The short-term mortality benefit of lower tidal volume ventilation (LTVV) for patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has been demonstrated in a large, multi-center randomized trial. However, the impact of LTVV and other critical care therapies on the longer-term outcomes of ALI/ARDS survivors remains uncertain. The Improving Care of ALI Patients (ICAP) study is a multi-site, prospective cohort study that aims to evaluate the longer-term outcomes of ALI/ARDS survivors with a particular focus on the effect of LTVV and other critical care therapies.
Consecutive mechanically ventilated ALI/ARDS patients from 11 intensive care units (ICUs) at four hospitals in the city of Baltimore, MD, USA, will be enrolled in a prospective cohort study. Exposures (patient-based, clinical management, and ICU organizational) will be comprehensively collected both at baseline and throughout patients' ICU stay. Outcomes, including mortality, organ impairment, functional status, and quality of life, will be assessed with the use of standardized surveys and testing at 3, 6, 12, and 24 months after ALI/ARDS diagnosis. A multi-faceted retention strategy will be used to minimize participant loss to follow-up.
On the basis of the historical incidence of ALI/ARDS at the study sites, we expect to enroll 520 patients over two years. This projected sample size is more than double that of any published study of long-term outcomes in ALI/ARDS survivors, providing 86% power to detect a relative mortality hazard of 0.70 in patients receiving higher versus lower exposure to LTVV. The projected sample size also provides sufficient power to evaluate the association between a variety of other exposure and outcome variables, including quality of life.
The ICAP study is a novel, prospective cohort study that will build on previous critical care research to improve our understanding of the longer-term impact of ALI/ARDS, LTVV and other aspects of critical care management. Given the paucity of information about the impact of interventions on long-term outcomes for survivors of critical illness, this study can provide important information to inform clinical practice.
Acute lung injury (ALI) is associated with high mortality. Low tidal volume (Vt) ventilation has been shown to reduce mortality in ALI patients in the Intensive Care Unit.
Anesthesiologists do not routinely provide lung protective ventilation strategies to patients with ALI in the operating room. We hypothesized an alert recommending lung protective ventilation regarding patients with potential ALI would result in lower Vt administration.
We conducted a randomized controlled trial on anesthesia providers caring for patients with potential ALI. Patients with an average or last collected ratio of partial pressure of arterial oxygen to inspired fraction of oxygen < 300 were randomized to providers being sent an alert with a recommended Vt of 6 cc/kg predicted body weight or conventional care. Primary outcomes were Vt and Vt/kg predicted body weight administered to patients. Secondary outcomes included ventilator parameters, length of postoperative ventilation and death.
The primary outcome was a clinically significant reduction in mean Vt from 508 to 458 cc (p=0.033), with a reduction in Vt when measured in cc/kg predicted body weight from 8 to 7.2 cc/kg predicted body weight (p=0.040). There were no statistically significant changes in other outcomes or adverse events associated with either arm.
Automated alerts generated for patients at risk of having ALI resulted in a statistically significant reduction in Vt administered when compared to a control group. Further research is required to determine if a reduction in Vt results in decreased mortality and/or postoperative duration of mechanical ventilation.
Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.
We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.
One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.
Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.
We sought to develop a simple point score that would accurately capture the risk of hospital death for patients with acute lung injury (ALI).
This is a secondary analysis of data from two randomized trials. Baseline clinical variables collected within 24 hours of enrollment were modeled as predictors of hospital mortality using logistic regression and bootstrap resampling to arrive at a parsimonious model. We constructed a point score based on regression coefficients.
Medical centers participating in the Acute Respiratory Distress Syndrome Clinical Trials network (ARDSnet).
Model development: 414 patients with non-traumatic ALI participating in the low tidal volume arm of the ARDSnet ARMA study. Model validation: 459 patients participating in the ARDSnet ALVEOLI study.
Measurements and Main Results
Variables comprising the prognostic model were: hematocrit <26% (1 point), bilirubin ≥ 2 mg/dl (1 point), fluid balance greater than 2.5 liters positive (1 point), and age (1 point for age 40–64, 2 points for age ≥ 65 years). Predicted mortality (95% confidence interval) for 0, 1, 2, 3, and 4+ point totals was 8% (5–14%), 17% (12–23%), 31% (26–37%), 51% (43–58%), and 70% (58–80%), respectively. There was excellent agreement between predicted and observed mortality in the validation cohort. Observed mortality for 0, 1, 2, 3, and 4+ point totals in the validation cohort was 12%, 16%, 28%, 47%, and 67%, respectively. Compared to the APACHE III score, areas under the receiver operating characteristic curve for the point score were greater in the development cohort (0.72 vs. 0.67, p=0.09) and lower in the validation cohort (0.68 vs. 0.75, p=0.03).
