Cortisol levels and mortality in severe sepsis

OBJECTIVE: Serum cortisol levels rise in response to the stress of critical illness but the optimal range of serum cortisol in such settings is not clearly defined. The objectives of this study were to determine the range of serum cortisol levels in a group of medical intensive care unit patients with severe sepsis/septic shock using uniform criteria, and to correlate serum cortisol levels to mortality. DESIGN AND PATIENTS: In a prospective observational fashion, 100 medical intensive care unit patients at Northwestern Memorial Hospital in Chicago were enrolled within 48 h of developing severe sepsis/septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine. MEASUREMENTS: A serum cortisol level was measured during the morning hours in the first 48 h of developing severe sepsis/septic shock. The severity of critical illness was measured by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS: The average patient age was 63 +/- 17 years, 54 patients were men. The average APACHE II score for all patients was 23 +/- 7. In-hospital and 90-day mortality were 51% and 60%, respectively. Four patient groups were defined a priori based on morning serum cortisol levels and their in-hospital mortalities were as follows: group 1 (cortisol < or = 345 nmol/l), n = 11, mortality 54%; group 2 (cortisol 345-552 nmol/l), n = 19, mortality 53%; group 3 (cortisol 552-1242 nmol/l), n = 54, mortality 41%; and group 4 (cortisol > or = 1242 nmol/l), n = 16, mortality 81% (P < 0.01). CONCLUSIONS: Cortisol levels were elevated in most patients with septic shock. Cortisol levels less than 552 nmol/l occurred in 30% of patients with septic shock but the mortality in these patients was not significantly increased. Serum cortisol levels > or = 1242 nmol/l were associated with significantly higher mortality.     

Urinary free cortisol excretion shortly after ischaemic stroke

The cortisol axis and catecholamine excretion were studied in 20 patients within the first week after acute ischaemic stroke. Urine free cortisol and plasma cortisol levels after dexamethasone were significantly higher in stroke patients than in 80-year-old volunteers (n = 32; P = 0.03 and P = 0.003, respectively). Catecholamine excretion was found to be significantly correlated with urine cortisol concentration (r = 0.54, P less than 0.05) and limb paresis (r = 0.52, P less than 0.05). In a multiple regression analysis, urine cortisol values were shown to be positively associated with limb paresis (P = 0.003), disorientation (P = 0.03) and body temperature (P = 0.03). High cortisol excretion was associated with a poorer functional outcome in a discriminant analysis (P = 0.001). Thus acute ischaemic stroke is associated with an increased activity in the cortisol axis. This may have a number of negative effects on organ functioning, and is a predictor of a poorer functional outcome.     

Pituitary-thyroid axis, prolactin and growth hormone in patients with acute stroke

The pituitary-thyroid axis, serum prolactin and growth hormone levels were studied in 29 patients within 9 d of onset of acute ischaemic stroke. When compared to a control group of 80-year-old volunteers (n = 33), stroke patients were found to have elevated free thyroxine indices (P = 0.008), after adjustment for age and sex. Seventeen (81%) of the stroke patients showed a paradoxical rise in growth hormone in response to thyrotropin releasing hormone (TRH). In a multiple regression model, disorientation was associated with a low thyrotropin response to TRH (P = 0.02 and P = 0.04; 20 and 60 min after TRH, respectively). Disorientation was also positively correlated with the prolactin response to TRH (P = 0.045 after 60 min). Growth hormone levels were predicted by extensive motor impairment (P = 0.02). In conclusion, changes in pituitary and thyroid hormones were commonly observed after stroke and were closely associated with cognitive and/or motor impairment.     

Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing''s syndrome

OBJECTIVE: To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushing's syndrome. DESIGN: An evaluation of the standard clinical practice at one institution. PATIENTS: Ninety-one patients with Cushing's syndrome: 57 pituitary-dependent Cushing's disease, 10 adrenocortical adenomas, six adrenocortical carcinomas and 18 ectopic ACTH syndrome. MEASUREMENTS: The acute response to metyrapone was assessed by measuring cortisol, 11-desoxycortisol and ACTH at 0, 1, 2, 3, 4 hours after a test dose of 750 mg of metyrapone. The longer-term effect of metyrapone was judged by measuring serum cortisol at 0900, 1200, 1500, 1800, 2100 and sometimes 2400 h and calculating a mean. RESULTS: A test dose of 750 mg of metyrapone decreased serum cortisol levels within 2 hours in all groups of patients and this effect was sustained at 4 hours. At the same time, serum 11-desoxycortisol levels increased in all patients, while plasma ACTH increased in patients with pituitary Cushing's disease and the ectopic ACTH-syndrome. Fifty-three patients with Cushing's disease were followed on short-term metyrapone therapy (1 to 16 weeks) before other more definitive therapy. Their mean cortisol levels (median 654 nmol/l, range 408-2240) dropped to the target range of less than 400 nmol/l in 40 patients (75%) on a median metyrapone dose of 2250 mg/day (range 750-6000). Metyrapone was given long term in 24 patients with Cushing's disease who had been given pituitary irradiation, for a median of 27 months (range 3-140) with adequate control of hypercortisolaemia in 20 (83%). In 10 patients with adrenocortical adenomas and six with adrenocortical carcinomas, metyrapone in a median dose of 1750 mg/day (range 750-6000) reduced their mean cortisol levels (median 847 nmol/l, range 408-2000) to less than 400 nmol/l in 13 patients (81%). In 18 patients with the ectopic ACTH-syndrome the 'mean cortisol levels', obtained from five or six samples on the test day (median 1023 nmol/l, range 823-6354) were reduced to less than 400 nmol/l in 13 patients (70%), on a median dose of 4000 mg/day (range 1000-6000). Reduction of cortisol levels was clearly associated with clinical and biochemical improvement. The medication was well tolerated. Transient hypoadrenalism and hirsutism were unusual but were the most common side-effects. CONCLUSIONS: In our experience metyrapone remains a most useful agent for controlling cortisol levels in the management of Cushing's syndrome of all types.     

Comparison of one week 0900 h serum cortisol, low and standard dose synacthen tests with a 4 to 6 week insulin hypoglycaemia test after pituitary surgery in assessing HPA axis

OBJECTIVE: To compare the use of 0900 h serum cortisol and both low and standard dose Synacthen tests, one week after pituitary surgery with an insulin hypoglycaemia test performed 4-6 weeks after surgery in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: 0900 h basal serum cortisol was measured on days 6 and 7 after pituitary surgery (24 h off replacement hydrocortisone) followed by a low dose Synacthen test (1 microg intravenously) on day 6 and a standard dose Synacthen test (250 microg intramuscularly) on day 7. Three to 5 weeks later an insulin hypoglycaemia test was performed on all patients. Both low and standard dose Synacthen tests were performed on control subjects using an identical protocol. SUBJECTS: Forty-two patients (21 male, 21 female), median age 49 years (range 23-73) who had pituitary surgery (Cushing's disease excluded). One patient had undergone repeat surgery for residual tumour and was studied following each operation. Sixteen healthy normal volunteers, median age 37 years (range 21-55). MEASUREMENTS: Serum cortisol measured by radioimmunoassay. RESULTS: Two standard deviations below the mean serum cortisol (logarithmic transformation) in the normal volunteers 30 minutes after low dose Synacthen (1 microg) was 496 nmol/l and after standard dose Synacthen (250 microg) was 504 nmol/l. A normal response was therefore taken as serum cortisol > 500 nmol/l at 30 minutes in both tests (using 496 and 504 nmol/l did not alter results). 0900 h serum cortisols 1 week after surgery were > 250 nmol/l in 31 patients and 29 of these had a normal response to hypoglycaemia (peak serum cortisol > 550 nmol/l). Of the remaining two patients, one had 0900 h serum cortisol on day 6 and 7 after surgery of 405 and 441 nmol/l with a peak serum cortisol response to hypoglycaemia of 451 nmol/l; the other patient had 0900 h serum cortisols of 416 and 251 nmol/l and a peak cortisol response to hypoglycaemia of 498 nmol/l. All eight patients who had a 0900 h serum cortisol < 100 nmol/l failed a subsequent insulin hypoglycaemia test. Seven discrepancies were noted between the low dose Synacthen test and the insulin hypoglycaemia test in the 41 patients who had both tests. In six of these, a subnormal response to low dose Synacthen was followed by a normal response to hypoglycaemia. Three discrepancies were noted between the standard dose Synacthen test and the insulin hypoglycaemia test in the 40 patients who had both tests. In all three cases a normal response to Synacthen was followed by a subnormal response to hypoglycaemia. CONCLUSIONS: A 0900 h serum cortisol < 100 nmol/l (24 h off replacement hydrocortisone) indicated ACTH deficiency and need for lifelong steroid replacement. A 0900 h serum cortisol > 450 nmol/l one week after pituitary surgery is highly suggestive of a normal cortisol response to hypoglycaemia. A 0900 h serum cortisol between 250 and 450 nmol/l one week after pituitary surgery permits safe withdrawal of steroid therapy pending an insulin hypoglycaemia test 1 month after surgery. Patients with 0900 h serum cortisol between 100 and 250 nmol/l should continue replacement steroids until definitive testing. Low dose and standard dose Synacthen tests 1 week after pituitary surgery are unreliable and should not be used.     

