Monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor (CCR2) are elevated in chronic heart failure facilitating lung monocyte infiltration and differentiation which may contribute to lung fibrosis.

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.

Bolus intravenous 0.9% saline leads to interstitial permeability pulmonary edema in healthy volunteers.

PURPOSE: Bolus intravenous administration of 0.9% saline has been associated with the development of pulmonary edema, and increased mortality. An animal model has previously demonstrated that rapid intravenous administration of 0.9% saline was associated with non-hydrostatic lung injury with increased lung lavage protein. We hypothesized that this non-hydrostatic effect would also occur in human volunteers. METHODS: In a randomized, cross-over study of 14 healthy male subjects, the lung lavage protein concentration and cardiorespiratory effects of an intervention with rapid intravenous administration of 30 mL/kg of 0.9% saline were compared with sham intervention. Bronchoalveolar lavage (BAL) was performed after fluid administration. Doppler echocardiography, lung ultrasound, pulmonary function tests, and blood sampling were performed before and after each intervention. RESULTS: The BAL total protein concentration was greater after 0.9% saline administration than with sham (196.1 µg/mL (SD 87.6) versus 129.8 µg/mL (SD 55.4), respectively (p = 0.020). Plasma angiopoietin-2 concentration was also increased to 2.26 ng/mL (SD 0.87) after 0.9% saline administration compared with sham 1.53 ng/mL (SD 0.69) (p < 0.001). There were small increases in stroke volume (from 58 mL (IQR 51-74) to 66 mL (IQR 58-74), p = 0.045) and Doppler echocardiography left ventricle E/e' ratio (from 5.0 (IQR 4.5-6.0) to 5.7 (IQR 5.3-6.3), p = 0.007), but no changes to right ventricular function. CONCLUSION: Rapid intravenous administration of 0.9% saline leads to interstitial permeability pulmonary edema in healthy human volunteers. Further research is now warranted to understand these effects in critically ill patients.

A retrospective audit of cumulative ionising radiation levels in hospitalised pregnant patients.

BACKGROUND: Among hospitalised patients, diagnostic radiation is possibly used least on pregnant patients due to the fear of ionising radiation on the fetus; however, what levels are currently being prescribed. AIMS: To assess the cumulative levels of ionising radiation received by pregnant patients during a single admission to a tertiary hospital. MATERIALS AND METHODS: A retrospective audit of pregnant patients admitted to Flinders Medical Centre, South Australia, Australia, between 2013 and 2017 inclusive was performed. All procedures utilising ionising radiation were collected including conventional radiology, computed tomography, fluoroscopy and nuclear medicine. Individual and cumulative effective doses for mother and fetus were calculated using patient dose reports and published conversion factors. RESULTS: From 547 patients, the median cumulative effective dose was 0.02 mSv and only five patients received more than 10 mSv, with 19.07 mSv the highest dose received. The median fetal cumulative effective dose was 0.01 mSv but only three fetuses received more than 10 mSv, likely due to fetal exclusion in some procedural fields of view. Stays longer than ten days were associated with significantly higher cumulative effective dose, as did those with maternal cardiovascular related admission, for both maternal and fetal exposures. CONCLUSION: These results suggest that pregnant patients are exposed to low doses of ionising radiation, in both individual procedures and cumulative doses. The detrimental risks associated with these levels of ionising radiation are not overt and so clinicians should question which risk is higher, the ionising radiation from the radiological procedures received or the lack of diagnostic information if avoided?

Systemic Markers of Monocyte Activation in Acute Pulmonary Oedema.

