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Papers by John Pickard

Research paper thumbnail of Head injury monitoring using cerebral microdialysis and Paratrend multiparameter sensors

Zentralblatt für Neurochirurgie, 2000

Following head injury complex pathophysiological changes occur in brain metabolism. The objective... more Following head injury complex pathophysiological changes occur in brain metabolism. The objective of the study was to monitor brain metabolism using the Paratrend multiparameter sensor and microdialysis catheters. Following approval by the Local Ethics Committee and consent from the relatives, patients with severe head injury were studied using a triple bolt inserted into the frontal region, transmitting an intracranial pressure monitor, microdialysis (10 mm or 30 mm membrane; glucose, lactate, pyruvate, glutamate) catheter and Paratrend multiparameter (oxygen, carbon dioxide, pH and temperature) sensor. A Paratrend sensor was also inserted into the femoral artery for continuous blood gas analysis. 21 patients were studied with cerebral microdialysis for a total of 91 monitoring days (range 19 hours to 12 days). Of these, 14 patients were also studied with cerebral and arterial Paratrend sensors. The mean (+/- 95% confidence intervals) arterial and cerebral oxygen levels were 123 +/- 10.9 mmHg and 27.9 +/- 5.71 mmHg respectively. The arterial and cerebral carbon dioxide levels were 34.3 +/- 2.35 mmHg and 45.3 +/- 3.07 mmHg respectively. Episodes of systemic hypoxia and hypotension resulting in falls in cerebral oxygen and rises in cerebral carbon dioxide were rapidly detected by the arterial and cerebral Paratrend sensors. Systemic pyrexia was reflected in the brain with the cerebral Paratrend sensor reading 0.17 degree C (mean) higher than the arterial sensor. Elevations of cerebral glucose were detected, but the overall cerebral glucose was low (mean 1.57 +/- 0.53 mM 10 mm membrane; mean 1.95 +/- 0.68 mM 30 mm membrane) with periods of undetectable glucose in 6 patients. Lactate concentrations (mean 5.08 +/- 0.73 mM 10 mm membrane; mean 8.27 +/- 1.31 mM 30 mm membrane) were higher than glucose concentrations in all patients. The lactate/pyruvate ratio was 32.1 +/- 5.16 for the 10 mm membrane and 30.6 +/- 2.17 for the 30 mm membrane. Glutamate concentrations varied between patients (mean 15.0 +/- 10.5 microM 10 mm membrane; mean 28.8 +/- 17.8 microM 30 mm membrane). The combination of microdialysis catheters and Paratrend sensors enabling the monitoring of substrate delivery and brain metabolism, and the detection of secondary metabolic insults has the potential to assist in the management of head-injured patients.

Research paper thumbnail of Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension

The New England journal of medicine, Sep 7, 2016

Background The effect of decompressive craniectomy on clinical outcomes in patients with refracto... more 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 re...

Research paper thumbnail of A hierarchy of event-related potential markers of auditory processing in disorders of consciousness

NeuroImage: Clinical, 2016

The version in the Kent Academic Repository may differ from the final published version. Users ar... more The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Research paper thumbnail of Spectral Signatures of Reorganised Brain Networks in Disorders of Consciousness

PLoS Computational Biology, 2014

Theoretical advances in the science of consciousness have proposed that it is concomitant with ba... more Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment.

Research paper thumbnail of Continuous Assessment of the Cerebral Vasomotor Reactivity in Head Injury

Neurosurgery, 1997

Academ ic Neurosurgical Unit (M C, PS, PK, RJL, JDP) and Department of Anaesthesia (DM), Addenbro... more Academ ic Neurosurgical Unit (M C, PS, PK, RJL, JDP) and Department of Anaesthesia (DM), Addenbrooke's H ospital, C am bridge, England O B JEC T IV E: C ereb ro vascu lar vasom otor reactivity reflects changes in smooth m uscle tone in the arterial w all in response to changes in transm ural pressure or the concentration of carbon dioxide in blood. W e investigated w hether slow w aves in arterial blood pressure (ABP) and intracranial pressure (ICP) may be used to derive an index that reflects the reactivity of vessels to changes in ABP. M ET H O D S: A method for the continuous m onitoring of the association between slow spontaneous w aves in IC P and arterial pressure w as adopted in a group of 82 patients w ith head injuries. A BP, IC P, and transcranial doppler blood flow velocity in the m iddle cerebral artery w as recorded daily (20-to 120-m in time periods). A Pressure-Reactivity Index (PRx) w as calculated as a moving correlation coefficient between 40 consecutive sam ples of values for ICP and A BP averaged for a period of 5 seconds. A m oving correlation coefficient (Mean Index) between spontaneous fluctuations of mean flow velocity and cerebral perfusion pressure, w hich w as previously reported to describe cerebral blood flow autoregulation, w as also calcu lated. RESULTS: A positive PRx correlated w ith high IC P (r = 0 .3 6 6 ; P < 0 .0 01), low adm ission G lasg o w C o m a Scale score