Mortality in ALI patients can be predicted using an index of four readily-available clinical variables with good calibration. This index may help inform prognostic discussions, but validation in non-clinical trial populations is necessary before widespread use.
Acute respiratory distress syndrome; acute lung injury; Respiratory Distress Syndrome; Adult; Human ARDS; Statistical Model; logistic models; mortality determinants; Mortality; In-Hospital; Acute Physiology and Chronic Health Evaluation; APACHE III; Bayesian Prediction; Prognosis
Lung-protective ventilation aims at using low tidal volumes (VT) at optimum positive end-expiratory pressures (PEEP). Optimum PEEP should recruit atelectatic lung regions and avoid tidal recruitment and end-inspiratory overinflation. We examined the effect of VT and PEEP on ventilation distribution, regional respiratory system compliance (CRS), and end-expiratory lung volume (EELV) in an animal model of acute lung injury (ALI) and patients with ARDS by using electrical impedance tomography (EIT) with the aim to assess tidal recruitment and overinflation.
EIT examinations were performed in 10 anaesthetized pigs with normal lungs ventilated at 5 and 10 ml/kg body weight VT and 5 cmH2O PEEP. After ALI induction, 10 ml/kg VT and 10 cmH2O PEEP were applied. Afterwards, PEEP was set according to the pressure-volume curve. Animals were randomized to either low or high VT ventilation changed after 30 minutes in a crossover design. Ventilation distribution, regional CRS and changes in EELV were analyzed. The same measures were determined in five ARDS patients examined during low and high VT ventilation (6 and 10 (8) ml/kg) at three PEEP levels.
In healthy animals, high compared to low VT increased CRS and ventilation in dependent lung regions implying tidal recruitment. ALI reduced CRS and EELV in all regions without changing ventilation distribution. Pressure-volume curve-derived PEEP of 21±4 cmH2O (mean±SD) resulted in comparable increase in CRS in dependent and decrease in non-dependent regions at both VT. This implied that tidal recruitment was avoided but end-inspiratory overinflation was present irrespective of VT. In patients, regional CRS differences between low and high VT revealed high degree of tidal recruitment and low overinflation at 3±1 cmH2O PEEP. Tidal recruitment decreased at 10±1 cmH2O and was further reduced at 15±2 cmH2O PEEP.
Tidal recruitment and end-inspiratory overinflation can be assessed by EIT-based analysis of regional CRS.
We assessed factors associated with underutilization of lung protective ventilation (LPV) in patients with acute lung injury (ALI).
Secondary analysis of ARDSNet trial data, 1999-2005. Tidal volumes recorded prior to trial randomization were analyzed to determine receipt of LPV [tidal volume ≤ 6.5 cc/kg of predicted body weight (PBW)].
430/1385 (31.2%) participants received LPV. Average tidal volume was 7.65±1.82 cc/kg PBW; measured tidal volumes were greater than “lung protective” tidal volumes predicted by 6.5cc/kg PBW (mean difference 67±108cc, p<0.0001). Multivariate predictors of LPV underutilization were older age [odds ratio (OR) per standard deviation (std) year 1.18 (95% confidence interval: 1.02-1.38)], white race [OR, 1.40 (1.05-1.88)], shorter stature [OR per std centimeter 0.55 (0.48-0.63)], lower Simplified Acute Physiology Score (SAPS)II [OR per std, 0.78 (0.67-0.92)], lower lung injury score [OR per std 0.83 (0.70-0.95)], decreased serum bicarbonate [OR per std mmol/l 0.83 (0.71-0.97)], shorter pre-enrollment ICU stay [OR per std day 0.84 (0.73-0.98)], and use of non-volume-controlled ventilation [OR 3.07 (1.78, 5.27)]. Setting tidal volumes to 450ml (men) or 350ml (women) would provide LPV to 80% of patients with ALI.
Simple interventions could substantially improve adherence with LPV among patients with ALI and warrant prospective study.
acute lung injury; risk factors; quality improvement
Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute lung injury (ALI). The low tidal volume lung-protective ventilation strategy is associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of lung-protective positive pressure ventilation in spontaneously ventilating patients with ALI exacerbates pre-existing lung injury by using measurements of biomarkers of lung injury before and after intubation.
