Effect of mechanical power on mortality in invasively ventilated ICU patients without the acute respiratory distress syndrome: An analysis of three randomised clinical trials.

BACKGROUND: The mechanical power of ventilation (MP) has an association with outcome in invasively ventilated patients with the acute respiratory distress syndrome (ARDS). Whether a similar association exists in invasively ventilated patients without ARDS is less certain. OBJECTIVE: To investigate the association of mechanical power with mortality in ICU patients without ARDS. DESIGN: This was an individual patient data analysis that uses the data of three multicentre randomised trials. SETTING: This study was performed in academic and nonacademic ICUs in the Netherlands. PATIENTS: One thousand nine hundred and sixty-two invasively ventilated patients without ARDS were included in this analysis. The median [IQR] age was 67 [57 to 75] years, 706 (36%) were women. MAIN OUTCOME MEASURES: The primary outcome was the all-cause mortality at day 28. Secondary outcomes were the all-cause mortality at day 90, and length of stay in ICU and hospital. RESULTS: At day 28, 644 patients (33%) had died. Hazard ratios for mortality at day 28 were higher with an increasing MP, even when stratified for its individual components (driving pressure ( P  < 0.001), tidal volume ( P  < 0.001), respiratory rate ( P  < 0.001) and maximum airway pressure ( P  = 0.001). Similar associations of mechanical power (MP) were found with mortality at day 90, lengths of stay in ICU and hospital. Hazard ratios for mortality at day 28 were not significantly different if patients were stratified for MP, with increasing levels of each individual component. CONCLUSION: In ICU patients receiving invasive ventilation for reasons other than ARDS, MP had an independent association with mortality. This finding suggests that MP holds an added predictive value over its individual components, making MP an attractive measure to monitor and possibly target in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02159196, ClinicalTrials.gov Identifier: NCT02153294, ClinicalTrials.gov Identifier: NCT03167580.

Mechanical ventilation of the healthy lungs: lessons learned from recent trials.

PURPOSE OF REVIEW: Although there is clear evidence for benefit of protective ventilation settings [including low tidal volume and higher positive end-expiratory pressure (PEEP)] in patients with acute respiratory distress syndrome (ARDS), it is less clear what the optimal mechanical ventilation settings are for patients with healthy lungs. RECENT FINDINGS: Use of low tidal volume during operative ventilation decreases postoperative pulmonary complications (PPC). In the critically ill patients with healthy lungs, use of low tidal volume is as effective as intermediate tidal volume. Use of higher PEEP during operative ventilation does not decrease PPCs, whereas hypotension occurred more often compared with use of lower PEEP. In the critically ill patients with healthy lungs, there are conflicting data regarding the use of a higher PEEP, which may depend on recruitability of lung parts. There are limited data suggesting that higher driving pressures because of higher PEEP contribute to PPCs. Lastly, use of hyperoxia does not consistently decrease postoperative infections, whereas it seems to increase PPCs compared with conservative oxygen strategies. SUMMARY: In patients with healthy lungs, data indicate that low tidal volume but not higher PEEP is beneficial. Thereby, ventilation strategies differ from those in ARDS patients.

Myocardial Function during Low versus Intermediate Tidal Volume Ventilation in Patients without Acute Respiratory Distress Syndrome.

BACKGROUND: Mechanical ventilation with low tidal volumes has the potential to mitigate ventilation-induced lung injury, yet the clinical effect of tidal volume size on myocardial function has not been clarified. This cross-sectional study investigated whether low tidal volume ventilation has beneficial effects on myocardial systolic and diastolic function compared to intermediate tidal volume ventilation. METHODS: Forty-two mechanically ventilated patients without acute respiratory distress syndrome (ARDS) underwent transthoracic echocardiography after more than 24 h of mechanical ventilation according to the Protective Ventilation in Patients without ARDS (PReVENT) trial comparing a low versus intermediate tidal volume strategy. The primary outcome was left ventricular and right ventricular myocardial performance index as measure for combined systolic and diastolic function, with lower values indicating better myocardial function and a right ventricular myocardial performance index greater than 0.54 regarded as the abnormality threshold. Secondary outcomes included specific systolic and diastolic parameters. RESULTS: One patient was excluded due to insufficient acoustic windows, leaving 21 patients receiving low tidal volumes with a tidal volume size (mean ± SD) of 6.5 ± 1.8 ml/kg predicted body weight, while 20 patients were subjected to intermediate tidal volumes receiving a tidal volume size of 9.5 ± 1.6 ml/kg predicted body weight (mean difference, -3.0 ml/kg; 95% CI, -4.1 to -2.0; P < 0.001). Right ventricular dysfunction was reduced in the low tidal volume group compared to the intermediate tidal volume group (myocardial performance index, 0.41 ± 0.13 vs. 0.64 ± 0.15; mean difference, -0.23; 95% CI, -0.32 to -0.14; P < 0.001) as was left ventricular dysfunction (myocardial performance index, 0.50 ± 0.17 vs. 0.63 ± 0.19; mean difference, -0.13; 95% CI, -0.24 to -0.01; P = 0.030). Similarly, most systolic parameters were superior in the low tidal volume group compared to the intermediate tidal volume group, yet diastolic parameters did not differ between both groups. CONCLUSIONS: In patients without ARDS, intermediate tidal volume ventilation decreased left ventricular and right ventricular systolic function compared to low tidal volume ventilation, although without an effect on diastolic function.

Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial.

Importance: It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS). Objective: To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy. Design, Setting, and Participants: A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands. Interventions: Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484). Main Outcomes and Measures: The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax. Results: In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, -0.27 [95% CI, -1.74 to 1.19]; P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [-1.09 to 1.89]; P = .58) and hospital (median, 14 vs 15 days; -0.60 [-3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55). Conclusions and Relevance: In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy. Trial Registration: ClinicalTrials.gov Identifier: NCT02153294.

Lung-Protective Ventilation With Low Tidal Volumes and the Occurrence of Pulmonary Complications in Patients Without Acute Respiratory Distress Syndrome: A Systematic Review and Individual Patient Data Analysis.

OBJECTIVE: Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients. DESIGN: Individual patient data analysis. PATIENTS: ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation. INTERVENTIONS: Mechanical ventilation with low tidal volume. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a "low tidal volume group" (tidal volumes ≤ 7 mL/kg predicted body weight), an "intermediate tidal volume group" (> 7 and < 10 mL/kg predicted body weight), and a "high tidal volume group" (≥ 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 ± 10.9 vs 13.8 ± 11.6 d; p < 0.01 and 6.1 ± 8.1 vs 8.9 ± 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01). CONCLUSIONS: Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome.

How to ventilate patients without acute respiratory distress syndrome?

PURPOSE OF REVIEW: There is convincing evidence for benefit from lung-protective mechanical ventilation with lower tidal volumes in patients with the acute respiratory distress syndrome (ARDS). It is uncertain whether this strategy benefits critically ill patients without ARDS also. The present article summarizes the background and clinical evidence for ventilator settings that have the potential to protect against ventilator-induced lung injury. RECENT FINDINGS: There has been a paradigm shift from treating ARDS to preventing ARDS. In surgical patients, anesthesiologists should consider ventilating patients with a tidal volume of 6-8 ml/kg predicted body weight (PBW), levels of positive end-expiratory pressure (PEEP) between 0 and 2 cmH(2)O, and higher levels of FiO(2). Finally, in critically ill patients without ARDS, intensive care physicians could consider ventilating with a PEEP level of 5 cmH(2)O and lower levels of FiO(2). There is insufficient evidence for the benefit of lower tidal volumes in these patients. There is, however, some evidence that tidal volumes of 6 ml/kg PBW or less are associated with better outcomes. SUMMARY: There is increasing and convincing evidence that the use of lower tidal volumes during mechanical ventilation of patients without ARDS prevents against ventilator-induced lung injury.

Effect of a low versus intermediate tidal volume strategy on pulmonary complications in patients at risk of acute respiratory distress syndrome-a randomized clinical trial.

Introduction: There is no consensus on whether invasive ventilation should use low tidal volumes (VT) to prevent lung complications in patients at risk of acute respiratory distress syndrome (ARDS). The purpose of this study is to determine if a low VT strategy is more effective than an intermediate VT strategy in preventing pulmonary complications. Methods: A randomized clinical trial was conducted in invasively ventilated patients with a lung injury prediction score (LIPS) of >4 performed in the intensive care units of 10 hospitals in Spain and one in the United States of America (USA) from 3 November 2014 to 30 August 2016. Patients were randomized to invasive ventilation using low VT (≤ 6 mL/kg predicted body weight, PBW) (N = 50) or intermediate VT (> 8 mL/kg PBW) (N = 48). The primary endpoint was the development of ARDS during the first 7 days after the initiation of invasive ventilation. Secondary endpoints included the development of pneumonia and severe atelectases; the length of intensive care unit (ICU) and hospital stay; and ICU, hospital, 28- and 90-day mortality. Results: In total, 98 patients [67.3% male], with a median age of 65.5 years [interquartile range 55-73], were enrolled until the study was prematurely stopped because of slow recruitment and loss of equipoise caused by recent study reports. On day 7, five (11.9%) patients in the low VT group and four (9.1%) patients in the intermediate VT group had developed ARDS (risk ratio, 1.16 [95% CI, 0.62-2.17]; p = 0.735). The incidence of pneumonia and severe atelectasis was also not different between the two groups. The use of a low VT strategy did neither affect the length of ICU and hospital stay nor mortality rates. Conclusions: In patients at risk for ARDS, a low VT strategy did not result in a lower incidence of ARDS than an intermediate VT strategy.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02070666.

