Maureen O. Meade

Evaluation of A ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome

BACKGROUNDnA strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome. The goal is to reduce lung injury due to overdistention. However, the efficacy of this approach has not been established.nnnMETHODSnWithin 24 hours of intubation, patients at high risk for the acute respiratory distress syndrome were randomly assigned to either pressure- and volume-limited ventilation (limited-ventilation group), with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less, or to conventional ventilation (control group), with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram. All other ventilatory variables were similar in the two groups.nnnRESULTSnA total of 120 patients with similar clinical features underwent randomization (60 in each group). The patients in the limited-ventilation and control groups were exposed to different mean (+/-SD) tidal volumes (7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram, respectively; P<0.001) and peak inspiratory pressures (23.6+/-5.8 vs. 34.0+/-11.0 cm of water, P<0.001). Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group (relative risk, 1.07; 95 percent confidence interval, 0.72 to 1.57; P=0.72). In the limited-ventilation group, permissive hypercapnia (arterial carbon dioxide tension, >50 mm Hg) was more common (52 percent vs. 28 percent, P=0.009), more marked (54.4+/-18.8 vs. 45.7+/-9.8 mm Hg, P=0.002), and more prolonged (146+/-265 vs. 25+/-22 hours, P=0.017) than in the control group. The incidence of barotrauma, the highest multiple-organ-dysfunction score, and the number of episodes of organ failure were similar in the two groups; however, the numbers of patients who required paralytic agents (23 vs. 13, P=0.05) and dialysis for renal failure (13 vs. 5, P= 0.04) were greater in the limited-ventilation group than in the control group.nnnCONCLUSIONSnIn patients at high risk for the acute respiratory distress syndrome, a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity.

Using and understanding sedation scoring systems: a systematic review

Objective: To systematically review instruments for measuring the level and effectiveness of sedation in adult and pediatric ICU patients.¶Study identification: We searched MEDLINE, EMBASE, the Cochrane Library and reference lists of the relevant articles. We selected studies if the sedation instrument reported items related to consciousness and one or more additional items related to the effectiveness or side effects of sedation.¶Data abstraction: We extracted data on the description of the instrument and on their measurement properties (internal consistency, reliability, validity and responsiveness).¶Results: We identified 25 studies describing relevant sedation instruments. In addition to the level of consciousness, agitation and synchrony with the ventilator were the most frequently assessed aspects of sedation. Among the 25 instruments, one developed in pediatric ICU patients (the Comfort Scale), and 3 developed in adult ICU patients (the Ramsay scale, the Sedation-Agitation-Scale and the Motor Activity Assessment Scale), were tested for both reliability and validity. None of these instruments were tested for their ability to detect change in sedation status over time (responsiveness).¶Conclusion: Many instruments have been used to measure sedation effectiveness in ICU patients. However, few of them exhibit satisfactory clinimetric properties. To help clinicians assess sedation at the bedside, to aid readers critically appraise the growing number of sedation studies in the ICU literature, and to inform the design of future investigations, additional information about the measurement properties of sedation effectiveness instruments is needed.

