Maneesh Sud

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.

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.

Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis

Background: Mechanical ventilation in the prone position is used to improve oxygenation and to mitigate the harmful effects of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). We sought to determine the effect of prone positioning on mortality among patients with ARDS receiving protective lung ventilation. Methods: We searched electronic databases and conference proceedings to identify relevant randomized controlled trials (RCTs) published through August 2013. We included RCTs that compared prone and supine positioning during mechanical ventilation in patients with ARDS. We assessed risk of bias and obtained data on all-cause mortality (determined at hospital discharge or, if unavailable, after longest follow-up period). We used random-effects models for the pooled analyses. Results: We identified 11 RCTs (n = 2341) that met our inclusion criteria. In the 6 trials (n = 1016) that used a protective ventilation strategy with reduced tidal volumes, prone positioning significantly reduced mortality (risk ratio 0.74, 95% confidence interval 0.59–0.95; I2 = 29%) compared with supine positioning. The mortality benefit remained in several sensitivity analyses. The overall quality of evidence was high. The risk of bias was low in all of the trials except one, which was small. Statistical heterogeneity was low (I2 < 50%) for most of the clinical and physiologic outcomes. Interpretation: Our analysis of high-quality evidence showed that use of the prone position during mechanical ventilation improved survival among patients with ARDS who received protective lung ventilation.

A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing

Proximal promoter DNA methylation has been shown to be important for regulating gene expression. However, its relative contribution to the cell-specific expression of endothelial cell (EC)-enriched genes has not been defined. We used methyl-DNA immunoprecipitation and bisulfite conversion to analyze the DNA methylation profile of EC-enriched genes in ECs vs nonexpressing cell types, both in vitro and in vivo. We show that prototypic EC-enriched genes exhibit functional differential patterns of DNA methylation in proximal promoter regions of most (eg, CD31, von Willebrand factor [vWF], VE-cadherin, and intercellular adhesion molecule-2), but not all (eg, VEGFR-1 and VEGFR-2), EC-enriched genes. Comparable findings were evident in cultured ECs, human blood origin ECs, and murine aortic ECs. Promoter-reporter episomal transfection assays for endothelial nitric oxide synthase, VE-cadherin, and vWF indicated functional promoter activity in cell types where the native gene was not active. Inhibition of DNA methyltransferase activity indicated important functional relevance. Importantly, profiling DNA replication timing patterns indicated that EC-enriched gene promoters with differentially methylated regions replicate early in S-phase in both expressing and nonexpressing cell types. Collectively, these studies highlight the functional importance of promoter DNA methylation in controlling vascular EC gene expression.

CKD Stage at Nephrology Referral and Factors Influencing the Risks of ESRD and Death

BACKGROUND Patients with chronic kidney disease (CKD) stages 3-5 are at increased risk of progressing to end-stage renal disease (ESRD) or dying prior to the development of ESRD compared with patients with less severe CKD. The magnitude of these risks may vary by stage, which has important implications for therapy. Our objective was to apply a competing risk analysis in order to estimate these risks in a referred cohort of patients with CKD by stage at referral and identify risk factors associated with each outcome. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 3,273 patients with CKD stages 3-5 who were referred to the nephrology clinic at Sunnybrook Health Sciences Centre, Toronto, prior to December 31, 2008, with follow-up data available prior to December 31,2008. PREDICTORS CKD stage at time of referral; demographic, laboratory, and clinical characteristics. OUTCOMES ESRD, defined as the initiation of dialysis therapy or pre-emptive kidney transplantation, and death from any cause prior to ESRD. MEASUREMENTS Baseline laboratory data. RESULTS Over a median follow-up of 2.98 years, 459 patients (14%) developed ESRD and 540 (16%) died. Rates per 100 patient-years of ESRD versus death prior to ESRD for CKD stage 3A were 0.6 (95% CI, 0.1-1.0) versus 2.2 (95% CI, 1.2-3.1; P<0.001); for CKD stage 3B, 1.4 (95% CI, 0.8-2.1) versus 4.4 (95% CI, 3.3-5.6; P<0.001); for CKD stage 4, 7.7 (95% CI, 5.9-9.4) versus 8.0 (95% CI, 6.2-9.8; P=0.6); and for CKD stage 5, 41.4 (95% CI, 34.4-48.4) versus 9.4 (95% CI, 5.2-13.4; P<0.001). For those with CKD stage 4, we identified 12 variables associated with higher risk of ESRD and 7 variables associated with higher risk of death prior to ESRD. LIMITATIONS A cohort analyzed retrospectively. CONCLUSIONS ESRD and death prior to ESRD incidence was most similar in CKD stage 4. We identified variables easily assessed at the time of referral that could discriminate between these risks.

Risk of End-Stage Renal Disease and Death After Cardiovascular Events in Chronic Kidney Disease

Background— Patients with chronic kidney disease stages 3 to 5 (glomerular filtration rate <60 mL/min/1.73m2) are at increased risk of cardiovascular (CV) disease when compared with patients with less severe chronic kidney disease. How CV events modify the subsequent risk of progression to end-stage-renal disease (ESRD) or all-cause mortality (ACM) before ESRD is not well known. Methods and Results— This retrospective cohort study involved 2964 chronic kidney disease subjects referred between January 2001 and December 2008 to the nephrology clinic at Sunnybrook Health Sciences Center, Toronto, Ontario. Interim CV events (heart failure, myocardial infarction, and stroke), ESRD, and ACM were ascertained from administrative data. Over a median follow-up time of 2.76 years (interquartile range, 1.45–4.62), 447 (15%) subjects had a CV event. In the same time period, 318 (11%) developed ESRD, and 446 (15%) experienced ACM before ESRD (156 [5%] from a CV and 290 [10%] from a non–CV-related cause). When analyzed as a time-dependent variable, an interim CV event was associated with a higher risk of subsequent ESRD (hazard ratio, 5.33; 95% confidence interval, 3.74–7.58) and ACM before ESRD (hazard ratio, 4.15, hazard ratio, 3.30–5.23). The hazard ratio for CV-related death versus non–CV-related death before ESRD was 12.38 (95% confidence interval, 8.30–18.45) versus 2.13 (95% confidence interval, 1.57–2.87). Conclusions— CV events are common in patients with chronic kidney disease stages 3 to 5 and are associated with a substantial increase in the risk of ESRD and ACM before ESRD. Intensive primary and secondary prevention strategies may help attenuate this risk.

