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Physiological and Psychological Influences on Postoperative Fatigue

Hall, George M., MB BS, PhD, DSc (Med), FiBiol, FRCA*,; Salmon, Peter, BA, MSc, DPhil, FBPs

doi: 10.1097/00000539-200211000-00064

Fatigue is common after major surgery and delays recovery. We studied the role of physiological and psychological factors in determining fatigue and physical well being after surgery in 102 patients undergoing primary hip arthroplasty. Self-administered questionnaires were used to measure the intensity of feelings of fatigue, vigor, depression, and subjective physical well being on the day before surgery, on the third and seventh postoperative days, and 1 and 6 mo after surgery. The physiological response to surgery was determined by sequential measurements of circulating norepinephrine, epinephrine, cortisol, interleukin-6, and C-reactive protein during the 7 days after surgery. The peak value of each variable was used for statistical analysis. Physical well being decreased significantly at 3 and 7 days but increased significantly at 1 and 6 mo. Fatigue decreased significantly at 1 and 6 mo. Multiple regression analysis showed that the main predictor of worse physical well being at 3 days was the size of the C-reactive protein response. Subsequently, the main predictor was the level of preoperative well being. The severity of fatigue and vigor after surgery were predicted mostly by the preoperative levels of the respective variable. We conclude that fatigue after hip arthroplasty was not predicted by physiological variables but was largely predicted by preoperative levels of fatigue.

*Department of Anaesthesia and Intensive Care Medicine, St. George’s Hospital Medical School, London, United Kingdom; and †Department of Clinical Psychology, University of Liverpool, Whelan Building, Liverpool, United Kingdom

Supported by the UK Medical Research Council.

August 7, 2002.

Address correspondence and reprint requests to George M. Hall, Department of Anesthesia and Intensive Care Medicine, St. George’s Hospital Medical School, London SW17 0RE. Address e-mail to

The malaise that patients feel after major surgery has been described in the medical literature as “fatigue”(1). Postoperative fatigue occurs as long as 90 days after major abdominal surgery, whereas it does not follow ear surgery (2,3). It has usually been attributed to the physiological response to surgery, with the assumption that the more severe the surgery, the more severe and prolonged the fatigue (3,4). We have argued that this is unlikely (5). For instance, some patients do not experience fatigue after major surgery, indicating that fatigue cannot be solely a component of the physiological response (3).

Despite arguments to the contrary, (6), we propose that the occurrence and severity of fatigue depend on preoperative psychological factors, particularly the presence of preoperative fatigue, depression, or both (5). In this study, we have examined the role of physiological and psychological factors in determining subjective physical well being and, specifically, fatigue after major orthopedic surgery. If the “physiological” theory of postoperative fatigue is predominant, then because hip arthroplasty results in large neuroendocrine and inflammatory responses, it should result in marked fatigue, the severity of which is determined by the size of the physiological changes.

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After local Ethics Committee approval, patients admitted for unilateral, primary, elective hip arthroplasty for osteoarthritis were studied. Exclusion criteria included rheumatoid arthritis; major systemic illness, such as diabetes mellitus, that was likely to alter neuroendocrine and inflammatory changes; and steroid medication within the past 6 mo. Of 128 suitable patients, 23 declined to participate, and 3 subsequently withdrew from the study, so 102 patients were included.

Patients were premedicated with an oral benzodiazepine before transfer to the operating room. They received thiopental or propofol, atracurium, and N2O/oxygen/isoflurane. Intraoperative analgesia was provided with IV morphine or fentanyl. Regional anesthetic techniques were not used. Standard intraoperative monitoring was performed, and crystalloid solution was used for IV fluid replacement. Packed red cells or whole blood was transfused to maintain a hemoglobin concentration of 10 g/dL. Postoperative analgesia was provided by patient-controlled analgesia with morphine and then with oral analgesics—coproxamol, diclofenac, or dihydrocodeine.

