Dopaminergic brainstem disconnection is common to pharmacological and pathological consciousness perturbation.

Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA-PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA-PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem-cortical interplay for consciousness.

Reduced emergent character of neural dynamics in patients with a disrupted connectome.

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as "Integrated Information Decomposition," which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems - including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients' structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be related to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

Network dynamics scale with levels of awareness.

Small world topologies are thought to provide a valuable insight into human brain organisation and consciousness. However, functional magnetic resonance imaging studies in consciousness have not yielded consistent results. Given the importance of dynamics for both consciousness and cognition, here we investigate how the diversity of small world dynamics (quantified by sample entropy; dSW-E1) scales with decreasing levels of awareness (i.e., sedation and disorders of consciousness). Paying particular attention to result reproducibility, we show that dSW-E is a consistent predictor of levels of awareness even when controlling for the underlying functional connectivity dynamics. We find that dSW-E of subcortical, and cortical areas are predictive, with the former showing higher and more robust effect sizes across analyses. We find that the network dynamics of intermodular communication in the cerebellum also have unique predictive power for levels of awareness. Consequently, we propose that the dynamic reorganisation of the functional information architecture, in particular of the subcortex, is a characteristic that emerges with awareness and has explanatory power beyond that of the complexity of dynamic functional connectivity.

Metabolic derangements are associated with impaired glucose delivery following traumatic brain injury.

Metabolic derangements following traumatic brain injury are poorly characterized. In this single-centre observational cohort study we combined 18F-FDG and multi-tracer oxygen-15 PET to comprehensively characterize the extent and spatial pattern of metabolic derangements. Twenty-six patients requiring sedation and ventilation with intracranial pressure monitoring following head injury within a Neurosciences Critical Care Unit, and 47 healthy volunteers were recruited. Eighteen volunteers were excluded for age over 60 years (n = 11), movement-related artefact (n = 3) or physiological instability during imaging (n = 4). We measured cerebral blood flow, blood volume, oxygen extraction fraction, and 18F-FDG transport into the brain (K1) and its phosphorylation (k3). We calculated oxygen metabolism, 18F-FDG influx rate constant (Ki), glucose metabolism and the oxygen/glucose metabolic ratio. Lesion core, penumbra and peri-penumbra, and normal-appearing brain, ischaemic brain volume and k3 hotspot regions were compared with plasma and microdialysis glucose in patients. Twenty-six head injury patients, median age 40 years (22 male, four female) underwent 34 combined 18F-FDG and oxygen-15 PET at early, intermediate, and late time points (within 24 h, Days 2-5, and Days 6-12 post-injury; n = 12, 8, and 14, respectively), and were compared with 20 volunteers, median age 43 years (15 male, five female) who underwent oxygen-15, and nine volunteers, median age 56 years (three male, six female) who underwent 18F-FDG PET. Higher plasma glucose was associated with higher microdialysate glucose. Blood flow and K1 were decreased in the vicinity of lesions, and closely related when blood flow was <25 ml/100 ml/min. Within normal-appearing brain, K1 was maintained despite lower blood flow than volunteers. Glucose utilization was globally reduced in comparison with volunteers (P < 0.001). k3 was variable; highest within lesions with some patients showing increases with blood flow <25 ml/100 ml/min, but falling steeply with blood flow lower than 12 ml/100 ml/min. k3 hotspots were found distant from lesions, with k3 increases associated with lower plasma glucose (Rho -0.33, P < 0.001) and microdialysis glucose (Rho -0.73, P = 0.02). k3 hotspots showed similar K1 and glucose metabolism to volunteers despite lower blood flow and oxygen metabolism (P < 0.001, both comparisons); oxygen extraction fraction increases consistent with ischaemia were uncommon. We show that glucose delivery was dependent on plasma glucose and cerebral blood flow. Overall glucose utilization was low, but regional increases were associated with reductions in glucose availability, blood flow and oxygen metabolism in the absence of ischaemia. Clinical management should optimize blood flow and glucose delivery and could explore the use of alternative energy substrates.

