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author:("manta, Jean")
1.  Comfort and patient-centred care without excessive sedation: the eCASH concept 
Intensive Care Medicine  2016;42:962-971.
We propose an integrated and adaptable approach to improve patient care and clinical outcomes through analgesia and light sedation, initiated early during an episode of critical illness and as a priority of care. This strategy, which may be regarded as an evolution of the Pain, Agitation and Delirium guidelines, is conveyed in the mnemonic eCASH—early Comfort using Analgesia, minimal Sedatives and maximal Humane care. eCASH aims to establish optimal patient comfort with minimal sedation as the default presumption for intensive care unit (ICU) patients in the absence of recognised medical requirements for deeper sedation. Effective pain relief is the first priority for implementation of eCASH: we advocate flexible multimodal analgesia designed to minimise use of opioids. Sedation is secondary to pain relief and where possible should be based on agents that can be titrated to a prespecified target level that is subject to regular review and adjustment; routine use of benzodiazepines should be minimised. From the outset, the objective of sedation strategy is to eliminate the use of sedatives at the earliest medically justifiable opportunity. Effective analgesia and minimal sedation contribute to the larger aims of eCASH by facilitating promotion of sleep, early mobilization strategies and improved communication of patients with staff and relatives, all of which may be expected to assist rehabilitation and avoid isolation, confusion and possible long-term psychological complications of an ICU stay. eCASH represents a new paradigm for patient-centred care in the ICU. Some organizational challenges to the implementation of eCASH are identified.
PMCID: PMC4846689  PMID: 27075762
ICU; Pain; Analgesia; Sedation; eCASH
2.  Early Standard Electroencephalogram Abnormalities Predict Mortality in Septic Intensive Care Unit Patients 
PLoS ONE  2015;10(10):e0139969.
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.
PMCID: PMC4598037  PMID: 26447697
3.  Multicenter Testing of the Rapid Quantification of Radical Oxygen Species in Cerebrospinal Fluid to Diagnose Bacterial Meningitis 
PLoS ONE  2015;10(5):e0128286.
Meningitis is a serious concern after traumatic brain injury (TBI) or neurosurgery. This study tested the level of reactive oxygen species (ROS) in cerebrospinal fluid (CSF) to diagnose meningitis in febrile patients several days after trauma or surgery.
Febrile patients (temperature > 38°C) after TBI or neurosurgery were included prospectively. ROS were measured in CSF within 4 hours after sampling using luminescence in the basal state and after cell stimulation with phorbol 12-myristate 13-acetate (PMA). The study was conducted in a single-center cohort 1 (n = 54, training cohort) and then in a multicenter cohort 2 (n = 136, testing cohort) in the Intensive Care and Neurosurgery departments of two teaching hospitals. The performance of the ROS test was compared with classical CSF criteria, and a diagnostic decision for meningitis was made by two blinded experts.
The production of ROS was higher in the CSF of meningitis patients than in non-infected CSF, both in the basal state and after PMA stimulation. In cohort 1, ROS production was associated with a diagnosis of meningitis with an AUC of 0.814 (95% confidence interval (CI) [0.684–0.820]) for steady-state and 0.818 (95% CI [0.655–0.821]) for PMA-activated conditions. The best threshold value obtained in cohort 1 was tested in cohort 2 and showed high negative predictive values and low negative likelihood ratios of 0.94 and 0.36 in the basal state, respectively, and 0.96 and 0.24 after PMA stimulation, respectively.
The ROS test in CSF appeared suitable for eliminating a diagnosis of bacterial meningitis.
PMCID: PMC4444193  PMID: 26011286
4.  Sedation options for the morbidly obese intensive care unit patient: a concise survey and an agenda for development 
We offer some perspectives and commentary on the sedation of obese patients in the intensive care unit (ICU).
Sedation in morbidly obese patients should conform to the same broad principles now current in ICU practice. These include a general presumption against benzodiazepines as first-line agents. Opioids should be avoided in any situation where spontaneous breathing is required. Remifentanil is the preferred agent where continuous stable opioid levels using an infusion are required, because of its lack of context-sensitive accumulation. Volatile anaesthetics may be an option for the same reason but there are no substantial, controlled demonstrations of effectiveness/safety in short-term use in the ICU setting. Propofol is a valuable resource in the morbidly obese patients but the duration of continuous sedation should not exceed 6 days, in order to avoid propofol infusion syndrome. Alpha-2 agonists offer a range of theoretically positive features for the sedation of morbidly obese patients, but at present there is a lack of pharmacokinetic data and a critical mass of high-grade clinical data. Dexmedetomidine has the attraction of not causing respiratory depression or obstructive breathing during sedation and its sympatholytic effects should help deliver stable blood pressure and heart rate. Ketamine has a poor tolerability profile in adults so its use in the ICU context is largely confined to paediatrics.
