Marta Mucchetti

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.

Reducing Mortality in Acute Kidney Injury Patients: Systematic Review and International Web-Based Survey

OBJECTIVE To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting. DESIGN AND SETTING Systematic literature review and international web-based survey. PARTICIPANTS More than 300 physicians from 62 countries. INTERVENTIONS Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality. MEASUREMENTS AND MAIN RESULTS Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions. CONCLUSION The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics.

The Fragility Index in Multicenter Randomized Controlled Critical Care Trials.

Objectives: Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality). Data Sources: Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine. Study Selection: We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis. Data Extraction: Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index. Data Synthesis: The median fragility index was 2 (interquartile range, 1–3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index. Conclusions: In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians.

Randomized Evidence for Reduction of Perioperative Mortality: An Updated Consensus Process

OBJECTIVE Of the 230 million patients undergoing major surgical procedures every year, more than 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. The authors have updated a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS The study comprised 500 clinicians from 61 countries. INTERVENTIONS A systematic literature search was performed to identify published literature about nonsurgical interventions, supported by randomized evidence, showing a statistically significant impact on mortality. A consensus conference of experts discussed eligible papers. The interventions identified by the conference then were submitted to colleagues worldwide through a web-based survey. MEASUREMENTS AND MAIN RESULTS The authors identified 11 interventions contributing to increased survival (perioperative hemodynamic optimization, neuraxial anesthesia, noninvasive ventilation, tranexamic acid, selective decontamination of the gastrointestinal tract, insulin for tight glycemic control, preoperative intra-aortic balloon pump, leuko-depleted red blood cells transfusion, levosimendan, volatile agents, and remote ischemic preconditioning) and 2 interventions showing increased mortality (beta-blocker therapy and aprotinin). Interventions then were voted on by participating clinicians. Percentages of agreement among clinicians in different countries differed significantly for 6 interventions, and a variable gap between evidence and clinical practice was noted. CONCLUSIONS The authors identified 13 nonsurgical interventions that may decrease or increase perioperative mortality, with variable agreement by clinicians. Such interventions may be optimal candidates for investigation in high-quality trials and discussion in international guidelines to reduce perioperative mortality.

Intraoperative prophylactic and therapeutic non-invasive ventilation: a systematic review

Non-invasive ventilation (NIV) has been used to prevent or to treat perioperative acute respiratory failure (ARF). Intraoperative prophylactic and therapeutic use of NIV could be of interest to patients with anticipated difficulty in postoperative weaning from mechanical ventilation or to patients refusing tracheal intubation. Intraoperative NIV might also be useful when deep sedation is required, as this can cause respiratory depression. PubMed, Embase, Google Scholar, and Cochrane Library were searched for pertinent studies. Inclusion criteria were NIV use during surgery and adult patients; the exclusion criteria were NIV application only in the preoperative or postoperative periods, paediatric patients, NIV applied as negative pressure ventilation. Thirty papers including 618 patients were included for final analysis. Intraoperative therapeutic NIV to treat ARF was reported for 92 patients and in all those cases, including six Caesarean sections, surgery was completed uneventfully. Intraoperative prophylactic NIV to avoid ARF was described in 24 patients with severe respiratory limitation and in 502 healthy patients during deep sedation. Three patients could not be successfully ventilated due to upper airway obstruction, but no further complication was reported. Intraoperative NIV appears feasible, safe, and potentially useful, particularly when tracheal intubation is best avoided. However, high-quality, randomized studies are required.

Administration of protein C concentrates in patients without congenital deficit: a systematic review of the literature

Endogenous protein C levels are frequently decreased in septic patients, probably due to increased conversion to activated protein C. Protein C levels inversely correlate with morbidity and mortality of septic patients regardless of age, infecting microorganisms, presence of shock, disseminated intravascular coagulation, degree of hypercoagulation, or severity of illness. Taken together, these considerations suggest a strong correlation between protein C pathways and survival from severe sepsis/septic shock, and reinforce the rationale for the attempts to normalize plasma activity of protein C to improve survival, hamper coagulopathy, and modulate inflammation. We therefore conducted a systematic review of all manuscripts describing protein C concentrates administration in adult and pediatric populations. We identified 28 studies, for a total of 340 patients, 70 of whom died (20.6%). Septic patients were the most represented in this review of case reports and case series. In the majority of these patients sepsis was associated with meningitis, purpura fulminans or disseminated intravascular coagulation. No bleeding complications related to the study drug were reported and most studies underlined normalization of inflammatory markers and of coagulation abnormalities. We conclude that protein C concentrate is an attractive option in septic patients (especially those with meningitis, purpura fulminans, or disseminated intravascular coagulation) and that its cost-benefit ratio must be studied with a large multicenter randomized control trial, possibly including also high risk patients with septic shock and multiple organ failure.

Auditory functional magnetic resonance in awake (nonsedated) and propofol-sedated children.

Functional Magnetic Resonance Imaging (fMRI) is often used in preoperative assessment before epilepsy surgery, tumor or cavernous malformation resection, or cochlear implantation. As it requires complete immobility, sedation is needed for uncooperative patients.

Use and reimbursement of off‐label drugs in pediatric anesthesia: the Italian experience

Most of the drugs used in anesthesia are off‐label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market).

Reducing Mortality in the Perioperative Period: A Continuous Update

According to the EUSOS study, perioperative mortality for noncardiac surgery is 1–4 % [1], considering that up to 230 million surgical procedures are performed each year in the world [2], even a small reduction would have a tremendous impact on public health.

Reducing Mortality in Patients with Acute Kidney Injury: A Systematic Update

Since the first international web-based Consensus Conference on mortality reduction in patients with or at risk for acute kidney injury was held, 13 more papers, dealing with ten interventions, have been published in a peer-reviewed journal showing a statistical significant effect on survival in this subset of patients. Seven interventions increased survival: preoperative renin-angiotensin system inhibitors and aspirin, aprotinin, and sedation with dexmedetomidine in cardiac surgery, continuous renal replacement therapy (CRRT) before and after percutaneous coronary intervention (PCI), angiotensin-converting enzyme inhibitors, and high-volume hemofiltration in severe acute pancreatitis. Three interventions increased mortality: fluid overload, high-volume hydration before PCI, and prophylactic sodium bicarbonate in cardiac surgery. However, the overall quality of these studies was low. Only two interventions (CRRT before PCI and fluid overload) were already included in the Consensus Conference, and the new studies identified may strengthen their role in affecting mortality. The others represent new hints for future research.