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Protective Mechanical Ventilation in Inflammatory and Ventilator-Associated Pneumonia Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Severe infections, trauma or major surgery can each cause a state of systemic inflammation. These causes for systemic inflammation often coexist and complicate each other. Mechanical ventilation is commonly used during major surgical procedures and when respiratory functions are failing in the intensive care setting. Although necessary, the use of mechanical ventilation can cause injury to the lungs and other organs especially under states of systemic inflammation. Moreover, a course of mechanical ventilator therapy can be complicated by ventilator-associated pneumonia, a factor greatly influencing mortality. The efforts to avoid additional ventilator-induced injury to patients are embodied in the expression ‘protective ventilation’.

With the use of pig models we have examined the impact of protective ventilation on systemic inflammation, on organ-specific inflammation and on bacterial growth during pneumonia. Additionally, with a 30-hour ventilator-associated pneumonia model we examined the influence of mechanical ventilation and systemic inflammation on bacterial growth. Systemic inflammation was initiated with surgery and enhanced with endotoxin. The bacterium used was Pseudomonas aeruginosa.

We found that protective ventilation during systemic inflammation attenuated the systemic inflammatory cytokine responses and reduced secondary organ damage. Moreover, the attenuated inflammatory responses were seen on the organ specific level, most clearly as reduced counts of inflammatory cytokines from the liver. Protective ventilation entailed lower bacterial counts in lung tissue after 6 hours of pneumonia. Mechanical ventilation for 24 h, before a bacterial challenge into the lungs, increased bacterial counts in lung tissue after 6 h. The addition of systemic inflammation by endotoxin during 24 h increased the bacterial counts even more. For comparison, these experiments used control groups with clinically common ventilator settings.

Summarily, these results support the use of protective ventilation as a means to reduce systemic inflammation and organ injury, and to optimize bacterial clearance in states of systemic inflammation and pneumonia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 84 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1208
Keyword [en]
Mechanical ventilation, Systemic inflammation, Pneumonia, Ventilator-associated pneumonia, Endotoxin
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-282602ISBN: 978-91-554-9546-6 (print)OAI: oai:DiVA.org:uu-282602DiVA: diva2:917239
Public defence
2016-05-28, Scenkonst Sörmland, John Engellaus Gata 3, 633 42, Eskilstuna, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2016-05-02 Created: 2016-04-05 Last updated: 2016-05-12
List of papers
1. Lung protective ventilation induces immunotolerance and nitric oxide metabolites in porcine experimental postoperative sepsis
Open this publication in new window or tab >>Lung protective ventilation induces immunotolerance and nitric oxide metabolites in porcine experimental postoperative sepsis
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, e83182- p.Article in journal (Refereed) Published
Abstract [en]

Low tidal volume ventilation is beneficial in patients with severe pulmonary dysfunction and would, in theory, reduce postoperative complications if implemented during routine surgery. The study aimed to investigate whether low tidal volume ventilation and high positive end-expiratory pressure (PEEP) in a large animal model of postoperative sepsis would attenuate the systemic inflammatory response and organ dysfunction. Thirty healthy pigs were randomized to three groups: Group Prot-7h, i.e. protective ventilation for 7 h, was ventilated with a tidal volume of 6 mL x kg-1 for 7 h; group Prot-5h, i.e. protective ventilation for 5 h, was ventilated with a tidal volume of 10 mL x kg-1 for 2 h, after which the group was ventilated with a tidal volume of 6 mL x kg-1; and a control group that was ventilated with a tidal volume of 10 mL x kg-1 for 7 h. In groups Prot-7h and Prot-5h PEEP was 5 cmH2O for 2 h and 10 cmH2O for 5 h. In the control group PEEP was 5 cmH2O for the entire experiment. After surgery for 2 h, postoperative sepsis was simulated with an endotoxin infusion for 5 h. Low tidal volume ventilation combined with higher PEEP led to lower levels of interleukin 6 and 10 in plasma, higher PaO2/FiO2, better preserved functional residual capacity and lower plasma troponin I as compared with animals ventilated with a medium high tidal volume and lower PEEP. The beneficial effects of protective ventilation were seen despite greater reductions in cardiac index and oxygen delivery index. In the immediate postoperative phase low VT ventilation with higher PEEP was associated with reduced ex vivo plasma capacity to produce TNF-α upon endotoxin stimulation and higher nitrite levels in urine. These findings might represent mechanistic explanations for the attenuation of systemic inflammation and inflammatory-induced organ dysfunction.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-213610 (URN)10.1371/journal.pone.0083182 (DOI)000328731800101 ()24349457 (PubMedID)
Available from: 2013-12-30 Created: 2013-12-30 Last updated: 2017-12-06Bibliographically approved
2. Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis
Open this publication in new window or tab >>Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis
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2015 (English)In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 15, 60Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Protective ventilation with lower tidal volume (VT) and higher positive end-expiratory pressure (PEEP) reduces the negative additive effects of mechanical ventilation during systemic inflammatory response syndrome. We hypothesised that protective ventilation during surgery would affect the organ-specific immune response in an experimental animal model of endotoxin-induced sepsis-like syndrome.

