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Acta Anaesthesiol Scand 2013; 57: 171177 Printed in Singapore.

All rights reserved

2012 The Authors Acta Anaesthesiologica Scandinavica 2012 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/j.1399-6576.2012.02731.x

High thoracic epidural analgesia decreases stress hyperglycemia and insulin need in cardiac surgery patients
J. Greisen, D. V. Nielsen, E. Sloth and C.-J. Jakobsen
Department of Anaesthesiology & Intensive Care, Aarhus University Hospital, Aarhus, Denmark

Objective: Assuming that high thoracic epidural analgesia (HTEA) with the sympathetic block might decrease postoperative blood glucose (BG) level and reduce the need of insulin, the aim was to evaluate the effect of HTEA on the BG level and insulin requirement in patients undergoing cardiac surgery. Materials and methods: Forty-two low-risk patients age 6579 years scheduled for elective coronary artery bypass grafting with or without aortic valve replacement were randomised to receive HTEA as supplement for general anaesthesia. BG and lactate were measured before and after cardiopulmonary bypass and postoperatively at least every 3 h together with administration of insulin. Postoperative pain was evaluated 30 min, 2, 4 and 6 h after extubation, and before discharge from the intensive care unit. Results: Overall BG levels showed great variation over time (P < 0.001). No statistically signicant difference was found in

perioperative BG, but postoperative lower BG levels were found in HTEA patients (P = 0.042). The number of patients not receiving insulin in postoperative period was signicantly higher in HTEA group (9 vs. 2, P = 0.032). No differences were seen in lactate levels. Patients in the HTEA group had signicant lower pain scores (P < 0.001). Conclusion: HTEA preserves glucose metabolism better and leads to a lesser degree of stress hyperglycaemia in cardiac surgery patients.
Accepted for publication 14 May 2012 2012 The Authors Acta Anaesthesiologica Scandinavica 2012 The Acta Anaesthesiologica Scandinavica Foundation

yperglycaemia in perioperative cardiac surgery patients is associated with an increased mortality and morbidity. Insulin resistance has been proposed as a marker of surgical stress1 as insulin resistance increases in the surgical patient in a dose response-like manner. In 2001, the rst Leuven study2 demonstrated a reduction in mortality of 43% in a group of patients with targeted blood glucose (BG) of 80110 mg/dl compared to a group with BG of 180200 mg/dl. Other studies have shown that tight glycaemic control in the cardiac surgery patients has benecial effects on mortality, infection rates, and organ performance.36 The way of controlling BG has been through injections or infusions of insulin. Other ways of controlling the stress hyperglycaemia have gained less attention but effective pain management and reduction of the sympathetic outow which can be achieved with high thoracic epidural analgesia (HTEA) are possible benecial treatments in the cardiac surgery patients. Liem

et al.7 showed decreased levels of postoperative pain as well as decreased levels of catecholamines and cortisol in a randomised group of coronary artery bypass grafting (CABG) patients with HTEA compared with a conventional group, but this study did not contain BG data. Moore found no difference in BG within 24 h in a small randomised study with and without HTEA.8 Stenseth randomised 30 patients in three groups in which two groups had HTEA and found a blunting and delaying in the increase in BG at the time of skin incision but could not demonstrate differences in postoperative BG.9 Anderson investigated in a non-randomised study 104 patients with and without diabetes and with and without HTEA. A difference in BG was found in the rst 24 h, but it disappeared over time and was non-signicant after 3 days.10 The mean age of the investigated patients in the above mentioned studies were 52, 57, 55, and 65 years, respectively. Furthermore, severe pain per se has been shown to reduce insulin sensitivity by 22%

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in healthy volunteers.11 As patient age was considerably lower in the previous studies with conicting results and because the Anderson study was not randomised, we found a need for a randomised clinical study of a relevant age group. Assuming that the HTEA sympathetic block might reduce the need of insulin in postoperative BG control, the aim of the present investigation was to evaluate the effect of HTEA on the postoperative BG level and insulin requirement in patients undergoing cardiac surgery.

