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Local metabolic changes in subcutaneous adipose tissue during intravenous andepidural analgesia.

Ederoth, Per; Flisberg, Per; Ungerstedt, U; Nordström, C-H; Lundberg, Johan

Published in:Acta Anaesthesiologica Scandinavica

DOI:10.1034/j.1399-6576.2002.460517.x

2002

Link to publication

Citation for published version (APA):Ederoth, P., Flisberg, P., Ungerstedt, U., Nordström, C-H., & Lundberg, J. (2002). Local metabolic changes insubcutaneous adipose tissue during intravenous and epidural analgesia. Acta Anaesthesiologica Scandinavica,46(5), 585-591. https://doi.org/10.1034/j.1399-6576.2002.460517.x

Total number of authors:5

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Acta Anaesthesiol Scand 2002; 46: 585–591 Copyright C Acta Anaesthesiol Scand 2002Printed in Denmark. All rights reserved

ACTA ANAESTHESIOLOGICA SCANDINAVICA

0001-5172

Local metabolic changes in subcutaneous adipose tissueduring intravenous and epidural analgesia

P. EDEROTH1, P. FLISBERG1, U. UNGERSTEDT2, C.-H. NORDSTRÖM3 and J. LUNDBERG1

Departments of 1Anesthesiology and Intensive Care and 2Neurosurgery, Lund University Hospital, Sweden and 3Department of Pharmacology,Karolinska Institute, Stockholm

Background: This clinical study aimed at investigating the im-pact of postoperative thoracic epidural analgesia on extracellu-lar glycerol concentration and glucose metabolism in subcutane-ous adipose tissue, using the microdialysis technique. The sym-pathetic nervous activity, which can be attenuated by epiduralanesthesia, influences lipolysis and the release of glycerol.Methods: Fourteen patients who underwent major abdominalor thoraco-abdominal surgery were studied postoperativelyover 3days. For postoperative analgesia the patients were pros-pectively randomized to receive either thoracic epidural anal-gesia with a bupivacaine/morphine infusion (EPI-group, nΩ6)or a continuous i.v. infusion of morphine (MO-group, nΩ8). Theconcentration of glycerol, glucose and lactate in the abdominaland deltoid subcutaneous adipose tissue were measured usinga microdialysis technique.Results: The abdominal glycerol levels were equal in bothgroups. In the deltoid region of the EPI-group, glycerol concen-trations started to increase on Day 2, and reached significantly

PREVIOUS studies on metabolic effects of epiduralanalgesia have focused on the quantifying meta-

bolic markers in blood (1, 2) or urine (3) to representwhole body estimates. Some investigators havestudied regional effects (4, 5), but little is known aboutthe tissue’s local metabolism within and outside theanesthetized area during long-term postoperative epi-dural anesthesia.

The microdialysis technique provides possibilitiesof monitoring interstitial chemical events in varioustissues. It was originally developed to monitor thebrain (6) and has become a standard experimentaltechnique. The technique has recently been intro-duced in clinical practice (7, 8). With the microdialysistechnique it is possible to monitor substances such asglycerol, glucose and lactate in various tissues underclinical conditions. The biochemical changes in theextracellular fluid adjacent to the microdialysis cath-eter can be estimated with short-time intervals forseveral days (9).

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higher levels on Day 3 compared with the MO-group. The glu-cose and lactate levels showed no differences between groupsin the two regions.Conclusion: The uniform glycerol levels in abdominal subcuta-neous adipose tissue in conjunction with the difference in gly-cerol levels in the deltoid area indicate that the local lipolysis isdifferent in the two study groups. This might be explained by aregional metabolic influence of thoracic epidural analgesia,possibly via the sympathetic nervous system.

Received 11 June, accepted for publication 13 December 2001

Key words: anesthesia epidural; analgesia epidural; autonomicnerve block; microdialysis; adipose tissue; postoperative period;lipolysis; glycerol; adult.

c Acta Anaesthesiologica Scandinavica 46 (2002)

Previous investigations have shown that interstitialglycerol concentration in the subcutaneous adiposetissue may serve as a marker for the intracellular lipo-lytic rate (10). Subcutaneous lipolysis is activated bythe sympathetic nervous system (11–13), and the ac-tivity in the sympathetic nerve fibers could be blockedwithin the area covered by epidural anesthesia (14,15). Therefore, we hypothesized that epidural anal-gesia would attenuate the regional lipolysis within thearea covered by the epidural analgesia, reflected asdecreased glycerol concentrations as measured usingthe microdialysis technique. We expected the glycerollevels in areas not covered by the epidural analgesiato remain unaltered.

