Valeria Conte

Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome.

ObjectiveTo determine whether gas exchange improvement in response to the prone position is associated with an improved outcome in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). DesignRetrospective analysis of patients in the pronation arm of a controlled randomized trial on prone positioning and patients enrolled in a previous pilot study of the prone position. SettingTwenty-eight Italian and two Swiss intensive care units. PatientsWe studied 225 patients meeting the criteria for ALI or ARDS. InterventionsPatients were in prone position for 10 days for 6 hrs/day if they met ALI/ARDS criteria when assessed each morning. Respiratory variables were recorded before and after 6 hrs of pronation with unchanged ventilatory settings. Measurements and Main ResultsWe measured arterial blood gas alterations to the first pronation and the 28-day mortality rate. The independent risk factors for death in the general population were the Pao2/Fio2 ratio (odds ratio, 0.992; confidence interval, 0.986–0.998), the minute ventilation/Paco2 ratio (odds ratio, 1.003; confidence interval, 1.000–1.006), and the concentration of plasma creatinine (odds ratio, 1.385; confidence interval, 1.116–1.720). Pao2 responders (defined as the patients who increased their Pao2/Fio2 by ≥20 mm Hg, 150 patients, mean increase of 100.6 ± 61.6 mm Hg [13.4 ± 8.2 kPa]) had an outcome similar to the nonresponders (59 patients, mean decrease −6.3 ± 23.7 mm Hg [−0.8 ± 3.2 kPa]; mortality rate 44% and 46%, respectively; relative risk, 1.04; confidence interval, 0.74–1.45, p = .65). The Paco2 responders (defined as patients whose Paco2 decreased by ≥1 mm Hg, 94 patients, mean decrease −6.0 ± 6 mm Hg [−0.8 ± 0.8 kPa]) had an improved survival when compared with nonresponders (115 patients, mean increase 6 ± 6 mm Hg [0.8 ± 0.8 kPa]; mortality rate 35.1% and 52.2%, respectively; relative risk, 1.48; confidence interval, 1.07–2.05, p = .01). ConclusionALI/ARDS patients who respond to prone positioning with reduction of their Paco2 show an increased survival at 28 days. Improved efficiency of alveolar ventilation (decreased physiologic deadspace ratio) is an important marker of patients who will survive acute respiratory failure.

Evaluation of pharmacological treatment strategies in traumatic brain injury.

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.

Arterio-jugular Difference of Oxygen Content and Outcome After Head Injury

This study investigated AJDo2 (arterio-jugular difference of oxygen content) in a large sample of severely head-injured patients to identify its pattern during the first days after injury and to describe the relationship of AJDo2 with acute neurological severity and with outcome 6 mo after trauma. In 229 comatose head-injured patients, we monitored intracranial pressure, cerebral perfusion pressure, and AJDo2. Outcome was defined 6 mo after injury. Jugular hemoglobin oxygen saturation (Sjo2) averaged 68%. The mean AJDo2 was 4.24 vol% (sd, 1.3 vol%). There were 80 measurements (4.6%) with Sjo2 <5% and 304 (17.6%) with saturation >75%. AJDo2 was higher than 8.7 vol% in 8 measurements (0.4%) and was lower than 3.9 vol% in 718 (42%) measurements. AJDo2 was higher during the first tests and decreased steadily over the next few days. Cases with a favorable outcome had a higher mean AJDo2 (4.3 vol%; sd, 0.3 vol%) than patients with severe disability or vegetative status (3.8 vol%; sd, 1.3 vol%) and patients who died (3.6 vol%; sd, 1 vol%). This difference was significant (P < 0.001). We conclude that low levels of AJDo2 are correlated with a poor prognosis, whereas normal or high levels of AJDo2 are predictive of better results.

Quantitative assessments of traumatic axonal injury in human brain: concordance of microdialysis and advanced MRI