Materials and methods
A prospective observational cohort study was conducted in the intensive care unit of a tertiary care university hospital. Twenty-five intubated, mechanically ventilated patients with ALI were enrolled. Physiologic data and serum samples were collected within 6 hours before intubation and at two different time points within the first 24 hours after intubation to measure the concentration of interleukin (IL)-6, IL-8, intercellular adhesion molecule 1 (ICAM-1), and von Willebrand factor (vWF). The differences in biomarker levels before and after intubation were analysed using repeated measures analysis of variance and a paired t test with correction for multiple comparisons.
Before endotracheal intubation, all of the biological markers (IL-8, IL-6, ICAM-1, and vWF) were elevated in the spontaneously breathing patients with ALI. After intubation and the institution of positive pressure ventilation (tidal volume 7 to 8 ml/kg per ideal body weight), none of the biological markers was significantly increased at either an early (3 ± 2 hours) or later (21 ± 5 hours) time point. However, the levels of IL-8 were significantly decreased at the later time point (21 ± 5 hours) after intubation. During the 24-hour period after intubation, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio significantly increased and the plateau airway pressure significantly decreased.
Levels of IL-8, IL-6, vWF, and ICAM-1 are elevated in spontaneously ventilating patients with ALI prior to endotracheal intubation. The institution of a lung-protective ventilation strategy with positive pressure ventilation does not further increase the levels of biological markers of lung injury. The results suggest that the institution of a lung-protective positive pressure ventilation strategy does not worsen the pre-existing lung injury in most patients with ALI.
To evaluate the association between plasma granulocyte colony-stimulating factor (G-CSF) levels and clinical outcomes including mortality in patients with acute lung injury (ALI) and to determine whether lower tidal volume ventilation was associated with a more rapid decrease in plasma G-CSF over time in patients with ALI.
Retrospective measurement of G-CSF levels in plasma samples that were collected prospectively as part of a large multicenter clinical trial.
Intensive care units in ten university centers.
The study included 645 patients enrolled in the NHBLI ARDS Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for ALI.
Measurements and Main Results
Baseline plasma levels of G-CSF were associated with an increased risk of death and a decrease in ventilator-free and organ failure-free days (VFD and OFD) in multivariate analyses controlling for ventilation strategy, age, and sex (OR death 1.2/log10 increment G-CSF, 95% CI 1.01 to 1.4). Stratification of G-CSF levels into quartiles revealed a strong association between the highest levels of G-CSF and increased risk of death and decreased VFD and OFD in multivariate analyses controlling for ventilation strategy, APACHE III score, PF ratio, creatinine, and platelet count (p<0.05). Subgroup multivariate analysis of patients with sepsis as their risk factor for ALI revealed a U-shaped association between mortality and G-CSF levels such that risk increased linearly from the second through fourth (highest) quartiles, yet also increased in the first (lowest) quartile. G-CSF levels decreased over time in both tidal volume groups and there was no statistical difference in the extent of decrease between ventilator strategies.
In patients with ALI, plasma G-CSF levels are associated with morbidity and mortality, yet these levels are not influenced by tidal volume strategy. In patients with sepsis-related ALI we find a bimodal association between baseline plasma G-CSF levels and subsequent morbidity and mortality from this disease.
ALI; ARDS; G-CSF; low tidal volume ventilation; sepsis
Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.
Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation.
Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed.
Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.
Protective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de-recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume.
PEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method.
Progressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas.
The PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration.
Studies from single centers have suggested that mortality from acute lung injury (ALI) has declined over time. However, recent trends in ALI mortality from centers across the U.S. are unknown. Whether recent advances in the treatment of ALI or related critical illnesses have resulted in decreased mortality from ALI is not clear.
In a study of 2451 mechanically ventilated patients with ALI enrolled in the Acute Respiratory Distress Syndrome (ARDS) Network randomized controlled trials between 1996-2005, we evaluated whether there was a temporal improvement in 60-day mortality. We also investigated whether there were temporal improvements in mortality specific to individual causes of lung injury (pneumonia, sepsis, trauma, aspiration, transfusion).
Crude mortality was 35% in 1996-1997 and declined during each subsequent time period to a low of 26% in 2004-2005 (test for trend p<0.0005). After adjusting for demographic and clinical covariates, including receipt of lower tidal volume ventilation and severity of illness, the temporal trend persisted (test for trend p=0.002). When analyzed by individual causes of lung injury, there were not any statistically significant temporal trends in 60-day mortality for the most common causes of lung injury (pneumonia, sepsis, aspiration, trauma).
