High positive end-expiratory pressure ventilation mitigates the progression from unilateral pulmonary contusion to ARDS: An animal study.

BACKGROUND: Pulmonary contusion (PC) is common in severely traumatized patients and can lead to respiratory failure requiring mechanical ventilation (MV). Ventilator-induced lung injury (VILI) might aggravate lung damage. Despite underrepresentation of trauma patients in trials on lung-protective MV, results are extrapolated to these patients, potentially disregarding important pathophysiological differences. METHODS: Three MV protocols with different positive end-expiratory pressure (PEEP) levels: ARDSnetwork lower PEEP (ARDSnet-low), ARDSnetwork higher PEEP (ARDSnet-high), and open lung concept (OLC) were applied in swine for 24 hours following PC. Gas exchange, lung mechanics, quantitative computed tomography, and diffuse alveolar damage (DAD) score were analyzed. Results are given as median (interquartile range) at 24 hours. Statistical testing was performed using general linear models (group effect) over all measurement points and pairwise Mann-Whitney U tests for DAD. RESULTS: There were significant differences between groups: PEEP ( p < 0.0001) ARDSnet-low (8 [8-10] cmH 2 O), ARDSnet-high (12 [12-12] cmH 2 O), OLC (21 [20-22] cmH 2 O). The fraction of arterial partial pressure of oxygen and inspired oxygen fraction ( p = 0.0016) was lowest in ARDSnet-low (78 (73-111) mm Hg) compared with ARDSnet-high (375 (365-423) mm Hg) and OLC (499 (430-523) mm Hg). The end-expiratory lung volume (EELV) differed significantly ( p < 0.0001), with highest values in OLC (64% [60-70%]) and lowest in ARDSnet-low (34% [24-37%]). Costa's surrogate for mechanical power differed significantly ( p < 0.0001), with lowest values for ARDSnet-high (73 [58-76]) compared with OLC (105 [108-116]). Diffuse alveolar damage was lower in ARDSnet-high compared with ARDSnet-low (0.0007). CONCLUSION: Progression to ARDS, 24 hours after PC, was mitigated by OLC and ARDSnet-high. Both concepts restored EELV. ARDSnet-high had the lowest mechanical power surrogate and DAD. Our data suggest, that ARDSnet-high restored oxygenation and functional lung volume and reduced physiological and histological surrogates for VILI. ARDSnet-low generated unfavorable outcomes, such as loss of EELV, increased mechanical power and DAD after PC in swine. The high respiratory rate in the OLC may blunt favorable effects of lung recruitment.

Detection of posttraumatic pneumothorax using electrical impedance tomography-An observer-blinded study in pigs with blunt chest trauma.

INTRODUCTION: Posttraumatic pneumothorax (PTX) is often overseen in anteroposterior chest X-ray. Chest sonography and Electrical Impedance Tomography (EIT) can both be used at the bedside and may provide complementary information. We evaluated the performance of EIT for diagnosing posttraumatic PTX in a pig model. METHODS: This study used images from an existing database of images acquired from 17 mechanically ventilated pigs, which had sustained standardized blunt chest trauma and had undergone repeated thoracic CT and EIT. 100 corresponding EIT/CT datasets were randomly chosen from the database and anonymized. Two independent and blinded observers analyzed the EIT data for presence and location of PTX. Analysis of the corresponding CTs by a radiologist served as reference. RESULTS: 87/100 cases had at least one PTX detected by CT. Fourty-two cases showed a PTX > 20% of the sternovertebral diameter (PTXtrans20), whereas 52/100 PTX showed a PTX>3 cm in the craniocaudal diameter (PTXcc3), with 20 cases showing both a PTXtranscc and a PTXcc3. We found a very low agreement between both EIT observers considering the classification overall PTX/noPTX (κ = 0.09, p = 0.183). For PTXtrans20, sensitivity was 59% for observer 1 and 17% for observer 2, with a specificity of 48% and 50%, respectively. For PTXcc3, observer 1 showed a sensitivity of 60% with a specificity of 51% while the sensitivity of observer 2 was 17%, with a specificity of 89%. By programming a semi-automatized detection algorithm, we significantly improved the detection rate of PTXcc3, with a sensitivity of 73% and a specificity of 70%. However, detection of PTXtranscc was not improved. CONCLUSION: In our analysis, visual interpretation of EIT without specific image processing or comparison with baseline data did not allow clinically useful diagnosis of posttraumatic PTX. Multimodal imaging approaches, technical improvements and image postprocessing algorithms might improve the performance of EIT for diagnosing PTX in the future.

The effects of hemoglobin glutamer-200 and iNO on pulmonary vascular tone and arterial oxygenation in an experimental acute respiratory distress syndrome.

INTRODUCTION: Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions. Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction. In acute lung injury, an excess of nitric oxide results in a general vasodilation, reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction. Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch. We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange. METHODS: ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion. Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses. RESULTS: Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups. CONCLUSION: Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS.

Mapping Regional Differences of Local Pressure-Volume Curves With Electrical Impedance Tomography.

