Niall D. Ferguson

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.

Evolution of Mortality over Time in Patients Receiving Mechanical Ventilation

RATIONALE Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear. OBJECTIVES To estimate whether mortality in mechanically ventilated patients has changed over time. METHODS Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models. MEASUREMENTS AND MAIN RESULTS We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an increase in applied positive end-expiratory pressure (mean 4.2 cm H2O [SD = 3.8] in 1998 to 7.0 cm of H2O [SD = 3.0] in 2010). Crude mortality in the intensive care unit decreased in 2010 compared with 1998 (28 versus 31%; odds ratio, 0.87; 95% confidence interval, 0.80-0.94), despite a similar complication rate. Hospital mortality decreased similarly. After adjusting for baseline and management variables, this difference remained significant (odds ratio, 0.78; 95% confidence interval, 0.67-0.92). CONCLUSIONS Patient characteristics and ventilation practices have changed over time, and outcomes of mechanically ventilated patients have improved. Clinical trials registered with www.clinicaltrials.gov (NCT01093482).

Sepsis incidence and outcome: contrasting the intensive care unit with the hospital ward

Objective:To describe the outcome of patients with sepsis according to location on a ward or in an intensive care unit. Design:Prospective multicentered observational study. Setting:Three academic hospitals in Madrid, Spain. Patients:Consecutive patients with sepsis admitted to participating hospitals from March 1 to June 30, 2003. Interventions:None. Measurements and Main Results:During the study period, 15,852 patients >18 yrs of age were admitted. Sepsis was identified in 702 patients, giving an estimated cumulative incidence rate of 367 cases per 100,000 adult area residents per year and a cumulative incidence rate among patients admitted to the hospital of 4.4%. Most septic patients had a community-acquired infection (71%). Severe sepsis developed in 199 patients (incidence rate, 104 cases per 100,000 adult area residents per year), and 59 patients developed septic shock (incidence rate, 31 cases per 100,000 adult area residents per year). Most of the patients met the criteria for severe sepsis or septic shock on the same day that they would have qualified for the septic status one step down the scale. In the other patients, the median time between sepsis and severe sepsis was 2 days (interquartile range, 2–5) and between severe sepsis and septic shock was 3 days (interquartile range, 1–4). Only 32% of severe sepsis patients received intensive care. The hospital mortality for all septic patients was 12.8%; for severe sepsis, 20.7%; and for septic shock, 45.7%. Conclusions:This study shows the high incidence of sepsis in a general population of patients admitted to hospital. A significant proportion of patients with severe sepsis are not transferred to the intensive care unit.

Recruitment maneuvers for acute lung injury: A systematic review

RATIONALE There are conflicting data regarding the safety and efficacy of recruitment maneuvers (RMs) in patients with acute lung injury (ALI). OBJECTIVES To summarize the physiologic effects and adverse events in adult patients with ALI receiving RMs. METHODS Systematic review of case series, observational studies, and randomized clinical trials with pooling of study-level data. MEASUREMENTS AND MAIN RESULTS Forty studies (1,185 patients) met inclusion criteria. Oxygenation (31 studies; 636 patients) was significantly increased after an RM (PaO2): 106 versus 193 mm Hg, P = 0.001; and PaO2/FiO2 ratio: 139 versus 251 mm Hg, P < 0.001). There were no persistent, clinically significant changes in hemodynamic parameters after an RM. Ventilatory parameters (32 studies; 548 patients) were not significantly altered by an RM, except for higher PEEP post-RM (11 versus 16 cm H2O; P = 0.02). Hypotension (12%) and desaturation (9%) were the most common adverse events (31 studies; 985 patients). Serious adverse events (e.g., barotrauma [1%] and arrhythmias [1%]) were infrequent. Only 10 (1%) patients had their RMs terminated prematurely due to adverse events. CONCLUSIONS Adult patients with ALI receiving RMs experienced a significant increase in oxygenation, with few serious adverse events. Transient hypotension and desaturation during RMs is common but is self-limited without serious short-term sequelae. Given the uncertain benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence on clinical outcomes, the routine use of RMs cannot be recommended or discouraged at this time. RMs should be considered for use on an individualized basis in patients with ALI who have life-threatening hypoxemia.

Comparison of Clinical Criteria for the Acute Respiratory Distress Syndrome with Autopsy Findings

Context Do all patients who meet clinical criteria for the acute respiratory distress syndrome (ARDS) have diffuse alveolar damage? Contribution Of 382 patients who had autopsies after dying in an intensive care unit, 127 met clinical criteria for ARDS. The sensitivity and specificity of clinical criteria for identifying patients with diffuse alveolar damage at autopsy were 75% and 84%, respectively. People with extrapulmonary risk factors, such as sepsis syndrome, more often had findings of diffuse alveolar damage than did those with only pulmonary risk factors, such as pneumonia. Implications In severely ill patients, clinical criteria and pathologic findings for ARDS are not closely linked. The Editors In 1967, Ashbaugh and colleagues (1) reported a syndrome characterized by the acute onset of tachypnea, hypoxemia, and loss of lung adherence that occurred after various stimuli. Over the subsequent 2 decades, the acute respiratory distress syndrome (ARDS) remained very loosely defined even in clinical trials. In a systematic overview of the incidence of and risk factors for ARDS, Garber and colleagues (2) found that 51% of 83 articles identified did not specifically define this syndrome. In 1992, however, the AmericanEuropean Consensus Conference on ARDS was formed with the goal of bringing clarity and uniformity to the definition of acute lung injury and acute respiratory distress syndrome (3). The resultant AmericanEuropean Consensus Conference definition of ARDS requires the acute onset of bilateral chest radiographic infiltrates with hypoxemia but without left atrial hypertension (3). Diffuse alveolar damage is the histopathologic finding that corresponds to the clinical entity of ARDS. Katzenstein and colleagues (4) described diffuse alveolar damage in 1976, and their criteria remain in use today. We are unaware, however, of any study that has systematically analyzed the correlation between clinical criteria for ARDS and histologic findings. This may be important because several diseases with different histopathologic findings, such as bacterial pneumonia, pulmonary hemorrhage, and bronchiolitis obliteransorganizing pneumonia, may present with a clinical picture identical to that of ARDS. In addition, ARDS associated with pulmonary risk factors may differ from that associated with extrapulmonary risk factors, a concept introduced by the AmericanEuropean Consensus Conference (3). Several studies have documented differences in the radiologic pattern (5), the respiratory mechanics (6), and the response to prone position (7) between pulmonary and extrapulmonary cases of ARDS. These findings suggest that we are faced with 2 different clinical entities or that the AmericanEuropean Consensus Conference definition operates differently depending on the origin of ARDS. To interpret the results of both observational and interventional research in ARDS, we must be confident that these studies are truly examining patients with ARDS and diffuse alveolar damage. We therefore need a measure of the validity of the widely used AmericanEuropean Consensus Conference definition. We evaluated the criterion validity of the definition of ARDS proposed by the AmericanEuropean Consensus Conference (3) by using autopsy findings as the reference standard. Second, we analyzed whether the validity of this definition was modified according to the presence of pulmonary or extrapulmonary risk factors. Methods Patients We included all patients who died in the intensive care unit of the Hospital Universitario de Getafe, Madrid, Spain, between June 1991 and December 2002 and whose relatives gave informed consent to perform a clinical autopsy. We approached the families of all patients who died except those who became organ donors (because donated organs were not available for autopsy) and those whose autopsies were legally mandated (because these autopsies were performed outside the hospital and we could not access their results). The institutional ethics committee approved the study. Clinical Criteria for ARDS After a patients death, 2 intensivists, who were blinded to the autopsy findings, reviewed clinical charts together. They recorded the following data for each patient: age, sex, date of admission to intensive care unit, date of initiation of mechanical ventilation, principal diagnosis, risk factor for ARDS (pulmonary [pneumonia, aspiration, near-drowning, inhalational injury, or lung contusion] or extrapulmonary [sepsis syndrome, multiple trauma, several blood transfusions, shock, or pancreatitis]), date when all AmericanEuropean Consensus Conference criteria were first met, date of death, and clinical condition at the time of the death. If a patient had 2 or more risk factors for ARDS, we recorded the risk factor that presented first. The clinical condition at the time of death was considered to be shock with hypoxemia, shock without hypoxemia, or hypoxemia without shock. Shock