Jan O. Friedrich

Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review.

RATIONALE It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing. OBJECTIVES To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality. METHODS We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models. MEASUREMENTS AND MAIN RESULTS Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled weighted mortality was 44.3% (95% confidence interval [CI], 41.8-46.9). Mortality decreased with time in observational studies conducted before 1994; no temporal associations with mortality were demonstrated in RCTs (any time) or observational studies (after 1994). Pooled mortality from 1994 to 2006 was 44.0% (95% CI, 40.1-47.5) for observational studies, and 36.2% (95% CI, 32.1-40.5) for RCTs. Meta-regression identified study type (observational versus RCT, odds ratio, 1.36; 95% CI, 1.08-1.73) and patient age (odds ratio per additional 10 yr, 1.27; 95% CI, 1.07-1.50) as the only factors associated with mortality. CONCLUSIONS A decrease in ARDS mortality was only seen in observational studies from 1984 to 1993. Mortality did not decrease between 1994 (when a consensus definition was published) and 2006, and is lower in RCTs than observational studies.

Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death

Dopamine is a catecholamine with dose-dependent effects on the systemic and renal vasculature. In healthy participants, low-dose dopamine increases renal blood flow and promotes natriuresis through stimulation of renal D1, D2, and D4 receptors and thus may protect the kidney from acute tubular necrosis (1). The concept of low-dose or renal-dose dopamine has persisted since the first clinical description of its use in patients with congestive heart failure (2). Few controlled trials have demonstrated any benefit, and as a result, several editorials have discouraged its use (3-6). Nevertheless, recent surveys have documented dopamines continued popularity. For example, 17 of 24 New Zealand intensive care units (7) and 18 of 19 pediatric and neonatal intensive care units in the Netherlands (8) use low-dose dopamine to treat renal dysfunction or oliguria. Moreover, this therapy continues to attract substantial research resources: Several randomized trials have been published each year, and at least 1 large trial is ongoing (9). Two recent systematic reviews have addressed low-dose dopamine. Both reviews (10, 11) had several methodologic limitations. Neither review analyzed dopamines effects on urine output and adverse events. Other authors (12) have discussed the limitations of 1 review (10) and have called for a rigorous, updated meta-analysis conducted by independent researchers (13). Given the limited scope and methodologic concerns of previous systematic reviews and the ongoing widespread use and study of low-dose dopamine, we conducted a systematic review and meta-analysis by using a comprehensive search strategy to determine its effect on a broad range of clinical and renal physiologic outcomes and adverse events. Methods Search Strategy We searched the OVID versions of MEDLINE (1966January, week 4, 2005), EMBASE (1980week 5, 2005), CANCERLIT (1975October 2002), CINAHL (1982January, week 3, 2005), and CENTRAL (Cochrane Central Register of Controlled Trials, The Cochrane Library, fourth quarter, 2004). We also searched the Renal Health Library (available at www.update-software.com/publications/Renal/) on 3 February 2005. Two authors conducted independent search strategies. The first MEDLINE search strategy retrieved citations containing the subject heading dopamine (limited to the publication types clinical trial and meta-analysis) or the text words low dose dopamine or renal dose dopamine. The second MEDLINE search strategy retrieved citations containing the subject heading dopamine combined with exploded subject headings describing renal disease (kidney diseases and kidney) and physiology (kidney function tests, urine, and renal circulation) or text words describing low-dose dopamine appearing in close proximity to each other (low, renal, kidney, dose, and dopamine). We limited citations from the second search to randomized, controlled trials using a maximally sensitive strategy (14). We modified these searches for other databases. Full details of both search strategies are available from the authors. We screened reference lists from all retrieved articles and from recent review articles (8, 10, 11, 15-24) to identify additional studies. There were no language restrictions. Study Selection and Characteristics We selected parallel-group randomized, controlled trials that included any patient sample, compared low-dose dopamine (5 g/kg of body weight per minute) with placebo or no therapy, and recorded any of the following outcomes: all-cause mortality, requirement for renal replacement therapy, renal physiologic variables (urine output, serum creatinine level, or measured creatinine clearance on days 1, 2, or 3 after starting therapy), or adverse effects. We also included trials in which patients were allocated in alternating fashion or by hospital registry number (quasi-randomization) and trials with pharmacologic co-interventions (such as mannitol, diuretics, or diltiazem) that were equally applied to both groups. We defined a priori adverse effects of interest likely to be detected by routine patient monitoring: arrhythmias, myocardial ischemia, and limb or cutaneous ischemia. Data Abstraction Two reviewers independently screened studies for inclusion; retrieved all potentially relevant studies; and extracted data on study sample, intervention, prespecified