Prognostic classification based on P/F and PEEP in invasively ventilated ICU patients with hypoxemia-insights from the MARS study.

BACKGROUND: Outcome prediction in patients with acute respiratory distress syndrome (ARDS) greatly improves when patients are reclassified based on predefined arterial oxygen partial pressure to fractional inspired oxygen ratios (PaO2/FiO2) and positive end-expiratory pressure (PEEP) cutoffs 24 h after the initial ARDS diagnosis. The aim of this study was to test whether outcome prediction improves when patients are reclassified based on predefined PaO2/FiO2 and PEEP cutoffs 24 h after development of mild hypoxemia while not having ARDS. METHODS: Post hoc analysis of a large prospective, multicenter, observational study that ran in the ICUs of two academic hospitals in the Netherlands between January 2011 and December 2013. Patients were classified into four groups using predefined cutoffs for PaO2/FiO2 (250 mmHg) and PEEP (5 cm H2O), both at onset of hypoxemia and after 24 h: PaO2/FiO2 ≥ 250 mmHg and PEEP < 6 cm H2O (group I), PaO2/FiO2 ≥ 250 mmHg and PEEP ≥ 6 cm H2O (group II), PaO2/FiO2 < 250 mmHg and PEEP < 6 cm H2O (group III), and PaO2/FiO2 < 250 mmHg and PEEP ≥ 6 cm H2O (group IV), to look for trend association with all-cause in-hospital mortality, the primary outcome. Secondary outcome were ICU- and 90-day mortality, and the number of ventilator-free days or ICU-free days and alive at day 28. RESULTS: The analysis included 689 consecutive patients. All-cause in-hospital mortality was 35%. There was minimal variation in mortality between the four groups at onset of hypoxemia (33, 36, 38, and 34% in groups I to IV, respectively; P = 0.65). Reclassification after 24 h resulted in a strong trend with increasing mortality from group I to group IV (31, 31, 37, and 48% in groups I to IV, respectively; P < 0.01). Similar trends were found for the secondary endpoints. CONCLUSIONS: Reclassification using PaO2/FiO2 and PEEP cutoffs after 24 h improved classification for outcome in invasively ventilated ICU patients with hypoxemia not explained by ARDS, compared to classification at onset of hypoxemia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01905033. Registered on July 11, 2013. Retrospectively registered.

Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients.

BACKGROUND: Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). METHODS: This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. RESULTS: In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1-4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43-0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39-0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. CONCLUSIONS: These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS.

Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study.

PURPOSE: To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification. METHODS: Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24 h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification. RESULTS: Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01-1.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal. CONCLUSIONS: ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02010073.

Potentially modifiable respiratory variables contributing to outcome in ICU patients without ARDS: a secondary analysis of PRoVENT.

BACKGROUND: The majority of critically ill patients do not suffer from acute respiratory distress syndrome (ARDS). To improve the treatment of these patients, we aimed to identify potentially modifiable factors associated with outcome of these patients. METHODS: The PRoVENT was an international, multicenter, prospective cohort study of consecutive patients under invasive mechanical ventilatory support. A predefined secondary analysis was to examine factors associated with mortality. The primary endpoint was all-cause in-hospital mortality. RESULTS: 935 Patients were included. In-hospital mortality was 21%. Compared to patients who died, patients who survived had a lower risk of ARDS according to the 'Lung Injury Prediction Score' and received lower maximum airway pressure (Pmax), driving pressure (ΔP), positive end-expiratory pressure, and FiO2 levels. Tidal volume size was similar between the groups. Higher Pmax was a potentially modifiable ventilatory variable associated with in-hospital mortality in multivariable analyses. ΔP was not independently associated with in-hospital mortality, but reliable values for ΔP were available for 343 patients only. Non-modifiable factors associated with in-hospital mortality were older age, presence of immunosuppression, higher non-pulmonary sequential organ failure assessment scores, lower pulse oximetry readings, higher heart rates, and functional dependence. CONCLUSIONS: Higher Pmax was independently associated with higher in-hospital mortality in mechanically ventilated critically ill patients under mechanical ventilatory support for reasons other than ARDS. Trial Registration ClinicalTrials.gov (NCT01868321).

