Duration of adrenal inhibition following a single dose of etomidate in critically ill patients

Objective To determine the incidence and duration of adrenal inhibition induced by a single dose of etomidate in critically ill patients. Design Prospective, observational cohort study. Setting Three intensive care units in a university hospital. Patients Forty critically ill patients without sepsis who received a single dose of etomidate for facilitating endotracheal intubation. Measurements and main results Serial serum cortisol and 11β-deoxycortisol samples were taken at baseline and 60 min after corticotropin stimulation test (250 μg 1–24 ACTH) at 12, 24, 48, and 72 h after etomidate administration. Etomidate-related adrenal inhibition was defined by the combination of a rise in cortisol less than 250 nmol/l (9 μg/dl) after ACTH stimulation and an excessive accumulation of serum 11β-deoxycortisol concentrations at baseline. At 12 h after etomidate administration, 32/40 (80%) patients fulfilled the diagnosis criteria for etomidate-related adrenal insufficiency. This incidence was significantly lower at 48 h (9%) and 72 h (7%). The cortisol to 11β-deoxycortisol ratio (F/S ratio), reflecting the intensity of the 11β-hydroxylase enzyme blockade, improved significantly over time. Conclusions A single bolus infusion of etomidate resulted in wide adrenal inhibition in critically ill patients. However, this alteration was reversible by 48 h following the drug administration. The empirical use of steroid supplementation for 48 h following a single dose of etomidate in ICU patients without septic shock should thus be considered. Concomitant serum cortisol and 11β-deoxycortisol dosages are needed to provide evidence for adrenal insufficiency induced by etomidate in critically ill patients. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Financial support: All of the authors have disclosed that they have no financial relationship with or interest in any commercial companies.     

One single dose of etomidate negatively influences adrenocortical performance for at least 24 h in children with meningococcal sepsis

Objective To investigate the effect of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis. Design Retrospective study conducted between 1997 and 2004. Setting University-affiliated paediatric intensive care unit (PICU). Patients and participants Sixty children admitted to the PICU with meningococcal sepsis, not treated with steroids. Interventions Adrenal hormone concentrations were determined as soon as possible after PICU admission, and after 12 h and 24 h. To assess disease severity, PRISM score and selected laboratory parameters were determined. Measurements and main results On admission, before blood was drawn, 23 children had been intubated with etomidate, 8 without etomidate and 29 were not intubated. Children who were intubated had significantly higher disease severity parameters than those not intubated, whereas none of these parameters significantly differed between children intubated with or without etomidate. Children who received etomidate had significantly lower cortisol, higher ACTH and higher 11-deoxycortisol levels than those who did not receive etomidate. Arterial glucose levels were significantly lower in children who were intubated with etomidate than in non-intubated children. When children were intubated with etomidate, cortisol levels were 3.2 times lower for comparable 11-deoxycortisol levels. Eight children died, seven of whom had received etomidate. Within 24 h cortisol/ACTH and cortisol/11-deoxycortisol ratios increased significantly in children who received etomidate, but not in children who did not, resulting in comparable cortisol/ACTH ratios with still significantly lowered cortisol/11-deoxycortisol ratios 24 h after admission. Conclusions Our data imply that even one single bolus of etomidate negatively influences adrenal function for at least 24 h. It might therefore increase risk of death.     

Diminished adrenal sensitivity to endogenous and exogenous adrenocorticotropic hormone in critical illness: a prospective cohort study

