Previous studies indicate that in published reports, trial results can be distorted by the use of "spin" (specific reporting strategies, intentional or unintentional, emphasizing the beneficial ...effect of the experimental treatment). We aimed to (1) evaluate the presence of "spin" in press releases and associated media coverage; and (2) evaluate whether findings of randomized controlled trials (RCTs) based on press releases and media coverage are misinterpreted.
We systematically searched for all press releases indexed in the EurekAlert! database between December 2009 and March 2010. Of the 498 press releases retrieved and screened, we included press releases for all two-arm, parallel-group RCTs (n = 70). We obtained a copy of the scientific article to which the press release related and we systematically searched for related news items using Lexis Nexis. "Spin," defined as specific reporting strategies (intentional or unintentional) emphasizing the beneficial effect of the experimental treatment, was identified in 28 (40%) scientific article abstract conclusions and in 33 (47%) press releases. From bivariate and multivariable analysis assessing the journal type, funding source, sample size, type of treatment (drug or other), results of the primary outcomes (all nonstatistically significant versus other), author of the press release, and the presence of "spin" in the abstract conclusion, the only factor associated, with "spin" in the press release was "spin" in the article abstract conclusions (relative risk RR 5.6, 95% CI 2.8-11.1, p < 0.001). Findings of RCTs based on press releases were overestimated for 19 (27%) reports. News items were identified for 41 RCTs; 21 (51%) were reported with "spin," mainly the same type of "spin" as those identified in the press release and article abstract conclusion. Findings of RCTs based on the news item was overestimated for ten (24%) reports.
"Spin" was identified in about half of press releases and media coverage. In multivariable analysis, the main factor associated with "spin" in press releases was the presence of "spin" in the article abstract conclusion.
The use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a salvage therapy in cardiogenic shock is becoming of current practice. While VA-ECMO is potentially a life-saving technique, ...results are sometimes mitigated, emphasising the need for selecting the right indication in the right patient. This relies upon a clear definition of the individual therapeutic project, including the potential for recovery as well as the possible complications associated with VA-ECMO. To maximise the benefits of VA-ECMO, the basics of extracorporeal circulation should be perfectly understood since VA-ECMO can sometimes be detrimental. Hence, to be successful, VA-ECMO should be used by teams with sufficient experience and initiated after a thorough multidisciplinary discussion considering patient's medical history, pathology as well the anticipated evolution of the disease.
Objective:
Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their ...activation in the latter context are poorly understood, particularly the involvement of N‐methyl‐D‐aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation.
Methods and Results:
We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP+/+LysM Cre+/− mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury.
Interpretation:
Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain. ANN NEUROL 2012;72:536–549
Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of α2-adrenergic receptors, also provides ...neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury.
The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 μM of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures.
Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size ± SD: 577 ± 148 μm vs. 1028 ± 213 μm, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures.
These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.
Astrocytes represent a major non‐neuronal cell population actively involved in brain functions and pathologies. They express a large amount of gap junction proteins that allow communication between ...adjacent glial cells and the formation of glial networks. In addition, these membrane proteins can also operate as hemichannels, through which “gliotransmitters” are released, and thus contribute to neuroglial interaction. There are now reports demonstrating that alterations of astroglial gap junction communication and/or hemichannel activity impact neuronal and synaptic activity. Two decades ago we reported that several general anesthetics inhibited gap junctions in primary cultures of astrocytes (Mantz et al., (1993) Anesthesiology 78(5):892‐901). As there are increasing studies investigating neuroglial interactions in anesthetized mice, we here updated this previous study by employing acute cortical slices and by characterizing the effects of general anesthetics on both astroglial gap junctions and hemichannels. As hemichannel activity is not detected in cortical astrocytes under basal conditions, we treated acute slices with the endotoxin LPS or proinflammatory cytokines to induce hemichannel activity in astrocytes, which in turn activated neuronal hemichannels. We studied two extensively used anesthetics, propofol and ketamine, and the more recently developed dexmedetomidine. We report that these drugs have differential inhibitory effects on gap junctional communication and hemichannel activity in astrocytes when used in their respective, clinically relevant concentrations, and that dexmedetomidine appears to be the least effective on both channel functions. In addition, the three anesthetics have similar effects on neuronal hemichannels. Altogether, our observations may contribute to optimizing the selection of anesthetics for in vivo animal studies. GLIA 2016;64:524–536
Main points
Three general anesthetics inhibit gap junctions and hemichannels activated by LPS or cytokines in cortical astrocytes.
The cytokines also activate hemichannels in cortical neurons, which are similarly inhibited by the anesthetics.
Purpose
To characterize the perceived utilization of physical restraint (PR) in mechanically ventilated intensive care unit (ICU) patients and to identify clinical and structural factors influencing ...PR use.