Research paper thumbnail of Monitoring cerebral autoregulation after head injury. Which component of transcranial Doppler flow velocity is optimal?

Neurocritical Care, 2011

Background Cerebral autoregulation assessed using transcranial Doppler (TCD) mean flow velocity (... more Background Cerebral autoregulation assessed using transcranial Doppler (TCD) mean flow velocity (FV) in response to various physiological challenges is predictive of outcome after traumatic brain injury (TBI). Systolic and diastolic FV have been explored in other diseases. This study aims to evaluate the systolic, mean and diastolic FV for monitoring autoregulation and predicting outcome after TBI. Methods 300 head-injured patients with blood pressure (ABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and FV recordings were studied. Autoregulation was calculated as a correlation of slow changes in diastolic, mean and systolic components of FV with CPP (Dx, Mx, Sx, respectively) and ABP (Dxa, Mxa, Sxa, respectively) from 30 consecutive 10 s averaged values. The relationship with age, severity of injury, and dichotomized 6 months outcome was examined. Results Association with outcome was significant for Mx and Sx. For favorable/unfavorable and death/survival outcomes Sx showed the strongest association (F = 20.11; P = 0.00001 and F = 13.10; P = 0.0003, respectively). Similarly, indices derived from ABP demonstrated the highest discriminatory value when systolic FV was used (F = 12.49; P = 0.0005 and F = 5.32; P = 0.02, respectively). Indices derived from diastolic FV demonstrated significant differences (when calculated using CPP) only when comparing between fatal and non-fatal outcome. Conclusions Systolic flow indices (Sx and Sxa) demonstrated a stronger association with outcome than the mean flow indices (Mx and Mxa), irrespective of whether CPP or ABP was used for calculation.

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

Journal of Neurotrauma, 2010

Monitoring of cerebrovascular pressure reactivity (PRx) has diagnostic and prognostic value in he... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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.

Research paper thumbnail of A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

Journal of Neurosurgery, 1998

Object. The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroi... more Object. The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. Methods. A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4–8) and 15% (163) had sustained a moderate head injury (GCS score 9–12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p = 0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p = 0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head inj...

Research paper thumbnail of Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography

Journal of Neurosurgery, 1998

Object. The authors studied the reliability of a new method for noninvasive assessment of cerebra... more Object. The authors studied the reliability of a new method for noninvasive assessment of cerebral perfusion pressure (CPP) in head-injured patients in which mean arterial blood pressure (ABP) and transcranial Doppler middle cerebral artery mean and diastolic flow velocities are measured. Methods. Cerebral perfusion pressure was estimated (eCPP) over periods of continuous monitoring (20 minutes—2 hours, 421 daily examinations) in 96 head-injured patients (Glasgow Coma Scale score < 13) who were admitted to the intensive care unit. All patients were sedated, paralyzed, and ventilated. The eCPP and the measured CPP (ABP minus intracranial pressure, measured using an intraparenchymal microsensor) were compared. The correlation between eCPP and measured CPP was r = 0.73; p < 10−6. In 71% of the examinations, the estimation error was less than 10 mm Hg and in 84% of the examinations, the error was less than 15 mm Hg. The method had a high positive predictive power (94%) for detecti...

