Hermann Wrigge

Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries

IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02010073.

Meta-analysis: Ventilation Strategies and Outcomes of the Acute Respiratory Distress Syndrome and Acute Lung Injury

Context Ventilation strategies to protect the lungs of patients with the acute respiratory distress syndrome (ARDS) include low tidal volume, limited airway pressures, and medium to high positive end-expiratory pressure (PEEP), but the adoption of these strategies has been slow in some clinical settings. Contribution This review of randomized trial evidence for low tidal volume and high PEEP ventilation on mortality of patients with ARDS or acute lung injury found that trials were limited in number but showed mortality benefits with lower versus higher tidal volume. High PEEP did not improve mortality in unselected patients but may help patients with life-threatening hypoxemia despite other interventions. Implication Lower tidal volume ventilation strategies should be used for patients with ARDS or acute lung injury. The Editors The acute respiratory distress syndrome (ARDS) is clinically characterized by sudden onset, severe hypoxemia, radiographic evidence of bilateral pulmonary infiltration, and absence of left heart failure (13). Acute lung injury is a subset of ARDS with less severe impairment in oxygenation. Despite apparent improvement in management and outcome of ARDS, the mortality rate in persons with the disease remains high, ranging from 35% to 65% (4). Although mechanical ventilation provides essential life support, it can worsen lung injury (5). Computed tomography images of patients with ARDS show nonhomogeneous distribution of pulmonary aeration. Normally aerated lung regions are relatively small but, when they receive the largest part of tidal volume (Vt) (6, 7), may be exposed to excessive alveolar wall tension and stress because of overdistention (8, 9). Atelectatic lung regions are prone to cyclic recruitment and derecruitment, leading to shear stress in adjacent aerated and nonaerated alveoli (1012). Ventilator-induced lung injury is caused by excessive stress or strain to lung tissues that occurs during mechanical ventilation and aggravates inflammation and diffuse alveolar damage (5, 13). Lung-protective ventilation strategies include ventilation with low Vt and limited airway pressure to reduce ventilator-induced lung injury from overdistention while allowing hypercapnia and medium to high positive end-expiratory pressure (PEEP) to keep alveoli open throughout the ventilator cycle (14). Hypercapnia and acidosis may increase intracranial pressure, induce pulmonary hypertension, depress myocardial contractility, decrease renal blood flow, and release endogenous catecholamines (15). In addition, prevention of cyclic derecruitment with higher PEEP may contribute to overdistention of normally aerated alveoli, counterbalancing the benefits from low Vt and limited airway pressure ventilation cycles (14). The effect of different lung-protective ventilatory strategies in patients with acute lung injury or ARDS has been investigated in randomized, controlled trials (RCTs) testing higher versus lower Vt ventilation at similar PEEP (1619), higher versus lower PEEP strategies during low Vt ventilation (2022), and lower Vt and PEEP titrated greater than the lower inflection point of the individual pressure volume curve versus higher Vt and lower PEEP (23, 24). Results were partially conflicting because of differences in study design and number of enrolled patients. This may explain why most critically ill patients are still ventilated with high Vt at lower or even no PEEP (4, 25). Our objective was to determine whether the different lung-protective ventilatory strategies improve outcome in critically ill adults with acute lung injury or ARDS. Methods Data Sources and Searches We aimed to identify all RCTs assessing the efficacy and outcomes of lower Vt ventilation, higher PEEP application, or a combination of both in adults with acute lung injury or ARDS. The electronic search strategy applied standard filters for identification of RCTs. We searched the Cochrane Central Register of Controlled Trials, MEDLINE (from inception to March 2009), and EMBASE (from inception to March 2009). Our search included the following keywords: acute lung injury, ALI, adult respiratory distress syndrome, ARDS, protective ventilation, lung protective ventilation strategy, pressure-limited ventilation, tidal volume, positive end-expiratory pressure, PEEP, and random. We did not apply language restrictions. In addition to the electronic search, we checked out cross-references from original articles and reviews. Selection of Studies We restricted the analysis to RCTs to guarantee control of selection bias. We did not include study designs containing inadequately adjusted planned co-interventions and quasi-randomized or crossover trials. We considered RCTs that reported mortality as a predefined end point and compared lower versus higher Vt ventilation, lower versus higher PEEP application, or a