Over the past decade, there appears to be a clear temporal improvement in survival among patients with ALI treated at ARDS Network centers. Our findings strongly suggest that other advancements in critical care, aside from lower tidal volume ventilation, accounted for this improvement in mortality.
acute respiratory distress syndrome; acute lung injury; mortality; temporal trend; epidemiology
Low tidal volumes have been associated with improved outcomes in patients with established acute lung injury. The role of low tidal volume ventilation in patients without lung injury is still unresolved. We hypothesized that such a strategy in patients undergoing elective surgery would reduce ventilator-associated lung injury and that this improvement would lead to a shortened time to extubation
A single-center randomized controlled trial was undertaken in 149 patients undergoing elective cardiac surgery. Ventilation with 6 versus 10 ml/kg tidal volume was compared. Ventilator settings were applied immediately after anesthesia induction and continued throughout surgery and the subsequent intensive care unit stay. The primary endpoint of the study was time to extubation. Secondary endpoints included the proportion of patients extubated at 6 h and indices of lung mechanics and gas exchange as well as patient clinical outcomes.
Median ventilation time was not significantly different in the low tidal volume group; a median (interquartile range) of 450 (264–1,044) min was achieved compared with 643 (417–1,032) min in the control group (P = 0.10). However, a higher proportion of patients in the low tidal volume group was free of any ventilation at 6 h: 37.3% compared with 20.3% in the control group (P = 0.02). In addition, fewer patients in the low tidal volume group required rein-tubation (1.3 vs. 9.5%; P = 0.03).
Although reduction of tidal volume in mechanically ventilated patients undergoing elective cardiac surgery did not significantly shorten time to extubation, several improvements were observed in secondary outcomes. When these data are combined with a lack of observed complications, a strategy of reduced tidal volume could still be beneficial in this patient population.
The aim of this study was to describe the epidemiology and management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in Ireland.
As part of a 10-week prospective national audit of patient demographics and organ failure incidence in intensive care in Ireland, all patients with ALI/ARDS in 14 participating centres were prospectively identified using American European Consensus Conference definitions.
There were 1,029 admissions during the study period; of these, 728 patients were invasively ventilated. A total of 196 (19%) patients had ALI/ARDS, and 141 of these (72%) had ALI/ARDS on admission and a further 55 (28%) developed ALI/ARDS after admission. For the patients with ALI/ARDS, the mean (± standard deviation) age was 58 ± 17 years and 62% were male. The most common predisposing risk factors were pneumonia (50%) and nonpulmonary sepsis (26%). Mean (± standard deviation) tidal volume/kg was 7.0 ± 1.7 ml/kg. Median (interquartile range) duration of ventilation was 6.8 (2.0 to 12.8) days. Median (interquartile range) length of stay in the intensive care unit was 10.0 (5.0 to 18.5) days. The overall intensive care unit mortality for ALI/ARDS was 32.3%. Lower baseline arterial oxygen tension/fraction of inspired oxygen ratio and higher Sequential Organ Failure Assessment scores were associated with increased mortality. Although not significant, patients receiving treatment with a statin during admission had a 73% lower odds of death (odds ratio 0.27, 95% confidence interval 0.06 to 1.21; P = 0.09).
The incidence of ALI/ARDS is high and is associated with significant mortality. Protective lung ventilation is used commonly throughout participating centres. With low tidal volume ventilation, the degree of hypoxaemia is associated with outcome. These data will inform future multicentre clinical trials in ALI/ARDS in Ireland.
To provide an update to the original Surviving Sepsis Campaign clinical management guidelines, “Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock,” published in 2004.
Modified Delphi method with a consensus conference of 55 international experts, several subsequent meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. This process was conducted independently of any industry funding.
We used the GRADE system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations. A strong recommendation  indicates that an intervention's desirable effects clearly outweigh its undesirable effects (risk, burden, cost), or clearly do not. Weak recommendations  indicate that the tradeoff between desirable and undesirable effects is less clear. The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. In areas without complete agreement, a formal process of resolution was developed and applied. Recommendations are grouped into those directly targeting severe sepsis, recommendations targeting general care of the critically ill patient that are considered high priority in severe sepsis, and pediatric considerations.
Key recommendations, listed by category, include: early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures prior to antibiotic therapy (1C); imaging studies performed promptly to confirm potential source of infection (1C); administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D); reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D); source control with attention to the balance of risks and benefits of the chosen method (1C); administration of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥ 65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C); stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for post-operative patients). In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C); protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B); institution of glycemic control (1B) targeting a blood glucose < 150 mg/dL after initial stabilization ( 2C ); equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent upper GI bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D).
Recommendations specific to pediatric severe sepsis include: greater use of physical examination therapeutic end points (2C); dopamine as the first drug of choice for hypotension (2C); steroids only in children with suspected or proven adrenal insufficiency (2C); a recommendation against the use of recombinant activated protein C in children (1B).
There was strong agreement among a large cohort of international experts regarding many level 1 recommendations for the best current care of patients with severe sepsis. Evidenced-based recommendations regarding the acute management of sepsis and septic shock are the first step toward improved outcomes for this important group of critically ill patients.
Sepsis; Severe sepsis; Septic shock; Sepsis syndrome; Infection; GRADE; Guidelines; Evidence-based medicine; Surviving Sepsis Campaign; Sepsis bundles
Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain important causes of morbidity and mortality in the critically ill patient, with far-reaching short-term and long-term implications for individual patients and for healthcare providers. It is well accepted that mechanical ventilation can worsen lung injury, potentially worsening systemic organ function, and can thus impact on mortality in acute lung injury (ALI)/ARDS. Unfortunately, although the concept of minimizing such damage via lung-protective ventilatory strategies is widely acknowledged, effective integration of such an approach into clinical practice remains more elusive. The study by the Irish Critical Care Trials Group published in the previous edition of Critical Care describes a 10-week real-life survey of all intensive care unit admissions across Ireland, detailing for the first time the epidemiology of ALI/ARDS in this population and clinician's attempts to deliver lung-protective ventilation. The authors also report hypothesis-generating data on the implications of statin use in this population. The present commentary reviews aspects of this work, with particular attention to the implementation of low-tidal-volume/lung-protective ventilatory strategies in ALI/ARDS.
Lung protective ventilation (LPV) has been shown to improve survival and the duration of mechanical ventilation in acute lung injury (ALI) patients. Mortality of ALI may vary by gender, which could result from treatment variability. Whether gender is associated with the use of LPV is not known.
A total of 421 severe sepsis-related ALI subjects in the Consortium to Evaluate Lung Edema Genetics from seven teaching hospitals between 2002 and 2008 were included in our study. We evaluated patients' tidal volume, plateau pressure and arterial pH to determine whether patients received LPV during the first two days after developing ALI. The odds ratio of receiving LPV was estimated by a logistic regression model with robust and cluster options.
Women had similar characteristics as men with the exception of lower height and higher illness severity, as measured by Acute Physiology and Chronic Health Evaluation (APACHE) II score. 225 (53%) of the subjects received LPV during the first two days after ALI onset; women received LPV less frequently than men (46% versus 59%, P < 0.001). However, after adjustment for height and severity of illness (APACHE II), there was no difference in exposure to LPV between men and women (P = 0.262).
Short people are less likely to receive LPV, which seems to explain the tendency of clinicians to adhere to LPV less strictly in women. Strategies to standardize application of LPV, independent of differences in height and severity of illness, are necessary.
Ventilation using low tidal volumes with permission of hypercapnia is recommended to protect the lung in acute respiratory distress syndrome. However, the most lung protective tidal volume in association with hypercapnia is unknown. The aim of this study was to assess the effects of different tidal volumes with associated hypercapnia on lung injury and gas exchange in a model for acute respiratory distress syndrome.
In this randomized controlled experiment sixty-four surfactant-depleted rabbits were exposed to 6 hours of mechanical ventilation with the following targets: Group 1: tidal volume = 8–10 ml/kg/PaCO2 = 40 mm Hg; Group 2: tidal volume = 4–5 ml/kg/PaCO2 = 80 mm Hg; Group 3: tidal volume = 3–4 ml/kg/PaCO2 = 120 mm Hg; Group 4: tidal volume = 2–3 ml/kg/PaCO2 = 160 mm Hg. Decreased wet-dry weight ratios of the lungs, lower histological lung injury scores and higher PaO2 were found in all low tidal volume/hypercapnia groups (group 2, 3, 4) as compared to the group with conventional tidal volume/normocapnia (group 1). The reduction of the tidal volume below 4–5 ml/kg did not enhance lung protection. However, oxygenation and lung protection were maintained at extremely low tidal volumes in association with very severe hypercapnia and no adverse hemodynamic effects were observed with this strategy.
Ventilation with low tidal volumes and associated hypercapnia was lung protective. A tidal volume below 4–5 ml/kg/PaCO2 80 mm Hg with concomitant more severe hypercapnic acidosis did not increase lung protection in this surfactant deficiency model. However, even at extremely low tidal volumes in association with severe hypercapnia lung protection and oxygenation were maintained.
Lung fibrosis, reduced lung compliance, and severe hypoxemia found in patients with acute lung injury often result in a need for the support of mechanical ventilation. High-tidal-volume mechanical ventilation can increase lung damage and fibrogeneic activity but the mechanisms regulating the interaction between high tidal volume and lung fibrosis are unclear. We hypothesized that high-tidal-volume ventilation increased pulmonary fibrosis in acute lung injury via the serine/threonine kinase-protein kinase B (Akt) and mitogen-activated protein kinase pathways.
After 5 days of bleomycin administration to simulate acute lung injury, male C57BL/6 mice, weighing 20 to 25 g, were exposed to either high-tidal-volume mechanical ventilation (30 ml/kg) or low-tidal-volume mechanical ventilation (6 ml/kg) with room air for 1 to 5 hours.
High-tidal-volume ventilation induced type I and type III procollagen mRNA expression, microvascular permeability, hydroxyproline content, Masson's trichrome staining, S100A4/fibroblast specific protein-1 staining, activation of Akt and extracellular signal-regulated kinase (ERK) 1/2, and production of macrophage inflammatory protein-2 and 10 kDa IFNγ-inducible protein in a dose-dependent manner. High-tidal-volume ventilation-induced lung fibrosis was attenuated in Akt-deficient mice and in mice with pharmacologic inhibition of ERK1/2 activity by PD98059.
We conclude that high-tidal-volume ventilation-induced microvascular permeability, lung fibrosis, and chemokine production were dependent, in part, on activation of the Akt and ERK1/2 pathways.
Mechanical ventilation is necessary for patients with acute respiratory failure, but can cause or propagate lung injury. We previously identified cyclooxygenase-2 as a candidate gene in mechanical ventilation–induced lung injury. Our objective was to determine the role of cyclooxygenase-2 in mechanical ventilation–induced lung injury and the effects of cyclooxygenase-2 inhibition on lung inflammation and barrier disruption. Mice were mechanically ventilated at low and high tidal volumes, in the presence or absence of pharmacologic cyclooxygenase-2–specific inhibition with 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404). Lung injury was assessed using markers of alveolar–capillary leakage and lung inflammation. Cyclooxygenase-2 expression and activity were measured by Western blotting, real-time PCR, and lung/plasma prostanoid analysis, and tissue sections were analyzed for cyclooxygenase-2 staining by immunohistochemistry. High tidal volume ventilation induced lung injury, significantly increasing both lung leakage and lung inflammation relative to control and low tidal volume ventilation. High tidal volume mechanical ventilation significantly induced cyclooxygenase-2 expression and activity, both in the lungs and systemically, compared with control mice and low tidal volume mice. The immunohistochemical analysis of lung sections localized cyclooxygenase-2 expression to monocytes and macrophages in the alveoli. The pharmacologic inhibition of cyclooxygenase-2 with CAY10404 significantly decreased cyclooxygenase activity and attenuated lung injury in mice ventilated at high tidal volume, attenuating barrier disruption, tissue inflammation, and inflammatory cell signaling. This study demonstrates the induction of cyclooxygenase-2 by mechanical ventilation, and suggests that the therapeutic inhibition of cyclooxygenase-2 may attenuate ventilator-induced acute lung injury.
cyclooxygenase-2; mechanical ventilation; lung injury
In lung cancer surgery, large tidal volume and elevated inspiratory pressure are known risk factors of acute lung (ALI). Mechanical ventilation with low tidal volume has been shown to attenuate lung injuries in critically ill patients. In the current study, we assessed the impact of a protective lung ventilation (PLV) protocol in patients undergoing lung cancer resection.
We performed a secondary analysis of an observational cohort. Demographic, surgical, clinical and outcome data were prospectively collected over a 10-year period. The PLV protocol consisted of small tidal volume, limiting maximal pressure ventilation and adding end-expiratory positive pressure along with recruitment maneuvers. Multivariate analysis with logistic regression was performed and data were compared before and after implementation of the PLV protocol: from 1998 to 2003 (historical group, n = 533) and from 2003 to 2008 (protocol group, n = 558).