BACKGROUND: Hydrostatic lung injury followed by pulmonary remodelling variably complicates cardiogenic acute pulmonary oedema (APO). Pulmonary remodelling may be regulated by the balance between distinct phenotypes of pulmonary macrophages; activated/inflammatory (M1), and reparative/anti-inflammatory (M2), derived from circulating monocyte populations. The aim of this study was to identify biomarkers in peripheral blood that are consistent with hydrostatic lung injury and pulmonary remodelling in APO and which follow the variable clinical course. METHODS: To examine peripheral markers of lung inflammation, resolution and remodelling, 18 patients, admitted to the intensive care unit (ICU) with a clinical diagnosis of APO, were enrolled. Admission, 12- and 24-hour post-admission bloods were assayed for cytokines by ELISA (R&D Systems, Minneapolis, MN, USA) and leukocyte surface markers by flow cytometry. RESULTS: Admission PaO2 to FiO2 ratio was positively correlated with Mon 2 (intermediate) monocyte prevalence, through increasing ratio of CD16+ monocytes to CD11b+ and CD40+ monocytes, and negatively correlated with Mon 1 (classical) monocyte prevalence, through decreasing ratio of CD16+ monocytes to CD62L+. Secondary cohort analysis compared 10 APO patients with established chronic heart failure (CHF) to eight without CHF. An increase in monocyte chemotactic peptide (MCP)-1, monocyte prevalence, and CD16-CD62L+ monocytes with CHF, all characteristic of monocyte activation to a Mon 1 phenotype, were found in the CHF APO patients. CONCLUSIONS: Increased systemic monocyte prevalence and expression of cell surface markers suggest a Mon 1 profile in CHF patients during episodes of APO. Future studies should define the role of systemic monocyte prevalence and activation in decompensated CHF.

Reduced Surfactant Contributes to Increased Lung Stiffness Induced by Rapid Inspiratory Flow.

INTRODUCTION: The mechanism of fast inspiratory flow rate (VI') induced lung injury is unclear. As fast VI' increases hysteresis, a measure of surface tension at the air-liquid interface, surfactant release or function may be important. This experimental study examines the contribution of impaired surfactant release or function to dynamic-VILI. METHODS: Isolated perfused lungs from male Sprague Dawley rats were randomly allocated to four groups: a long or short inspiratory time (Ti = 0.5 s; slow VI' or Ti = 0.1 s; fast VI') at PEEP of 2 or 10 cmH2O. Tidal volume was constant (7 ml/kg), with f = 60 breath/min. Forced impedance mechanics (tissue elastance (Htis), tissue resistance (Gtis) and airway resistance (Raw) were measured at 30, 60 and 90 min following which the lung was lavaged for surfactant phospholipids (PL) and disaturated PL (DSP). RESULTS: Fast VI' resulted in a stiffer lung. Concurrently, PL and DSP were decreased in both tubular myelin rich and poor fractions. Phospholipid decreases were similar with PEEP. In a subsequent cohort, laser confocal microscopy-based assessment demonstrated increased cellular injury with increased VI' at both 30 and 90 min ventilation. CONCLUSION: Rapid VI' may contribute to ventilator induced lung injury (VILI) through reduced surfactant release and/or more rapid reuptake despite unchanged tidal stretch.

Immune biomarkers predicting bronchiolitis disease severity: A systematic review.

Bronchiolitis is one of the leading causes of hospitalisation in infancy, with highly variable clinical presentations ranging from mild disease safely managed at home to severe disease requiring invasive respiratory support. Identifying immune biomarkers that can predict and stratify this variable disease severity has important implications for clinical prognostication/disposition. A systematic literature search of the databases Embase, PubMed, ScienceDirect, Web of Science, and Wiley Online Library was performed. English language studies that assessed the association between an immune biomarker and bronchiolitis disease severity among children aged less than 24 months were included. 252 distinct biomarkers were identified across 90 studies. A substantial degree of heterogeneity was observed in the bronchiolitis definitions, measures of disease severity, and study designs. 99 biomarkers showed some significant association with disease severity, but only 18 were significant in multiple studies. However, all of these candidate biomarkers had comparable studies that reported conflicting results. Conclusion: The heterogeneity among included studies and the lack of a consistently significant biomarker highlight the need for consensus on bronchiolitis definitions and severity measures, as well as further studies assessing their clinical utility both in isolation and in combination.

Prevention and Amelioration of Rodent Ventilation-Induced Lung Injury with Either Prophylactic or Therapeutic feG Administration.

PURPOSE: Mechanical ventilation is a well-established therapy for patients with acute respiratory failure. However, up to 35% of mortality in acute respiratory distress syndrome may be attributed to ventilation-induced lung injury (VILI). We previously demonstrated the efficacy of the synthetic tripeptide feG for preventing and ameliorating acute pancreatitis-associated lung injury. However, as the mechanisms of induction of injury during mechanical ventilation may differ, we aimed to investigate the effect of feG in a rodent model of VILI, with or without secondary challenge, as a preventative treatment when administered before injury (prophylactic), or as a therapeutic treatment administered following initiation of injury (therapeutic). METHODS: Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a rodent model of ventilation-induced lung injury, with or without secondary intratracheal lipopolysaccharide challenge. RESULTS: Prophylactic feG administration resulted in significant improvements in arterial blood oxygenation and respiratory mechanics, and decreased lung oedema, bronchoalveolar lavage protein concentration, histological tissue injury scores, blood vessel activation, bronchoalveolar lavage cell infiltration and lung myeloperoxidase activity in VILI, both with and without lipopolysaccharide. Therapeutic feG administration similarly ameliorated the severity of tissue damage and encouraged the resolution of injury. feG associated decreases in endothelial adhesion molecules may indicate a mechanism for these effects. CONCLUSIONS: This study supports the potential for feG as a pharmacological agent in the prevention or treatment of lung injury associated with mechanical ventilation.

Fluid-induced lung injury-role of TRPV4 channels.

Administration of bolus intravenous fluid is associated with respiratory dysfunction and increased mortality, findings with no clear mechanistic explanation. The objective of this study was to examine whether bolus intravenous (i.v.) fluid administration results in acute lung injury in a rat model and further, to examine whether this injury is associated with transient receptor potential vallinoid (TRPV)4 channel function and endothelial inflammatory response. Healthy male Sprague-Dawley rats were administered 60 ml/kg 0.9% saline i.v. over 30 min. Manifestation of acute lung injury was assessed by lung physiology, morphology, and markers of inflammation. The role of TRPV4 channels in fluid-induced lung injury was subsequently examined by the administration of ruthenium red (RR) in this established rat model and again in TRPV4 KO mice. In endothelial cell culture, permeability and P-selectin expression were measured following TRPV4 agonist with and without antagonist; 0.9% saline resulted in an increase in lung water, lavage protein and phospholipase A2, and plasma angiopoietin-2, with worsening in arterial blood oxygen (PaO2), lung elastance, surfactant activity, and lung histological injury score. These effects were ameliorated following i.v. fluid in rats receiving RR. TRPV4 KO mice did not develop lung edema. Expression of P-selectin increased in endothelial cells following administration of a TRPV4 agonist, which was ameliorated by simultaneous addition of RR. Bolus i.v. 0.9% saline resulted in permeability pulmonary edema. Data from ruthenium red, TRPV4 KO mice, and endothelial cell culture suggest activation of TRPV4 and release of angiopoietin 2 and P-selectin as the central mechanism.

Pulmonary effects of chronic elevation in microvascular pressure differ between hypertension and myocardial infarct induced heart failure.