Single Center Experience in Cerebrospinal Fluid Dynamics Testing.

Normal pressure hydrocephalus is more complex than a simple disturbance of the cerebrospinal fluid (CSF) circulation. Nevertheless, an assessment of CSF dynamics is key to making decisions about shunt insertion, shunt malfunction, and for further management if a patient fails to improve. We summarize our 25 years of single center experience in CSF dynamics assessment using pressure measurement and analysis. 4473 computerized infusion tests have been performed. We have shown that CSF infusion studies are safe, with incidence of infection at less than 1%. Raised resistance to CSF outflow positively correlates (p < 0.014) with improvement after shunting and is associated with disturbance of cerebral blood flow and its autoregulation (p < 0.02). CSF infusion studies are valuable in assessing possible shunt malfunction in vivo and for avoiding unnecessary revisions. Infusion tests are safe and provide useful information for clinical decision-making for the management of patients suffering from hydrocephalus.

Coupling of CSF and sagittal sinus pressure in adult patients with pseudotumour cerebri.

OBJECTIVE: Pseudotumour cerebri syndrome (PTCS including idiopathic intracranial hypertension) is characterised by the symptoms and signs of raised cerebrospinal fluid pressure (CSFp) in the absence of ventricular dilatation or an intracranial mass lesion. Its aetiology is unknown in the majority of cases but there is much evidence for impaired CSF absorption. Traditionally, sagittal sinus pressure has been considered to be independent of CSF pressure in adults. However, the discovery of stenoses of intracranial venous sinuses and introduction of venous sinus stenting has highlighted the importance of the venous drainage in PTCS. In this study, we have explored the relationship between CSFp and SSp before and during a CSF infusion test and during CSF drainage. MATERIALS AND METHODS: Ten patients (9 females:1 male) with PTCS underwent infusion studies in parallel with direct retrograde cerebral venography. Both SSp and CSFp were recorded at a baseline and during CSFp elevation in a course of a CSF infusion test. The drainage of CSF after the CSF infusion was performed in 7 patients. In 5 cases, jugular venous pressure was also measured. RESULTS: CSFp and SSp including their amplitudes correlated significantly and strongly both at baseline (R = 0.96; p = 0.001) and during infusion (R = 0.92; p = 0.0026). During drainage, this correlation was maintained until SSp reached a stable value, whereas CSFp continued to decrease. CONCLUSIONS: In this series of ten patients with PTCS, CSFp and SSp were coupled, both at baseline and during infusion. The implications of such coupling for the calculation of CSF outflow resistance are discussed.

Shunt infusion studies: impact on patient outcome, including health economics.

OBJECTIVES: The diagnosis of shunt malfunction is often not straightforward. We have explored, in symptomatic shunted patients with hydrocephalus or pseudotumour cerebri syndrome (PTCS), the accuracy of CSF infusion tests in differentiating a functioning shunt from one with possible problems, and the health economic consequences. METHODS: Participants: hydrocephalus/PTCS patients with infusion tests performed from January 2013 until December 2015. We followed patients up after 6 and 12 months from the test to determine whether they had improved, had persisting symptoms or had required urgent revision. We calculated the total cost savings of revision versus infusion tests and standard protocol of revision and ICP monitoring versus infusion tests. RESULTS: Three hundred sixty-five shunt infusion tests had been performed where a shunt prechamber/reservoir was present. For hydrocephalus patients, more than half of the tests (~ 55%, 155 out of 280) showed no shunt malfunction versus 125 with possible malfunction (ages 4 months to 90 years old). For PTCS patients aged 10 to 77 years old, 47 had possible problems and 38 no indication for shunt malfunction. Overall, > 290 unnecessary revisions were avoided over 3 years' time. Two hundred fifty-eight (> 85%) of those non-surgically managed, remained well, did not deteriorate and did not require surgery. No infections were associated with infusion studies. For Cambridge, the overall savings from avoiding revisions was £945,415 annually. CONCLUSIONS: Our results provide evidence of the importance of shunt testing in vivo to confirm shunt malfunction. Avoiding unnecessary shunt revisions carries a strong health benefit for patients that also translates to a significant financial benefit for the National Health Service and potentially for other healthcare systems worldwide.

Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension.

BACKGROUND: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. METHODS: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. RESULTS: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). CONCLUSIONS: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).

Current epidemiology of cerebrospinal fluid shunt surgery in the UK and Ireland (2004-2013).

OBJECTIVES: To determine current epidemiology and clinical characteristics of cerebrospinal fluid (CSF) shunt surgery, including revisions. METHODS: A retrospective, multicentre, registry-based study was conducted based on 10 years' data from the UK Shunt Registry, including primary and revision shunting procedures reported between 2004 and 2013. Incidence rates of primary shunts, descriptive statistics and shunt revision rates were calculated stratified by age group, geographical region and year of operation. RESULTS: 41 036 procedures in 26 545 patients were submitted during the study period, including 3002 infants, 4389 children and 18 668 adults. Procedures included 20 947 (51.0%) primary shunt insertions in 20 947 patients, and 20 089 (49.0%) revision procedures. Incidence rates of primary shunt insertions for infants, children and adults were 39.5, 2.4 and 3.5 shunts per 100 000 person-years, respectively. These varied by geographical subregion and year of operation. The most common underlying diagnoses were perinatal intraventricular haemorrhage (35.3%) and malformations (33.9%) in infants, tumours (40.5%) and malformations (16.3%) in children, and tumours (24.6%), post-haemorrhagic hydrocephalus (16.2%) and idiopathic normal pressure hydrocephalus (14.2%) in adults. Ninety-day revision rates were 21.9%, 18.6% and 12.8% among infants, children and adults, respectively, while first-year revision rates were 31.0%, 25.2% and 17.4%. The main reasons for revision were underdrainage and infection, but overdrainage and mechanical failure continue to pose problems. CONCLUSIONS: Our report informs patients, carers, clinicians, providers and commissioners of healthcare, researchers and industry of the current epidemiology of shunting for CSF disorders, including the potential risks of complications and frequency of revision.

Structural correlates of cognitive impairment in normal pressure hydrocephalus.

OBJECTIVES: The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures. METHODS: Fourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency and measures of apathy and depression pre- and postshunt surgery. Additionally, patients underwent 3 Tesla T1-weighted magnetic resonance imaging at baseline and 6 months postoperatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients. RESULTS: Volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens (NAcc) were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy. CONCLUSIONS: Striatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH.

Do ICP-Derived Parameters Differ in Vegetative State from Other Outcome Groups After Traumatic Brain Injury?

OBJECTIVE: In nearly 1,000 traumatic brain injury (TBI) patients monitored in the years 1992-2014, we identified 18 vegetative state (VS) cases. Our database provided access to continuous computer-recorded signals, which we used to compare primary signals, intracranial pressure (ICP)-derived indices and demographic data between VS patients, patients who survived but who were not VS (S), and patients who died (D). METHOD: Mean values of ICP, arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) from the whole monitoring periods were compared between the different outcome groups. Secondary indices included pressure reactivity index (PRx), the magnitude of slow ICP vasogenic waves, the pulse amplitude of the first harmonic component of the ICP waveform and heart rate (HR). RESULTS: Mean blood pressure was lowest in the VS group-significantly in comparison to those who died (p = 0.02) and almost significantly (p = 0.1) in comparison to the patients who survived. Mean ICP in VS patients was lower than those who died (VS, 13 ± 5 mmHg; D, 22 ± 14 mmHg; p < 0.001), but not significantly different from those who survived (p > 0.05). The magnitude of slow vasogenic ICP waves was the same in VS patients and those who died, but significantly lower than in those who survived (S, 1.04 ± 0.57 mmHg; VS, 0.74 ± 0.45; p = 0.01). CONCLUSION: Patients who progress to a VS differ from non-VS survivors in displaying decreased power of slow vasogenic waves and from those who die by not experiencing as high a burden of intracranial hypertension.