Relative adrenal insufficiency: an identifiable entity in nonseptic critically ill patients?

OBJECTIVE: To determine whether relative adrenal insufficiency (RAI) can be identified in nonseptic hypotensive patients in the intensive care unit (ICU). DESIGN: Retrospective study in a medical-surgical ICU of a university hospital. PATIENTS: One hundred and seventy-two nonseptic ICU patients (51% after trauma or surgery), who underwent a short 250 microg ACTH test because of > 6 h hypotension or vasopressor/inotropic therapy. MEASUREMENTS: On the test day, the Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) score were calculated to estimate disease severity. The ICU mortality until day 28 was recorded. Best discriminative levels of baseline cortisol, increases and peaks were established using receiver operating characteristic curves. These and corticosteroid treatment (in n = 112, 65%), among other variables, were examined by multiple logistic regression and Cox proportional hazard regression analyses to find independent predictors of ICU mortality until day 28. RESULTS: ICU mortality until day 28 was 23%. Nonsurvivors had higher SAPS II and SOFA scores. Baseline cortisol levels correlated directly with albumin levels and SAPS II. In the multivariate analyses, a cortisol baseline > 475 nmol/l and cortisol increase < 200 nmol/l predicted mortality, largely dependent on disease severity but independent of albumin levels. Corticosteroid (hydrocortisone) treatment was not associated with an improved outcome, regardless of the ACTH test results. CONCLUSION: In nonseptic hypotensive ICU patients, a low cortisol/ACTH response and treatment with corticosteroids do not contribute to mortality prediction by severity of disease. The data thus argue against RAI identifiable by cortisol/ACTH testing and necessitating corticosteroid substitution treatment in these patients.     

Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.     

Cortisol axis abnormalities early after stroke--relationships to cytokines and leptin

OBJECTIVE: To assess the relationships between circulating levels of proinflammatory cytokines and adrenocortical hormones and leptin early after stroke. DESIGN: Blood samples were collected four times daily the first two days after stroke, twice daily the next 4 days and four times at day 7. Cognitive function and functional outcome was measured at admittance and at day 7. SETTING: Consecutive inclusion of patients admitted to the stroke unit at Umea University Hospital. SUBJECTS: Eight men and 4 women with acute stroke and 10 healthy volunteers. MAIN OUTCOME MEASURES: Levels and diurnal variations of plasma proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), serum adrenocortical hormones (cortisol and DHEA) and leptin, and MMSE, SSS, and ADL scores. RESULTS: A significant correlation was present between IL-6 and cortisol levels the first two days after stroke (P < 0.05). In patients with a disturbed diurnal rhythm of cortisol, cortisol and leptin levels were increased (68% and 81% increase, respectively), whilst DHEA levels were unaltered. Half of the patients displayed an abnormal diurnal rhythmicity of leptin at the end of the week. Median TNF-alpha levels for the first two days after stroke also correlated to median leptin levels at the end of the week (P < 0.05). Median IL-6 levels correlated to severity of paresis on days 1 and 7 and to MMSE scores on day 7 (P < 0.05). CONCLUSIONS: Neuroendocrine disturbances are common and often profound early after stroke. Cytokines seem to be important modulators of these disturbances, including diurnal rhythmicity of cortisol and leptin.     

