Lincoln S. Smith

Pediatric Acute Respiratory Distress Syndrome: Consensus Recommendations From the Pediatric Acute Lung Injury Consensus Conference

OBJECTIVE To describe the final recommendations of the Pediatric Acute Lung Injury Consensus Conference. DESIGN Consensus conference of experts in pediatric acute lung injury. SETTING Not applicable. SUBJECTS PICU patients with evidence of acute lung injury or acute respiratory distress syndrome. INTERVENTIONS None. METHODS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published, data were lacking a modified Delphi approach emphasizing strong professional agreement was used. MEASUREMENTS AND MAIN RESULTS A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published data were lacking a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the following topics related to pediatric acute respiratory distress syndrome: 1) Definition, prevalence, and epidemiology; 2) Pathophysiology, comorbidities, and severity; 3) Ventilatory support; 4) Pulmonary-specific ancillary treatment; 5) Nonpulmonary treatment; 6) Monitoring; 7) Noninvasive support and ventilation; 8) Extracorporeal support; and 9) Morbidity and long-term outcomes. There were 132 recommendations with strong agreement and 19 recommendations with weak agreement. Once restated, the final iteration of the recommendations had none with equipoise or disagreement. CONCLUSIONS The Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.

Mechanisms of acute respiratory distress syndrome in children and adults: a review and suggestions for future research.

Objectives: To provide a current overview of the epidemiology and pathophysiology of acute respiratory distress syndrome in adults and children, and to identify research questions that will address the differences between adults and children with acute respiratory distress syndrome. Data Sources: Narrative literature review and author-generated data. Data Selection: The epidemiology of acute respiratory distress syndrome in adults and children, lung morphogenesis, and postnatal lung growth and development are reviewed. The pathophysiology of acute respiratory distress syndrome is divided into eight categories: alveolar fluid transport, surfactant, innate immunity, apoptosis, coagulation, direct alveolar epithelial injury by bacterial products, ventilator-associated lung injury, and repair. Data Extraction and Synthesis: Epidemiologic data suggest significant differences in the prevalence and mortality of acute respiratory distress syndrome between children and adults. Postnatal lung development continues through attainment of adult height, and there is overlap between the regulation of postnatal lung development and inflammatory, apoptotic, alveolar fluid clearance, and repair mechanisms. Therefore, there is a different biological baseline network of gene and protein expression in children as compared with adults. Conclusions: There are significant obstacles to performing research on children with acute respiratory distress syndrome. However, epidemiologic, clinical, and animal studies suggest age-dependent differences in the pathophysiology of acute respiratory distress syndrome. In order to reduce the prevalence and improve the outcome of patients with acute respiratory distress syndrome, translational studies of inflammatory, apoptotic, alveolar fluid clearance, and repair mechanisms are needed. Understanding the differences in pathophysiologic mechanisms in acute respiratory distress syndrome between children and adults should facilitate identification of novel therapeutic interventions to prevent or modulate lung injury and improve lung repair.

Pediatric acute respiratory distress syndrome: Definition, incidence, and epidemiology: Proceedings from the Pediatric Acute Lung Injury Consensus Conference