Study protocol
All preoperative cardiac medication was continued until the morning of surgery. All patients received standard premedication, consisting of benzodiazepine 510 mg together with paracetamol 2 g, 6090 min before surgery. The primary study had four arms where patients were randomised by standard envelope method to HTEA (HTEA group) or no HTEA (control group) together with either propofol or sevourane anaesthesia. From end of surgery and in recovery until extubation, all patients were sedated with propofol.

Patients and methods


This study was a subgroup of a mono-centre, randomised, and controlled clinical trial, and took place at the Department of Anaesthesiology and Intensive Care, Aarhus University Hospital-Skejby in Denmark. The study was approved by the regional ethics committee and Danish Medicines Agency (EudraCT 2005-000617-35) and was carried out in accordance with the Helsinki II declaration. The study period was from 01.03.07 to 31.03.09. Patients aged 6580, who were scheduled for elective CABG, aortic valve replacement (AVR), or combined surgery and did not meet the exclusion criteria, were approached for participation in the study. Patients were approached by the same study-nurse, and written as well as oral information was obtained. The identication of the patients was performed in a consecutive manner in the study period. Due to other running studies in the department during the study period, patients for this study were mainly operated on Tuesdays and Wednesdays. Patients with ejection fraction less than 0.3, myocardial infarction within the last 4 weeks, diagnosed diabetes, severe pulmonary or arterial hypertension, contraindication for epidural catheter, ongoing anti-platelets therapy, and without preoperative optimal echocardiographic imaging were not included. Beyond the scope of the primary study, the department in March 2007 changed the observation and handling of BG to a more rm and xed regime, which in the following time was incorporated into the ongoing study protocol. The new regime consisted of BG control every 23 h, keeping the BG between 5.0 and 8.5 during the postoperative stay in the cardiac recovery unit. Power calculation was based on a hypothetic 25% insulin reduction (13 5 to 9.75 5 IU). With the two sided a error set at 0.05 and b error set at 0.2 nineteen patients were needed in each group. With 42 patients remaining in the primary study the number was sufcient to this subgroup study.

HTEA
In HTEA patients, the epidural catheter was inserted the day before surgery via the second or third thoracic (Th2-Th4) vertebral interspace. The epidural block was initiated with a bolus dose of 57 ml 5.0 mg/ml bupivacaine (Marcaine, Astra, Sdertalje, Sweden) together with sufentanil 2.5 mg/ml. The sensory blockade was not evaluated before continuing anaesthesia. After start of surgery, the blockade was continued with a mixture of bupivacaine 2.5 mg/ml/sufentanil 1 mg/ml 46 ml/h, by discretion of the attending anaesthesiologist, until end of surgery. Shortly after arrival in the intensive care unit (ICU), the epidural mixture was changed to bupivacaine 1 mg/ml together with sufentanil 1 mg/ml and continued after discharge from the ICU until the second postoperative day. According to protocol, postoperative anticoagulation therapy, except low-dose fragmin (dalteparin), was not initiated until 4 h following removal of epidural catheter.

Outcome parameters
Primary end points were postoperative levels of arterial BG and administered units of insulin. Secondary parameters were postoperative arterial blood lactate together with postoperative pain level and need for vasoactive drugs. BG and lactate were measured (ABL, Radiometer, Copenhagen, Denmark) before and after cardiopulmonary bypass and postoperatively at least every 3 h. BG target was between 5.0 and 8.5 mmol/l. Fast acting insulin (Actrapid, Novo-Nordisk, Copenhagen, Denmark) was given as intravenous boluses according to department protocol: BG 8.510.0 mmol/l: Actrapid 4 IE; BG 10.012.0 mmol/l: Actrapid 6 IE; BG > 12.0 mmol/l: Actrapid 8 IE. After administration of insulin, BG was measured after 30 min and insulin administered until BG was 5.08.5 mmol/l in two successive measurements. Hereafter, BG was

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measured hourly for 2 h, every 2 h for 4 h, and nally taken every 4 h in 8 h. If insulin was administered, the protocol started over again with 30-min measurement intervals. A protocol was available for hypoglycaemia and patients weighing less than 60 kg were given half doses of insulin. No glucose infusions were intended to be given at any time during the study. Peroral intake after extubation was registered in the patient data management system and carbohydrate content of this was calculated. Postoperative pain was evaluated as part of the ICU score,12 where 12 objective or semi-objective parameters are used to estimate when patients are eligible for discharge from ICU. Scoring was performed 30 min, 2, 4, and 6 h after extubation, and shortly before discharge from ICU. Scoring was performed with the patient at rest and scored as no pain (Visual Analogue Scale (VAS 0-1)); light pain (VAS 24); moderate pain (VAS 57); severe pain (VAS 810) expressed as 0, 1, 2, and 3 points, respectively.