IntroductionAdrenal dysfunction may represent critical illness-related corticosteroid insufficiency (CIRCI), as evidenced by a diminished cortisol response to exogenous adrenocorticotropic hormone (ACTH), but this concept and its clinical significance remain highly controversial. We studied the adrenal response to exogenous ACTH as a function of the endogenous cortisol-to-ACTH ratio, a measure of adrenal sensitivity, and of clinical variables, during critical illness and recovery from the acute phase.MethodsWe prospectively included 59 consecutive septic and nonseptic patients in the intensive care unit with treatment-insensitive hypotension in whom CIRCI was suspected; patients having received etomidate and prolonged corticosteroids were excluded. An ACTH test (250 μg) was performed, followed by a second test after ≥7 days in acute-phase survivors. Serum total and free cortisol, ACTH, and clinical variables were assessed. Patients were divided according to responses (delta, Δ) of cortisol to ACTH at the first and second tests.ResultsPatients with low (<250 nM) Δ cortisol (n = 14 to 17) had higher baseline cortisol and ACTH but lower cortisol/ACTH ratios than patients with a normal Δ cortisol (≥250 nM) in the course of time. A low Δ cortisol in time was associated with more-severe disease, culture-positive sepsis, and prolonged activated prothrombin time. Results for free cortisol were similar.ConclusionsEven though the pituitary-adrenal axis is activated after stress during critical illness, diminished adrenal sensitivity to endogenous ACTH predicts a low increase of cortisol to exogenous ACTH, suggesting adrenal dysfunction, irrespective of the stage of disease. The data further suggest a role of disease severity and culture-positive sepsis.     

Adrenal defect in adrenomyelodystrophy

Adrenomyelodystrophy (AMD), a variant of adrenoleukodystrophy, is associated with both neurologic and adrenal dysfunction. Data from an endocrinologic evaluation of a 41-year-old pigmented white man with AMD showed elevation in basal plasma ACTH, 11-deoxycortisol, 17-alpha OH-progesterone and progesterone concentrations, and low normal plasma cortisol levels. Free urinary cortisol and 17-ketosteroid secretion values were within normal limits. These data suggest that the principal adrenal enzymatic defect in this patient was a partial block of 11-hydroxylase and that the elevation of precursors was ACTH-dependent. However, this patient may have other enzymatic defects.     

Effect of ketoconazole on the 11-hydroxylation step of adrenal steroidogenesis

We studied the effect of ketoconazole on glucocorticoid metabolism in three patients before and after a continuous four-hour infusion of ACTH. A single 400 mg oral dose of ketoconazole caused a decrease in serum cortisol concentration, while the concentration of 11-deoxycortisol and its ratio to cortisol increased. The decrease in serum cortisol levels was not accompanied by an increase in plasma ACTH concentration. A four-hour continuous infusion of ACTH resulted in an appropriate elevation of serum cortisol, but with a marked increase in serum concentration of 11-deoxycortisol and its ratio to serum cortisol. We conclude that 400 mg of ketoconazole can decrease cortisol synthesis apparently through a partial block of the 11-beta-hydroxylation step; the observed degree of inhibition may not be sufficient to stimulate the hypothalamic-pituitary-adrenal axis or to cause overt symptoms or signs of adrenal insufficiency; and this partial block of the 11-beta-hydroxylation step becomes more evident during a continuous infusion of ACTH, which can stimulate a normal response of cortisol.     

Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells

The direct effects of etomidate, ketoconazole, miconazole and metyrapone were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of a normal individual and four patients with Cushing's syndrome. The drugs interfered with adrenocorticotropic hormone-stimulated cortisol secretion in a dose-dependent way. Desoxycortisol concentrations in the medium were increased after the addition of metyrapone and low doses of etomidate but were suppressed with higher doses of etomidate. The production of 17-hydroxy-progesterone was stimulated by miconazole and metyrapone but was strongly suppressed by the high doses of etomidate. Ketoconazole caused a stimulation of progesterone release, whereas the release of 17-hydroxyprogesterone was suppressed. Finally, the concentration of progesterone was strongly enhanced with high doses of miconazole, whereas etomidate suppressed progesterone production. It is concluded that etomidate at a low concentration (IC50, 10(-8) M) inhibits 11 beta-hydroxylase, whereas, at higher concentrations (10(-7)-10(-6) M), the side-chain cleavage enzyme system is also inhibited; metyrapone is a weaker (IC50, 10(-7) M) but pure 11 beta-hydroxylase inhibitor; miconazole inhibits adrenal 21-hydroxylase at 10(-6) M; and ketoconazole inhibits 17-hydroxylase. Etomidate, ketoconazole, miconazole and metyrapone inhibit cortisol biosynthesis in the human adrenal gland in different manners, which appear to involve the four cytochrome P-450-dependent monooxygenase reactions. Interestingly, these drugs affect corticosteroidogenesis by normal, hyperplastic and adenomatous adrenal cells in a similar manner.     

Corticotropin releasing factor as an aid in the diagnosis of Cushing syndrome

6 patients with Cushing's syndrome were investigated with regard to the effect of synthetic ovine corticotropin-releasing factor (o-CRF), administered as an intravenous bolus of 100 micrograms, on peripheral plasma concentrations of ACTH and cortisol. The purpose of this study was to evaluate the usefulness of this "CRF test" in the differential diagnosis of Cushing's syndrome as compared with conventional diagnostic procedures. 100 micrograms CRF caused a rise in plasma ACTH and cortisol in patients with bilateral adrenal hyperplasia (n = 3). However, in patients with cortisol-producing adrenal adenoma (n = 2) and ectopic ACTH overproduction (n = 1), no increase in plasma cortisol and ACTH was induced by exogenous CRF. We conclude from these findings that the CRF test will prove a valuable diagnostic tool to differentiate pituitary from extrapituitary forms of endogenous hypercortisolism in patients with Cushing's syndrome.     

Glucocorticoid insufficiency in patients who present to the hospital with severe sepsis: a prospective clinical trial

OBJECTIVE: To identify the incidence of secondary adrenal insufficiency in severe sepsis. DESIGN: Prospective clinical trial testing 100 patients with a 250-microg adrenocorticotropic hormone (ACTH) stimulation test. SETTING: County-university teaching hospital. PATIENTS: One hundred patients with sepsis and septic shock. Forty patients had bacteremia and 17% shock. INTERVENTIONS: ACTH, cortisol, aldosterone, and electrolyte concentrations were measured at baseline. Cortisol and aldosterone were measured 30 and 60 mins after ACTH (250 microg). MEASUREMENTS AND MAIN RESULTS: Nine of the 100 patients (9%) failed the ACTH stimulation test (all serum cortisol <20 microg/dL). The 91 patients with sepsis began with a serum cortisol at 29.3 +/- 2.5, and it increased to 40.1 +/- 2.6 and 46.9 +/- 2.7 microg/dL at times 30 and 60 mins, respectively. Serum cortisol in nine septic patients who failed the ACTH stimulation test had an initial concentration of 11.3 +/- 1.8 microg/dL, and it increased at time 30 mins to 14.0 +/- 1.9 microg/dL and at 60 mins to 15.7 +/- 1.8 microg/dL. Four of the nine patients had secondary adrenal insufficiency as determined by a normal aldosterone response to ACTH. The remaining five patients had an absent aldosterone response to ACTH and baseline ACTH concentrations that were not elevated, suggesting adrenal dysfunction. Serum sodium (128 +/- 4 vs. 138 +/- 1 mmol/L, p <.05) and glucose concentrations (121 +/- 20 vs. 163 +/- 11 mg/dL, p <.05) were reduced in the nine patients. Of the four patients with secondary adrenal insufficiency, two had a history of amenorrhea after birth of their children many years earlier. CONCLUSIONS: These data demonstrate that 9% of adults with sepsis fail the ACTH stimulation test due to a mixture of etiologies. A reduced sodium or glucose concentration may be helpful in identifying glucocorticoid (adrenal) insufficiency in patients with sepsis.     

The effect of etomidate on adrenal function in critical illness: a systematic review

Purpose  

Although etomidate is a preferred anesthetic agent for rapid sequence intubation (RSI) in critical illness, as an inhibitor of cortisol synthesis (11β-hydroxylase), it may be associated with adrenal dysfunction. The objectives are to review the effects of etomidate versus comparator anesthetics in critical illness for: primary outcome of mortality and secondary outcome of adrenal insufficiency (AI).     