None of the agents currently available is ideal for every situation encountered in the management of morbidly obese patients. This article identifies additional research needed to place sedation practice of obese patients on a more systematic footing.
PMCID: PMC4399437  PMID: 25883785
Clonidine; Dexmedetomidine; Intensive care; Ketamine; Obesity; Opioids; Propofol; Sedation; Volatile anaesthetics; Benzodiazepines
5.  Sedation in non-invasive ventilation: do we know what to do (and why)? 
This review examines some of the issues encountered in the use of sedation in patients receiving respiratory support from non-invasive ventilation (NIV). This is an area of critical and intensive care medicine where there are limited (if any) robust data to guide the development of best practice and where local custom appears to exert a strong influence on patterns of care.
We examine aspects of sedation for NIV where the current lack of structure may be contributing to missed opportunities to improve standards of care and examine the existing sedative armamentarium. No single sedative agent is currently available that fulfils the criteria for an ideal agent but we offer some observations on the relative merits of different agents as they relate to considerations such as effects on respiratory drive and timing, and airways patency. The significance of agitation and delirium and the affective aspect(s) of dyspnoea are also considered.
We outline an agenda for placing the use of sedation in NIV on a more systematic footing, including clearly expressed criteria and conditions for terminating NIV and structural and organizational conditions for prospective multicentre trials.
PMCID: PMC4333891  PMID: 25699177
Agitation; Benzodiazepines; Delirium; Dexmedetomidine; Dyspnoea; Ketamine; Non-invasive ventilation; Opioids; Propofol; Sedation
6.  Sedation and weaning from mechanical ventilation: time for ‘best practice’ to catch up with new realities? 
Delivery of sedation in anticipation of weaning of adult patients from prolonged mechanical ventilation is an arena of critical care medicine where opinion-based practice is currently hard to avoid because robust evidence is lacking. We offer some views on this subject, hoping to stimulate debate among colleagues.
PMCID: PMC4252852  PMID: 25473522
Intensive care; Mechanical ventilation; Sedation; Weaning
7.  GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration 
Annals of neurology  2013;73(5):10.1002/ana.23868.
The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.
We combined in vivo systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation.
We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.
Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.
PMCID: PMC3837433  PMID: 23494575
8.  Misrepresentation of Randomized Controlled Trials in Press Releases and News Coverage: A Cohort Study 
PLoS Medicine  2012;9(9):e1001308.
A study conducted by Amélie Yavchitz and colleagues examines the factors associated with “spin” (specific reporting strategies, intentional or unintentional, that emphasize the beneficial effect of treatments) in press releases of clinical trials.
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.
Methods and Findings
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.
Editors' Summary
The mass media play an important role in disseminating the results of medical research. Every day, news items in newspapers and magazines and on the television, radio, and internet provide the general public with information about the latest clinical studies. Such news items are written by journalists and are often based on information in “press releases.” These short communications, which are posted on online databases such as EurekAlert! and sent directly to journalists, are prepared by researchers or more often by the drug companies, funding bodies, or institutions supporting the clinical research and are designed to attract favorable media attention to newly published research results. Press releases provide journalists with the information they need to develop and publish a news story, including a link to the peer-reviewed journal (a scholarly periodical containing articles that have been judged by independent experts) in which the research results appear.
Why Was This Study Done?
In an ideal world, journal articles, press releases, and news stories would all accurately reflect the results of health research. Unfortunately, the findings of randomized controlled trials (RCTs—studies that compare the outcomes of patients randomly assigned to receive alternative interventions), which are the best way to evaluate new treatments, are sometimes distorted in peer-reviewed journals by the use of “spin”—reporting that emphasizes the beneficial effects of the experimental (new) treatment. For example, a journal article may interpret nonstatistically significant differences as showing the equivalence of two treatments although such results actually indicate a lack of evidence for the superiority of either treatment. “Spin” can distort the transposition of research into clinical practice and, when reproduced in the mass media, it can give patients unrealistic expectations about new treatments. It is important, therefore, to know where “spin” occurs and to understand the effects of that “spin”. In this study, the researchers evaluate the presence of “spin” in press releases and associated media coverage and analyze whether the interpretation of RCT results based on press releases and associated news items could lead to the misinterpretation of RCT results.
What Did the Researchers Do and Find?
