Surgery causes an increase of catabolic hormones and an inhibition of the action or secretion of anabolic hormones, which results in hypermetabolism, hyperthermia, leucocytosis, immunosuppression and negative nitrogen balance . The sympathetic response is followed by an increase in prostanoid concentrations [2–4], of which thromboxane A2 has potentially deleterious effects being a very potent vasoconstricting and platelet-aggregating factor. Additionally, surgical procedures trigger an early inflammatory response, which is proven by the release of TNF-α, cortisol and of the proinflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8. IL-6, a hepatocyte-stimulating protein, is the principal inducer of the acute-phase protein synthesis such as the C-reactive protein. The systemic response (inflammatory, endocrine and metabolic) may cause intra- and postoperative complications, i.e. myocardial insufficiency, pulmonary and thromboembolic complications and a delayed convalescence because of fatigue. The results may be a postponement of the ability to work and an increase of costs . The degree of the systemic response depends on the extent of surgery .
Therefore, less traumatic surgical techniques have been searched for, e.g. laparoscopically assisted surgery. During recent years, laparoscopically assisted vaginal hysterectomy has gained wide popularity because of patients’ shorter hospital stay and sick leave compared with traditional abdominal hysterectomy [7,8]. The faster recovery is believed to originate from the lesser surgical trauma after laparoscopically assisted vaginal compared with abdominal hysterectomy . However, the literature concerning the systemic response after open and laparoscopic surgery is inconclusive [10–12]. Laparoscopically assisted vaginal hysterectomy differs from other laparoscopic surgery, as it is not a sole laparoscopic procedure, but needs a vaginal approach as well, which increases the extent of surgical trauma.
When different types of surgery are to be compared a large battery of biochemical tests is usually used. Many of these tests are used to evaluate the effect of different anaesthetic or pain treatment modalities on the intra- and postoperative stress response. However, some of these trauma markers may not be sensitive enough to discriminate between the stress responses to different types of surgery. In the present prospective case-control study, we wanted to compare clinically (by measuring postoperative pain and fatigue) and biologically (by means of several biochemical tests) the systemic response after laparoscopically assisted vaginal compared with abdominal hysterectomy. Additionally, we wanted to assess the changes and sensitivity (resolution power) of trauma markers in blood and urine before and during the first postoperative 44 h after both types of surgery. In order to minimize the interindividual variability we used matched pairs of patients.
Patients and methods
Forty patients (ASA physical status I) scheduled for elective hysterectomy because of benign gynaecological diseases (uterine fibroids, menorrhagia, endometriosis), who were willing to stay at the hospital until the second postoperative morning, were studied after approval of the study by the local Ethics Committee. Written informed consent was obtained from all patients.
Twenty otherwise unselected patients underwent laparoscopically assisted vaginal hysterectomy . For each patient (case) we selected a control, matching for age, body measurements, medical history and social status, who was scheduled for abdominal hysterectomy. In controls, abdominal hysterectomy was performed using a transverse incision (Pfannenstiel). All patients were operated on by two experienced gynaecologists (EK, KT).
Anaesthesia and postoperative pain treatment
Anaesthesia was identical in both groups. Premedication was with diazepam 10 mg given orally approximately 1 h before the start of surgery. Induction of anaesthesia was with intravenous (i.v.) thiopental 4–6 mg kg−1. Anaesthesia was maintained with enflurane, 1–2 vol% in 66% N2O in O2. Muscle relaxation was controlled with alcuronium. Before the start of surgery, 0.2 mg of fentanyl was given i.v. and boluses of 0.1 mg of fentanyl were administered when indicated by rise of heart rate and/or arterial pressure. Mechanical ventilation of the lungs was adjusted to keep end-tidal CO2 between 4.5% and 5%. One litre of Ringer’s acetate was given intraoperatively, a second litre during the first 6 postoperative hours and 1 L of 0.3-molar sodium in 5% glucose during the next 12 h. Blood losses of more than 400 mL were substituted with an equal volume of 6% hydroxyethyl starch. Postoperative pain was treated with oxycodone on demand, 0.06–0.07 mg kg−1 adjusted to the nearest 1 mg i.v. in the recovery room, and 0.12–0.14 mg kg−1 adjusted to the nearest 1 mg intramuscularly (i.m.) in the ward.