combination of these strategies in intubated and mechanically ventilated critically ill adults with acute lung injury or ARDS from any cause. Acute lung injury and ARDS had to be defined by the American-European Consensus Conference criteria (26) or by the Lung Injury Severity Score (27). Trials with a low Vt ventilation strategy had to use lower Vt, maximal inspiratory plateau pressure (Pei) of 30 cm H2O or less, or a combination, which resulted in Vt of 8 mL/kg of body weight or less, compared with conventional mechanical ventilation that used Vt ranging between 10 and 15 mL/kg. Regardless of the strategy used to deliver the lower Vt, the 2 study groups had to differ only for Vt and not for other variables associated with a low Vt ventilation strategy. Trials with high PEEP ventilation strategies had to use higher PEEP based on Fio 2PEEP scales, titrating PEEP to greater than the lower inflection point of the individual static or quasi-static pressure volume curve at enrollment or titrating PEEP as high as possible without increasing the maximal Pei to greater than 30 cm H2O compared with conventional mechanical ventilation that used lower PEEP based on fixed Fio 2PEEP scales or lower PEEP at higher Fio 2 to ensure adequate arterial oxygenation. We excluded studies in postoperative patients and those published only in abstract form. We contacted authors to clarify details of trials when necessary. Outcome Measures The primary outcome was mortality, evaluated at hospital discharge. Secondary outcomes included mortality at the end of the planned follow-up, barotrauma, use of rescue therapies owing to life-threatening hypoxemia, ventilator settings, and pulmonary function variables. Barotrauma was defined as any new pneumothorax, pneumomediastinum, subcutaneous emphysema, or pneumatocele after random assignment. Data Extraction and Quality Assessment Two pairs of independent reviewers performed the initial selection by screening titles and abstracts. Citations were selected for further evaluation if the studies they referred to were RCTs of lung-protective ventilatory strategies in critical ill adults or if the title or abstract did not give enough information to make an assessment. For detailed evaluation, we obtained the full text of all possibly relevant studies. Data from each study were extracted independently by the paired reviewers by using a prestandardized data abstraction form. One pair of reviewers was not informed about authors, journal, institutional affiliation, and date of publication. Data extracted from the publications were checked by another reviewer for accuracy. Quality assessment of these studies included use of randomization, reporting of allocation concealment, blinding, adequate selection and description of study population with respect to inclusion and exclusion criteria, similarity of the groups at baseline, use of a predefined treatment protocol, absence of confounders, absence of co-interventions, a priori definition of primary and secondary outcome variables, use of intention-to-treat analysis, extent of follow-up, a priori calculation of sample size, number of patients screened and included in the trial, reports on patients lost to follow-up, and planned or premature termination of the RCT. Two reviewers independently used these criteria to abstract trial quality. We resolved any disagreements by consensus in consultation with a third reviewer if needed. Data Synthesis and Analysis We studied the following comparisons: lower versus higher Vt ventilation using similar PEEP strategies, lower versus higher PEEP level during low Vt ventilation, and the combination of higher Vt and lower PEEP level versus lower Vt and higher PEEP level. Qualitative Analysis We used a narrative summary approach to describe study characteristics and variation in quality indicators among studies and to consider how these factors affect our understanding of the outcomes of the RCTs included in the Cochrane review (28, 29). Quantitative Analysis The meta-analysis was performed according to the Cochrane Collaboration guidelines (30). All statistical analyses were performed with Review Manager, version 4.2 (The Nordic Cochrane Center, Copenhagen, Denmark), the Cochrane Collaborations software for preparing and maintaining Cochrane systematic reviews (30). The pooled effects estimates for binary variables were expressed as odds ratios with 95% CIs, whereas continuous variables were expressed as weighted mean differences with 95% CIs. We tested the difference in estimates of treatment effect between the treatment and control groups for each hypothesis by using a 2-sided z test with statistical significance considered at a P value of less than 0.05. We examined heterogeneity by using the Cochran Q and the I 2 test (31, 32). We predefined heterogeneity as low, moderate, and high, with I 2 statistics greater than 25%, 50%, and 75%, respectively (32). Meta-analysis with a random-effects model was applied with I 2 statistics greater than 25% (33). Otherwise, we performed meta-analysis by using a fixed-effects model. However, the possibil

