Stylianos Tsagarakis

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine

Objective:To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients. Participants:A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate. Design/Methods:The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence. Results:The task force coined the term critical illness–related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness–related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness–related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of <9 &mgr;g/dL after adrenocorticotrophic hormone (250 &mgr;g) administration or a random total cortisol of <10 &mgr;g/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (Pao2/Fio2 of <200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for ≥7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg·kg−1·day−1 for ≥14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness–related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation. Conclusion:Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.

Hypothalamic-pituitary-adrenal axis dysfunction in critically ill patients with traumatic brain injury: incidence, pathophysiology, and relationship to vasopressor dependence and peripheral interleukin-6 levels.

ObjectiveTo investigate hypothalamic-pituitary-adrenal axis function in patients requiring mechanical ventilation for traumatic brain injury and to assess the relation of hypothalamic-pituitary-adrenal axis abnormalities with vasopressor dependence and peripheral cytokine levels. DesignProspective study. SettingGeneral intensive care unit in a university teaching hospital. PatientsForty patients (33 men and 7 women) with moderate to severe traumatic brain injury (mean age, 37 ± 16 yrs) were studied the day after termination of mechanical ventilation (7–60 days after trauma). InterventionsFirst, a morning blood sample was obtained to measure baseline cortisol, corticotropin, interleukin-6, and tumor necrosis factor alpha. Subsequently, 1 &mgr;g of synthetic corticotropin was injected intravenously, and 30 mins later, a second blood sample was drawn to determine stimulated plasma cortisol. Based on data derived from healthy volunteers, patients having stimulated cortisol levels <18 &mgr;g/dL were defined as nonresponders to the low-dose stimulation test. Thirty-one patients underwent also a human corticotropin releasing hormone test. Measurements and Main ResultsIn traumatic brain injury patients, mean baseline and low-dose stimulation test-stimulated cortisol levels were 17.2 ± 5.4 &mgr;g/dL and 24.0 ± 6.6 &mgr;g/dL, respectively. The median increment in cortisol was 5.9 &mgr;g/dL. Basal corticotropin levels ranged from 3.9 to 118.5 pg/mL. Six of the 40 patients (15%) failed the low-dose stimulation test. The human corticotropin releasing hormone test (performed in 26 responders and five nonresponders) revealed diminished cortisol release only in the low-dose stimulation test nonresponder patients. Corticotropin responses to corticotropin releasing hormone were consistent with both primary (three patients) and/or secondary (two patients) adrenal dysfunction. In retrospect, nonresponders to the low-dose stimulation test more frequently required vasopressors (6/6 [100%] vs. 16/34 [47%]; p = .02) and for a longer time interval (median, 0 vs. 293 hrs; p = .006) compared with responders. Furthermore, nonresponders had higher interleukin-6 levels compared with responders (56.03 vs. 28.04 pg/mL; p = .01), whereas tumor necrosis factor alpha concentrations were similar in the two groups (2.42 vs. 1.55 pg/mL; p = .53). ConclusionsAdrenal cortisol secretion after dynamic stimulation is deficient in a subset of critically ill patients with moderate to severe head injury. This disorder is associated with prior vasopressor dependency and higher interleukin-6 levels.

High incidence of neuroendocrine dysfunction in long-term survivors of aneurysmal subarachnoid hemorrhage.

