EXpert consensus On Diaphragm UltraSonography in the critically ill (EXODUS): a Delphi consensus statement on the measurement of diaphragm ultrasound-derived parameters in a critical care setting.

BACKGROUND: Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research. METHODS: To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question. RESULTS: Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established. CONCLUSION: This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG .

Assisted mechanical ventilation promotes recovery of diaphragmatic thickness in critically ill patients: a prospective observational study.

BACKGROUND: Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors. METHODS: This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters. RESULTS: Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH2O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction. CONCLUSION: Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.

The Brachiocephalic Vein as a Safe and Viable Alternative to Internal Jugular Vein for Central Venous Cannulation.

BACKGROUND: Although many studies have compared success and complication rates for central line insertion sites with and without ultrasound, few have examined the use of the brachiocephalic vein for central venous access. The aim of this study was to describe the brachiocephalic vein as an alternative site for elective ultrasound vascular cannulation in adults, and to compare it with the more commonly used internal jugular vein site in terms of procedural difficulties, first pass failure rate, overall failure rate, and safety. METHODS: In this single-center, retrospective cohort study, clinical data from consecutive adult patients undergoing elective ultrasound-guided central venous catheterization of upper body were retrieved from the department database. All of these central venous catheters were requested by department team, none was positioned for surgery. Seven hundred nine patients underwent central venous catheterization via the internal jugular approach and 285 patients via the brachiocephalic route. Patients catheterized via the brachiocephalic vein approach were then compared with those catheterized via the internal jugular vein in terms of ease of catheterization, success rate, and complications. Differences between approaches were assessed by univariate analyses and multivariable analysis. RESULTS: Overall, 994 patients underwent central venous catheterization. A total of 87% had a successful catheter implantation at the first attempt, 6.7% of insertions were difficult, 5.7% were complicated, and 3.4% failed. Procedural difficulty was more frequent with the internal jugular than with the brachiocephalic approach (odds ratio, 0.38; 95% confidence interval, 0.19-0.76; P = .007) after correction for potential confounders. Differences between groups in complication rate (6.3% vs 4.1%) or failure rate (3.4% vs 3.5%) were not significant. CONCLUSIONS: Brachiocephalic cannulation is a reasonable alternative to ultrasound-guided internal jugular vein catheterization.

Closed-Loop Delivery Systems Versus Manually Controlled Administration of Total IV Anesthesia: A Meta-analysis of Randomized Clinical Trials.

Bispectral Index Scale (BIS)-guided closed-loop delivery of anesthetics has been extensively studied. We performed a meta-analysis of all the randomized clinical trials comparing efficacy and performance between BIS-guided closed-loop delivery and manually controlled administration of total IV anesthesia. Scopus, PubMed, EMBASE, and the Cochrane Central Register of clinical trials were searched for pertinent studies. Inclusion criteria were random allocation to treatment and closed-loop delivery systems versus manually controlled administration of total IV anesthesia in any surgical setting. Exclusion criteria were duplicate publications and nonadult studies. Twelve studies were included, randomly allocating 1284 patients. Use of closed-loop anesthetic delivery systems was associated with a significant reduction in the dose of propofol administered for induction of anesthesia (mean difference [MD] = 0.37 [0.17-0.57], P for effect <0.00001, P for heterogeneity = 0.001, I = 74%) and a significant reduction in recovery time (MD = 1.62 [0.60-2.64], P for effect <0.0001, P for heterogeneity = 0.06, I = 47%). The target depth of anesthesia was preserved more frequently with closed-loop anesthetic delivery than with manual control (MD = -15.17 [-23.11 to -7.24], P for effect <0.00001, P for heterogeneity <0.00001, I = 83%). There were no differences in the time required to induce anesthesia and the total propofol dose. Closed-loop anesthetic delivery performed better than manual-control delivery. Both median absolute performance error and wobble index were significantly lower in closed-loop anesthetic delivery systems group (MD = 5.82 [3.17-8.46], P for effect <0.00001, P for heterogeneity <0.00001, I = 90% and MD = 0.92 [0.13-1.72], P for effect = 0.003, P for heterogeneity = 0.07, I = 45%). When compared with manual control, BIS-guided anesthetic delivery of total IV anesthesia reduces propofol requirements during induction, better maintains a target depth of anesthesia, and reduces recovery time.

Mechanical Ventilation and Diaphragmatic Atrophy in Critically Ill Patients: An Ultrasound Study.