Monitoring during anaesthesia comprised continuous electrocardiogram (lead V5) and heart rate, pulse oximetry, non-invasive arterial pressure measurement at 5 min-intervals, end-tidal CO2 (Capnograph®, Datex, Helsinki, Finland) and end-tidal enflurane concentrations (Normac®, Datex, Helsinki, Finland).
Clinical assessment of postoperative pain and fatigue
Postoperative pain and fatigue levels and cumulative oxycodone consumption were assessed in every participating patient. The use of a 0- to 100-mm visual analogue scale (VAS) was explained to the patients during the preanaesthetic round the day before surgery. The VAS scores of pain at rest, during coughing, active leg elevation (VAS 0 mm=no pain at all, 100 mm=unbearable pain) and fatigue (VAS 0 mm=fit, 100 mm=physically totally exhausted) were assessed during the preoperative round, at arrival in the operation theatre, and 2, 8, 20 and 44 h after the end of surgery. The need for additional pain treatment was evaluated by the frequency and amount of oxycodone boluses administered on demand. At the end of the observation period, the patients were asked to express their opinion concerning the efficacy of the pain relieving treatment.
Biochemical markers of the systemic response
The day before surgery, after induction of anaesthesia but before start of surgery, after extirpation of the uterus and 2, 8, 20 and 44 h after the end of surgery, blood samples were drawn from the first 10 patients in each group for the determination of haematocrit, white cell count, C-reactive protein, glucose, cortisol, adrenocorticotrophic hormone (ACTH), β-endorphin immunoreactivity and IL-6 (IL-6 was not analysed from samples drawn during surgery). The staff performing the laboratory determinations were unaware to which aspect of the study the patient belonged.
Blood glucose concentrations were measured enzymatically (E. Merck, Darmstadt, Germany). Serum C-reactive protein was measured using immunoturbidometry. Serum-cortisol was analysed by radioimmunoassay (Orion Diagnostica, Espoo, Finland). The intra- and interassay coefficients of variation for the determination of blood glucose were 0.98% and 1.84%, for serum C-reactive protein 4.11% (level 15.06 mg L−1) and 3.20% (level 14.96 mg L−1), and for serum cortisol 2.0% (level 525 nmol L−1) and 3.8% (level 499 nmol L−1), respectively. Haematocrit, white cell count, glucose, C-reactive protein and cortisol were determined on the day the samples were taken.
For the following plasma/serum determinations, the blood was collected into ethylene diamine tetra acetic acid (EDTA) tubes. The tubes were centrifuged within 30 min, and the plasmas and sera stored at −70°C. For ACTH and β-endorphin immunoreactivity measurements, 2-mL plasma samples were extracted with Sep-Pak C18 cartridges using a Gilson ASPEC automatic sample preparation system. The Sep-Pak eluates were dried in Speed-Vac, reconstituted with radioimmunoassay (RIA) buffer, and measured in ACTH and β-endorphin immunoreactivity RIASs . The ACTH antiserum (West) was kindly donated by the Finnish National Institute of Diabetes and Kidney Diseases, Helsinki, Finland. The recovery of the synthetic ACTH 1-39 and human β-endorphin immunoreactivity was 60.9 ± 3.2% and 68.0 ± 5.8%, respectively. The intra- and interassay coefficients of variation of the used RIA were 2.0–3.7% (level 101–908 nmol L−1) and 3.6–4.3% (level 95–865 nmol L−1), respectively.
Plasma IL-6 concentrations were determined by the Pelikine compact™ human IL-6 enzyme immunoassay kit (Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands), according to the manufacturer’s instructions. The sensitivity of detection is 0.5 pg mL−1.