Increased cortisol response to surgery in patients with alcohol problems who developed postoperative confusion

BACKGROUND: Patients with alcohol problems often develop postoperative confusion and have impaired cortisol, ACTH, and norepinephrine. However, the relationship between neuroendocrine responses to surgical stress and postoperative confusion remains unclear in patients with alcohol problems. METHODS: Plasma cortisol, ACTH, and norepinephrine concentrations during and after surgery in 30 patients with alcohol problems and 30 control patients who underwent lower abdominal surgery were measured before the induction of anesthesia, 15 and 60 min after skin incision, 60 min after the end of surgery, the next day, and the second day after the operation. RESULTS: Plasma cortisol concentrations (21.2 +/- 4.7 microg x dl) of patients with alcohol problems before anesthesia were significantly higher than 15.6 +/- 4.8 microg x dl(-1) of control patients. Plasma cortisol and ACTH responses to surgery in patients with alcohol problems were not significantly increased compared with preoperative values. The incidence of postoperative confusion was significantly higher in patients with alcohol problems than that of control patients (33% vs. 3%). Plasma cortisol concentrations (29.7 +/- 7.0, 31.2 +/- 6.6, 30.3 +/- 8.0, and 28.4 +/- 6.2 microg x dl(-1)) 15 and 60 min after the skin incision, 60 min after the end of surgery, and the next day after operation in postoperatively confused patients with alcohol problems were significantly higher than those of nonconfused patients with alcohol problems (23.0 +/- 5.8, 22.7 +/- 4.1, 22.4 +/- 7.2, and 21.9 +/- 5.5 microg x dl(-1)). CONCLUSION: The cortisol response to surgical stress increases in patients with alcohol problems who develop postoperative confusion, although cortisol response to surgical stress decreases in patients with alcohol problems without postoperative confusion.     

Serum cortisol levels in patients admitted to the department of medicine: Prognostic correlations and effects of age, infection, and comorbidity

BACKGROUND: In contrast to healthy adults or critically ill patients, data on serum cortisol levels in noncritically ill patients admitted to general internal medicine wards has not been well characterized. We aimed to describe the distribution and range of serum cortisol levels in patients admitted to the department of medicine, to discover whether old age, severe infections, or comorbidity induced a blunted hypothalamic-pituitary-adrenal (HPA) response and whether initial serum cortisol value had a prognostic significance. METHODS: Morning (8 am) serum cortisol level together with epidemiologic, clinical, and laboratory data were analyzed for 252 consecutive adult (age > or = 18 yrs) patients admitted to the department of internal medicine during a 6-weeks period. RESULTS: The mean serum cortisol level (541 +/- 268 nmol/L) was within the normal range. Only one patient had a low serum cortisol level of 72 nmol/L, whereas the majority of patients had either normal (80%) or increased (19%) serum cortisol levels. Older age, sepsis, prolonged duration of fever, higher comorbidity score, and higher serum creatinine level were each associated with significantly higher serum cortisol level. In addition, a higher serum cortisol level was significantly related to longer hospitalization and higher in-hospital mortality rate. CONCLUSIONS: Serum cortisol level positively correlated with age, disease severity, and outcome. All admitted patients, except one, had normal to high serum cortisol. Whether this increased cortisol level is an adequate HPA response or less than required for the disease-induced stress should be investigated in further studies.     

Serum homocysteine, folate and risk of stroke: Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study.

