Ivan Timofeev

Decompressive craniectomy in traumatic brain injury: the randomized multicenter RESCUEicp study (www.RESCUEicp.com)

The RESCUEicp (Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of intracranial pressure) study has been established to determine whether decompressive craniectomy has a role in the management of patients with traumatic brain injury and raised intracranial pressure that does not respond to initial treatment measures. We describe the concept of decompressive craniectomy in traumatic brain injury and the rationale and protocol of the RESCUEicp study.

Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients

Secondary insults can adversely influence outcome following severe traumatic brain injury. Monitoring of cerebral extracellular chemistry with microdialysis has the potential for early detection of metabolic derangements associated with such events. The objective of this study was to determine the relationship between the fundamental biochemical markers and neurological outcome in a large cohort of patients with traumatic brain injury. Prospectively collected observational neuromonitoring data from 223 patients were analysed. Monitoring modalities included digitally recorded intracranial pressure, cerebral perfusion pressure, cerebrovascular pressure reactivity index and microdialysis markers glucose, lactate, pyruvate, glutamate, glycerol and the lactate/pyruvate ratio. Outcome was assessed using the Glasgow Outcome Scale at 6 months post-injury. Patient-averaged values of parameters were used in statistical analysis, which included univariate non-parametric methods and multivariate logistic regression. Monitoring with microdialysis commenced on median (interquartile range) Day 1 (1-2) from injury and median (interquartile range) duration of monitoring was 4 (2-7) days. Averaged over the total monitoring period levels of glutamate (P = 0.048), lactate/pyruvate ratio (P = 0.044), intracranial pressure (P = 0.006) and cerebrovascular pressure reactivity index (P = 0.01) were significantly higher in patients who died. During the initial 72 h of monitoring, median glycerol levels were also higher in the mortality group (P = 0.014) and median lactate/pyruvate ratio (P = 0.026) and lactate (P = 0.033) levels were significantly lower in patients with favourable outcome. In a multivariate logistic regression model (P < 0.0001), which employed data averaged over the whole monitoring period, significant independent positive predictors of mortality were glucose (P = 0.024), lactate/pyruvate ratio (P = 0.016), intracranial pressure (P = 0.029), cerebrovascular pressure reactivity index (P = 0.036) and age (P = 0.003), while pyruvate was a significant independent negative predictor of mortality (P = 0.004). The results of this study suggest that extracellular metabolic markers are independently associated with outcome following traumatic brain injury. Whether treatment-related improvement in biochemistry translates into better outcome remains to be established.

The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury.

Objective:There is evidence to suggest that anemia after severe traumatic brain injury (sTBI) is detrimental. However, there is a paucity of evidence supporting the use of transfusion of packed red blood cells in patients with sTBI. To understand the acute effect of packed red blood cell transfusion on cerebral oxygenation and metabolism in patients with sTBI. Design:Prospective clinical study. Setting:Addenbrooke’s Neurosciences Critical Care Unit, a 21-bed tertiary academic unit. Patients:Thirty patients with sTBI. Interventions:Patients were randomized by computer random number generator to one of three transfusion thresholds: 8, 9, or 10 g/dL. When the patients’ hemoglobin concentration fell below their assigned threshold, two units of packed red blood cells were transfused over 2 hours. A 1-hour period of stabilization was observed before final data collection. Measurements and Main Results:The primary outcome was change in brain tissue oxygen (Pbto2). Secondary outcomes included dependence of baseline hemoglobin concentration and baseline Pbto2 on the relationship of transfusion and Pbto2, and the effect of transfusion on lactate pyruvate ratio (LPR) and brain pH as markers of cerebral metabolic state. Fifty-seven percent of patients experienced an increase in Pbto2 during the course of the study, whereas in 43% of patients, Pbto2 either did not change or decreased. Multivariable generalized estimating equation analysis revealed change in hemoglobin concentration to significantly and positively associated with change in Pbto2 [0.10 kPa/(g/dL) 95% confidence interval 0.03–0.17, p = 0.003]. Improvement in Pbto2 was not associated with baseline hemoglobin concentration or low Pbto2 (<1 kPa). Fifty-six percent of patients experienced an increase in LPR. No significant relationship between change in LPR or transfusion on pHbt and change in hemoglobin could be demonstrated. Conclusions:Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism. Trial Registration:ISRCTN89085577.