Thoracic epidural anesthesia has not been demon-strated to alter the glucose metabolism peri- or post-operatively during or after major surgery (16). How-ever, little is known about the local glucose met-abolism in subcutaneous adipose tissue during neuralblockade in patients. Accordingly, we studied the en-

P. Ederoth et al.

ergy metabolism (glucose and lactate) and our hy-pothesis was that epidural anesthesia would not affectextracellular glucose or lactate concentrations.

For 3 postoperative days, we studied patients aftermajor non-cardiac surgery when either thoracic epi-dural analgesia or intravenous morphine was used toachieve similar postoperative pain relief. Interstitialfluid from the subcutaneous adipose tissue was ana-lyzed for glycerol, glucose and lactate, and the micro-dialysis catheters were positioned inside and outsidethe area covered by the epidural blockade.

Materials and methods

Twenty-four patients (14 men and 10 women) admittedto the Department of Surgery for major abdominal(aortic surgery, gastrectomy, and BII-resection) andthoraco-abdominal surgery (esophagectomy) were in-cluded in the study. The Ethics Committee at Lund Uni-versity Hospital approved the study. All patients weregiven detailed written and oral information regardingthe study, and each patient gave their written consent.

The day before surgery the patients were ran-domized, using a closed envelope system, to receiveeither thoracic epidural anesthesia (EPI; nΩ12) or in-travenous morphine (MO; nΩ12). In the EPI-group,five patients were excluded on Day 2 because of epi-dural catheter failure (nΩ2), atrial fibrillation requir-ing cardioversion, respiratory failure, and postopera-tive confusion, respectively. One patient was excludedon Day 3 because of protocol violation. In the MO-group, four patients were excluded: two patients wereexcluded perioperatively because of technical errors,one patient was excluded on Day 2 because of a surgi-cal complication, and another patient wished to be ex-cluded on Day 3. Thus, eight patients in the MO-group and six patients in the EPI-group participatedduring the study period.

Preoperatively, patients in the EPI-group had an epi-dural catheter inserted via a vertebral interspace be-tween T7 and T10 while under local anesthesia. In allpatients general anesthesia was induced with thio-pental, N2O/O2 and isoflurane or desflurane. TheEPI-group subsequently received an epidural bolus of6–10 ml mepivacaine (Carbocain 2%, AstraA, Sweden)followed by a continuous infusion of 5–8 ml hª1 de-pending on age and height. Epidural morphine 3–4mg (Morfin SpecialA 0.4 mg mlª1, Astra, Sweden) wasadministered simultaneously with the bolus infusion,and repeated after 8 h if surgery continued. The MO-group received an i.v. infusion of fentanyl (2 mgkgª1hª1), which was gradually reduced and termin-ated at the end of surgery.

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Patients in the EPI-group received an epidural in-fusion of bupivacaine (2.5 mg mlª1) and morphine(0.05 mg mlª1) before the termination of general anes-thesia. The infusion rate was initially 3–5 ml hª1 de-pending on age and height. The MO-group receivedan intravenous infusion of morphine (1 mg mlª1) at 1–3 mg hª1 with a patient-controlled analgesia option of1 mg with a lockout interval of 10 min. For all patientsthe analgesic agents dosage was adjusted during thestudy to score a visual analog scale (VAS 0–10) of be-low four. All patients received paracetamol 1 g¿4 rec-tally four times daily during the study.