For the measurement of urinary catecholamines, urine was collected from each patient starting at 18:00 h in the preoperative evening until 44 h after the end of surgery. The patients, at first, voided spontaneously. Just after starting anaesthesia, a urinary catheter was placed, the residual urine was discarded, and the catheter removed 24 h later. Urine fractions were collected as follows: the morning just before surgery, after extirpation of the uterus, and 2 h, 8 h, 20 h and 44 h after the end of surgery. The collected urine was immediately acidified. Urine volumes were measured and 10-mL aliquots were separated for the measurement of catecholamine concentrations. The pH was adjusted to 7.0 with 0.15 M phosphate buffer (15 mL), and 0.1 mM (20 mL) 3,4-dihydrobenzylamine (internal standard) was added. The aliquots were purified with a Bio-Rex 70 column (Bio-Rad Laboratories, Richmond, CA, USA) using 0.7 M sulphuric acid (1.1 mL) as an acidifying agent, and then eluated with 2 M ammonium sulphate (4 mL). The catecholamines were extracted from the eluate by aluminium oxide , and analysed by high-pressure liquid chromotography using electrochemical detection and a Chromosep C18-column in conjunction with a C18-guard column (Chrompack, Middleburg, The Netherlands). The mobile phase was (per 1000 mL): 11.3 NaAcH2O, 6.8 g NaH2PO4H2O, 1.2 g l-heptanesuphonic acid sodium salt, 0.15 g EDTA, 10 mL 2 M HCl, approximately 1 mL H2PO4 for adjustment of pH to 4.85, and 27.5 mL actonitril [16,17]. Urine creatinine concentrations were measured by cation exchange HPLC as described elsewhere . The excretion of urine catecholamines was calculated on the basis of creatinine excretion.
The data are presented as mean (SD), and range. Data analysis is based on the analysis of variance for repeated measures, where we analysed pair-wise differences at each time point. The post-hoc testing, when necessary, was made using the least significance difference (LSD) test. The post-hoc testing was made only in those cases where the analysis of variance for repeated measures showed a significant effect. The bivariate testing is based on Student’s t-test. The correlation analysis is based on Spearman’s rank correlation. P-values < 0.05 were regarded as significant. The analysis and graphics were made using Statistica/Win Software (Version ‘97 Edition, StatSoft, Inc, Tulsa, OK, USA).
There were no differences in demographic data between the two groups (Table 1). In the abdominal hysterectomy group, a total hysterectomy was performed in nine patients and in 11 patients an additional bilateral salpingo-oophorectomy was carried out. The equivalent numbers in the laparoscopically assisted vaginal hysterectomy group were 12 and 8 patients, respectively. No surgical complications were encountered. Durations of anaesthesia and surgery were approximately twice as long and varied more in the laparoscopically assisted vaginal hysterectomy group compared with the abdominal hysterectomy group (P < 0.0001) (Table 1). The duration of anaesthesia minus duration of surgery was twice as long in the laparoscopically assisted vaginal hysterectomy group compared with the abdominal hysterectomy group (the set-up time for each type of surgery is not included in the calculation). Blood loss was virtually the same in both groups (Table 1) as was the decrease of the haematocrit over time (see Table 3 a).
There were no clinically significant differences in preoperative scores for fatigue and pain during rest and mobilization (Table 2). VAS scores of postoperative pain at rest did not differ between the two groups during the observation period, i.e. until 44 h after the end of the surgery (Table 2). However, pain intensities during coughing and active leg elevation as well as the postoperative fatigue levels differed over time between both groups. The detailed analysis showed that this was due to the time points 20 and 44 h (Table 2). On the first postoperative morning, 20 h after the end of anaesthesia, patients in the laparoscopically assisted vaginal hysterectomy group complained of only minor, at the most moderate pain during coughing and leg elevation; the pain decreased to nearly preoperative levels during the next 24 h. Patients of the abdominal hysterectomy group complained of moderate pain during coughing and leg elevation until 44 h after the end of anaesthesia. Fatigue scores were similar to pain scores during both coughing and leg elevation (r =0.6317, P =0.004), but not to pain scores at rest (r =0.3556, P =0.135). The demand for additional pain treatment with opioids (oxycodone) did not differ significantly between the two groups over time; there was a wide standard deviation (Table 2).
