Decreased cytosolic glucocorticoid receptor levels in critically ill patients.
Dexamethasone does not suppress cortisol and ACTH levels in critically ill patients to the extent found in controls (5,6). Based on these data, Reincke et al concluded that these patients have an altered responsiveness to glucocorticoids, indicating an impaired glucocorticoid feedback5. It has been speculated that these changes may be caused by proinflammatory cytokines, such as TNF, IL-1[beta] or IL-6 which are found to be significantly elevated during severe illness such as acute respiratory distress syndrome or sepsis (2,7). Another explanation for the reduced responsiveness to glucocorticoids could be an alteration of glucocorticoid binding to the cytosolic glucocorticoid receptors (GR).
The effects of glucocorticoids are mediated by GR, a member of the nuclear hormone receptor superfamily of transcription factors, present in all cells. Interaction of glucocorticoids with GR is followed by activation and translocation of the GR complex into the nucleus. The receptor-steroid complex interacts with specific sequences in promoter regions, finally leading to modulation of gene transcription. Up to 2000 genes up- and down-regulated by GR have been identified (8). The exact mechanism causing the disturbance of the hypothalamic-pituitary-adrenal axis during severe inflammation of disease is not known.
There is no evidence suggesting impaired cortisol entry into cells in critically ill patients. A decrease of GR affinity for its ligand could be found after administration of lipopolysaccharide (LPS) to an animal model (9). Investigations on the regulation of GR gene expression yielded contradicting results (2).
The aim of the present study was to examine the coherence between the number of GR, serum ACTH and cortisol levels, serum levels of inflammatory cytokines and disease score at different time-points in critically ill patients to further elucidate the changes in the hypothalamic-pituitary-adrenal axis.
MATERIALS AND METHODS
Study design and patients
The study was approved by the ethics committee of the University of Regensburg and performed in accordance with the declaration of Helsinki. Critical care patients (n=50) who met inclusion criteria (artificial ventilation, age between 18 to 99 years and written informed consent by their legal guardian) and without exclusion criteria (no chronic systemic steroid therapy, no administration of hydrocortisone during intensive care treatment) were recruited prospectively in medical, surgical and cardiac-surgical intensive care units.
[FIGURE 1 OMITTED]
As an indicator for severity of disease we calculated the Acute Physiology and Chronic Health Evaluation (APACHE) II (10) and Simplified Acute Physiology Score (SAPS) II score (11) for each patient at the time of intubation or, in the case of postoperative patients, at the time of intensive care unit admission (in 49 out of 50 patients available). Patients were divided into two groups according to their APACHE II score. Those with an APACHE II score above the median represented severely critically ill patients (Group A), while those with an APACHE II score below the median suffered a milder disease and comprised a group of postoperative patients monitored in an intensive care unit (Group B) (Figure 1).
Blood samples (50 ml) were collected within 24 hours after intubation and within three days after extubation, each in a tube with added citrate. Control samples were collected from 20 healthy persons from hospital staff (control group). All blood samples were drawn between 0900 and 1200 hours to minimise changes related to circadian rhythm.
Isolation of peripheral blood mononuclear cells
Blood was centrifuged in 50 ml tubes at 1200 rpm for 10 minutes at room temperature. The buffy coat was re-suspended in 20 ml sterile phosphate buffered saline (Gibco, Grand Island, NY, USA). The cell suspension was carefully placed above 20 ml Ficoll[R] (Ficoll[R] 400, Pharmacia, Uppsala, Sweden). Centrifugation was performed at 5000 rpm in a Heraeus-centrifuge[R] (Kendro, Langenselbold, Germany) for 10 minutes resulting in more than 95% mononuclear cells in the supernatant. The cells were re-suspended in sterile RPMI (Gibco, Grand Island, NY, USA) and washed with RPMI at 1200 rpm.
Preparation of cytosol
Cells were re-suspended in 8 ml phosphate buffered saline and sonified on ice for 5x10 seconds. The homogenates were then centrifuged for 10 minutes at 2880 g = 3900 rpm to remove parts of the plasma membrane and large cell fragments. The supernatant was discarded. The pellet was re-suspended and centrifuged again as described. This was followed by an ultracentrifugation of the combined supernatants for 60 minutes at 100,000 g (=30,000 rpm; Beckmann ultracentrifuge; 50.4 Ti Rotor, Krefeld, Germany) at 4[degrees]C. The pellet containing the microsomal fraction was discarded; the supernatant with the cytosolic fraction was used for the 3H-dexamethasone binding assay.
[sup.3]H-dexamethasone binding assay was quantified by incubation of cytosols with [sup.3]H-dexamethasone using a commercially available kit according to the manufacturer's instructions (DDV Bichemie[R], Hoechst, Frankfurt, Germany). A 20-fold excess of unlabeled dexamethasone was used to determine unspecific binding. Unbound dexamethasone was removed by adsorption to charcoal.