Background and Purpose— To investigate the incidence, pattern, and magnitude of neuroendocrine changes in long-term survivors of aneurysmal subarachnoid hemorrhage (SAH). Methods— Thirty patients (16 women) with a mean age of 50±13 years underwent endocrine assessment between 12 and 24 months after aneurysmal SAH. SAH severity was graded clinically by the Hunt & Hess scale (median, II) and radiologically by the Fisher classification (median, II). Patients underwent measurement of basal hormone levels and dynamic assessment by the low-dose (1 &mgr;g) corticotropin stimulation test. Functional outcome was examined concurrently with endocrine testing by the modified Rankin Scale and the Barthel Index. Results— Of the 30 patients tested, 14 patients (47%) showed isolated or combined endocrine abnormalities. These included low insulin-like growth factor 1 levels compatible with growth hormone deficiency in 37%, hypogonadism in 13%, and cortisol hyporesponsiveness to the low-dose corticotropin stimulation test in 10%; thyroid dysfunction in the form of subclinical hypothyroidism was observed in 7% of patients. Median modified Rankin Scale and Barthel Index at the time of endocrine testing were 1 and 100, respectively. There was no correlation between the presence of endocrine dysfunction and SAH severity indices or functional outcome scores. Conclusions— Long-term survivors of aneurysmal SAH frequently exhibit endocrine changes, with growth hormone and gonadal deficiencies predominating. Thus, screening of pituitary function is recommended in patients surviving SAH. The relationship between late hormonal alterations and functional outcome in patients with SAH warrants further study.

High prevalence of decreased cortisol reserve in brain-dead potential organ donors.

ObjectiveTo investigate the adrenocortical function in brain-dead patients, potential organ donors. DesignProspective study. SettingIntensive care units in two teaching hospitals. PatientsA total of 37 patients (28 men, nine women) with severe brain injury, having a mean age of 42 ± 18 yrs, were included in the study. Group A consisted of 20 brain-injured patients who did not deteriorate to brain death. Group B included 17 brain-injured patients who were brain dead; of these, ten patients developed brain death during ICU stay and seven patients were admitted to the ICU after clinical brain death. InterventionsIn all patients (group A and group B), a morning blood sample was obtained at admission to the ICU to determine baseline plasma cortisol. Subsequently, 1 &mgr;g of corticotropin (adrenocorticotropic hormone, Synacthen) was administered intravenously, and a blood sample was taken 30 mins after the injection. In group B patients who became brain dead while being treated in the ICU (n = 10), the same procedure was repeated the morning after the confirmation of brain death. Patients having a cortisol level of at least 18 &mgr;g/dL after the administration of adrenocorticotropic hormone were defined as responders. Measurements and Main ResultsAfter the occurrence of brain death, group B patients had significantly lower values for baseline (8.5 ± 6.2 vs. 17.0 ± 6.6 &mgr;g/dL, p < .001) and stimulated (16.9 ± 6.3 vs. 23.9 ± 5.7 &mgr;g/dL, p = .001) plasma cortisol compared with group A patients. Thirteen group B patients (76%) and two group A patients (10%) were nonresponders to adrenocorticotropic hormone (p < .001). In group B patients, baseline and stimulated cortisol concentrations were significantly related (r = .71, p = .001), whereas there was no correlation between baseline cortisol and the increment in cortisol (r = −.37, p = .15). Mean hormonal data of the ten brain-dead patients studied at admission in the ICU and after the occurrence of brain death were the following: baseline plasma cortisol (23.5 ± 11.4 vs. 6.8 ± 4.2 &mgr;g/dL, p = .003) and stimulated serum cortisol (28.8 ± 9.9 vs. 16.3 ± 4.3 &mgr;g/dL, p = .008). ConclusionsAdrenal cortisol secretion after dynamic stimulation is deficient in a substantial proportion of brain-dead potential organ donors.

Bilateral Inferior Petrosal Sinuses Sampling in the Routine Investigation of Cushing's Syndrome: A Comparison with MRI