Research paper thumbnail of Evaluation of the transient hyperemic response test in head-injured patients

Journal of Neurosurgery, 1997

✓ The transient hyperemic response test has been shown to provide an index of cerebral autoregula... more ✓ The transient hyperemic response test has been shown to provide an index of cerebral autoregulation in healthy individuals and in patients who have suffered a subarachnoid hemorrhage. In this study, the test was applied to patients who had received a severe head injury, and the value of the test was assessed by comparing its result with the individual's clinical condition (Glasgow Coma Scale [GCS] score), cerebral perfusion pressure (CPP), transcranial Doppler wave form—derived index for cerebral autoregulation (relationship between the CPP and the middle cerebral artery flow velocity), and outcome (Glasgow Outcome Scale [GOS] score). Forty-seven patients, aged 16 to 63 years, with head injuries were included in the study. Signals of intracranial pressure, arterial blood pressure, flow velocity, and cortical microcirculatory flux were digitized and recorded for a period of 30 minutes using special computer software. Two carotid compressions were performed at the beginning of e...

Research paper thumbnail of Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: a pilot study

Journal of Neurology, Neurosurgery & Psychiatry, 1998

The objective of this study was to analyse the temporal course of the jugular venousarterial grad... more The objective of this study was to analyse the temporal course of the jugular venousarterial gradient of S-100B protein after severe head injury and the correlation between the absolute concentrations of serum S-100B protein and outcome, CT findings, and clinical variables. Fifteen patients were included in this pilot study. All patients were treated according to a standard therapy protocol targeted to maintain cerebral perfusion pressure. The serum concentration of S-100 protein was measured daily for five consecutive days after injury by a monoclonal two site immunoluminometric assay. Nine patients showed favourable and six unfavourable outcome after 6 months with a mortality rate of 33% (five patients). The mean gradient between jugular venous and arterial blood was 8.2% (p<0.05). Patients showing an unfavourable outcome had significantly higher jugular venous or arterial S-100 values compared with those with a favourable outcome (jugular venous S-100B 2.78 µg/l v 1.22 µg/l, p<0.05; arterial S-100B 2.48 µg/l v 1.19 µg/l, p<0.05). All patients with an initial or secondary increase in S-100B value of >2 µg/l were found to have an unfavourable outcome. S-100B was found to be an independent predictor of outcome after severe head injury. The persisting increase of S-100B for three to five days even in patients with favourable outcome and no signs of secondary insults might reflect continuing damage to the bloodbrain barrier or ongoing glial cell death.

Research paper thumbnail of Contribution of mathematical modelling to the interpretation of bedside tests of cerebrovascular autoregulation

Journal of Neurology, Neurosurgery & Psychiatry, 1997

Objectives-Cerebral haemodynamic responses to short and longlasting episodes of decreased cerebra... more Objectives-Cerebral haemodynamic responses to short and longlasting episodes of decreased cerebral perfusion pressure contain information about the state of autoregulation of cerebral blood flow. Mathematical simulation may help to elucidate which of the indices, that can be derived using transcranial Doppler ultrasonography and trends of intracranial pressure and blood pressure, are useful in clinical tests of autoregulatory reserve. Methods-Time dependent interactions between pressure, flow, and volume of cerebral blood and CSF were modelled using a set of non-linear diVerential equations. The model simulates changes in arterial blood inflow and storage, arteriolar and capillary blood flow controlled by cerebral autoregulation, venous blood storage and venous outflow modulated by changes in ICP, and CSF storage and reabsorption. The model was used to simulate patterns of blood flow during either short or longlasting decreases in cerebral perfusion pressure. These simulations can be considered as clinically equivalent to a short compression of the common carotid artery, systemic hypotension, and intracranial hypertension. Simulations were performed in autoregulating and nonautoregulating systems and compared with recordings obtained in patients. Results-After brief compression of the common carotid artery, a subsequent transient hyperaemia can be interpreted as evidence of intact autoregulation. During longlasting sustained hypoperfusion, a gradual increase in the systolic value of the blood flow velocity waveform along with a decrease in the diastolic value is specific for an autoregulating cerebrovascular system. Conclusion-Modelling studies help to interpret both clinical and experimental cerebral haemodynamic phenomena and their dependence on the state of autoregulation.

