Exposure of cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury.

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.

Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial.

Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg/kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg/kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study.

BACKGROUND: Mitochondrial dysfunction is a major limiting factor in neuronal recovery following traumatic brain injury. Cyclosporin A (CsA) has been recently proposed for use in the early phase after severe head injury, for its ability to preserve mitochondrial bioenergetic state, potentially exerting a neuroprotective effect. The aim of this study was, therefore, to evaluate the effect of CsA on brain energy metabolism, as measured by cerebral microdialysis, and on cerebral hemodynamics, in a group of severely head injured patients. METHODS: Fifty adult patients with a severe head injury were enrolled in this randomized, double-blind, placebo-controlled study. Patients received 5 mg/kg of CsA over 24 h, or placebo, within 12 h of the injury. A microdialysis probe was placed in all patients, who were managed according to standard protocols for the treatment of severe head injury. FINDINGS: The most robust result of this study was that, over most of the monitoring period, brain dialysate glucose was significantly higher in the CsA treated patients than in placebo. Both lactate and pyruvate were also significantly higher in the CsA group. Glutamate concentration and lactate/pyruvate ratio were significantly higher in the placebo group than in CsA treated patients, respectively 1 to 2 days, and 2 to 3 days after the end of the 24-h drug infusion. The administration of CsA was also associated with a significant increase in mean arterial pressure (MAP) and cerebral perfusion pressure (CPP). CONCLUSIONS: The administration of CsA in the early phase after head injury resulted in significantly higher extracellular fluid glucose and pyruvate, which may be evidence of a beneficial effect. The early administration of CsA was also associated with a significant increase in MAP and CPP and such a potentially beneficial hemodynamic effect might contribute to a neuroprotective effect.

Repetitive cortical spreading depolarizations in a case of severe brain trauma.

OBJECTIVE AND IMPORTANCE: Cortical spreading depolarizations (CSD) are waves of mass tissue depolarization that mediate progressive development of cortical infarction in animal models and occur in approximately 50% of patients with acute brain injury. Here we performed multi-modal cerebral monitoring to investigate pathologies associated with CSD occurrence in a case of severe traumatic brain injury. CLINICAL PRESENTATION: A 20 years old male suffering severe traumatic brain injury from a fall had extensive frontal subdural and intraparenchymal hemorrhage with mass effect. Craniectomy was performed for hematoma evacuation and decompression. INTERVENTION: During surgery, a subdural electrocorticography (ECoG) electrode strip, along with microdialysis and PtiO2 probes, was placed beside injured cortex for CSD monitoring. Within 13-81 hours post-injury, 34 CSD occurred. CSD incidence increased during spontaneous hyperthermia and decreased during induced normothermia. Periods of CSD activity were also associated with low brain glucose (<0.10 mmol/l), elevated glutamate (>40 mmol/l) and lactate/pyruvate (>40), and PtiO2<10 mmHg. CSD caused progressive deterioration of ECoG activity only in regions with infarction at follow-up on day 27. CONCLUSION: Repetitive mass tissue depolarizations accompanied a negative course of hemorrhagic lesion progression in the presence of ischemic conditions after traumatic brain injury. Whether as cause or effect, CSD may represent an inherent component of progressive metabolic failure leading to tissue death, and temperature appears to be an important factor influencing their occurrence. Continuous ECoG is a valuable tool for monitoring subclinical events such as CSD and seizures and for translational research in acute brain injury mechanisms and therapeutics.

Severe human traumatic brain injury, but not cyclosporin a treatment, depresses activated T lymphocytes early after injury.

Severe traumatic brain injury (TBI) leads to an immunocompromised state responsible for an increased morbidity and mortality. Our understanding of the mechanisms responsible for this brain damage is incomplete. Damage maybe mediated by a complex cascade of neuroinflammation, and cytokine activation. In addition, translocation and accumulation of T cells in the brain parenchyma could take place and be related to detrimental effects. Our aims in this prospective randomized pilot study, were to detect the early effect of severe TBI upon cell-mediated immunity, to verify if early immunologic impairment correlates with neurologic outcome, and finally, to test the effect of early administration of iv infusion of cyclosporin A upon cell-mediated immunologic function. Forty-nine patients with severe TBI were studied. Thirty-six of these patients received a 24-h intravenous infusion of Cyclosporin A, or two 24-h infusions of the drug. 10 patients were in the placebo group. Three patients, not enrolled in the cyclosporin trial, were studied only for the relationship between cellular immunity, neurological outcome, and infection rate. T cell counts and microbiological cultures were performed in all patients. Sixty-five percent of patients demonstrated reduced T lymphocyte counts on admission. Furthermore, reduction of T cell numbers was related with significantly worse neurologic outcome and an increase in pulmonary infection. There was no significant difference between the placebo and CsA treated patients for the studied immunological parameters, or for incidence of infection. We also observed sequestration/diapedesis of T cells into the brain parenchyma, around contusions, after human TBI and we speculate that this could be responsible for further brain damage.

