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Implications for critical care of a new in vivo human vascular microdosing technique for giving noradrenaline and nitroglycerine by microdialysis
Linköping University, Department of Medicine and Health Sciences, Anesthesiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre.
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
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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: urn:nbn:se:liu:diva-59517OAI: oai:DiVA.org:liu-59517DiVA: diva2:351996
Available from: 2010-09-17 Created: 2010-09-17 Last updated: 2010-09-17Bibliographically approved
In thesis
1. Effects of burns and vasoactive drugs on human skin: Clinical and Experimental studies using microdialysis
Open this publication in new window or tab >>Effects of burns and vasoactive drugs on human skin: Clinical and Experimental studies using microdialysis
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:nbn:se:liu:diva-59519 (URN)978-91-7393-342-1 (ISBN)
Public defence
2010-10-08, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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Supervisors
Available from: 2010-09-17 Created: 2010-09-17 Last updated: 2012-05-09Bibliographically approved

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Samuelsson, AndersFarnebo, SimonMagnusson, BeatriceAnderson, ChrisTesselaar, ErikSjöberg, Folke

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Samuelsson, AndersFarnebo, SimonMagnusson, BeatriceAnderson, ChrisTesselaar, ErikSjöberg, Folke
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Anesthesiology Faculty of Health SciencesAnaesthesiology and Surgical CentreSurgery Dermatology and Venerology Department of Dermatology and Venerology in ÖstergötlandDepartment of Clinical and Experimental MedicineBurn Unit Department of Plastic Surgery, Hand surgery UHL
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