Research paper thumbnail of Commentary on Oh H. and Seo W. (2003) Sensory stimulation programme to improve recovery in comatose patients. Journal of Clinical Nursing 12, 394-404

Journal of Clinical Nursing, 2004

Research paper thumbnail of Early metabolic characteristics of lesion and nonlesion tissue after head injury

Journal of Cerebral Blood Flow & Metabolism, 2009

We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up i... more We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up in patients recovering from head injury. Early metabolic characteristics in these regions of interest (ROIs) were compared with physiology in healthy volunteers. Fourteen patients with severe head injury had positron emission tomography within 72 h, and magnetic resonance imaging at 3 to 18 months after injury. Cerebral blood flow (CBF), oxygen utilization (CMRO2), and oxygen extraction fraction (OEF) were all lower in lesion ROIs, compared with nonlesion and control ROIs ( P < 0.001); however, there was substantial overlap in physiology. Control ROIs showed close coupling among CBF, blood volume (CBV), and CMRO2, whereas relationships within lesion and nonlesion ROIs were abnormal. The relationship between CBF and CMRO2 generally remained coupled but the slope was reduced; that for CBF and OEF was variable; whereas that between CBF and CBV was highly variable. There was considerable h...

Research paper thumbnail of The Cytokine Response to Human Traumatic Brain Injury: Temporal Profiles and Evidence for Cerebral Parenchymal Production

Journal of Cerebral Blood Flow & Metabolism, 2010

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pat... more 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,...

Research paper thumbnail of Sustained moderate reductions in arterial CO2 after brain trauma Time-course of cerebral blood flow velocity and intracranial pressure

Intensive Care Medicine, 2004

Research paper thumbnail of Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury

Critical Care Medicine, 2002

C erebrovasCular pressure reactivity reflects the capability of smooth muscle tone in the walls o... more C erebrovasCular pressure reactivity reflects the capability of smooth muscle tone in the walls of cerebral arteries and arterioles to react to changes in transmural pressure (cerebral vessels constrict in response to an increase in CPP, and vice versa). Cerebro-vascular pressure reactivity represents a key element of cerebral autoregulation, although the two terms should not be used interchangeably because vascular responses can occur outside the range of cerebral autoregulation. 7,25 With increasing ABP, intact cerebrovascular pressure reactivity will lead to vasoconstriction and a reduction of cerebral blood volume. Under the condition of a finite pressure-volume compensatory reserve, this reduction of cerebral blood volume will produce a decrease in ICP, a condition that is usually not met in patients after a decompressive craniectomy or in those with an external ventricular drain. When cerebrovascular pressure reac

Research paper thumbnail of Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients

Critical Care Medicine, 2004

To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with a... more To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. Prospective randomized crossover trial. Neurosciences critical care unit of a university hospital. Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.

Research paper thumbnail of Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent

British Journal of Clinical Pharmacology, 2002

Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatmen... more Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into bene®t during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain. Methods Multimodality monitoring including cerebral and peripheral microdialysis was applied to ®ve head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min x1) intravenous loading infusion for 5 min followed by a slow (1 ml min x1) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bispectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids. Results Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients. Conclusions Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.

Research paper thumbnail of Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Brain, 2004

Recent changes in published guidelines for the management of patients with severe head injury are... more Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO 2) and oxygen extraction fraction (OEF) using 15 O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 6 4 to 90 6 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO 2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO 2 were associated with the greatest reduction in OEF (r 2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 6 16 to 5 6 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r 2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 6 1.5 versus 4.3 6 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO 2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO 2 and neuronal electrical function will require further study.

Research paper thumbnail of Head injury monitoring using cerebral microdialysis and Paratrend multiparameter sensors