Selecting and Appraising Studies for a Systematic Review

Systematic Review Series Series Editors: Cynthia Mulrow, MD, MSc Deborah Cook, MD, MSc The last article in this series outlined methods with which to search the literature for studies on the clinical question that generates a systematic review [1]. Herein, we discuss the subsequent steps of selecting and appraising studies for a review. Both of these steps involve important judgments that can influence the results of a review. In selecting studies, reviewers judge the relevance of the studies to the review question. In appraising studies, reviewers judge numerous features of design and analysis. Some of these judgments are easy to make; others are more difficult and prone to error. To be confident in their decisions, reviewers should use methods that are reliable (the results do not change if the procedure is repeated), impartial (not influenced by the study results), and explicit (unambiguous) [2]. These strategies for selection and appraisal are sensible, and they distinguish most systematic reviews from most narrative reviews. However, evidence to support the importance of some of the methods we suggest is either scant or conflicting; readers are referred to the original research on these approaches for more details. Selecting Studies for Systematic Reviews If reviewers perform a comprehensive search of the literature using the methods described previously in this series [1], they will probably have assembled a large sample of articles. This sample will include most (ideally, all) studies that are relevant to the review question (that is, the sensitivity of the search will be high). Inevitably, because such a wide net is cast, articles not pertinent to the clinical question will be retrieved (that is, the specificity of the search will be modest). Thus, the reviewers next task is to sort through all of the potentially relevant articles and select those that will be included in the review. To do so, reviewers adopt several of the tactics listed in Table 1 and Table 2 for planning and executing the selection process (in effect, improving the specificity of the search); these tactics are described below. Table 1. Planning Study Selection Table 2. Strategies for Selecting and Appraising Studies Begin with a Well-Built Clinical Question Reviewers should ensure that the question for review includes the four elements of a well-built clinical question [3, 4]: the patients of interest, the main interventions under investigation, the comparison interventions, and the clinical outcomes of interest. By including these four elements, reviewers can better focus the selection process. Choose Selection Criteria That Fit the Clinical Question Consider a systematic review of the effectiveness of a drug treatment (for example, a proton-pump inhibitor) for patients with a particular disorder (such as esophageal reflux). Reviewers need to decide whether to include studies of patients with any symptoms of reflux, only those with classic symptoms, or only those in whom definitive diagnostic tests have confirmed the presence of reflux. In addition, reviewers might choose to include studies of patients with different comorbid conditions; patients from different demographic or geographic or cultural backgrounds; or patients from different health systems, such as inpatient or community populations. Similarly, reviewers should use selection criteria that reflect the main and comparison interventions of interest. In our esophageal reflux example, reviewers would need to decide whether to include studies of a particular drug or studies of all agents in that drugs class and whether to include studies of any dose and regimen or only studies with a specific regimen. For the comparison interventions, the reviewers would decide whether to include studies that compare the experimental drug with alternate treatments (such as antacids or histamine-2-receptor antagonists), with placebo, or with both. For the clinical outcomes, reviewers have analogous tasks of defining the outcomes and translating them into criteria. In our example, the reviewers would start by listing each clinical outcome (for example, whether the outcome was endoscopic or clinical and whether it focused on cure or persistence) and then decide whether to include studies that reported any outcome or only those with certain clinically important outcomes (such as improvement in symptoms at 1 year). After thoroughly considering each element of the review question, reviewers compile a set of explicit selection criteria. When these criteria are not explicit, the results of the review are more prone to error [5, 6]. Reporting the selection criteria used in a review is extremely important to readers because the criteria indicate the relevance of the review to the readers clinical practice. Specify the Types of Study Design To Be Included After creating selection criteria that appropriately reflect the review question, reviewers should consider which