BACKGROUND: Chronic heart failure (CHF) following coronary artery ligation and myocardial infarction in the rat leads to a homeostatic reduction in surface tension with associated alveolar type II cell hyperplasia and increased surfactant content, which functionally compensates for pulmonary collagen deposition and increased tissue stiffness. To differentiate the effects on lung remodelling of the sudden rise in pulmonary microvascular pressure (Pmv) with myocardial infarction from its consequent chronic elevation, we examined a hypertensive model of CHF. METHODS: Cardiopulmonary outcomes due to chronic pulmonary capillary hypertension were assessed at six and 15 weeks following abdominal aortic banding (AAB) in the rat. RESULTS: At six weeks post-surgery, despite significantly elevated left ventricular end-diastolic pressure, myocardial hypertrophy and increased left ventricular internal circumference in AAB rats compared with sham operated controls (p≤0.003), lung weights and tissue composition remained unchanged, and lung compliance was normal. At 15 weeks post-surgery increased lung oedema was evident in AAB rats (p=0.002) without decreased lung compliance or evidence of tissue remodelling. CONCLUSION: Despite chronically elevated Pmv, comparable to that resulting from past myocardial infarction (LVEDP>19mmHg), there is no evidence of pulmonary remodelling in the AAB model of CHF.

Prevention and amelioration of rodent endotoxin-induced lung injury with administration of a novel therapeutic tripeptide feG.

BACKGROUND: The synthetic tripeptide feG is a novel pharmacological agent that decreases neutrophil recruitment, infiltration, and activation in various animal models of inflammatory disease. In human and rat cell culture models, feG requires pre-stimulation in order to decrease in vitro neutrophil chemotaxis. We aimed to investigate the effect of feG on neutrophil chemotaxis in a lipopolysaccharide-induced acute lung injury model without pre-stimulation. METHODS: The efficacy of feG as both a preventative treatment, when administered before lung injury (prophylactic), or as a therapeutic treatment, administered following lung injury (therapeutic), was investigated. RESULTS: Prophylactic or therapeutic feG administration significantly reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function. feG was demonstrated to significantly decrease bronchoalveolar lavage cell infiltration, lung myeloperoxidase activity, lung oedema, histological tissue injury scores, and improve arterial blood oxygenation and respiratory mechanics. CONCLUSIONS: feG reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function when administered prophylactically or therapeutically in a rodent model of lipopolysaccharide-induced acute lung injury, without the need for pre-stimulation, suggesting a direct rather than indirect mechanism of action in the lung.

Evaluation of GSK2789917-induced TRPV4 inhibition in animal models of fluid induced lung injury.

Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and oedema through rapid administration of intravenous fluid in rats was reduced by a non-specific antagonist of transient receptor potential vanilloid 4 (TRPV4) channels. The aims of this study were to determine the effect of selective TRPV4 inhibition on fluid-induced lung injury (FILI) and compare the potency of FILI inhibition to that of an established model of TRPV4 agonist-induced lung oedema. In a series of experiments, rats received specific TRPV4 inhibitor (GSK2789917) at high (15 µg/kg), medium (5 µg/kg) or low (2 µg/kg) dose or vehicle prior to induction of lung injury by intravenous infusion of TRPV4 agonist (GSK1016790) or saline. GSK1016790 significantly increased lung wet weight/body weight ratio by 96% and lung wet-to-dry weight ratio by 43% in vehicle pre-treated rats, which was inhibited by GSK2789917 in a dose-dependent manner (IC50 = 3 ng/mL). Similarly, in a single-dose study, bolus saline infusion significantly increased lung wet weight/body weight by 17% and lung wet-to-dry weight ratio by 15%, which was attenuated by high dose GSK2789917. However, in a final GSK2789917 dose-response study, inhibition did not reach significance and an inhibitory potency was not determined due to the lack of a clear dose-response. In the FILI model, TRPV4 may have a role in lung injury induced by rapid-fluid infusion, indicated by inconsistent amelioration with high dose TRPV4 antagonist.

Lung injury in acute pancreatitis: mechanisms underlying augmented secondary injury.