was defined as a systolic blood pressure persistently below 90 mm Hg during the 6 hours before death, and hypoxemia was defined as arterial oxygenation saturation persistently below 85% during the final 6 hours. We used a case report form that was specifically designed to define and uniformly capture the variables of interest. A diagnosis of ARDS was established when all criteria defined by the AmericanEuropean Consensus Conference were met: acute onset, evidence on chest radiographs of airspace changes in all 4 quadrants, ratio of Po 2 to inspired fraction of oxygen of less than 200, and pulmonary artery wedge pressure less than 18 mm Hg or no clinical evidence of left atrial hypertension (3). Pathologic Criteria for Diffuse Alveolar Damage We used a predefined protocol, described previously (8), for the pathologic examination and clinicalpathologic correlation. Postmortem study was performed within 12 hours of death. After removal from the thorax, the lungs were inflated with 10% formalin to a pressure of 35 cm of H2O and were fixed in block with 10% formalin. After 48 hours, the lungs were cut into slices 3 cm thick. We took samples for microscopic analysis from each pulmonary lobe and additional samples from areas with macroscopic injuries. Two pathologists independently analyzed each sample, and a third pathologist resolved any discrepancies. Criteria for diffuse alveolar damage were hyaline membranes plus at least 1 of the following: alveolar cell type I or endothelial cell necrosis, edema, organizing interstitial fibrosis, or prominent alveolar cell type II proliferation (4, 9). Histologic criteria for the diagnosis of acute pneumonia included the presence of intense neutrophilic infiltration in the interstitium and intra-alveolar spaces, particularly around terminal bronchioles. Alveoli had to be at least partially full with neutrophils, fibrinous exudates, and cellular debris to establish a histologic diagnosis of acute pneumonia. Alveolar hemorrhage was diagnosed when acute hemorrhage was observed in alveoli and airways, along with the presence of macrophages staining positive for hemosiderin. Statistical Analysis Data are expressed as means (SD), medians (interquartile ranges), or proportions (95% CIs), as appropriate. All P values are 2-sided. We performed 3 analyses to evaluate the validity of the clinical criteria of ARDS: including all patients, including patients with any risk factor for ARDS, and separating patients with risk factors according to pulmonary or extrapulmonary origin. We calculated operative indexes, including sensitivity, specificity, and likelihood ratios, according to standard criteria (10). We used chi-square tests to compare sensitivity and specificity (11) and the Cochran Q-test to compare likelihood ratios between the cohort with pulmonary risk factors and the cohort with extrapulmonary risk factors (12). We used SPSS 11.5 (SPSS Inc., Chicago, Illinois) and Meta-Disc for Windows (Ramn y Cajal Hospital, Madrid, Spain [13]) for statistical analysis. Role of the Funding Source The funding source had no role in the design, conduct, or analysis of the data or in the decision to submit the manuscript for publication. Results During the study period, 8157 patients were admitted to the intensive care unit and 1399 (17%) died. We subsequently excluded 104 organ donors and 90 patients with legally mandated autopsies. We obtained consent and performed a clinical autopsy in 406 (34%) of the remaining patients. Twenty-four (6%) of these patients were excluded from the analysis because the hospital clinical records were lost and the information needed to determine both risk factor and clinical definition status was therefore unavailable. Table 1 shows the patient demographic and clinical characteristics. Organ donors and patients who required legally mandated autopsy were younger than other patients, and more of them had trauma as a risk factor for ARDS. Organ donors were more likely to be admitted to the intensive care unit with a neurologic problem, and patients with legally mandated autopsy were more likely to be men. Patients whose relatives declined autopsy were similar to the patients included in the study. Study patients had a median duration of mechanical ventilation of 4 days (interquartile range, 1 to 11 days) and a median length of stay in the intensive care unit of 5 days (interquartile range, 1 to 12 days). Table 1. Characteristics of the Patients Who Died in the Intensive Care Unit during the Study A total of 127 patients (33%) met the AmericanEuropean Consensus Conference criteria. After first meeting these criteria, they had a median time to death of 3 days (interquartile range, 1 to 6 days). Meanwhile, 112 patients (29%) met the pathologic criteria for diffuse alveolar damage. Table 2 shows the agreement between the clinical and pathologic diagnoses of ARDS and the operative indexes calculated by using these data. In all patients, the sensitivity of the AmericanEuropean Consensus Conference criteria was 75% (95% CI