Risk stratification using SpO2/FiO2 and PEEP at initial ARDS diagnosis and after 24 h in patients with moderate or severe ARDS.

BACKGROUND: We assessed the potential of risk stratification of ARDS patients using SpO2/FiO2 and positive end-expiratory pressure (PEEP) at ARDS onset and after 24 h. METHODS: We used data from a prospective observational study in patients admitted to a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Risk stratification was by cutoffs for SpO2/FiO2 and PEEP. The primary outcome was in-hospital mortality. Patients with moderate or severe ARDS with a length of stay of > 24 h were included in this study. Patients were assigned to four predefined risk groups: group I (SpO2/FiO2 ≥ 190 and PEEP < 10 cm H2O), group II (SpO2/FiO2 ≥ 190 and PEEP ≥ 10 cm), group III (SpO2/FiO2 < 190 and PEEP < 10 cm H2O) and group IV (SpO2/FiO2 < 190 and PEEP ≥ 10 cm H2O). RESULTS: The analysis included 456 patients. SpO2/FiO2 and PaO2/FiO2 had a strong relationship (P < 0.001, R 2 = 0.676) that could be described in a linear regression equation (SpO2/FiO2 = 42.6 + 1.0 * PaO2/FiO2). Risk stratification at initial ARDS diagnosis resulted in groups that had no differences in in-hospital mortality. Risk stratification at 24 h resulted in groups with increasing mortality rates. The association between group assignment at 24 h and outcome was confounded by several factors, including APACHE IV scores, arterial pH and plasma lactate levels, and vasopressor therapy. CONCLUSIONS: In this cohort of patients with moderate or severe ARDS, SpO2/FiO2 and PaO2/FiO2 have a strong linear relationship. In contrast to risk stratification at initial ARDS diagnosis, risk stratification using SpO2/FiO2 and PEEP after 24 h resulted in groups with worsening outcomes. Risk stratification using SpO2/FiO2 and PEEP could be practical, especially in resource-limited settings.

Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study.

BACKGROUND: Scant information exists about the epidemiological characteristics and outcome of patients in the intensive care unit (ICU) at risk of acute respiratory distress syndrome (ARDS) and how ventilation is managed in these individuals. We aimed to establish the epidemiological characteristics of patients at risk of ARDS, describe ventilation management in this population, and assess outcomes compared with people at no risk of ARDS. METHODS: PRoVENT (PRactice of VENTilation in critically ill patients without ARDS at onset of ventilation) is an international, multicentre, prospective study undertaken at 119 ICUs in 16 countries worldwide. All patients aged 18 years or older who were receiving mechanical ventilation in participating ICUs during a 1-week period between January, 2014, and January, 2015, were enrolled into the study. The Lung Injury Prediction Score (LIPS) was used to stratify risk of ARDS, with a score of 4 or higher defining those at risk of ARDS. The primary outcome was the proportion of patients at risk of ARDS. Secondary outcomes included ventilatory management (including tidal volume [VT] expressed as mL/kg predicted bodyweight [PBW], and positive end-expiratory pressure [PEEP] expressed as cm H2O), development of pulmonary complications, and clinical outcomes. The PRoVENT study is registered at ClinicalTrials.gov, NCT01868321. The study has been completed. FINDINGS: Of 3023 patients screened for the study, 935 individuals fulfilled the inclusion criteria. Of these critically ill patients, 282 were at risk of ARDS (30%, 95% CI 27-33), representing 0·14 cases per ICU bed over a 1-week period. VT was similar for patients at risk and not at risk of ARDS (median 7·6 mL/kg PBW [IQR 6·7-9·1] vs 7·9 mL/kg PBW [6·8-9·1]; p=0·346). PEEP was higher in patients at risk of ARDS compared with those not at risk (median 6·0 cm H2O [IQR 5·0-8·0] vs 5·0 cm H2O [5·0-7·0]; p<0·0001). The prevalence of ARDS in patients at risk of ARDS was higher than in individuals not at risk of ARDS (19/260 [7%] vs 17/556 [3%]; p=0·004). Compared with individuals not at risk of ARDS, patients at risk of ARDS had higher in-hospital mortality (86/543 [16%] vs 74/232 [32%]; p<0·0001), ICU mortality (62/533 [12%] vs 66/227 [29%]; p<0·0001), and 90-day mortality (109/653 [17%] vs 88/282 [31%]; p<0·0001). VT did not differ between patients who did and did not develop ARDS (p=0·471 for those at risk of ARDS; p=0·323 for those not at risk). INTERPRETATION: Around a third of patients receiving mechanical ventilation in the ICU were at risk of ARDS. Pulmonary complications occur frequently in patients at risk of ARDS and their clinical outcome is worse compared with those not at risk of ARDS. There is potential for improvement in the management of patients without ARDS. Further refinements are needed for prediction of ARDS. FUNDING: None.