Quantification of cytokines, cortisol and ACTH
The levels of ACTH (Phoenix Pharmaceuticals, Belmont, CA, USA), IL-1, IL-6, TNF (Amersham International Plc., Amersham, UK) and cortisol (EIA-1887, DRG Instruments GmbH, Marburg, Germany) were quantified from plasma samples using commercially enzyme-linked immunosorbent assays according to the manufacturers' instructions.
Data are expressed as mean [+ or -] SD. Statistical analysis was performed by analysis of variance one-way analysis and Pearson's correlation. Differences were considered significant at P values of <0.05.
Eight females and 42 males with an average age of 59.3 [+ or -] 10.6 years and a mean duration of ventilator therapy of 3.3 [+ or -] 5.9 days were included. All of the patients received catecholamine therapy (47 were treated with dopamine, 19 with dobutamine, 10 with noradrenaline and seven with adrenaline) and five patients required renal replacement therapy. Mean value of APACHE II scores (in 49 out of 50 patients available) was 9.6 [+ or -] 10.9 (median=5) and mean value of SAPS II scores (in 49 out of 50 patients available) was 26.9 [+ or -] 20.4 (median=18) (Figure 1).
Sixteen patients were hospitalised on a medical intensive care unit and showed a mean APACHE II score of 18.3 [+ or -] 15.5 (median=14.5) and a mean SAPS II score of 44.1 [+ or -] 25.6 (median=43.5), respectively. The other 34 patients were attended at surgical and cardiac-surgical intensive care units, most of them for postoperative monitoring. The mean APACHE II score of these patients (in 33 out of 34 patients available) was 5.4 [+ or -] 3.5 (median=5) and mean SAPS II score(in 33 out of 34 patients available) 18.7 [+ or -] 10.5 (median=18).
[sup.3]H-dexamethasone binding as indicator of glucocorticoid receptor status
Specific binding of 3H-dexamethasone at the beginning of ventilator therapy was significantly decreased in the sample group compared to the control group (69.62 [+ or -] 61.37 dpm/mg cytosolic protein vs 155.45 [+ or -] 108.05 dpm/mg cytosolic protein, P <0.001). Similar results were obtained after extubation (58.34 [+ or -] 57.41 dpm/mg cytosolic protein vs 155.45 [+ or -] 108.05 dpm/mg cytosolic protein, P <0.001) (Figure 2).
After grouping patients, there was a trend to an inverse relation between severity of illness as described by the APACHE II score and [sup.3]H-dexamethasone binding. However, at the beginning as well as after ventilator therapy, the differences did not reach significance (P=0.13 and 0.08, respectively). Furthermore, no significant correlation between APACHE II or SAPS II scores and 3H dexamethasone binding could be found (Figure 3).
[FIGURE 3 OMITTED]
Plasma cortisol and ACTH levels
Plasma cortisol levels did not differ significantly between the sample group after intubation and the control group (124.13 [+ or -] 127.90 ng/ml vs 105.73 [+ or -] 54.68 ng/ml, P=0.54). However, within 72 hours of ceasing ventilatory therapy, plasma cortisol levels were significantly increased (176.01 [+ or -] 65.92 ng/ml vs 105.73 [+ or -] 54.68 ng/ml P <0.001; Figure 4). Similar results could be obtained by comparing the APACHE II groups with the control group. After intubation no significant difference between the groups and controls could be found. After extubation both groups showed significantly higher values (see table within Figure 4).
Similarly, ACTH levels following intubation were not significantly different from ACTH levels in the control group (0.38 [+ or -] 0.22 g/ml vs 0.43 [+ or -] 0.21 pg/ml, P=0.37); whereas a significant difference was observed after extubation (0.26 [+ or -] 0.13pg/ml, 0.43 [+ or -] 0.21 pg/ml, P <0.001).
Values of IL-6 after intubation in the sample group were clearly higher compared to the control group (97.95 [+ or -] 141.65 pg/ml vs 1.77 [+ or -] 2.65pg/ml, P=0.004). This difference was less pronounced after extubation, but still significant (25.78 [+ or -] 24.78 vs 1.77 [+ or -] 2.65, P <0.001).
TNF levels did not vary significantly at either timepoint (at intubation: 2.29 [+ or -] 3.13 pg/ml, at extubation: 3.10 [+ or -] 2.09 pg/ml, control group: 2.09 [+ or -] 2.86 pg/ml, P=0.81 and P=0.26, respectively).
No correlation was seen between inflammatory mediators and specific binding of [sup.3]H-dexamethasone (IL-6: r=0.181, P=0.21; TNF: r=-0.051, P=0.73). Similarly no correlation between cortisol (IL-6: r=0.026, P=0.86; TNF: r=-0.035, P=0.81) and the inflammatory mediators could be detected.