study designs to include. Ideally, reviewers choose study designs that are most likely to produce valid results. For example, to answer questions about therapy or harm, reviewers may want to include randomized trials [7] because they provide more accurate estimates of benefit or harm than do cohort studies, casecontrol studies, and case series [8]. In reality, however, randomized trials may not be conducted to address questions of harm [9]. Therefore, reviewers need to consider which study designs are likely to be available to answer their question; this information may necessitate modification of originally conceptualized selection criteria to incorporate observational (nonexperimental) studies. Specify Criteria Related to Type and Form of Publication Reviewers also need to consider issues related to type and form of publication. Ideally, all of the relevant studies would be published as peer-reviewed journal articles. However, some completed studies may be published only as abstracts, in non-peer-reviewed form, or not at all. Reviewers decide whether to include these incompletely reported studies when planning their literature search. By including all articles in various stages of publication and subjecting them to rigorous critical appraisal, reviewers minimize the threat of publication bias (the preferential reporting of studies with positive results) [10-12], which could generate misleading reviews. Other studies may be reported more than once. To avoid over-representing duplicate studies in the review, investigators should plan to look for and exclude duplicate publications [13]. Finally, because studies may be published in different languages and because excluding studies published in different languages may bias the results of reviews [14, 15], articles should be included, as appropriate, regardless of the language of publication (translating as necessary). Limited time and resources, however, may preclude such an approach. Construct and Pretest Selection Forms After deciding on selection criteria, reviewers can prepare customized forms that contain checklists of the selection criteria (Figure 1). Using these forms can simplify the selection process, increase reliability, and provide a record of the judgments made about each study. After drafting form prototypes, reviewers pretest these forms for clarity, ease of application, and reliability. To pretest the forms, two or more independent reviewers typically apply them to a random sample of studies identified by the literature search. Reviewers compare their results to identify sources of ambiguity and then revise the forms accordingly. If the revisions are substantial, this process may need to be repeated before the forms can be used. Figure 1. Example of a form that might be developed for the selection of studies for a systematic review evaluating the efficacy of -blockers for secondary prevention of variceal bleeding. Write a Detailed Protocol Having a selection protocol as part of a larger protocol for the entire review helps reviewers in two ways. First, it provides a document that explicitly states the review question and the selection criteria, making the process accountable. Reviewers can later return to the protocol for guidance in resolving disagreements about article selection. Second, the selection protocol identifies what work will be done, by whom, in what manner, when, and for what reason; thus, it provides a mode of communication within the review team. When reviewers have a very large sample of studies from which to select, they can simplify this task by reviewing all of the titles, then the abstracts, and then the full articles, excluding studies that do not meet one or more selection criteria at each step. In doing so, reviewers should record (on the selection forms) the reasons for exclusion. After reviewers have selected studies for the systematic review, they will move to the next task of critical appraisal. This procedure also requires careful planning. Appraising Studies for Systematic Reviews Reviewers appraise the studies selected for review with three objectives in mind: 1) to understand the validity of the studies, 2) to uncover reasons for differences among study results other than chance, and 3) to provide readers with sufficient information with which to judge for themselves the applicability of the systematic review to their clinical practice. To achieve these goals, reviewers use the strategies outlined in Table 2 and Table 3 to carefully reexamine many important features of the primary studies. Table 3. Planning Study Appraisal Examine Important Clinical Features Although the selection criteria for a systematic review define the population, interventions, and outcomes of interest, the appraisal process involves a detailed assessment of the patients (for example, high, medium, or low risk), the study interventions (for example, frequency, degree, and duration), and the outcome measurements (for example, definitions and degree of surveillance) in

