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CRITICAL CARE AND TRAUMA

A Single Adrenocorticotropic Hormone Stimulation Test Does Not Reveal Adrenal Insufficiency in Septic Shock

Pekka Loisa, MD^*, Ari Uusaro, MD, and Esko Ruokonen, MD

*Department of Intensive Care, Päijät-Häme Central Hospital, Lahti, Finland; Department of Intensive Care, Kuopio University Hospital, Kuopio, Finland; Department of Intensive Care, Tampere University Hospital, Tampere, Finland

Address correspondence to Pekka Loisa, MD, Department of Intensive Care, Päijät-Häme Central Hospital, Keskussairaalankatu 7, Fin – 15900 Lahti, Finland. Address e-mail to pekka.loisa{at}phks.fi.

	Abstract

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The diagnosis of adrenocortical insufficiency in critically ill patients is complex. The adrenocorticotropic hormone (ACTH) stimulation test is a widely accepted method for assessing the adequacy of adrenal function in intensive care units, but it is possible that there may be wide variations in responses to the test over a short period of time. In this prospective study, we investigated the reproducibility of the ACTH stimulation test in 20 patients with sepsis, in 20 patients with septic shock, and in 20 critically ill patients without sepsis. Two consecutive ACTH stimulation tests were performed within 24 h after intensive care unit admission or at the onset of sepsis. In patients without sepsis there was good correlation between ACTH responses on days 1 and 2 (Pearson's correlation coefficient, 0.689; P = 0.001). In contrast, in patients with septic shock no correlation was observed between the two ACTH responses (Pearson's correlation coefficient, 0.401; P = 0.080). We conclude that the results of the ACTH stimulation tests are poorly reproducible in septic shock and a single ACTH stimulation test may not be the best method to diagnose adrenal insufficiency in these patients.

	Introduction

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Activation of the hypothalamic-pituitary-adrenal axis is a homeostasis-sustaining mechanism in severely ill patients (1,2). Glucocorticoids play a vital role in the maintenance of vascular tone, endothelial integrity, and vascular permeability (3). Especially in sepsis and septic shock, plasma cortisol levels can be extremely high (4). Although most patients have increased cortisol levels, some patients with sepsis may have impaired adrenocortical function (5). Relative adrenal insufficiency, which is characterized by a blunted cortisol response after adrenocorticotropic hormone (ACTH) stimulation, is a well documented phenomenon in sepsis that is associated with poor prognosis (6–8). It may also play an important role in the pathogenesis of prolonged multiple organ failure (9). The early identification of patients who have impaired cortisol production is an important clinical challenge because these patients may benefit from corticosteroid therapy. In one study, a 7-day treatment with a hydrocortisone-fludrocortisone combination for septic shock showed a significant reduction in mortality in those patients who had a poor adrenal response in the ACTH stimulation test (10).

However, the diagnosis of adrenocortical insufficiency in critically ill patients is very complex. Thus far, exact and uniformly accepted diagnostic criteria for adrenal dysfunction are lacking, and there is no consensus on how to interpret the results of the ACTH stimulation test. The most obvious problem is that, particularly in septic shock, there may be enormous variations in cortisol production (4). Plasma cortisol levels may change rapidly over a short time (11,12), and it is possible that the results of the ACTH stimulation test may also change very rapidly.

Bouachour et al. (13) performed 2 consecutive ACTH stimulation tests in 22 patients with septic shock. The first test was performed within 24 h of the onset of septic shock and the second test was performed 48 h after onset. The cortisol response on day 1 did not correlate with the cortisol response on day 2. It is therefore possible that the single ACTH stimulation test may not be a suitable method of identifying those patients who would benefit from hydrocortisone therapy.

The hypothesis of our study was that the results of the ACTH stimulation test are not consistent in critical illness and that the test is not sensitive enough to identify those patients who might benefit from corticosteroid treatment. The purpose of our study was to evaluate the results of the repetitive ACTH stimulation tests in critically ill patients, especially in patients with sepsis and septic shock.

	Methods

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This prospective study was conducted between August 2003 and January 2005 in. the Intensive Care Units (ICU) of Kuopio University Hospital, Tampere University Hospital, and Päijät-Häme Central Hospital, Finland. The study protocol was approved by the local ethics committees, and informed consent was obtained from the patients or their first-degree relatives.

Sixty critically ill patients were enrolled in the study. Two consecutive short ACTH stimulation tests were performed in three separate study groups. The first group comprised patients with sepsis (n = 20), the second group patients with septic shock (n = 20), and the third group critically ill patients without sepsis (n = 20). The first ACTH stimulation test was performed within 24 h of the diagnosis of sepsis or septic shock in Groups 1 and 2 or within 24 h of ICU admission in Group 3 (day 1). Tetracosactin 0.25 mg (Synacthen®; Ciba-Geigy, France) was infused and blood samples were taken immediately before the test for the determination of basal serum cortisol concentration and at 30 min and 60 min thereafter. The corticotropin stimulation test was repeated 24 h after the first ACTH stimulation test (day 2). After centrifugation, serum samples were stored at 4°C and analyzed within 24 h. If the assay was delayed, samples were stored frozen at –20°C. Cortisol was measured by fluoroimmunoassay at Tampere University Hospital and at Päijät-Häme Central Hospital and by enzyme immunoassay at Kuopio University Hospital. Both ACTH stimulation tests were obtained in the morning. Absolute adrenal insufficiency was defined as a maximum cortisol concentration <500 nmol/L (18 µg/dL) after the ACTH stimulation test (18). An increase in serum cortisol concentration <248 (9 µg/dL) irrespective of basal cortisol level was used as the criterion for relative adrenal insufficiency (8).

Sepsis was defined according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (14). Sepsis was defined as the presence of systemic inflammatory response syndrome and documented source of infection. Systemic inflammatory response was manifested by 2 or more of the following criteria: fever (temperature >38°C) or hypothermia (temperature <35.5°C), tachycardia (>90 bpm), tachypnea (>20 breaths/min), and leukocytosis or leukopenia (white blood cell count >12,000 or <4,000/mm³) (14). The criterion for septic shock was sepsis associated with hypotension despite adequate fluid resuscitation (systolic blood pressure <90 mm Hg or a decrease in systolic blood pressure by 40 mm Hg or more from the baseline) (14). All patients receiving glucocorticoids or patients having a corticosteroid treatment within the preceding month were excluded from the study. Etomidate was not used in study patients and hydrocortisone treatments were not initiated between the ACTH tests.

Acute Physiology and Chronic Health Evaluation II scores (15) and Simplified Acute Physiology Scores II (16) were calculated, and the severity of organ dysfunction was assessed using the Sepsis-related Organ Failure Assessment score (17) at the time of ICU admission. Hemodynamic and laboratory data were recorded at the time the ACTH stimulation tests were performed. A pulmonary artery catheter was used in 19 patients (95%) with septic shock, in 16 (80%) patients with sepsis, and in 14 (70%) patients in the control group.

Descriptive statistics are reported as mean ± sd. One-way analysis of variance with a Bonferroni's test was used to compare the continuous variables among the groups, and the analysis of variance test for repeated measurements was used for within-group comparisons. Categorical data were analyzed using a ² test. Pearson's correlation coefficient was used to assess the correlation between the results of the ACTH stimulation tests on day 1 and day 2. A P value < 0.05 was considered significant. Statistical analysis was performed using the SPSS 11.5 for Windows software (SPSS Inc., Chicago, IL).

	Results

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Sixty patients were enrolled in the study. Demographic data in study groups are presented in Table 1, and the clinical characteristics of the patients and the primary diagnosis are presented in Tables 2 and 3, respectively. There were no differences in the basal cortisol levels among the study groups, but the cortisol response was clearly blunted in septic shock patients when compared with the control group. On both study days the differences in cortisol responses were statistically significant (Table 1). Day 2 baseline cortisol concentrations were slightly smaller than day 1 concentrations in all study groups, but the statistical difference within the group was observed only in control patients.

View larger version (16K): [in this window] [in a new window]   Figure 1. Individual cortisol profiles in the adrenocorticotropic hormone (ACTH) stimulation tests in three study groups on days 1 and 2. A, nonseptic critically ill patients; B, patients with sepsis; C, septic shock patients.

According to criteria used in this study, 8 (40%) patients with septic shock, 2 (10%) patients with sepsis, and 3 (15%) patients in the control group had impaired adrenal function as shown by the first ACTH stimulation test. Accordingly, impaired adrenal function was found on the second day in 9 patients (45%) in the septic shock group, 2 patients (10%) in the sepsis group, and 2 patients (10%) in the control group. In patients with septic shock, 5 of 8 patients who had impaired adrenal response on the first day demonstrated a normal adrenal response on the second day, and 6 patients with septic shock (30%) who had a normal adrenal function on the first day demonstrated impaired adrenal function on the second day. Only in 3 patients with septic shock was an impaired adrenal response seen in both stimulation tests; 2 of these patients had absolute adrenal insufficiency. The cortisol responses in the ACTH stimulation tests in the three study groups are presented in Figure 2. There was a good correlation in cortisol responses on day 1 and day 2 among the nonseptic critically ill patients (Pearson's correlation coefficient 0.689, P = 0.001) (Fig. 2a). Also, in patients with sepsis the correlation was rather good (Pearson's correlation coefficient, 0.540; P = 0.014) (Fig. 2b). In septic shock patients no correlation between the two cortisol responses was observed (Pearson's correlation coefficient, 0.401; P = 0.080) (Fig. 2c). Similarly, we could not demonstrate any correlation between norepinephrine requirements and basal cortisol levels or cortisol responses in patients with septic shock (data not shown).

