E. R. Zanier

Impact of pyrexia on neurochemistry and cerebral oxygenation after acute brain injury.

Background: Postischaemic pyrexia exacerbates neuronal damage. Hyperthermia related cerebral changes have still not been well investigated in humans. Objective: To study how pyrexia affects neurochemistry and cerebral oxygenation after acute brain injury. Methods: 18 acutely brain injured patients were studied at the onset and resolution of febrile episodes (brain temperature ⩾38.7°C). Intracranial pressure (ICP), brain tissue oxygen tension (Pbro2), and brain tissue temperature (Tbr) were recorded continuously; jugular venous blood was sampled intermittently. Microdialysis probes were inserted in the cerebral cortex and in subcutaneous tissue. Glucose, lactate, pyruvate, and glutamate were measured hourly. The lactate to pyruvate ratio was calculated. Results: Mean (SD) Tbr rose from 38 (0.5) to 39.3 (0.3)°C. Arteriojugular oxygen content difference (AJDo2) fell from 4.2 (0.7) to 3.8 (0.5) vol% (p<0.05) and Pbro2 rose from 32 (21) to 37 (22) mm Hg (p<0.05). ICP increased slightly and no significant neurochemical alterations occurred. Opposite changes were recorded when brain temperature returned towards baseline. Conclusions: As long as substrate and oxygen delivery remain adequate, hyperthermia on its own does not seem to induce any further significant neurochemical alterations. Changes in cerebral blood volume may, however, affect intracranial pressure.

Intracranial pressure monitoring in intensive care: clinical advantages of a computerized system over manual recording

IntroductionThe presence of intracranial hypertension (HICP) after traumatic brain injury (TBI) affects patient outcome. Intracranial pressure (ICP) data from electronic monitoring equipment are usually calculated and recorded hourly in the clinical chart by trained nurses. Little is known, however, about how precisely this method reflects the real patterns of ICP after severe TBI. In this study, we compared hourly manual recording with a validated and continuous computerized reference standard.MethodsThirty randomly selected patients with severe TBI and HICP admitted to the neuroscience intensive care unit (Policlinico University Hospital, Milan, Italy) were retrospectively studied. A 24-hour interval with ICP monitoring was randomly selected for each patient. The manually recorded data available for analysis covered 672 hours corresponding to 36,492 digital data points. The two methods were evaluated using the correlation coefficient and the Bland and Altman method. We used the proportion test to analyze differences in the number of episodes of HICP (ICP > 20 mm Hg) detected with the two methods and the paired t test to analyze differences in the percentage of time of HICP.ResultsThere was good agreement between the digitally collected ICP and the manual recordings of the end-hour values. Bland and Altman analysis confirmed a mean difference between the two methods of 0.05 mm Hg (standard deviation 3.66); 96% of data were within the limits of agreement (+7.37 and -7.28). The average percentages of time of ICP greater than 20 mm Hg were 39% calculated from the digital measurements and 34% from the manual observations. From the continuous digital recording, we identified 351 episodes of ICP greater than 20 mm Hg lasting at least five minutes and 287 similar episodes lasting at least ten minutes. Conversely, end-hour ICP of greater than 20 mm Hg was observed in only 204 cases using manual recording methods.ConclusionAlthough manually recorded end-hour ICP accurately reflected the computerized end-hour and mean hour values, the important omission of a number of episodes of high ICP, some of long duration, results in a clinical picture that is not accurate or informative of the true pattern of unstable ICP in patients with TBI.

Heart-fatty acid-binding and tau proteins relate to brain injury severity and long-term outcome in subarachnoid haemorrhage patients

BACKGROUND Vasospasm and other secondary neurological insults may follow subarachnoid haemorrhage (SAH). Biomarkers have the potential to stratify patient risk and perhaps serve as an early warning sign of delayed ischaemic injury. METHODS Serial cerebrospinal fluid (CSF) samples were collected from 38 consecutive patients with aneurysmal SAH admitted to the neurosurgical intensive care unit. We measured heart-fatty acid-binding protein (H-FABP) and tau protein (τ) levels in the CSF to evaluate their association with brain damage, and their potential as predictors of the long-term outcome. H-FABP and τ were analysed in relation to acute clinical status, assessed by the World Federation of Neurological Surgeons (WFNS) scale, radiological findings, clinical vasospasm, and 6-month outcome. RESULTS H-FABP and τ increased after SAH. H-FABP and τ were higher in patients in poor clinical status on admission (WFNS 4-5) compared with milder patients (WFNS 1-3). Elevated H-FABP and τ levels were also observed in patients with early cerebral ischaemia, defined as a CT scan hypodense lesion visible within the first 3 days after SAH. After the acute phase, H-FABP, and τ showed a delayed increase with the occurrence of clinical vasospasm. Finally, patients with the unfavourable outcome (death, vegetative state, or severe disability) had higher peak levels of both proteins compared with patients with good recovery or moderate disability. CONCLUSIONS H-FABP and τ show promise as biomarkers of brain injury after SAH. They may help to identify the occurrence of vasospasm and predict the long-term outcome.