The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: altered response to corticotropin-releasing hormone

OBJECTIVE: To investigate the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe sepsis by stimulating with corticotropin-releasing hormone (CRH). DESIGN: Prospective observational study in consecutive intensive care unit patients with severe sepsis. SETTING: Surgical intensive care unit and outpatient department of endocrinology in a university hospital. PATIENTS: The study included 20 patients with the diagnosis of severe sepsis; six critically ill, nonseptic patients after major surgery; ten patients with primary adrenal insufficiency; ten patients with anterior pituitary insufficiency; and ten individuals without clinical signs of HPA axis disturbance. INTERVENTIONS: CRH tests were performed with an intravenous bolus injection of 100 microg of human CRH. MEASUREMENTS AND MAIN RESULTS: We studied the functional integrity of the HPA axis in patients with severe sepsis by performing the CRH test. In addition, during the period of severe sepsis, we repeatedly measured basal plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol. The mean basal plasma cortisol concentration was decreased significantly in nonsurvivors with severe sepsis (288.8 +/- 29.1 [sem] nmol/L) compared with survivors (468.1+/- 18.6 nmol/L; p <.01). By calculating the ACTH/cortisol indices, we found no evidence for adrenal insufficiency in patients with severe sepsis. The mean ACTH/cortisol indices of nonsurvivors with severe sepsis (0.02 +/- 0.008) and survivors (0.01 +/- 0.002) were significantly lower compared with the index of patients with primary adrenal insufficiency (6.8 +/- 1.0; p <.001). In contrast, in nonsurvivors with severe sepsis, the plasma cortisol response to CRH stimulation was impaired compared with survivors: The mean basal cortisol concentration within the CRH test was 269.4 +/- 39.8 nmol/L in nonsurvivors compared with 470.8 +/- 48.4 nmol/L in survivors and increased to a peak value of 421.6 +/- 72.6 nmol/L in nonsurvivors and 680.7 +/- 43.8 nmol/L in survivors (p <.02). However, the change in plasma cortisol, expressed as mean +/- sem and calculated by subtracting the basal cortisol from the peak cortisol after CRH stimulation, was not significantly different in survivors with severe sepsis (243.5 +/- 36.1, range 111.0-524.0 nmol/L, n = 15) compared with nonsurvivors (161.0 +/- 38.9, range 42.0-245.0 nmol/L, n = 5; p >.05). CONCLUSIONS: We found lower basal plasma cortisol concentrations in nonsurvivors compared with survivors of severe sepsis. In addition, the plasma cortisol response to a single CRH stimulation was impaired in nonsurvivors compared with survivors. Reduced responses to CRH stimulation may reflect a state of endocrinologic organ dysfunction in severe sepsis.     

Adrenal inhibition following a single dose of etomidate in intubated traumatic brain injury victims

ABSTRACTBackground:Etomidate is frequently used to intubate traumatic brain injury (TBI) victims, even though it has been linked to adrenal insufficiency (AI) in some populations. Few studies have explored the risk of prolonged etomidate-induced AI among TBI victims.Objective:To determine the risk and the length of AI induced by etomidate in patients intubated for moderate and severe TBI.Methods:Participants in this observational study were moderate to severe intubated TBI victims aged ≥ 16 years. The anesthetic used (etomidate versus others) was determined solely by the treating emergency physician. Adrenocorticotropic hormone (ACTH) stimulation tests (250 μg) were performed 24, 48, and 168 hours after intubation. AI was defined as an increase in serum cortisol 1 hour post-ACTH test (delta cortisol) of less than 248.4 nmol/L.Results:Forty subjects (participation 42.6%) underwent ACTH testing. Fifteen received etomidate, and 25 received another anesthetic. There were no statistically significant differences between groups as to the cumulative incidence of AI at any measurement time. However, at 24 hours, exploratory post hoc analyses showed a significant decrease in delta cortisol (adjusted means: etomidate group: 305.1 nmol/L, 95% CI 214.7-384.8 versus other anesthetics: 500.5 nmol/L, 95% CI 441.8-565.7). This decrease was not present at 48 and 168 hours.Conclusion:In TBI victims, although a single dose of etomidate does not increase the cumulative incidence of AI as defined, it seems to decrease the adrenal response to an ACTH test for 24 hours. The clinical impacts of this finding remain to be determined.     