The patients spent the first postoperative night in apostoperative care unit, and the amount of analgesicsadministered was continuously adjusted to individualdemands. On the first postoperative day all the pa-tients returned to the surgical ward. The efficacy ofthe analgesia was continuously checked via VAS scor-ing. During the 3-day study period the patients weremonitored by the attending ward nurse who regardedthe VAS at rest and during mobilization. The painscore and the dose of analgesics were evaluated dailyby an anesthesiologist. Two liters of glucose 100 mgmlª1 were given each day for nutritional needs. Oneliter was started at 09:00 and the next at approximate-ly 16:00. In addition, one patient in the EPI-groupstarted oral nutrition on day one and one patient inthe MO-group on day two. All patients were encour-aged to mobilize as early as possible with the help ofa physiotherapist.

MicrodialysisAfter the induction of the general anesthesia twomicrodialysis catheters (CMA 60A, CMA, Solna,Sweden; membrane length 30 mm with a molecularcut-off at 20 kDa) were inserted into the subcutaneousadipose tissue. One catheter was placed on the leftside of the abdominal wall in the region representingthe T10 dermatome, approximately 10–12 cm from themidline. The second catheter was inserted into theadipose tissue in the deltoid area of the left arm. Eachcatheter was connected to a microdialysis pump(CMA 106A, CMA, Solna, Sweden) and perfused withRinger’s solution at 0.3 ml minª1. Capped microvials(Microvials, prod. no P000001, CMA, CMA, Solna,Sweden) containing the dialysate were exchangedhourly from 06:00 to 21:00 throughout the studyperiod starting on the first postoperative day at 06:00.They were stored at ª18æC for later biochemicalanalyses (glucose, lactate, and glycerol) with enzy-matic techniques (CMA 600A, CMA, Solna, Sweden).The concentration of a compound obtained by micro-dialysis is influenced by various technical factors. The

Local metabolism and epidural analgesia

Table1

Postoperative pain scores at rest and during mobilization.

VAS Day 1 Day 2 Day 3

EPI-group Rest 2.3∫0.3 1.6∫0.3 2.2∫0.6Mobilization 5.1∫0.6 3.2∫0.5 3.9∫0.6

MO-group Rest 1.8∫0.4* 0.8∫0.2* 0.7∫0.2*Mobilization 3.8∫0.5 4.0∫0.5 3.4∫0.5

Postoperative pain scoring according to the visual analog scale (VAS; 0–10cm), mean∫SEM, measured daily at rest and during mobilizationin the postoperative patients with thoracic epidural analgesia (EPI) or intravenous morphine (MO).*Significantly lower (P,0.05) VAS values at rest in the MO-group compared with the EPI-group.There were no differences between the groups during mobilization.

relative recovery of extracellular substances with themicrodialysis technique represents the concentrationin the outgoing dialysate divided by the true concen-tration in the extracellular space¿100 (17). With themicrodialysis membrane used in the present studyand a perfusion rate of 0.3 ml minª1 the relative recov-ery for glycerol is almost 100%, for lactate 100%, andfor glucose 79–90% (18).

Statistical methodsFor statistical comparisons between the groups thedaily area under the curve (AUC) was calculated forglucose, lactate and glycerol levels. Analysis of vari-ance (ANOVA) was performed, and thereafter Stu-dent’s unpaired and paired t-tests were used for spe-cific comparisons if the ANOVA indicated a differencebetween or within the groups. Visual analog scaledata are presented as mean∫SEM.

Results

There were no differences between the groups regard-ing gender, age, weight, or height. The distribution ofsurgical procedures, duration of surgery and intra-operative blood loss did not differ between the groups.The amount of glucose given per patient dayª1 did notdiffer between the groups during the 3 postoperativedays. The mean VAS scores at rest were below four dur-ing the whole study period in both groups (Table 1) inaccordance with the intentions in the study protocol.However, the VAS scores at rest were lower in the MO-group (P,0.05). The mean dose of bupivacaine 2.5 mgmlª1 and morphine 0.05 mg mlª1 given epidurally was4.7∫0.14 ml hª1 (mean∫SEM), 4.2∫0.12 ml hª1, and3.8∫0.12 ml hª1 on the first, second, and third post-operative day, respectively. On the first postoperativeday, two patients in the EPI-group received one doseeach of 2.0 and 2.5 mg IV ketobemidone, respectively.Thereafter no parenteral opioids were given to patientsin the EPI-group. The mean dose of IV morphine in the

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MO group was 2.0∫0.11 mg hª1, 1.5∫0.10 mg hª1, and1.4∫0.15 mg hª1 on the first, second, and third post-operative day, respectively.