Increased levels of CSF heart-type fatty acid-binding protein and tau protein after aneurysmal subarachnoid hemorrhage

BACKGROUND Heart-type Fatty Acid-Binding Protein (H-FABP) and tau protein (tau) have been shown to be novel biomarkers associated with brain injury and, therefore, they could represent a useful diagnostic tool in patients with subarachnoid hemorrhage (SAH). The goal of this study was to measure H-FABP and tau in cerebrospinal fluid (CSF) following SAH to test the hypothesis that a relationship exists between SAH severity and H-FABP/tau values. METHODS Twenty-seven consecutive SAH patients admitted to our ICU were studied. Serial CSF samples were obtained in every patient starting on the day of SAH and daily for up to 2 weeks post-SAH. H-FABP/tau levels were measured by enzyme-linked immunosorbent assay. RESULTS Patients with severe SAH showed significantly higher peak levels of H-FABP and tau compared to mild-SAH patients (FABP: p = 0.02; tay: p = 0.002). In addition the peak concentrations of H-FABP and tau in CSF from SAH patients correlated significantly with Glasgow Coma Scale motor score (H-FABP: Spearman r = -0.52, p = 0.006; tau: Spearman r = -0.63, p = 0.0004). Based on outcome at discharge from the hospital, patients were categorized into survivors and non-survivors. Peak concentrations of both proteins in the non-survivors group were significantly higher than in the survivors. CONCLUSIONS H-FABP and tau CSF levels are proportional to SAH severity and may be novel biomarkers that can be used to predict the severity of outcome following clinical SAH.

The genetics of small-vessel disease

Cerebral small-vessel disease (SVD) is a well-known cause of stroke, dementia and death, but its pathogenesis is not yet completely understood. The spectrum of neuroradiological manifestations associated with SVD is wide and may result from chronic and diffuse or acute and focal ischemia (leukoaraiosis and lacunar infarction) as well as from small-vessel rupture (cerebral microbleeds and intracerebral hemorrhage). Several lines of evidence from family and twin studies support the hypothesis that genetic factors may contribute to SVD pathogenesis. Identification of genetic susceptibility factors for SVD may improve our knowledge of SVD pathogenesis and help to identify new therapeutic targets to reduce the burden of SVD-related cognitive decline and stroke disability. A number of monogenic conditions presenting with clinical features of SVD have been described. Although monogenic disorders account for only a small proportion of SVD, study of these diseases may provide further insight into the pathogenesis of SVD. In most cases, however, SVD is thought to be a multifactorial disorder. Several genetic association studies, conducted using the candidate gene and, more recently, the genome-wide approach, have so far failed to demonstrate a convincing association between SVD and genetic variants. Methodological issues, particularly related to inaccurate or heterogeneous phenotyping and insufficient sample sizes, have been invoked as possible reasons for this. Large collaborative efforts and robust replication, as well as implementation of new genetic approaches, are necessary to identify genetic susceptibility factors for complex SVD.

Neuroprotective effect of C1-inhibitor following traumatic brain injury in mice

BACKGROUND The goal of the study was to evaluate the effects of Cl-inhibitor (C1-INH), an endogenous glycoprotein endowed with multiple anti-inflammatory actions, on cognitive and histological outcome following controlled cortical impact (CCI) brain injury. METHODS Male C57B1/6 mice (n=48) were subjected to CCI brain injury. After brain injury, animals randomly received an intravenous infusion of either C1-INH (15 U either at 10 minutes or 1 hour postinjury) or saline (equal volume, 150 microl at 10 min postinjury). Uninjured control mice received identical surgery and saline injection without brain injury. Cognitive function was evaluated at 4 weeks postinjury using the Morris Water Maze. Mice were subsequently sacrificed, the brains were frozen and serial sections were cut. Traumatic brain lesion was assessed by dividing the area of the ipsilateral hemisphere for the area of the contralateral one at the level of the injured area of the brain. FINDINGS Brain-injured mice receiving C1-INH at 10 min postinjury showed attenuated cognitive dysfunction compared to brain-injured mice receiving saline (p < 0.01). These mice also showed a significantly reduced traumatic brain lesion compared to mice receiving saline (p < 0.01). Mice receiving C1-INH at 1 hour post injury did not show a significant improvement in either cognitive or histological outcome. Conclusions Our results suggest that administration of C1-INH at 10 minutes postinjury attenuates cognitive deficits and histological damage associated with traumatic brain injury.