Objectives: Although there are similarities in the pathophysiology of acute respiratory distress syndrome in adults and children, pediatric-specific practice patterns, comorbidities, and differences in outcome necessitate a pediatric-specific definition. We sought to create such a definition. Design: A subgroup of pediatric acute respiratory distress syndrome investigators who drafted a pediatric-specific definition of acute respiratory distress syndrome based on consensus opinion and supported by detailed literature review tested elements of the definition with patient data from previously published investigations. Settings: International PICUs. Subjects: Children enrolled in published investigations of pediatric acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Several aspects of the proposed pediatric acute respiratory distress syndrome definition align with the Berlin Definition of acute respiratory distress syndrome in adults: timing of acute respiratory distress syndrome after a known risk factor, the potential for acute respiratory distress syndrome to coexist with left ventricular dysfunction, and the importance of identifying a group of patients at risk to develop acute respiratory distress syndrome. There are insufficient data to support any specific age for “adult” acute respiratory distress syndrome compared with “pediatric” acute respiratory distress syndrome. However, children with perinatal-related respiratory failure should be excluded from the definition of pediatric acute respiratory distress syndrome. Larger departures from the Berlin Definition surround 1) simplification of chest imaging criteria to eliminate bilateral infiltrates; 2) use of pulse oximetry–based criteria when PaO2 is unavailable; 3) inclusion of oxygenation index and oxygen saturation index instead of PaO2/FIO2 ratio with a minimum positive end-expiratory pressure level for invasively ventilated patients; 4) and specific inclusion of children with preexisting chronic lung disease or cyanotic congenital heart disease. Conclusions: This pediatric-specific definition for acute respiratory distress syndrome builds on the adult-based Berlin Definition, but has been modified to account for differences between adults and children with acute respiratory distress syndrome. We propose using this definition for future investigations and clinical care of children with pediatric acute respiratory distress syndrome and encourage external validation with the hope for continued iterative refinement of the definition.

EFFECT OF TOLL-LIKE RECEPTOR 4 BLOCKADE ON PULMONARY INFLAMMATION CAUSED BY MECHANICAL VENTILATION AND BACTERIAL ENDOTOXIN

Mechanical ventilation (MV) and lipopolysaccharide (LPS) synergistically increase inflammation and lung injury. The goal of this study was to determine whether blockade of CD14 or Toll-like receptor 4 (TLR4) would reduce inflammation caused by LPS and MV. Rabbits were pretreated with anti-TLR4 or anti-CD14 monoclonal antibodies, followed by endobronchial LPS and MV. Blockade of TLR4 reduced the number of neutrophils and the amount of CXCL8 in bronchoalveolar lavage fluid. In contrast, blockade of CD14 did not significantly decrease the number of neutrophils or the amount of CXCL8. These data show that TLR4 blockade reduces pulmonary inflammation caused by the combination of LPS and Mechanical ventilation.

Invasive Mechanical Ventilation and Mortality in Pediatric Hematopoietic Stem Cell Transplantation: A Multicenter Study.

Objective: To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. Design: Retrospective cohort between 2009 and 2014. Setting: Twelve children’s hospitals in the United States. Patients: Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. Interventions: None. Measurements and Main Results: PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2–3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3–4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7–6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. Conclusions: This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may offer an opportunity to improve outcomes.

Effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice.

Children have a lower incidence and mortality from acute lung injury (ALI) than adults, and infections are the most common event associated with ALI. To study the effects of age on susceptibility to ALI, we investigated the responses to microbial products combined with mechanical ventilation (MV) in juvenile (21-d-old) and adult (16-wk-old) mice. Juvenile and adult C57BL/6 mice were treated with inhaled Escherichia coli 0111:B4 lipopolysaccharide (LPS) and MV using tidal volume = 15 ml/kg. Comparison groups included mice treated with LPS or MV alone and untreated age-matched control mice. In adult animals treated for 3 hours, LPS plus MV caused synergistic increases in neutrophils (P < 0.01) and IgM in bronchoalveolar lavage fluid (P = 0.03) and IL-1β in whole lung homogenates (P < 0.01) as compared with either modality alone. Although juvenile and adult mice had similar responses to LPS or MV alone, the synergistic interactions between LPS and MV did not occur in juvenile mice. Computational analysis of gene expression array data suggest that the acquisition of synergy with increasing age results, in part, from the loss of antiapoptotic responses and the acquisition of proinflammatory responses to the combination of LPS and MV. These data suggest that the synergistic inflammatory and injury responses to inhaled LPS combined with MV are acquired with age as a result of coordinated changes in gene expression of inflammatory, apoptotic, and TGF-β pathways.