Results
Forty-four patients were approached for participation in the study, two patients declined to participate and 42 patients were enrolled in the study. No statistically signicant differences in any haemodynamic and demographic parameters, administration of insulin, or postoperative BG levels were seen between propofol and sevourane patients, and, thus, the subgroup study evaluates the effect of HTEA only in 42 patients, randomised to 21 patients in the HTEA group and 21 patients in the control group. Written informed consent was obtained in each patient. No misadventures occurred during the placement of the catheters, that is, no blood or cerebrospinal uid was seen after aspiration on the catheter. All patients intended to receive an epidural catheter had an epidural catheter been successfully placed. No patients had displaced catheters when they arrived for surgery. All the patients in both groups completed the study. Preoperative demographics are shown in Table 1. There were no statistically signicant differences between patients in HTEA group and control group. Furthermore, we found no statistically signicant differences regarding anaesthesia, operation, cardiopulmonary bypass, and cross-clamp time. Signicantly more patients in control group received vasodilators, while signicantly more patients in HTEA group received vasoconstrictors (Table 2).

Statistical analysis
Comparisons between groups were evaluated using independent samples t-test together with one-way or two-way analysis of variance (ANOVA) where appropriate. Categorical variables were evaluated with c2-test. Data in tables are reported as mean, standard deviation of the mean, or as count and percentage. A P < 0.05 was considered signicant for all the statistical tests. Statistic calculations were performed using the MedCalc software version 11.5.1 (Mariakerke, Belgium).

Table 1
Selected preoperative demographics. Control Demographic/Cardiac variables Age (Years) Body mass index (kg/m2) EuroScore Female sex Preoperative beta-blockers Preoperative Ca-antagonists Preoperative ejection fraction AVR/CABG/CABG + AVR Anaesthesia and surgery Anaesthesia time (min) Operations time (min) Cross-clamp time (min) Cardiopulmonary bypass time (min) 71.7 4.4 26.6 4.3 5.6 2.1 7 (33.3) 12 (57.1) 9 (42.9) 49.5 8.8 7/6/8 239 164 54 80 36 34 24 25 HTEA 71.0 4.5 26.3 3.2 5.0 1.7 10 (47.6) 11 (52.3) 7 (33.3) 52.1 10.6 9/8/4 249 172 57 90 52 52 30 34 P-value 0.607* 0.751* 0.268* 0.530 1.000 0.751 0.393* 0.393 0.483* 0.499* 0.695* 0.284*

*Independent samples t-test.c2-test for categorical data. Euroscore according to denitions http://www.euroscore.org. AVR, aortic valve replacement; CABG, coronary artery bypass grafting; HTEA, high thoracic epidural analgesia.

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Table 2
Postoperative vasodilators. Type No medical support Vasodilators Vasoconstrictors Inotropics use of inotropics, vasoconstrictors, and

Postoperative medical support Control 2 17 0 2 HTEA 3 8 9 1

P-value 1.0 0.011 0.001 1.0

Statistics c2-test. HTEA, high thoracic epidural analgesia.

Fig. 2. Average no. of units insulin and peroral carbohydrates given in the postoperative period, divided on time after arrival at the intensive care unit. The total number of given units was 13.1 8.7 in the control group and 7.7 8.4 in the high thoracic epidural analgesia (HTEA) group. (P = 0.047, independent samples t-test). The total number of carbohydrates was 5.0 10.4 g in the control group and 11.0 29.2 g in the HTEA group (P = 0.384, independent samples t-test).

Fig. 1. Blood glucose levels in the postoperative period divided on high thoracic epidural analgesia (HTEA) or control group. Blood glucose showed variation over time (P < 0.001) and was lower in HTEA patients (P = 0.042, two-way analysis of variance).