Zentralblatt für Neurochirurgie, 2000

Following head injury complex pathophysiological changes occur in brain metabolism. The objective... more Following head injury complex pathophysiological changes occur in brain metabolism. The objective of the study was to monitor brain metabolism using the Paratrend multiparameter sensor and microdialysis catheters. Following approval by the Local Ethics Committee and consent from the relatives, patients with severe head injury were studied using a triple bolt inserted into the frontal region, transmitting an intracranial pressure monitor, microdialysis (10 mm or 30 mm membrane; glucose, lactate, pyruvate, glutamate) catheter and Paratrend multiparameter (oxygen, carbon dioxide, pH and temperature) sensor. A Paratrend sensor was also inserted into the femoral artery for continuous blood gas analysis. 21 patients were studied with cerebral microdialysis for a total of 91 monitoring days (range 19 hours to 12 days). Of these, 14 patients were also studied with cerebral and arterial Paratrend sensors. The mean (+/- 95% confidence intervals) arterial and cerebral oxygen levels were 123 +/- 10.9 mmHg and 27.9 +/- 5.71 mmHg respectively. The arterial and cerebral carbon dioxide levels were 34.3 +/- 2.35 mmHg and 45.3 +/- 3.07 mmHg respectively. Episodes of systemic hypoxia and hypotension resulting in falls in cerebral oxygen and rises in cerebral carbon dioxide were rapidly detected by the arterial and cerebral Paratrend sensors. Systemic pyrexia was reflected in the brain with the cerebral Paratrend sensor reading 0.17 degree C (mean) higher than the arterial sensor. Elevations of cerebral glucose were detected, but the overall cerebral glucose was low (mean 1.57 +/- 0.53 mM 10 mm membrane; mean 1.95 +/- 0.68 mM 30 mm membrane) with periods of undetectable glucose in 6 patients. Lactate concentrations (mean 5.08 +/- 0.73 mM 10 mm membrane; mean 8.27 +/- 1.31 mM 30 mm membrane) were higher than glucose concentrations in all patients. The lactate/pyruvate ratio was 32.1 +/- 5.16 for the 10 mm membrane and 30.6 +/- 2.17 for the 30 mm membrane. Glutamate concentrations varied between patients (mean 15.0 +/- 10.5 microM 10 mm membrane; mean 28.8 +/- 17.8 microM 30 mm membrane). The combination of microdialysis catheters and Paratrend sensors enabling the monitoring of substrate delivery and brain metabolism, and the detection of secondary metabolic insults has the potential to assist in the management of head-injured patients.

Research paper thumbnail of Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension

The New England journal of medicine, Sep 7, 2016

Background The effect of decompressive craniectomy on clinical outcomes in patients with refracto... more 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 re...

Research paper thumbnail of A hierarchy of event-related potential markers of auditory processing in disorders of consciousness

NeuroImage: Clinical, 2016

The version in the Kent Academic Repository may differ from the final published version. Users ar... more The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record.

Research paper thumbnail of Spectral Signatures of Reorganised Brain Networks in Disorders of Consciousness

PLoS Computational Biology, 2014

Theoretical advances in the science of consciousness have proposed that it is concomitant with ba... more Theoretical advances in the science of consciousness have proposed that it is concomitant with balanced cortical integration and differentiation, enabled by efficient networks of information transfer across multiple scales. Here, we apply graph theory to compare key signatures of such networks in high-density electroencephalographic data from 32 patients with chronic disorders of consciousness, against normative data from healthy controls. Based on connectivity within canonical frequency bands, we found that patient networks had reduced local and global efficiency, and fewer hubs in the alpha band. We devised a novel topographical metric, termed modular span, which showed that the alpha network modules in patients were also spatially circumscribed, lacking the structured long-distance interactions commonly observed in the healthy controls. Importantly however, these differences between graph-theoretic metrics were partially reversed in delta and theta band networks, which were also significantly more similar to each other in patients than controls. Going further, we found that metrics of alpha network efficiency also correlated with the degree of behavioural awareness. Intriguingly, some patients in behaviourally unresponsive vegetative states who demonstrated evidence of covert awareness with functional neuroimaging stood out from this trend: they had alpha networks that were remarkably well preserved and similar to those observed in the controls. Taken together, our findings inform current understanding of disorders of consciousness by highlighting the distinctive brain networks that characterise them. In the significant minority of vegetative patients who follow commands in neuroimaging tests, they point to putative network mechanisms that could support cognitive function and consciousness despite profound behavioural impairment.

Research paper thumbnail of Continuous Assessment of the Cerebral Vasomotor Reactivity in Head Injury