Fig.1. Hourly concentrations from 06:00–21:00 of glycerol measuredwith microdialysis in the abdominal (a) and the deltoid (b) subcutane-ous adipose tissue for 3 postoperative days after major non-cardiacsurgery in the thoracic epidural analgesia group (EPI-group, brokenline) and the intravenous morphine group (MO-group, solid line).EPI- vs. MO-group on postoperative Day 3, *P,0.05. PostoperativeDay 3 vs. Day 1 in the EPI-group, †P,0.05.

P. Ederoth et al.

Table2

Max.–min. area under the curve per hour of glycerol in subcutaneousadipose tissue.

Deltoid MO Abdominal MOEPI EPI

Day 1 112–312 83–289 141–423 187–518Day 2 151–388 129–271 101–512 220–574Day 3 151–501 107–325 114–635 235–574

Max.–min. values for glycerol area under the curve per hour (mmollª1 h) measured with microdialysis in the abdominal and the deltoidsubcutaneous adipose tissue for 3 postoperative days in the patientstreated with either thoracic epidural analgesia (EPI) or intravenousmorphine infusion (MO).

Figure 1 shows the abdominal and deltoid subcuta-neous glycerol concentrations in the EPI- and MO-group. In the abdominal region there was no signifi-cant difference between the EPI- and MO-groups dur-ing any of the 3 study days. In the deltoid region theglycerol concentration was similar in both groups onDay 1. On Day 2 the levels in the EPI-group startedto increase, and on Day 3 there was a significant dif-ference (P,0.05) between the groups with higher del-toid glycerol levels in the EPI-group compared withthe MO-group (Fig. 1b). The glycerol levels in the del-toid region within the EPI-group were also signifi-cantly higher on Day 3 than on Day 1 (P,0.05). Themax.–min. values regarding glycerol AUC hª1 are pre-sented by groups, sites and days in Table 2.

There were no significant differences between theMO- and EPI-groups regarding the glucose concen-trations in subcutaneous adipose tissue neither in theabdominal region nor in the deltoid region (Fig. 2).During the study period the interstitial mean glucosevalues ranged between 5.2 and 11.0 mmol lª1 in theMO-group and between 5.1 and 11.6 mmol lª1 in theEPI-group. A difference in the daily variations in glu-cose concentration was observed between Day 1 andthe following 2 days. Glucose levels remained almostconstant on the first postoperative day, and were lowin the morning with a nadir of approximately 5 mmollª1 at 08:00–09:00 on Day 2 and 3. Thereafter, a steepincrease in glucose concentration reached a peakvalue of approximately 10 mmol lª1 in the afternoon.This pattern was similar between the groups and alsobetween the studied regions.

There were no significant differences between theMO- and EPI-groups regarding the lactate concen-tration in the subcutaneous adipose tissue (Fig. 3). Themean lactate levels ranged between 1.1 and 3.2 mmollª1 in the MO-group and between 1.2 and 3.2 mmollª1 in the EPI-group.

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Fig.2. Hourly concentrations from 06:00–21:00 of glucose measuredwith microdialysis in the abdominal (a) and the deltoid (b) subcutane-ous adipose tissue for 3 postoperative days after major non-cardiacsurgery in the thoracic epidural analgesia group (EPI-group, brokenline) and the intravenous morphine group (MO-group, solid line).

Discussion

The main observation in the present study was the uni-form glycerol levels in the abdominal subcutaneousadipose tissue together with the difference in the gly-cerol levels in the deltoid area for patients treated withpostoperative epidural and intravenous analgesia.

These observations indicate that regional lipolysisdiffers according to the postoperative analgesic regi-men, but the results should be interpreted with cau-tion. An increased concentration of a compound in theinterstitial fluid might depend on several factors, e.g.increased transport from the cells or from the blood,or a decreased uptake by the cells or a decreasedclearance via the blood. It might also be a result ofchanges in the relative recovery of the compound.