Methods
A questionnaire was personally handed to one intensivist in 130 ICUs in France then collected on-site 2 weeks later.
Results
The questionnaire was returned by 121 ICUs (response rate, 93 %), 66 % of which were medical-surgical ICUs. Median patient-to-nurse ratio was 2.8 (2.5–3.0). In 82 % of ICUs, PR is used at least once during mechanical ventilation in more than 50 % of patients. In 65 % of ICUs, PR, when used, is applied for more than 50 % of mechanical ventilation duration. Physical restraint is often used during awakening from sedation and when agitation occurs and is less commonly used in patients receiving deep sedation or neuromuscular blockers or having severe tetraparesis. In 29 % of ICUs, PR is used in more than 50 % of awake, calm and co-operative patients. PR is started without written medical order in more than 50 % of patients in 68 % of ICUs, and removed without written medical order in more than 50 % of patients in 77 % of ICUs. Only 21 % of ICUs have a written local procedure for PR use.
Conclusions
This survey in a country with a relatively high patient-to-nurse ratio shows that PR is frequently used in patients receiving mechanical ventilation, with wide variations according to patient condition. The common absence of medical orders for starting or removing PR indicates that these decisions are mostly made by the nurses.
Proper prehospital triage of trauma patients is a cornerstone for the process of care of trauma patients. In France, emergency physicians perform this process according to a national triage algorithm ...called Vittel Triage Criteria (VTC), introduced in 2002 to help the triage decision-making process. The aim of this two-center study was to evaluate the performance of the triage process based on the VTC to identify major trauma patients in the Paris area.
This was a retrospective analysis of two cohorts. The first cohort consisted of all patients admitted between January 2011 and September 2012 in two trauma referral centers in the region of Paris (Ile de France) and allowed estimation of overtriage. Undertriage was assessed in a second cohort made up of all prehospital trauma interventions from one emergency medicine sector during the same period. Adequate triage was defined by a direct admission of patients with an Injury Severity Score (ISS) greater than 15 into one of the regional trauma centers, and undertriage was defined as an initial nonadmission to a trauma center. Overtriage was defined by an admission of patients with an ISS of 15 or lower to a trauma center. The performance of the VTC was evaluated according to a strict to-the-letter application of the VTC and termed as theoretical triage. Logistic regression was performed to identify VTC criteria able to predict major trauma.
Among 998 admitted patients of the first cohort, 173 patients (17%) were excluded because they were not directly admitted in the first 24 hours. In the first cohort (n = 825), adequate triage was 58% and overtriage was 42%. In the second cohort (n = 190), adequate triage was 40%, overtriage was 60%, and undertriage was less than 1%. Theoretical triage generated a nonsignificantly lower overtriage and a higher undertriage compared with observed triage. The most powerful predictors of major trauma were paralysis (odds ratio OR, 0.09; 95% confidence interval CI, 0.03-0.22), flail chest (OR, 0.1; 95% CI, 0.01-0.03), and Glasgow Coma Scale (GCS) score of less than 13 (OR, 0.28; 95% CI, 0.17-0.45), whereas global assessments of speed and mechanism alone were poor predictors (positive likelihood ratio, 0.92-1.4).
In the Paris area, the French physician-based prehospital triage system for patients with suspicion of major trauma showed a high rate of overtriage and a low rate of undertriage. Criteria of global assessment of speed and mechanism alone were poor predictors of major trauma.
Postoperative liver failure after hepatectomy has been identified by the association of prothrombin time <50% and serum bilirubin >50 micromol/L (the "50-50" criteria). Whether these criteria are of ...prognostic value in a prospective study remains unknown.
To determine prospectively the prognostic value of the 50-50 criteria on day 3 and day 5 in intensive care unit (ICU) patients after hepatectomy.
From January 2005 to February 2007, among 436 elective liver resections, 99 (23%) consecutive patients aged 58 +/- 17 years were admitted postoperatively in ICU with a mean SAPSII 25 +/- 10. Malignant disease was present in 87 and major resections (< or =3 segments) were performed in 79 (80%) cases. The underlying liver parenchyma was abnormal in 59 (59%) cases including cirrhosis, fibrosis, or steatosis >30% in 19, 23, and 17 patients, respectively.
The 50-50 criteria were present on day 3 in 10 patients and on day 5 in 13. Ten patients (10, 6%) died in ICU. Survivors with these criteria were characterized by early aggressive support including reoperation and/or liver assist system. Nonsurvivors were more often cirrhotic, had significantly higher SAPS II and more frequently postoperative prolonged mechanical ventilation. The 50-50 criteria on days 3 and 5 were predictors of death on multivariate analysis OR (95% CI): 12.7 (2.3-71.4), OR (95% CI): 29.4 (4.9-167), respectively.