OBJECTIVE Identifying the cause of Cushings syndrome (CS) is a perplexing issue. Bilateral inferior petrosal sinuses sampling (BIPSS) is an invasive and elaborate but established procedure in distinguishing Cushings disease (CD) from ectopic adrenocorticotropic hormone (ACTH) syndrome. We compare the diagnostic performance of BIPSS and MRI in detecting an ACTH-secreting source, and we suggest the diagnostic protocol that we found beneficial for the management of patients with CS. MATERIALS AND METHODS Seventy-eight consecutive patients with CS were included. All patients underwent biochemical investigation and pituitary MRI. Consequently, patients were routinely referred for BIPSS; 25 received stimulation with corticotropin-releasing hormone (CRH) and 53 with CRH and desmopressin. The diagnosis of CD was established on the basis of complementary biochemical, imaging, and BIPSS criteria. The diagnostic performances of BIPSS and MRI were calculated for patients with final diagnosis. RESULTS A final diagnosis was available for 54 patients (46 CD confirmed, five ectopic confirmed, three adrenals). No (known) patient was misclassified based on our suggested diagnostic criteria. MRI rendered 25 false-negatives and two false-positives (incidentalomas). Successful BIPSS yielded two false-negatives and three false-positives (adrenals). The calculated accuracy for detecting a pituitary source of ACTH was 50% and 88% for MRI and successful BIPSS, respectively. CONCLUSION MRI is of only limited diagnostic performance, while BIPSS is the most accurate way to establish the diagnosis of CD. The routine use of a multimodality diagnostic approach including BIPSS, MRI, and biochemical tests is suggested to avoid the risk of mismanagement for patients with CS.

The application of a combined stimulation with CRH and desmopressin during bilateral inferior petrosal sinus sampling in patients with Cushing's syndrome

BACKGROUND Bilateral inferior petrosal sinus sampling (BIPSS) is a useful investigative technique in the differential diagnosis of ACTH‐dependent Cushings syndrome (CS). The diagnostic sensitivity of this procedure is improved by the administration of CRH to stimulate ACTH secretion. It has been reported recently that the combined administration of CRH and desmopressin is a more potent stimulus for ACTH release from corticotroph adenomas. We therefore hypothesized that the combined stimulation of ACTH secretion with CRH plus desmopressin may further improve the diagnostic outcome of this procedure.

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management

Objective  The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported.

Hypothalamic-pituitary dysfunction in critically ill patients with traumatic and nontraumatic brain injury

BackgroundA significant number of studies have shown that critically ill patients with brain injury (BI) frequently exhibit abnormal pituitary hormonal responses during the immediate postinjury period.DiscussionThe elucidation of endocrine alterations depends on the criteria used, the diagnostic tests applied, and the timing of testing in relation to BI. The pattern of the detected hormonal abnormalities shows considerable variability. Altered endocrine responses are due mostly to hypothalamic changes rather than to pituitary dysfunction. Several studies have examined the correlation between hormonal alterations and BI severity, but the results are inconsistent. Furthermore, it remains currently unclear whether and how pituitary abnormalities adversely affect the clinical course of BI patients during the period of critical illness. On the basis of current knowledge, with the exception of clinically significant relative adrenal deficiency and diabetes insipidus, the other endocrine alterations do not seem to require any therapeutic intervention in severely ill BI patients. It is also uncertain whether hormonal abnormalities detected in the early post-BI period persist for the rest of these patients’ lives.ConclusionsIn view of current evidence indicating a high incidence of pituitary dysfunction even years following BI it is recommended that repetition of endocrine evaluation should be performed during the rehabilitation phase in all patients.

Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome

objective  Several studies have demonstrated impaired GH secretion in patients with active Cushings syndrome (CS). It has been suggested that persistence of GH deficiency, despite treatment of cortisol excess, may delay the recovery of these patients and therefore temporary treatment with GH may have some benefit. However, the time course of restoration of GH secretion after successful treatment of CS has only been investigated in a limited number of mostly paediatric reports. The aim of the present study was the evaluation of GH reserve in adult patients with CS before and after correction of cortisol excess.

Serial changes in adiponectin and resistin in critically ill patients with sepsis: Associations with sepsis phase, severity, and circulating cytokine levels☆☆☆

PURPOSE The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels. MATERIALS AND METHODS An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls. RESULTS The patients had higher adiponectin (10.9 ± 6.1 μg/mL vs 6.0 ± 2.9 μg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted. CONCLUSIONS Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis.