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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2045-2048
Copyright © 2003 by The Endocrine Society

Free Cortisol Index Is Better Than Serum Total Cortisol in Determining Hypothalamic-Pituitary-Adrenal Status in Patients Undergoing Surgery

C. W. le Roux, G. A. Chapman, W. M. Kong, W. S. Dhillo, J. Jones and J. Alaghband-Zadeh

Department of Metabolic Medicine, Hammersmith Hospitals Trust (C.W.l.R., W.M.K., W.S.D., J.J., J.A.-Z.), London, United Kingdom W12 0NN; and Department of Anesthesiology, Bradford Royal Infirmary (G.A.C.), Bradford, United Kingdom

Address all correspondence and requests for reprints to: Dr. Carel le Roux, Department of Metabolic Medicine, Hammersmith Hospital, London, United Kingdom W12 0NN. E-mail: c.leroux{at}ic.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Serum total cortisol has traditionally been used for the interpretation of tests of the hypothalamic-pituitary-adrenal axis. Approximately 80% of total cortisol is bound to cortisol-binding globulin (CBG), and variation in CBG significantly affects serum total cortisol levels. Reliable assessment of hypothalamic-pituitary-adrenal axis reserve is difficult in severely ill patients, because CBG falls substantially during the acute phase response. The free cortisol index (FCI), defined as the ratio of total cortisol/CBG, correlates well with serum free cortisol. We evaluated the FCI in the context of severe stress and the acute phase response by measuring total cortisol and CBG pre- and postoperatively in 31 patients undergoing major elective surgery. Serum total cortisol increased by 55% from 453 ± 35.2 (mean ± SEM) nmol/liter (range, 88–882) to 700 ± 47.2 (range, 294-1631) nmol/liter. Serum CBG decreased by 30% from 45 ± 1.7 (range, 26.6–64.1) to 31.4 ± 1.62 (range, 16.1–51.9) mg/liter, but FCI increased by 130% from 10 ± 0.8 (range, 2–18) to 23 ± 1.7 (range, 13–58) nmol/mg. In seven patients (23%), postoperative serum total cortisol was less than 500 nmol/liter, but their postoperative CBG levels were significantly lower than levels in the rest of the group (P < 0.01). However, there was no difference in the FCI between this subgroup and the rest of the group. This study demonstrates the importance of CBG measurement and the calculation of FCI for the interpretation of serum total cortisol in situations where CBG changes significantly.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PATIENTS WHO ARE cortisol deficient have greatly increased morbidity and mortality when faced with severe stress (1). However, accurate assessment of the hypothalamic-pituitary-adrenal (HPA) axis in patients who are severely ill has proved difficult. Annane et al. (2) reported that patients on intensive care units (ICU) with septic shock and elevated serum total cortisol values in combination with a reduced response to the short Synacthen test (SST) seem to be at greatest risk of death. However, prognostic classification of patients, from a heterogeneous group, such as patients in ICU or who have undergone major surgery, with average serum total cortisol results and average rises after the SST remains difficult to interpret (3, 4, 5, 6, 7).

We have previously shown that variation in cortisol-binding globulin (CBG) can significantly affect serum cortisol levels in healthy volunteers (8). Patients in the ICU typically show an acute phase response associated with a substantial fall in CBG (9, 10), and this may explain the difficulties in interpreting serum total cortisol values in patients in the ICU.

Serum total cortisol is approximately 80% bound to serum CBG and 10% bound to serum albumin (11). The free cortisol index (FCI), which is the serum total cortisol/CBG ratio, has been shown to correlate with serum free cortisol, which is the biologically active component (12).

We hypothesized that in situations associated with an acute phase response, serum total cortisol might not be an accurate indication of maximal HPA axis reserve, because of the changes in CBG. In 1967 Plumpton and Besser (13) used major surgery to validate the insulin tolerance test. We therefore evaluated the HPA axis response to major elective surgery, which produces both severe stress and an acute phase response, in a controlled environment. We hypothesized that the FCI would be a better indication of HPA axis reserve than serum total cortisol.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Twenty-one females and 10 males undergoing major elective surgery were investigated. Females receiving estrogen therapy, patients with known endocrine disease, patients receiving any steroid preparation, and patients receiving etomidate (which has been reported to suppress adrenal function) (14) were excluded. All patients were assessed preoperatively by an anesthetist and were considered fit for surgery (American Society Anesthetists’ score <2). All surgical procedures were scheduled between 0830–1000 h, and the patients were recumbent for more than 30 min before surgery commenced. Venous blood was obtained preoperatively, approximately 5 min before intubation, and postoperatively, within 5 min after extubation. Full ethical approval was obtained, and the patients gave written informed consent.

Methods

Serum total cortisol was measured using an ELISA technique (ES700, Roche, Lewes, UK) with a coefficient of variation of 3% at 498 nmol/liter. Serum CBG was measured by RIA (Biosource Technologies, Inc. Europe S.A., Nivelle, Belgium) with a coefficient of variation of 3.8% at 62.2 mg/liter. The FCI was calculated by serum total cortisol/CBG (nanomoles/milligrams). We have previously shown that a normal 30-min FCI response to a standard 250 µg tertracosactrin is 12 or more (8).

