Management of acute respiratory failure is an important component of intensive care. In this review, we analyze 21 original research articles published last year in Critical Care in the field of respiratory and critical care medicine. The articles are summarized according to the following topic categories: acute respiratory distress syndrome, mechanical ventilation, adjunctive therapies, and pneumonia.
Since acute respiratory distress syndrome (ARDS) was first described in 1967 there has been large number of studies addressing its pathogenesis and therapies. Despite this intense research activity, there are very few effective therapies for ARDS other than the use of lung protection strategies. This lack of therapeutic modalities is not only related to the complex pathogenesis of this syndrome but also the insensitive and nonspecific diagnostic criteria to diagnose ARDS. This review article will summarize the key features of the new definition of ARDS, and provide a brief overview of innovative therapeutic options that are being assessed in the management of ARDS.
Acute respiratory distress syndrome (ARDS); pathogenesis; therapeutic options
Despite over 40 years of research, there is no specific lung-directed therapy for the acute respiratory distress syndrome (ARDS). Although much has evolved in our understanding of its pathogenesis and factors affecting patient outcome, supportive care with mechanical ventilation remains the cornerstone of treatment. Perhaps the most important advance in ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI). This improved understanding of ARDS and VILI has been important in designing lung-protective ventilatory strategies aimed at attenuating VILI and improving outcomes. Considerable effort has been made to enhance our mechanistic understanding of VILI and to develop new ventilatory strategies and therapeutic interventions to prevent and ameliorate VILI with the goal of improving outcomes in patients with ARDS. In this review, we will review the pathophysiology of VILI, discuss a number of novel physiological approaches for minimizing VILI, therapies to counteract biotrauma, and highlight a number of experimental studies to support these concepts.
Acute lung injury; Acute respiratory distress syndrome; Critical illness; Cytokines; Extracorporeal membrane oxygenation; Heat shock response; Mechanical ventilation; Ventilatory support
Acute respiratory distress syndrome is characterized by damage to the lung caused by various insults, including ventilation itself, and tidal hyperinflation can lead to ventilator induced lung injury (VILI). We investigated the effects of a low tidal volume (VT) strategy (VT ≈ 3 ml/kg/predicted body weight [PBW]) using pumpless extracorporeal lung assist in established ARDS.
Seventy-nine patients were enrolled after a ‘stabilization period’ (24 h with optimized therapy and high PEEP). They were randomly assigned to receive a low VT ventilation (≈3 ml/kg) combined with extracorporeal CO2 elimination, or to a ARDSNet strategy (≈6 ml/kg) without the extracorporeal device. The primary outcome was the 28-days and 60-days ventilator-free days (VFD). Secondary outcome parameters were respiratory mechanics, gas exchange, analgesic/sedation use, complications and hospital mortality.
Ventilation with very low VT’s was easy to implement with extracorporeal CO2-removal. VFD’s within 60 days were not different between the study group (33.2 ± 20) and the control group (29.2 ± 21, p = 0.469), but in more hypoxemic patients (PaO2/FIO2 ≤150) a post hoc analysis demonstrated significant improved VFD-60 in study patients (40.9 ± 12.8) compared to control (28.2 ± 16.4, p = 0.033). The mortality rate was low (16.5 %) and did not differ between groups.
The use of very low VT combined with extracorporeal CO2 removal has the potential to further reduce VILI compared with a ‘normal’ lung protective management. Whether this strategy will improve survival in ARDS patients remains to be determined (Clinical trials NCT 00538928).
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2787-6) contains supplementary material, which is available to authorized users.
Lung protective ventilation; Pumpless extracorporeal lung support; Carbon dioxide removal; Acute respiratory distress syndrome; Ultraprotective ventilation
In this review, 21 original papers published last year in the respirology and critical care sections of Critical Care are classified and analyzed in the following categories: mechanical ventilation, lung recruitment maneuvers, and weaning; the role of positive end-expiratory pressure in acute lung injury models; animal models of ventilator-induced lung injury; diaphragmatic dysfunction; the role of mechanical ventilation in heart-lung interaction; and miscellanea.