The relative recovery for glycerol was nearly 100%using the present microdialysis technique (18). As wedid not determine the relative recovery in this study

Local metabolism and epidural analgesia

there is the possibility of variation in this parameter,and hence microdialysis is only semiquantitative. If achange in relative recovery should occur over time, adecrease would be the most logical development re-sulting from, e.g. a tissue reaction around the mem-brane (19), causing a decrease in glycerol over time ata constant extracellular concentration.

Regional differences in glycerol concentration canoccur (20), but there are no previous studies on gly-cerol comparing the subcutaneous adipose tissue inthe deltoid and abdominal regions. In resting healthyvolunteers the abdominal tissue glycerol concen-tration ranges from 185 to 350 mM (18). In the presentstudy a considerable variation was obtained withvalues mainly in the upper normal range or above. Asnormal values for glycerol concentrations in the del-toid region are not available, we do not know if theMO-group or the EPI-group in our study representsthe normal physiologic concentrations. We can only

Fig.3. Hourly concentrations from 06:00–21:00 of lactate measuredwith microdialysis in the abdominal (a) and the deltoid (b) subcutane-ous adipose tissue for 3 postoperative days after major non-cardiacsurgery in the thoracic epidural analgesia group (EPI-group, brokenline) and the intravenous morphine group (MO-group, solid line).

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conclude that there is a difference, and that we shouldcompare the concentrations in the corresponding sitesbetween the groups and not the deltoid vs. the ab-dominal concentrations between or within the groups.Microdialysis glycerol values from subcutaneous adi-pose tissue should not be compared to mixed venousglycerol levels because the plasma glycerol concen-tration represents a whole-body mean value. How-ever, the obtained plasma level is a regional value, themore peripherally the sample is drawn, as demon-strated by Landau et al. (21). They found that theplasma glycerol concentration in a superficial forearmvein was 140% of the arterial concentration, whichwas interpreted as a regional glycerol release from thesubcutaneous adipose tissue.

Variations in local blood flow around the microdi-alysis membrane may influence the metabolite levelsobtained. For a substance produced in the tissue, suchas glycerol, an increase in local blood flow will in-crease the transport away from the adipose tissue anddecrease the extracellular concentration during con-stant lipolysis (22), and vice versa. Also, the extracel-lular glucose concentration is partly dependent on lo-cal blood flow (23), but in the opposite way, as glucoseis mainly transported to the adipose tissue. If thehigher deltoid glycerol levels in the EPI-group were aresult of an altered local blood flow, a lower deltoidblood flow (lower glycerol clearance from the adiposetissue) in the EPI-group than in the MO-group wouldbe the cause. If so, a lower deltoid glucose level inthe EPI-group would have been logical. Although lesslikely, the role of a decreased local blood flow as acause for the increased deltoid glycerol levels in theEPI-group cannot be ruled out.

The metabolism of glycerol is closely related to glu-cose metabolism via a-glycerophosphate and dihy-droxyacetone phosphate. Theoretically, an alteration inthe glucose metabolism could result in a decreased con-sumption of glycerol, resulting in increased intracellu-lar glycerol concentrations, and thus increased concen-trations in the extracellular compartment. Alterna-tively, increased synthesis of glycerol from the glucosemetabolism could occur. To what degree glucose met-abolism affects intracellular glycerol concentrations insubcutaneous adipose tissue is difficult to estimate.But, as postoperative patients have an increased lipoly-sis (24), it seems unlikely that carbohydrate metabolismis the major cause of the increased deltoid glycerol con-centration in the EPI-group.

The most probable cause of the increased deltoidglycerol levels in the EPI-group is, in our view, lipoly-sis. The reason for an increased lipolysis remainsspeculative, but it is known that lipolysis is stimulated

P. Ederoth et al.

by sympathetic nervous activity (11–13). A parallelchange in plasma catecholamines and interstitial gly-cerol levels has also been demonstrated duringsurgery (25). The lipolysis rate is accelerated duringgeneral anesthesia and abdominal surgery because ofincreased catecholamine production (26). Lumbar, butnot thoracic, epidural anesthesia, is demonstrated todecrease whole body lipolysis in lower, but not upper,abdominal surgery, probably because of insufficientafferent sympathetic blockade during thoracic epi-dural anesthesia (16, 27, 28). Therefore, we would notanticipate any difference in whole body lipolysis be-tween the groups in our study.