Serum albumin was measured using an automated clincal chemistry analyzer (AU600, Olympus Corp., London, UK) with a coefficient of variation of 2.6% at 38 g/liter. The cortisol/albumin ratio was calculated by serum total cortisol/albumin (nanomoles/grams). Hemoglobin was measured using a Cell Dyn 4000 (Abbott Diagnostics, Maidenhead, UK) with a coefficient of variation of 1% at 12.1 g/dl.

Statistics

Values shown are the mean ± SEM, with the range of values shown in parentheses. Statistical analysis was performed using the SigmaStat package (SPSS, Inc., Chicago, IL). For continuously normally distributed data the paired t test was used to evaluate within-patient differences between pre- and postoperative values, and the unpaired t test was used to evaluate between-subject differences. The Mann-Whitney rank-sum test was used to evaluate differences in the maximal FCI and increase in FCI between the subgroup of patients who did not have a maximal response of cortisol above 500 nmol/liter and the rest of the group. The Pearson product-moment correlation coefficient was used for the correlation between serum total cortisol and FCI.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the demographic details of the patients included in the study. The surgical procedures lasted a mean of 2 h and 20 min (range, 1–4 h). The intraoperative fluids consisted of crystalloids and colloids. The average volume was 1250 ml, with only four patients receiving a maximum of 2000 ml. All patients made an uneventful recovery, without any postoperative complications, and the median hospital stay was 5 d.


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  		Table 1. Demographics of patients undergoing major elective surgery

 
Table 2Go shows the pre- and postoperative values for serum total cortisol, serum CBG, and FCI, and the percentage changes are demonstrated in Fig. 1Go. Serum total cortisol rose by only 55%; however, the FCI increased by 130%, reflecting a 30% fall in CBG. All of these patients had an FCI above 13 (ranging to 24).


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  		Table 2. Results of pre- and postoperative changes in total cortisol, CBG, FCI, albumin, and hemoglobin in 31 patients undergoing major elective surgery

 


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  		Figure 1. Percentage changes from pre- to postoperative values for serum total cortisol, serum CBG, and FCI.

 
Unexpectedly, seven patients had a maximum serum total cortisol less than 500 nmol/liter; the lowest value was 294 nmol/liter (Table 3Go). There was, however, no clinical evidence that any of these patients had HPA axis insufficiency; all made uneventful recoveries, and the median hospital stay was 4.5 d. Figure 1Go shows that the mean total cortisol in this subgroup decreased postoperatively from 459 ± 63 (range, 259–683) to 424 ± 25.8 (range, 294–498) nmol/liter. These seven patients had significantly lower CBG levels (23.3 ± 2.3 mg/liter; range, 16.1–31.6) than the rest of the group (31.4 ± 1.6 mg/liter; range, 16.1–51.9; P < 0.01), although they received a similar amount of intraoperative fluids [1333 ± 307 (range, 500-2000 ml) vs. 1182 ± 107 (range, 120-2000) ml; P = 0.242]. However, there was no difference in the postoperative FCI of 24 ± 2.1 (range, 15–58) nmol/mg between patients with postoperative cortisol levels greater than 500 nmol/liter and those with cortisol levels less than 500 nmol/liter (19 ± 1.7; range, 13.5–25 nmol/mg; P = 0.12). The preoperative FCI values between the two subgroups were also similar (P = 0.85), and no significant differences existed in age (P = 0.07), sex (P = 0.98), or type of surgery (P = 0.60) between the two subgroups.


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  		Table 3. Results of pre- and postoperative total cortisol, CBG, and FCI in the subgroup of patients with maximal serum total cortisol response of less than 500 nmol/liter

 
Analysis of the data from all patients showed that changes in serum albumin correlated with changes in CBG (r2 = 0.6; P < 0.001), decreasing by 26% from 41.1 ± 0.94 (range, 28–49) to 30.6 ± 1 (range, 23–40) g/liter, whereas hemoglobin decreased by 13% from 13.4 ± 0.3 (range, 10.4–15.9) to 11.6 ± 0.3 (range, 8.9–14.2) g/dl. The decrease in hemoglobin showed no correlation with the decrease in CBG (P = 0.55).

The cortisol/albumin ratio was calculated in all postoperative samples in every patient (mean, 23.5 ± 1.9 nmol/g; range, 13.7–64.2) and correlated with the FCI (r2 = 0.73, P < 0.001).

The rate of decrease in CBG was evaluated in three patients by obtaining venous blood samples every 30 min during their respective laparotomies, which lasted, 90, 150, and 150 min, respectively. Table 4Go shows that postoperative serum total cortisol rose by 108%; however, the FCI increased by 164%, reflecting a 27% fall in CBG. Most of the fall in CBG occurred in the first 30 min, and the total cortisol started rising between 30 and 60 min and was near or at a maximum at the end of the operation. The FCI showed the most dramatic increase between 30 and 60 min and was never less than 12.4 nmol/mg.


