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Effects of burns and vasoactive drugs on human skin: Clinical and Experimental studies using microdialysis
Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Anaesthesiology and Intensive Care VHN.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients who require critical care, including those with burns, are affected by a systemic inflammatory reaction, which at times has consequences such as multiple organ dysfunction and failure. It has become increasingly evident that other factors important in the development of organ dysfunction are disturbances at the tissue level, in the microcirculation. Such disturbances activate cascade systems including stress hormones, all of which have local effects on organ function.

Despite this knowledge, monitoring and treatment in critical illness today relies mainly on central haemodynamics and blood sampling.

Microdialysis is a minimally invasive technique that enables us to study the chemical composition and changes in biochemistry in the extracellular, extravascular space in living tissues. Most of our current experience is from animal models, but the technique has also been used in humans and has become routine in many neurosurgical intensive care units to monitor brain biochemistry after severe injury. In skin, this experience is limited. During the first half of this thesis we studied the injured and uninjured skin of severely burned patients. The results show that there are severe local metabolic disturbances in both injured and uninjured skin. Most interesting is a sustained tissue acidosis, which is not detectable in systemic (blood) sampling. We also recorded considerable alterations in the glucose homeostasis locally in the skin, suggesting a cellular or mitochondrial dysfunction. In parallel, we noted increased tissue glycerol concentrations, which indicated appreciable traumainduced lipolysis.

We also examined serotonin kinetics in the same group of patients, as serotonin has been claimed to be a key mediator of the vasoplegia and permeability disturbances found in patients with burns. We have shown, for the first time in humans to our knowledge, that concentrations of serotonin in skin are increased tenfold, whereas blood and urine concentrations are just above normal. The findings support the need for local monitoring of substances with rapid local reabsorption, or degradation, or both. The results also indicate that serotonin may be important for the systemic response that characterises burn injuries.

In the second half of the thesis we evaluated the effects of microdosing in skin on metabolism and blood flow of vasoactive, mainly stress-response-related, drugs by the microdialysis system. The objectives were to isolate the local effects of the drugs to enable a better understanding of the complex relation between metabolic effects and effects induced by changes in local blood flow. In the first of these two studies we showed that by giving noradrenaline and nitroglycerine into the skin of healthy subjects we induced anticipated changes in skin metabolism and blood flow. The results suggest that the model may be used to examine vascular and metabolic effects induced locally by vasoactive compounds. Data from the last study indicate that conventional pharmacodynamic models (Emax) for time and dose response modelling may be successfully used to measure the vascular and metabolic response in this microdosing model.

