ADH, ACTH, cortisol(Table 3). In all groups, initial plasma concentrations of ADH were comparatively above the normal range. Values declined significantly thereafter (P < 0.001). Fifteen minutes after the start of postoperative pain management, concentrations in the EDA group were higher than in the three-in-one patients; after 120 and 180 min, concentrations in the EDA patients were higher than in both other groups (P = 0.001). In addition, the initial concentrations of ACTH and cortisol were comparatively above the normal range in all groups. Over time, the concentrations of ACTH decreased significantly in all groups (P < 0.001) and approached the normal range or reached it in the EDA group, respectively. No differences between the groups were found. Concentrations of cortisol showed significant changes over time within the groups (P = 0.007), but altogether the concentrations remained constantly above the normal range, and no group differences occurred.
Circulatory variables (Table 4)
The systolic arterial pressure significantly decreased in all groups over time (P = 0.001). This decrease was significantly pronounced in the EDA patients (P < 0.001), where values after 15, 30, 60 and 120 min were lower than for the three-in-one and the PCA patients. For HR, only minor changes occurred. In the PCA group, values were significantly higher 30 and 60 min after the start of postoperative pain management. Means of SPO2 were comparable at all measurements; and no fall ≤90% was observed.
Nausea occurred in six patients with the three-in-one block, in 12 patients with the EDA and in eight patients with the PCA system; vomiting occurred in three patients with the three-in-one block, in five patients with the EDA method and in six patients with the PCA system. These differences did not reach significance. All patients were satisfied with their individual scheme of postoperative pain management. The plasma concentrations of bupivacaine for the patients receiving the three-in-one block are given in Table 4.
Selye [6,7] defined stress as a 'general adaptation syndrome' evolving in three consecutive stages and emphasized the role of cortisol. The dual stress concept of Henry  distinguished two basic reactions without imperative chronological succession . The primary and active reaction is determined by epinephrine and norepinephrine according to Cannon and de la Paz's 'fight or flight' . The release of catecholamines allows the fast mobilization of cardiovascular, respiratory and metabolic reserves of the threatened organism, while intestinal circulation and function are reduced. The simultaneous release of ADH protects the fluid reserves of the organism; beyond this, ADH serves as a reserve circulation hormone [11-13]. Interactions between the central sympathetic system, ADH and release of ACTH (and subsequently cortisol) are evident, but have not yet been sufficiently examined . A connection to the secondary stage of stress is possible. This second stress stage is dominated by the activated pituitary-adrenal axis. According to Henry , this primary slower response indicates tolerance, adaptation and loss of control in the reaction to the stressor. With similar intention, Selye  characterized cortisol as a 'syntoxic hormone' for maintenance of life under stress, meaning a 'coexistence' between the organism and stressor without attacking the noxes.
During the intraoperative period, the aim of the different methods of general or regional anaesthesia is the moderation of the endocrine stress response. Moderation means avoidance of an overwhelming stress response as well as total suppression of this principally physiological and necessary response . After the operation, this role is taken over by the method of management of postoperative pain.
In this study, all patients scheduled for total knee arthroplasty received standardized premedication and balanced anaesthesia to establish comparable conditions for the assessment of postoperative pain management. Allocation to the procedure for postoperative pain management (three-in-one, EDA or PCA) followed a randomized, prospective design, and postoperative pain management started immediately with the first expression of pain. The groups were comparable; differences in body weight were insignificant for the methods of regional anaesthesia used and were compensated by weight-dependent doses in the PCA group.
The analgesic potency of the three methods was comparable. Within 15 min, VAS were reduced from >40 to <10 mm and were stabilized there for 180 min. This result led to resultant satisfaction scores in all groups of patients. VAS in all was significantly lower than in comparable studies in orthopaedic patients [16,17]. However, the limited observation of 180 min has to be considered .
In contrast to the equivalent efficacy of these methods regarding pain scores, differences in the effects on the endocrine stress response were found. All groups showed a considerable endocrine stress response before the start of postoperative pain management, and the concentrations of the stress hormones examined were far above normal ranges at this time. The intraoperative stress response was not investigated in this study. Nevertheless and corresponding to other studies , an acceptable intraoperative stress reduction is assumed, and the significant increases in stress response are assigned to the recovery phase from general anaesthesia.