Baseline patient characteristics were similar in the two cohorts, except for a higher cardiovascular risk profile in the intervention group. During one-lung ventilation, protocol-managed patients had lower tidal volume (5.3 ± 1.1 vs. 7.1 ± 1.2 ml/kg in historical controls, P = 0.013) and higher dynamic compliance (45 ± 8 vs. 32 ± 7 ml/cmH2O, P = 0.011). After implementing PLV, there was a decreased incidence of acute lung injury (from 3.7% to 0.9%, P < 0.01) and atelectasis (from 8.8 to 5.0, P = 0.018), fewer admissions to the intensive care unit (from 9.4% vs. 2.5%, P < 0.001) and shorter hospital stay (from 14.5 ± 3.3 vs. 11.8 ± 4.1, P < 0.01). When adjusted for baseline characteristics, implementation of the open-lung protocol was associated with a reduced risk of acute lung injury (adjusted odds ratio of 0.34 with 95% confidence interval of 0.23 to 0.75; P = 0.002).
Implementing an intraoperative PLV protocol in patients undergoing lung cancer resection was associated with improved postoperative respiratory outcomes as evidence by significantly reduced incidences of acute lung injury and atelectasis along with reduced utilization of intensive care unit resources.
Sepsis could induce indirect acute lung injury(ALI), and pulmonary vasomotor dysfunction. While low tidal volume is advocated for treatment of ALI patients. However, there is no evidence for low tidal volume that it could mitigate pulmonary vasomotor dysfunction in indirect ALI. Our study is to evaluate whether low tidal volume ventilation could protect the pulmonary vascular function in indirect lipopolysaccharide (LPS) induced acute lung injury rats.
An indirect ALI rat model was induced by intravenous infusion of LPS. Thirty rats (n = 6 in each group) were randomly divided into (1)Control group; (2) ALI group; (3) LV group (tidal volume of 6mL/kg); (4) MV group (tidal volume of 12mL/kg); (5)VLV group (tidal volume of 3mL/kg). Mean arterial pressure and blood gas analysis were monitored every 2 hours throughout the experiment. Lung tissues and pulmonary artery rings were immediately harvested after the rats were bled to be killed to detect the contents of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) and TNF-α. Acetylcholine (Ache)-induced endothelium-dependent and sodium nitroprusside (SNP)-induced endothelium-independent relaxation of isolated pulmonary artery rings were measured by tensiometry.
There was no difference within groups concerning blood pressure, PaCO2 and SNP-induced endothelium-independent relaxation of pulmonary artery rings. Compared with MV group, LV group significantly reduced LPS-induced expression of ET-1 level (113.79 ± 7.33pg/mL vs. 152.52 ± 12.75pg/mL, P < 0.05) and TNF-α (3305.09 ± 334.29pg/mL vs.4144.07 ± 608.21pg/mL, P < 0.05), increased the expression of eNOS (IOD: 15032.05 ± 5925.07 vs. 11454.32 ± 6035.47, P < 0.05). While Ache (10-7mol/L-10-4mol/L)-induced vasodilatation was ameliorated 30% more in LV group than in MV group.
Low tidal volume could protect the pulmonary vasodilative function during indirect ALI by decreasing vasoconstrictor factors, increasing expressions of vasodilator factors in pulmonary endothelial cells, and inhibiting inflammation injuries.
Endothelium; Mechanical ventilation; Vascular reactivity; Vascular injury; Lung injury; Pulmonary hypertension
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS.
Methods and Findings
We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMed™, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10–15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03).
This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents.
To characterize the use of mechanical ventilation in the emergency department (ED), with respect to ventilator settings, monitoring, and titration; and to determine the incidence of progression to acute lung injury (ALI) after admission, examining the influence of factors present in the ED on ALI progression.
This was a retrospective, observational cohort study of mechanically ventilated patients with severe sepsis and septic shock (June 2005 to May 2010), presenting to an academic ED with an annual census of >95,000 patients. All patients in the study (n = 251) were analyzed for characterization of mechanical ventilation use in the ED. The primary outcome variable of interest was the incidence of ALI progression after ICU admission from the ED and risk factors present in the ED associated with this outcome. Secondary analyses included ALI present in the ED and clinical outcomes comparing all patients progressing to ALI versus no ALI. To assess predictors of progression to ALI, statistically significant variables in univariable analyses at a p ≤ 0.10 level were candidates for inclusion in a bidirectional, stepwise, multivariable logistic regression analysis.
