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Aspects on ventilation induced stress and strain on regional and global inflammation in experimental acute respiratory distress syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. (Hedenstierna Laboratory)
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1235
Keyword [en]
ARDS, VILI, respiratory rate, strain, PET
National Category
Anesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-296952ISBN: 978-91-554-9612-8OAI: oai:DiVA.org:uu-296952DiVA: diva2:940293
Public defence
2016-09-06, Hedstrandsalen, Akademiska sjukhuset, Ing 70, 751 85 Uppsala, UPPSALA, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Heart Lung Foundation, K2015-99X-22731-01-4
Available from: 2016-08-16 Created: 2016-06-20 Last updated: 2016-08-16
List of papers
1. Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation
Open this publication in new window or tab >>Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation
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2014 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 18, no 5, 505- p.Article in journal (Refereed) Published
Abstract [en]

Introduction

When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation.

Methods

A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls.

Results

Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm3. There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the VT20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1β and cytokine-induced neutrophil chemoattractant-1 between regions.

Conclusions

The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.

National Category
Clinical Medicine
Research subject
Clinical Physiology
Identifiers
urn:nbn:se:uu:diva-233429 (URN)10.1186/s13054-014-0505-1 (DOI)000351850600024 ()25200702 (PubMedID)
Available from: 2014-10-03 Created: 2014-10-03 Last updated: 2016-08-25Bibliographically approved
2. High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
Open this publication in new window or tab >>High respiratory rate is associated with early reduction of lung edema clearance in an experimental model of ARDS
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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.

National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-264211 (URN)10.1111/aas.12596 (DOI)000368139400010 ()26256848 (PubMedID)
Funder
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
3. Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury
Open this publication in new window or tab >>Open lung approach ventilation abolishes the negative effects of respiratory rate in experimental lung injury
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2016 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 60, no 8, 1131-1141 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We recently reported that a high respiratory rate was associated with less inflammation than a low respiratory rate, but caused more pulmonary edema in a model of ARDS when an ARDSNet ventilatory strategy was used. We hypothesized that an open lung approach (OLA) strategy would neutralize the independent effects of respiratory rate on lung inflammation and edema. This hypothesis was tested in an ARDS model using two clinically relevant respiratory rates during OLA strategy.

METHODS: Twelve piglets were subjected to an experimental model of ARDS and randomized into two groups: LRR (20 breaths/min) and HRR (40 breaths/min). They were mechanically ventilated for 6 h according to an OLA strategy. We assessed respiratory mechanics, hemodynamics, and extravascular lung water (EVLW). At the end of the experiment, wet/dry ratio, regional histology, and cytokines were evaluated.

RESULTS: After the ARDS model was established, Cdyn,rs decreased from 21 ± 3.3 to 9.0 ± 1.8 ml/cmH2 O (P < 0.0001). After the lung recruitment maneuver, Cdyn,rs increased to the pre-injury value. During OLA ventilation, no differences in respiratory mechanics, hemodynamics, or EVLW were observed between groups. Wet/dry ratio and histological scores were not different between groups. Cytokine quantification was similar and showed a homogeneous distribution throughout the lung in both groups.

CONCLUSION: Contrary to previous findings with the ARDSNet strategy, respiratory rate did not influence lung inflammatory response or pulmonary edema during OLA ventilation in experimental ARDS. This indicates that changing the respiratory rate when OLA ventilation is used will not exacerbate lung injury.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-296932 (URN)10.1111/aas.12735 (DOI)000380960400012 ()27110871 (PubMedID)
External cooperation:
Funder
Swedish Heart Lung FoundationSwedish Research Council, K2015-99X-22731-01-4
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2016-09-15Bibliographically approved
4. Regional pulmonary deformation is positively correlated with regional lung inflammation assessed by 18F-FDG positron emission tomography / computed tomography
Open this publication in new window or tab >>Regional pulmonary deformation is positively correlated with regional lung inflammation assessed by 18F-FDG positron emission tomography / computed tomography
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Objective: Lung deformation beyond of physiological capacity is associated with cell death and inflammation. Lung strain has been estimated as a global strain, but uneven strain distribution may lead to regional stress concentrations and lung damage. Local lung inflammation can be estimated using PET imaging of [18F]fluoro-2-deoxy-D-glucose. We hypothesized that local lung deformation correlates well with local inflammation. The aim of this study was to assess local tidal deformations by using a new mathematical model of finite-elements to analyze CT images, and to correlate them with local inflammation in a porcine experimental model of early acute respiratory distress syndrome.

Design: Retrospective images analysis, laboratory investigation.

Setting: University animal research laboratory.

Subjects: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy ventilated controls.

Intervention: Lung injury was induced by repeated lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [18F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration. Then maps of deformation were constructed and regional deformation was estimated. We divided the lung parenchyma in 10 horizontal ROIs, and correlations of local volumetric strain and [18F]fluoro-2-deoxy-D-glucose uptake were analyzed in each ROI.

Measurements and Main Results: The deformation maps showed a heterogeneous distribution with a greater concentration in the intermediate gravitational regions. We found a strong correlation between local strain and inflammation (R2 > 0.5) for the whole lung, when we eliminate the 3/10 dorsal ROIs R2 increased until>0.8.

Conclusion: the present findings suggest that the greater local stretches were mainly concentrated in the intermediate gravitational zones of injured heterogeneous lungs. Additionally, local lung deformations correlated well with local inflammation in this experimental model of VILI. And the new proposed image-based estimation of regional volumetric strain based on finite element interpolations has the potential to give new insights of local pathogenic mechanisms of VILI and how best design protective-ventilations strategies.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-296945 (URN)
Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2016-06-29Bibliographically approved

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