The aim was to characterize the neural breathing pattern in non-intubated preterm infants. The diaphragm electrical activity (EAdi) and heart rate were simultaneously measured repeatedly for 1 hour over several days using a modified feeding tube equipped with miniaturized sensors. The EAdi waveform was quantified for phasic and tonic activity, neural timings, and prevalence of recurring patterns, including central apnea. Ten infants with mean age 7 days (range 3–13) were studied. Their birth weight was 1512 g (1158–1800g), and gestational age (GA) at birth 31 weeks (28–36). Neural inspiratory and expiratory times were 278 ms (195–450 ms) and 867 ms (668–1436 ms), and correlated with GA (p<0.001). Tonic EAdi represented 29.5% of phasic EAdi (16–40%), and was related to GA (r=0.61, p<0.001). For the group, 68% of the time was regular phasic breathing (without tonic activity), and 29% of the time with elevated tonic activity. Central apneas >5s occurred on average 10 times per hour (2–29). Heart rate reductions were correlated to central apnea duration. In conclusion, esophageal recordings of the EAdi waveform demonstrate that neural breathing pattern is variable, with regards to timing, amplitude and pattern with a distinct amount of tonic diaphragm activity.
Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS.
After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings.
Using a novel screening methodology, we identified a compound – CKT0103 – with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and sepsis-induced ALI/ARDS.
To perform a meta-analysis of gene expression microarray data from animal studies of lung injury, and to identify an injury-specific gene expression signature capable of predicting the development of lung injury in humans.
We performed a microarray meta-analysis using 77 microarray chips across six platforms, two species and different animal lung injury models exposed to lung injury with or/and without mechanical ventilation. Individual gene chips were classified and grouped based on the strategy used to induce lung injury. Effect size (change in gene expression) was calculated between non-injurious and injurious conditions comparing two main strategies to pool chips: (1) one-hit and (2) two-hit lung injury models. A random effects model was used to integrate individual effect sizes calculated from each experiment. Classification models were built using the gene expression signatures generated by the meta-analysis to predict the development of lung injury in human lung transplant recipients.
Two injury-specific lists of differentially expressed genes generated from our meta-analysis of lung injury models were validated using external data sets and prospective data from animal models of ventilator-induced lung injury (VILI). Pathway analysis of gene sets revealed that both new and previously implicated VILI-related pathways are enriched with differentially regulated genes. Classification model based on gene expression signatures identified in animal models of lung injury predicted development of primary graft failure (PGF) in lung transplant recipients with larger than 80% accuracy based upon injury profiles from transplant donors. We also found that better classifier performance can be achieved by using meta-analysis to identify differentially-expressed genes than using single study-based differential analysis.
Taken together, our data suggests that microarray analysis of gene expression data allows for the detection of “injury" gene predictors that can classify lung injury samples and identify patients at risk for clinically relevant lung injury complications.
Based on the hypothesis that failure of weaning from mechanical ventilation is caused by respiratory demand exceeding the capacity of the respiratory muscles, we evaluated whether extubation failure could be characterized by increased respiratory drive and impaired efficiency to generate inspiratory pressure and ventilation.
Airway pressure, flow, volume, breathing frequency, and diaphragm electrical activity were measured in a heterogeneous group of patients deemed ready for a spontaneous breathing trial. Efficiency to convert neuromuscular activity into inspiratory pressure was calculated as the ratio of negative airway pressure and diaphragm electrical activity during an inspiratory occlusion. Efficiency to convert neuromuscular activity into volume was calculated as the ratio of the tidal volume to diaphragm electrical activity. All variables were obtained during a 30-minute spontaneous breathing trial on continuous positive airway pressure (CPAP) of 5 cm H2O and compared between patients for whom extubation succeeded with those for whom either the spontaneous breathing trial failed or for those who passed, but then the extubation failed.
Of 52 patients enrolled in the study, 35 (67.3%) were successfully extubated, and 17 (32.7%) were not. Patients for whom it failed had higher diaphragm electrical activity (48%; P < 0.001) and a lower efficiency to convert neuromuscular activity into inspiratory pressure and tidal volume (40% (P < 0.001) and 53% (P < 0.001)), respectively. Neuroventilatory efficiency demonstrated the greatest predictability for weaning success.