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are common complications of acute pancreatitis (AP). ALI/ARDS contribute to the majority of AP-associated deaths, particularly in the setting of secondary infection. Following secondary pulmonary infection there can be an exacerbation of AP-associated lung injury, greater than the sum of the individual injuries alone. The precise mechanisms underlying this synergism, however, are not known. In this review we discuss the main factors contributing to the development of augmented lung injury following secondary infection during AP and review the established models of AP in regard to the development of associated ALI.

Evaluation of lung injury and respiratory mechanics in a rat model of acute pancreatitis complicated with endotoxin.

BACKGROUND: Acute lung injury (ALI) is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths, particularly in the setting of secondary infection. This 'two-hit' model mimics clinical cases where the presentation of AP is associated with mild lung injury that, following a secondary direct lung infection, can result in respiratory dysfunction and death. We therefore aimed to characterize lung injury in a clinically-relevant 'two-hit' rat model of caerulein-induced AP combined with intratracheal endotoxin. METHODS: Rats received 7 hourly intraperitoneal injections of caerulein (50 µg/kg). Twenty four hours following the first caerulein injection, rats were anaesthetised and LPS (15 mg/kg) was instilled intratracheally. Following LPS instillation, rats were ventilated for a total of 2 h. RESULTS: In the present study, AP results in mild pulmonary injury indicated by increased lung myeloperoxidase (MPO) activity and edema, but with no alteration of respiratory function, while intratracheal instillation of LPS results in more substantial pulmonary injury. The induction of AP challenged with secondary intratracheal LPS results in an exacerbation of lung damage indicated by further increased lung edema, plasma and bronchoalveolar (BAL) CINC-1 concentration, lung damage histology score, and lung tissue resistance and elastance, compared with LPS alone. CONCLUSIONS: In conclusion, the addition of instilled LPS acted as a "second-hit" and exacerbated caerulein-induced AP, compared with the induction of AP alone or the instillation of LPS alone. Given its clinical relevance, this model could prove useful for examination of therapeutic interventions for ALI following secondary infection.

Systemic inflammation and cell activation reflects morbidity in chronic heart failure.

Chronic heart failure (CHF) leads to complex effects distant from the heart. As these changes may be reflected in the balance of systemic inflammatory and fibrotic immunomodulators we measured these potential biomarkers in ambulatory CHF patients. Using the New York Heart Association (NYHA; levels II-IV) functional classification, 30 CHF patients were compared with 21 age and gender matched controls. Peripheral blood levels of regulatory cytokines (TNF-α, TGF-ß, KGF, IL-8, IL-10 and IL-12) and markers of cellular activation (CD11b, CD16, CD18, CD34, HLADR, CXCR1 and CCR5) were analysed by ELISA and flow cytometry, respectively. NYHA classification, which reflected increasing pulmonary microvascular pressure (E:E') but not ejection fraction, was positively associated with TGF-ß and IL-10 (p≤0.03). Similarly, monocytes, as well as cell surface expression of the neutrophil adhesion molecule CD11b, and the macrophage complement receptor complex (CD11b/CD18), were increased in CHF patients (p≤0.03), while the chemokine receptor CXCR1 was decreased on cells of CHF patients. Twenty month follow-up of CHF subjects identified monocyte number as a powerful prognostic factor for cardio-pulmonary adverse events (p=0.001); however, no concurrent relationship with cellular activation marker expression was found. In subjects with CHF, monocytes, TGF-ß, IL-10, CD11b/CD18 and CXCR1 expression in peripheral blood may act as novel biomarkers of immune activation and remodelling. Given the importance of dyspnea and the relationship of pulmonary microvascular pressure to the NYHA classification, we suggest these findings may reflect a contribution by the lung.

Nasopharyngeal prostaglandin E(2) in infant bronchiolitis.