BACKGROUND: Homocysteine and folate have been suggested to have opposite effects on the risk of stroke, although the results are controversial. DESIGN AND METHODS: The purpose of this study was to assess the effects of serum total homocysteine (tHcy) and serum folate levels on the risk of stroke in a prospective cohort study. The subjects were 1015 men aged 46-64 years and free of prior stroke, examined in 1991-1993 in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. RESULTS: At baseline the mean serum tHcy concentration was 10.9 micromol/l (SD 3.4). During an average follow-up time of 9.6 years, 49 men experienced a stroke, of which 34 were ischaemic. In Cox proportional hazards models, men in the highest tHcy third had a risk factor-adjusted hazard rate ratio (RR) of 2.77 [95% confidence interval (CI): 1.23-6.24] for any stroke and 2.61 (95% CI: 1.02-6.71) for ischaemic stroke, compared with men in the lowest third. The mean baseline serum folate concentration was 10.4 nmol/l (SD 4.1). Men in the highest third of serum folate (>11.2 nmol/l) had an adjusted RR for any stroke of 0.35 (95% CI: 0.14-0.87) and for ischaemic stroke of 0.40 (95% CI: 0.15-1.09), compared with men in the lowest third. CONCLUSION: Elevated serum tHcy is associated with increased risk of all strokes and ischaemic strokes in middle-aged eastern Finnish men free of prior stroke. On the other hand, high serum folate concentration may protect against stroke.     

Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma

PURPOSE: Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function. SUBJECTS AND METHODS: After a 10-day placebo run-in, we evaluated the effects of 200 microg, 400 microg, and 800 microg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 years (mean +/- SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor. RESULTS: For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 microg (low dose) and 800 microg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 microg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose. CONCLUSIONS: In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.     

Inflammatory markers and in-hospital mortality in acute ischaemic stroke

BACKGROUND: There is substantial evidence that cerebral ischaemia triggers an inflammatory response. We examined the short-term prognostic value on mortality of C-reactive protein (CRP), interleukin-6 (IL-6) and serum amyloid A (SAA) in patients with ischaemic stroke. METHODS: We recruited 203 consecutive patients, under the age of 66 years (mean age=54.2+/-8.1 years, men=132) who admitted to the Neurology Department with the diagnosis of non-haemorrhagic stroke. Patients in atrial fibrillation or with evidence of inflammatory or malignant disease were excluded. The diagnosis was confirmed with a computed tomography or magnetic resonance imaging of the brain within 24h of admission. CRP, IL-6 and SAA levels were determined within 12h from admission. RESULTS: Fourteen (6.9%) patients died during hospitalization. Serum concentrations of CRP, IL-6 and SAA were significantly higher in patients who died compared with those who survived and were independently associated with early death, after adjusting for various confounding factors. For one unit increase in IL-6, CRP and SAA there was an 18%, 14% and 9% higher risk of dying during hospitalization, respectively. Comparisons of the areas under the ROC curve showed that IL-6 had the best predictive ability. Age-adjusted cut-off point analysis showed that IL-6 levels >13 pg/ml were the optimal point that discriminated those who died from the rest of the patients (sensitivity=85% and specificity=93%). CONCLUSIONS: We demonstrated that in-hospital mortality in ischaemic stroke is associated with an exacerbation of inflammatory response as it is reflected by the higher serum levels of IL-6, CRP and SAA. From the inflammatory markers high IL-6 levels had the strongest independent predictive value for in-hospital mortality.     

Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction.

PURPOSE: The thyroid hormone system may be downregulated temporarily in patients who are severely ill. This "euthyroid sick syndrome" may be an adaptive response to conserve energy. However, thyroid hormone also has beneficial effects on the cardiovascular system, such as improving cardiac function, reducing systemic vascular resistance, and lowering serum cholesterol levels. We investigated whether thyroid hormone levels obtained at the time of myocardial infarction are associated with subsequent mortality. PATIENTS AND METHODS: Serum levels of thyroid hormones (triiodothyronine [T3], reverse T3, free thyroxine [T4], and thyroid-stimulating hormone) were measured in 331 consecutive patients with acute myocardial infarction (mean age [+/- SD], 68 +/- 12 years), from samples obtained at the time of admission. RESULTS: Fifty-three patients (16%) died within 1 year. Ten percent (16 of 165) of patients with reverse T3 levels (an inactive metabolite) >0.41 nmol/L (the median value) died within the first week after myocardial infarction, compared with none of the 166 patients with lower levels (P <0.0004). After 1 year, the corresponding figures were 24% (40 of 165) versus 7.8% (13 of 166; P <0.0001). Reverse T3 levels >0.41 nmol/L were associated with an increased risk of 1-year mortality (hazard ratio = 3.0; 95% confidence interval: 1.4 to 6.3; P = 0.005), independent of age, previous myocardial infarction, prior angina, heart failure, serum creatinine level, and peak serum creatine kinase-MB fraction levels. CONCLUSION: Determination of reverse T3 levels may be a valuable and simple aid to improve identification of patients with myocardial infarction who are at high risk of subsequent mortality.     