View larger version (12K): [in this window] [in a new window]   Figure 2. Cortisol responses in the adrenocorticotropic hormone (ACTH) stimulation tests in three study groups on days 1 and 2. A, nonseptic critically ill patients; B, patients with sepsis; C, septic shock patients. Correlation between cortisol responses was good (P = 0.001) among the nonseptic critically ill patients and in patients with sepsis (P = 0,014). No correlation was observed in septic shock patients (P = 0.080). Dotted lines indicate the threshold of 248 nmol/L.

	Discussion

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The main finding in the present study was that the results of the consecutive ACTH stimulation tests are poorly reproducible in patients with septic shock. In septic shock no correlation was seen between the cortisol responses on day 1 and day 2. The majority of those patients who had a poor cortisol response on the first day demonstrated a preserved adrenal function on the second day. More importantly, we were able to demonstrate that in 6 patients, adequate adrenal response on the first day was inadequate on the second day, and only in 3 patients was impaired adrenal function seen in both tests. It seems that in septic shock, changes in cortisol production can occur within very short periods of time, and a single assessment of cortisol production may not detect adrenal insufficiency. Thus, our study confirms the earlier findings obtained by Bouachour et al. (13). In contrast to the septic shock patients, the reproducibility of the ACTH stimulation test was good in nonseptic critically ill patients, although the severity of illness was similar to that of patients with septic shock. It is therefore obvious that the rapid changes in adrenocortical function are specifically associated with septic shock.

The rapid changes in adrenocortical function may explain why different studies report very different cortisol concentrations in septic shock. In our study the cortisol concentrations were relatively small, but these figures are quite similar to those of a study by Rothwell et al. (6). However, there are studies which report significantly higher cortisol values during septic shock (9,18). It is possible that the time interval between ICU admission and the ACTH test has a great impact on observed cortisol values. If the ACTH test is performed immediately after ICU admission, cortisol values are very likely to be high. Fluid resuscitation and hemodilution may also decrease cortisol values, especially in septic shock patients.

Moreover, different methods used for cortisol measurements may be a source of variation in the ACTH results. Different assay methods may have variations when compared with high performance liquid chromatography as the reference method (25). In our study, cortisol samples were analyzed in local hospitals, and two different methods were used for cortisol analysis (fluoroimmunoassay and enzyme immunoassay). This may cause a maximum of 10% variation in the measured cortisol values. However, in individual patients all samples were analyzed in the same laboratory, and within-assay repeatability was good in both methods (3.5% and 6.8%, respectively).

The prompt identification of those patients who have impaired cortisol production in septic shock is a clinically important challenge. In critical illness, corticosteroid insufficiency may cause prolonged vasopressor dependency and unresolving systemic inflammation, and it may also play an important role in the pathogenesis of prolonged multiple organ failure (3,9,19). In previous studies, stress doses of hydrocortisone improved hemodynamic stability in septic shock (20,21), and in a prospective trial in vasopressor-dependent septic shock, 7-day treatment with a hydrocortisone-fludrocortisone combination decreased mortality. This was seen in a subgroup of patients who had impaired adrenal response (<248 nmol/L) in the ACTH stimulation test (10). However, according to our study, it is possible that cortisol production can change dramatically after the ACTH test, and there may be additional patients who may also benefit from hydrocortisone therapy even if the ACTH response is normal at the onset of septic shock.

In addition to its poor reproducibility, one of the major problems with the ACTH stimulation test is that precise criteria for relative adrenal insufficiency in critical illness are still lacking. Most investigators have introduced their own criteria for the diagnosis of adrenocortical insufficiency (5,7,8), and many of these criteria are broadly similar to the values used in the overall hospital population. Because exact diagnostic criteria are lacking, the reported incidences of adrenocortical insufficiency in sepsis also vary between 0% and 54% (5,6,8). In the study by Annane et al. (8), the 3-level classification system of adrenal function was introduced based on the results of multivariate analysis. The best cut-off value to discriminate between survivors and nonsurvivors in cortisol response in the large-dose ACTH stimulation test was 248 nmol/L (8). This criterion was used in Annane et al.'s randomized, controlled study, and the incidence of adrenal insufficiency in their prospective trial was 77% (10). It should be emphasized that this frequent incidence was because the criteria of increase in cortisol concentration <248 nmol/L was used irrespective of the basal cortisol level. However, if the basal cortisol levels are extremely high it is probable that cortisol response is blunted in septic shock (22,23). Whether this represents a maximally stimulated and appropriately functioning adrenal cortex or true relative adrenocortical insufficiency is still a matter of debate (3,22,24). In our study we could not demonstrate the association between high baseline cortisol levels and low cortisol responses in septic shock patients.

