Crit Care Med  2009;37:1594-1603

Controversy remains as to whether low-dose corticosteroids can reduce the mortality and morbidity of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) without increasing the risk of adverse reactions. We aimed to evaluate all studies investigating prolonged corticosteroids in low-to-moderate dose in ALI or ARDS.

Datasources
MEDLINE, EMBASE, Current Content, and Cochrane Central Register of Controlled Trials, and bibliographies of retrieved articles.

Study selection
Randomized controlled trials (RCTs) and observational studies reported in any language that used 0.5-2.5 mg^.kg^-1.d^-1 of methylprednisolone or equivalent to treat ALI/ARDS.

Data extraction
Data were extracted independently by two reviewers and included study design, patient characteristics, interventions, and mortality and morbidity outcomes.

Data synthesis
Both cohort studies (five studies, n = 307) and RCTs (four trials, n = 341) showed a similar trend toward mortality reduction (RCTs relative risk 0.51, 95% CI 0.24-1.09; p = 0.08; cohort studies relative risk 0.66, 95% CI 0.43-1.02; p = 0.06). The overall relative risk was 0.62 (95% CI 0.43-0.91; p = 0.01). There was also improvement in length of ventilation-free days, length of intensive care unit stay, Multiple Organ Dysfunction Syndrome Score, Lung Injury Scores, and improvement in PaO₂/FiO₂. There was no increase in infection, neuromyopathy, or any major complications. There was significant heterogeneity in the pooled studies. Subgroup and meta-regression analyses showed that heterogeneity had minimal effect on treatment efficacy; however, these findings were limited by the small number of studies used in the analyses.

Conclusion
The use of low-dose corticosteroids was associated with improved mortality and morbidity outcomes without increased adverse reactions. The consistency of results in both study designs and all outcomes suggests that they are an effective treatment for ALI or ARDS. The mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial.

Crit Care Med 2008:36;1796-1802

Transfusion-related acute lung injury may contribute to the development of acute lung injury in the critically ill, due to plasma from female donors containing antileukocyte antibodies. In July 2003, the U.K. National Blood Service stopped using female donor plasma for the production of fresh frozen plasma. Patients undergoing repair of a ruptured abdominal aortic aneurysm receive large amounts of fresh frozen plasma and often develop acute lung injury. We investigated whether the change to male fresh frozen plasma was associated with a change in the frequency of acute lung injury in these patients.

Design
A retrospective, before and after, observational, single-center study.

Setting
Tertiary care center and a regional blood center.

Patients
The study included 211 patients undergoing open repair of a ruptured abdominal aortic aneurysm between 1998 and 2006.

Interventions
None.

Measurements and main results
Primary outcome was the development of acute lung injury in the first 6 hrs after surgery. Secondary outcomes were significant hypoxia (Pao2/Fio2 ratio <300), time to extubation, and survival at 30 days. Groups were well matched and received similar volumes of intravenous fluids and blood components. There was significantly less acute lung injury following the change to male fresh frozen plasma (36% before vs. 21% after, p = .04). At 6 hrs after surgery, fewer patients were hypoxic (87% before vs. 62% after, p < .01). In multivariate analysis, the change in donor policy was associated with a decreased risk of developing acute lung injury (odds ratio 0.39; 95% confidence interval, 0.16ñ0.90). Time to extubation and survival at 30 days were not statistically different between groups.

Conclusions
The policy to exclude female donors from the production of fresh frozen plasma was associated with a decrease in the frequency of acute lung injury in patients undergoing repair of a ruptured abdominal aortic aneurysm.

Intensive Care Med 2008:34;1487-1491

We examined the effect on survival of prone positioning as an early and continuous treatment in ARDS patients already treated with protective ventilation.

Design and setting
Open randomized controlled trial in 17 medical-surgical ICUs.

Patients
Forty mechanically ventilated patients with early and refractory ARDS despite protective ventilation in the supine position.
Interventions  Patients were randomized to remain supine or be moved to early (within 48h) and continuous (=20h/day) prone position until recovery or death. The trial was prematurely stopped due to a low patient recruitment rate.