Neurosurgery, 1997

Academ ic Neurosurgical Unit (M C, PS, PK, RJL, JDP) and Department of Anaesthesia (DM), Addenbro... more Academ ic Neurosurgical Unit (M C, PS, PK, RJL, JDP) and Department of Anaesthesia (DM), Addenbrooke's H ospital, C am bridge, England O B JEC T IV E: C ereb ro vascu lar vasom otor reactivity reflects changes in smooth m uscle tone in the arterial w all in response to changes in transm ural pressure or the concentration of carbon dioxide in blood. W e investigated w hether slow w aves in arterial blood pressure (ABP) and intracranial pressure (ICP) may be used to derive an index that reflects the reactivity of vessels to changes in ABP. M ET H O D S: A method for the continuous m onitoring of the association between slow spontaneous w aves in IC P and arterial pressure w as adopted in a group of 82 patients w ith head injuries. A BP, IC P, and transcranial doppler blood flow velocity in the m iddle cerebral artery w as recorded daily (20-to 120-m in time periods). A Pressure-Reactivity Index (PRx) w as calculated as a moving correlation coefficient between 40 consecutive sam ples of values for ICP and A BP averaged for a period of 5 seconds. A m oving correlation coefficient (Mean Index) between spontaneous fluctuations of mean flow velocity and cerebral perfusion pressure, w hich w as previously reported to describe cerebral blood flow autoregulation, w as also calcu lated. RESULTS: A positive PRx correlated w ith high IC P (r = 0 .3 6 6 ; P < 0 .0 01), low adm ission G lasg o w C o m a Scale score

Research paper thumbnail of Monitoring cerebral autoregulation after head injury. Which component of transcranial Doppler flow velocity is optimal?

Neurocritical Care, 2011

Background Cerebral autoregulation assessed using transcranial Doppler (TCD) mean flow velocity (... more Background Cerebral autoregulation assessed using transcranial Doppler (TCD) mean flow velocity (FV) in response to various physiological challenges is predictive of outcome after traumatic brain injury (TBI). Systolic and diastolic FV have been explored in other diseases. This study aims to evaluate the systolic, mean and diastolic FV for monitoring autoregulation and predicting outcome after TBI. Methods 300 head-injured patients with blood pressure (ABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), and FV recordings were studied. Autoregulation was calculated as a correlation of slow changes in diastolic, mean and systolic components of FV with CPP (Dx, Mx, Sx, respectively) and ABP (Dxa, Mxa, Sxa, respectively) from 30 consecutive 10 s averaged values. The relationship with age, severity of injury, and dichotomized 6 months outcome was examined. Results Association with outcome was significant for Mx and Sx. For favorable/unfavorable and death/survival outcomes Sx showed the strongest association (F = 20.11; P = 0.00001 and F = 13.10; P = 0.0003, respectively). Similarly, indices derived from ABP demonstrated the highest discriminatory value when systolic FV was used (F = 12.49; P = 0.0005 and F = 5.32; P = 0.02, respectively). Indices derived from diastolic FV demonstrated significant differences (when calculated using CPP) only when comparing between fatal and non-fatal outcome. Conclusions Systolic flow indices (Sx and Sxa) demonstrated a stronger association with outcome than the mean flow indices (Mx and Mxa), irrespective of whether CPP or ABP was used for calculation.

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

Journal of Neurotrauma, 2010

Monitoring of cerebrovascular pressure reactivity (PRx) has diagnostic and prognostic value in he... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 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.

Research paper thumbnail of A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

Journal of Neurosurgery, 1998

Object. The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroi... more Object. The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. Methods. A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4–8) and 15% (163) had sustained a moderate head injury (GCS score 9–12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p = 0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p = 0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head inj...

Research paper thumbnail of Cerebral perfusion pressure in head-injured patients: a noninvasive assessment using transcranial Doppler ultrasonography

Journal of Neurosurgery, 1998

Object. The authors studied the reliability of a new method for noninvasive assessment of cerebra... more Object. The authors studied the reliability of a new method for noninvasive assessment of cerebral perfusion pressure (CPP) in head-injured patients in which mean arterial blood pressure (ABP) and transcranial Doppler middle cerebral artery mean and diastolic flow velocities are measured. Methods. Cerebral perfusion pressure was estimated (eCPP) over periods of continuous monitoring (20 minutes—2 hours, 421 daily examinations) in 96 head-injured patients (Glasgow Coma Scale score < 13) who were admitted to the intensive care unit. All patients were sedated, paralyzed, and ventilated. The eCPP and the measured CPP (ABP minus intracranial pressure, measured using an intraparenchymal microsensor) were compared. The correlation between eCPP and measured CPP was r = 0.73; p < 10−6. In 71% of the examinations, the estimation error was less than 10 mm Hg and in 84% of the examinations, the error was less than 15 mm Hg. The method had a high positive predictive power (94%) for detecti...

Research paper thumbnail of Evaluation of the transient hyperemic response test in head-injured patients

Journal of Neurosurgery, 1997

✓ The transient hyperemic response test has been shown to provide an index of cerebral autoregula... more ✓ The transient hyperemic response test has been shown to provide an index of cerebral autoregulation in healthy individuals and in patients who have suffered a subarachnoid hemorrhage. In this study, the test was applied to patients who had received a severe head injury, and the value of the test was assessed by comparing its result with the individual's clinical condition (Glasgow Coma Scale [GCS] score), cerebral perfusion pressure (CPP), transcranial Doppler wave form—derived index for cerebral autoregulation (relationship between the CPP and the middle cerebral artery flow velocity), and outcome (Glasgow Outcome Scale [GOS] score). Forty-seven patients, aged 16 to 63 years, with head injuries were included in the study. Signals of intracranial pressure, arterial blood pressure, flow velocity, and cortical microcirculatory flux were digitized and recorded for a period of 30 minutes using special computer software. Two carotid compressions were performed at the beginning of e...

Research paper thumbnail of Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: a pilot study

Journal of Neurology, Neurosurgery & Psychiatry, 1998

The objective of this study was to analyse the temporal course of the jugular venousarterial grad... more The objective of this study was to analyse the temporal course of the jugular venousarterial gradient of S-100B protein after severe head injury and the correlation between the absolute concentrations of serum S-100B protein and outcome, CT findings, and clinical variables. Fifteen patients were included in this pilot study. All patients were treated according to a standard therapy protocol targeted to maintain cerebral perfusion pressure. The serum concentration of S-100 protein was measured daily for five consecutive days after injury by a monoclonal two site immunoluminometric assay. Nine patients showed favourable and six unfavourable outcome after 6 months with a mortality rate of 33% (five patients). The mean gradient between jugular venous and arterial blood was 8.2% (p<0.05). Patients showing an unfavourable outcome had significantly higher jugular venous or arterial S-100 values compared with those with a favourable outcome (jugular venous S-100B 2.78 µg/l v 1.22 µg/l, p<0.05; arterial S-100B 2.48 µg/l v 1.19 µg/l, p<0.05). All patients with an initial or secondary increase in S-100B value of >2 µg/l were found to have an unfavourable outcome. S-100B was found to be an independent predictor of outcome after severe head injury. The persisting increase of S-100B for three to five days even in patients with favourable outcome and no signs of secondary insults might reflect continuing damage to the bloodbrain barrier or ongoing glial cell death.

Research paper thumbnail of Contribution of mathematical modelling to the interpretation of bedside tests of cerebrovascular autoregulation

Journal of Neurology, Neurosurgery & Psychiatry, 1997

Objectives-Cerebral haemodynamic responses to short and longlasting episodes of decreased cerebra... more Objectives-Cerebral haemodynamic responses to short and longlasting episodes of decreased cerebral perfusion pressure contain information about the state of autoregulation of cerebral blood flow. Mathematical simulation may help to elucidate which of the indices, that can be derived using transcranial Doppler ultrasonography and trends of intracranial pressure and blood pressure, are useful in clinical tests of autoregulatory reserve. Methods-Time dependent interactions between pressure, flow, and volume of cerebral blood and CSF were modelled using a set of non-linear diVerential equations. The model simulates changes in arterial blood inflow and storage, arteriolar and capillary blood flow controlled by cerebral autoregulation, venous blood storage and venous outflow modulated by changes in ICP, and CSF storage and reabsorption. The model was used to simulate patterns of blood flow during either short or longlasting decreases in cerebral perfusion pressure. These simulations can be considered as clinically equivalent to a short compression of the common carotid artery, systemic hypotension, and intracranial hypertension. Simulations were performed in autoregulating and nonautoregulating systems and compared with recordings obtained in patients. Results-After brief compression of the common carotid artery, a subsequent transient hyperaemia can be interpreted as evidence of intact autoregulation. During longlasting sustained hypoperfusion, a gradual increase in the systolic value of the blood flow velocity waveform along with a decrease in the diastolic value is specific for an autoregulating cerebrovascular system. Conclusion-Modelling studies help to interpret both clinical and experimental cerebral haemodynamic phenomena and their dependence on the state of autoregulation.

Research paper thumbnail of Commentary on Oh H. and Seo W. (2003) Sensory stimulation programme to improve recovery in comatose patients. Journal of Clinical Nursing 12, 394-404

Journal of Clinical Nursing, 2004

Research paper thumbnail of Early metabolic characteristics of lesion and nonlesion tissue after head injury

Journal of Cerebral Blood Flow & Metabolism, 2009

We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up i... more We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up in patients recovering from head injury. Early metabolic characteristics in these regions of interest (ROIs) were compared with physiology in healthy volunteers. Fourteen patients with severe head injury had positron emission tomography within 72 h, and magnetic resonance imaging at 3 to 18 months after injury. Cerebral blood flow (CBF), oxygen utilization (CMRO2), and oxygen extraction fraction (OEF) were all lower in lesion ROIs, compared with nonlesion and control ROIs ( P < 0.001); however, there was substantial overlap in physiology. Control ROIs showed close coupling among CBF, blood volume (CBV), and CMRO2, whereas relationships within lesion and nonlesion ROIs were abnormal. The relationship between CBF and CMRO2 generally remained coupled but the slope was reduced; that for CBF and OEF was variable; whereas that between CBF and CBV was highly variable. There was considerable h...

Research paper thumbnail of The Cytokine Response to Human Traumatic Brain Injury: Temporal Profiles and Evidence for Cerebral Parenchymal Production

Journal of Cerebral Blood Flow & Metabolism, 2010

The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pat... more 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,...

Research paper thumbnail of Sustained moderate reductions in arterial CO2 after brain trauma Time-course of cerebral blood flow velocity and intracranial pressure

Intensive Care Medicine, 2004

Research paper thumbnail of Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury

Critical Care Medicine, 2002

C erebrovasCular pressure reactivity reflects the capability of smooth muscle tone in the walls o... more C erebrovasCular pressure reactivity reflects the capability of smooth muscle tone in the walls of cerebral arteries and arterioles to react to changes in transmural pressure (cerebral vessels constrict in response to an increase in CPP, and vice versa). Cerebro-vascular pressure reactivity represents a key element of cerebral autoregulation, although the two terms should not be used interchangeably because vascular responses can occur outside the range of cerebral autoregulation. 7,25 With increasing ABP, intact cerebrovascular pressure reactivity will lead to vasoconstriction and a reduction of cerebral blood volume. Under the condition of a finite pressure-volume compensatory reserve, this reduction of cerebral blood volume will produce a decrease in ICP, a condition that is usually not met in patients after a decompressive craniectomy or in those with an external ventricular drain. When cerebrovascular pressure reac

Research paper thumbnail of Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients

Critical Care Medicine, 2004

To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with a... more To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. Prospective randomized crossover trial. Neurosciences critical care unit of a university hospital. Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.

Research paper thumbnail of Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent

British Journal of Clinical Pharmacology, 2002

Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatmen... more Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into bene®t during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain. Methods Multimodality monitoring including cerebral and peripheral microdialysis was applied to ®ve head-injured patients on the neuro-intensive care unit. Chlormethiazole (0.8%) was administered as a rapid (10 ml min x1) intravenous loading infusion for 5 min followed by a slow (1 ml min x1) continuous infusion for 60 min. The following parameters were monitored: heart rate, mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, continuous arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial temperature, cerebral tissue oxygen pressure, cerebral tissue carbon dioxide pressure, cerebral pH, cerebral temperature, electroencephalograph (EEG), bispectral index, plasma glucose, plasma chlormethiazole, and cerebral and peripheral microdialysis assay for chlormethiazole, glucose, lactate, pyruvate and amino acids. Results Despite achieving adequate plasma concentrations, chlormethiazole was not detected in the peripheral or cerebral microdialysis samples. The drug was well tolerated and did not induce hypotension, hyperglycaemia or withdrawal seizures. The drug did not change the values of the physiological or chemical parameters including levels of GABA, lactate/pyruvate ratio and glutamate. The drug did, however, induce EEG changes, including burst suppression in two patients. Conclusions Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.

Research paper thumbnail of Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Brain, 2004

Recent changes in published guidelines for the management of patients with severe head injury are... more Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO 2) and oxygen extraction fraction (OEF) using 15 O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 6 4 to 90 6 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO 2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO 2 were associated with the greatest reduction in OEF (r 2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 6 16 to 5 6 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r 2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 6 1.5 versus 4.3 6 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO 2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO 2 and neuronal electrical function will require further study.