The researchers identified 70 press releases indexed in EurekAlert! over a 4-month period that described two-arm, parallel-group RCTs. They used Lexis Nexis, a database of news reports from around the world, to identify associated news items for 41 of these press releases and then analyzed the press releases, news items, and abstracts of the scientific articles related to each press release for “spin”. Finally, they interpreted the results of the RCTs using each source of information independently. Nearly half the press releases and article abstract conclusions contained “spin” and, importantly, “spin” in the press releases was associated with “spin” in the article abstracts. The researchers overestimated the benefits of the experimental treatment from the press release as compared to the full-text peer-reviewed article for 27% of reports. Factors that were associated with this overestimation of treatment benefits included publication in a specialized journal and having “spin” in the press release. Of the news items related to press releases, half contained “spin”, usually of the same type as identified in the press release and article abstract. Finally, the researchers overestimated the benefit of the experimental treatment from the news item as compared to the full-text peer-reviewed article in 24% of cases.
What Do These Findings Mean?
These findings show that “spin” in press releases and news reports is related to the presence of “spin” in the abstract of peer-reviewed reports of RCTs and suggest that the interpretation of RCT results based solely on press releases or media coverage could distort the interpretation of research findings in a way that favors experimental treatments. This interpretation shift is probably related to the presence of “spin” in peer-reviewed article abstracts, press releases, and news items and may be partly responsible for a mismatch between the perceived and real beneficial effects of new treatments among the general public. Overall, these findings highlight the important role that journal reviewers and editors play in disseminating research findings. These individuals, the researchers conclude, have a responsibility to ensure that the conclusions reported in the abstracts of peer-reviewed articles are appropriate and do not over-interpret the results of clinical research.
Additional Information
Please access these Web sites via the online version of this summary at
The PLOS Hub for Clinical Trials, which collects PLOS journals relating to clinical trials, includes some other articles on “spin” in clinical trial reports
EurekAlert is an online free database for science press releases
The UK National Health Service Choices website includes Beyond the Headlines, a resource that provides an unbiased and evidence-based analysis of health stories that make the news for both the public and health professionals
The US-based organization HealthNewsReview, a project supported by the Foundation for Informed Medical Decision Making, also provides expert reviews of news stories
PMCID: PMC3439420  PMID: 22984354
9.  Adjunctive remifentanil infusion in deeply sedated and paralyzed ICU patients during fiberoptic bronchoscopy procedure: a prospective, randomized, controlled study 
Even with an adequate pain assessment, critically ill patients under sedation experience pain during procedures in the intensive care unit (ICU). We evaluated the effects of adjunctive administration of Remifentanil, a short-acting drug, in deeply sedated patient on variation of Bispectral Index (BIS) during a fiberoptic bronchoscopy.
A prospective, randomized, blinded, placebo-controlled study was conducted in 18-bed ICU. Patients needing a tracheal fibroscopy under deep sedation (midazolam (0.1 mg/kg per hour) fentanyl (4 μg/kg per hour)) and neuromuscular blocking (atracurium 0.5 mg/kg) were included in the study. A continuous monitoring of BIS, arterial pressure, and heart rate were realized before, during, and after the fiberoptic exam. An adjunctive continuous placebo or Remifentanil infusion was started just before the fiberoptic exam with a target effect-site concentration of 4 ng/ml using a Base Primea pump.
Mean arterial pressure and heart rates were comparable between the placebo and Remifentanil groups at all times of the procedure. We did not observe differences in the variation of BIS values between the two groups during procedure. We described no change in BIS values relative to the placebo group in this population.
In deeply sedated and paralyzed patients, receiving analgesic support based on a scale score an additional administration of short-acting analgesic drug, such as Remifentanil, seems not to be necessary for acute pain control.
Trial registration
PMCID: PMC3487977  PMID: 22800647
Pain; Intensive care; Bispectral index; Remifentanil
10.  Delphi-Consensus Weights for Ischemic and Bleeding Events to Be Included in a Composite Outcome for RCTs in Thrombosis Prevention 
PLoS ONE  2011;6(4):e18461.
Background and Objectives
To weight ischemic and bleeding events according to their severity to be used in a composite outcome in RCTs in the field of thrombosis prevention.
Using a Delphi consensus method, a panel of anaesthesiology and cardiology experts rated the severity of thrombotic and bleeding clinical events. The ratings were expressed on a 10-point scale. The median and quartiles of the ratings of each item were returned to the experts. Then, the panel members evaluated the events a second time with knowledge of the group responses from the first round. Cronbach's a was used as a measure of homogeneity for the ratings. The final rating for each event corresponded to the median rating obtained at the last Delphi round.