outcomes, and methods from included trials. In both phases, disagreements between reviewers that remained after contacting study authors were resolved by consensus. We assessed agreement between the 2 reviewers on the selection of articles for inclusion by using Cohens (25). Validity Assessment We extracted methodologic information important for the assessment of internal validity: method of allocation and concealment of the randomization schedule, blinding of caregivers and outcomes assessors, and the number of and reasons for postrandomization withdrawals. We determined whether fluid and diuretic therapies were standardized or equally applied in dopamine and control groups. We attempted to contact all authors of trials that met our inclusion criteria. Quantitative Data Synthesis For each outcome of interest, we pooled all studies reporting the outcome on the basis of the a priori expectation of similar direction and magnitude of treatment effect. For mortality and renal replacement therapy, we combined studies reporting these outcomes at any time after randomization. For studies with 2 or more dopamine groups receiving different doses, we combined data from all doses to determine an overall outcome measure for the dopamine group. We used Review Manager 4.2 (The Cochrane Collaboration, Oxford, United Kingdom) to aggregate data for each outcome by using a random-effects model (26), and we considered a P value of 0.05 or less to be statistically significant. All pooled effect estimates are presented with 95% CIs, and all P values are 2-sided. Results for binary outcomes (mortality, need for renal replacement therapy, and adverse effects) are reported as relative risks. For studies with no events in one arm, 0.5 is added to all cells. (Studies with no events in either arm are not included in the pooled analysis.) The summary relative risk is calculated on the natural logarithm scale. The weight of each study is calculated as the inverse of the variance of the natural logarithm of its relative risk. In the presence of between-study heterogeneity, each studys weight is adjusted (26). Because clinical outcomes occurred infrequently in many trials, we also analyzed these outcomes by using other effect measures, including Petos odds ratios and random-effects risk differences (by using Review Manager 4.2) and exact odds ratios (by using StatXact 6.1 [Cytel Software Corp., Cambridge, Massachusetts]). These alternate methods gave very similar pooled treatment effects and CIs, and we therefore present only the random-effects relative risk data. Some papers reported 2 of the renal physiologic outcomes, urine output and creatinine clearance, in units that were adjusted for body weight or body surface area. However, trials did not consistently provide average patient weights, which are required to convert these measures into values with identical units, and they enrolled highly variable study samples that included adults, children, and neonates. Identical measurement units are necessary to statistically analyze the results by using weighted mean difference as the measure of treatment effect. One alternative approach would have pooled these measures by using the standardized mean difference (the absolute treatment effect in pooled SD units). However, we chose to summarize the treatment effect for each continuous outcome by using the relative change in the dopamine group compared with the control group. This approach provides a more clinically meaningful summary of treatment effect than the standardized mean difference. For each continuous outcome, we calculated the ratio of the mean value in the dopamine group to the mean value in the control group for each study and calculated a standard error for the natural logarithmtransformed ratio (see Appendix). We aggregated the natural logarithmtransformed ratios across studies by using the generalized inverse variance method (27). In studies where investigators obtained the total urine output over 24 hours by addition of urine outputs over several time periods, we calculated the variance of the total urine output by using the method of Follmann and colleagues (28). We assumed a moderate correlation ( ) of 0.4 between urine outputs at different time periods. Sensitivity analyses using correlations of 0 and 0.8 did not change the results. We considered only first-order correlations. We assessed between-study homogeneity for each pooled comparison by using the Cochran Q-test (29), with a P value of 0.10 or less indicating significant heterogeneity (30). We also report the I2 statistic, which is the proportion of total variation among studies that is explained by between-study heterogeneity rather than chance (31, 32). Substantial heterogeneity exists when I2 exceeds 50%. We developed several a priori hypotheses to explain statistically significant heterogeneity: 1) populationgreater treatment effect in trials enrolling surgical patients (fewer comorbid conditions) compared with medical patients; 2) baseline riskgreater treatment effect when low-dose dopamine was given for treatment rather than prevention of acute renal failure; 3) doseresponse relationshipgreater treatment effect with a dopamine dose 3 g/kg per minute vs. <3 g/kg per minute; 4) duration of therapygreater treatment effect in trials where dopamine was given for the entire time period before measurement of the outcome; and methodssmaller treatment effect 5) in studies with adequate allocation concealment (vs. all other studies) and 6) in studies with blinding of caregivers. For each hypothesis, we statistically tested the difference in estimates of treatment

Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis

Objective To review the literature on the use of inhaled nitric oxide to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and to summarise the effects of nitric oxide, compared with placebo or usual care without nitric oxide, in adults and children with ALI or ARDS. Design Systematic review and meta-analysis. Data sources Medline, CINAHL, Embase, and CENTRAL (to October 2006), proceedings from four conferences, and additional information from authors of 10 trials. Review methods Two reviewers independently selected parallel group randomised controlled trials comparing nitric oxide with control and extracted data related to study methods, clinical and physiological outcomes, and adverse events. Main outcome measures Mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, adverse events. Results 12 trials randomly assigning 1237 patients met inclusion criteria. Overall methodological quality was good. Using random effects models, we found no significant effect of nitric oxide on hospital mortality (risk ratio 1.10, 95% confidence interval 0.94 to 1.30), duration of ventilation, or ventilator-free days. On day one of treatment, nitric oxide increased the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) (13%, 4% to 23%) and decreased the oxygenation index (14%, 2% to 25%). Some evidence suggested that improvements in oxygenation persisted until day four. There was no effect on mean pulmonary arterial pressure. Patients receiving nitric oxide had an increased risk of developing renal dysfunction (1.50, 1.11 to 2.02). Conclusions Nitric oxide is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm. We do not recommend its routine use in these severely ill patients.

Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data

BackgroundMeta-analysis handles randomized trials with no outcome events in both treatment and control arms inconsistently, including them when risk difference (RD) is the effect measure but excluding them when relative risk (RR) or odds ratio (OR) are used. This study examined the influence of such trials on pooled treatment effects.MethodsAnalysis with and without zero total event trials of three illustrative published meta-analyses with a range of proportions of zero total event trials, treatment effects, and heterogeneity using inverse variance weighting and random effects that incorporates between-study heterogeneity.ResultsIncluding zero total event trials in meta-analyses moves the pooled estimate of treatment effect closer to nil, decreases its confidence interval and decreases between-study heterogeneity. For RR and OR, inclusion of such trials causes small changes, even when they comprise the large majority of included trials. For RD, the changes are more substantial, and in extreme cases can eliminate a statistically significant effect estimate.ConclusionTo include all relevant data regardless of effect measure chosen, reviewers should also include zero total event trials when calculating pooled estimates using OR and RR.