Failure of somatostatin analogue to control Cushing''s syndrome in two cases of ACTH-producing carcinoid tumours

OBJECTIVE--To determine the effectiveness of somatostatin analogue (octreotide) in controlling hypercortisolism in two patients with ectopic ACTH-producing carcinoid tumours, and to review the literature. DESIGN--The two patients were treated with octreotide administered by subcutaneous injection, for 5 days with 150 micrograms three times daily and for 7 days with 100 micrograms three times daily respectively. They were subsequently treated with oral metyrapone 250 mg three times daily. PATIENTS--Patient 1 had a metastatic carcinoid tumour but the primary was not identified. Patient 2 had a pulmonary carcinoid. Cushing's syndrome due to ectopic ACTH syndrome was established by demonstration of failure of cortisol suppression by dexamethasone, elevated ACTH levels, and immunoperoxidase staining for ACTH within the tumours. MEASUREMENTS--Urinary free cortisol (UFC) was measured on consecutive days during treatment with octreotide. Serum cortisol and ACTH levels were taken daily in patient 2, and on days 0 and 3 in patient 1. RESULTS--Patient 1 had a baseline 24-hour urinary free cortisol of 5340 nmol/24 h, serum cortisol of 915 nmol/l, and serum ACTH of 163 ng/l (ACTH ng/l x 0.23 = pmol/l). After 3 days of octreotide, serum cortisol was 782 nmol/l and ACTH 164 ng/l. Twenty-four hour urinary free cortisol was 4136 nmol/24 h after 7 days of treatment. Metyrapone, however, resulted in a rapid fall in urinary free cortisol to 290 nmol/24 h, with marked clinical improvement. Patient 2 had a baseline 24-hour urinary free cortisol of 2520 nmol/24 h, serum cortisol of 747 nmol/l, and ACTH of 103 ng/l. Urinary free cortisol rose to 2970 nmol/24 h on day 6 of treatment with octreotide. Serum cortisol and ACTH levels fell slightly to 611 nmol/l and 70 ng/l respectively. On changing to metyrapone, the urinary free cortisol fell to 821 nmol/24 h in 4 days. CONCLUSIONS--Octreotide failed to significantly reduce 24-hour urinary free cortisol, serum cortisol and ACTH in the two patients reported. We conclude that it should probably not be regarded as primary treatment for control of hypercotisolism in patients with ACTH-producing carcinoids, but reserved as adjunctive therapy.     

Assessment of adrenal function in cirrhotic patients using concentration of serum‐free and salivary cortisol

Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid‐binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum‐free and salivary cortisol concentrations. Methods: We assessed basal (T₀) and post‐synacthen (T₆₀) serum total cortisol, serum‐free and salivary cortisol in 125 consecutive cirrhotics (95 non‐septic and 30 septic patients with a Child>8). Results: Serum total cortisol levels significantly decreased from the Child A–C non‐septic group, as did albumin and CBG levels, with a non‐significant rise in serum‐free cortisol concentrations. Non‐septic patients with low albumin (≤25 g/L) or CBG levels (≤35 mg/L) had lower T₀ serum total cortisol levels than patients with near‐normal albumin (303.4 vs. 382.6 nmol/L; P=0.0035) or with normal CBG levels (289.9 vs. 441.4 nmol/L; P<0.0001), respectively, despite similar serum‐free cortisol or salivary cortisol concentrations. Subnormal T₆₀ serum total cortisol concentrations (<510.4 nmol/L) were measured in 7.2% of all patients (Child C: 14.5% vs. Child A and B: 0%; P=0.0013) but no patients exhibited symptoms suggesting adrenal insufficiency. Patients with or without subnormal T₆₀ total cortisol had similar T₀ salivary cortisol and serum‐free cortisol concentrations. A trend was observed towards high serum‐free cortisol concentrations and mortality in multivariate analysis. Conclusions: Serum total cortisol levels overestimated the prevalence of adrenal dysfunction in cirrhotics with end‐stage liver disease. Since serum‐free cortisol cannot be measured routinely, salivary cortisol testing could represent a useful approach but needs to be standardized.     