This study shows that a mixed group of critically ill patients for whom weaning fails have increased neural respiratory drive and impaired ability to convert neuromuscular activity into tidal ventilation, in part because of diaphragm weakness.
Clinicaltrials.gov identifier NCT01065428. ©2012 Liu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.
Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.
Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.
During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.
Ventilator-induced lung injury; acute lung injury; sepsis; cytokines; lung histology; mechanical ventilation.
Mechanical ventilation (MV) with high tidal volumes (VT) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI.
Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (n = 6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (VT) (6 mL/kg) or high VT (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-VT MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-VT MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels.
Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI.
Rationale: Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority.
Objectives: To identify specific molecular regulators involved in the development of VILI.
Methods: We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene–deficient mice to wild-type mice in an in vivo model of VILI.
Measurements and Main Results: ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cis-regulatory regions was significantly altered in ATF3-deficient mice.
Conclusions: ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume–induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.
mechanotransduction; transcriptional profiling; acute respiratory distress syndrome; bioinformatics; transgenic mice
Neurally adjusted ventilatory assist (NAVA) is a pneumatically-independent mode of mechanical ventilation controlled by diaphragm electrical activity (EAdi), and has not yet been implemented in very small species.
The aims of the study were to evaluate the feasibility of applying NAVA in very small species and to compare this to pressure support ventilation (PSV) in terms of ventilatory efficiency and breathing pattern, and evaluate the impact of instrumental dead space on breathing pattern during both modes.
Nine healthy rats (mean weight 385 ± 4 g) were studied while breathing on PSV or NAVA, at baseline or with added dead space.
A clear difference in breathing pattern between NAVA and PSV was observed during both baseline and dead space, where PSV – despite similar EAdi and tidal volume as during NAVA – caused shortened inspiratory time (p < 0.05) and increased the respiratory rate (p < 0.05). A higher minute ventilation (p < 0.05) in order to reach the same arterial CO2 was observed. Ineffective inspiratory efforts occurred only during PSV and decreased with the dead space.
This study demonstrates, in a small group of animals, that NAVA can deliver assist in very small species with a higher efficiency than PSV in terms of eliminating CO2 for a given minute ventilation.
Neurally adjusted ventilatory assist; Pressure support ventilation; Diaphragm electrical activity; Instrumental dead space
In this month's issue of Critical Care, Determann and colleagues report the results of a randomized controlled trial comparing the effects of mechanical ventilation (MV) with two tidal volumes (6 versus 10 ml/kg predicted body weight) on cytokine levels in lung lavage fluid and plasma as a surrogate for early identification of acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The study was stopped early after an interim analysis - when 150 patients were enrolled - showing that the incidence of ALI/ARDS according to the current definition was 10.9% higher in the 10 ml/kg group, although duration of MV and mortality was similar in both groups. We examine these interesting results after providing a brief historical perspective and discuss the limitations and implications of the study.
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.
Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI).
To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI.
Design, Setting, and Participants
Multicenter, double-blind, randomized, placebo-controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients.
A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting.
Main Outcome Measure
Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or ≤4).
The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE ≤4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, −4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, −4.0% to 9.7%]; P=.67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P=.88).
Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival.
clinicaltrials.gov Identifier: NCT00316004
The Canadian Institutes of Health Research and the Multiple Sclerosis (MS) Society of Canada recently convened an Invitational Panel to consider the scientific evidence linking chronic cerebrospinal venous insufficiency (CCSVI) and MS. The panel supported studies to determine whether CCSVI causes MS, but felt that there is currently so much uncertainty about the relationship between CCSVI and MS that a clinical trial is not indicated at this time. This commentary argues that the decision about whether a clinical trial is warranted must be informed by science, but should be addressed from a broader societal perspective. We suggest that members of the public should be more actively involved in scientifically based, but patient-relevant and emotionally charged issues considered by organizations that fund health research.
Original research contributions published in Critical Care in 2008 in the fields of respirology and critical care medicine are summarized. Eighteen articles were grouped into the following categories: acute lung injury and acute respiratory distress syndrome, mechanical ventilation, mechanisms of ventilator-induced lung injury, and tracheotomy decannulation and non-invasive ventilation.
Rationale: A well-known clinical paradox is that severe bacterial infections persist in the lungs of patients with cystic fibrosis (CF) despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of a high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown.