Axonal injury is a major contributor to adverse outcomes following brain trauma. However, the extent of axonal injury cannot currently be assessed reliably in living humans. Here, we used two experimental methods with distinct noise sources and limitations in the same cohort of 15 patients with severe traumatic brain injury to assess axonal injury. One hundred kilodalton cut-off microdialysis catheters were implanted at a median time of 17 h (13-29 h) after injury in normal appearing (on computed tomography scan) frontal white matter in all patients, and samples were collected for at least 72 h. Multiple analytes, such as the metabolic markers glucose, lactate, pyruvate, glutamate and tau and amyloid-β proteins, were measured every 1-2 h in the microdialysis samples. Diffusion tensor magnetic resonance imaging scans at 3 T were performed 2-9 weeks after injury in 11 patients. Stability of diffusion tensor imaging findings was verified by repeat scans 1-3 years later in seven patients. An additional four patients were scanned only at 1-3 years after injury. Imaging abnormalities were assessed based on comparisons with five healthy control subjects for each patient, matched by age and sex (32 controls in total). No safety concerns arose during either microdialysis or scanning. We found that acute microdialysis measurements of the axonal cytoskeletal protein tau in the brain extracellular space correlated well with diffusion tensor magnetic resonance imaging-based measurements of reduced brain white matter integrity in the 1-cm radius white matter-masked region near the microdialysis catheter insertion sites. Specifically, we found a significant inverse correlation between microdialysis measured levels of tau 13-36 h after injury and anisotropy reductions in comparison with healthy controls (Spearmans r = -0.64, P = 0.006). Anisotropy reductions near microdialysis catheter insertion sites were highly correlated with reductions in multiple additional white matter regions. We interpret this result to mean that both microdialysis and diffusion tensor magnetic resonance imaging accurately reflect the same pathophysiological process: traumatic axonal injury. This cross-validation increases confidence in both methods for the clinical assessment of axonal injury. However, neither microdialysis nor diffusion tensor magnetic resonance imaging have been validated versus post-mortem histology in humans. Furthermore, future work will be required to determine the prognostic significance of these assessments of traumatic axonal injury when combined with other clinical and radiological measures.

Analysis of propofol/remifentanil infusion protocol for tumor surgery with intraoperative brain mapping.

Background There is no general consensus about the best anesthesiologic approach to use during craniotomies with intraoperative brain mapping, and large prospective studies evaluating the complications associated with different approaches are lacking. Objective of this study was to prospectively collect and evaluate data about a large series of consecutive asleep-awake and asleep-asleep craniotomies. Methods We analyzed 238 consecutive procedures from January 2005 to December 2008. During asleep-awake procedures, patients were initially ventilated through a laryngeal mask which was removed to allow language testing. During asleep-asleep procedures, patients remained sedated and intubated to permit motor testing. Results In asleep-awake craniotomies [n=135, age 42 y (range: 16 to 72 y), American Society of Anesthologists classification (ASA) 1 (1 to 3), and body mass index 24.2±3.7 kg/m2], 43% of the procedures were free of complications. Most common complications were hypertension (27%) and brief clinical seizures (16%), but also hypotension (10%), vomiting (7%), brief periods of apnea (4%), and agitation (6%) were observed. In 7% of the procedures, seizures required pharmacologic treatment. Fifty-nine percent of the asleep-asleep procedures [n=103, age 51 y (range: 21 to 76 y), ASA 1 (1 to 3), body mass index 25.4±3.9 kg/m2, P<0.05 vs. asleep-awake] were free of complications. Clinical seizures were observed in 31% of the cases. The administration of boluses of hypnotics was rarely necessary (6%) and safer because of secured airways. Conclusions With this study, we demonstrated the feasibility and safety of our protocols on large prospective case series. Asleep-awake protocol can be safely used when intraoperative language mapping is planned, whereas an asleep-asleep protocol with secured airway might be preferred when motor testing only is required.

Neurotrophic Factors: Pathophysiology and Therapeutic Applications in Traumatic Brain Injury

AbstractNeurotrophic factors (NTFs) are endogenous molecules that play a crucial role in the maintenance, survival and differentiation of various neuronal populations within the developing and adult brain. In vitro and in vivo studies have shown that NTFs can attenuate neuronal injury initiated by cascades that are activated by traumatic brain injury (TBI) including excitotoxic damage, ischemia, and apoptosis. NTFs may also play a role in repair-regeneration processes such as axonal regeneration, neuronal plasticity and neurogenesis that could be critical for recovery after TBI. Nerve growth factor (NGF), insulin like growth factor I (IGF-I) and basic fibroblast growth factor (bFGF) and glial cell-derived neurotrophic factor (GDNF) have been shown to be effective in reducing neurobehavioral dysfunction and/or histopathological damage in experimental models of TBI. NTFs appear to be promising therapeutic tools for TBI, although more studies are necessary to elucidate their potential application and to test delivery systems that allow local, regulated supply to specific populations of neurons. This article provides an overview of the pathophysiology and potential therapeutic application of neurotrophic factors in TBI.