The mechanism by which severe bronchiolitis can result in the development of recurrent childhood wheeze is unclear. However, mucosal inflammation and immune activation may play a major role. Prostaglandin (PG) E(2) has been highlighted as a possible therapeutic target for both the treatment of bronchiolitis and the prevention of subsequent airway hyperresponsiveness. The aim of this pilot study was to examine PGE(2) in the airways of infants hospitalised with bronchiolitis. Nasopharyngeal aspirates (NPA) were collected from 18 infants within 12 hours of admission and assayed by enzyme immunoassays for PGE(2), interleukin (IL)-10, and IL-12, as well as cyclooxygenase (COX) 1 and 2 activity. NPA PGE(2) concentration correlated with length of illness preadmission, but was not related to disease severity, causal virus, or IL-10. NPA COX 1 and 2 activity and IL-12 were all below the level of detection. Neither NPA PGE(2) nor disease severity was related to development of recurrent wheeze over 3 years following bronchiolitis. These data suggest that nasopharygeal PGE(2) at hospital admission may be neither directly causal or diagnostic of severity of infant bronchiolitis, or prognostic of development of recurrent wheeze. However, large-cohort temporal examinations are required to adequately define this mediator as a therapeutic target for bronchiolitis.

Caerulein-induced acute pancreatitis results in mild lung inflammation and altered respiratory mechanics.

Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize lung injury in caerulein-induced AP. Male Sprague Dawley rats (n = 7-8/group) received 7 injections of caerulein (50 µg/kg) at 12, 24, 48, 72, 96, or 120 hours before measurement of lung impedance mechanics. Bronchoalveolar lavage (BAL), plasma, pancreatic, and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 12 and 24 hours, as indicated by increased plasma amylase activity and pancreatic myeloperoxidase (MPO) activity, edema, and abnormal acinar cells, before beginning to resolve by 48 hours. In the lung, MPO activity peaked at 12 and 96 hours, with BAL cytokine concentrations peaking at 12 hours, followed by lung edema at 24 hours, and BAL cell count at 48 hours. Importantly, no significant changes in BAL protein concentration or arterial blood gas-pH levels were evident over the same period, and only modest changes were observed in respiratory mechanics. Caerulein-induced AP results in minor lung injury, which is not sufficient to allow protein permeability and substantially alter respiratory mechanics.

L-Arginine-induced acute pancreatitis results in mild lung inflammation without altered respiratory mechanics.

Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize acute lung injury in L-arginine-induced AP. Seven groups of male Sprague-Dawley rats (n = 4-10/group) received 2 intraperitoneal (i.p.) injections of L-arginine (250 mg/100 g) at 6, 12, 24, 36, 48, or 72 hours before measurement of lung impedance mechanics. Control rats (n = 10) received i.p. saline. Bronchoalveolar lavage (BAL), plasma, and pancreatic and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 6 and 36 hours, as indicated by increased pancreatic abnormal acinar cells, myeloperoxidase (MPO) activity, edema, and plasma amylase activity, before beginning to resolve by 72 hours. In the lung, MPO activity increased (2.4-fold) from 12 hours, followed by a modest increase in lung edema at 48 hours, with increased BAL cell count (2.5-fold) up to 72 hours (P < .05). In contrast, no significant changes in lung mechanics were evident over the same period. Despite measurable lung inflammation, no significant deterioration in respiratory function resulted from L-arginine-induced AP.

Understanding Restrictive Versus Liberal Fluid Therapy for Major Abdominal Surgery Trial Results: Did Liberal Fluids Associate With Increased Endothelial Injury Markers?