Objectives: This study examined several possible mechanisms to understand this paradox.
Methods: PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from patients with CF were used to stimulate healthy PMN followed by phagocytic tests.
Measurements and Main Results: PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fcγ RIII, actin-filament remodeling, enhanced intracellular Ca2+, and degranulation. Treatment of PMN with an intracellular Ca2+ blocker or α1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in α1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared with wild-type mice.
Conclusions: HNP or PMN alone exert antimicrobial ability, which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.
inflammation; innate immunity; lung injury
Concerns have been raised about the enrollment of racial and ethnic minorities in research in the emergency setting when it is not possible to obtain informed consent. However, there is a paucity of data related to the validity of such claims.
Retrospective comparison of registry enrollment (4/1/06–3/31/07) and trial enrollment (4/1/07–3/31/08) from 3 sites in the Resuscitation Outcomes Consortium. Subjects compared met the following criteria: 1) Shock, defined by blunt or penetrating force to the body with either systolic blood pressure (SBP) ≤ 70 mmHg or SBP 71–90 mmHg and heart rate ≥ 108 beats/min; and/or 2) Traumatic Brain Injury (TBI), defined by blunt force to the head with out-of- hospital Glasgow Coma Score ≤ 8.
Overall, compared to a registry there were no differences in the percent of racial or ethnic groups enrolled in the clinical trial [Odds Ratio (OR) for Blacks versus Whites: 0.87, 95% Confidence Interval (CI) 0.65–1.16, p=.34; OR for Hispanics versus Whites 1.04; CI 0.72–1.49, p=.85]. However, Blacks were less likely than Whites to be enrolled in the TBI cohort [OR 0.58 (0.34–0.97); p=.04].
Despite some discordance in subgroups, there was no overall difference in the racial and ethnic distribution of subjects enrolled in a multi-center clinical trial of severe trauma compared to a registry accounting for study entry criteria. These findings help address justice concerns about enrollment of racial and ethnic minorities in trauma research performed using an exception from informed consent under emergency circumstances.
Neurally Adjusted Ventilatory Assist (NAVA), a mode of mechanical ventilation controlled by diaphragmatic electrical activity (EAdi), may improve patient-ventilator interaction. We examined patient-ventilator interaction by comparing EAdi to ventilator pressure during conventional ventilation and NAVA delivered invasively and non-invasively. Seven intubated infants (birth weight 936g (range 676–1266g); gestational age 26 weeks (range 25–29)) were studied before and after extubation, initially during CV, and then NAVA. NAVA-intubated and NAVA-extubated demonstrated similar delays between onset of EAdi and onset of ventilator pressure of 74± 17 and 72±23 ms (p=0.698), respectively. During CV, the mean trigger delays were not different from NAVA, however 13±8.5% of ventilator breaths were triggered on average 59±27 ms prior to onset of EAdi. There was no difference in off-cycling delays between NAVA-intubated and extubated (32±34 vs. 28±11 ms). CV cycled-off prior to NAVA (120±66 ms prior, p<0.001). During NAVA, EAdi and ventilator pressure were correlated (mean determination coefficient (NAVA-intubated 0.8±0.06 and NAVA-extubated 0.73±0.22)). Pressure delivery during conventional ventilation was not correlated to EAdi. Neural expiratory time was longer (p=0.044), and respiratory rate was lower (p=0.004) during NAVA. We conclude that in low birth weight infants, NAVA can improve patient-ventilator interaction, even in the presence of large leaks.
Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury.
Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (VT) (20 ml/kg) and low VT (6 ml/kg). Histological evaluation, TLR2, TLR4, IRAK3 gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IκBα), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL6) gene expression in the lungs and TNF-α and IL-6 protein serum concentrations were analyzed.
High VT mechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of IRAK3 lung gene expression and protein levels, a significant decrease of IκBα, and a higher lung expression and serum concentrations of pro-inflammatory cytokines.
The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.
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.
All original research contributions published in Critical Care in 2007 in the field of respirology and critical care medicine are summarized in this article. Fifteen papers were grouped in the following categories: acute lung injury and acute respiratory distress syndrome, mechanical ventilation, ventilator-induced lung injury, imaging, and other topics.