METHODS: 30 pigs were laparotomised for 2 hours (h), after which a continuous endotoxin infusion was started at 0.25 micrograms × kg(-1) × h(-1) for 5 h. Catheters were placed in the carotid artery, hepatic vein, portal vein and jugular bulb. Animals were randomised to two protective ventilation groups (n = 10 each): one group was ventilated with VT 6 mL × kg(-1) during the whole experiment while the other group was ventilated during the surgical phase with VT of 10 mL × kg(-1). In both groups PEEP was 5 cmH2O during surgery and increased to 10 cmH2O at the start of endotoxin infusion. A control group (n = 10) was ventilated with VT of 10 mL × kg(-1) and PEEP 5 cm H20 throughout the experiment. In four sample locations we a) simultaneously compared cytokine levels, b) studied the effect of protective ventilation initiated before and during endotoxemia and c) evaluated protective ventilation on organ-specific cytokine levels.

RESULTS: TNF-alpha levels were highest in the hepatic vein, IL-6 levels highest in the artery and jugular bulb and IL-10 levels lowest in the artery. Protective ventilation initiated before and during endotoxemia did not differ in organ-specific cytokine levels. Protective ventilation led to lower levels of TNF-alpha in the hepatic vein compared with the control group, whereas no significant differences were seen in the artery, portal vein or jugular bulb.

CONCLUSIONS: Variation between organs in cytokine output was observed during experimental sepsis. We see no implication from cytokine levels for initiating protective ventilation before endotoxemia. However, during endotoxemia protective ventilation attenuates hepatic inflammatory cytokine output contributing to a reduced total inflammatory burden.

National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-253174 (URN)10.1186/s12890-015-0052-9 (DOI)000354840700001 ()25958003 (PubMedID)
Available from: 2015-05-23 Created: 2015-05-23 Last updated: 2017-12-04Bibliographically approved
3. Protective Ventilation Reduces Pseudomonas Aeruginosa Growth in a Porcine Pneumonia Model
Open this publication in new window or tab >>Protective Ventilation Reduces Pseudomonas Aeruginosa Growth in a Porcine Pneumonia Model
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(English)Manuscript (preprint) (Other academic)
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-282600 (URN)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2016-05-12
4. Exposure to Mechanical Ventilation and Endotoxin for 24 Hours Before Infection Influences Pseudomonas Aeruginosa Growth During Experimental Porcine Ventilator-Associated Pneumonia
Open this publication in new window or tab >>Exposure to Mechanical Ventilation and Endotoxin for 24 Hours Before Infection Influences Pseudomonas Aeruginosa Growth During Experimental Porcine Ventilator-Associated Pneumonia
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(English)Manuscript (preprint) (Other academic)
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-282601 (URN)
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2016-05-12

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