OBJECTIVE: Mechanical ventilation contributes to diaphragmatic atrophy and dysfunction, and few techniques exist to assess diaphragmatic function: the purpose of this study was to quantify diaphragm atrophy in a population of critically ill mechanically ventilated patients with ultrasound and to identify risk factors that can worsen diaphragmatic activity. DESIGN: Prospective observational study. SETTING: ICU of a 1,200-bed university hospital. PATIENTS: Newly intubated adult critically ill patients. INTERVENTIONS: Diaphragm thickness in the zone of apposition was measured daily with ultrasound, from the first day of mechanical ventilation till discharge to the main ward. MEASUREMENTS AND MAIN RESULTS: Daily atrophy rate (ΔTdi/d) was calculated as the reduction in percentage from the previous measurement. To analyze the difference in atrophy rate (ΔTdi/d), ventilation was categorized into four classes: spontaneous breathing or continuous positive airway pressure; pressure support ventilation 5-12 cm H2O (low pressure support ventilation); pressure support ventilation greater than 12 cm H2O (high pressure support ventilation); and controlled mechanical ventilation. Multivariate analysis with ventilation support and other clinical variables was performed to identify risk factors for atrophy. Forty patients underwent a total of 153 ultrasonographic evaluations. Mean (SD) ΔTdi/d was -7.5% (12.3) during controlled mechanical ventilation, -5.3% (12.9) at high pressure support ventilation, -1.5% (10.9) at low pressure support ventilation, +2.3% (9.5) during spontaneous breathing or continuous positive airway pressure. At multivariate analysis, only the ventilation support was predictive of diaphragm atrophy rate. Pressure support predicted diaphragm thickness with coefficient -0.006 (95% CI, -0.010 to -0.002; p = 0.006). CONCLUSIONS: In critically ill mechanically ventilated patients, there is a linear relationship between ventilator support and diaphragmatic atrophy rate.

Long-Term Survival Rate in Patients With Acute Respiratory Failure Treated With Noninvasive Ventilation in Ordinary Wards.

OBJECTIVE: Noninvasive ventilation is a life-saving technique increasingly used to treat acute respiratory failure. Noninvasive ventilation has been applied mostly in ICUs, but several reasons brought to an increasing application of noninvasive ventilation in ordinary wards. Few articles evaluated the outcomes of patients receiving noninvasive ventilation including long-term follow-up. The aim of the present study was to assess 1-year survival rate of patients treated with noninvasive ventilation outside the ICU for acute respiratory failure of heterogeneous causes and to identify the predictors of long-term mortality. DESIGN: Prospective, observational, pragmatic study. SETTING: Ordinary wards of a teaching hospital. PATIENTS: Consecutive patients treated with noninvasive ventilation for acute respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred and twenty-patients were enrolled. Mortality rates at 30-day, 90-days, and 1-year follow-up were 20%, 26%, and 34%. When excluding patients with "do-not-resuscitate" status, mortality rates were 13%, 19%, and 28%. The multivariate analyses identified solid cancer, pneumonia in hematologic patients, and do-not-resuscitate status as independent predictors of mortality with postoperative acute respiratory failure associated with improved survival. The same predictors were confirmed when excluding do-not-resuscitate patients from the analyses. CONCLUSIONS: Noninvasive ventilation applied in ordinary wards was effective, with long-term outcomes not different from those reported for ICU settings. Solid cancer, pneumonia in hematologic malignancies, and do-not-resuscitate status predicted mortality, whereas patients with postoperative acute respiratory failure had the best survival rate. Additional studies are required to evaluate noninvasive ventilation efficacy in the wards compared with ICU.

Worldwide Opinion on Multicenter Randomized Interventions Showing Mortality Reduction in Critically Ill Patients: A Democracy-Based Medicine Approach.

OBJECTIVES: Democracy-based medicine is a combination of evidence-based medicine (systematic review), expert assessment, and worldwide voting by physicians to express their opinions and self-reported practice via the Internet. The authors applied democracy-based medicine to key trials in critical care medicine. DESIGN AND SETTING: A systematic review of literature followed by web-based voting on findings of a consensus conference. PARTICIPANTS: A total of 555 clinicians from 61 countries. INTERVENTIONS: The authors performed a systematic literature review (via searching MEDLINE/PubMed, Scopus, and Embase) and selected all multicenter randomized clinical trials in critical care that reported a significant effect on survival and were endorsed by expert clinicians. Then they solicited voting and self-reported practice on such evidence via an interactive Internet questionnaire. Relationships among trial sample size, design, and respondents' agreement were investigated. The gap between agreement and use/avoidance and the influence of country origin on physicians' approach to interventions also were investigated. MEASUREMENTS AND MAIN RESULTS: According to 24 multicenter randomized controlled trials, 15 interventions affecting mortality were identified. Wide variabilities in both the level of agreement and reported practice among different interventions and countries were found. Moreover, agreement and reported practice often did not coincide. Finally, a positive correlation among agreement, trial sample size, and number of included centers was found. On the contrary, trial design did not influence clinicians' agreement. CONCLUSIONS: Physicians' clinical practice and agreement with the literature vary among different interventions and countries. The role of these interventions in affecting survival should be further investigated to reduce both the gap between evidence and clinical practice and transnational differences.

Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect.

OBJECTIVES: We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians' opinion and usual practice for the selected interventions. DATA SOURCES: MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. STUDY SELECTION: We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. DATA EXTRACTION: For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. DATA SYNTHESIS: We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. CONCLUSIONS: We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

Monitoring of central retinal artery and vein with color Doppler ultrasound during heart surgery as an alternative to transcranial Doppler ultrasonography: a case report.

Cardiac surgery can have severe neurologic complications. The noninvasive monitoring of intracranial circulation during heart surgery is usually performed with transcranial Doppler ultrasonography. We present the case of a 66-year-old man who underwent elective cardiac surgery for aortic valve replacement and coronary artery bypass graft, in whom monitoring was performed by simultaneously assessing blood flow velocity in the central retinal artery and vein.

A comprehensive appraisal of meta-analyses focusing on nonsurgical treatments aimed at decreasing perioperative mortality or major cardiac complications.

PURPOSE: Millions of patients worldwide who undergo surgical procedures face significant morbidity and mortality risks. Several systematic reviews have been performed on ancillary treatments aimed at improving surgical outcomes, but their features and scholarly impact are unclear. We describe characteristics of meta-analyses on ancillary treatments aimed at improving surgical outcomes and explore factors associated with scholarly citations. METHODS: Systematic reviews published up to 2008 were searched without language restrictions in MEDLINE/PubMed. Reviews focusing on nonsurgical treatments aimed at decreasing mortality or major cardiac complications were included. Associations between content, quality, and bibliometric details and scholarly citations in several indexes were systematically appraised. RESULTS: From 2,239 citations, 84 systematic reviews were identified. Patients most commonly underwent cardiovascular surgery (40.2%), and were tested for cardiovascular drugs (25.8%), with placebo acting as control (38.1%). Internal validity appeared largely robust, as most (50.5%) reviews were at low risk of bias. Normalized yearly citations for the included reviews ranged between 5.6 in Google Scholar and 4.3 in Web of Science. Multivariable analysis showed that citations were significantly and positively associated with number of authors, North American corresponding author, number of studies included, number of patients included, noncardiothoracic surgical scope, explicit funding, and lack of competing interests (all p < 0.05). CONCLUSIONS: Systematic reviews currently represent a key element in defining state of the art ancillary treatments of patients undergoing surgery. However, the citation success of available meta-analyses is not significantly associated with prognostically relevant findings or quality features.

Reducing mortality in cardiac surgery with levosimendan: a meta-analysis of randomized controlled trials.

OBJECTIVES: The authors performed a meta-analysis to evaluate whether levosimendan is associated with improved survival in patients undergoing cardiac surgery. DESIGN: A meta-analysis. SETTING: Hospitals. PARTICIPANTS: A total of 440 patients from 10 randomized controlled studies were included in the analysis. INTERVENTIONS: None. MEASURMENTS AND MAIN RESULTS: Four investigators independently searched BioMedCentral and PubMed. Inclusion criteria were random allocation to treatment, comparison of levosimendan versus control, and cardiac surgery patients. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no mortality data. The primary endpoint was postoperative mortality. Levosimendan was associated with a significant reduction in postoperative mortality (11/235 [4.7%] in the levosimendan group v 26/205 [12.7%] in the control arm, odds ratio = 0.35 [0.18-0.71], p for effect = 0.003, p for heterogeneity = 0.22, I(2) = 27.4% with 440 patients included), cardiac troponin release, and atrial fibrillation. No difference was found in terms of myocardial infarction, acute renal failure, time on mechanical ventilation, intensive care unit, and hospital stay. CONCLUSIONS: Levosimendan has cardioprotective effects that could result in a reduced postoperative mortality. A large randomized controlled study is warranted in this setting.

Comparisons of two diaphragm ultrasound-teaching programs: a multicenter randomized controlled educational study.

BACKGROUND: This study aims to ascertain whether (1) an educational program is sufficient to achieve adequate Diaphragm Ultrasound (DUS) assessments on healthy volunteers and (2) combining a video tutorial with a practical session is more effective in making learners capable to obtain accurate DUS measurements, as opposed to sole video tutorial. RESULTS: We enrolledstep 1: 172 volunteers naïve to ultrasound. After watching a video tutorial, a questionnaire was administered and considered to be passed when at least 70% of the questions were correctly answered. Course participants who passed the theoretical test were randomized to either intervention or control group. Learners randomized to the interventional group underwent to a practical training, tutored by an expert, before accessing DUS examination. Participants randomized to the control group directly accessed DUS examination, without any practical training. DUS measurements by learners and tutors were recorded and checked for accuracy, according to predefined criteria. Detection of both acoustic windows and accurate DUS assessment was achieved by 83.7% learners of the intervention group while 3.5% only among controls (p < 0.0001). The subcostal view of the diaphragm was correctly identified by 92% and 65% learners in the intervention and control groups, respectively (p < 0.0001) while the apposition zone by 86% and 71% learners, respectively (p = 0.026). An accurate diaphragm displacement (DD) measurement was obtained by 91% and 45% learners in the intervention and control groups, respectively (p < 0.0001) while an accurate thickening fraction (TF) measurement by 99% and 21%, respectively (p < 0.0001). DD measurements by both groups of learners were significantly correlated with those assessed by expert tutors; however, a significant improvement of measurement accuracy was found in learners randomized to receive also the practical training, compared to controls. CONCLUSIONS: A combined approach consisting of a theoretical module followed by a practical training is more effective in managing acoustic windows and performing accurate measurements when compared to an exclusively theoretical course. Trial registration prospectively registered on clinicaltrials.gov (Identifier: NCT03704129; release date 17th October 2018).

Mortality rates for patients with acute lung injury/ARDS have decreased over time.

BACKGROUND: Over the last decade, several studies have suggested that survival rates for patients with acute lung injury (ALI) or ARDS may have improved. We performed a systematic analysis of the ALI/ARDS literature to document possible trends in mortality between 1994 and 2006. METHODS: We used the Medline database to select studies with the key words "acute lung injury," "ARDS," "acute respiratory failure," and "mechanical ventilation." All studies that reported mortality rates for patients with ALI/ARDS defined according to the criteria of the American European Consensus Conference were selected. We excluded studies with < 30 patients and studies limited to specific subgroups of ARDS patients such as sepsis, trauma, burns, or transfusion-related ARDS. RESULTS: Seventy-two studies were included in the analysis. There was a wide variation in mortality rates among the studies (15 to 72%). The overall pooled mortality rate for all studies was 43% (95% confidence interval, 40 to 46%). Metaregression analysis suggested a significant decrease in overall mortality rates of approximately 1.1%/yr over the period analyzed (1994 to 2006). The mortality reduction was also observed for hospital but not for ICU or 28-day mortality rates. CONCLUSIONS: In this literature review, the data are consistent with a reduction in mortality rates in general populations of patients with ALI/ARDS over the last 10 years.

Assessment of diaphragmatic dysfunction in the critically ill patient with ultrasound: a systematic review.

PURPOSE: Diaphragmatic dysfunction (DD) has a high incidence in critically ill patients and is an under-recognized cause of respiratory failure and prolonged weaning from mechanical ventilation. Among different methods to assess diaphragmatic function, diaphragm ultrasonography (DU) is noninvasive, rapid, and easy to perform at the bedside. We systematically reviewed the current literature assessing the usefulness and accuracy of DU in intensive care unit (ICU) patients. METHODS: Pubmed, Cochrane Database of Systematic Reviews, Embase, Scopus, and Google Scholar Databases were searched for pertinent studies. We included all original, peer-reviewed studies about the use of DU in ICU patients. RESULTS: Twenty studies including 875 patients were included in the final analysis. DU was performed with different techniques to measure diaphragmatic inspiratory excursion, thickness of diaphragm (Tdi), and thickening fraction (TF). DU is feasible, highly reproducible, and allows one to detect diaphragmatic dysfunction in critically ill patients. During weaning from mechanical ventilation and spontaneous breathing trials, both diaphragmatic excursion and diaphragmatic thickening measurements have been used to predict extubation success or failure. Optimal cutoffs ranged from 10 to 14 mm for excursion and 30-36 % for thickening fraction. During assisted mechanical ventilation, diaphragmatic thickening has been found to be an accurate index of respiratory muscles workload. Observational studies suggest DU as a reliable method to assess diaphragm atrophy in patients undergoing mechanical ventilation. CONCLUSIONS: Current literature suggests that DU could be a useful and accurate tool to detect diaphragmatic dysfunction in critically ill patients, to predict extubation success or failure, to monitor respiratory workload, and to assess atrophy in patients who are mechanically ventilated.