We demonstrated a clear down-regulation of 3H-dexamethasone binding in ventilated patients. This down-regulation was rapid and occurred within the first 24 hours of ventilator therapy.
Elevated plasma levels of the classical stress hormone cortisol can be found during severe illness. In fact, cortisol is an indicator for severity of disease and poor survival in critically ill patients2. In accordance with this, we found a significant increase of cortisol levels after extubation in all patients as an indicator of stress but no significant cortisol increase compared to healthy controls at the time of intubation. The initial absence of cortisol alteration could be explained by the early measurement time-point in the course of critical illness.
Our study demonstrated that down-regulation of [sup.3]H-dexamethasone binding clearly preceded the increase in cortisol levels. Consistent with our findings, Molijn et al found no correlation between cortisol plasma-concentrations and glucocorticoid receptor number or affinity (12), indicating that there might not be a simple interaction between these two parameters. The decrease of [sup.3]H-dexamethasone binding could be observed both in postoperative patients, who were monitored on an intensive care unit, and also in critically ill patients, with a more pronounced but not significantly different effect in the latter. Presumably due to the small number of critically ill patients with high disease scores, no significant correlation could be found between APACHE II/SAPS II scores and [sup.3]H-dexamethasone binding (Figure 3).
A number of studies involving critically ill patients in intensive care units have found markedly altered responsiveness of pituitary ACTH-release following suppression with dexamethasone and stimulation with hCRH (5,6). An altered pituitary glucocorticoid feedback and/or hypersecretion of peptides with CRH-like activity (vasopressin and cytokines) during critical illness are believed to cause this effect. Briegel et al concluded that the adrenocortical response to ACTH is attenuated in patients with septic shock (13,14). They assumed that this reaction could be explained by the effects of circulating mediators from the systemic inflammatory response. Therefore, we measured ACTH levels as well as pro-inflammatory cytokines. Unchanged ACTH levels within the first 24 hours after intubation compared to healthy persons argue against a primary response of the pituitary gland with consequently elevated cortisol levels followed by down-regulation of GR.
Pro-inflammatory cytokines might play an important role in modifying the response of the pituitary-adrenal gland axis (7,15,16). Modification of GR function has been shown in a number of studies for other cytokines as well in T-cells and mononuclear cells. IL-6 and TNF are both produced in the adrenal gland and evidence has been presented that these cytokines are able to modify steroid secretion (17,18). Our patients showed significantly elevated IL-6 plasma levels compared to healthy persons. Similar results were published by Dimopoulou et al (19) in critically ill patients. After comparison of IL-6 levels and response to ACTH-stimulation they concluded that IL-6 might be a major player in the alteration of the pituitary-adrenal axis leading to relative adrenal insufficiency (19). However, we failed to demonstrate a correlation between this cytokine and GR levels, suggesting that the mediators tested in this study are not responsible for down-regulation of GR.
Pariante et al have demonstrated that cytokines can induce GR resistance by inhibition of GR translocation from cytoplasm to the nucleus and down-regulation of GR-mediated gene transcription (2,20). Furthermore, there is evidence that TNF[alpha] induces glucocorticoid resistance by influencing nuclear factor-[kappa]B (8,16,21) and by inhibiting the stimulatory actions of ACTH and angiotensin II on adrenal cells (21,22). However, our patients did not show a significant alteration in TNF[alpha] levels.
Earlier publications on the modification of GR expression yielded heterogeneous findings. Studies which included patients or cells from patients with chronic sepsis or long-term treatment with IL-1 showed GR up-regulation (23), whereas investigations after short-term treatment with IL-1 or early phase of sepsis revealed down-regulation of GR (9,12,24).
We demonstrated down-regulation of 3Hdexamethasone binding capacity in an early phase of critical illness and in postoperative patients. The method used in our experiments only measures cytosolic receptors, not translocated nuclear receptors. Therefore, receptor molecules which are potentially ready to bind therapeutically applied glucocorticoids were determined. At the time of extubation we found a slightly lower 3Hdexamethasone binding compared to the time of intubation, whereas cortisol levels simultaneously were increased. The decrease of [sup.3]H-dexamethasone binding could be due to a competitive antagonism between endogenous cortisol and the testing substance and therefore be biased. With only two time points for measurement, there might be a variation during the course of critical illness, which we did not record.
Dehydroepiandrosterone sulphate (DHEAS) levels were significantly lower compared to healthy controls. Dehydroepiandrosterone and its DHEAS are the most abundant steroids secreted by the adrenal cortex (25). In critically ill patients there is a clear dissociation between high levels of plasma-cortisol and low levels of DHEAS (26,27), suggesting an exhausted adrenal gland adaptation. DHEAS seems to be a prognostic marker like cortisol, because non-survivors of sepsis and trauma patients as well as patients with relative adrenal insufficiency present the lowest DHEAS values (26,28,29). Depletion of DHEAS together with increased levels of serum-cortisol during critical illness could hypothetically play a role in susceptibility to infectious complications (25).