We conclude that the microdialysis technique can be successfully used to monitor skin metabolism and iso late a mediator (serotonin) of the local skin response in burned patients. It was also feasible to develop a vascular model in skin based on microdialysis to deliver vasoactive substances locally to the skin of healthy volunteers. This model provided a framework in which the metabolic effects of hypoperfusion and reperfusion in skin tissues could be examined further.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1195
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-59519ISBN: 978-91-7393-342-1 (print)OAI: oai:DiVA.org:liu-59519DiVA: diva2:352001
Public defence
2010-10-08, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-09-17 Created: 2010-09-17 Last updated: 2012-05-09Bibliographically approved
List of papers
1. Microdialysis shows metabolic effects in skin during fluid resuscitation in burn-injured patients
Open this publication in new window or tab >>Microdialysis shows metabolic effects in skin during fluid resuscitation in burn-injured patients
2006 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 10, no 6, Art.no: R172- p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Established fluid treatment formulas for burn injuries have been challenged as studies have shown the presence of tissue hypoxia during standard resuscitation. Such findings suggest monitoring at the tissue level. This study was performed in patients with major burn injuries to evaluate the microdialysis technique for the continuous assessment of skin metabolic changes during fluid resuscitation and up to four days postburn. Methods: We conducted an experimental study in patients with a burn injury, as represented by percentage of total body surface area burned (TBSA), of more than 25% in a university eight-bed burns intensive care unit serving about 3.5 million inhabitants. Six patients with a median TBSA percentage of 59% (range 33.5% to 90%) and nine healthy controls were examined by intracutaneous MD, in which recordings of glucose, pyruvate, lactate, glycerol, and urea were performed. Results: Blood glucose concentration peaked on day two at 9.8 mmol/l (6.8 to 14.0) (median and range) and gradually declined on days three and four, whereas skin glucose in MD continued to increase throughout the study period with maximum values on day four, 8.7 mmol/l (4.9 to 11.0). Controls had significantly lower skin glucose values compared with burn patients, 3.1 mmol/l (1.5 to 4.6) (p < 0.001). Lactate from burn patients was significantly higher than controls in both injured and uninjured skin (MD), 4.6 mmol/l (1.3 to 8.9) and 3.8 mmol/l (1.6 to 7.5), respectively (p < 0.01). The skin lactate/pyruvate ratio (MD) was significantly increased in burn patients on all days (p < 0.001). Skin glycerol (MD) was significantly increased at days three and four in burn patients compared with controls (p < 0.01). Conclusion: Despite a strategy that fulfilled conventional goals for resuscitation, there were increased lactate/pyruvate ratios, indicative of local acidosis. A corresponding finding was not recorded systemically. We conclude that MD is a promising tool for depicting local metabolic processes that are not fully appreciated when examined systemically. Because the local response in glucose, lactate, and pyruvate metabolism seems to differ from that recorded systemically, this technique may offer a new method of monitoring organs. © 2006 Samuelsson et al., licensee BioMed Central Ltd.

Place, publisher, year, edition, pages
London, UK: BioMed Central, 2006
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-37628 (URN)10.1186/cc5124 (DOI)000247718500020 ()17166287 (PubMedID)36806 (Local ID)36806 (Archive number)36806 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2014-09-24Bibliographically approved
2. Serotonin kinetics in patients with burn injuries: A comparison between the local and systemic responses measured by microdialysis-A pilot study
Open this publication in new window or tab >>Serotonin kinetics in patients with burn injuries: A comparison between the local and systemic responses measured by microdialysis-A pilot study
2008 (English)In: Burns, ISSN 0305-4179, Vol. 34, no 5, 617-622 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: To investigate serotonin (5HT) locally in burned and uninjured skin (intracutaneous) by microdialysis, and simultaneously record urinary and blood values in the same subjects. For comparison, serotonin values were also measured in skin of healthy controls. Design and setting: An experimental study in burned patients with of more than 25% TBSA (total burn surface area) % in an 8-bed tertiary burns unit, serving about 3.5 million persons. Patients and methods: Six subjects with a median TBSA% of 59% (range 33.5-90), and five healthy controls were examined by intracutaneous microdialysis of the skin. Results: 5HT was increased in burned patients, compared with controls. This increase was tenfold in skin and was noted both in uninjured and burned skin. The highest values were recorded on day 1 (median 16.1 nmol in uninjured and 9.5 nmol in burned skin) and day 2 (15.6 nmol in uninjured and 13.4 nmol in burned skin). A rapid reduction was noted on day 3 (4.9 nmol in uninjured and 3.8 nmol in burned skin). The corresponding value for control subjects was 1.3 nmol. The 5HT in blood was twice normal on day 2, and gradually reduced on days 3 and 4 (3189, 3035 and 2573 nmol, respectively). Urinary 5HT concentrations were increased only on day 2 at 1755 nmol and thereafter returned to the normal range on days 3 and 4 (1248 and 1344 nmol, respectively). Conclusions: We showed that microdialysis may be used in the critical care of burns, and local skin serotonin concentrations examined continuously for several days. The findings of significantly raised tissue serotonin concentrations, compared to that in blood and urine, suggests that serotonin may be important in local vascular control and formation of oedema. © 2007 Elsevier Ltd and ISBI.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43419 (URN)10.1016/j.burns.2007.08.003 (DOI)73800 (Local ID)73800 (Archive number)73800 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-01-10
3. Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysis
Open this publication in new window or tab >>Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Skin has a large dynamic capacity for alterations in blood flow, and is therefore often used for recruitment of blood during states of hypoperfusion. Little is known, however, about the metabolic consequences seen in skin secondary to hyporperfusion, particularly when the effects of vasoactive drugs are involved. The aims of this study were: to develop an in vivo, human microdosing model based on microdialysis in skin; and to investigate the effects on blood flow and metabolism of administering noradrenaline and nitroglycerine locally.

Method: Nine healthy volunteers each had two or three microdialysis catheters placed intradermally in the volar surface of the lower arm. After a stabilisation period, the catheters were perfused with buffers containing noradrenaline 0.5 or 5 μg/ml for 60 minutes, and after a second period of equilibrium of 60 minutes, all catheters were perfused with buffer containing nitroglycerine (0.5mg/ml). Changes in the blood flow in the skin were measured by laser Doppler imaging urea and ethanol clearance. Simultaneous changes in tissue glucose, lactate, and pyruvate concentrations were recorded.

Results: Perfusing skin with noradrenaline and nitroglycerine induced appreciable changes in all variables studied, depending on time and dose. The changes in glucose and lactate concentrations correlated with the change in blood flow assessed by either laser Doppler imaging or urea clearance. The changes in glucose and lactate that were induced by vasoconstriction (noradrenaline) continued until vasodilatation was induced by nitroglycerine.

Conclusion: Noradrenaline given by microdialysis in healthy volunteers induced reproducible and dose-dependent hypoperfusion and ischaemia with simultaneous metabolic consequences. Among these, we particularly note that: tissue glucose concentrations responded rapidly to hypoperfusion but remained considerably higher than zero, which suggests an energy-dependent deficiency in cellular uptake; and vasoconstriction remained after cessation of the noradrenaline perfusion, implicating vasospasm and a lack of autoregulatory (recovery) capacity in skin. These findings are particularly interesting from the critical care perspective, where noradrenaline is used extensively for circulatory support. The metabolic consequences may be underestimated and our results suggest that further investigations are warranted.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59517 (URN)
Available from: 2010-09-17 Created: 2010-09-17 Last updated: 2010-09-17Bibliographically approved
4. A human vascular model based on microdialysis for the assessment of the vasoconstrictive dose-response effects of noradrenaline and vasopressin in skin: in JOURNAL OF VASCULAR RESEARCH, vol 48, pp 320-320
Open this publication in new window or tab >>A human vascular model based on microdialysis for the assessment of the vasoconstrictive dose-response effects of noradrenaline and vasopressin in skin: in JOURNAL OF VASCULAR RESEARCH, vol 48, pp 320-320
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2011 (English)In: JOURNAL OF VASCULAR RESEARCH, Karger , 2011, 320-320 p.Conference paper, Published paper (Refereed)
Abstract [en]

Microdialysis is a well-established technique for continuous sampling of small, water-soluble molecules within the extracellular fluid space in vivo. It also allows the use of microdoses of drugs, and the simultaneous evaluation of their related effects at the site of action. The present study was an experimental, randomized microdose trial to develop a human vascular model of dose response. We aimed to evaluate a microdialysis dosing method using urea clearance as a marker of druginduced changes in dermal blood flow and metabolism (glucose and lactate) in 12 healthy volunteers. We found that asymptomatic vasoconstriction can be detected by continuous microdialysis measurements of urea clearance in dermal tissue. More importantly, dose-effect relations using the Emax model could be constructed using the corresponding data on drug doses and both the urea clearance-based flow estimates and the changes in concentrations of tissue metabolites. This in vivo human experimental skin model offers an interesting tool with which both the dose-response effects on blood flow and concentrations of tissue metabolites of potent vasoactive substances can be evaluated.

Place, publisher, year, edition, pages
Karger, 2011
Keyword
Microdialysis; Urea; Skin; Noradrenalin; Vasopressin; micro dose; dose-response; pharmacodynamics; human; vasoconstriction
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59518 (URN)000294760800317 ()
Available from: 2010-09-17 Created: 2010-09-17 Last updated: 2012-03-21Bibliographically approved

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