High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis

Objective To determine clinical and physiological effects of high frequency oscillation compared with conventional ventilation in patients with acute lung injury/acute respiratory distress syndrome (ARDS). Design Systematic review and meta-analysis. Data sources Electronic databases to March 2010, conference proceedings, bibliographies, and primary investigators. Study selection Randomised controlled trials of high frequency oscillation compared with conventional ventilation in adults or children with acute lung injury/ARDS. Data selection Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. Analyses used random effects models. Results Eight randomised controlled trials (n=419 patients) were included; almost all patients had ARDS. Methodological quality was good. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16-24% higher in patients receiving high frequency oscillation. There were no significant differences in oxygenation index because mean airway pressure rose by 22-33% in patients receiving high frequency oscillation (P≤0.01). In patients randomised to high frequency oscillation, mortality was significantly reduced (risk ratio 0.77, 95% confidence interval 0.61 to 0.98, P=0.03; six trials, 365 patients, 160 deaths), and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) resulting in discontinuation of assigned therapy was less likely (0.67, 0.46 to 0.99, P=0.04; five trials, 337 patients, 73 events). Other risks were similar. There was substantial heterogeneity between trials for physiological (I2=21-95%) but not clinical (I2=0%) outcomes. Pooled results were based on few events for most clinical outcomes. Conclusion High frequency oscillation might improve survival and is unlikely to cause harm. As ongoing large multicentre trials will not be completed for several years, these data help clinicians who currently use or are considering this technique for patients with ARDS.

Comparison of coronary artery bypass surgery and percutaneous coronary intervention in patients with diabetes: a meta-analysis of randomised controlled trials

BACKGROUND The choice between coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) for revascularisation in patients with diabetes and multivessel coronary artery disease, who account for 25% of revascularisation procedures, is much debated. We aimed to assess whether all-cause mortality differed between patients with diabetes who had CABG or PCI by doing a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing CABG with PCI in the modern stent era. METHODS We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from Jan 1, 1980, to March 12, 2013, for studies reported in English. Eligible studies were those in which investigators enrolled adult patients with diabetes and multivessel coronary artery disease, randomised them to CABG (with arterial conduits in at least 80% of participants) or PCI (with stents in at least 80% of participants), and reported outcomes separately in patients with diabetes, with a minimum of 12 months of follow-up. We used random-effects models to calculate risk ratios (RR) and 95% CIs for pooled data. We assessed heterogeneity using I(2). The primary outcome was all-cause mortality in patients with diabetes who had CABG compared with those who had PCI at 5-year (or longest) follow-up. FINDINGS The initial search strategy identified 3414 citations, of which eight trials were eligible. These eight trials included 7468 participants, of whom 3612 had diabetes. Four of the RCTs used bare metal stents (BMS; ERACI II, ARTS, SoS, MASS II) and four used drug-eluting stents (DES; FREEDOM, SYNTAX, VA CARDS, CARDia). At mean or median 5-year (or longest) follow-up, individuals with diabetes allocated to CABG had lower all-cause mortality than did those allocated to PCI (RR 0.67, 95% CI 0.52-0.86; p=0.002; I(2)=25%; 3131 patients, eight trials). Treatment effects in individuals without diabetes showed no mortality benefit (1.03, 0.77-1.37; p=0.78; I(2)=46%; 3790 patients, five trials; p interaction=0.03). We identified no differences in outcome whether PCI was done with BMS or DES. When present, we identified no clear causes of heterogeneity. INTERPRETATION In the modern era of stenting and optimum medical therapy, revascularisation of patients with diabetes and multivessel disease by CABG decreases long-term mortality by about a third compared with PCI using either BMS or DES. CABG should be strongly considered for these patients.

Effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis

Background: Mechanical ventilation in the prone position is used to improve oxygenation in patients with acute hypoxemic respiratory failure. We sought to determine the effect of mechanical ventilation in the prone position on mortality, oxygenation, duration of ventilation and adverse events in patients with acute hypoxemic respiratory failure. Methods: In this systematic review we searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Science Citation Index Expanded for articles published from database inception to February 2008. We also conducted extensive manual searches and contacted experts. We extracted physiologic data and clinically relevant outcomes. Results: Thirteen trials that enrolled a total of 1559 patients met our inclusion criteria. Overall methodologic quality was good. In 10 of the trials (n = 1486) reporting this outcome, we found that prone positioning did not reduce mortality among hypoxemic patients (risk ratio [RR] 0.96, 95% confidence interval [CI] 0.84–1.09; p = 0.52). The lack of effect of ventilation in the prone position on mortality was similar in trials of prolonged prone positioning and in patients with acute lung injury. In 8 of the trials (n = 633), the ratio of partial pressure of oxygen to inspired fraction of oxygen on day 1 was 34% higher among patients in the prone position than among those who remained supine (p < 0.001); these results were similar in 4 trials on day 2 and in 5 trials on day 3. In 9 trials (n = 1206), the ratio in patients assigned to the prone group remained 6% higher the morning after they returned to the supine position compared with patients assigned to the supine group (p = 0.07). Results were quantitatively similar but statistically significant in 7 trials on day 2 and in 6 trials on day 3 (p = 0.001). In 5 trials (n = 1004), prone positioning was associated with a reduced risk of ventilator-associated pneumonia (RR 0.81, 95% CI 0.66–0.99; p = 0.04) but not with a reduced duration of ventilation. In 6 trials (n = 504), prone positioning was associated with an increased risk of pressure ulcers (RR 1.36, 95% CI 1.07–1.71; p = 0.01). Most analyses found no to moderate between-trial heterogeneity. Interpretation: Mechanical ventilation in the prone position does not reduce mortality or duration of ventilation despite improved oxygenation and a decreased risk of pneumonia. Therefore, it should not be used routinely for acute hypoxemic respiratory failure. However, a sustained improvement in oxygenation may support the use of prone positioning in patients with very severe hypoxemia, who have not been well-studied to date.

The ratio of means method as an alternative to mean differences for analyzing continuous outcome variables in meta-analysis: A simulation study

BackgroundMeta-analysis of continuous outcomes traditionally uses mean difference (MD) or standardized mean difference (SMD; mean difference in pooled standard deviation (SD) units). We recently used an alternative ratio of mean values (RoM) method, calculating RoM for each study and estimating its variance by the delta method. SMD and RoM allow pooling of outcomes expressed in different units and comparisons of effect sizes across interventions, but RoM interpretation does not require knowledge of the pooled SD, a quantity generally unknown to clinicians.Objectives and methodsTo evaluate performance characteristics of MD, SMD and RoM using simulated data sets and representative parameters.ResultsMD was relatively bias-free. SMD exhibited bias (~5%) towards no effect in scenarios with few patients per trial (n = 10). RoM was bias-free except for some scenarios with broad distributions (SD 70% of mean value) and medium-to-large effect sizes (0.5–0.8 pooled SD units), for which bias ranged from -4 to 2% (negative sign denotes bias towards no effect). Coverage was as expected for all effect measures in all scenarios with minimal bias. RoM scenarios with bias towards no effect exceeding 1.5% demonstrated lower coverage of the 95% confidence interval than MD (89–92% vs. 92–94%). Statistical power was similar. Compared to MD, simulated heterogeneity estimates for SMD and RoM were lower in scenarios with bias because of decreased weighting of extreme values. Otherwise, heterogeneity was similar among methods.ConclusionSimulation suggests that RoM exhibits comparable performance characteristics to MD and SMD. Favourable statistical properties and potentially simplified clinical interpretation justify the ratio of means method as an option for pooling continuous outcomes.

Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged ICU length of stay: a cohort study

IntroductionAnemia among the critically ill has been described in patients with short to medium length of stay (LOS) in the intensive care unit (ICU), but it has not been described in long-stay ICU patients. This study was performed to characterize anemia, transfusion, and phlebotomy practices in patients with prolonged ICU LOS.MethodsWe conducted a retrospective chart review of consecutive patients admitted to a medical-surgical ICU in a tertiary care university hospital over three years; patients included had a continuous LOS in the ICU of 30 days or longer. Information on transfusion, phlebotomy, and outcomes were collected daily from days 22 to 112 of the ICU stay.ResultsA total of 155 patients were enrolled. The mean age, admission Acute Physiology and Chronic Health Evaluation II score, and median ICU LOS were 62.3 ± 16.3 years, 23 ± 8, and 49 days (interquartile range 36–70 days), respectively. Mean hemoglobin remained stable at 9.4 ± 1.4 g/dl from day 7 onward. Mean daily phlebotomy volume was 13.3 ± 7.3 ml, and 62% of patients received a mean of 3.4 ± 5.3 units of packed red blood cells at a mean hemoglobin trigger of 7.7 ± 0.9 g/dl after day 21. Transfused patients had significantly greater acuity of illness, phlebotomy volumes, ICU LOS and mortality, and had a lower hemoglobin than did those who were not transfused. Multivariate logistic regression analysis identified the following as independently associated with the likelihood of requiring transfusion in nonbleeding patients: baseline hemoglobin, daily phlebotomy volume, ICU LOS, and erythropoietin therapy (used almost exclusively in dialysis dependent renal failure in this cohort of patients). Small increases in average phlebotomy (3.5 ml/day, 95% confidence interval 2.4–6.8 ml/day) were associated with a doubling in the odds of being transfused after day 21.ConclusionAnemia, phlebotomy, and transfusions, despite low hemoglobin triggers, are common in ICU patients long after admission. Small decreases in phlebotomy volume are associated with significantly reduced transfusion requirements in patients with prolonged ICU LOS.

The association between renal replacement therapy modality and long-term outcomes among critically ill adults with acute kidney injury: a retrospective cohort study*.

Objective:Among critically ill patients with acute kidney injury, the impact of renal replacement therapy modality on long-term kidney function is unknown. Compared with conventional intermittent hemodialysis, continuous renal replacement therapy may promote kidney recovery by conferring greater hemodynamic stability; yet continuous renal replacement therapy may not enhance patient survival and is resource intense. Our objective was to determine whether continuous renal replacement therapy was associated with a lower risk of chronic dialysis as compared with intermittent hemodialysis, among survivors of acute kidney injury. Design:Retrospective cohort study. Setting:Linked population-wide administrative databases in Ontario, Canada. Patients:Critically ill adults who initiated dialysis for acute kidney injury between July 1996 and December 2009. In the primary analysis, we considered those who survived to at least 90 days after renal replacement therapy initiation. Interventions:Initial receipt of continuous renal replacement therapy versus intermittent hemodialysis. Measurements and Main Results:Continuous renal replacement therapy recipients were matched 1:1 to intermittent hemodialysis recipients based on a history of chronic kidney disease, receipt of mechanical ventilation, and a propensity score for the likelihood of receiving continuous renal replacement therapy. Cox proportional hazards were used to evaluate the relationship between initial renal replacement therapy modality and the primary outcome of chronic dialysis, defined as the need for dialysis for a consecutive period of 90 days. We identified 2,315 continuous renal replacement therapy recipients of whom 2,004 (87%) were successfully matched to 2,004 intermittent hemodialysis recipients. Participants were followed over a median duration of 3 years. The risk of chronic dialysis was significantly lower among patients who initially received continuous renal replacement therapy versus intermittent hemodialysis (hazard ratio, 0.75; 95% CI, 0.65–0.87). This relation was more prominent among those with preexisting chronic kidney disease (p value for interaction term = 0.065) and heart failure (p value for interaction term = 0.035). Conclusions:Compared with intermittent hemodialysis, initiation of continuous renal replacement therapy in critically ill adults with acute kidney injury is associated with a lower likelihood of chronic dialysis.