The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Effect of decompressive craniectomy on intracranial pressure and cerebrospinal compensation following traumatic brain injury

OBJECTIVE Decompressive craniectomy is an advanced treatment option for intracranial pressure (ICP) control in patients with traumatic brain injury. The purpose of this study was to evaluate the effect of decompressive craniectomy on ICP and cerebrospinal compensation both within and beyond the first 24 hours of craniectomy. METHODS This study was a retrospective analysis of the physiological parameters from 27 moderately to severely head-injured patients who underwent decompressive craniectomy for progressive brain edema. Of these, 17 patients had undergone prospective digital recording of ICP with estimation of ICP waveform-derived indices. The pressure-volume compensatory reserve (RAP) index and the cerebrovascular pressure reactivity index (PRx) were used to assess those parameters. The values of parameters prior to and during the 72 hours after decompressive craniectomy were included in the analysis. RESULTS Decompressive craniectomy led to a sustained reduction in median (interquartile range) ICP values (21.2 mm Hg [18.7; 24.2 mm Hg] preoperatively compared with 15.7 mm Hg [12.3; 19.2 mm Hg] postoperatively; p = 0.01). A similar improvement was observed in RAP. A significantly lower mean arterial pressure (MAP) was needed after decompressive craniectomy to maintain optimum cerebral perfusion pressure (CPP) levels, compared with the preoperative period (99.5 mm Hg [96.2; 102.9 mm Hg] compared with 94.2 mm Hg [87.9; 98.9 mm Hg], respectively; p = 0.017). Following decompressive craniectomy, the PRx had positive values in all patients, suggesting acquired derangement in pressure reactivity. CONCLUSIONS In this study, decompressive craniectomy led to a sustained reduction in ICP and improvement in cerebral compliance. Lower MAP levels after decompressive craniectomy are likely to indicate a reduced intensity of treatment. Derangement in cerebrovascular pressure reactivity requires further studies to evaluate its significance and influence on outcome.

Effect of hyperoxia on regional oxygenation and metabolism after severe traumatic brain injury: preliminary findings.

Objective:To determine the effect of normobaric hyperoxia on cerebral metabolism in patients with severe traumatic brain injury. Design:Prospective clinical investigation. Setting:Neurosciences critical care unit of a university hospital. Patients:Eleven patients with severe traumatic brain injury. Interventions:Cerebral microdialysis, brain tissue oximetry (Pbo2), and oxygen-15 positron emission tomography (15O-PET) were undertaken at normoxia and repeated at hyperoxia (Fio2 increase of between 0.35 and 0.50). Measurements and Main Results:Established models were used to image cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction. Physiology was characterized in a focal region of interest (surrounding the microdialysis catheter) and correlated with microdialysis and oximetry. Physiology was also characterized in a global region of interest (including the whole brain), and a physiologic region of interest (defined using a critical cerebral metabolic rate of oxygen threshold). Hyperoxia increased mean ± sd Pbo2 from 28 ± 21 mm Hg to 57 ± 47 mm Hg (p = .015). Microdialysate lactate and pyruvate were unchanged, but the lactate/pyruvate ratio showed a statistically significant reduction across the study population (34.1 ± 9.5 vs. 32.5 ± 9.0, p = .018). However, the magnitude of reduction was small, and its clinical significance doubtful. The focal region of interest and global 15O-PET variables were unchanged. “At-risk” tissue defined by the physiologic region of interest, however, showed a universal increase in cerebral metabolic rate of oxygen from a median (interquartile range) of 23 (22–25) &mgr;mol·100 mL−1·min−1 to 30 (28–36) &mgr;mol·100 mL−1·min−1 (p < .01). Conclusions:In severe traumatic brain injury, hyperoxia increases Pbo2 with a variable effect on lactate and lactate/pyruvate ratio. Microdialysis does not, however, predict the universal increases in cerebral metabolic rate of oxygen in at-risk tissue, which imply preferential metabolic benefit with hyperoxia.

Continuous monitoring of cerebrovascular pressure reactivity in patients with head injury