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  		Table 4. Total cortisol, CBG, and FCI in three patients after the start of laparotomy

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we measured the serum total cortisol and CBG responses to major elective surgery in patients with no evidence of HPA axis insufficiency. We found that serum total cortisol only increased by 55%, whereas the FCI increased by 130%. The likely explanation for this observation is the dramatic fall in the CBG of 30%.

Major elective surgery is a severe stress that occurs in a controlled environment. Our decision to use major surgery was also based on the fact that it was the reference against which the insulin tolerance test was validated (13). No data exist on the serum free cortisol response to major surgery or the minimum serum free cortisol requirement to survive such a stress. Any cut-off points for serum total cortisol after dynamic function tests also remain controversial (15). A value for serum total cortisol less than 500 or 550 nmol/liter (depending on assay used) after dynamic function testing has been proposed to demonstrate HPA axis insufficiency (15). Seven patients (23%) had inadequate cortisol responses if the criterion of 500 nmol was applied, and if the criterion of 550 nmol/liter were applied, 10 patients (32%) would have been classified with HPA insufficiency. The 7 patients had no history of steroid use or pathology affecting the HPA axis. Further, all made uneventful recoveries, with no evidence of HPA insufficiency.

The serum total cortisol response did not seem to be a true reflection of the maximal HPA axis reserve. The most likely explanation for the unexpectedly low total cortisol levels is the dramatic fall in CBG seen in these patients. The fall was presumably part of the acute phase response (9, 10). The dramatic fall in CBG during major elective surgery in this study mirrored that in serum albumin and was not correlated with hemoglobin changes and therefore was unlikely to be due to dilutional effect. The intraoperative fluids were also restricted because the patients were adequately hydrated for the elective surgical procedures in which no significant blood loss occurred. The percentage decrease in hemoglobin is much less than the percentage decrease in CBG or albumin. Similar changes in serum CBG are also likely to occur in most patients admitted to the ICU, and this study demonstrated that variable serum CBG could influence the interpretation of serum total cortisol.

CBG and T4-binding globulin are members of the serine protease inhibitor (serpin) superfamily and are vulnerable to proteolytic cleavage (16). The reason for the decrease in CBG, like that in albumin, could, however, be due to several factors during the acute phase response, including increased permeability of vasculature (17), decreased liver production (17), or degradation by elastase (18). The measurement of serum total cortisol is therefore difficult to interpret in patients postoperatively or when on the ICU, where CBG is likely to change substantially. Measurement of serum free cortisol would overcome this problem, but is not available for routine clinical use. Our results suggest that CBG concentrations must be considered when interpreting total cortisol results in this context.

We corrected for variations in CBG using the FCI. The FCI as a surrogate for the serum free cortisol showed a consistent response in all patients above 13, and this is similar to the FCI response of 12 or above found in healthy volunteers undergoing an SST (8). Furthermore, there was no difference in the FCI between patients with postoperative cortisol above or below 500 nmol/liter. The absolute value for the cortisol/albumin ratio is above 13.7 nmol/g for all patients postoperatively, and this may be a useful clinical marker to decide whether measuring CBG is justified to calculate the FCI. Albumin is also subject to other influences, however, which fall outside the spectrum of this study.

Our results suggest that decisions based on total serum cortisol, especially in acutely ill patients, may be improved by taking into account the influence of binding proteins. It would be ideal to have an accurate and precise measurement of serum free cortisol; however, current serum free cortisol assays are too time consuming for routine clinical use. Therefore, in the absence of routine measurement of free cortisol we propose that CBG should be measured and used to correct total cortisol by calculating the FCI. Comparison of the FCI with free cortisol in healthy volunteers has shown that FCI is a satisfactory surrogate (12), but evaluation in clinically relevant situations will be important in establishing its future role.

The implications of this study extend to any situation where an acute phase response is present, especially after surgery and in patients admitted to the ICU. The interpretation of cut-off values after insulin tolerance or SSTs should also be evaluated in light of these findings, with particular interest in patients receiving exogenous estrogen therapy, in whom elevated CBG levels are seen (19).

This study demonstrates the limitations of serum total cortisol in situations when CBG changes significantly. Twenty-three percent of the patients evaluated would have been misdiagnosed with HPA axis insufficiency if current criteria were used. The FCI provides a simple and accurate way of evaluating the HPA axis reserve in such situations.


   Footnotes
 
Abbreviations: CBG, Cortisol-binding globulin; FCI, free cortisol index; HPA, hypothalamic-pituitary-adrenal; ICU, intensive care unit; SST, short Synacthen test.

Received October 2, 2002.

Accepted February 10, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  6. Rotwell PM, Udwadia ZF, Lawler PG 1991 Cortisol response to corticotrophin and survival in septic shock. Lancet 337:582–583[CrossRef][Medline]
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  8. Dhillo WS, Kong WM, le Roux CW, Alaghband-Zadeh J, Jones J, Carter G, Mendoza N, Meeran M, O’Shea D 2002 Cortisol binding globulin is important in the interpretation of dynamic tests of the hypothalamic-pituitary-adrenal axis. Eur J Endocrinol 146:231–235[Abstract]
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