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On microvascular blood flow assessment with the new microdialysis urea clearance technique
Linköping University, Department of Clinical and Experimental Medicine, Plastic Surgery, Hand Surgery and Burns. Linköping University, Faculty of Health Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to develop and evaluate a new way of monitoring blood flow with microdialysis. A thin catheter consisting of a semipermeable membrane is implanted in the tissue being studied. The catheter is perfused by a solution that closely resembles interstitial fluid, and small water-soluble substances are allowed to diffuse passively through the pores of the membrane with the aim at reaching equilibrium with the surrounding tissue.  The minimally invasive character of microdialysis, and its ability to sample from the organ being studied, make microdialysis attractive in most research settings as well as for clinical surveillance. It has, however, become increasingly evident that microdialysis under conditions of non-equilibrium - for example, fluctuating regional blood flow, will alter the results gained. We have therefore aimed to explore the possibilities of developing a new marker of blood flow that will yield information about changes in blood flow that occur in the area of the microdialysis catheter itself.

We hypothesised that the changes in the diffusion of exogenous urea could be used as markers of changes in tissue blood flow. The theoretical basis for this approach is that the mass transfer of urea will increase across the dialysis membrane secondary to increased blood flow. As removal of urea from the vicinity of the dialysis membrane increases with increased blood flow, the concentration gradient of urea between the perfusate and tissue will also increase. This in turn will result in a greater loss of urea from the perfusate. The changes noted in retrieval of urea from dialysate by the system are therefore thought to be inversely related to changes in blood flow. We tested our hypothesis in two species of animal (rat and pig) and in man, and in three organ systems (muscle, liver, and skin), and present four papers that indicate that the urea clearance technique provides reliable and reproducible results. The technique was evaluated against conventional metabolic markers (lactate and glucose), the ethanol clearance technique (microdialysis), laser Doppler perfusion imaging (LDPI), and polarisation light spectroscopy (TiVi).

We present evidence that the urea clearance technique can be used to assess blood flow in the organs studied reliably and reproducibly with microdialysis. The microdialysis technique is minimally invasive and safe for the recipient, and catheters can easily be implanted during operation to monitor organs at risk. Urea is easily analysed as a standard assay among other “basic” metabolic markers (in a standard microdialysis kit) and has favourable characteristics with a standardised measurement system that is routinely used for monitoring metabolites in the clinic. The technique is also effective when used at lower perfusate flow rates (<1 μl/minute), which is advantageous as the recovery of metabolic markers increases at low perfusate flow rates.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1204
Keyword [en]
microdialysis, microcirculation
National Category
Surgery
Identifiers
URN: urn:nbn:se:liu:diva-63116ISBN: 978-91-7393-320-9 (print)OAI: oai:DiVA.org:liu-63116DiVA: diva2:376552
Public defence
2010-12-03, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-12-28 Created: 2010-12-11 Last updated: 2012-03-13Bibliographically approved
List of papers
1. Continuous assessment of concentrations of cytokines in experimental injuries of the extremity
Open this publication in new window or tab >>Continuous assessment of concentrations of cytokines in experimental injuries of the extremity
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2009 (English)In: International Journal of Clinical and Experimental Medicine, ISSN 1940-5901, Vol. 2, no 4, 354-362 p.Article in journal (Refereed) Published
Abstract [en]

Background. Inflammation plays an important part in the healing process. Little is known about the extent local inflammatory trauma response interacts with the central circulation and inflammation produced by central organs. The aim of the present study was to examine whether high cut-off microdialysis catheters offer potential to in real time assess interstitial cytokines variations in conjunction to markers of metabolism distal to a blunt vascular contusion. Methods. In a standardised contusion trauma model, microdialysis catheters (high MW (100kDa)) were inserted in the gracilis muscle distal to the trauma for the local assessment of IL-6, IL-8, TNF-a, total protein and the metabolic mediators (glycerol, puruvate and lactate). The contra lateral uninjured leg served as control of the centrally mediated inflammation propagated to the extremities. Results. The trauma led to a significant and quantitatively large (8-10 fold) increase in inflammatory cytokines (IL6 and 8) as measured both in the injured and control legs. There was only a minor, and not significant increase in concentrations of cytokines in the injured leg compared to the control leg.. There were no signs of ischemia in either leg. Conclusion. The new finding in this study is that both central, and local, inflammatory responses as well as metabolic mediators may be assessed continuously in skeletal muscle tissue distal to a major injury in an animal model. The findings suggest that the large trauma elicits a generalised inflammatory response to trauma rather than propagating a local one distal to the trauma.