The Effects of Different Ventilatory Settings on Pulmonary and Systemic Inflammatory Responses During Major Surgery

Mechanical ventilation with high tidal volumes (VT) and zero or low positive end-expiratory pressure increased mediator release to inflammatory stimuli or acute lung injury. We studied whether mechanical ventilation modifies the inflammatory responses during major thoracic or abdominal surgery. Sixty-four patients undergoing elective thoracotomy (n = 34) or laparotomy (n = 30) were randomized to receive either mechanical ventilation with VT = 12 or 15 mL/kg ideal body weight, respectively, and zero end-expiratory pressure, or VT = 6 mL/kg ideal body weight with positive end-expiratory pressure of 10 cm H2O. In 62 patients who completed the study, arterial oxygena- tion was not different between groups. Tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12 were determined by cytometric bead array in plasma after 0, 1, 2, and 3 h and in tracheal aspirates after 3 h of mechanical ventilation. Data were log-transformed and analyzed using parametric or nonparametric tests, as indicated. All plasma mediators increased more during abdominal than during thoracic surgery, although the differences were small. However, neither time course nor concentrations of pulmonary or systemic mediators differed between the two ventilatory settings. Our data suggest that the ventilatory settings we studied do not affect inflammatory reactions during major surgery within 3 h.

Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function.

BackgroundMechanical ventilation with high tidal volumes (VT) in contrast to mechanical ventilation with low VT has been shown to increase plasma levels of proinflammatory and antiinflammatory mediators in patients with acute lung injury. The authors hypothesized that, in patients without previous lung injury, a conventional potentially injurious ventilatory strategy with high VT and zero end-expiratory pressure (ZEEP) will not cause a cytokine release into systemic circulation. MethodsA total of 39 patients with American Society of Anesthesiologists physical status I–II and without signs of systemic infection scheduled for elective surgery with general anesthesia were randomized to receive mechanical ventilation with either (1) VT = 15 ml/kg ideal body weight on ZEEP, (2) VT = 6 ml/kg ideal body weight on ZEEP, or (3) VT = 6 ml/kg ideal body weight on positive end-expiratory pressure of 10 cm H2O. Plasma levels of proinflammatory and antiinflammatory mediators tumor necrosis factor, interleukin (IL)-6, IL-10, and IL-1 receptor antagonist were determined before and 1 h after the initiation of mechanical ventilation. ResultsPlasma levels of all cytokines remained low in all settings. IL-6, tumor necrosis factor, and IL-1 receptor antagonist did not change significantly after 1 h of mechanical ventilation. IL-10 was below the detection limit (10 pg/ml) in 35 of 39 patients. There were no differences between groups. ConclusionsInitiation of mechanical ventilation for 1 h in patients without previous lung injury caused no consistent changes in plasma levels of studied mediators. Mechanical ventilation with high VT on ZEEP did not result in higher cytokine levels compared with lung-protective ventilatory strategies. Previous lunge damage seems to be mandatory to cause an increase in plasma cytokines after 1 h of high VT mechanical ventilation.

Spontaneous breathing improves lung aeration in oleic acid-induced lung injury.

Background Experimental and clinical studies have shown reduction in intrapulmonary shunt with improved oxygenation by spontaneous breathing with airway pressure release ventilation (APRV) in acute lung injury. The mechanisms of these findings are not clear. The authors hypothesized that spontaneous breathing results in better aeration of lung tissue and that improvement in oxygenation can be explained by these changes. This hypothesis was studied in a porcine model of oleic acid–induced lung injury. Methods Two hours after induction of lung injury, 24 pigs were randomly assigned to APRV with or without spontaneous breathing at a positive end-expiratory pressure of 5 cm H2O. Hemodynamics, spirometry, and end-expiratory lung volume by nitrogen washout were measured at baseline, after 2 h of lung injury, and after 2 and 4 h of mechanical ventilation in the specific mode. Finally, spiral computed tomography of the chest was performed at end-expiratory lung volume in 22 pigs. Results Arterial carbon dioxide tension and mean and end-inspiratory airway pressures were comparable between settings. Four hours of APRV with spontaneous breathing resulted in improved oxygenation compared with APRV without spontaneous breathing (arterial oxygen tension, 144 ± 65 vs. 91 ± 50 mmHg, P < 0.01 for interaction time × mode), higher end-expiratory lung volume (786 ± 320 vs. 384 ± 148 ml, P < 0.001), and better aeration. End-expiratory lung volume and venous admixture were both correlated with the amount of lung reaeration (r2 = 0.62 and r2 = 0.61, respectively). Conclusions The results support the hypothesis that spontaneous breathing during APRV improves oxygenation mainly by recruitment of nonaerated lung and improved aeration of the lungs.