Dalteparin versus unfractionated heparin in critically ill patients.

BACKGROUNDnThe effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients.nnnMETHODSnIn this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle.nnnRESULTSnThere was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046).nnnCONCLUSIONSnAmong critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

The Timing of Tracheotomy: A Systematic Review

STUDY OBJECTIVEnTo examine the impact of the timing of tracheotomy on the duration of mechanical ventilation, the secondary changes to the trachea, and the clinical course of critically ill patients in the ICU.nnnDESIGNnA systematic review of the literature.nnnMETHODSnTwo independent reviewers conducted a MEDLINE search for relevant literature in the form of randomized or observational controlled clinical studies. Studies were selected for review by criteria determined a priori; and the methodologic quality of selected studies was evaluated by duplicate independent review, also using criteria determined a priori.nnnRESULTSnFive studies were identified, of which three were quasirandomized and none were blinded. Agreement between reviewers of methodologic quality was high (kappa=0.87).nnnCONCLUSIONSnThere is insufficient evidence to support that the timing of tracheotomy alters the duration of mechanical ventilation or extent of airway injury in critically ill patients.

Long-term follow-up of survivors of acute lung injury: lack of effect of a ventilation strategy to prevent barotrauma.

OBJECTIVESnTo determine the effect of a ventilation strategy to prevent barotrauma on long-term outcome in survivors of acute lung injury.nnnDESIGNnProspective blinded cohort analysis.nnnSETTINGnThree university-affiliated medical-surgical intensive care units.nnnPATIENTSnA total of 28 survivors of acute lung injury, 1-2 yrs after diagnosis, from a multicenter prospective randomized controlled trial comparing pressure (peak inflation pressure < or =30 cm H2O) and volume (tidal volume < or =8 mL/kg) limited ventilation to a conventional (peak inflation pressure < or =50 cm H2O, tidal volume 10-15 mL/kg) ventilation strategy.nnnMEASUREMENTS AND MAIN RESULTSnPhysicians blinded as to treatment group evaluated 20 of 28 survivors (treatment group, 7; control group, 13). Exercise tolerance in the 6-minute walk test was comparable to patients with chronic respiratory disease and equivalent between groups (treatment group, 373+/-171 m vs. control group, 375+/-129 m; p = .84). Pulmonary function testing showed reduced diffusing capacity (treatment group, 64+/-29% predicted vs. control group, 74+/-14% predicted; p = .68) and normal volumes, flows, and blood gases. Two domains of disease-specific Health Related Quality of Life assessed by the Chronic Respiratory Questionnaire were worse for patients in the treatment group compared with the control group (Emotional Function 3.8+/-1.4 vs. 5.1+/-0.08; p = .05, Mastery 4.7+/-1.7 vs. 6.2+/-0.8; p = .03). There were no between-group differences in the scores of the Spitzer Quality of Life Index (a generic Health Related Quality of Life instrument), although they were reduced (7.5+/-1.9) and comparable to patients with chronic disease.nnnCONCLUSIONSnWe found that 1-2 yrs after the onset of their illness, survivors of acute lung injury have reductions in quality of life and exercise tolerance which are similar to patients with chronic diseases. We were unable to show that a limited ventilation strategy improves either long-term pulmonary function or quality of life in survivors of acute lung injury.

Oxygenation Response to Positive End-Expiratory Pressure Predicts Mortality in Acute Respiratory Distress Syndrome. A Secondary Analysis of the LOVS and ExPress Trials

RATIONALEnPrevious trials of higher positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) failed to demonstrate mortality benefit, possibly because of differences in lung recruitability among patients with ARDS.nnnOBJECTIVESnTo determine whether the physiological response to increased PEEP is associated with mortality.nnnMETHODSnIn a secondary analysis of the Lung Open Ventilation Study (LOVS, n = 983), we examined the relationship between the initial response to changes in PEEP after randomization and mortality. We sought to corroborate our findings using data from a different trial of higher PEEP (ExPress, n = 749).nnnMEASUREMENTS AND MAIN RESULTSnThe oxygenation response (change in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen: P/F) after the initial change in PEEP after randomization varied widely (median, 9.5 mm Hg; interquartile range, -16 to 47) and was only weakly related to baseline P/F or the magnitude of PEEP change. Among patients in whom PEEP was increased after randomization, an increase in P/F was associated with reduced mortality (multivariable logistic regression; adjusted odds ratio, 0.80 [95% confidence interval, 0.72-0.89] per 25-mm Hg increase in P/F), particularly in patients with severe disease (baseline P/F [less-than-or-equal-to] 150 mm Hg). Changes in compliance and dead space were not associated with mortality. These findings were confirmed by a similar analysis of data from the ExPress trial.nnnCONCLUSIONSnPatients with ARDS who respond to increased PEEP by improved oxygenation have a lower risk of death. The oxygenation response to PEEP might be used to predict whether patients will benefit from higher versus lower PEEP.

