Sustained inflation at birth did not protect preterm fetal sheep from lung injury

Sustained lung inflations (SI) at birth may recruit functional residual capacity (FRC). Clinically, SI increase oxygenation and decrease need for intubation in preterm infants. We tested whether a SI to recruit FRC would decrease lung injury from subsequent ventilation of fetal, preterm lambs. The preterm fetus (128 ± 1 day gestation) was exteriorized from the uterus, a tracheostomy was performed, and fetal lung fluid was removed. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: 1) positive end-expiratory pressure (PEEP) 8 cmH2O ( n = 4), 2) 20 s SI to 50 cmH2O then PEEP 8 cmH2O ( n = 10), 3) mechanical ventilation at tidal volume (VT) 7 ml/kg ( n = 13), or 4) 20 s SI then ventilation at VT 7 ml/kg ( n = 13). Lambs were ventilated with 95% N2/5% CO2 and PEEP 8 cmH2O. Volume recruitment was measured during SI, and fetal tissues were collected after an additional 30 min on placental support. SI achieved a mean FRC recruitment of 15 ml/kg (range 8–27). Fifty percent of final FRC was achieved by 2 s, 65% by 5 s, and 90% by 15 s, demonstrating prolonged SI times are needed to recruit FRC. SI alone released acute-phase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines and acute-phase response genes in the lung. Mechanical ventilation further increased all markers of lung injury. SI before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth.

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Sustained Inflation at Birth Did Not Alter Lung Injury from Mechanical Ventilation in Surfactant-Treated Fetal Lambs

PLoS ONE ◽

10.1371/journal.pone.0113473 ◽

2014 ◽

Vol 9 (11) ◽

pp. e113473 ◽

Cited By ~ 20

Author(s):

Noah H. Hillman ◽

Matthew W. Kemp ◽

Yuichiro Miura ◽

Suhas G. Kallapur ◽

Alan H. Jobe

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Sustained Inflation

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One-hit Models of Ventilator-induced Lung Injury

Anesthesiology ◽

10.1097/aln.0000000000001605 ◽

2017 ◽

Vol 126 (5) ◽

pp. 909-922 ◽

Cited By ~ 23

Author(s):

Dennis Lex ◽

Stefan Uhlig

Keyword(s):

Blood Pressure ◽

Mechanical Ventilation ◽

Lung Injury ◽

Plateau Pressure ◽

Conventional Mechanical Ventilation ◽

Positive End Expiratory Pressure ◽

Ventilator Induced Lung Injury ◽

Proinflammatory Responses ◽

Lung Failure ◽

H 20

Abstract Background One important explanation for the detrimental effects of conventional mechanical ventilation is the biotrauma hypothesis that ventilation may trigger proinflammatory responses that subsequently cause lung injury. This hypothesis has frequently been studied in so-called one-hit models (overventilation of healthy lungs) that so far have failed to establish an unequivocal link between inflammation and hypoxemic lung failure. This study was designed to develop a one-hit biotrauma model. Methods Mice (six per group) were ventilated for up to 7 h (positive end-expiratory pressure 2 cm H2O) and received 300 μl/h fluid support. Series_1: initial plateau pressures of 10, 24, 27, or 30 cm H2O. Series_2: ventilation with pressure release at 34 cm H2O and initial plateau pressure of 10, 24, 27, or 30 cm H2O. To study the significance of inflammation, the latter groups were also pretreated with the steroid dexamethasone. Results Within 7 h, 20 of 24 mice ventilated with plateau pressure of 27 cm H2O or more died of a catastrophic lung failure characterized by strongly increased proinflammatory markers and a precipitous decrease in pulmonary compliance, blood pressure, and oxygenation. Pretreatment with dexamethasone reduced inflammation, but prolonged median survival time by 30 min. Conclusions Our findings demonstrate a sharp distinction between ventilation with 24 cm H2O that was well tolerated and ventilation with 27 cm H2O that was lethal for most animals due to catastrophic lung failure. In the former case, inflammation was benign and in the latter, a by-product that only accelerated lung failure. The authors suggest that biotrauma—when defined as a ventilation-induced and inflammation-dependent hypoxemia—is difficult to study in murine one-hit models of ventilation, at least not within 7 h. (Anesthesiology 2017; 126:909-22)

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Acute Phase Proteins as Predictors of Survival in Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease Requiring Mechanical Ventilation

COPD Journal of Chronic Obstructive Pulmonary Disease ◽

10.1080/15412555.2019.1698019 ◽

2019 ◽

Vol 17 (1) ◽

pp. 22-28 ◽

Cited By ~ 2

Author(s):

Arora Sneh ◽

Tiwari Pawan ◽

Guleria Randeep ◽

Mohan Anant ◽

Kalaivani Mani ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Mechanical Ventilation ◽

Pulmonary Disease ◽

Acute Exacerbation ◽

Acute Phase ◽

Acute Phase Proteins ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

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Amiloride inhibits arginine vasopressin-induced decrease in fetal lung liquid secretion

Journal of Applied Physiology ◽

10.1152/jappl.1993.75.5.1925 ◽

1993 ◽

Vol 75 (5) ◽

pp. 1925-1929 ◽

Cited By ~ 23

Author(s):

S. Cassin ◽

A. M. Perks

Keyword(s):

Arginine Vasopressin ◽

Fetal Lung ◽

Secretion Rate ◽

Tracer Technique ◽

Fetal Sheep ◽

Indwelling Catheters ◽

Lung Fluid ◽

Lung Liquid

The effects of arginine vasopressin (AVP) and amiloride were studied in 16 unanesthetized fetal sheep (129–135 days of age) with indwelling catheters. Secretion was measured by an impermeant tracer technique. Control fetuses showed no change in lung liquid secretion over a 5-h period with an average secretion rate of 3.6 +/- 0.31 ml.kg-1.h-1. Infusion of AVP (23.4 +/- 2.23 mU.kg-1.min-1) in seven fetuses (134–140 days of age) produced significant decreases (from control) in the secretion rate over a 5-h period: the secretion rate decreased by 68% in the last hour. Amiloride placed in the lung liquid during infusion of AVP, but after AVP effects had taken place, reversed the AVP-induced decrease in lung liquid secretion. AVP in conjunction with other hormones that are elevated during the stress of birth (epinephrine and cortisol) may be important in the removal of lung fluid at birth.