Under these conditions, EDA led to a fast and marked reduction especially of the sympathoadrenergic stress response. Significant analgesia together with segment-dependent sympatholysis induced a considerable decrease in norepinephrine concentrations and was accompanied by a reduction of epinephrine concentrations. The small initial increase in ADH concentrations can be interpreted as compensation for impaired sympathoadrenergic function [11-13]. A corresponding temporary reduction of systolic arterial pressure without significant hypotension occurred, but compensatory increases in HR were missing. In addition, ACTH concentrations were influenced by EDA. In contrast to the other methods, normal ranges were regained at the end of the observation period. There was no clear influence on the cortisol level, but concomitant reactions were to be expected after a certain delay. A reduction of endocrine stress response was also found in the three-in-one group. The extent was smaller than in EDA patients, especially with regard to norepinephrine concentrations. Despite comparable analgesia, the endocrine stress variables in the PCA group showed a consistently different course. The sympathoadrenergic stress response was attenuated only after a considerable delay, and an initial increase of catecholamines occurred. ADH remained on a clearly higher level than in the EDA and the three-in-one patients. However, the stress-lowering effect on the pituitary-adrenal axis corresponded to the other methods.
A distinct postoperative endocrine stress response, despite subjectively acceptable analgesia, is well documented in the literature [4,19-23]. Hjortsø and colleagues  even found no differences in endocrine reactions despite a differing quality of analgesia, but the methodology of catecholamine detection in the present study is outdated. Other authors [2,24] could at least verify a partial association of pain intensity and stress response; however, this may also be interpreted as a sign of insufficient analgesia.
No significant differences in side-effects were found. Arterial oxygen saturation was comparable in all groups, and the critical threshold of 90% was not reached. The incidence of nausea and vomiting was statistically comparable too, and the use of pirinitramide had no special negative consequences in the PCA group. The initial reduction in arterial pressure may have contributed to the surprisingly high incidence of nausea in the EDA group. Altogether the incidence of nausea and vomiting was high and requires further preventative efforts. Nevertheless, satisfaction expressed by the patients was excellent. The plasma concentrations of bupivacaine in patients with the three-in-one block, which have not yet been studied as extensively as concentrations during EDA, etc., stayed far below toxicologically relevant limits .
The study verifies that postoperative pain management with either a three-in-one block, EDA or PCA admirably eliminates postoperative pain in patients after total knee arthroplasty. In contrast to these comparable clinical results, the effects on endocrine stress response were distinctly different. In this respect, EDA was superior, especially in the reduction of sympatho-adrenergic stress response. Stress reduction in PCA patients was significantly poorer, while the three-in-one block was intermediate. Despite considerable reduction, the EDA group still showed a significant endocrine stress response. This suggests that pain is not the main stressor in the immediate postoperative period, and sufficient analgesia with subjective well-being does not indicate a stress-free state. In this early postoperative period, other stressors than pain predominate. These humoral and neural stressors have their origin in tissue trauma with release of mediators such as cytokines, which is not prevented by adequate peripheral or central sensory blockade. In this context, pain becomes a secondary stressor. Although a reduction of morbidity by adequate postoperative pain management is not evident , there are at least indications for the reduction of myocardial ischaemia in high-risk patients . The superior stress-moderating effect of EDA shown here, therefore, would be suitable for patients with hypertension, coronary heart disease and diabetes mellitus, where the 'hidden' stress reduction beyond freedom of pain is of significance. Postoperative pain management with EDA may contribute to avoidance of sympathoadrenergic circulatory disorders, e.g. hypertension and myocardial ischaemia, but undesired hypotension has to be prevented as well. In addition, EDA counteracts stress-induced metabolic effects. Altogether, the stressor 'pain' is only one of numerous postoperative stressors, and a considerable stress response cannot be avoided, but only be reduced.
Despite excellent pain control by postoperative pain management, endocrine stress variables remained elevated after total knee arthroplasty, thus characterizing postoperative pain as a secondary stressor. When compared with a three-in-one block and PCA, epidural anaesthesia was superior in reduction of sympatho-adrenergic stress response.
1. Choinière M, Rittenhouse BE, Perreault S, et al.
Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology
2. Rutberg H, Håkanson E, Anderberg B, Jorfeldt L, Martensson J, Schildt B. Effects of the extradural administration of morphine, or bupivacaine, on the endocrine response to upper abdominal surgery. Br J Anaesth
3. Hjortsø N-C, Christensen NJ, Andersen T, Kehlet, H. Effects of the extradural administration of local anaesthetic agents and morphine on the urinary excretion of cortisol, catecholamines and nitrogen following abdominal surgery. Br J Anaesth
4. Scheinin B, Scheinin M, Asantila R, Lindberg R, Viinamäki O. Sympatho-adrenal and pituitary hormone responses during and immediately after thoracic surgery - modulation by four different pain treatments. Acta Anaesthesiol Scand
5. Adams HA, Biscoping J, Ludolf K, Borgmann A, Bachmann-M B, Hempleman G. Die quantitative Analyse von Amid-Lokalanaesthetika mittels Hochdruck Flüssigkeits-Chromatographie und UV-Detektion (HPLC-UV). Reg Anaesth
6. Selye H. A syndrome produced by diverse nocuous agents. Nature
7. Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol
8. Henry JP. Present concept of stress
theory. In: Usdin E, Kvetnansky R, Kopin IJ, eds. Catecholamines and Stress: Recent Advances.