The effects of prone positioning on intraabdominal pressure and cardiovascular and renal function in patients with acute lung injury.

To detect any harmful effects of prone positioning on intraabdominal pressure (IAP) and cardiovascular and renal function, we studied 16 mechanically ventilated patients with acute lung injury randomly in prone and supine positions, without minimizing the restriction of the abdomen. Effective renal blood flow index and glomerular filtration rate index were determined by the paraaminohippurate and inulin clearance techniques. Prone positioning resulted in an increase in IAP from 12 ± 4 to 14 ± 5 mm Hg (P < 0.05), Pao2/fraction of inspired oxygen from 220 ± 91 to 267 ± 82 mm Hg (P < 0.05), cardiac index from 4.1 ± 1.1 to 4.4 ± 0.7 L/min (P < 0.05), mean arterial pressure from 77 ± 10 to 82 ± 11 mm Hg (P < 0.01), and oxygen delivery index from 600 ± 156 to 648 ± 95 mL · min−1 · m−2 (P < 0.05). Renal fraction of cardiac output decreased from 19.1% ± 12.5% to 15.5% ± 8.8% (P < 0.05), and renal vascular resistance index increased from 11762 ± 6554 dynes · s · cm−5 · m2 to 15078 ± 10594 dynes · s · cm−5 · m2 (P < 0.05), whereas effective renal blood flow index, glomerular filtration rate index, filtration fraction, urine volume, fractional sodium excretion, and osmolar and free water clearances remained constant during prone positioning. Prone positioning, when used in patients with acute lung injury, although it is associated with a small increase in IAP, contributes to improved arterial oxygenation and systemic blood flow without affecting renal perfusion and function. Apparently, special support to allow free chest and abdominal movement seems unnecessary when mechanically ventilated, hemodynamically stable patients without abdominal hypertension are proned to improve gas exchange.

Protective versus Conventional Ventilation for Surgery: A Systematic Review and Individual Patient Data Meta-analysis.

Background:Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end–expiratory pressure (PEEP) level and occurrence of PPC. Methods:Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. Results:Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 patients (8.9%) assigned to ventilation with low VT and high PEEP levels and 63 cases in 525 patients (12%) assigned to ventilation with low VT and low PEEP levels (adjusted relative risk, 0.93; 95% CI, 0.64 to 1.37; P = 0.72). A dose–response relationship was found between the appearance of PPC and VT size (R2 = 0.39) but not between the appearance of PPC and PEEP level (R2 = 0.08). Conclusions:These data support the beneficial effects of ventilation with use of low VT in patients undergoing surgery. Further trials are necessary to define the role of intraoperative higher PEEP to prevent PPC during nonopen abdominal surgery.

Electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury

Objective:To determine the validity of functional electric impedance tomography to monitor regional ventilation distribution in experimental acute lung injury, and to develop a simple electric impedance tomography index detecting alveolar recruitment. Design:Randomized prospective experimental study. Setting:Academic research laboratory. Subjects:Sixteen anesthetized, tracheotomized, and mechanically ventilated pigs. Interventions:Acute lung injury was induced either by acid aspiration (direct acute lung injury) or by abdominal hypertension plus oleic acid injection (indirect acute lung injury) in ten pigs. Six pigs with normal lungs were studied as a control group and with endotracheal suction-related atelectasis. After 4 hrs of mechanical ventilation, a slow inflation was performed. Measurements and Main Results:During slow inflation, simultaneous measurements of regional ventilation by electric impedance tomography and dynamic computed tomography were highly correlated in quadrants of a transversal thoracic plane (r2 = .63–.88, p < .0001, bias <5%) in both direct and indirect acute lung injury. Variability between methods was lower in direct than indirect acute lung injury (11 ± 2% vs. 18 ± 3%, respectively, p < .05). Electric impedance tomography indexes to detect alveolar recruitment were determined by mathematical curve analysis of regional impedance time curves. Empirical tests of different methods revealed that regional ventilation delay, that is, time delay of regional impedance time curve to reach a threshold, correlated well with recruited volume as measured by CT (r2 = .63). Correlation coefficients in subgroups were r2 = .71 and r2 = .48 in pigs with normal lungs with and without closed suction related atelectasis and r2 = .79 in pigs subject to indirect acute lung injury, respectively, whereas no significant correlation was found in pigs undergoing direct acute lung injury. Conclusions:Electric impedance tomography allows assessment of regional ventilation distribution and recruitment in experimental models of direct and indirect acute lung injury as well as normal lungs. Except for pigs with direct acute lung injury, regional ventilation delay determined during a slow inflation from impedance time curves appears to be a simple index for clinical monitoring of alveolar recruitment.