No glucose infusions were given at any time during the study. Two-thirds of the patients in each group did not receive any carbohydrate containing peroral intake before the last BG was taken. The distribution of intake on time and group can be seen from Fig. 2. Number of patients receiving peroral intake are comparable and a higher accumulated amount of carbohydrates are given in the HTEA group. Overall postoperative BG levels showed great variation over time (P < 0.001, two-way ANOVA) (Fig. 1). Pre-cardiopulmonary bypass (CPB) BG levels were 5.9 0.7 (control) and 6.0 0.6 (HTEA) mmol/l. An increase was seen after 6 h in ICU where a plateau was reached lasting until discharge (7.8 1.0 mmol/l in the HTEA group vs. 8.3 1.2 mmol/l in the control group). Postoperative levels of BG were statistically, signicantly lower in HTEA patients (P = 0.042, two-way ANOVA).

The number of patients not receiving insulin in the postoperative period was signicantly higher in the HTEA group (nine vs. two, P = 0.032, c2-test). The average number of insulin units given in different postoperative time periods is given in Fig. 2. Overall, the average number of insulin units was statistically, signicantly lower in the HTEA group (7.7 vs. 13.1 units, P = 0.047, independent samples t-test). However, the major difference between the groups was due to the signicantly lower number of patients receiving insulin as the average units of insulin in patients receiving insulin was 14.5 8.0 vs. 13.5 6.6. More females, although not statistically signicant, received insulin, 88% compared to 64% in males (P = 0.151, c2-test), and, furthermore, the HTEA effect on insulin need was statistically, signicantly less in females as they received insulin more frequently (90% vs. 27%, P = 0,007, c2-test). The blood content of lactate is shown in Fig. 3. Overall, the levels showed time variation (P < 0.001, two-way ANOVA) but no difference between groups. Analysing only on postoperative levels, no differences were found either with time or between groups. The postoperative pain scores were low in both groups. Totally 69% of all scores was no pain (VAS 01), 26% was light pain (VAS 24), and 5% was moderate pain (VAS 57). No patient had severe pain. The distribution of scores demonstrated that patients in the HTEA group scored signicantly

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Fig. 3. Blood lactate levels in the postoperative period divided on high thoracic epidural analgesia (HTEA) or control group. Twoway analysis of variance did not show statistically signicant variation either over time (P = 0.278) or between groups (P = 0.593).

Table 3
Postoperative pain scores distributed on occurrence of pain levels and HTEA/control. Group Control HTEA VAS 01 56 (54.9%) 81 (79.4%) VAS 24 42 (41.2%) 14 (13.7%) VAS 57 4 (3.9%) 7 (6.9%)

Signicant lower pain in HTEA group (P = 0.0001, c2-test). HTEA, high thoracic epidural analgesia.

lower (P = 0.0001, c2-test) than patients in the control group (Table 3).

Discussion
This study demonstrates that high epidural analgesia as an adjunct to general anaesthesia results in lower levels of BG and insulin need postoperatively in patients undergoing cardiac surgery. This is interpreted as a lower level of the obligatory stress hyperglycaemia elicited by anaesthesia, CPB, and surgery due to HTEA. The stress hyperglycaemia probably reects a state of insulin resistance in which whole body glucose disposal as shown by the glucose clamp technique is decreased as well as insulin-mediated suppression of endogenous glucose release.1 As no infusions of glucose were given and peroral carbohydrate intake postoperatively was comparable and even slightly more in the HTEA group, exogenous glucose cannot account for the ndings of lower BG and less insulin given in the HTEA group.

