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.

Cerebral acid-base homeostasis after severe traumatic brain injury.

OBJECT: Brain tissue acidosis is known to mediate neuronal death. Therefore the authors measured the main parameters of cerebral acid-base homeostasis, as well as their interrelations, shortly after severe traumatic brain injury (TBI) in humans. METHODS: Brain tissue pH, PCO2, PO2, and/or lactate were measured in 151 patients with severe head injuries, by using a Neurotrend sensor and/or a microdialysis probe. Monitoring was started as soon as possible after the injury and continued for up to 4 days. During the 1st day following the trauma, the brain tissue pH was significantly lower, compared with later time points, in patients who died or remained in a persistent vegetative state. Six hours after the injury, brain tissue PCO2 was significantly higher in patients with a poor outcome compared with patients with a good outcome. Furthermore, significant elevations in cerebral concentrations of lactate were found during the 1st day after the injury, compared with later time points. These increases in lactate were typically more pronounced in patients with a poor outcome. Similar biochemical changes were observed during later hypoxic events. CONCLUSIONS: Severe human TBI profoundly disturbs cerebral acid-base homeostasis. The observed pH changes persist for the first 24 hours after the trauma. Brain tissue acidosis is associated with increased tissue PCO2 and lactate concentration; these pathobiochemical changes are more severe in patients who remain in a persistent vegetative state or die. Furthermore, increased brain tissue PCO2 (> 60 mm Hg) appears to be a useful clinical indicator of critical cerebral ischemia, especially when accompanied by increased lactate concentrations.

Association between elevated brain tissue glycerol levels and poor outcome following severe traumatic brain injury.

OBJECT: Glycerol is considered to be a marker of cell membrane degradation and thus cellular lysis. Recently, it has become feasible to measure via microdialysis cerebral extracellular fluid (ECF) glycerol concentrations at the patient's bedside. Therefore the aim of this study was to investigate the ECF concentration and time course of glycerol after severe traumatic brain injury (TBI) and its relationship to patient outcome and other monitoring parameters. METHODS: As soon as possible after injury for up to 4 days, 76 severely head-injured patients were monitored using a microdialysis probe (cerebral glycerol) and a Neurotrend sensor (brain tissue PO2) in uninjured brain tissue confirmed by computerized tomography scanning. The mean brain tissue glycerol concentration in all monitored patients decreased significantly from 206 +/- 31 micromol/L on Day 1 to 9 +/- 3 micromol/L on Day 4 after injury (p < 0.0001). Note, however, that there was no significant difference in the time course between patients with a favorable outcome (Glasgow Outcome Scale [GOS] Scores 4 and 5) and those with an unfavorable outcome (GOS Scores 1-3). Significantly increased glycerol concentrations were observed when brain tissue PO2 was less than 10 mm Hg or when cerebral perfusion pressure was less than 70 mm Hg. CONCLUSIONS: Based on results in the present study one can infer that microdialysate glycerol is a marker of severe tissue damage, as seen immediately after brain injury or during profound tissue hypoxia. Given that brain tissue glycerol levels do not yet add new clinically significant information, however, routine monitoring of this parameter following traumatic brain injury needs further validation.