Are Slow Waves of Intracranial Pressure Suppressed by General Anaesthesia?

OBJECTIVES: Slow waves of intracranial pressure (ICP) are spontaneous oscillations with a frequency of 0.3-4 cycles/min. They are often associated with pathological conditions, following vasomotor activity in the cranial enclosure. This study quantifies the effects of general anaesthesia (GA) on the magnitude of B-waves compared with natural sleep and the conscious state. MATERIALS AND METHODS: Four groups of 30 patients each were formed to assess the magnitude of slow waves. Group A and group B consisted of normal pressure hydrocephalus (NPH) patients, each undergoing cerebrospinal fluid (CSF) infusion studies, conscious and under GA respectively. Group C comprised conscious, naturally asleep hydrocephalic patients undergoing overnight ICP monitoring; group D, which included deeply sedated head injury patients monitored in the intensive care unit (ICU), was compared with group C. RESULTS: The average amplitude for group A patients was higher (0.23 ± 0.10 mmHg) than that of group B (0.15 ± 0.10 mmHg; p = 0.01). Overnight magnitude of slow waves was higher in group C (0.20 ± 0.13 mmHg) than in group D (0.11 ± 0.09 mmHg; p = 0.002). CONCLUSION: Slow waves of ICP are suppressed by GA and deep sedation. When using slow waves in clinical decision-making, it is important to consider the patients' level of consciousness to avoid incorrect therapeutic and management decisions.

Is There a Link Between ICP-Derived Infusion Test Parameters and Outcome After Shunting in Normal Pressure Hydrocephalus?

OBJECTIVE: The term "hydrocephalus" encompasses a range of disorders characterised by clinical symptoms, abnormal brain imaging and derangement of cerebrospinal fluid (CSF) dynamics. The ability to elucidate which patients would benefit from CSF diversion (a shunt or third ventriculostomy) is often unclear. Similar difficulties are encountered in shunted patients to predict the scope for improvement by shunt re-adjustment or revision. MATERIALS AND METHODS: We compared retrospective pre-shunting infusion test results performed in 310 adult patients diagnosed with normal pressure hydrocephalus (NPH) and their improvement after shunting. RESULTS: Resistance to CSF outflow correlated significantly with improvement (p < 0.05). Other markers known from the literature, such as amplitude in CSF pulse pressure, the slope of the amplitude-pressure regression line, or elasticity did not show any correlation with outcome. CONCLUSION: Outcome following shunting in adult NPH is associated with resistance to CSF outflow; however, the latter cannot be taken as an absolute predictor of shunt response.

Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury.

PRIMARY OBJECTIVE: To investigate functional improvement late (>6 months) after traumatic brain injury (TBI). To this end, we conducted a double-blind, placebo-controlled experimental medicine study to test the hypothesis that a widely used cognitive enhancer would benefit patients with TBI. RESEARCH DESIGN: We focused on motor control function using a sequential finger opposition fMRI paradigm in both patients and age-matched controls. METHODS AND PROCEDURES: Patients' fMRI and DTI scans were obtained after randomised administration of methylphenidate or placebo. Controls were scanned without intervention. To assess differences in motor speed, we compared reaction times from the baseline condition of a sustained attention task. MAIN OUTCOMES AND RESULTS: Patients' reaction times correlated with wide-spread motor-related white matter abnormalities. Administration of methylphenidate resulted in faster reaction times in patients, which were not significantly different from those achieved by controls. This was also reflected in the fMRI findings in that patients on methylphenidate activated the left inferior frontal gyrus significantly more than when on placebo. Furthermore, stronger functional connections between pre-/post-central cortices and cerebellum were noted for patients on methylphenidate. CONCLUSIONS: Our findings suggest that residual functionality in patients with TBI may be enhanced by a single dose of methylphenidate.