Liberal fluid strategies in critically ill patients are associated with harm, thought to be due to endothelial and glycocalyx injury. As the restrictive versus liberal fluid therapy for major abdominal surgery trial not only failed to report survival benefit with restrictive fluids but was associated with a higher rate of acute kidney injury, we hypothesized that factors other than endothelial and glycocalyx injury were likely to account for these findings. Consequently, we measured injury biomarkers in a cohort of the restrictive versus liberal fluid therapy for major abdominal surgery trial. DESIGN: The restrictive versus liberal fluid therapy for major abdominal surgery trial was an international, randomized, assessor-blinded trial comparing restrictive with liberal IV fluid regimens that represented traditional care in patients undergoing major abdominal surgery. SETTING AND PATIENTS: Cohort of restrictive versus liberal fluid therapy for major abdominal surgery bloods was collected at a single major site (161 patients) prior to, day 1 and day 3 after surgery. INTERVENTION: Bloods were blindly and randomly batch analyzed for plasma markers of endothelial/glycocalyx injury-angiopoietin-1, angiopoietin-2, soluble tyrosine-protein kinase-2 receptor, soluble intracellular adhesion molecule-1, syndecan, and tumor necrosis factor-α. Data were examined as restrictive versus liberal enrollment groups and high versus low (± 5,000 mL) fluid groups. Differences were examined by linear mixed modeling. MEASUREMENT AND MAIN RESULTS: There were no significant differences in any biomarkers between the restrictive (n = 75) and liberal (n = 86) groups. When examined as low (n = 81) and high (n = 79) fluid groups, plasma angiopoietin-2 (p = 0.009) and soluble intracellular adhesion molecule-1 (p = 0.01) were elevated in the high fluid group. There were no differences in other biomarkers. CONCLUSIONS: Although these results are consistent with previous findings of vascular injury following liberal fluid therapy, they suggest alternative mechanisms underlie the clinical outcomes from restrictive versus liberal fluid therapy for major abdominal surgery study. CLINICALTRIALSGOV IDENTIFIER: NCT01424150.

Unchanged cardiovascular and respiratory outcomes in healthy C57Bl/6 mice after in utero exposure to ionizing radiation.

BACKGROUND: Advancements in medical technologies that utilize ionizing radiation have led to improved diagnosis and patient outcomes, however, the effect of ionizing radiation on the patient is still debated. In the case of pregnancy, the potential effects are not only to the mother but also to the fetus. The aim of this study was to determine if exposure from ionizing radiation during pregnancy alters the development of the cardiovascular and respiratory system of the offspring. MATERIALS AND METHODS: Pregnant C57Bl/6 mice were whole-body irradiated at gestational day 15 with a 137Cs gamma radiation emitting source at 0 mGy (sham), 50 mGy, 300 mGy, or 1000 mGy. Post weaning weight and blood pressure measurements were taken weekly for both male and female pups until euthanasia at 16-17 weeks postnatal age. Immediately following, the trachea was cannulated, and the lungs and heart excised. The lung was then examined to assess respiratory physiological outcomes. RESULTS AND CONCLUSIONS: In utero exposures to 1000 mGy caused significant growth reduction compared to sham irradiated, which remained persistent for both male and female pups. Growth restriction was not observed for lower exposures. There was no significant change in any cardiovascular or respiratory outcomes measured. Overall, intrauterine exposures to ionizing radiation does not appear to significantly alter the development of the cardiovascular and respiratory system in C57Bl/6 pups up to 17 weeks postnatal age.

Lower interleukin-8 levels in airway aspirates from breastfed infants with acute bronchiolitis.

Breastfeeding during the first 12 months of life confers demonstrable immunologic benefit against infective pathogens, including those of the respiratory tract. However, the mechanism by which the ingestion of human milk modifies immunologic defense against such pathogens remains elusive. Bronchiolitis, caused predominantly by respiratory syncytial virus, is the most common clinical presentation of severe upper respiratory illness requiring hospitalization in infants and remains one of the developed world's leading causes of infant mortality and morbidity over both the short and long term. The mechanism by which an early, severe case of bronchiolitis can result in the development of recurrent childhood wheeze or asthma is unclear; however, mucosal inflammation and pulmonary neutrophilia are believed to play a significant role. The aim of this study was to examine the immune response of breastfed infants hospitalized with severe bronchiolitis, compared with formula-fed controls. Nasopharyngeal aspirates (NPA) were collected from 18 infants (aged