Measurements and results
Clinical characteristics, oxygenation, lung pressures, and hemodynamics were monitored. Need for sedation, complications, length of MV, ICU, and hospital stays, and outcome were recorded. PaO₂/FIO₂ tended to be higher in prone than in supine patients after 6h (202±78 vs. 165±70mmHg); this difference reached statistical significance on day 3 (234±85 vs. 159±78). Prone-related side effects were minimal and reversible. Sixty-day survival reached the targeted 15% absolute increase in prone patients (62% vs. 47%) but failed to reach significance due to the small sample.

Conclusions
Our study adds data that reinforce the suggestion of a beneficial effect of early continuous prone positioning on survival in ARDS patients.

Crit Care Med 2008;36:3080-3084

Acute lung injury (ALI) is a well known complication following the transfusion of blood products and is commonly referred to as transfusion-related acute lung injury (TRALI). The objectives of this review are to summarize current knowledge of TRALI with an emphasis on issues pertinent to the intensivist and to define the newly recognized “Delayed TRALI syndrome.”

Data synthesis
The classic TRALI syndrome is an uncommon condition characterized by the abrupt onset of respiratory failure within hours of the transfusion of a blood product. It is usually caused by anti-leukocyte antibodies, resolves rapidly, and has a low mortality. A single unit of packed cells or blood component product is usually implicated in initiating this syndrome. It has, however, recently been recognized that the transfusion of blood products in critically ill or injured patients increases the risk (odds ratio 2.13; 95% confidence interval 1.75-2.52) for the development of the ALI 6-72 hours after the transfusion. This “delayed TRALI syndrome” is common, occurring in up to 25% of critically ill patients receiving a blood transfusion, and is associated with a mortality of up to 40%. While the delayed TRALI syndrome can develop after the transfusion of a single unit, the risk increases as the number of transfused blood products increase. The management of both the classic and delayed TRALI syndromes is essentially supportive.

Conclusions
Both the classic and delayed TRALI syndromes are among the most important complications following the transfusion of blood products and are associated with significant morbidity and increased mortality. The risk and benefits of all blood products should be assessed before transfusion.

Crit Care Med 2008;36:2302-2308

Pentraxin 3 is a fluid phase receptor involved in innate immunity. It belongs to the Pentraxins family, as C-reactive protein does. Pentraxin 3 is produced by a variety of tissue cells, whereas only the liver produces C-reactive protein. Pentraxin 3 plays a unique role in the regulation of inflammation. Acute lung injury and acute respiratory distress syndrome are characterized by an important inflammatory reaction. We investigated the role of pentraxin 3 as a marker of severity and outcome predictor of acute lung injury and acute respiratory distress syndrome.

Design
We measured circulating pentraxin 3 and C-reactive protein levels within 24 hrs from intubation (day 1), after 24 hrs from the first sample, then every 3 days for the first month and then once a week, until discharge from the intensive care unit. Pentraxin 3 was also measured in bronchoalveolar lavages, performed when clinically indicated.

Setting
One university medical center general intensive care unit.

Patients
The study included 21 patients affected by acute lung injury and acute respiratory distress syndrome (1994 Consensus Conference criteria).

Interventions
None.

Measurements and main results
Pentraxin 3 plasma levels were high with a peak on the first day (median 71.05 ng/mL, interquartile range 52.37-117.38 ng/mL, normal values <2 ng/mL), declining thereafter. C-reactive protein peaked later and remained at relatively high values. Out of several day 1 parameters, pentraxin 3 was the only significant difference between survivors and nonsurvivors. Pentraxin 3 levels were positively correlated with lung injury score values (p < 0.001) and number of organ failures (p < 0.001). Pentraxin 3 was present in bronchoalveolar lavages fluids (5.03 ng/mL, interquartile range 1.52-8.48 ng/mL) and bronchoalveolar lavages positive to bacterial culture were associated with significantly higher pentraxin 3 values (p < 0.05).

Conclusions
The results presented here show that pentraxin 3 is elevated in acute lung injury and acute respiratory distress syndrome and that its levels correlate with parameters of lung injury and systemic involvement. The clinical and pathophysiological significance of pentraxin 3 in acute lung injury and acute respiratory distress syndrome deserves further scrutiny.

Crit Care Med 2008;36:2322-2327

Patients with acute respiratory distress syndrome suffer from profound cardiac and pulmonary derangement, including right ventricular strain and noncardiogenic pulmonary edema, which may potentially alter concentrations of cardiac natriuretic peptides. We sought to determine whether N-terminal probrain natriuretic peptide (NT-proBNP) levels are elevated in acute respiratory distress syndrome and whether they can serve as a marker of prognosis in this setting.