Thalamic and extrathalamic mechanisms of consciousness after severe brain injury.

OBJECTIVE: What mechanisms underlie the loss and recovery of consciousness after severe brain injury? We sought to establish, in the largest cohort of patients with disorders of consciousness (DOC) to date, the link between gold standard clinical measures of awareness and wakefulness, and specific patterns of local brain pathology-thereby possibly providing a mechanistic framework for patient diagnosis, prognosis, and treatment development. METHODS: Structural T1-weighted magnetic resonance images were collected, in a continuous sample of 143 severely brain-injured patients with DOC (and 96 volunteers), across 2 tertiary expert centers. Brain atrophy in subcortical regions (bilateral thalamus, basal ganglia, hippocampus, basal forebrain, and brainstem) was assessed across (1) healthy volunteers and patients, (2) clinical entities (eg, vegetative state, minimally conscious state), (3) clinical measures of consciousness (Coma Recovery Scale-Revised), and (4) injury etiology. RESULTS: Compared to volunteers, patients exhibited significant atrophy across all structures (p < 0.05, corrected). Strikingly, we found almost no significant differences across clinical entities. Nonetheless, the clinical measures of awareness and wakefulness upon which differential diagnosis rely were systematically associated with tissue atrophy within thalamic and basal ganglia nuclei, respectively; the basal forebrain was atrophied in proportion to patients' response to sensory stimulation. In addition, nontraumatic injuries exhibited more extensive thalamic atrophy. INTERPRETATION: These findings provide, for the first time, a grounding in pathology for gold standard behavior-based clinical measures of consciousness, and reframe our current models of DOC by stressing the different links tying thalamic mechanisms to willful behavior and extrathalamic mechanisms to behavioral (and electrocortical) arousal.

Who Needs a Revision? 20 Years of Cambridge Shunt Lab.

Shunt testing independent of manufacturers provides knowledge that can significantly improve the management of patients with hydrocephalus. The Cambridge Shunt Evaluation Laboratory was created 20 years ago. Thanks to financial support from the Department of Health (1993-1998), all shunts in use in the UK were systematically evaluated, with "blue reports" being published. Later new devices were tested as they appeared in public domain.Twenty-six models have been evaluated. The majority of the valves had a non-physiologically low hydrodynamic resistance that may result in over-drainage, both related to posture and during nocturnal cerebral vasogenic waves. A long distal catheter increases the resistance of these valves by 100-200 %. Drainage through valves without a siphon-preventing mechanism is very sensitive to body posture. Shunts with siphon-preventing accessories offer a reasonable resistance to negative outlet pressure. Bench parameters were used to test shunt performance in vivo using infusion tests. A criterion for correctly performing a shunt procedure was established. Pressure measured in the shunt prechamber during the plateau phase of infusion should not remain more than 5 mmHg above the le shunt's operating pressure plus hydrodynamic resistance of the valve multiplied by the infusion rate. "Critical levels" for every shunt and every performance level have been used in the shunt testing wizard of ICM+ software.

Continuous Monitoring of the Complexity of Intracranial Pressure After Head Injury.

Multiscale entropy (MSE) has been increasingly used to investigate the complexity of biological signals. Our previous study demonstrated that the complexity of mean intracranial pressure (ICP), assessed by MSE based on the whole recording periods, is associated with the outcome after traumatic brain injury (TBI). To improve the feasibility of MSE in a clinical setting, this study examined whether the complexity of ICP waveforms based on shorter periods could be a reliable predictor of the outcome in patients with TBI. Results showed that the complexity of ICP slow waves, calculated in 3-h moving windows, correlates with the outcome of patients with TBI. Thus, the complexity of ICP may be a promising index to be incorporated into multimodal monitoring in patients with TBI.