Stable Respiratory Activity Requires Both P/Q-Type and N-Type Voltage-Gated Calcium Channels

P/Q-type voltage-gated calcium channels (Cav2.1) play critical presynaptic and postsynaptic roles throughout the nervous system and have been implicated in a variety of neurological disorders. Here we report that mice with a genetic ablation of the Cav2.1 pore-forming α1A subunit (α1A−/−) encoded by CACNA1a (Jun et al., 1999) suffer during postnatal development from increasing breathing disturbances that lead ultimately to death. Breathing abnormalities include decreased minute ventilation and a specific loss of sighs, which was associated with lung atelectasis. Similar respiratory alterations were preserved in the isolated in vitro brainstem slice preparation containing the pre-Bötzinger complex. The loss of Cav2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Cav2.2). Blocking N-type calcium channels with conotoxin GVIA had only minor effects on respiratory activity in slices from control (CT) littermates, but abolished respiratory activity in all slices from α1A−/− mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from α1A−/− mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α1A−/− mice, while the EPSP amplitude was reduced by only 30% in CT mice. Moreover, neuromodulation was significantly altered as muscarine abolished respiratory network activity in α1A−/− mice but not in CT mice. We conclude that excitatory synaptic transmission dependent on N-type and P/Q-type calcium channels is required for stable breathing and sighing. In the absence of P/Q-type calcium channels, breathing, sighing, and neuromodulation are severely compromised, leading to early mortality.

The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs.

Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by β-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI.

Pediatric Acute Respiratory Distress Syndrome in Pediatric Allogeneic Hematopoietic Stem Cell Transplants: A Multicenter Study

Objective: Immunodeficiency is both a preexisting condition and a risk factor for mortality in pediatric acute respiratory distress syndrome. We describe a series of pediatric allogeneic hematopoietic stem cell transplant patients with pediatric acute respiratory distress syndrome based on the recent Pediatric Acute Lung Injury Consensus Conference guidelines with the objective to better define survival of this population. Design: Secondary analysis of a retrospective database. Setting: Twelve U.S. pediatric centers. Patients: Pediatric allogeneic hematopoietic stem cell transplant recipients requiring mechanical ventilation. Interventions: None. Measurements and Main Results: During the first week of mechanical ventilation, patients were categorized as: no pediatric acute respiratory distress syndrome or mild, moderate, or severe pediatric acute respiratory distress syndrome based on oxygenation index or oxygen saturation index. Univariable logistic regression evaluated the association between pediatric acute respiratory distress syndrome and PICU mortality. A total of 91.5% of the 211 patients met criteria for pediatric acute respiratory distress syndrome using the Pediatric Acute Lung Injury Consensus Conference definition: 61.1% were severe, 27.5% moderate, and 11.4% mild. Overall survival was 39.3%. Survival decreased with worsening pediatric acute respiratory distress syndrome: no pediatric acute respiratory distress syndrome 66.7%, mild 63.6%, odds ratio = 1.1 (95% CI, 0.3–4.2; p = 0.84), moderate 52.8%, odds ratio = 1.8 (95% CI, 0.6–5.5; p = 0.31), and severe 24.6%, odds ratio = 6.1 (95% CI, 2.1–17.8; p < 0.001). Nonsurvivors were more likely to have multiple consecutive days at moderate and severe pediatric acute respiratory distress syndrome (p < 0.001). Moderate and severe patients had longer PICU length of stay (p = 0.01) and longer mechanical ventilation course (p = 0.02) when compared with those with mild or no pediatric acute respiratory distress syndrome. Nonsurvivors had a higher median maximum oxygenation index than survivors at 28.6 (interquartile range, 15.5–49.9) versus 15.0 (interquartile range, 8.4–29.6) (p < 0.0001). Conclusion: In this multicenter cohort, the majority of pediatric allogeneic hematopoietic stem cell transplant patients with respiratory failure met oxygenation criteria for pediatric acute respiratory distress syndrome based on the Pediatric Acute Lung Injury Consensus Conference definition within the first week of invasive mechanical ventilation. Length of invasive mechanical ventilation, length of PICU stay, and mortality increased as the severity of pediatric acute respiratory distress syndrome worsened.

c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction

Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes.