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Ventilation/Perfusion Matching and its Effect on Volatile Pharmacokinetics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.ORCID iD: 0000-0002-5285-2737
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mismatching of alveolar ventilation and perfusion (VA/Q) is the major determinant of impaired gas exchange. The gold standard for analyzing VA/Q distribution is the multiple inert gas elimination technique (MIGET), conventionally based on gas chromatography (GC), and, although simple in principle, a technically demanding procedure limiting its use. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) combined MIGET with mass spectrometry, simplifying the sample handling process, and potentially providing VA/Q distributions for a general clinical approach.

The kinetics of volatile anesthetics are well known in patients with healthy lungs. The uptake and distribution of inhaled anesthetics have usually been modeled by physiologic models. However, these models have limitations, and they do not consider ventilation/perfusion matching. Respiratory diseases account for a large part of morbidity and mortality and are associated with pulmonary VA/Q mismatch that may affect uptake and elimination of volatile anesthetics.

The objectives of the studies were firstly to investigate assessment of VA/Q mismatch by MMIMS and secondly to investigate the effects of asthma-like VA/Q mismatch on the kinetics of volatile anesthetics in an experimental porcine model.

Anesthetized and mechanically ventilated piglets were studied.

In study I, a direct comparison of MIGET by MMIMS with the conventional MIGET by GC in three animal models that covered a wide range of VA/Q distributions was preformed. The two methods agreed well, and parameters derived from both methods showed good agreement with externally measured references.

In studies II–IV, a stable method of inducing and maintaining asthma-like VA/Q mismatch with methacholine (MCh) administration was established, and the effect of VA/Q mismatch on the pharmacokinetics of desflurane and isoflurane was investigated. The present model of bronchoconstriction demonstrates a delay in volatile anesthetic uptake and elimination, related to the heterogeneity of MCh-inhalation induced ventilation. The difference in solubility of volatile anesthetics has a significant influence on their uptake and elimination under VA/Q mismatch. The higher blood soluble isoflurane is affected to a lesser degree than the fairly insoluble desflurane.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1269
Keyword [en]
Anesthesia, Animal models in research, Mass spectrometry, Gas chromatography, MIGET, Ventilation-perfusion, Desflurane, Isoflurane, Bronchoconstriction
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-304298ISBN: 978-91-554-9732-3OAI: oai:DiVA.org:uu-304298DiVA: diva2:1037116
Public defence
2016-12-08, Enghoffsalen, Akademiska sjukhuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-14 Created: 2016-10-03 Last updated: 2016-11-16
List of papers
1. Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry-a comparison with reference gas chromatography
Open this publication in new window or tab >>Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry-a comparison with reference gas chromatography
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2013 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 115, no 8, 1107-1118 p.Article in journal (Refereed) Published
Abstract [en]

The mismatching of alveolar ventilation and perfusion (V-A/Q) is the major determinant of impaired gas exchange. The gold standard for measuring V-A/Q distributions is based on measurements of the elimination and retention of infused inert gases. Conventional multiple inert gas elimination technique (MIGET) uses gas chromatography (GC) to measure the inert gas partial pressures, which requires tonometry of blood samples with a gas that can then be injected into the chromatograph. The method is laborious and requires meticulous care. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) facilitates the handling of blood and gas samples and provides nearly real-time analysis. In this study we compared MIGET by GC and MMIMS in 10 piglets: 1) 3 with healthy lungs; 2) 4 with oleic acid injury; and 3) 3 with isolated left lower lobe ventilation. The different protocols ensured a large range of normal and abnormal V-A/Q distributions. Eight inert gases (SF6, krypton, ethane, cyclopropane, desflurane, enflurane, diethyl ether, and acetone) were infused; six of these gases were measured with MMIMS, and six were measured with GC. We found close agreement of retention and excretion of the gases and the constructed V-A/Q distributions between GC and MMIMS, and predicted Pa-O2 from both methods compared well with measured Pa-O2. V-A/Q by GC produced more widely dispersed modes than MMIMS, explained in part by differences in the algorithms used to calculate V-A/Q distributions. In conclusion, MMIMS enables faster measurement of V-A/Q, is less demanding than GC, and produces comparable results.

