 'dissociated vasoparalysis'. The theoretical combination of preserved CO2-reactivity and impaired or abolished autoregulation can have many clinical implications in the daily management of brain injured patients. To optimize their treatment, a bedside assessment of autoregulation and CO2-reactivity is desirable. When cerebral metabolic rate of oxygen is constant, changes in arterio-jugular differences of oxygen (AVDO2) reflect changes in CBF. In these situations relative changes in AVDO2 can be viewed as inverse changes in CBF and used as an evaluation method of CO2-reactivity and autoregulation. In 39 consecutive severe head injury patients with a mean age of 28 +/- 17 years and a diffuse brain injury, cerebrovascular response to changes in pCO2 was tested in the acute phase after injury (18 +/- 8 hours). In 28 of those cases autoregulation was also assessed. A relative CBF value (1/AVDO2) was calculated from baseline AVDO2 and was expressed as 100%. Changes in 1/AVDO2 after inducing pCO2 changes give a good estimate of changes in global CBF. Two different indexes were calculated for CO2-reactivity: 1) absolute CO2-reactivity (CO2RABS) and 2) percentage reactivity (CO2R%). CO2R% was used to separate patients with impaired/abolished CO2-reactivity from those with preserved CO2-reactivity. Patients with CO2R% above 1% were considered in the intact CO2-reactivity group and patients in whom CO2R% was below or equal to 1% were included in the impaired/abolished CO2-reactivity group. Only five cases (12.8%) presented an impaired/abolished CO2-reactivity. AVDO2 response to induced hypertension was studied in a subset of 28 patients. Phenylephrine was used to increase MABP about 25%. All AVDO2 values were corrected for changes in pCO2. Patients with changes in 1/AVDO2 less than or equal to 20% were included in the intact autoregulation group. Patients with estimated CBF changes above 20% were classified as having an impaired autoregulation (impaired/abolished). In 12 patients (43%) autoregulation was intact. In the remaining 16 patients (57%) autoregulation was imparied. Of the 28 cases, CO2-reactivity was impaired in only five cases. All patients with an impaired CO2-reactivity also had an impaired autoregulation. Monitoring relative changes in AVDO2 permits a reliable study of CO2-reactivity and autoregulation at the bedside. Introducing these variables into the day-to-day management should be considered in treatment protocols.

Ischaemic brain lesions still have a high prevalence in fatally head injured patients and are the single most important cause of secondary brain damage. The present study was undertaken to explore the acute phase of severely head injured patients in order to detect early ischaemia using Robertson's approach of estimating cerebral blood flow (CBF) from calculated arterio-jugular differences of oxygen (AVDO2), lactates (AVDL), and the lactate-oxygen index (LOI). Twenty-eight cases with severe head injury were included (Glasgow Coma Scale Score below or equal to 8). All patients but one had a non-missile head injury. All the patients had a diffuse brain injury according to the admission CT scan. ICP measured at the time of admission was below 20 mmHg in 17 cases (61%). All patients were evaluated with the ischaemia score (IS) devised in our center to evaluate risk factors for developing ischaemia. Mean time from injury to the first AVDO2/AVDL study was 23.9 +/- 9.9 hours. According to Robertson's criteria, 13 patients (46%) had a calculated LOI (-AVDL/AVDO2) value above or equal to 0.08 and therefore an ischaemia/infarction pattern in the first 24 hours after the accident. Of the 15 patients without the ischaemia/infarction pattern, in three cases the CBF was below the metabolic demands and therefore in a situation of compensated hypoperfusion. No patient in our series had hyperaemia. Comparing different variables in ischaemic and non-ischaemic patients, only arterial haemoglobin and ischaemia score (IS) was significantly different in both groups. The ischaemia score had mean of 4.3 +/- 1.7 in the ischaemic group and 2.7 +/- 1.4 in non-ischaemic patients (p = 0.01). It is concluded that ischaemia is highly prevalent in the early period after severe head injury. Factors potentially responsible of early ischaemia are discussed.