New York, USA: Elsevier-North Holland, 1980: 557-571.
9. Adams HA, Hempelmann G. Die endokrine Streßreaktion in Anästhesie und Chirurgie-Ursprung und Bedeutung. Anästhesiol Intensivmed Notfallmed Schmerzther
10. Cannon WB, de la Paz D. Emotional stimulation of adrenal secretion. Am J Physiol
11. Möhring J, Glänzer K, Maciel JA Jr, et al.
Greatly enhanced pressor response to antidiuretic hormone in patients with impaired cardiovascular reflexes due to idiopathic orthostatic hypotension. J Cardiovasc Pharmacol
12. Peters J, Schlaghecke R, Thouet H, Arndt JO. Endogenous vasopressin supports blood pressure and prevents severe hypotension during epidural anesthesia in conscious dogs. Anesthesiology
13. Carp H, Vadhera R, Jayaram A, Garvey D. Endogenous vasopressin and renin-angiotensin systems support blood pressure after epidural block in humans. Anesthesiology
14. Schürmeyer T, Wagner TOF. Grundlagen der Endokrinologie. In: Schedlowski M, Tewes U, eds. Psychoneuroimmunologie.
Heidelberg, Germany: Spektrum Akademischer Verlag, 1996: 69-106.
15. Selye H. Hormone und Widerstandsfähigkeit. Münch Med Wschr
16. Rundshagen I, Kochs E, Standl T, Schnabel K, Schulte am Esch J. Subarachnoid and intravenous PCA versus bolus administration for postoperative pain relief in orthopaedic patients. Acta Anaesthesiol Scand
17. Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM. Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg
18. Silvasti M, Pitkänen M. Continuous epidural analgesia with bupivacaine-fentanyl versus patient-controlled analgesia with i.v. morphine for postoperative pain relief after knee ligament surgery. Acta Anaesthesiol Scand
19. Scott NB, Mogensen T, Bigler D, Kehlet H. Comparison of the effects of continuous intrapleural vs epidural administration of 0.5% bupivacaine on pain, metabolic response and pulmonary function following cholecystectomy. Acta Anaesthesiol Scand
20. Scott NB, Mogensen T, Bigler D, Lund C, Kehlet H. Continuous thoracic extradural 0.5% bupivacaine with or without morphine: effect on quality of blockade, lung function and the surgical stress
response. Br J Anaesth
21. Salomäki TE, Leppäluoto J, Laitinen JO, Vuolteenaho O, Nuutinen LS. Epidural versus intravenous fentanyl for reducing hormonal, metabolic, and physiologic responses after thoracotomy. Anesthesiology
22. Eriksson-Mjöberg M, Kristiansson M, Carlström K, Eklund J, Gustafsson LL, Olund A. Preoperative infiltration of bupivacaine - effects on pain relief and trauma response (cortisol and interleukin-6). Acta Anaesthesiol Scand
23. Klasen JA, Opitz SA, Melzer C, Thiel A, Hempelmann G. Intraarticular, epidural, and intravenous analgesia after total knee arthroplasty. Acta Anaesthesiol Scand
24. Møller IW, Dinesen K, Søndergård S, Knigge U, Kehlet H. Effect of patient-controlled analgesia on plasma catecholamine, cortisol and glucose concentrations after cholecystectomy. Br J Anaesth
25. Fitzgibbons DC, Moore DC, Balfour RI. Convulsant blood levels of bupivacaine. Anesthesiology
26. Seeling W, Bothner U, Eifert B, et al.
Patientenkontrollierte Analgesie versus Epiduralanalgesie mit Bupivacain oder Morphin nach großen abdominellen Eingriffen. Kein Unterschied in der postoperativen Morbidität. Anaesthesist
27. Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Can J Anaesth
Keywords:© 2002 European Academy of Anaesthesiology
ANAESTHESIA, anaesthesia conduction, anaesthesia epidural, anaesthesia nerve block; CATECHOLAMINES, EPINEPHRINE, NOREPINEPHRINE; ENDOCRINE SYSTEM; PAIN, postoperative; STRESS