Acute respiratory distress syndrome: Underrecognition by clinicians and diagnostic accuracy of three clinical definitions*

Objective:To determine and compare the diagnostic accuracy of three clinical definitions of acute respiratory distress syndrome (ARDS): (1) the American-European consensus conference definition; (2) the lung injury score; and (3) a recently developed Delphi definition. A second objective was to determine the accuracy of clinical diagnoses of ARDS made in daily practice. Design:Independent comparison of autopsy findings with the daily status of clinical definitions, constructed with data abstracted retrospectively from medical records. Setting:Tertiary intensive care unit. Patients:One hundred thirty-eight patients from the period 1995 through 2001 who were autopsied after being mechanically ventilated. Interventions:Clinical ARDS diagnoses were determined daily without knowledge of autopsy results. Charts were reviewed for any mention of ARDS in the clinical notes. Autopsies were reviewed independently by two pathologists for the presence of diffuse alveolar damage. The sensitivity and specificity of the definitions were determined with use of diffuse alveolar damage at autopsy as the reference standard. Measurements and Main Results:Diffuse alveolar damage at autopsy was documented in 42 of 138 cases (30.4%). Only 20 of these 42 patients (47.6%) had any mention of ARDS in their chart. Sensitivities and specificities (95% confidence intervals) were as follows: American-European definition, 0.83 (0.72–0.95), 0.51 (0.41–0.61); lung injury score, 0.74 (0.61–0.87), 0.77 (0.69–0.86); and Delphi definition, 0.69 (0.55–0.83), 0.82 (0.75–0.90). Specificity was significantly higher for both the lung injury score and Delphi definition than for the American-European definition (p < .001 for both), whereas comparisons of sensitivity, which was higher for the American-European definition, were not significantly different (p = .34 and p = .07, respectively). Conclusions:Acute respiratory distress syndrome appears underrecognized by clinicians in patients who die with this syndrome. In this population, the specificities of existing clinical definitions vary considerably, which may be problematic for clinical trials.

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.

Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients

The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use. Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely. This position paper represents the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO. The aim of this paper is to provide physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients. Importantly, this will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions. Given the need for further evidence, we encourage restraint in the widespread use of ECMO until we have a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.

Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome

Objective:To determine the usual practice for setting tidal volume and other ventilatory parameters in patients with acute respiratory distress syndrome (ARDS) in the late 1990s and to determine the independent effects of these practices on intensive care unit mortality. Design:Subanalysis of a prospective observational study. Multivariable logistic regression was used to analyze the effects of ventilatory management on mortality. Setting:A total of 361 intensive care units in 20 countries in March 1998. Patients:A total of 467 mechanically ventilated patients with ARDS. Interventions:None. Measurements and Main Results:The mean tidal volume used in the first week of ARDS was 8.8 mL/kg measured body weight, and there was great variability in these tidal volumes (sd = 2.0). Tidal volumes were significantly lower in patients with (n = 265) than without (n = 202) a recorded plateau pressure (8.6 vs. 9.1 mL/kg, p = .01). The overall intensive care unit mortality rate was 60.2%. In addition to the strong influence of organ failures and higher levels of inspired oxygen, late-onset ARDS (onset after >48 hrs of mechanical ventilation; odds ratio, 2.09) was independently associated with mortality. In addition, lower levels of positive end-expiratory pressure were independently associated with higher mortality (odds ratio, 0.91; 1 cm of H2O increments). Neither inspiratory pressures nor tidal volumes were independently associated with mortality, and there was no evidence of increased mortality with the use of lower inspiratory pressures. Conclusions:This descriptive study demonstrated considerable interpatient variability in tidal volumes during the study period. In addition to traditional prognostic indicators, timing of ARDS onset and the use of low levels of positive end-expiratory pressure or no positive end-expiratory pressure during the first week may adversely influence outcome in ARDS patients.

Characteristics and Outcomes of Ventilated Patients According to Time to Liberation from Mechanical Ventilation

RATIONALE A new classification of patients based on the duration of liberation of mechanical ventilation has been proposed. OBJECTIVES To analyze outcomes based on the new weaning classification in a cohort of mechanically ventilated patients. METHODS Secondary analysis included 2,714 patients who were weaned and underwent scheduled extubation from a cohort of 4,968 adult patients mechanically ventilated for more than 12 hours. MEASUREMENTS AND MAIN RESULTS Patients were classified according to a new weaning classification: 1,502 patients (55%) as simple weaning,1,058 patients (39%) as difficult weaning, and 154 (6%) as prolonged weaning.Variables associated with prolonged weaning(.7d)were: severity at admission (odds ratio [OR] per unit of Simplified Acute Physiology Score II, 1.01; 95% confidence interval [CI], 1.001–1.02), duration of mechanical ventilation before first attempt of weaning (OR per day, 1.10; 95% CI, 1.06–1.13), chronic pulmonary disease other than chronic obstructive pulmonary disease (OR,13.23; 95% CI, 3.44–51.05), pneumonia as the reason to start mechanical ventilation (OR, 1.82; 95% CI, 1.07–3.08), and level of positive end-expiratory pressure applied before weaning (OR per unit,1.09; 95% CI, 1.04–1.14). The prolonged weaning group had a nonsignificant trend toward a higher rate of reintubation (P ¼ 0.08),tracheostomy (P ¼ 0.15), and significantly longer length of stay and higher mortality in the intensive care unit (OR for death, 1.97;95%CI, 1.17–3.31). The adjusted probability of death remained constant until Day 7, at which point it increased to 12.1%.