ESRD and Death after Heart Failure in CKD

CKD is a risk factor for heart failure, but there is no data on the risk of ESRD and death after recurrent hospitalizations for heart failure. We sought to determine how interim heart failure hospitalizations modify the subsequent risk of ESRD or death before ESRD in patients with CKD. We retrospectively identified 2887 patients with a GFR between 15 and 60 ml/min per 1.73 m2 referred between January of 2001 and December of 2008 to a nephrology clinic in Toronto, Canada. We ascertained interim first, second, and third heart failure hospitalizations as well as ESRD and death before ESRD outcomes from administrative data. Over a median follow-up time of 3.01 (interquartile range=1.56-4.99) years, interim heart failure hospitalizations occurred in 359 (12%) patients, whereas 234 (8%) patients developed ESRD, and 499 (17%) patients died before ESRD. Compared with no heart failure hospitalizations, one, two, or three or more heart failure hospitalizations increased the adjusted hazard ratio of ESRD from 4.89 (95% confidence interval [95% CI], 3.21 to 7.44) to 10.27 (95% CI, 5.54 to 19.04) to 14.16 (95% CI, 8.07 to 24.83), respectively, and the adjusted hazard ratio death before ESRD from 3.30 (95% CI, 2.55 to 4.27) to 4.20 (95% CI, 2.82 to 6.25) to 6.87 (95% CI, 4.96 to 9.51), respectively. We conclude that recurrent interim heart failure is associated with a stepwise increase in the risk of ESRD and death before ESRD in patients with CKD.

Progression to Stage 4 chronic kidney disease and death, acute kidney injury and hospitalization risk: a retrospective cohort study

BACKGROUND Chronic kidney disease (CKD) Stage 4 is on the path to kidney failure, but there is little information on the risks associated with progression to Stage 4 per se. The objective of this study is to determine how progression from Stage 3 to Stage 4 CKD alters morbidity and mortality in a referred cohort of patients. METHODS We conducted a retrospective cohort study consisting of 1607 patients with estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73 m(2) referred to a nephrologist at a tertiary care center in Ontario, Canada, between January 2001 and December 2008. Interim progression from Stage 3 to Stage 4 chronic kidney disease was defined by two independent outpatient eGFR values <30 mL/min/1.73 m(2). Death, acute kidney injury (AKI) and all-cause hospitalizations subsequent to Stage 4 progression, but prior to the development of end-stage renal disease (ESRD), ascertained from administrative databases. RESULTS The mean (standard deviation) baseline eGFR was 43 (8) mL/min/1.73 m(2). Over 2.66 years (interquartile range: 1.42-4.45), 344 (21%) patients progressed to Stage 4, 47 (3%) developed ESRD, 188 (12%) patients died, 143 (9%) were hospitalized with AKI and 688 (43%) were hospitalized for any reason. Compared with patients who did not progress to Stage 4, those who did progress had significantly higher adjusted risks of death [hazard ratio (HR) = 2.56, 95% confidence interval (95% CI): 1.75-3.75], AKI (HR = 2.32, 95% CI: 1.44-3.74) and all-cause hospitalization (HR = 1.87, 95% CI: 1.45-2.42). CONCLUSIONS Progression from Stage 3 to Stage 4 CKD is associated with increased risks of death, AKI and hospitalization prior to ESRD.

Effect of prone positioning in patients with acute respiratory distress syndrome and high Simplified Acute Physiology Score Ii

Characterization of a new clinically more interpretable techniques to pool continuous outcomes in meta-analysis.

The Economics of Transcatheter Valve Interventions

A subset of patients who require correction of a stenotic or incompetent valve are deemed to be at excessive surgical risk, which precludes surgical repair or replacement. Transcatheter valve interventions are viable alternatives in these patients. However, these technologies are costly, and in the setting of a constrained Canadian health care budget, economic value is an important consideration to allow for fair allocation of scarce resources. Accordingly, we review the economic literature on transcatheter valve interventions, targeting a general audience. Our specific goals are highlighting how best to interpret these studies and discuss the implications of these technologies on the Canadian health care system. Transcatheter aortic valve replacement (TAVR) is a cost-effective alternative for inoperable patients who otherwise would receive medical therapy. When compared with surgical aortic valve replacement (SAVR), TAVR is associated with significant reductions in postprocedure hospital resource use, which offsets the substantially higher cost of the TAVR valve system relative to SAVR valves. Although cost-effectiveness estimates for TAVR in high-risk operable candidates vary widely across studies, based on contemporary data from the perspective of the Canadian health care system, TAVR is likely to provide economic value. Recent studies suggest that when compared with medical therapy for severe degenerative mitral regurgitation, the MitraClip (Abbott, Abbott Park, IL) may offer economic value in high-risk patients; however, in the absence of randomized controlled trials, this is speculative. Nonetheless, these transcatheter technologies represent a paradigm shift in the management of valvular disease; their dissemination will have substantial impact in cardiovascular care delivery.