Low-dose ACTH (1 microg) salivary test: a potential alternative to the classical blood test

OBJECTIVES: Salivary cortisol is unaffected by cortisol binding globulin (CBG) and hence allows CBG-related variations in serum total cortisol to be bypassed. We assessed whether or not salivary cortisol can be used for the low-dose (1 microg) ACTH test in subjects with presumed normal and elevated levels of CBG. PATIENTS/METHODS: We measured serum and salivary cortisol responses to intravenous administration of 1 microg ACTH in 14 healthy volunteers, 14 'hyperoestrogenic' women [in their first or early second trimester of pregnancy, using oral contraceptives (OC) or on hormone replacement therapy (HRT)] and 10 patients with secondary hypoadrenalism. Cortisol levels were recorded before as well as 30 and 60 min (+30; +60 min) after ACTH administration. RESULTS: Baseline salivary cortisol did not differ significantly between the hypoadrenal and healthy patients (7.11+/-1.4 and 12.13+/-1.59 nmol/l; P=0.48) but there was a significant difference between hypoadrenal and hyperoestrogenic patients (18.94+/- 3.44 nmol/l; P=0.01). The largest difference between hypoadrenal patients and healthy individuals was observed at+30 min (9.16+/-2.8, 52.65+/-8.78 and 48.81+/- 6.9 nmol/l, in the hypoadrenal, healthy and hyperoestrogenic patients, respectively; P< 0.05). At this time-point values< 24.28 nmol/l were found in all hypoadrenal patients and cortisol levels >or= 27.6 nmol/l were found in 26 out of 28 healthy volunteers. ACTH-stimulated serum cortisol but not salivary cortisol was significantly higher in hyperoestrogenic women than in the healthy volunteers at either+30 or+60 min. CONCLUSIONS: The salivary low-dose ACTH test yields results that parallel the response of circulating cortisol to ACTH and may provide an alternative to the blood test, particularly in situations where increased CBG levels complicate the changes in serum cortisol levels.     

Osteoprotegerin concentrations and prognosis in acute ischaemic stroke

Abstract. Jensen JK, Ueland T, Atar D, Gullestad L, Mickley H, Aukrust P, Januzzi JL (Odense University Hospital, Denmark; Rikshospitalet, Oslo, Norway; Massachusetts General Hospital, USA). Osteoprotegerin concentrations and prognosis in acute ischaemic stroke. J Intern Med 2010; 267 : 410–417. Aim. Concentrations of osteoprotegerin (OPG) have been associated with the presence of vascular and cardiovascular diseases, but the knowledge of this marker in the setting of ischaemic stroke is limited. Methods and results. In 244 patients with acute ischaemic stroke (age: 69 ± 13 years), samples of OPG were obtained serially from presentation to day 5. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all‐cause mortality as the sole end‐point. Multivariable predictors of OPG values at presentation included haemoglobin (T = ?2.82; P = 0.005), creatinine (T = 4.56; P < 0.001), age (T = 9.66; P < 0.001), active smoking (T = 2.25; P = 0.025) and pulse rate (T = 3.23; P = 0.001). At follow‐up 72 patients (29%) had died. Patients with OPG ≤2945 pg mL^?1 at baseline had a significantly improved survival rate on univariate analysis (P < 0.0001); other time‐points did not add further prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C‐reactive protein levels, troponin T levels, heart and renal failure concentrations of OPG independently predicted long‐term mortality after stroke (adjusted hazard ratio, 2.3; 95% CI: 1.1 to 4.9; P = 0.024). Conclusion. Osteoprotegerin concentrations measured at admission of acute ischaemic stroke are associated with long‐term mortality.     