Design
Prospective study.

Setting
Tertiary-care academic medical center.

Patients
One hundred seventy-seven acute respiratory distress syndrome subjects enrolled in a prospective intensive care unit cohort.

Interventions
None

Measurements and main results
NT-proBNP was measured from blood taken within 48 hrs of acute respiratory distress syndrome onset. Patients were followed for the primary outcome of 60-day mortality and secondary outcomes of organ dysfunction and ventilator-free days. Seventy patients died (40%). Median NT-proBNP level was 3181 ng/L (interquartile range 723-9246 ng/L). NT-proBNP levels were significantly higher among nonsurvivors (p < .0001). Receiver operating curve analysis revealed an optimal NT-proBNP cut-point of 6813 ng/L for predicting death. Patients with levels above the cut-point had significantly higher odds of mortality on multivariable analysis (odds ratio 2.36, 95% confidence interval 1.11-4.99, p = .02) than those with levels below the cut-point. Kaplan-Meier survival analysis showed that this difference emerged early and was sustained (p < .0001). Patients with elevated NT-proBNP also had higher organ dysfunction scores (p < .0001) and fewer ventilator free days (p = .03) than those with lower NT-proBNP levels.

Conclusions
NT-proBNP levels are elevated among acute respiratory distress syndrome patients and parallel the severity of the syndrome and likelihood for morbidity and mortality. This demonstrates the potential utility of this biomarker for prognosis in this disease.

JAMA 2008;299:637-645

Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality.

Objective
To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original “open-lung approach,” combining low tidal volume, lung recruitment maneuvers, and high positive-end–expiratory pressure.

Design and setting
Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia.

Patients
Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250.

Interventions
The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475).

Main outcome measure
All-cause hospital mortality.

Results
Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045).

Conclusions
For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This “open-lung” strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies.

JAMA. 2008;299:646-655

The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated.

Objective
To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI.

Design, setting and patients
A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005.

Intervention
Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385).

Main outcome measures
The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. RESULTS: The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements.

Conclusions
A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure.

N Engl J Med 2006;354:1671–1684  http://content.nejm.org/cgi/content/abstract/354/16/1671

Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death. Because previous reports suggested that corticosteroids may improve survival, we performed a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS.

Methods
We randomly assigned 180 patients with ARDS of at least seven days’ duration to receive either methylprednisolone or placebo in a double-blind fashion. The primary end point was mortality at 60 days. Secondary end points included the number of ventilator-free days and organ-failure–free days, biochemical markers of inflammation and fibroproliferation, and infectious complications.

Results
At 60 days, the hospital mortality rate was 28.6 percent in the placebo group (95 percent confidence interval, 20.3 to 38.6 percent) and 29.2 percent in the methylprednisolone group (95 percent confidence interval, 20.8 to 39.4 percent; P=1.0); at 180 days, the rates were 31.9 percent (95 percent confidence interval, 23.2 to 42.0 percent) and 31.5 percent (95 percent confidence interval, 22.8 to 41.7 percent; P=1.0), respectively. Methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. Methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy. As compared with placebo, methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness.

Conclusions
These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death.

Critical Care Medicine 2007;35:787-793

Objectives
To investigate respiratory and hemodynamic changes during lung recruitment and descending optimal positive end-expiratory pressure (PEEP) titration.

Design
Prospective auto-control clinical trial.

Setting
Adult general intensive care unit in a university hospital.

Patients
Eighteen patients with acute respiratory distress syndrome.

Interventions
Following baseline measurements (T0), PEEP was set at 26 cm H₂O and lung recruitment was performed (40/40-maneuver). Then tidal volume was set at 4 mL/kg (T26R) and PEEP was lowered by 2 cmH₂O in every 4 mins. Optimal PEEP was defined at 2 cmH₂O above the PEEP where PaO₂ dropped by >10%. After setting the optimal PEEP, the 40/40-maneuver was repeated and tidal volume set at 6 mL/kg (Tend).

Measurements and Main Results
Arterial blood gas analysis was done every 4 mins and hemodynamic measurements every 8 mins until Tend, then in 30 (T30) and 60 (T60) mins. The PaO₂ increased from T0 to Tend (203 +/- 108 vs. 322 +/- 101 mm Hg, p < .001), but the extravascular lung water (EVLW) did not change significantly. Cardiac index (CI) and the intrathoracic blood volume (ITBV) decreased from T0 to T26R (CI, 3.90 +/- 1.04 vs. 3.62 +/- 0.91 L/min/m², p < .05; ITBVI, 832 +/- 205 vs. 795 +/- 188 mL/m², p < .05). There was a positive correlation between CI and ITBVI (r = .699, p < .01), a negative correlation between CI and central venous pressure (r = -.294, p < .01), and no correlation between CI and mean arterial pressure (MAP).

Conclusions
Following lung recruitment and descending optimal PEEP titration, the PaO₂ improves significantly, without any change in the EVLW up to 1 hr. This suggests a decrease in atelectasis as a result of recruitment rather than a reduction of EVLW. There is a significant change in CI during the maneuver, but neither central venous pressure, heart rate, nor MAP can reflect these changes.

BMJ, doi:10.1136/bmj.39139.716794.55

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

Critical Care 2007, 11:206     doi:10.1186/cc5159

See related commentary by Pelosi and Rocco.

Distal airways are less than 2 mm in diameter, comprising a relatively large cross-sectional area that allows for slower, laminar airflow. The airways include both membranous bronchioles and gas exchange ducts, and have been referred to in the past as the ‘quiet zone’, in part because these structures were felt to contribute little to lung mechanics and in part because they were difficult to study directly. More recent data suggest that distal airway dysfunction plays a significant role in acute respiratory distress syndrome. In addition, injurious mechanical ventilation strategies may contribute to distal airway dysfunction. The presence of elevated airway resistance, intrinsic positive end-expiratory pressure or a lower inflection point on a pressure–volume curve of the respiratory system may indicate the presence of impaired distal airway function. There are no proven specific treatments for distal airway dysfunction, and protective ventilation strategies to minimize distal airway injury may be the best therapeutic approach at this time.

N Engl J Med 2006; 354:1775-1786

In the acute respiratory distress syndrome (ARDS), positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by keeping lung regions open that otherwise would be collapsed. Since the effects of PEEP probably depend on the recruitability of lung tissue, we conducted a study to examine the relationship between the percentage of potentially recruitable lung, as indicated by computed tomography (CT), and the clinical and physiological effects of PEEP.

Methods
Sixty-eight patients with acute lung injury or ARDS underwent whole-lung CT during breath-holding sessions at airway pressures of 5, 15, and 45 cm of water. The percentage of potentially recruitable lung was defined as the proportion of lung tissue in which aeration was restored at airway pressures between 5 and 45 cm of water.

Results
The percentage of potentially recruitable lung varied widely in the population, accounting for a mean (±SD) of 13±11 percent of the lung weight, and was highly correlated with the percentage of lung tissue in which aeration was maintained after the application of PEEP (r2=0.72, P<0.001). On average, 24 percent of the lung could not be recruited. Patients with a higher percentage of potentially recruitable lung (greater than the median value of 9 percent) had greater total lung weights (P<0.001), poorer oxygenation (defined as a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen) (P<0.001) and respiratory-system compliance (P=0.002), higher levels of dead space (P=0.002), and higher rates of death (P=0.02) than patients with a lower percentage of potentially recruitable lung. The combined physiological variables predicted, with a sensitivity of 71 percent and a specificity of 59 percent, whether a patient's proportion of potentially recruitable lung was higher or lower than the median.

Conclusions
In ARDS, the percentage of potentially recruitable lung is extremely variable and is strongly associated with the response to PEEP.

Critical Care Medicine 2006;34(9):2287-2293

Acute respiratory distress syndrome (ARDS) is frequently associated with increased pulmonary vascular resistance and thus with systolic load of the right ventricle. We hypothesized that levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS.

Design
Prospective, randomized, placebo-controlled, pilot study.

Setting
Twenty-two-bed multidisciplinary intensive care unit of a university hospital.

Patients
Thirty-five patients with ARDS in association with septic shock.