Self-rated questionnaires (see below) were completed by the patient on the day before surgery and in the hospital at noon on the third and seventh postoperative days. Patients were visited at home by a research nurse who administered questionnaires 1 and 6 mo after surgery.

Most previous studies of fatigue after surgery have used simple linear analog scales, which are of doubtful validity (5). Therefore, in this study we used scales from the self-completed Profile of Mood States (POMS) to measure the intensity of feelings of depression, fatigue, and vigor (7). Each mood score is the sum of ratings of several mood adjectives on a five-point intensity scale (scored 0–4). Subjective physical well being was measured by the Recovery Inventory (high scores indicate comfort) (8). The Inventory provides a single score from the sum of the patient’s ratings (on a six-point Likert scale) of aspects of bodily function, including appetite, sleep, stomach and bowel function, and mobility, and is used to measure recovery after major surgery. Both scales have been used extensively in clinical research and have demonstrated reliability and validity. This has been summarized periodically for the POMS (9,10). For the Recovery Inventory, convergent validity is described in the source article (8); additional construct validity arises from the time course of its response to surgery, showing rapid deterioration and gradual recovery (11). Because reliability information is not available, internal consistency reliability was established by Cronbach’s α on each measurement in this study. Values ranged from 0.78 to 0.85, indicating acceptable reliability.

Blood samples were collected before the induction of anesthesia (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 venipuncture. Plasma and serum were separated from the blood sample within 30 min of collection, stored at −70°C, and analyzed for norepinephrine, epinephrine, cortisol, interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations by methods described in detail previously (12). Plasma catecholamines were measured for the first 24 h after surgery only, and the remaining variables were measured for 7 days. These variables were chosen to represent the physiological response to hip arthroplasty after a detailed examination of endocrine, metabolic, and inflammatory changes (12).

Statistical evaluation of the data was undertaken with SPSS 10.0 (SPSS Inc., Chicago, IL). The results were examined to ensure that the residuals approximated to a normal distribution and were amenable to parametric analysis. One POMS scale, depression, was not normally distributed and was recorded so that scores 0–1 were set to 0 and scores ≥2 were set to 1. Circulating variables were log-transformed (log10 + 1). The number of missing data was noted, and Little’s test of missing completely at random was calculated for the complete set of variables, including age and sex (13). Missing values were interpolated by the expectation maximization algorithm devised by Little and Rubin (14). For each variable, all measurements were interpolated in a single set.

Changes in fatigue, vigor, and physical well being were examined by repeated-measures analysis of variance. Significance was tested after adjustment of degrees of freedom by Greenhouse-Geisser ε, where departure from sphericity was significant. Significant main effects of time were followed by post hoc comparisons of each postoperative value with baseline by the least significant difference test. The criterion of significance was P < 0.01 for F and P < 0.05 for post hoc tests, because these were protected by significant F.

A multiple regression analysis was undertaken in which fatigue, vigor, and physical well being at each time point were regressed on the preoperative subjective state and circulating variables. To avoid collinearity, biochemical values were indicated only by the peak value: catecholamines (4 h), cortisol (8 h), IL-6 (24 h), and CRP (Day 2). Analysis was stepwise with a P value of F-to-enter = 0.01 and a P value to exclude = 0.05. In reporting the results of the multiple regression analyses, coefficients were taken from the final model.

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Details of the patients studied are shown in Table 1. Missing data accounted for 5.7% of the observations, but Little’s test indicated that this was not significant. Patients who declined to participate or withdrew did not differ significantly from participants in age or sex. A detailed description of the endocrine and inflammatory responses in these 102 patients undergoing primary hip arthroplasty has been published recently (15). Details of functional recovery, duration of hospital stay, and postoperative complications have been reported previously (15,16).

Table 1

Table 1

There were significant changes in physical well being (F4,98 = 98.80, P < 0.001), fatigue (F4,98 = 9.67, P < 0.001), and vigor (F4,98 = 18.47, P < 0.001) (Table 2). Post hoc comparisons showed that physical well being decreased significantly at 3 and 7 days but improved significantly at 1 and 6 mo. Fatigue decreased significantly at 1 and 6 mo; vigor decreased significantly at 3 days and increased significantly at 6 mo.

Table 2

Table 2

The main predictor of worse physical well being at 3 days was the size of the CRP response (Fig. 1), although the level of depression added significantly to the prediction (Table 2). Subsequently, the main predictor was the level of preoperative well being. The severity of fatigue and vigor after surgery were predicted mostly by preoperative levels of the respective variable. A larger norepinephrine response was followed at 3 and 7 days by more fatigue and less vigor, respectively. CRP correlated with vigor at 1 mo.

Figure 1

Figure 1

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The main finding of this study was that fatigue showed only a small and transient increase after hip arthroplasty despite a major, prolonged physiological response. Furthermore, the levels of fatigue and vigor were predicted by the preoperative value of these subjective variables throughout the study (Table 2). In contrast, of the five circulating variables measured, only the peak norepinephrine value was an additional predictor for fatigue and vigor at three and seven days, respectively, and peak CRP concentration was an additional predictor for vigor at one month. It was notable that the inflammatory markers did not predict fatigue and vigor in the hospital. These results and other evidence suggest that explanations of fatigue after surgery should no longer be sought in physiological mechanisms. Instead, future research should address psychological mechanisms.

In contrast to fatigue, subjective physical well being, as measured by the Recovery Inventory, showed the expected sharp decline after three and seven days, and the main predictor at three days was the peak CRP value (Table 2). It is not surprising that the size of the inflammatory response affected this variable (which included appetite, sleep, and mobility). The results are in keeping with our previous work showing that IL-6 and CRP changes were important in determining functional recovery in the hospital after arthroplasty, but not at one and six months (15). We also observed in this study that the inflammatory markers were unrelated to physical well being at one and six months, indicating the limited duration of the effects of the physiological response to surgery. In contrast, preoperative levels of vigor and well being predicted the outcome of this variable at one and six months, respectively (Table 2).

It is usual in modern anesthetic practice to control the sympathoadrenal response to surgery to prevent deleterious effects on the myocardium and peripheral vasculature. The results of this study and previous work suggest other advantages from obtunding the norepinephrine response—less fatigue, more vigor, and enhanced functional recovery (15,17). Why epinephrine does not have similar effects is unclear but may be related to the more transient nature of adrenomedullary secretion. These novel aspects of the catecholamine response to surgery merit verification experimentally.

We have consistently failed to show a significant increase in fatigue after major joint arthroplasty (18), despite subjective deterioration in well being, yet it is common for 20–30 days after major abdominal surgery (3). The severity of surgery, as assessed by indices of surgical stress, such as circulating cortisol and catecholamines, is similar for the two operations. Why is fatigue apparently more after abdominal surgery? In many studies, the methods used to measure fatigue have been inadequate, and the level of preoperative fatigue has been ignored (5). Here, we have shown the importance of the latter in determining the severity of postoperative fatigue. In addition to methodological inadequacies, consideration must be given to the expectations of the patients undergoing the two surgical procedures. Patients having a hip arthroplasty expect an improvement in the quality of their life, with enhanced mobility and less pain, and we have shown that these expectations are met (19). However, major abdominal surgery is often life-threatening, particularly when undertaken for malignancy, and is rarely life-enhancing. Therefore, a marked difference in the emotional responses to the two procedures is to be expected.

In conclusion, we suggest that the lack of progress in understanding postoperative fatigue is due to the emphasis on physiological changes and the failure to consider psychological factors. However, the emotional variables in this study did not predict fatigue.

We thank Denise Peerbhoy and Chris Parker for data collection and Alan Shenkin for biochemical assays.

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© 2002 International Anesthesia Research Society