After hepatic resection, results of this prospective study validate the 50-50 criteria as a predictive factor of mortality in ICU on both days 3 and 5. These criteria allow an early diagnosis of postoperative liver failure, which may contribute to reduce mortality in ICU patients after hepatectomy.
Sepsis is associated with increased mortality, delirium and long-term cognitive impairment in intensive care unit (ICU) patients. Electroencephalogram (EEG) abnormalities occurring at the acute stage ...of sepsis may correlate with severity of brain dysfunction. Predictive value of early standard EEG abnormalities for mortality in ICU septic patients remains to be assessed.
In this prospective, single center, observational study, standard EEG was performed, analyzed and classified according to both Synek and Young EEG scales, in consecutive patients acutely admitted in ICU for sepsis. Delirium, coma and the level of sedation were assessed at the time of EEG recording; and duration of sedation, occurrence of in-ICU delirium or death were assessed during follow-up. Adjusted analyses were carried out using multiple logistic regression.
One hundred ten patients were included, mean age 63.8 (±18.1) years, median SAPS-II score 38 (29-55). At the time of EEG recording, 46 patients (42%) were sedated and 22 (20%) suffered from delirium. Overall, 54 patients (49%) developed delirium, of which 32 (29%) in the days after EEG recording. 23 (21%) patients died in the ICU. Absence of EEG reactivity was observed in 27 patients (25%), periodic discharges (PDs) in 21 (19%) and electrographic seizures (ESZ) in 17 (15%). ICU mortality was independently associated with a delta-predominant background (OR: 3.36; 95% CI 1.08 to 10.4), absence of EEG reactivity (OR: 4.44; 95% CI 1.37-14.3, PDs (OR: 3.24; 95% CI 1.03 to 10.2), Synek grade ≥ 3 (OR: 5.35; 95% CI 1.66-17.2) and Young grade > 1 (OR: 3.44; 95% CI 1.09-10.8) after adjustment to Simplified Acute Physiology Score (SAPS-II) at admission and level of sedation. Delirium at the time of EEG was associated with ESZ in non-sedated patients (32% vs 10%, p = 0.037); with Synek grade ≥ 3 (36% vs 7%, p< 0.05) and Young grade > 1 (36% vs 17%, p< 0.001). Occurrence of delirium in the days after EEG was associated with a delta-predominant background (48% vs 15%, p = 0.001); absence of reactivity (39% vs 10%, p = 0.003), Synek grade ≥ 3 (42% vs 17%, p = 0.001) and Young grade >1 (58% vs 17%, p = 0.0001).
In this prospective cohort of 110 septic ICU patients, early standard EEG was significantly disturbed. Absence of EEG reactivity, a delta-predominant background, PDs, Synek grade ≥ 3 and Young grade > 1 at day 1 to 3 following admission were independent predictors of ICU mortality and were associated with occurence of delirium. ESZ and PDs, found in about 20% of our patients. Their prevalence could have been higher, with a still higher predictive value, if they had been diagnosed more thoroughly using continuous EEG.
There is an increasing interest in the use of dexmedetomidine for anesthesia and sedation. Here, we used the mouse organotypic hippocampal slice culture to investigate whether dexmedetomidine ...exhibits postconditioning properties against oxygen and glucose deprivation (OGD). The role of the focal adhesion and extracellular-regulated kinases pathways in these effects were examined in both postconditioning and preconditioning.
Slices were obtained from P5 mouse. In postconditioning experiments, Dexmedetomidine (1 microm) was incubated 60 min after the end of OGD. In preconditioning experiments, dexmedetomidine was applied 3 h before OGD. Pharmacologic modulation of the studied pathways was achieved by using selective inhibitors of these cascades. Cell death was assessed 72 h after OGD using propidium iodide labeling and protein expression of activated caspase 3.
Maximum cell death increased with the duration of OGD. Dexmedetomidine induced a postconditioning effect in the CA1 (but not dentate gyrus) subfield area, which was significantly reduced by modulators of the focal adhesion and the extracellular-regulated kinases pathways. The combination of the inhibitors of the two pathways completely abolished the postconditioning effect of dexmedetomidine. The preconditioning effect of dexmedetomidine against ischemia-induced injury was observed in all hippocampal subfield areas. Results obtained with the pharmacologic modulation used for postconditioning also applied to dexmedetomidine-induced preconditioning.
Dexmedetomidine exhibits significant, but moderate, postconditioning properties against oxygen and glucose deprivation-induced injury. Activation of focal adhesion and the imidazoline 1 receptors-extracellular-regulated kinases pathways is involved in dexmedetomidine-induced postconditioning and preconditioning as well.
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