Severe hyponatremia due to hypopituitarism with adrenal insufficiency: report on 28 cases

OBJECTIVE: Severe hyponatremia due to hypopituitarism and adrenal insufficiency can be life-threatening, and treatment with glucocorticoids is very effective once the diagnosis of the underlying disorder has been made. In our experience, the diagnosis of hypopituitarism in hyponatremic patients is often overlooked. METHODS: In a retrospective study we screened the files of 185 patients with severe hyponatremia (<130 mmol/l) that had been seen in one endocrinological unit of a university hospital between 1981 and 2001 in order to describe the clinical spectrum of patients with hyponatremia and hypopituitarism including secondary adrenal insufficiency. RESULTS: In 139 cases it was possible to clearly ascribe the patients to the pathophysiological groups of (i) primary sodium deficiency, (ii) edematous disorders, and (iii) normovolemic disorders including the "syndrome of inappropriate secretion of antidiuretic hormone" (SIADH). Twenty-eight patients with severe "normovolemic hyponatremia" (serum sodium: 116+/-7 mmol/l, mean+/-s.d.) had hypopituitarism and secondary adrenal insufficiency as shown by basal cortisol measurements and dynamic tests of adrenal function. In 25 cases of this group hypopituitarism (mostly due to empty sella, Sheehan's syndrome and pituitary tumors) had not been recognized previously, and in 12 cases recurrent hyponatremia during previous hospital admissions (up to four times) could be documented. The mean age of these patients (21 women, seven men) was 68 Years. The most frequently occurring clinical signs were missing or scanty pubic and axillary hair, pale and doughy skin, and small testicles in the men. Frequent symptoms like nausea and vomiting, confusion, disorientation, somnolence or coma were similar to those in 91 patients with SIADH. Basal serum cortisol levels in the acutely ill state ranged from 20 to 439 nmol/l (mean+/-s.d.: 157+/-123), while in 30 other severely hyponatremic patients it ranged from 274 to 1732 nmol/l (732+/-351 nmol/l). In most patients with hyponatremic hypopituitarism, plasma antidiuretic hormone levels were inappropriately high, probably due to a failure of endogenous cortisol to suppress the hormone in a stressful situation. All patients recovered after low-dose hydrocortisone substitution. Most patients had other pituitary hormone deficiencies and were appropriately substituted subsequently. CONCLUSIONS: Hypopituitarism including secondary adrenal insufficiency seems to be a frequently overlooked cause of severe hyponatremia. A high level of suspicion is the best way to recognize the underlying disorder. Treatment with hydrocortisone is very effective.     

Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke

BACKGROUND AND SCOPE: Recent literature has demonstrated that inflammation contributes to all phases of atherosclerosis and brain damage caused by stroke. In acute phase of cerebrovascular diseases biochemical markers of inflammation, such as C-reactive protein (CRP), could represent an indicator of severity of stroke, but few studies have verified this hypothesis, especially in very old patients. The aim of this study was to evaluate the role of CRP on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. MATERIALS AND METHODS: We retrospectively evaluated CRP values (nephelometric method), performed within 12 h from hospital admission, in 196 elderly patients (124 females and 72 males with mean age+/-SD 83.32+/-10.46 years), discharged with diagnosis of acute ischaemic stroke, 68 of them with atherothrombotic large vessel stroke, 38 with lacunar stroke and 90 with cardioembolic stroke. We studied the relationship between CRP values and short-term prognosis [30-day mortality, length of hospitalization (LOS) and physical disability measured by modified Rankin scale and long-term prognosis (12-month mortality and re-hospitalization)]. RESULTS: Mean values of CRP were significantly higher in patients with cardioembolic stroke compared with atherothrombotic large vessel and lacunar stroke, in patients who died in the first 30 days from the acute event compared with survivors. LOS and physical disability score rose with increasing values of CRP for all subtypes of stroke. Higher CRP values were associated with the 12-month re-hospitalization for cerebrovascular events, whereas it did not influence the 12-month cumulative re-hospitalization and 12-month mortality. CONCLUSIONS: Elevation of CRP values at hospital admission could represent a negative prognostic index in elderly patients with ischaemic stroke, in particular, for short-term prognosis.