There were no differences between the two groups in any of the preoperative laboratory tests. Induction of anaesthesia had no effect on white cell count, glucose, cortisol, ACTH and β-endorphin immunoreactivity (Tables 3a, b). However, during and after surgery these and IL-6 (Figure 1) increased and reached their maximum at 2 h after the end of surgery. C-reactive protein started to increase on the first postoperative day and achieved peak levels at the end of the observation period (Figure 2). Urine epinephrine and norepinephrine concentrations decreased during anaesthesia and increased thereafter (Table 3b). There were no significant differences between the two groups in urine catecholamine excretion after the start of anaesthesia. The cumulative values of urine epinephrine and norepinephrine excretion were also within the same range in both groups (data not presented).
In the postoperative period, C-reactive protein and IL-6-values differed significantly over time between the two groups. The detailed analysis showed that this was due to the time points 20 and 44 h for the C-reactive protein measurements, and 8, 20 and 44 h for the IL-6 measurements, respectively. In all other biochemical tests, there were no or only occasional significant differences in the post-hoc comparisons. IL-6 concentrations correlated best with postoperative pain scores during coughing and active leg elevation, and fatigue levels (r =0.4748–0.949, P =0.046–0.0001).
In the present study, IL-6 and C-reactive protein, and the scores of postoperative pain during mobilization and of fatigue were lower in the laparoscopically assisted vaginal hysterectomy group compared with the abdominal hysterectomy group. Thus, the systemic response is lower after laparoscopically assisted vaginal hysterectomy. Except for the C-reactive protein, which is known to reach its peak not before the 3rd to 5th day after trauma, the trauma marker IL-6 and the scores of postoperative pain (especially during mobilization) and fatigue also decreased significantly faster in the laparoscopically assisted vaginal hysterectomy patients, and reached almost preoperative levels on the second postoperative morning, i.e. 44 h after the end of surgery.
Like others [18,19], we found that IL-6 was an excellent and sensitive marker for the degree of trauma reaching its peak during the immediate postoperative period (Figure 1). However, no differences in IL-6 concentrations after laparoscopically assisted vaginal hysterectomy and abdominal hysterectomy were found in a recent Swedish study . A reason for that might be the different timing of blood sampling. Ellström and her colleagues  used corresponding start points for sampling from the beginning of surgery, whereas we started at the extirpation of the uterus because this represents the time of the greatest surgical trauma during a hysterectomy. The time course of the development of the surgical trauma differs between the two techniques of surgery (laparoscopically assisted vaginal hysterectomy vs. abdominal hysterectomy, Table 1). Another reason for the equal rise of IL-6 in the study of Ellström and her colleagues might be the extensive use of electrocautery in their laparoscopically assisted vaginal hysterectomy patients . It has been demonstrated that electrocautery enhances tissue damage when compared with steel-scalpel incisions .
During the whole observation period, pain scores at rest were of the same magnitude in both groups. Pain scores at rest, obviously, are of limited value for pain studies. In both groups, pain scores during coughing and active leg elevation were significantly higher (up to 2.5 times) at each measurement time compared with those at rest. Obviously, our patients asked for pain relieving medication according to their pain scores at rest. The pain scores during coughing and leg elevation were still considerably high even on the second postoperative morning especially in the abdominal hysterectomy group. For early patient mobilization one should aim at pain relief during mobilization. Clinically important may also be the close correlation between fatigue levels and pain scores during mobilization (r =0.6317, P =0.004) and the weak correlation between fatigue levels and pain scores at rest (R =0.3556, P =0.135).