Our nding of a 0.5 mmol/l lower BG level in the postoperative period is in line with the previous nding of Anderson.10 The question is whether this represents a decrease in insulin sensitivity which is important for outcome. Since the rst Leuven study, the level of glycaemic control has been debated and the optimum level is still uncertain. A recent study on diabetic and non-diabetic cardiac surgery patients which were investigated with hyperinsulinaemic euglycaemic clamp technique concluded that every decrease in insulin sensitivity (1 mg/kg/ min) resulted in increased incidence of major complications within 30 days of surgery.13 The population of cardiac surgery patients is becoming older. The average age for patients in The West Danish Heart Database for CABG and combined CABG and AVR is 68 years. The ndings in the present study in which mean age is 71 years may be more relevant than previous studies on glucose metabolism and HTEA. Acute and short-term regulation of insulin action, in the setting of surgical stress, involves many events including insulin binding to the insulin receptor, intracellular signal transduction pathways and translocation and function of glucose transport proteins.14 In the context of an acute stress stimulus, muscle contractions as a single bout of exercise15,16 or as prolonged work17 and insulin itself18 are stimulators of glucose uptake in skeletal muscle. In our study, the patients are anaesthetised and paralysed in both groups perioperatively, but the lower pain scores in the HTEA group postoperatively could theoretically result in an increased motor activity facilitated by a better pain control in the HTEA group, thereby enhancing insulin action. However, we did not measure whole body motor activity in the study. The stress hormones epinephrine,19,20 cortisol,21,22 and growth hormone23,24 all impair insulin action on both glucose uptake and on endogenous glucose output. We did not measure any of these hormones, but Liem7 earlier showed decreased circulating levels of catecholamines and cortisol in cardiac patients with a HTEA. The autonomic nervous system modulates glucose metabolism. Direct sympathetic nerve bre innervation of muscle25,26 enhances glucose uptake even in the anaesthetised individual. Sympathetic nervous system activity promotes increased glucose output from the liver by direct innervation27 and through activation of hormones which in turn has metabolic effects on the organ.28 We assume that the HTEA group did have a decreased sympathetic activity as blood pressure

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and pain rating were less in this group and thus presumable decreased glucose release. Furthermore, pain in itself has been shown to elicit insulin resistance in part by release of counter-regulatory hormones.11 Cardiopulmonary bypass increases postoperative glycaemia and insulin consumption in both diabetic and non-diabetic patients.29 This study also demonstrated that cardiopulmonary bypass during coronary artery surgery in diabetic women was associated with a more difcult glycaemic control in the early postoperative period. Although we had no diabetic patients in this study, our ndings support the previous ndings as women in our study received more insulin than men. The relation between sympathetic stimulation, glucose uptake, and insulin action is very complex. A very early study in patients with acute myocardial infarction disclosed a highly signicant correlation between plasma noradrenaline and the fasting glucose concentration and the glucose tolerance.30 A later study showed that noradrenaline infusion had no signicant inuence on plasma insulin or glucose levels and only led to increased levels of circulating free fatty acids.31 This is in accordance with the ndings in our study where there was no statistically signicant difference in the frequency of insulin administration in HTEA patients receiving noradrenalin or not (44%% vs. 33%, P = 0.673, c2-test). A relatively high number of patients received a vasodilator drug during recovery (Table 3), but we did not nd any difference in need of insulin between patients receiving vasodilators (76%) or not (68%) which is in accordance with earlier study showing no impact on glucose uptake in normal doses of sodium nitroprusside.32 Insertion of an epidural catheter in patients undergoing subsequent full heparinisation carries a risk of eliciting epidural haematoma with severe neurological consequences. There are no rm risk estimates in the literature, but Ruppen et al.33 calculated a risk of 1 : 4600 for epidural haematoma based on a study on 14,000 patients undergoing cardiac, thoracic, or vascular surgery in which no events were reported. In the latest two reviews on epidural anaesthesia and cardiac surgery, no estimates could be made due to lack of events.34,35 We consider the risk extremely small based on the gures earlier and because we placed the catheters the day before surgery. We informed the patients about the risk before participation in the study. The insertion of HTEA the day before surgery is time consuming compared to not inserting, but in our organisation,

the patients are admitted to the department the day before surgery so patients are readily available.

Limitations of the study


We aimed at a clinical impact study and thus considered measurements of BG and insulin consumption only. To investigate in more detail the dynamics of glucose metabolism and regulatory aspects of HTEA, a larger setup would be needed including glucose clamp and tracer methodology as well as measurement of regulatory hormones.

Conclusion
In summary, HTEA in the cardiac surgery patient preserves glucose metabolism better and leads to a minor degree of stress hyperglycaemia than in patients conventionally anaesthetised. Conict of interest: None. Funding: None.

References
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