Ultrasound-tagged near-infrared spectroscopy does not disclose absent cerebral circulation in brain-dead adults

Background: Near‐infrared spectroscopy, a non‐invasive technique for monitoring cerebral oxygenation, is widely used, but its accuracy is questioned because of the possibility of extra‐cranial contamination. Ultrasound‐tagged near‐infrared spectroscopy (UT‐NIRS) has been proposed as an improvement over previous methods. We investigated UT‐NIRS in healthy volunteers and in brain‐dead patients. Methods: We studied 20 healthy volunteers and 20 brain‐dead patients with two UT‐NIRS devices, CerOx™ and c‐FLOW™ (Ornim Medical, Kfar Saba, Israel), which measure cerebral flow index (CFI), a parameter related to changes in cerebral blood flow (CBF). Monitoring started after the patients had been declared brain dead for a median of 34 (range: 11–300) min. In 11 cases, we obtained further demonstration of absent CBF. Results: In healthy volunteers, CFI was markedly different in the two hemispheres in the same subject, with wide variability amongst subjects. In brain‐dead patients (median age: 64 yr old, 45% female; 20% traumatic brain injury, 40% subarachnoid haemorrhage, and 40% intracranial haemorrhage), the median (inter‐quartile range) CFI was 41 (36–47), significantly higher than in volunteers (33; 27–36). Conclusions: In brain‐dead patients, where CBF is absent, the UT‐NIRS findings can indicate an apparently perfused brain. This might reflect an insufficient separation of signals from extra‐cranial structures from a genuine appraisal of cerebral perfusion. For non‐invasive assessment of CBF‐related parameters, the near‐infrared spectroscopy still needs substantial improvement.

Comment on “Levels of vancomycin in the cerebral interstitial fluid after severe head injury” by Caricato et al.

We read with interest the brief report “Levels of vancomycin in the cerebral interstitial fluid after severe head injury” by Caricato and coauthors [1]. The use of microdialysis (MD) to explore the extracellular brain space is well documented, and in recent years this technique has been employed for the crucial in vivo measurement of the tissue concentrations of several antibiotics [2]. The paper by Caricato et al. on vancomycin levels measured by MD in human brain tissue is especially interesting since published data on this topic are scarce. Nonetheless, the study has some limitations, which must be borne in mind. The concentrations of endogenous substances in the dialysate account for only a fraction of the concentration in the extracellular fluid around the probe and the relationship between the two is indicated as “recovery”. In vitro, a number of parameters influence recovery, principally the length and permeability of the MD probe and the composition and flow rate of the infused fluid. In vivo, the characteristics of the tissue may also influence recovery. Using CMA 70 catheters for cerebral MD at an infusion rate as low as 0.3 μl/min, in vitro recovery for small molecules like glucose and lactate is high, close to 80% with artificial CSF. This percentage might be lower for bigger molecules, particularly in vivo, where tissue tortuosity and shrinkage of extracellular space both reduce the actual diffusion coefficient of analytes in tissue [3, 4]. Additionally, in edematous brain tissue, we might expect an impairment in antibiotic diffusion because of the lower capillary density, and also a lower concentration due to the edema. We are currently exploring the recovery of a number of substrates in experimental conditions using catheters with different permeability infused with different fluids. This is because the literature reports variable recoveries, and even using low infusion rates they cannot simply be assumed [5, 6]. Since the concentration of vancomycin in fluid sampled from brain tissue was 5–6 times lower than in subcutaneous tissue fluid samples, it is likely that the real tissue concentration of the drug was low, and thus the main message of the investigation still stands. However, vancomycin recovery through the MD membrane is not known, and was not measured by the authors. Without knowing the dynamic changes in actual surface area and the recovery efficiency of the dialysis system in vivo, MD data can provide only a qualitative measure of the changes in concentration of any substance in the diseased brain. Therefore, the conclusion that the concentration is at most 1.2 μg/ml requires further investigation. When comprehensive data are not yet available, as in the case of this pioneering work on vancomycin, in vitro and in vivo tests on recovery are needed for confirmation. References