Why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? Implications for management.

Acute respiratory distress syndrome (ARDS) affects some 10% to 15% of ICU patients and is associated with mortality rates of 40% to 50%. Although ARDS is the most severe form of acute respiratory failure, refractory hypoxia is an uncommon cause of death in these patients. The majority of patients who have ARDS die from multiple-organ dysfunction syndrome (MODS), and ARDS should, therefore, be seen as a systemic disease. Improved understanding of the systemic factors involved in the development and evolution of ARDS and MODS should facilitate the development of new therapeutic agents that will improve outcomes in these patients.

Positivity of cytomegalovirus antibodies predicts a better clinical and radiological outcome in multiple sclerosis patients.

OBJECTIVES: To establish the relationship between the presence and titer of virus-specific serum- and cerebrospinal fluid (CSF)-antibodies in multiple sclerosis (MS) patients and disease severity measured with different quantitative magnetic resonance imaging (MRI) techniques. METHODS: We investigated an association between clinical and MRI measures of disease activity and the presence and titer of IgG antibodies against seven common viruses (measles, rubella, herpes simplex virus type 1 and 2, varicella zoster virus, cytomegalovirus (CMV) and Epstein-Barr virus). One hundred and forty (90 female/50 male) patients with definite MS and 131 age and sex-matched controls participated in the study. Antibody positivity and titer were ascertained by the enzyme linked immunosorbent assay (ELISA) technique and clinical assessment was performed by evaluating the expanded disability status scale (EDSS) score and the lifetime relapse rate (LRR). T1- and T2-lesion loads (LL) and the brain parenchymal fraction (BPF) were calculated. RESULTS: Multiple analyses showed that there was an association between antibody positivity against CMV and higher titer and better clinical and MRI outcomes. The cluster analyses indicated that patients positive for antibodies against CMV had significantly older age at onset (uncorr p = 0.001 and corr p = 0.009), lower LRR (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.004 and pcorr p = 0.04). CMV-positive patients who had higher antibody titer showed lower T2-LL (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.006 and corr p = 0.05). DISCUSSION: Surprisingly, our results focused attention on the 'protective' role of a particular virus. CMV is probably capable of triggering some immunomodulating/immune evasion mechanisms which may decrease immune reactivity in MS patients. Further studies are needed to confirm and elucidate our study results on a larger sample of MS patients and in animal model studies.

Methylene blue as a vasopressor: a meta-analysis of randomised trials.

OBJECTIVE: To evaluate the efficacy of methylene blue in raising mean arterial pressure in hypotensive patients. DESIGN: A meta-analysis of randomised controlled trials. DATA SOURCES: We searched BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials. DATA EXTRACTION: Inclusion criteria were random allocation to treatment and comparison of methylene blue versus any comparator. Exclusion criteria were duplicate publications, non-adult studies and no data on main outcomes. The primary end point was mean arterial blood pressure value 1 hour after the study drug administration; the secondary end points were mortality at the longest follow-up available, and cardiac index. DATA SYNTHESIS: Data from 174 patients in five randomised controlled studies were analysed. Mean arterial pressure rose in patients receiving methylene blue (weighted mean difference = 6.93 mmHg; 95% CI, 1.67 to 12.18; P for effect = 0.01; P for heterogeneity = 0.17; I2 = 41%). Only two studies reported the values of cardiac index with a non-statistically significant improvement in the methylene blue group (mean difference = 0.76 L/min/m2; 95% CI, ? 0.32 to 1.84; P for effect = 0.2). The overall mortality rate was 16% (14/88) among methylene blue treated patients and 23% (20/86) in the control group (odds ratio = 0.65; 95% CI, 0.21 to 2.08; P for effect = 0.5). CONCLUSIONS: Methylene blue increases arterial blood pressure and systemic vascular resistances in vasoplegic patients without a detrimental effect on survival.