Lung-borne systemic inflammation in mechanically ventilated infant rats due to high PEEP, oxygen, and hypocapnia.

BACKGROUND: Intensive care practice calls for ventilator adjustments due to fast-changing clinical conditions in ventilated critically ill children. These adaptations include positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO2), and respiratory rate (RR). It is unclear which alterations in ventilator settings trigger a significant systemic inflammatory response. METHODS: Fourteen-day old Wistar rat pups were randomized to the following groups: (a) "control" with tidal volume ~8 mL/kg, PEEP 5 cmH2O, FiO2 0.4, RR 90 min-1, (b) "PEEP 1", (c) "PEEP 9" (d) "FiO2 0.21", (e) "FiO2 1.0", (f) "hypocapnia" with RR of 180 min-1, and (g) "hypercapnia" with RR of 60 min-1. Following 120 min of mechanical ventilation, plasma for inflammatory biomarker analyses was obtained by direct cardiac puncture at the end of the experiment. RESULTS: Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were driven by FiO2 0.4 and 1.0 (P=0.02, P<0.01, respectively), tissue plasminogen activator inhibitor type-1 (tPAI-1) was increased by high PEEP (9 cmH2O, P<0.05) and hypocapnia (P<0.05), and TNF-α was significantly lower in hypercapnia (P<0.01). Tissue inhibitor of metalloproteinase-1 (TIMP-1), cytokine-induced neutrophil chemoattractant 1 (CINC-1), connective tissue growth factor (CTGF), and monocyte chemoattractant protein-1 (MCP-1) remained unaffected. CONCLUSION: Alterations of PEEP, FiO2, and respiratory frequency induced a significant systemic inflammatory response in plasma of infant rats. These findings underscore the importance of lung-protective ventilation strategies. However, future studies are needed to clarify whether ventilation induced systemic inflammation in animal models is pathophysiologically relevant to human infants.

Mechanical ventilation strategies alter cardiovascular biomarkers in an infant rat model.

Mechanical ventilation (MV) is routinely used in pediatric general anesthesia and critical care, but may adversely affect the cardiocirculatory system. Biomarkers are increasingly measured to assess cardiovascular status and improve clinical treatment decision-making. As the impact of mechanical ventilation strategies on cardiovascular biomarkers in ventilated infants is largely unknown, we conducted this retrospective study in a healthy in vivo infant rat ventilation model using 14-days old Wistar rats. We hypothesized that 2 h of mechanical ventilation with high and low positive end-expiratory pressure (PEEP), hyperoxemia, hypoxemia, hypercapnia, and hypocapnia would significantly impact B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), and endothelin-1 (ET-1). We found BNP to be driven by both high (9 cmH2 O) and low (1 cmH2 O) PEEP compared to ventilated control animals (P < 0.05). VEGF concentrations were associated with high PEEP, hyperoxemia, hypoxemia, and hypocapnia (P < 0.05), whereas ET-1 levels were changed only in response to hypoxemia (P < 0.05). In conclusion, the mode of mechanical ventilation alters plasma biomarker concentrations. Moreover, BNP and VEGF might serve as surrogate parameters for ventilation induced cardiovascular compromise and lung tissue damage. Furthermore, our data support the hypothesis, that sudden onset of hyperoxemia may trigger a quick VEGF release as a possible cellular survival reflex.

Determinants of plasma copeptin: a systematic investigation in a pediatric mechanical ventilation model.

Copeptin, the C-terminal part of the arginine vasopressin precursor peptide, holds promise as a diagnostic and prognostic plasma biomarker in various acute clinical conditions. Factors influencing copeptin response in the critical care setting are only partially established and have not been investigated systematically. Using an in vivo infant ventilation model (Wistar rats, 14 days old), we studied the influence of commonly occurring stressors in critically ill children. In unstressed ventilated rats basal median copeptin concentration was 22pmol/L. In response to respiratory alkalosis copeptin increased 5-fold, while exposure to hypoxemia, high PEEP, hemorrhage, and psycho-emotional stress produced a more than 10-fold increase. Additionally, we did not find a direct association between copeptin and acidosis, hypercapnia, and hyperthermia. Clinicians working in the acute critical care setting should be aware of factors influencing copeptin plasma concentrations. Moreover, our results do have implications for animal studies in the field of stress research.

Airway cells after swimming outdoors or in the sea in nonasthmatic athletes.

BACKGROUND: Marathon runners and elite swimmers showed increased inflammatory cells in the airways at baseline. Although airway neutrophils increase further after a marathon race, the airway response to swimming is unknown. The aim of this study was to assess the effects of swimming on airway cells. To avoid the concomitant effects of chronic exposure to chlorine, the study was conducted in seven nonasthmatic swimmers [mean age (SD): 23.3 +/- 7.7 yr, training: 32 +/- 15 km.wk-1] habitually training in an outdoor pool (OP), i.e., a low-chlorine environment. METHODS: Spirometry, exhaled nitric oxide (NO), induced sputum, and peripheral blood samples were obtained at baseline, after a 5-km trial in OP, and after a 5-km race in the sea (S), i.e., hypertonic airway exposure. RESULTS: Airway neutrophil differential counts at baseline were higher in swimmers than in sedentary controls (N = 10), but cell counts, neutrophil elastase, and eosinophil cationic protein were unaffected by 5-km swimming. After swimming, L-selectin expression on airway cells decreased, suggesting exercise-induced cell mobilization into the airways and/or direct effects of hyperventilation on airway cells. After S, airway eosinophil differential counts increased slightly. Exhaled NO concentration was 19 +/- 6 ppb at baseline, 8 +/- 4 ppb after OP, and 21 +/- 7 ppb after S (P < 0.005 for OP vs baseline and S). CONCLUSIONS: In swimmers not chronically exposed to high chlorine concentrations, data obtained at baseline suggest a direct relationship between airway neutrophilia and endurance training. The low L-selectin expression by airway cells postexercise suggests hyperventilation-induced cell recruitment or modulation of cell function. Hypertonic exposure of airways during exercise may slightly increase airway eosinophils and exhaled NO. Overall, 5-km swimming exerted smaller effects on airway cells than running a marathon.

Circulating hematopoietic progenitor cells in runners.

Because endurance exercise causes release of mediators and growth factors active on the bone marrow, we asked whether it might affect circulating hematopoietic progenitor cells (HPCs) in amateur runners [n = 16, age: 41.8 +/- 13.5 (SD) yr, training: 93.8 +/- 31.8 km/wk] compared with sedentary controls (n = 9, age: 39.4 +/- 10.2 yr). HPCs, plasma cortisol, interleukin (IL)-6, granulocyte colony-stimulating factor (G-CSF), and the growth factor fms-like tyrosine kinase-3 (flt3)-ligand were measured at rest and after a marathon (M; n = 8) or half-marathon (HM; n = 8). Circulating HPC counts (i.e., CD34(+) cells and their subpopulations) were three- to fourfold higher in runners than in controls at baseline. They were unaffected by HM or M acutely but decreased the morning postrace. Baseline cortisol, flt3-ligand, IL-6, and G-CSF levels were similar in runners and controls. IL-6 and G-CSF increased to higher levels after M compared with HM, whereas cortisol and flt3-ligand increased similarly postrace. Our data suggest that increased HPCs reflect an adaptation response to recurrent, exercise-associated release of neutrophils and stress and inflammatory mediators, indicating modulation of bone marrow activity by habitual running.