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Injury and repair in the very immature lung following brief mechanical ventilation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00207.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. L917-L926 ◽

Cited By ~ 24

Author(s):

Nadine Brew ◽

Stuart B. Hooper ◽

Beth J. Allison ◽

Megan J. Wallace ◽

Richard Harding

Keyword(s):

Mechanical Ventilation ◽

Growth Factor ◽

Lung Injury ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Tissue Growth ◽

Mrna Levels ◽

Fetal Sheep ◽

Continue Development ◽

Immature Lung

Mechanical ventilation (MV) of very premature infants contributes to lung injury and bronchopulmonary dysplasia (BPD), the effects of which can be long-lasting. Little is currently known about the ability of the very immature lung to recover from ventilator-induced lung injury. Our objective was to determine the ability of the injured very immature lung to repair in the absence of continued ventilation and to identify potential mechanisms. At 125 days gestational age (days GA, 0.85 of term), fetal sheep were partially exposed by hysterotomy under anesthesia and aseptic conditions; they were intubated and ventilated for 2 h with an injurious MV protocol and then returned to the uterus to continue development. Necropsy was performed at either 1 day (short-term group, 126 days GA, n = 6) or 15 days (long-term group, 140 days GA, n = 5) after MV; controls were unventilated ( n = 7–8). At 1 day after MV, lungs displayed signs of injury, including hemorrhage, disorganized elastin and collagen deposition in the distal airspaces, altered morphology, significantly reduced secondary septal crest density, and decreased airspace. Bronchioles had thickened epithelium with evidence of injury and sloughing. Relative mRNA levels of early response genes ( connective tissue growth factor, cysteine-rich 61, and early growth response-1) and proinflammatory cytokines [ interleukins ( IL)- 1β, IL-6, IL-8, tumor necrosis factor-α, and transforming growth factor-β] were not different between groups 1 day after MV. At 15 days after MV, lung structure was normal with no evidence of injury. We conclude that 2 h of MV induces severe injury in the very immature lung and that these lungs have the capacity to repair spontaneously in the absence of further ventilation.

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Effectiveness of individualized lung recruitment strategies at birth: an experimental study in preterm lambs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00416.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. L32-L41 ◽

Cited By ~ 16

Author(s):

David G. Tingay ◽

Anushi Rajapaksa ◽

Emanuela Zannin ◽

Prue M. Pereira-Fantini ◽

Raffaele L. Dellaca ◽

...

Keyword(s):

Lung Injury ◽

Fetal Lung ◽

Lung Mechanics ◽

Impedance Tomography ◽

Antenatal Steroids ◽

Sustained Inflation ◽

Volume Response ◽

Distal Lung ◽

Study Completion ◽

Lung Liquid

Respiratory transition at birth involves rapidly clearing fetal lung liquid and preventing efflux back into the lung while aeration is established. We have developed a sustained inflation (SIOPT) individualized to volume response and a dynamic tidal positive end-expiratory pressure (PEEP) (open lung volume, OLV) strategy that both enhance this process. We aimed to compare the effect of each with a group managed with PEEP of 8 cmH2O and no recruitment maneuver (No-RM), on gas exchange, lung mechanics, spatiotemporal aeration, and lung injury in 127 ± 1 day preterm lambs. Forty-eight fetal-instrumented lambs exposed to antenatal steroids were ventilated for 60 min after application of the allocated strategy. Spatiotemporal aeration and lung mechanics were measured with electrical impedance tomography and forced-oscillation, respectively. At study completion, molecular and histological markers of lung injury were analyzed. Mean (SD) aeration at the end of the SIOPT and OLV groups was 32 (22) and 38 (15) ml/kg, compared with 17 (10) ml/kg (180 s) in the No-RM ( P = 0.024, 1-way ANOVA). This translated into better oxygenation at 60 min ( P = 0.047; 2-way ANOVA) resulting from better distal lung tissue aeration in SIOPT and OLV. There was no difference in lung injury. Neither SIOPT nor OLV achieved homogeneous aeration. Histological injury and mRNA biomarker upregulation were more likely in the regions with better initial aeration, suggesting volutrauma. Tidal ventilation or an SI achieves similar aeration if optimized, suggesting that preventing fluid efflux after lung liquid clearance is at least as important as fluid clearance during the initial inflation at birth.

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Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00328.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. L213-L223 ◽

Cited By ~ 12

Author(s):

Beth J. Allison ◽

Stuart B. Hooper ◽

Elise Coia ◽

Valerie A. Zahra ◽

Graham Jenkin ◽

...

Keyword(s):

Lung Injury ◽

Lung Inflammation ◽

Morphological Changes ◽

Weight Ratio ◽

Fetal Lung ◽

Growth Restriction ◽

Respiratory Morbidity ◽

Vascular Structure ◽

Fetal Sheep ◽

Ventilation Induced Lung Injury

Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

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