Interventions
Patients were randomly allocated to receive a 24-hr infusion of either levosimendan 0.2 ug/kg/min (n = 18) or placebo (n = 17). Data from right heart catheterization, cardiac magnetic resonance, arterial and mixed venous oxygen tensions and saturations, and carbon dioxide tensions were obtained before and 24 hrs after drug infusion.

Measurements and Main Results
At a mean arterial pressure between 70 and 80 mm Hg (sustained with norepinephrine infusion), levosimendan increased cardiac index (from 3.8 +/- 1.1 to 4.2 +/- 1.0 L/min/m²) and decreased mean pulmonary artery pressure (from 29 +/- 3 to 25 +/- 3 mm Hg) and pulmonary vascular resistance index (from 290 +/- 77 to 213 +/- 50 dynes/s/cm⁵/m²; each p < .05). Levosimendan also decreased right ventricular end-systolic volume and increased right ventricular ejection fraction (p < .05). In addition, levosimendan increased mixed venous oxygen saturation (from 63 +/- 8 to 70 +/- 8%; p < .01).

Conclusions
This study provides evidence that levosimendan improves right ventricular performance through pulmonary vasodilator effects in septic patients with ARDS. A large multiple-center trial is needed to investigate whether levosimendan is able to improve the overall prognosis of patients with sepsis and ARDS.

Critical Care 2006, 10:147

The selection of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) to receive noninvasive ventilation (NIV) is challenging, partly because there are few reliable selection criteria. The study by Rana and colleagues in the previous issue of Critical Care identifies metabolic acidosis and a lower oxygenation index as predictors of NIV failure, although it is unable to identify threshold values. It also demonstrates that treating patients with NIV for ALI/ARDS and shock is an exercise in futility. Future studies need to focus on criteria that will enable selection of patients for whom NIV will have a high likelihood of success

Critical Care 2006, 10:158

Many aspects of ventilatory management in patients with ARDS are still controversial and one of the major controversies is should HFO or CMV ideally be used to manage this patients. As shown by David et al. when the two approaches to ventilatory support are applied using similar principles the physiologic outcomes appear to be similar. With both approaches the use of lung recruitment maneuvers early in ARDS (1 to 3 day) after hemodynamic stabilization in patients without baratrauma is promising. The key to managing ARDS regardless of mode is to use an open lung protective ventilatory strategy. It is not the mode that makes the difference, it is the approach used to apply the mode!

N Engl J Med 2006;354: (not released yet)
Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion.

Methods
In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology.

Results
The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, -2.6 to 8.4 percent). The mean (±SE) cumulative fluid balance during the first seven days was -136±491 ml in the conservative-strategy group and 6992±502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved the oxygenation index ([mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen] x 100) and the lung injury score and increased the number of ventilator-free days (14.6±0.5 vs. 12.1±0.5, P<0.001) and days not spent in the intensive care unit (13.4±0.4 vs. 11.2±0.4, P<0.001) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days (10 percent vs. 14 percent, P=0.06).

Conclusions
Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury.

N Engl J Med 2006;354:2213-24

Background
The balance between the benefits and the risks of pulmonary-artery catheters (PACs) has not been established.

Methods
We evaluated the relationship of benefits and risks of PACs in 1000 patients with established acute lung injury in a randomized trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol. Mortality during the first 60 days before discharge home was the primary outcome.

Results
The groups had similar baseline characteristics. The rates of death during the first 60 days before discharge home were similar in the PAC and CVC groups (27.4 percent and 26.3 percent, respectively; P=0.69; absolute difference, 1.1 percent; 95 percent confidence interval, -4.4 to 6.6 percent), as were the mean (±SE) numbers of both ventilator-free days (13.2±0.5 and 13.5±0.5; P=0.58) and days not spent in the intensive care unit (12.0±0.4 and 12.5±0.5; P=0.40) to day 28. PAC-guided therapy did not improve these measures for patients in shock at the time of enrollment. There were no significant differences between groups in lung or kidney function, rates of hypotension, ventilator settings, or use of dialysis or vasopressors. Approximately 90 percent of protocol instructions were followed in both groups, with a 1 percent rate of crossover from CVC- to PAC-guided therapy. Fluid balance was similar in the two groups, as was the proportion of instructions given for fluid and diuretics. Dobutamine use was uncommon. The PAC group had approximately twice as many catheter-related complications (predominantly arrhythmias).