Place, publisher, year, edition, pages
e-Century Publishing Corporation, 2009
Keyword
Blunt trauma; Inflammation; Microcirculation; Microdialysis; Rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-57062 (URN)20057979 (PubMedID)
Available from: 2010-06-11 Created: 2010-06-09 Last updated: 2010-12-28
2. Urea clearance: a new method to register local changes in blood flow in rat skeletal muscle based on microdialysis
Open this publication in new window or tab >>Urea clearance: a new method to register local changes in blood flow in rat skeletal muscle based on microdialysis
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2010 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 30, no 1, 57-63 p.Article in journal (Refereed) Published
Abstract [en]

Pgreater thanIncreasing evidence suggests that local blood flow should be monitored during microdialysis (MD) as the recovery of analytes is affected by local blood flow. At present ethanol clearance is the standard technique for this purpose, but it is not functional at very low perfusion velocities. Here, we introduce a technique for MD whereby local tissue blood flow is recorded by the use of urea clearance (changes inflow/outflow concentration), in conjunction with measurements of tissue metabolism (glucose, lactate and puruvate). MD probes were inserted into the gracilis muscle of 15 rats and perfused with a medium containing urea (20 mmol l-1). Changes in muscle blood flow were made by addition of noradrenaline (5 mu g ml-1) to the perfusion medium at two perfusion velocities (0 center dot 6 and 0 center dot 4 mu l min-1). The clearance of urea from the perfusion medium was then calculated and examined in relation to the dose of noradrenaline and to the coexisting changes in extracellular metabolites. The results showed reproducible and dose-dependent changes in blood flow that were induced by noradrenaline. These were characterized by dose-dependent changes in the urea clearance as well as blood-flow-specific changes in the MD metabolic markers (reduction in glucose and increase in lactate). The sensitivity for blood flow changes as assessed by urea clearance (MD) was increased at 0 center dot 4 compared with the 0 center dot 6 mu l min-1 perfusion speed. The results indicate that inclusion of urea to the perfusion medium may be used to monitor changes in skeletal muscle blood flow at low perfusion velocities and in parallel assess metabolic variables with a high recovery (greater than 90%).

Keyword
extracellular fluid; glucose; lactate; metabolism; recovery
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52899 (URN)10.1111/j.1475-097X.2009.00904.x (DOI)
Available from: 2010-01-13 Created: 2010-01-12 Last updated: 2017-12-12
3. Urea Clearance: A New Technique Based on Microdialysis to Assess Liver Blood Flow Studied in a Pig Model of Ischemia/Reperfusion
Open this publication in new window or tab >>Urea Clearance: A New Technique Based on Microdialysis to Assess Liver Blood Flow Studied in a Pig Model of Ischemia/Reperfusion
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2010 (English)In: EUROPEAN SURGICAL RESEARCH, ISSN 0014-312X, Vol. 45, no 2, 105-112 p.Article in journal (Refereed) Published
Abstract [en]

Delayed detection of ischemia is one of the most feared postoperative complications. Early detection of impaired blood flow and close monitoring of the organ-specific metabolic status may therefore be critical for the surgical outcome. Urea clearance is a new technique for continuous monitoring of alterations in blood flow and metabolic markers with acceptable temporal characteristics. We compare this new microdialysis technique with the established microdialysis ethanol technique to assess hepatic blood flow. Six pigs were used in a liver ischemia/reperfusion injury model. Microdialysis catheters were placed in liver segment IV and all circulation was stopped for 80 min, followed by reperfusion for 220 min. Urea and ethanol clearance was calculated from the dialysate and correlated with metabolic changes. A laser Doppler probe was used as reference of restoration of blood flow. Both urea and ethanol clearance reproducibly depicted changes in liver blood flow in relation to metabolic changes and laser Doppler measurements. The two techniques highly correlated both overall and during the reperfusion phase (r = 0.8) and the changes were paralleled by altered perfusion as recorded by laser Doppler.

Place, publisher, year, edition, pages
S. Karger AG, 2010
Keyword
Liver perfusion, Lactate, Ethanol, Metabolism, Recovery
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-62299 (URN)10.1159/000319868 (DOI)000283851400006 ()
Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2012-03-20
4. Assessment of blood flow changes in human skin by microdialysis urea clearance
Open this publication in new window or tab >>Assessment of blood flow changes in human skin by microdialysis urea clearance
2011 (English)In: Microcirculation, ISSN 1073-9688, E-ISSN 1549-8719, Vol. 18, no 3, 198-204 p.Article, review/survey (Refereed) Published
Abstract [en]

Objective: The aim of this study was to evaluate the urea clearance technique for the measurement of drug-induced blood flow changes in human skin, and compare it with two non-invasive techniques: polarization light spectroscopy and laser Doppler perfusion imaging.

Methods: Fifteen microdialysis catheters were placed intracutaneously on the volar aspect of the forearms of healthy human subjects, and were perfused with nitroglycerine, noradrenaline, and again nitroglycerine, to induce local tissue hyperaemia, hypoperfusion, and hyperaemia, respectively.

Results: Urea clearance, but not the other techniques, detected the changes in blood flow during all three periods of altered flow.  The last hyperaemic response was detected by all three methods.

Conclusion: Urea clearance can be used as a relatively simple method to estimate blood flow changes during microdialysis of vasoactive substances, in particular when the tissue is preconditioned in order to enhance the contrast between baseline and the responses to the provocations. Our results support that, in the model described, urea clearance was superior to the optical methods as it detected both the increases and decrease in blood flow, and the returns to baseline between these periods.

Place, publisher, year, edition, pages
Wiley, 2011
Keyword
microcirculation; laser Doppler perfusion imaging; polarisation light spectroscopy; ischaemia; reperfusion; hypoperfusion; hyperaemia
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-63115 (URN)10.1111/j.1549-8719.2010.00077.x (DOI)000288759900004 ()
Note
The original title of article IV was "Assessment of blood flow changes in a new pharmacological model of microdosing in human skin by microdialysis urea clearance".Available from: 2010-12-11 Created: 2010-12-11 Last updated: 2017-12-11Bibliographically approved

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