1Department of Anaesthesia and Intensive Care Medicine, St Georges Hospital Medical School, London SW17 0RE, UK. 2Department of Clinical Psychology, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool L69 3GB, UK. 3Department of Clinical Chemistry, University of Liverpool, Duncan Building, Daulby Street, Liverpool L69 3GA, UK. 4Department of Anaesthesia, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK*Corresponding author
Accepted for publication: April 5, 2001
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Abstract |
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Br J Anaesth 2001; 87: 53742
Keywords: surgery, arthroplasty; recovery, postoperative; sympathetic nervous system, catecholamines; hormones, cortisol; polypeptides, cytokines
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Introduction |
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Endoscopic surgery is associated with improved recovery and more rapid discharge from hospital compared with the equivalent open surgical procedure.4 Neuroendocrine changes are similar for cholecystectomy by laparoscopy compared with laparotomy, but responses, such as those of interleukin 6 (IL-6) and C-reactive protein (CRP), are decreased.5 We have suggested that the inflammatory response is more important than neuroendocrine changes in determining recovery.6 The evidence is particularly strong for cholecystectomy but less clear for other surgical operations, such as colectomy. Suitable indices of recovery and surgical outcome are hard to define, and for many procedures functional recovery cannot be measured.
We set out to examine the relationship between the neuroendocrine and inflammatory changes and recovery from primary hip arthroplasty undertaken for osteoarthritis. This operation was chosen because it is a common procedure, causes a major physiological response and allows functional recovery to be assessed.
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Methods |
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Anaesthesia and surgery
Patients were premedicated with an oral benzodiazepine before transfer to the operating theatre. On arrival in the anaesthetic room an i.v. cannula was inserted and a blood sample collected. Anaesthesia was induced with thiopentone (n=88) or propofol (n=14) and, after the administration of a non-depolarizing neuromuscular blocking drug, the trachea was intubated and the lungs ventilated with nitrous oxide, oxygen and isoflurane. Intraoperative analgesia was usually provided with i.v. morphine (2.528 mg) and occasionally with i.v. fentanyl (50250 µg). Standard intraoperative monitoring was undertaken and crystalloid solution used for i.v. fluid replacement. Glucose-containing solutions were not given and packed red cells or whole blood were transfused when necessary. In 88 patients a standardized lateral approach was used for a Charnley hip replacement with a trochanteric osteotomy, and the remaining 14 patients had a Monk procedure with an uncemented femoral prosthesis. Postoperative analgesia was provided first by patient-controlled analgesia with morphine and then with oral analgesicscoproxamol, diclofenac or dihydrocodeine.
Procedure
Written informed consent was obtained. On the day before surgery a blood sample was collected, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was determined [7] and a set of psychological questionnaires was administered (not reported here). The WOMAC index measures arthritis-related disability in the hip joint by patients responses to questions (scored on a five-point Likert scale) about dysfunction, pain and stiffness during routine activities. Responses to several items are added to give separate scores for functional impairment, pain and stiffness, and these are combined to give a total WOMAC score. Patients were also included in a study of the effects of preoperative psychological preparation on postoperative outcome. In brief, patients were assigned randomly to one of three groups: control, relaxation and imagery. None of the variables described here was altered by the differing psychological management.
Blood samples were collected before induction of anaesthesia (0 h), 1, 2, 4, 8, 12 and 24 h after incision, and then daily for 7 days after surgery. Samples of blood were obtained from a cannula in a forearm vein during the first 24 h and subsequently by direct venepuncture.
Analysis of blood samples
Aliquots of plasma and serum were separated from the blood sample within 30 min of collection and stored at 70°C until analysis. Circulating norepinephrine, epinephrine, cortisol, IL-6 and CRP concentrations were measured by methods described in detail previously.8 Plasma catecholamines were measured for the first 24 h after surgery only and the remaining variables for 7 days.
Physiotherapy regimen
All patients were seen by a physiotherapist on the day after surgery for chest care and circulatory exercises while on bed rest. After a satisfactory radiograph, all patients were expected to leave the bed with assistance on the second day after surgery. Daily walking practice graduated from frame to crutches or sticks and the distance was increased gradually according to the patients ability. Before discharge from hospital, all patients were able to walk with aids safely and independently and to climb stairs.
Outcome assessment
The primary outcome measures were milestones in hospital, pain on discharge and function at 1 and 6 months. We have shown recently that the times to walk 10 and 25 m with standardized walking aids are a valid assessment of short-term functional recovery after hip arthroplasty and are sensitive to factors known to alter the rate of recovery, such as the age of the patient and different surgical regimens.9 The physiotherapists rating of pain on final mobilization was on the following scale: none, a little, moderate, severe. WOMAC questionnaires were completed at a home visit by one of the research team 1 and 6 months after surgery.
Statistical analysis
To normalize the distribution of the data and homogenize variances, all biochemical data were log10-transformed. For multivariate analyses only, missing data were imputed by a maximum likelihood procedure applied to all measurements of each variable in a single block (SPSS 10.0).
Bivariate analyses were undertaken using product-moment correlations. Multivariate analyses were used to confirm and clarify the findings of the bivariate analysis. The days on which the 10 and 25 m walks were achieved were used to indicate functional recovery and multiple regression was used to examine the prediction of each end-point by the biochemical variables. In multivariate analysis each variable was represented by the value of the peak response. The same procedure was applied to the physiotherapists final assessment of pain.