Conclusions
PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for the management of acute lung injury.

Critical Care 2006, 10:R79

The role of non-invasive positive pressure ventilation (NIPPV) in the treatment of acute lung injury (ALI) is controversial. We sought to assess the outcome of ALI that was initially treated with NIPPV and to identify specific risk factors for NIPPV failure.

Methods
In this observational cohort study at the two intensive care units of a tertiary center, we identified consecutive patients with ALI who were initially treated with NIPPV. Data on demographics, APACHE III scores, degree of hypoxemia, ALI risk factors and NIPPV respiratory parameters were recorded. Univariate and multivariate regression analyses were performed to identify risk factors for NIPPV failure.

Results
Of 79 consecutive patients who met the inclusion criteria, 23 were excluded because of a do not resuscitate order and two did not give research authorization. Of the remaining 54 patients, 38 (70.3%) failed NIPPV, among them all 19 patients with shock. In a stepwise logistic regression restricted to patients without shock, metabolic acidosis (odds ratio 1.27, 95% confidence interval (CI) 1.03 to 0.07 per unit of base deficit) and severe hypoxemia (odds ratio 1.03, 95%CI 1.01 to 1.05 per unit decrease in ratio of arterial partial pressure of O₂ and inspired O₂ concentration – PaO₂/FiO₂) predicted NIPPV failure. In patients who failed NIPPV, the observed mortality was higher than APACHE predicted mortality (68% versus 39%, p < 0.01).

Conclusion
NIPPV should be tried very cautiously or not at all in patients with ALI who have shock, metabolic acidosis or profound hypoxemia.

Critical Care Medicine 2006;34:1311-1318

Objective
It has been shown in a two-center study that high positive end-expiratory pressure (PEEP) and low tidal volume (LTV) improved outcome in ARDS. However, that study involved patients with underlying diseases unique to the study area, was conducted at only two centers, and enrolled a small number of patients. We similarly hypothesized that a ventilatory strategy based on PEEP above the lower inflection point of the pressure volume curve of the respiratory system (Pflex) set on day 1 with a low tidal volume would result in improved outcome in patients with severe and persistent acute respiratory distress syndrome (ARDS).

Design
Randomized, controlled clinical trial.

Setting
Network of eight Spanish multidisciplinary intensive care units (ICUs) under the acronym of ARIES (Acute Respiratory Insufficiency: Espana Study).

Patients
All consecutive patients admitted into participating Spanish ICUs from March 1999 to March 2001 with a diagnosis of ARDS were considered for the study. If 24 hrs after meeting ARDS criteria, the Pao2/Fio2 remained <=200 mm Hg on standard ventilator settings, patients were randomized into two groups: control and Pflex/LTV.

Interventions
In the control group, tidal volume was 9-11 mL/kg of predicted body weight (PBW) and PEEP >=5 cm H2O. In the Pflex/LTV group, tidal volume was 5-8 mL/kg PBW and PEEP was set on day 1 at Pflex + 2 cm H2O. In both groups, Fio2 was set to maintain arterial oxygen saturation >90% and Pao2 70-100 mm Hg, and respiratory rate was adjusted to maintain Paco2 between 35 and 50 mm Hg.

Measurements and Main Results
The study was stopped early based on an efficacy stopping rule as described in the methods. Of 103 patients who were enrolled (50 control and 53 Pflex), eight patients (five in control, three in Pflex) were excluded from the final evaluation because the random group assignment was not performed in one center according to protocol. Main outcome measures were ICU and hospital mortality, ventilator-free days, and nonpulmonary organ dysfunction. ICU mortality (24 of 45 [53.3%] vs. 16 of 50 [32%], p = .040), hospital mortality (25 of 45 [55.5%] vs. 17 of 50 [34%], p = .041), and ventilator-free days at day 28 (6.02 +/- 7.95 in control and 10.90 +/- 9.45 in Pflex/LTV, p = .008) all favored Pflex/LTV. The mean difference in the number of additional organ failures postrandomization was higher in the control group (p < .001).

Conclusions
A mechanical ventilation strategy with a PEEP level set on day 1 above Pflex and a low tidal volume compared with a strategy with a higher tidal volume and relatively low PEEP has a beneficial impact on outcome in patients with severe and persistent ARDS.