Charlotte Gilman

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.

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.

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

Abstract 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 (Tbr) were measured using a multiparameter probe. Microdialysis was performed to measure glucose, lactate, glutamate, and aspartate in the extracellular fluid. Mild hypothermia (34° – 36°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 pH i 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°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. [Neurol Res 2002; 24: 161-168]

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

Abstract 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 ∼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.

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.

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.