According to our findings, it seems to be futile to measure the established biochemical parameters (glucose, white cell count, cortisol, β-endorphin immunoreactivity, ACTH, urinary catecholamines) when comparing the systemic response of two different techniques of surgery. However, these biochemical tests are still valid when investigating the influence of different types of anaesthesia or intra- and postoperative pain treatment on the systemic response to surgery: propofol, opioids and sensory (subarachnoid or epidural) blocks above the fourth cervical segment attenuate the neuroendocrine response to upper abdominal surgery , but do not modulate the inflammatory and subsequent acute-phase response to surgical trauma [23–26].
The hypothalamo–pituary–adrenal axis response, evaluated in our study by serum cortisol, ACTH, β-endorphin immunoreactivity, and urinary catecholamine excretions, reflected an equal neuroendocrine response to the surgical procedure in both groups. The other laboratory markers of the systemic response, such as glucose concentration and white cell count, were not sensitive enough to discriminate between the two types of surgery. However, one has to bear in mind that laparoscopically assisted vaginal hysterectomy is not an exclusive laparoscopic procedure, because removal of the uterus needs a vaginal operation. During laparoscopically assisted vaginal and abdominal hysterectomy the extent of skin incision, which is often the site of major tissue trauma, does not differ as much, as, for example, in open vs. laparoscopic cholecystectomy. The equal intra- and postoperative increase in cortisol concentrations in our two patient groups is in accordance with previous results, where no differences were seen in cortisol levels after colectomy  or cholecystectomy  in patients operated upon either with an open or a laparoscopic technique.
We did not find any differences in catecholamine excretion in the urine between the two surgical groups. Plasma catecholamine concentrations almost only reflect the actual sympathetic stress at the moment of sampling and are very prone to changes caused by sampling time and mishandling. We employed urine collection instead of plasma sampling for alterations in catecholamine values within the desired time periods. Catecholamines in the urine give a more appropriate picture of the continuing postoperative stress. More pronounced differences were found in urine than in plasma catecholamine concentrations between two groups treated after myocardial revascularization either with midazolam/morphine bolus injections or a continuous infusion of propofol . Thus, in the studies investigating different types of intra- and postoperative pain, treatment or sedation differences in plasma and urine catecholamine concentrations might be found more reliably than when examining the stress response after surgery performed by different techniques .
In order to minimize the interindividual variability we used matched pairs of patients. Such a matching process helps to diminish possible confounding factors . Our matching criteria may not be entirely comprehensive, but in our opinion, when the sample size is small, the criteria used in our study will lead to more coherent solutions than using a simple random sample.
In conclusion, the different degree of surgical trauma induced either by laparoscopically assisted vaginal or abdominal hysterectomy became evident in the different scores of pain during mobilization and of postoperative fatigue. Of the biochemical trauma markers, only IL-6 and C-reactive protein were sensitive enough to distinguish between the two types of surgery. Postoperative fatigue levels correlated closely with pain scores during mobilization, but only weakly with pain scores at rest. IL-6 and C-reactive protein correlate well with pain scores during mobilization and fatigue levels, and seem to be the most sensitive laboratory markers for surgical damage and stress. The follow-up of the postoperative pain scores during mobilization and fatigue levels might be an easy tool for the evaluation of the postoperative recovery. The clinical impression that outcome after hysterectomy and thus recovery is smoother after laparoscopically assisted vaginal hysterectomy than after the ‘open’ surgical technique, finds its substrate in the results of our study as expressed by the different systemic responses. Under an identical anaesthetic technique the neuroendocrine response was of the same magnitude after both types of surgery.
This study was supported by grants from the Medical Research Fund of Tampere University Hospital, Tampere, Finland.
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Keywords:© 2001 European Academy of Anaesthesiology
PATHOLOGICAL CONDITIONS, SIGNS AND SYMPTOMS, fatigue; BIOLOGICAL MARKERS; DIAGNOSTIC TECHNIQUES, SURGICAL, endoscopy, laparoscopy; GYNAECOLOGICAL SURGICAL PROCEDURES, hysterectomy