Ficolin-3–mediated lectin complement pathway activation in patients with subarachnoid hemorrhage

Objectives: To assess the involvement of ficolin-3, the main initiator of the lectin complement pathway (LCP), in subarachnoid hemorrhage (SAH) pathology and outcome. Methods: In this preliminary exploratory study, plasma concentration of ficolin-3 and of ficolin-3–mediated functional LCP activity was measured, along with that of other LCP initiators (mannose-binding lectin, ficolin-2, and ficolin-1), C3 activation products, and soluble C5b-9 terminal complex, in a prospective cohort of 39 patients with SAH and 20 healthy controls. The following parameters were recorded: SAH severity, assessed using the World Federation of Neurosurgical Societies grading scale; vasospasm, defined as neuro-worsening with angiographic confirmation of vessel narrowing; cerebral ischemia, defined as hypodense lesion on CT scan performed before discharge; and 6-month outcome, assessed using the Glasgow Outcome Scale. Results: In patients, no changes were detected for ficolin-3 compared with controls. Notably, however, ficolin-3–mediated functional LCP activity was reduced. Low levels of plasma ficolin-3 and ficolin-3–mediated functional LCP activity were related to SAH severity, vasospasm, and cerebral ischemia. Moreover, ficolin-3 functional LCP activity was decreased in patients with unfavorable outcome. Conclusion: Our data provide evidence that LCP is activated after SAH and that the actual plasma concentrations of ficolin-3 reflect the severity of brain injury as evaluated by clinical and structural parameters. These results support the idea that ficolin-3–mediated functional LCP activity may be targeted to control injury progression in SAH.

Experimental subarachnoid haemorrhage results in multifocal axonal injury

The great majority of acute brain injury results from trauma or from disorders of the cerebrovasculature, i.e. ischaemic stroke or haemorrhage. These injuries are characterized by an initial insult that triggers a cascade of injurious cellular processes. The nature of these processes in spontaneous intracranial haemorrhage is poorly understood. Subarachnoid haemorrhage, a particularly deadly form of intracranial haemorrhage, shares key pathophysiological features with traumatic brain injury including exposure to a sudden pressure pulse. Here we provide evidence that axonal injury, a signature characteristic of traumatic brain injury, is also a prominent feature of experimental subarachnoid haemorrhage. Using histological markers of membrane disruption and cytoskeletal injury validated in analyses of traumatic brain injury, we show that axonal injury also occurs following subarachnoid haemorrhage in an animal model. Consistent with the higher prevalence of global as opposed to focal deficits after subarachnoid haemorrhage and traumatic brain injury in humans, axonal injury in this model is observed in a multifocal pattern not limited to the immediate vicinity of the ruptured artery. Ultrastructural analysis further reveals characteristic axonal membrane and cytoskeletal changes similar to those associated with traumatic axonal injury. Diffusion tensor imaging, a translational imaging technique previously validated in traumatic axonal injury, from these same specimens demonstrates decrements in anisotropy that correlate with histological axonal injury and functional outcomes. These radiological indicators identify a fibre orientation-dependent gradient of axonal injury consistent with a barotraumatic mechanism. Although traumatic and haemorrhagic acute brain injury are generally considered separately, these data suggest that a signature pathology of traumatic brain injury-axonal injury-is also a functionally significant feature of subarachnoid haemorrhage, raising the prospect of common diagnostic, prognostic, and therapeutic approaches to these conditions.

Spectral analysis of heart rate variability during asleep-awake craniotomy for tumor resection

Anesthesia during asleep-awake craniotomy should provide adequate analgesia and sedation whereas permitting language testing. In this work, we used the analysis of heart rate variability (HRV) to quantify the sympatho-vagal balance and better evaluate patients stress response during asleep-awake craniotomy. Patients admitted to our hospital for tumor resection with language testing were studied (n=21, age range: 22 to 53 y ). Heart rate and systolic arterial blood pressure were collected at 5 time points: T1: preanesthesia; T2: dura mater opening; T3: cortical mapping; T4: subcortical mapping; T5: dura mater suturing. Patients were anesthetized with propofol/remifentanil infusion and ventilated via laryngeal mask during T2, but were awakened for language testing at T3 and T4, and resedated with remifentanil during T5. At each time point, HRV was analyzed by power spectrum analysis: overall variance, very low frequency (VLF), low frequency (LF) and high frequency (HF) powers, and LF/HF ratio (an index of prevalence of sympathetic over parasympathetic tone) were derived. A significant increase in both heart rate and systolic arterial blood pressure was observed from time point T3 through T5 (P<0.05, compared with T1). HRV analysis revealed that the LF/HF ratio progressively increased to reach values during T4 that were significantly higher than preanesthesia values (P<0.05). During T5, LF/HF ratio returned to preanesthesia level. HRV analysis confirmed the presence of moderate intraoperative stress response, indicating a significant increase in the LF/HF ratio during the awake phases. This information might help in tailoring the protocol and the duration of awake phase according to the individual autonomic response.