In healthy persons there is a link between DHEAS and IL-6; IL-6 secretion from monocytes correlates inversely with DHEAS and dehydroepiandrosterone application leads to inhibition of IL-6 secretion (30). In accordance with Beishuizen et al, we found a negative correlation between age and DHEAS concentration, but in contrast to their study no significant correlation to IL-6 or cortisol values could be established. Differences in the severity of illness might be an explanation for these divergent findings.
In conclusion, we showed a dramatic down-regulation of [sup.3]H-dexamethasone binding in early stages of critical illness. This cannot be explained by a simple feed-back down-regulation of GR induced by elevated cortisol levels since elevation of the levels of this hormone was a later event. After extubation a significant increase of cortisol levels was detected, suggesting a modification of adrenal adaptation as a response to postoperative stress and in severe illness.
Our data add knowledge to the sequence in which alterations of the hypothalamic-pituitary-axis in critically ill patients occur. Understanding these alterations will answer the question as to whether it is useful to administer glucocorticoids to the critically ill patient. Since the number of free and functional receptors is down-regulated in these patients, glucocorticoid substitution might be of limited value.
Accepted for publication on June 24, 2009.
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Address for correspondence: Dr S. Siebig, Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. Email: Sylvia.firstname.lastname@example.org
S. SIEBIG *, A. MEINEL ([dagger]), G. ROGLER ([double dagger]), F. KLEBL ([section]), C. E. WREDE ([section]), C. GELBMANN ([section]), S. FROH ([section]), F. RoCKMANN ([section]), T. BRuENNLER ([section]), J. SCHOELMERICH ([double dagger]), J. LANGGARTNER ([section])
Department of Internal Medicine I, Hospital of the University of Regensburg, Regensburg, Germany
* M.D., Physician, Resident.
([dagger]) M.D., Medical Student.
([double dagger]) Ph.D., Professor.
([section]) M.D., Internist, Consultant.
Figure 2: The box plot graph pictures the results of specific binding of [sup.3]H-dexamethasone in control (CG) vs sample group (SG) after intubation (1) and after extubation (2). Sample group is divided into the two subgroups (SG A = APACHE score <5; SG B = APACHE score >5). The line refers to the mean, whereas the boxes refer to the interquartile ranges. The whiskers represent the 5th and 95th centiles, respectively. Mean values, standard deviations and the respective P values are shown in the table. Specific binding of Groups n [sup.3]H- dexamethasone P values [dpm/mg] after intubation (1) (* CG vs SG A/B) SG 50 69.63 [+ or -] 61.37 <0.001 CG 20 155.45 [+ or -] 108.05 SG A 28 81.53 [+ or -] 69.41 0.006 * SG B 21 54.18 [+ or -] 47.63 <0.001 * Specific binding of Groups [sup.3]H-dexamethasone P values [dpm/mg] after extubation (2) (* CG vs SG A/B) SG 58.34 [+ or -] 57.41 <0.001 CG 155.45 [+ or -] 108.05 SG A 71.80 [+ or -] 67.24 <0.001 * SG B 42.43 [+ or -] 36.91 0.002 * Figure 4: The box plot graph shows the results of cortisol values in control vs sample group at intubation (1) and after extubation (2). The line refers to the mean, whereas the boxes refer to the interquartile ranges. The whiskers represent the 5th and 95th centiles, respectively. In the table the mean values, SD and the respective P values are given. Mean values, standard deviations and the respective Cortisol [ng/ml] Groups n after intubation P values (* CG vs SG A/B) SG 50 124.13 [+ or -] 127.90 0.54 CG 20 105.73 [+ or -] 54.68 SG A 28 90.73 [+ or -] 38.89 0.27 * SG B 21 165.95 [+ or -] 185.68 0.17 * Cortisol [ng/ml] Groups after extubation (2) P values (* CG vs SG A/B) SG 176.01 [+ or -] 65.92 <0.001 CG 105.73 [+ or -] 54.68 SG A 179.11 [+ or -] 60.90 <0.001 * SG B 174.89 [+ or -] 73.65 0.002 * P values are shown in the table. CG = control group, SG = sample group, SG A = APACHE score <5; SG B = APACHE score >5.
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|Author:||Siebig, S.; Meinel, A.; Rogler, G.; Klebl, F.; Wrede, C.E.; Gelbmann, C.; Froh, S.; Rockmann, F.; Br|
|Publication:||Anaesthesia and Intensive Care|
|Article Type:||Clinical report|
|Date:||Jan 1, 2010|
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