PReVENT--protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial.

BACKGROUND: It is uncertain whether lung-protective mechanical ventilation using low tidal volumes should be used in all critically ill patients, irrespective of the presence of the acute respiratory distress syndrome (ARDS). A low tidal volume strategy includes use of higher respiratory rates, which could be associated with increased sedation needs, a higher incidence of delirium, and an increased risk of patient-ventilator asynchrony and ICU-acquired weakness. Another alleged side-effect of low tidal volume ventilation is the risk of atelectasis. All of these could offset the beneficial effects of low tidal volume ventilation as found in patients with ARDS. METHODS/DESIGN: PReVENT is a national multicenter randomized controlled trial in invasively ventilated ICU patients without ARDS with an anticipated duration of ventilation of longer than 24 hours in 5 ICUs in The Netherlands. Consecutive patients are randomly assigned to a low tidal volume strategy using tidal volumes from 4 to 6 ml/kg predicted body weight (PBW) or a high tidal volume ventilation strategy using tidal volumes from 8 to 10 ml/kg PBW. The primary endpoint is the number of ventilator-free days and alive at day 28. Secondary endpoints include ICU and hospital length of stay (LOS), ICU and hospital mortality, the incidence of pulmonary complications, including ARDS, pneumonia, atelectasis, and pneumothorax, the cumulative use and duration of sedatives and neuromuscular blocking agents, incidence of ICU delirium, and the need for decreasing of instrumental dead space. DISCUSSION: PReVENT is the first randomized controlled trial comparing a low tidal volume strategy with a high tidal volume strategy, in patients without ARDS at onset of ventilation, that recruits a sufficient number of patients to test the hypothesis that a low tidal volume strategy benefits patients without ARDS with regard to a clinically relevant endpoint. TRIAL REGISTRATION: The trial is registered at www.clinicaltrials.gov under reference number NCT02153294 on 23 May 2014.

Association between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis.

PURPOSE: Mechanical ventilation with lower tidal volumes (≤6 ml/kg of predicted body weight, PBW) could benefit patients without acute respiratory distress syndrome (ARDS). However, tidal volume reduction could be associated with increased patient discomfort and sedation needs, and consequent longer duration of ventilation. The aim of this individual patient data meta-analysis was to assess the associations between tidal volume size, duration of mechanical ventilation, and sedation needs in patients without ARDS. METHODS: Studies comparing ventilation with different tidal volume sizes in patients without ARDS were screened for inclusion. Corresponding authors were asked to provide individual participant data. Patients were assigned to three groups based on tidal volume size (≤6 ml/kg PBW, 6-10 ml/kg PBW, or ≥10 ml/kg PBW). Ventilator-free days, alive at day 28, and dose and duration of sedation (propofol and midazolam), analgesia (fentanyl and morphine), and neuromuscular blockade (NMB) were compared. RESULTS: Seven investigations (2,184 patients) were included in the analysis. The number of patients breathing without assistance by day 28 was higher in the group ventilated with tidal volume ≤6 ml/kg PBW compared to those ventilated with tidal volume ≥10 ml/kg PBW (93.1 vs. 88.6%; p = 0.027, respectively). Only two investigations (187 patients) could be included in the meta-analysis of sedation needs. There were neither differences in the percentage of study days that patients received sedatives, opioids, or NMBA nor in the total dose of benzodiazepines, propofol, opioids, and NMBA. CONCLUSIONS: This meta-analysis suggests that use of lower tidal volumes in patients without ARDS at the onset of mechanical ventilation could be associated with shorter duration of ventilation. Use of lower tidal volumes seems not to affect sedation or analgesia needs, but this must be confirmed in a robust, well-powered randomized controlled trial.