OBJECTIVES: Lung-protective mechanical ventilation aims to prevent alveolar collapse and overdistension, but reliable bedside methods to quantify them are lacking. We propose a quantitative descriptor of the shape of local pressure-volume curves derived from electrical impedance tomography, for computing maps that highlight the presence and location of regions of presumed tidal recruitment (i.e., elastance decrease during inflation, pressure-volume curve with upward curvature) or overdistension (i.e., elastance increase during inflation, downward curvature). DESIGN: Secondary analysis of experimental cohort study. SETTING: University research facility. SUBJECTS: Twelve mechanically ventilated pigs. INTERVENTIONS: After induction of acute respiratory distress syndrome by hydrochloric acid instillation, animals underwent a decremental positive end-expiratory pressure titration (steps of 2 cm H2O starting from ≥ 26 cm H2O). MEASUREMENTS AND MAIN RESULTS: Electrical impedance tomography-derived maps were computed at each positive end-expiratory pressure-titration step, and whole-lung CT taken every second steps. Airway flow and pressure were recorded to compute driving pressure and elastance. Significant correlations between electrical impedance tomography-derived maps and positive end-expiratory pressure indicate that, expectedly, tidal recruitment increases in dependent regions with decreasing positive end-expiratory pressure (p < 0.001) and suggest that overdistension increases both at high and low positive end-expiratory pressures in nondependent regions (p < 0.027), supporting the idea of two different scenarios of overdistension occurrence. Significant correlations with CT measurements were observed: electrical impedance tomography-derived tidal recruitment with poorly aerated regions (r = 0.43; p < 0.001); electrical impedance tomography-derived overdistension with nonaerated regions at lower positive end-expiratory pressures and with hyperaerated regions at higher positive end-expiratory pressures (r ≥ 0.72; p < 0.003). Even for positive end-expiratory pressure levels minimizing global elastance and driving pressure, electrical impedance tomography-derived maps showed nonnegligible regions of presumed overdistension and tidal recruitment. CONCLUSIONS: Electrical impedance tomography-derived maps of pressure-volume curve shapes allow to detect regions in which elastance changes during inflation. This could promote individualized mechanical ventilation by minimizing the probability of local tidal recruitment and/or overdistension. Electrical impedance tomography-derived maps might become clinically feasible and relevant, being simpler than currently available alternative approaches.

Search for an animal model to investigate selective pulmonary vasodilation.

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague-Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.

Cholinergic receptors in the murine oviduct: inventory and coupling to intracellular calcium concentration.

AIMS: In the oviduct, muscarinic acetylcholine receptors (MR) are linked with motility regulation and nicotinic receptors (nAChR) with ectopic pregnancy. We here aimed to determine the repertoire of cholinergic receptor expression in the murine oviduct and their functional coupling to regulation of intracellular calcium concentration ([Ca(2+)](i)). MAIN METHODS: Cholinergic receptor transcripts were assessed by RT-PCR in oviductal segments (ampulla, isthmus, uterotubar junction) in all cyclic stages and pregnancy, and in laser-microdissected samples of epithelium and smooth muscle, nAChR subunit α3 distribution in tissue sections using an appropriate genetic reporter mouse strain. [Ca(2+)](i) responses were monitored in ciliated and non-ciliated oviductal cells isolated from wild-type and MR subtypes 1 and 3 gene deficient mice. KEY FINDINGS: Transcripts for all MR subtypes (M1-M5) are constantly expressed whereas there is some variability in nAChR expression from individual to individual. The qualitative expression pattern is independent from the hormonal status of the animal, except for nAChR α7, which is less present during pregnancy. The epithelium expresses M1, M3, nAChR α7 (data from laser-assisted microdissection) and nAChR α3 (ultrastructural investigation of reporter mice). MR dominate over nAChR in increasing [Ca(2+)](i) with being M3 the major, but not sole subtype driving this effect. The general nAChR inhibitor mecamylamine enhances muscarinic and purinergic responses. SIGNIFICANCE: In conclusion, the murine oviduct is endowed with a multiplicity of muscarinic and nicotinic receptors subtypes that, with respect to regulation of [Ca(2+)](i), are inversely linked to each other. The major, but not sole, cholinergic receptor driving increase in [Ca(2+)](i) is M3.

Ciliary activity in the oviduct of cycling, pregnant, and muscarinic receptor knockout mice.

The transport of the oocyte and the embryo in the oviduct is managed by ciliary beating and muscular contractions. Because nonneuronally produced acetylcholine influences ciliary beating in the trachea via the muscarinic receptors M2 and M3, we supposed that components of the cholinergic system may also modulate ciliary activity in the oviduct. To address this issue, we analyzed the expression profile of muscarinic receptors (CHRMs) in the murine oviduct by RT-PCR and assessed ciliary beat frequency (CBF) and cilia-driven particle transport speed (PTS) on the mucosal surface of opened oviductal segments in correlation with histomorphological investigations. RT-PCR of laser-assisted microdissected epithelium revealed expression of Chrm subtypes Chrm1 and Chrm3. In opened isthmic segments, particle transport was barely seen, correlating with a significantly lower number of ciliated cells compared to the ampulla. In the ampulla, basal PTS and CBF were high (71 µm/sec and 21 Hz, respectively) both in cycling and pregnant wild-type mice and in mice with targeted deletion of the Chrm genes Chrm1, Chrm3, Chrm4, and Chrm5. In contrast to the trachea, where basal ciliary activity was low and largely enhanced by muscarinic stimulation, muscarinic agonists and antagonists did not affect the high ampullar PTS. Our results imply that this high oviductal autonomous ciliary activity is independent from the intrinsic cholinergic system and serves to maintain optimal clearance of the tube throughout all stages of the estrous cycle and early pregnancy.