Statistical analysis was undertaken with SPSS 10.0 and P<0.05 was considered statistically significant.
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Results |
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The mean total WOMAC score decreased from 62 (SEM 1.7) before surgery to 42 (1.6) at 1 month and 27 (2.0) after 6 months. The mean time to walk 10 m was 5 (0.3) days and to walk 25 m was 8 (0.5) days. Mean pain on discharge was 0.28 (0=no pain, 1=little pain).
Prediction of recovery in hospital
No significant correlations were found between preoperative WOMAC and norepinephrine, epinephrine, cortisol and IL-6 concentrations, but a significant correlation was observed with the early CRP response (day 1 to 12 h, P<0.05). Walking distances were achieved significantly later in patients with greater IL-6 and CRP concentrations (Fig. 1 and Table 3). This was particularly notable for the CRP results; significant correlations were found for the time to walk both 10 and 25 m from day 3 to day 7 (10 m, P<0.05 and P<0.01; 25 m, P<0.05). Patients with greater CRP concentrations had more severe pain on discharge (824 h and days 4 and 5, P<0.05; days 2 and 3, P<0.01).
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Recovery at 1 and 6 months
No significant correlations were found between the inflammatory and neuroendocrine variables and the 1 and 6 month WOMAC values.
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Discussion |
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Although the significant correlation coefficients for the inflammatory markers and functional recovery were not high, those for CRP in particular were consistent over several days (Table 3). Subsequent multivariate analysis confirmed the importance of the inflammatory response, as the peak IL-6 value was the unique predictor of time to walk 10 and 25 m and peak CRP predicted pain on discharge. Although perioperative factors, such as haemodilution, red cell transfusion and differing doses of opioids, could affect circulating hormonal and inflammatory variables, small changes in clinical management would have weakened the relationship of the measured variables with recovery. In this descriptive study we chose to reflect clinical practice and did not attempt to control perioperative management. The strengths of the investigation were the large number of patients investigated, the use of one operation for a single pathology, the prolonged sampling schedule and the measurement of functional recovery.
The lack of influence of circulating cortisol, norepinephrine and epinephrine on indices of recovery was in marked contrast to the inflammatory variables (Table 4). The significant negative correlations of cortisol concentrations on the day before surgery with times to walk 10 and 25 m and pain on discharge, were unexpected. It suggests that greater cortisol secretion improves recovery. The mechanism could perhaps be increased anti-inflammatory activity and the mood-enhancing effects of glucocorticoids.10 It is notable that this inverse relationship was not found for increased cortisol secretion after surgery except for an isolated significant correlation at 4 h. The influence of preoperative factors was also shown by the correlations between preoperative WOMAC scores and CRP concentrations for the first 12 h after surgery. It is probable that the severity of the osteoarthritis affected the early CRP response before the inflammatory changes induced by surgery became dominant after 12 h. An association between norepinephrine concentrations at 8, 12 and 24 h and times to walk 10 and 25 m was not found for epinephrine. The clinical relevance of these observations is unknown, but it is possible that suppression of adrenergic responses after surgery may confer benefits other than on the myocardium and vasculature.
These results support the hypothesis, deduced from a comparison of cholecystectomy by laparoscopy versus laparotomy, that the inflammatory response is the primary determinant of recovery.6 Furthermore, this hypothesis can explain why regional anaesthesia, in spite of excellent analgesia, has consistently failed to enhance recovery.3 11 Although regional anaesthesia may attenuate, and occasionally even abolish, the neuroendocrine response to surgery, the inflammatory changes are not affected.12 13 The inability of regional anaesthesia to modify the cytokine response to surgery confirms a seminal study in 1980 that found that extensive epidural blockade did not attenuate the acute-phase response to surgery.14
At present there are no anaesthetic techniques that have been shown to decrease the inflammatory response consistently. Large doses of the opioid alfentanil, when used as part of a total i.v. technique, suppressed IL-6 secretion transiently.15 Further studies with low- and high-dose fentanyl failed to confirm these findings.16 17 Glucocorticoids suppress IL-6 production by an action on cytokine gene expression18 and a clinical effect has been demonstrated with large doses given before surgery.19 Un fortunately, the dose needed (methylprednisolone 30 mg kg1) caused deleterious side-effects (failure of intestinal anastomosis and wound dehiscence) although a later study claimed that no major problems occurred.20 The important reciprocal interaction between IL-6 and glucocorticoids was shown in a study using etomidate, in which IL-6 release was increased transiently by inhibition of adrenal steroidogenesis.21
Non-steroidal anti-inflammatory drugs (NSAIDs) could decrease the inflammatory response to surgery and are widely used. The results are conflicting, although this may reflect the surgical models used and the dose regimens of the NSAIDs.2224 A new class of drugs for use in rheumatoid arthritis that not only acts as an NSAID but also inhibits cytokine synthesis offers the possibility of testing the hypothesis directly.25 At present, decreasing surgical trauma, either by laparoscopy or the use of a smaller incision, is the only way to reduce the inflammatory response.
In conclusion, the notion that the neuroendocrine response to surgery influences recovery is not tenable for primary hip arthroplasty. Instead, attention should be focused on the inflammatory changes that we have shown to be implicated in functional recovery.
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Acknowledgements |
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References |
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