Quantitation of ischemic events after severe traumatic brain injury in humans: a simple scoring system.

BACKGROUND: Cerebral ischemia is recognized as one of the most important mechanisms responsible for secondary brain damage following severe traumatic brain injury (TBI), contributing to an increased mortality and a worse neurologic outcome. METHOD: A simple 5-item scoring system, taking into account the occurrence of specific potentially brain-damaging events (hypoxemia, hypotension, low cerebral blood flow, herniation, and low cerebral perfusion pressure) has been tested in a large population of severe TBI patients. Aims of this retrospective study were to validate the ability of the proposed ischemic score to predict neurologic outcome and to correlate the ischemic score with the results of microdialysis-based neurochemical monitoring and brain tissue oxygen monitoring. FINDINGS: In a population of 172 severe TBI patients, a significant correlation was found between ischemic score and neurologic outcome, both at 3 months (r = -0.32; P < 0.01) and at 6 months (r = -0.31; P < 0.01). Significant correlations were also found with the most important neurochemical analytes. CONCLUSIONS: The ischemic score proposed here, may be determined during the acute intensive care unit period, and correlates closely with outcome, which can only be determined 3 to 6 months, after injury. It also shows a correlation with neurochemical analytes.

Normobaric hyperoxia--induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study.

OBJECT: The effect of normobaric hyperoxia (fraction of inspired O2 [FIO2] concentration 100%) in the treatment of patients with traumatic brain injury (TBI) remains controversial. The aim of this study was to investigate the effects of normobaric hyperoxia on five cerebral metabolic indices, which have putative prognostic significance following TBI in humans. METHODS: At two independent neurointensive care units, the authors performed a prospective study of 52 patients with severe TBI who were treated for 24 hours with 100% FIO2, starting within 6 hours of admission. Data for these patients were compared with data for a cohort of 112 patients who were treated in the past; patients in the historical control group matched the patients in our study according to their Glasgow Coma Scale scores after resuscitation and their intracranial pressure within the first 8 hours after admission. Patients were monitored with the aid of intracerebral microdialysis and tissue O2 probes. Normobaric hyperoxia treatment resulted in a significant improvement in biochemical markers in the brain compared with the baseline measures for patients treated in our study (patients acting as their own controls) and also compared with findings from the historical control group. In the dialysate the glucose levels increased (369.02 +/- 20.1 micromol/L in the control group and 466.9 +/- 20.39 micromol/L in the 100% O2 group, p = 0.001), whereas the glutamate and lactate levels significantly decreased (p < 0.005). There were also reductions in the lactate/glucose and lactate/pyruvate ratios. Intracranial pressure in the treatment group was reduced significantly both during and after hyperoxia treatment compared with the control groups (15.03 +/- 0.8 mm Hg in the control group and 12.13 +/- 0.75 mm Hg in the 100% O2 group, p < 0.005) with no changes in cerebral perfusion pressure. Outcomes of the patients in the treatment group improved. CONCLUSIONS: The results of the study support the hypothesis that normobaric hyperoxia in patients with severe TBI improves the indices of brain oxidative metabolism. Based on these data further mechanistic studies and a prospective randomized controlled trial are warranted.

Evaluation of topiramate neuroprotective effect in severe TBI using microdialysis.

Despite recent advances in our understanding of human traumatic brain injury (TBI) pathophysiology, we still need effective neuroprotective agents. The lack of rigorous drug pharmacokinetic studies in the "living" brain is an important cause of neuroprotection trials failure in human TBI research. In the past, several drugs have been labeled as inefficient, and even withdrawn from expensive trials, without knowing their actual penetration in the traumatized human brain. The injured brain is characterized by an increased diffusion distance, due to edema, and reduced blood flow that modulates drug transport across the blood-brain barrier (BBB). In the study reported in this paper, we used cerebral microdialysis to provide a safe and efficient tool for continuous in vivo evaluation of bioavailability and pharmacologic efficacy of topiramate, a glutamate release inhibitor. Topiramate crossed the BBB in neuroprotective concentrations, and showed a lowering effect on glutamate levels, thereby modifying the natural history of glutamate release after TBI. The use of cerebral microdialysis in phase II drug studies will allow the detection of the appropriate therapeutic window and dosage for the neuroprotective agent. This strategy represents a clear improvement compared to traditional clinical trial design, and will reduce the trial costs.