Adjudicating ventilator-associated pneumonia in a randomized trial of critically ill patients

PURPOSEnThe purpose of this study was to evaluate an adjudication strategy for diagnosing ventilator-associated pneumonia (VAP) in a randomized trial.nnnMATERIALS AND METHODSnIn a double-blind trial of sucralfate versus ranitidine, one of four pairs of adjudicators examined each case of clinically suspected VAP. Nurse and physician notes and all relevant laboratory data were allocated to each adjudication pair in groups of five patients. Each reader in the pair decided whether the patient had VAP; differences were resolved by consensus discussion.nnnRESULTSnThe overall unadjusted study odds ratio for VAP was 0.82 (P = .21) representing a trend toward less pneumonia with sucralfate compared with ranitidine. The odds ratio adjusted for adjudication pair was 0.85 (P = .27). The proportion of charts adjudicated as VAP positive among pairs ranged from 50% to 92%; crude agreement between readers in each pair varied from 50% to 82%. When adjudicators disagreed, the final consensus was split evenly between the two adjudicators initial opinions in two pairs; in the other two pairs, the final decision reflected one dominant initial opinion. Personnel time to adjudicate all patients with a suspicion of VAP was 74 days.nnnCONCLUSIONSnThough adjudication of outcomes such as VAP is time-consuming, consistent decision-making requires strict criteria, training, and calibration. Patients should be assigned to adjudication teams through random allocation.

Blood pressure targets for vasopressor therapy: a systematic review.

ABSTRACT Physicians often prescribe vasopressors to correct pathological vasodilation and improve tissue perfusion in patients with septic shock, but the evidence to inform practice on vasopressor dosing is weak. We undertook a systematic review of clinical studies evaluating different blood pressure targets for the dosing of vasopressors in septic shock. We searched MEDLINE, EMBASE, CENTRAL (to November 2013), reference lists from included articles, and trial registries for randomized controlled trials (RCTs) and observational and crossover intervention studies comparing different blood pressure targets for vasopressor therapy in septic shock. Two reviewers independently selected eligible studies and extracted data on standardized forms. We identified 2 RCTs and 10 crossover trials but no observational studies meeting our criteria. Only one RCT measured clinical outcomes after comparing mean arterial pressure targets of 80 to 85 mmHg versus 65 to 70 mmHg. There was no effect on 28-day mortality, but confidence intervals were wide (hazard ratio, 95% confidence interval [95% CI] 0.84 – 1.38). In contrast, this intervention was associated with a greater risk of atrial fibrillation (relative risk, 2.36; 95% CI, 1.18 – 4.72) and a lower risk of renal replacement therapy in hypertensive patients (relative risk, 0.75; 95% CI, 0.57 – 1.0). Crossover trials suggest that achieving higher blood pressure targets by increasing vasopressor doses increases heart rate and cardiac index with no effect on serum lactate. Our findings underscore the paucity of clinical evidence to guide the administration of vasopressors in critically ill patients with septic shock. Further rigorous research is needed to establish an evidence base for vasopressor administration in this population.

Clonidine in the sedation of mechanically ventilated children: a pilot randomized trial.

PURPOSEnClonidine is often used as a sedative in critically ill children, but its effectiveness has not been evaluated in a large, rigorous randomized controlled trial. Our objectives in this pilot trial were to assess the feasibility of a larger trial with respect to (1) effective screening, (2) recruitment, (3) timely drug administration, and (4) protocol adherence.nnnMATERIALS AND METHODSnThis is a randomized, blinded, placebo-controlled pilot trial. Mechanically ventilated children received enteral clonidine 5 μg/kg or placebo every 6 hours; additional sedatives were at the discretion of attending physicians.nnnRESULTSnWe enrolled 50 children. The median interquartile range (IQR) age was 2.5 (0.7-5.2) years, and Pediatric Risk of Mortality score on pediatric intensive care unit admission was 12 (8-15). In terms of feasibility outcomes, 90 (87%) of 104 eligible patients were approached for consent, and on average, 1.7 children were enrolled per month. Thirty-five (70%) were enrolled within 1 day of becoming eligible (mean, 1.2 days). Thereafter, 94% of doses were administered by protocol. Clinical outcomes and adverse effects were not significantly different between the groups.nnnCONCLUSIONSnThis pilot trial demonstrated feasibility of a larger randomized controlled trial. Some important challenges emerged, allowing refinement of the study protocol and enrolment estimates. We recommend that future trials capitalize on the experience gained and use these results to design a larger trial focusing on clinically important outcomes.