Keyword
MIGET, ventilation/perfusion distributions, inert gases, mass spectrometry, membrane inlet, gas chromatography
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210589 (URN)10.1152/japplphysiol.00072.2013 (DOI)000325869400001 ()
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2016-10-13Bibliographically approved
2. Effects of methacholine infusion on desflurane pharmacokinetics in piglets
Open this publication in new window or tab >>Effects of methacholine infusion on desflurane pharmacokinetics in piglets
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2015 (English)In: Data in brief, ISSN 2352-3409, Vol. 5, 939-947 p.Article in journal (Refereed) Published
Abstract [en]

The data of a corresponding animal experiment demonstrates that nebulized methacholine (MCh) induced severe bronchoconstriction and significant inhomogeneous ventilation and pulmonary perfusion (V̇A/Q̇) distribution in pigs, which is similar to findings in human asthma. The inhalation of MCh induced bronchoconstriction and delayed both uptake and elimination of desflurane (Kretzschmar et al., 2015) [1]. The objective of the present data is to determine V̇A/Q̇ matching by Multiple Inert Gas Elimination Technique (MIGET) in piglets before and during methacholine- (MCh-) induced bronchoconstriction, induced by MCh infusion, and to assess the blood concentration profiles for desflurane (DES) by Micropore Membrane Inlet Mass Spectrometry (MMIMS). Healthy piglets (n=4) under general anesthesia were instrumented with arterial, central venous, and pulmonary artery lines. The airway was secured via median tracheostomy with an endotracheal tube, and animals were mechanically ventilated with intermittent positive pressure ventilation (IPPV) with a FiO2 of 0.4, tidal volume (V T)=10 ml/kg and PEEP of 5cmH2O using an open system. The determination of V.A/Q. was done by MIGET: before desflurane application and at plateau in both healthy state and during MCh infusion. Arterial blood was sampled at 0, 1, 2, 5, 10, 20, and 30 min during wash-in and washout, respectively. Bronchoconstriction was established by MCH infusion aiming at doubling the peak airway pressure, after which wash-in and washout of the anesthetic gas was repeated. Anesthesia gas concentrations were measured by MMIMS. Data were analyzed by ANOVA, paired t-test, and by nonparametric Friedman׳s test and Wilcoxon׳s matched pairs test. We measured airway pressures, pulmonary resistance, and mean paO2 as well as hemodynamic variables in all pigs before desflurane application and at plateau in both healthy state and during methacholine administration by infusion. By MIGET, fractional alveolar ventilation and pulmonary perfusion in relation to the V.A/Q. compartments, data of logSDQ̇ and logSDV̇ (the second moments describing global dispersion, i.e. heterogeneity of distribution) were estimated prior to and after MCh infusion. The uptake and elimination of desflurane was determined by MMIMS.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-275036 (URN)10.1016/j.dib.2015.11.002 (DOI)26702425 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2016-01-28 Created: 2016-01-28 Last updated: 2016-10-13Bibliographically approved
3. Bronchoconstriction induced by inhaled methacholine delays desflurane uptake and elimination in a piglet model
Open this publication in new window or tab >>Bronchoconstriction induced by inhaled methacholine delays desflurane uptake and elimination in a piglet model
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2016 (English)In: Respiratory Physiology & Neurobiology, ISSN 1569-9048, E-ISSN 1878-1519, Vol. 220, 88-94 p.Article in journal (Refereed) Published
Abstract [en]

Bronchoconstriction is a hallmark of asthma and impairs gas exchange. We hypothesized that pharmacokinetics of volatile anesthetics would be affected by bronchoconstriction. Ventilation/perfusion (V̇A/Q̇) ratios and pharmacokinetics of desflurane in both healthy state and during inhalational administration of methacholine (MCh) to double peak airway pressure were studied in a piglet model. In piglets, MCh administration by inhalation (100μg/ml, n=6) increased respiratory resistance, impaired V̇A/Q̇ distribution, increased shunt, and decreased paO2 in all animals. The uptake and elimination of desflurane in arterial blood was delayed by nebulization of MCh, as determined by Micropore Membrane Inlet Mass Spectrometry (wash-in time to P50, healthy vs. inhalation: 0.5min vs. 1.1min, to P90: 4.0min vs. 14.8min). Volatile elimination was accordingly delayed. Inhaled methacholine induced severe bronchoconstriction and marked inhomogeneous V̇A/Q̇ distribution in pigs, which is similar to findings in human asthma exacerbation. Furthermore, MCh-induced bronchoconstriction delayed both uptake and elimination of desflurane. These findings might be considered when administering inhalational anesthesia to asthmatic patients.

National Category
Physiology Respiratory Medicine and Allergy
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-264207 (URN)10.1016/j.resp.2015.09.014 (DOI)000368045500012 ()26440992 (PubMedID)
External cooperation:
Funder
Swedish Research Council, 5315 X2015-99x-22731-01-04Swedish Heart Lung Foundation
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2016-10-13Bibliographically approved
4. The Effect of Bronchoconstriction-induced Ventilation/Perfusion-Mismatch on Uptake and Elimination of Isoflurane and Desflurane
Open this publication in new window or tab >>The Effect of Bronchoconstriction-induced Ventilation/Perfusion-Mismatch on Uptake and Elimination of Isoflurane and Desflurane
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2016 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175Article in journal (Other academic) Submitted
National Category
Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-304297 (URN)
Available from: 2016-10-03 Created: 2016-10-03 Last updated: 2016-10-13Bibliographically approved

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