The importance of brain temperature in patients after severe head injury: relationship to intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and outcome.

Brain temperature was continuously measured in 58 patients after severe head injury and compared to rectal temperature, intracranial pressure, cerebral blood flow, and outcome after 3 months. The temperature difference between brain and rectal temperature was also calculated. Mild hypothermia (34-36 degrees C) was also used to treat uncontrollable intracranial pressure (ICP) above 20 mm Hg when other methods failed. Brain and rectal temperature were strongly correlated (r = 0.866; p < 0.001). Four groups were identified. The mean brain temperature ranged from 36.9 +/- 0.4 degrees C in the normothermic group to 38.2 +/- 0.5 degrees C in the hyperthermic group, 35.3 +/- 0.5 degrees C in the mild therapeutic hypothermia group, and 34.3 +/- 1.5 degrees C in the hypothermia group without active cooling. The mean DeltaT(br-rect) was positive for patients with a T(br) above 36.0 degrees C (0.0 +/- 0.5 degrees C) and negative for patients during mild therapeutic hypothermia (-0.2 +/- 0.6 degrees C) and also in those with a brain temperature below 36 degrees C without active cooling (0.8 +/- -1.4 degrees C) - the spontaneous hypothermic group. The cerebral perfusion pressure (CPP) was increased significantly by active cooling compared to the normothermic and hyperthermic groups. The mean cerebral blood flow (CBF) in patients with a brain temperature between 36.0 degrees C and 37.5 degrees C was 37.8 +/- 14.0 mL/100 g/min. The lowest CBF was measured in patients with a brain temperature <36.0 degrees C and a negative brain-rectal temperature difference (17.1 +/- 14.0 mL/100 g/min). A positive trend for improved outcome was seen in patients with mild hypothermia. Simultaneous monitoring of brain and rectal temperature provides important diagnostic and prognostic information to guide the treatment of patients after severe head injury (SHI) and the wide differentials that can develop between the brain and core temperature, especially during rapid cooling, strongly supports the use of brain temperature measurement if therapeutic hypothermia is considered for head injury care.

Relationship between brain temperature, brain chemistry and oxygen delivery after severe human head injury: the effect of mild hypothermia.

We studied brain temperature and the effect of mild hypothermia in 58 patients after severe head injury (SHI). Brain tissue oxygen tension (ptiO2), carbon dioxide tension (ptiCO2), tissuie pH (pHti) and temperature (T.br) were measured using a multiparameter probe. Microdialysis was performed to measure glucose, lactate, glutamate, and aspartate in the extracellular fluid. Mild hypothermia (34 degrees-36 degrees C) was employed in 33 selected patients who had persistent increased intracranial pressure (ICP > 20 mmHg). Mild induced hypothermia decreased brain oxygen significantly from 33 +/- 24 mmHg to 30 +/- 22 mmHg (p < 0.05). The ptiCO2 (46 +/- 8 mmHg) was also significantly lower during mild hypothermia (40.4 +/- 4.0 mmHg), p < 0.0001). The pHti increased from 7.13 +/- 0.15 to 7.24 +/- 0.10 (p < 0.0001) under hypothermic conditions. Induced hypothermia may protect patients from secondary ischemic events by lowering the critical ptiO2 threshold, reducing anaerobic metabolism, and decreasing the release of excitatory aminoacids. However, patients with spontaneous brain hypothermia on admission (Tbr < 36.0 degrees C) showed significantly higher levels of glutamate as well as lactate, compared to all other patients, and had a worse outcome. Spontaneous brain hypothermia carries a poor prognosis, and was characterized by markedly abnormal brain metabolic indices.

Outcome measures for clinical trials in neurotrauma.

Under the auspices of the American Brain Injury Consortium and the Joint Section of Neurotrauma and Critical Care of the American Association of Neurological Surgeons, the authors have reviewed and formulated opinions based on the evidence on protocol design and the outcome measures used for clinical trials in patients with a severe or moderate traumatic brain injury (TBI). First, in view of the heterogeneity of the population under study, the authors suggest that block randomization and stratification should always be used in the design of neurotrauma trials. Second, although the Glasgow Outcome Scale (GOS) remains the most widely used and accepted instrument for TBI trials, the authors believe the eight-point expanded scale that has recently been designed will ultimately provide greater discrimination, and narrower categories and will ultimately prove superior for detecting more subtle changes in outcome. Furthermore, the authors recommend, in view of the profound cognitive impairment in survivors of TBI, that neuropsychological tests be explored further as an adjunct to the GOS. Future research should focus on the development of more sensitive and specific surrogate outcome measures such as magnetic resonance imaging, neurochemical, neuropsychological, and quality of life measures in order to detect a neuroprotective effect in patients with TBI.