In conclusion, the present study confirms the findings of Bouachour et al. (13). The reproducibility of the ACTH stimulation test is very poor in patients with septic shock, and rapid changes in cortisol production and secretion can cause difficulties in assessing the adequacy of adrenal function in sepsis. We were able to demonstrate that a seemingly adequate adrenal response observed at the onset of septic shock was inadequate on the next day in several patients. We believe that neither a single measurement of cortisol concentration nor a single ACTH stimulation test can identify all those patients who might benefit from hydrocortisone therapy, and there may be patients who will respond to corticosteroid therapy even if the results of the ACTH stimulation test are normal at the onset of septic shock.

	Footnotes

 
Supported, in part, by the Medical Research Fund of Tampere University Hospital, Tampere, Finland, and the Medical Research Fund of Päijät-Häme Central Hospital, Lahti, Finland.

Accepted for publication May 23, 2005.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Finlay WEI, McKee JI. Serum cortisol levels in severely stressed patients. Lancet 1982;1:1414–5.[Web of Science][Medline]
2. Melby JC, Spink WW. Comparative studies on adrenal cortical function and cortisol metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958;37:1791–8.
3. Lamberts SWJ, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J Med 1997;337:1285–92.[Free Full Text]
4. Schein RMH, Sprung CL, Marcial E, et al. Plasma cortisol levels in patients with septic shock. Crit Care Med 1990;18:259–63.[Web of Science][Medline]
5. Sibbald WJ, Short A, Cohen MP, Wilson RF. Variations in adrenocortical responsiveness during severe bacterial infections. Ann Surg 1977;186:29–33.[Web of Science][Medline]
6. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582–3.[Web of Science][Medline]
7. Soni A, Pepper GM, Wyrwinski PM, et al. Adrenal insufficiency occurring during septic shock: Incidence, outcome, and relationships to peripheral cytokine levels. Am J Med 1995;98:266–71.[Web of Science][Medline]
8. Annane D, Sébille V, Troché G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038–45.[Abstract/Free Full Text]
9. Loisa P, Rinne T, Kaukinen S. Adrenocortical function and multiple organ failure in severe sepsis. Acta Anaesth Scand 2002;46:145–51.[Web of Science][Medline]
10. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–71.[Abstract/Free Full Text]
11. Voerman HJ, Strack van Schijndel RJM, Groeneveld ABJ, et al. Pulsatile hormone secretion during severe sepsis: accuracy of different blood sampling regimens. Metabolism 1992;41:934–40.[Web of Science][Medline]
12. Rydvall A, Brändström AK, Banga R, et al. Plasma cortisol is often decreased in patients treated in an intensive care unit. Intensive Care Med 2000;26:545–51.[Web of Science][Medline]
13. Bouachour G, Roy PM, Guiraud MP. The repetitive short corticotropin stimulation test in patients with septic shock. Ann Intern Med 1995;123:962–3.[Free Full Text]
14. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74.[Web of Science][Medline]
15. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med 1985;13:818–29.[Web of Science][Medline]
16. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270:2957–63.[Abstract/Free Full Text]
17. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related organ failure assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22:707–10.[Web of Science][Medline]
18. Bouachour G, Tirot P, Gouello JP, et al. Adrenocortical function during septic shock. Intensive Care Med 1995;21:57–62.[Web of Science][Medline]
19. Annane D, Bellissant E, Sebille V, et al. Impaired pressor sensitivity to norepinephrine in septic shock patients with and without impaired adrenal reserve. Br J Clin Pharmacol 1998;46:589–97.[Web of Science][Medline]
20. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645–50.[Web of Science][Medline]
21. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723–32.[Web of Science][Medline]
22. Moran JL, Chapman MJ, O'Fatharaigh MS, et al. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock. Intensive Care Med 1994;20:489–95.[Web of Science][Medline]
23. Oppert M, Reincke A, Gräf KJ, et al. Plasma cortisol levels before and during hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock. Intensive Care Med 2000;26:1747–55.[Web of Science][Medline]
24. Marik P, Zaloga G. Prognostic value of cortisol response in septic shock. JAMA 2000;284:308–9.[Free Full Text]
25. Tunn S, Pappert G, Willnow P, et al. Multicenter evaluation of an enzyme-immunoassay for cortisol determination. J Clin Chem Clin Biochem 1990;12:929–35.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999