The impact of spontaneous breathing during mechanical ventilation.

Purpose of reviewIn patients with acute respiratory distress syndrome, controlled mechanical ventilation is generally used in the initial phase to ensure adequate alveolar ventilation, arterial oxygenation, and to reduce work of breathing without causing further damage to the lungs. Although introduced as weaning techniques, partial ventilator support modes have become standard techniques for primary mechanical ventilator support. This review evaluates the physiological and clinical effects of persisting spontaneous breathing during ventilator support in patients with acute respiratory distress syndrome. Recent findingsThe improvements in pulmonary gas exchange, systemic blood flow and oxygen supply to the tissue which have been observed when spontaneous breathing has been maintained during mechanical ventilation are reflected in the clinical improvement in the patients condition. Computer tomography observations demonstrated that spontaneous breathing improves gas exchange by redistribution of ventilation and end-expiratory gas to dependent, juxtadiaphragmatic lung regions and thereby promotes alveolar recruitment. Thus, spontaneous breathing during ventilator support counters the undesirable cyclic alveolar collapse in dependent lung regions. In addition, spontaneous breathing during ventilator support may prevent increase in sedation beyond a level of comfort to adapt the patient to mechanical ventilation which decreases duration of mechanical ventilator support, length of stay in the intensive care unit, and overall costs of care giving. SummaryIn view of the recently available data, it can be concluded that maintained spontaneous breathing during mechanical ventilation should not be suppressed even in patients with severe pulmonary functional disorders.

Association between driving pressure and development of postoperative pulmonary complications in patients undergoing mechanical ventilation for general anaesthesia: a meta-analysis of individual patient data.

BACKGROUND Protective mechanical ventilation strategies using low tidal volume or high levels of positive end-expiratory pressure (PEEP) improve outcomes for patients who have had surgery. The role of the driving pressure, which is the difference between the plateau pressure and the level of positive end-expiratory pressure is not known. We investigated the association of tidal volume, the level of PEEP, and driving pressure during intraoperative ventilation with the development of postoperative pulmonary complications. METHODS We did a meta-analysis of individual patient data from randomised controlled trials of protective ventilation during general anesthaesia for surgery published up to July 30, 2015. The main outcome was development of postoperative pulmonary complications (postoperative lung injury, pulmonary infection, or barotrauma). FINDINGS We included data from 17 randomised controlled trials, including 2250 patients. Multivariate analysis suggested that driving pressure was associated with the development of postoperative pulmonary complications (odds ratio [OR] for one unit increase of driving pressure 1·16, 95% CI 1·13-1·19; p<0·0001), whereas we detected no association for tidal volume (1·05, 0·98-1·13; p=0·179). PEEP did not have a large enough effect in univariate analysis to warrant inclusion in the multivariate analysis. In a mediator analysis, driving pressure was the only significant mediator of the effects of protective ventilation on development of pulmonary complications (p=0·027). In two studies that compared low with high PEEP during low tidal volume ventilation, an increase in the level of PEEP that resulted in an increase in driving pressure was associated with more postoperative pulmonary complications (OR 3·11, 95% CI 1·39-6·96; p=0·006). INTERPRETATION In patients having surgery, intraoperative high driving pressure and changes in the level of PEEP that result in an increase of driving pressure are associated with more postoperative pulmonary complications. However, a randomised controlled trial comparing ventilation based on driving pressure with usual care is needed to confirm these findings. FUNDING None.