Of 70 experts invited, 32 (46%) accepted to participate. Consensus was reached at the second round as indicated by Cronbach's a value (0.99 (95% CI 0.98-1.00)) so the Delphi was stopped. Severity ranged from under-popliteal venous thrombosis (median = 3, Q1 = 2; Q3 = 3) to ischemic stroke or intracerebral hemorrhage with severe disability at 7 days and massive pulmonary embolism (median = 9, Q1 = 9; Q3 = 9). Ratings did not differ according to the medical specialty of experts.
These ratings could be used to weight ischemic and bleeding events of various severity comprising a composite outcome in the field of thrombosis prevention.
PMCID: PMC3072399  PMID: 21490920
11.  Effect of the AutoPulse automated band chest compression device on hemodynamics in out-of-hospital cardiac arrest resuscitation 
Intensive Care Medicine  2010;36(7):1256-1260.
Guidelines for advanced life support (ALS) of cardiac arrest emphasize continuous and effective chest compressions as one of the main factors of cardiopulmonary resuscitation (CPR) success. The use of an automated load distributing chest compression device for CPR is promising but initial studies on survival show contradictory results. The aim of this study was to evaluate the effect of use of Autopulse™ on blood pressure (BP) in out-of-hospital cardiac arrest patients.
This prospective study included adult patients presenting with in refractory out-of-hospital cardiac arrest. Invasive arterial BP produced by AutoPulse™ was compared to BP generated by manual cardiopulmonary resuscitation (Active Compression Decompression). Systolic, diastolic and mean BP and end-tidal carbon dioxide were recorded before and after initiating up the automated band device for each patient. The comparison of diastolic BP produced by manual vs automated chest compressions was the primary end point.
Hemodynamics are reported and analyzed in 29 patients. Median diastolic BP increased after starting Autopulse™ from 17[11–25] mmHg to 23[18–28] mmHg (p<0.001). Median systolic BP increased from 72[55–105] mmHg to 106[78–135] mmHg (p=0.02). Mean BP increased from 29[25–38] mmHg to 36[30–15] mmHg (p=0.002). On the other hand, ETCO2 did not increase significantly with Autopulse™ (21[13–36] vs 22[12–35] mmHg, p=0.80)
In patients with out-of-hospital cardiac arrest, the use of AutoPulse™ is associated with an increased diastolic BP compared to manual chest compressions. Until its benefit on survival is demonstrated, the increase of diastolic and mean BP is promising of better outcomes.
PMCID: PMC2929359  PMID: 20213073
Hemodynamics; cardiac arrest; resuscitation; out-of-hospital
12.  Age-adapted morphine titration produces equivalent analgesia and adverse effects in younger and older patients 
To determine efficacy and safety of postoperative titrated morphine in elderly patients when intravenous boluses of morphine were adapted to age.
In the Post Anaesthesia Care Unit (PACU), patients complaining of pain received morphine until adequate pain relief. Intravenous morphine was titrated as 3 mg boluses for young (age ≤ 65 yrs) and 2 mg for elderly patients (> 65 yrs) respectively, every 5 min.
Three hundred fifty young and 68 elderly patients were included. No significant difference between the two groups was detected in Numerical Rating Scale (NRS, 0 = no pain; 10 = worst imaginable pain) at the onset of titration: 7.4 ± 1.7 vs 7.5 ± 1.7, the area under the curves of NRS versus morphine boluses: 97.7 ± 59.6 vs 98.2 ± 62, the number of boluses required to obtain pain relief: 3 ± 1.3 vs 3 ± 1.3, the percentage of titration failure: 10% vs 9% and the incidence of excessive sedation: 18% vs 21%. On the other hand, renal clearance was significantly reduced in elderly patients compared to the young: 55 ± 21 vs 85 ± 15 ml/min; p < 0.0001.
With a lower dose of morphine, elderly patients beneficiated comparable efficient and safe pain relief as younger. The decrease in renal clearance of morphine, support the reduction of intravenous bolus doses of morphine in patients aged > 65 yrs in the immediate postoperative period.
PMCID: PMC2652637  PMID: 18184441
Adult; Age Factors; Aged; Aged, 80 and over; Analgesics; Opioid; administration & dosage; Area Under Curve; Clinical Protocols; Female; Humans; Kidney Function Tests; Male; Middle Aged; Morphine; administration & dosage; Pain Measurement; methods; Pain, Postoperative; drug therapy; Prospective Studies; Treatment Outcome; Postoperative period; pain postoperative; morphine; aged; age groups

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