Lung-protective ventilation was used in 68 patients (27.1%), and did not differ based on ALI status. Delivered tidal volume was highly variable, with a median tidal volume delivered of 8.8 mL/kg ideal body weight (IBW) (IQR 7.8 to 10.0), and a range of 5.2 to 14.6 mL/kg IBW. Sixty-nine patients (27.5%) in the entire cohort progressed to ALI after admission to the hospital, with a mean onset of 2.1 days (SD ± 1 day). Multivariable logistic regression analysis demonstrated that a higher body mass index, higher Sequential Organ Failure Assessment score, and ED vasopressor use were associated with progression to ALI. There was no association between ED ventilator settings and progression to ALI. Compared to patients who did not progress to ALI, patients progressing to ALI after admission from the ED had an increase in mechanical ventilator duration, vasopressor dependence, and hospital length of stay.
Lung-protective ventilation is uncommon in the ED, regardless of ALI status. Given the frequency of ALI in the ED, the progression shortly after ICU admission, and the clinical consequences of this syndrome, the effect of ED-based interventions aimed at reducing the sequelae of ALI should be investigated further.
High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce the release of cytokines, including high-mobility group box-1 (HMGB1), oxygen radicals, neutrophil infiltration, and the disruption of epithelial and endothelial barriers. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between high tidal volume and hyperoxia are unclear. We hypothesized that subcutaneous injections of enoxaparin would decrease the effects of hyperoxia on high-tidal-volume ventilation-induced HMGB1 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway.
Male C57BL/6, either wild type or Akt+/-, aged between 6 and 8 weeks, weighing between 20 and 25 g, were exposed to high-tidal-volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 2 to 8 hours with or without 4 mg/kg enoxaparin administration. Nonventilated mice served as a control group. Evan blue dye, lung wet-to-dry weight ratio, free radicals, myeloperoxidase, Western blot of Akt, and gene expression of HMGB1 were measured. The expression of HMGB1 was studied by immunohistochemistry.
High-tidal-volume ventilation using hyperoxia induced microvascular permeability, Akt activation, HMGB1 mRNA expression, neutrophil infiltration, oxygen radicals, HMGB1 production, and positive staining of Akt in bronchial epithelium. Hyperoxia-induced augmentation of ventilator-induced lung injury was attenuated with Akt deficient mice and pharmacological inhibition of Akt activity by enoxaparin.
These data suggest that enoxaparin attenuates hyperoxia-augmented high-tidal-volume ventilation-induced neutrophil influx and HMGB1 production through inhibition of the Akt pathway. Understanding the protective mechanism of enoxaparin related with the reduction of HMGB1 may help further knowledge of the effects of mechanical forces in the lung and development of possible therapeutic strategies involved in acute lung injury.
A high respiratory rate associated with the use of small tidal volumes, recommended for acute lung injury (ALI), shortens time for gas diffusion in the alveoli. This may decrease CO2 elimination. We hypothesized that a post-inspiratory pause could enhance CO2 elimination and reduce PaCO2 by reducing dead space in ALI. In 15 mechanically ventilated patients with ALI and hypercapnia, a 20% post-inspiratory pause (Tp20) was applied during a period of 30 min between two ventilation periods without post-inspiratory pause (Tp0). Other parameters were kept unchanged. The single breath test for CO2 was recorded every 5 minutes to measure tidal CO2 elimination (VtCO2), airway dead space (VDaw) and slope of the alveolar plateau. PaO2, PaCO2, physiological and alveolar dead space (VDphys, VDalv) were determined at the end of each 30 minute period. The post-inspiratory pause, 0.7±0.2 s, induced on average less than 0.5 cm H2O of intrinsic PEEP. During Tp20, VtCO2 increased immediately by 28±10% (14±5 ml per breath compared to 11±4 for Tp0) and then decreased without reaching the initial value within 30 minutes. The addition of a post-inspiratory pause decreased significantly VDaw by 14% and VDphys by 11% with no change in VDalv. During Tp20, the slope of alveolar plateau initially fell to 65±10 % of baseline value and continued to decrease. Tp20 induced a 10±3% decrease in PaCO2 at 30 minutes (from 55±10 to 49±9 mmHg, p<0.001) with no significant variation in PaO2. Post-inspiratory pause has a significant influence on CO2 elimination when small tidal volumes are used during mechanical ventilation for ALI.
Adult; Aged; Aged, 80 and over; Blood Gas Analysis; Carbon Dioxide; blood; metabolism; Female; Humans; Lung Diseases; metabolism; physiopathology; Male; Middle Aged; Pneumonia; metabolism; physiopathology; Positive-Pressure Respiration; Respiration, Artificial; Respiratory Dead Space; physiology; Respiratory Distress Syndrome, Adult; metabolism; physiopathology; Respiratory Mechanics; physiology; Tidal Volume; physiology; Gas Exchange; Dead Space; Mechanical Ventilation; ARDS