When local anesthetics are administered epidurallythere is an attenuation of the sympathetic activity in theanesthetized area. This has been demonstrated by Lun-din et al. in humans, where a total blockade of sym-pathetic nerve activity in the skin and muscle of the legcould be obtained during lumbar epidural anesthesia(14, 15). Postoperative analgesia with a thoracic epi-dural technique aims at a low dose of local anestheticsepidurally to avoid systemic effects, e.g. orthostatic hy-potension. Accordingly, the attenuation of the sym-pathetic tone in the area covered by the epidural anal-gesia is most likely less profound than in Lundin’sstudies. Besides, thoracic epidural anesthesia gives adifferent regional attenuation of the sympathetic activ-ity, allowing unaffected sympathetic impulses to thelegs (29). We have not found any study of sympatheticactivity cranial to epidural segments (e.g. deltoid area)during a postoperative period. Taken together, we ex-pected a low attenuation of the sympathetic activitywithin the area covered by the thoracic epidural anal-gesia and no influence outside this area.

We did not measure the extent of epidural anesthesiain our study. A VAS score below four and a patient sat-isfied with the analgesia were our endpoints. We haveearlier examined the extension of the epidural anes-thesia (30, 31) in the same type of patients and found aconstant level of epidural anesthesia for several days.The same bupivacaine concentration was used but themorphine content was higher (0.125 mg mlª1 vs. 0,05mg mlª1) than in the present study. This does notguarantee a stable sensory blockade in our study, buttaken together with satisfying pain relief, it increasesthe probability of a stable neural blockade.

Unexpectedly, the patients in the MO-group hadlower VAS scores at rest than those in the EPI-group,which might be an effect of a small size study popula-tion. In another study performed at our department1670 patients received a postoperative epidural and1026 patients an intravenous morphine analgesia in asimilar way to the present study (Flisberg et al. unpub-

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lished observation). The EPI-group had overall lowerVAS scores, except on the fourth postoperative day.Also, it could be debated if the statistically significantdifference in the present study is clinically relevant be-cause the VAS scores at rest in both groups were low.

In contrast to our hypothesis, we found similar ab-dominal glycerol levels in the groups but higher del-toid glycerol concentrations in the EPI-group com-pared with the MO-group. With our study design wecan only speculate about the explanations. Our maintheory is that the increased deltoid glycerol levels inthe EPI-group reflect an increased lipolysis, which, inturn, is a result of an increased deltoid sympatheticactivity. The reason for similar abdominal sympatheticactivity in the groups but higher deltoid sympatheticactivity in the EPI-group might be a regional attenu-ation of the sympathetic activity within, but not out-side, the anesthetized area. Several possible expla-nations for an increased sympathetic activity in theEPI-group exist; for example the difference in VASscore does reflect a higher level of pain in the EPI-group, which increases the sympathetic activity (32),or a different degree of mobilization between thegroups (33, 34). Another hypothetical explanationmight be a compensatory increased sympathetic exci-tation of unblocked segments, as demonstrated byTaniguchi et al. (35). The same phenomenon mighthave a parallel in compensatory sweating in otherlocations after sympathectomy for palmar hyperhi-drosis (36). The difference in deltoid glycerol levelsappeared on day three only. Obviously, there is a timefactor of importance involved and the microdialysistechnique is well suited to this type of long-termstudy.

Conclusion

As evaluated with the microdialysis of the subcutane-ous adipose tissue, local glycerol concentrations, butnot glucose and lactate, were altered by the post-operative epidural analgesia, but not until the thirdpostoperative day. We interpret the increased deltoidglycerol concentration as an increased local lipolysis,and speculate that an increased lipolysis is the resultof increased sympathetic activity.

AcknowledgementsThe authors wish to thank Monika Borgsen, RN, for skillful as-sistance, and CMA, Stockholm, Sweden for providing part ofthe microdialysis equipment. This study has been supported bygrants from the University Hospital in Lund.

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Address:Per Ederoth, MDDepartment of Anesthesiology and Intensive CareUniversity HospitalS-221 85 LundSwedene-mail: per.ederoth/skane.se