Roy G. Brower

Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome

BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28. RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively. CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis.

CONTEXT Trials comparing higher vs lower levels of positive end-expiratory pressure (PEEP) in adults with acute lung injury or acute respiratory distress syndrome (ARDS) have been underpowered to detect small but potentially important effects on mortality or to explore subgroup differences. OBJECTIVES To evaluate the association of higher vs lower PEEP with patient-important outcomes in adults with acute lung injury or ARDS who are receiving ventilation with low tidal volumes and to investigate whether these associations differ across prespecified subgroups. DATA SOURCES Search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) plus a hand search of conference proceedings (2004-January 2010). STUDY SELECTION Two reviewers independently screened articles to identify studies randomly assigning adults with acute lung injury or ARDS to treatment with higher vs lower PEEP (with low tidal volume ventilation) and also reporting mortality. DATA EXTRACTION Data from 2299 individual patients in 3 trials were analyzed using uniform outcome definitions. Prespecified effect modifiers were tested using multivariable hierarchical regression, adjusting for important prognostic factors and clustering effects. RESULTS There were 374 hospital deaths in 1136 patients (32.9%) assigned to treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%) assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval [CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of ARDS, defined by a value of 200 mm Hg or less for the ratio of partial pressure of oxygen to fraction of inspired oxygen concentration (P = .02 for interaction). In patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90; 95% CI, 0.81-1.00; P = .049); in patients without ARDS (n = 404), there were 50 hospital deaths (27.2%) in the higher PEEP group and 44 (19.4%) in the lower PEEP group (adjusted RR, 1.37; 95% CI, 0.98-1.92; P = .07). Rates of pneumothorax and vasopressor use were similar. CONCLUSIONS Treatment with higher vs lower levels of PEEP was not associated with improved hospital survival. However, higher levels were associated with improved survival among the subgroup of patients with ARDS.

Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients

OBJECTIVE To assess the safety and potential efficacy of a mechanical ventilation strategy designed to reduce stretch-induced lung injury in acute respiratory distress syndrome. DESIGN Prospective, randomized, controlled clinical trial. SETTING Eight intensive care units in four teaching hospitals. PATIENTS Fifty-two patients with acute respiratory distress syndrome. INTERVENTIONS Traditional tidal volume patients: tidal volume 10-12 mL/kg ideal body weight, reduced if inspiratory plateau pressure was > 55 cm H2O (7.3 kPa). Small tidal volume patients: tidal volume 5-8 mL/kg ideal body weight, to keep plateau pressure < 30 cm H2O (4.0 kPa). MEASUREMENTS AND MAIN RESULTS Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg, respectively (p < .001), with mean plateau pressure = 30.6 and 24.9 cm H2O (3.3 kPa), respectively (p < .001). There were no significant differences in requirements for positive end-expiratory pressure or FIO2, fluid intakes/outputs, requirements for vasopressors, sedatives, or neuromuscular blocking agents, percentage of patients that achieved unassisted breathing, ventilator days, or mortality. CONCLUSIONS The reduced tidal volume strategy used in this study was safe. Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a) the sample size was too small to discern small treatment effects; b) the differences in tidal volumes and plateau pressures were modest; or c) reduced tidal volume ventilation is not beneficial.

Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit

ObjectiveTo determine whether caloric intake is associated with risk of nosocomial bloodstream infection in critically ill medical patients. DesignProspective cohort study. SettingUrban, academic medical intensive care unit. PatientsPatients were 138 adult patients who did not take food by mouth for ≥96 hrs after medical intensive care unit admission. MeasurementsDaily caloric intake was recorded for each patient. Participants subsequently were grouped into one of four categories of caloric intake: <25%, 25–49%, 50–74%, and ≥75% of average daily recommended calories based on the American College of Chest Physicians guidelines. Simplified Acute Physiology Score II and serum albumin were measured on medical intensive care unit admission. Serum glucose (average value and maximum value each day) and route of feeding (enteral, parenteral, or both) were collected daily. Nosocomial bloodstream infections were identified by infection control surveillance methods. Main ResultsThe overall mean (±sd) daily caloric intake for all study participants was 49.4 ± 29.3% of American College of Chest Physicians guidelines. Nosocomial bloodstream infection occurred in 31 (22.4%) participants. Bivariate Cox analysis revealed that receiving ≥25% of recommended calories compared with <25% was associated with significantly lower risk of bloodstream infection (relative hazard, 0.24; 95% confidence interval, 0.10–0.60). Simplified Acute Physiology Score II also was associated with risk of nosocomial bloodstream infection (relative hazard, 1.27; 95% confidence interval, 1.01–1.60). Average daily serum glucose, admission serum albumin, time to initiating nutritional support, and route of nutrition did not affect risk of bloodstream infection. After adjustment for Simplified Acute Physiology Score II in a multivariable analysis, receiving ≥25% of recommended calories was associated with a significantly lower risk of bloodstream infection (relative hazard, 0.27; 95% confidence interval, 0.11–0.68). ConclusionsIn the context of reducing risk of nosocomial bloodstream infections, failing to provide ≥25% of the recommended calories may be harmful. Higher caloric goals may be necessary to achieve other clinically important outcomes.

Incidence of acute lung injury in the United States

OBJECTIVE Recent estimates of acute respiratory distress syndrome (ARDS) incidence have varied from 1.3 to 22 per 100,000 person years (105 person.years); the incidence of acute lung injury (ALI) has varied from 17.9 to 34 cases per 105 person.years. Potential reasons for this wide range include differences in the definition of the syndrome, in the populations sampled, and in the assumptions made to estimate incidence. We hypothesized that careful, prospective, protocol-driven case identification that included the milder hypoxemia criterion for ALI would yield incidence numbers greater than previously reported. DESIGN Prospective cohort study with extrapolation to the U.S. population. SETTING National Heart, Lung, and Blood Institute-sponsored ARDS Network composed of 20 hospitals. PATIENTS As part of the National Institutes of Health-sponsored ARDS network, 20 hospitals prospectively identified patients with ALI from 1996 to 1999. Screening logs from this study were used to estimate ALI rates per intensive care unit (ICU) bed per year. We used the registry and data from the American Hospital Association to estimate the incidence of ALI in the United States. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The ALI per ICU bed incidence in the ARDS network registry varied from 0.7 to 5.8 cases of ALI per ICU bed per year with an average of 2.2 cases of ALI per ICU bed per year. We tested the robustness of the incidence estimate by performing a variety of sensitivity analyses. When we used the conservative assumptions that the ARDS network screening logs were complete at each of the participating hospitals and that ALI cases are limited to academic hospitals with > or =20 adult ICU beds, the incidence of ALI in adults in the United States is 22.4 cases per 105 person.years. Under the less conservative assumption that ALI cases occurred only at hospitals with > or =20 ICU beds, regardless of their academic status, the incidence of ALI in the United States is estimated at 64.2 cases per 105 person.years. CONCLUSIONS Based on this analysis, which used prospective clinical trial screening data and conservative assumptions about where patients with ALI are cared for, the incidence of ALI in the United States appears to be higher than previously reported.

CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury

Acute lung injury (ALI) is characterized by rapid alveolar injury, inflammation, cytokine induction, and neutrophil accumulation. Although early events in the pathogenesis of ALI have been defined, the mechanisms underlying resolution are unknown. As a model of ALI, we administered intratracheal (i.t.) LPS to mice and observed peak lung injury 4 days after the challenge, with resolution by day 10. Numbers of alveolar lymphocytes increased as injury resolved. To examine the role of lymphocytes in this response, lymphocyte-deficient Rag-1-/- and C57BL/6 WT mice were exposed to i.t. LPS. The extent of injury was similar between the groups of mice through day 4, but recovery was markedly impaired in the Rag-1-/- mice. Adoptive transfer studies revealed that infusion of CD4+CD25+Foxp3+ Tregs as late as 24 hours after i.t. LPS normalized resolution in Rag-1-/- mice. Similarly, Treg depletion in WT mice delayed recovery. Treg transfer into i.t. LPS-exposed Rag-1-/- mice also corrected the elevated levels of alveolar proinflammatory cytokines and increased the diminished levels of alveolar TGF-beta and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-beta inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3+CD4+CD25hiCD127loFoxp3+ cells. These results indicate that Tregs modify innate immune responses during resolution of lung injury and suggest potential targets for treating ALI, for which there are no specific therapies currently available.

