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High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Staffan Johansson)
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2016 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 1, 79-92 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The independent impact of respiratory rate on ventilator-induced lung injury has not been fully elucidated. The aim of this study was to investigate the effects of two clinically relevant respiratory rates on early ventilator-induced lung injury evolution and lung edema during the protective ARDSNet strategy. We hypothesized that the use of a higher respiratory rate during a protective ARDSNet ventilation strategy increases lung inflammation and, in addition, lung edema associated to strain-induced activation of transforming growth factor beta (TGF-β) in the lung epithelium.

METHODS: Twelve healthy piglets were submitted to a two-hit lung injury model and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated during 6 h according to the ARDSNet strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, the lungs were excised and wet/dry ratio, TGF-β pathway markers, regional histology, and cytokines were evaluated.

RESULTS: No differences in oxygenation, PaCO2 levels, systemic and pulmonary arterial pressures were observed during the study. Respiratory system compliance and mean airway pressure were lower in LRR group. A decrease in EVLW over time occurred only in the LRR group (P < 0.05). Wet/dry ratio was higher in the HRR group (P < 0.05), as well as TGF-β pathway activation. Histological findings suggestive of inflammation and inflammatory tissue cytokines were higher in LRR.

CONCLUSION: HRR was associated with more pulmonary edema and higher activation of the TGF-β pathway. In contrast with our hypothesis, HRR was associated with less lung inflammation.

Place, publisher, year, edition, pages
2016. Vol. 60, no 1, 79-92 p.
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
URN: urn:nbn:se:uu:diva-264211DOI: 10.1111/aas.12596ISI: 000368139400010PubMedID: 26256848OAI: oai:DiVA.org:uu-264211DiVA: diva2:859516
Swedish Heart Lung FoundationSwedish Research Council, K2015-99X-22731-01-4
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2016-08-25Bibliographically approved
In thesis
1. Aspects on ventilation induced stress and strain on regional and global inflammation in experimental acute respiratory distress syndrome
Open this publication in new window or tab >>Aspects on ventilation induced stress and strain on regional and global inflammation in experimental acute respiratory distress syndrome
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mechanical ventilation (MV) is a life-saving therapy in acute respiratory distress syndrome (ARDS), a condition that affects 3000 patients/year in Sweden with a mortality rate of about 40%. However, MV may induce or worsen lung injury causing “ventilator-induced lung injury (VILI)”. From a mechanical perspective strain (deformation, or relative change in lung volume) and stress (tension) have been postulated as main determinants of VILI. High respiratory rate is potentially another factor that may exacerbate VILI by amplifying the total energy transmitted to the lungs during MV. In this thesis in animal ARDS models the hypotheses were that 1) lung parenchyma inhomogeneities concentrate stress and amplify lung damage and inflammation, 2) higher respiratory rates increase lung inflammation and lung edema in heterogeneous ARDS, and 3) local lung deformation is related to local inflammation.

First, in a rat model the effect on inflammation and structural damage of regional lung collapse on the healthy surrounding lung tissue was assessed. Second, in porcine models the effect of respiratory rate on lung edema and inflammation was studied during two ventilatory modes; a) a permissive collapse mode and b) a homogenized lung parenchyma mode. Finally, lung deformation was correlated with lung inflammation assessed by positron emission tomography using 18F-FDG uptake.

It was found that; 1) local inhomogeneities can act as stress amplifiers, increasing lung tissue inflammation and damage in the healthy surrounded lung. 2) high respiratory rate increases lung edema but decreases lung inflammation when permissive lung collapse is used and that these effects are prevented with lung parenchyma homogenization; 3) local lung deformation and inflammation are well correlated.

In conclusion, lung inhomogeneities may aggravate VILI, respiratory rate may affect in different ways VILI progression depending on the ventilatory strategy, and finally, lung deformation is closely related to lung inflammation. With the caveat that the studies are performed in animal models, the results suggest that using ventilator strategies that homogenize the lungs, i.e., open collapsed lung regions and prevent re-collapse in ARDS will reduce VILI and in the end may decrease morbidity and the high mortality in this condition.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1235
ARDS, VILI, respiratory rate, strain, PET
National Category
Anesthesiology and Intensive Care
urn:nbn:se:uu:diva-296952 (URN)978-91-554-9612-8 (ISBN)
Public defence
2016-09-06, Hedstrandsalen, Akademiska sjukhuset, Ing 70, 751 85 Uppsala, UPPSALA, 09:00 (English)
Swedish Heart Lung Foundation, K2015-99X-22731-01-4
Available from: 2016-08-16 Created: 2016-06-20 Last updated: 2016-08-16

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Retamal, JaimeBorges, Joao BatistaCao, XiaofangHedenstierna, GöranJohansson, StaffanSuarez-Sipmann, FernandoLarsson, Anders
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Anaesthesiology and Intensive CareHedenstierna laboratoryDepartment of Medical Biochemistry and MicrobiologyClinical Physiology
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