The Correlation Between Intracranial Pressure and Cerebral Blood Flow Velocity During ICP Plateau Waves.

We previously showed that the flow-ICP index (Fix), a moving correlation coefficient between intracranial pressure (ICP) and cerebral blood flow velocity (CBFV), had marginally greater prognostic value for patients with traumatic brain injury (TBI) than an index of cerebral autoregulation (mean index, Mx). The aim of this study was to further examine the clinical and physiological relevance of Fix by studying its behaviour during ICP plateau waves in patients with TBI. Twenty-nine recordings of CBFV made during ICP plateau waves were analysed. Both Mx and Fix at baseline and peak ICP were significantly different, although the magnitude of Fix change was slightly greater. The correlation between Fix and cerebral perfusion pressure (CPP) was stronger than that between Mx and CPP. Unlike in our previous study, plotting Fix against CPP revealed a peak value in the range of "optimal" CPP, as indicated by the Mx versus CPP plot. The findings suggest that during periods of reduced CPP caused by plateau waves, the dynamic behaviour of Fix is similar to that of a measure of cerebral autoregulation. This conclusion needs to be verified against similar results obtained during episodes of supranormal CPP.

Noninvasive Assessment of ICP: Evaluation of New TBI Data.

BACKGROUND: In a previously introduced mathematical model, intracranial pressure (ICP) was noninvasively assessed using cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP). In this study this method is evaluated using new data from patients with traumatic brain injury (TBI). MATERIALS AND METHODS: Three hundred fifteen data recordings of 137 patients (114 men; age 14-78 years, mean age 37 ± 17 years) with severe TBI were studied. CBFV, ABP, and invasively assessed ICP were simultaneously recorded for 1 h. Noninvasive ICP (nICP) was calculated and compared with ICP. RESULTS: On 315 recordings, average deviation between ICP and nICP (± standard deviation) was 4.9 ± 3.3 mmHg. The standard deviation of differences (ICP - nICP) was 5.6 mmHg. The 95 % confidence interval of ICP prediction ranged from -9.6 to 12.3 mmHg. Mean ICP was 16.7 mmHg and mean nICP was 18.0 mmHg. When nICP was adjusted by their difference 1.3 mmHg (nICPadj = nICP - 1.3), the 95 % confidence limits of ICP prediction became ±11.0 mmHg. In recordings with highly dynamic ICP signals (n = 27), ICP and nICP correlated on average with R = 0.51 ± 0.47. CONCLUSIONS: nICP assessment showed reasonable accuracy and may be used in clinical studies of patients without any indication for ICP probe implantation.

Patient-Specific Thresholds and Doses of Intracranial Hypertension in Severe Traumatic Brain Injury.

Based on continuous monitoring of the pressure reactivity index (PRx), we defined individualized intracranial pressure (ICP) thresholds by graphing the relationship between ICP and PRx. We hypothesized that an "ICP dose" based on individually assessed ICP thresholds might correlate more closely with 6-month outcome compared with ICP doses derived from the recommended universal thresholds of 20 and 25 mmHg. Data from 327 patients with severe traumatic brain injury (TBI) were analyzed. ICP doses were computed as the cumulative area under the curve above the defined thresholds in graphing ICP versus time. The term Dose 20 (D20) was used to refer to an ICP threshold of 20 mm Hg. The markers D25 and DPRx were calculated similarly. The discriminative ability of each dose with regard to mortality was assessed by receiver operating characteristics analysis using fivefold cross-validation (CV). DPRx was found to be the best discriminator of mortality, despite the fact that D20 was twice as large as DPRx. Individualized doses of intracranial hypertension were stronger predictors of mortality than doses derived from the universal thresholds of 20 and 25 mm Hg. The PRx could offer a method of individualizing the ICP threshold.