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.

Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure.

ObjectivePositive end-expiratory pressure (PEEP) and recruitment maneuvers (RMs) may partially reverse atelectasis and reduce ventilation-associated lung injury. The purposes of this study were to assess a) magnitude and duration of RM effects on arterial oxygenation and on requirements for oxygenation support (Fio2/PEEP) in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) receiving ventilation with low tidal volumes and high levels of PEEP; and b) frequency of adverse respiratory and circulatory events attributable to RMs. DesignProspective, randomized, crossover study. SettingThirty-four intensive care units at 19 hospitals. PatientsSeventy-two patients with early ALI/ARDS. Baseline PEEP and Fio2 were 13.8 ± 3.0 cm H2O and 0.39 ± 0.10, respectively (mean ± sd). InterventionsWe conducted RMs by applying continuous positive airway pressure of 35–40 cm H2O for 30 secs. We conducted sham RMs on alternate days. We monitored oxyhemoglobin saturation by pulse oximetry (SpO2), Fio2/PEEP, blood pressure, and heart rate for 8 hrs after RMs and sham RMs. We examined chest radiographs for barotrauma. Measurements and Main ResultsResponses to RMs were variable. Greatest increments from baseline SpO2 within 10 mins after RMs were larger than after sham RMs (1.7 ± 0.2 vs. 0.6 ± 0.3 %, mean ± sem, p < .01). Systolic blood pressure decreased more within 10 mins after RMs (9.4 ± 1.1 vs. 3.1 ± 1.1 mm Hg, p < .01). Changes in Fio2/PEEP requirements were not significantly different at any time after RMs vs. sham RMs. Barotrauma was apparent on first radiographs after one RM and one sham RM. ConclusionsIn ALI/ARDS patients receiving mechanical ventilation with low tidal volumes and high PEEP, short-term effects of RMs as conducted in this study are variable. Beneficial effects on gas exchange in responders appear to be of brief duration. More information is needed to determine the role of recruitment maneuvers in the management of ALI/ARDS.

Fluid Balance, Diuretic Use, and Mortality in Acute Kidney Injury

BACKGROUND AND OBJECTIVES Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria. RESULTS 306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P=0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased. CONCLUSIONS A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance.

Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study

Objective To evaluate the association of volume limited and pressure limited (lung protective) mechanical ventilation with two year survival in patients with acute lung injury. Design Prospective cohort study. Setting 13 intensive care units at four hospitals in Baltimore, Maryland, USA. Participants 485 consecutive mechanically ventilated patients with acute lung injury. Main outcome measure Two year survival after onset of acute lung injury. Results 485 patients contributed data for 6240 eligible ventilator settings, as measured twice daily (median of eight eligible ventilator settings per patient; 41% of which adhered to lung protective ventilation). Of these patients, 311 (64%) died within two years. After adjusting for the total duration of ventilation and other relevant covariates, each additional ventilator setting adherent to lung protective ventilation was associated with a 3% decrease in the risk of mortality over two years (hazard ratio 0.97, 95% confidence interval 0.95 to 0.99, P=0.002). Compared with no adherence, the estimated absolute risk reduction in two year mortality for a prototypical patient with 50% adherence to lung protective ventilation was 4.0% (0.8% to 7.2%, P=0.012) and with 100% adherence was 7.8% (1.6% to 14.0%, P=0.011). Conclusions Lung protective mechanical ventilation was associated with a substantial long term survival benefit for patients with acute lung injury. Greater use of lung protective ventilation in routine clinical practice could reduce long term mortality in patients with acute lung injury. Trial registration Clinicaltrials.gov NCT00300248.