OBJECT Cerebrovascular pressure reactivity is the ability of cerebral vessels to respond to changes in transmural pressure. A cerebrovascular pressure reactivity index (PRx) can be determined as the moving correlation coefficient between mean intracranial pressure (ICP) and mean arterial blood pressure. METHODS The authors analyzed a database consisting of 398 patients with head injuries who underwent continuous monitoring of cerebrovascular pressure reactivity. In 298 patients, the PRx was compared with a transcranial Doppler ultrasonography assessment of cerebrovascular autoregulation (the mean index [Mx]), in 17 patients with the PET-assessed static rate of autoregulation, and in 22 patients with the cerebral metabolic rate for O(2). Patient outcome was assessed 6 months after injury. RESULTS There was a positive and significant association between the PRx and Mx (R(2) = 0.36, p < 0.001) and with the static rate of autoregulation (R(2) = 0.31, p = 0.02). A PRx > 0.35 was associated with a high mortality rate (> 50%). The PRx showed significant deterioration in refractory intracranial hypertension, was correlated with outcome, and was able to differentiate patients with good outcome, moderate disability, severe disability, and death. The graph of PRx compared with cerebral perfusion pressure (CPP) indicated a U-shaped curve, suggesting that too low and too high CPP was associated with a disturbance in pressure reactivity. Such an optimal CPP was confirmed in individual cases and a greater difference between current and optimal CPP was associated with worse outcome (for patients who, on average, were treated below optimal CPP [R(2) = 0.53, p < 0.001] and for patients whose mean CPP was above optimal CPP [R(2) = -0.40, p < 0.05]). Following decompressive craniectomy, pressure reactivity initially worsened (median -0.03 [interquartile range -0.13 to 0.06] to 0.14 [interquartile range 0.12-0.22]; p < 0.01) and improved in the later postoperative course. After therapeutic hypothermia, in 17 (70.8%) of 24 patients in whom rewarming exceeded the brain temperature threshold of 37 degrees C, ICP remained stable, but the average PRx increased to 0.32 (p < 0.0001), indicating significant derangement in cerebrovascular reactivity. CONCLUSIONS The PRx is a secondary index derived from changes in ICP and arterial blood pressure and can be used as a surrogate marker of cerebrovascular impairment. In view of an autoregulation-guided CPP therapy, a continuous determination of a PRx is feasible, but its value has to be evaluated in a prospective controlled trial.

Decompressive craniectomy in traumatic brain injury: outcome following protocol-driven therapy

Although decompressive craniectomy following traumatic brain injury is an option in patients with raised intracranial pressure (ICP) refractory to medical measures, its effect on clinical outcome remains unclear. The aim of this study was to evaluate the outcome of patients undergoing this procedure as part of protocol-driven therapy between 2000-2003. This was an observational study combining case note analysis and follow-up. Outcome was assessed at an interval of at least 6 months following injury using the Glasgow Outcome Scale (GOS) score and the SF-36 quality of life questionnaire. Forty-nine patients underwent decompressive craniectomy for raised and refractory ICP (41 [83.7%] bilateral craniectomy and 8 [16.3%] unilateral). Using the Glasgow Coma Scale (GCS), the presenting head injury grade was severe (GCS 3-8) in 40 (81.6%) patients, moderate (GCS 9-12) in 8 (16.3%) patients, and initially mild (GCS 13-15) in 1 (2.0%) patient. At follow-up, 30 (61.2%) patients had a favorable outcome (good recovery or moderate disability), 10 (20.48) remained severely disabled, and 9 (18.4%) died. No patients were left in a vegetative state. Overall the results demonstrated that decompressive craniectomy, when applied as part of protocol-driven therapy, yields a satisfactory rate of favorable outcome. Formal prospective randomized studies of decompressive craniectomy are now indicated.

Consensus statement from the 2014 International Microdialysis Forum

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

The Surgical Approach to the Management of Increased Intracranial Pressure After Traumatic Brain Injury

Increased intracranial pressure occurring after severe traumatic brain injury is a common and potentially devastating phenomenon. It has been clearly demonstrated that increased intracranial pressure that is refractory to initial medical measures is a poor prognostic sign. Current optimal management is based on a sequential, target-driven approach combining both medical and surgical treatment strategies. The surgical measures in current common practice include external ventricular drain insertion and decompressive craniectomy. There is evidence that both of these measures reduce intracranial pressure but the effect on outcome, particularly in the long term, is equivocal. Current Brain Trauma Foundation guidelines recommend timely evacuation of mass lesions and there is clear guidance regarding the indications for intracranial pressure monitoring; however, decompressive craniectomy is only cautiously recommended as a possible option for selected patients. In this review, we highlight the ongoing debate about the use of decompressive craniectomy to control intracranial pressure after traumatic brain injury; included is a summary of review of the most recent literature on the effect of decompressive craniectomy on increased intracranial pressure after traumatic brain injury and associated long-term outcome. The RESCUEicp and DECRA studies are discussed in detail. It is hoped that these 2 randomized controlled trials, which are evaluating the short- and longer-term outcomes of decompressive craniectomy, will provide conclusive evidence regarding the role of decompressive craniectomy in managing increased intracranial pressure after trauma.