Adrenal Insufficiency in Critically Ill Emergency Department Patients: A Taiwan Preliminary Study

OBJECTIVE: Unrecognized adrenal insufficiency can have serious consequences in critically ill emergency department (ED) patients. This prospective pilot study of adrenal function in patients with severe illness was undertaken to determine the prevalence of adrenal dysfunction and any relation to prior herbal drug use. METHODS: In a high-volume urban tertiary care ED, adult patients with sepsis or acute myocardial infarction (AMI) were eligible for the study. Over a two-month period, a convenience sample was enrolled by the authors on arrival to the ED. Inclusion criteria were systemic inflammatory response syndrome (SIRS) criteria plus evidence of at least one organ dysfunction or cardiac marker plus electrocardiogram-proven AMI. Exclusion criteria included known corticosteroid use. Serum cortisol was measured on arrival and for those patients with a level of <15 microg/dL (<414 nmol/L), an adrenocorticotropic hormone (ACTH) stimulation test was performed. RESULTS: Of the 30 enrolled patients, 23 (77%) were suffering from severe sepsis and the other seven (23%) had an AMI. Thirteen of the 30 patients (43%; 95% CI = 25% to 65%) had serum cortisol levels of <15 microg/dL, consistent with adrenal insufficiency, nine with severe sepsis and four with an AMI. Eight (62%; 95% CI = 32% to 86%) of the 13 patients with low cortisol levels reported using herbal medications, while only two (12%; 95% CI = 1% to 36%) of the 17 with normal cortisol levels reported taking herb drugs (p = 0.01). Only two (15%; 95% CI = 2% to 45%) of the patients with low cortisol levels failed their corticotropin stimulation test, suggestive of true adrenocortical insufficiency. Both reported using herbal preparations. CONCLUSIONS: These results indicate that adrenal dysfunction is common among a group of critically ill patients seen in this Taiwanese ED. Moreover, the use of herbal drugs was high in the patients with low serum cortisols. Further studies are required to both confirm these findings and clarify whether a number of herbal medications contain corticosteroids.     

Adrenal function in sepsis: the retrospective Corticus cohort study

OBJECTIVE: To refine the value of baseline and adrenocorticotropin hormone (ACTH)-stimulated cortisol levels in relation to mortality from severe sepsis or septic shock. DESIGN: Retrospective multicenter cohort study. SETTING: Twenty European intensive care units. PATIENTS: Patients included 477 patients with severe sepsis and septic shock who had undergone an ACTH stimulation test on the day of the onset of severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared with survivors, nonsurvivors had higher baseline cortisol levels (29.5 +/- 33.5 vs. 24.3 +/- 16.5 microg/dL, p = .03) but similar peak cortisol values (37.6 +/- 40.2 vs. 35.2 +/- 22.9 microg/dL, p = .42). Thus, nonsurvivors had lower Deltamax (i.e., peak cortisol minus baseline cortisol) (6.4 +/- 22.6 vs. 10.9 +/- 12.9 microg/dL, p = .006). Patients with either baseline cortisol levels <15 microg/dL or a Deltamax 相似文献   

Adrenocortical dysfunction in acute medical illness

To further characterize the adrenocortical response to acute illness, we measured basal and adrenocorticotropic hormone (ACTH)-stimulated 11-deoxycortisol, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). Acutely ill patients had higher ACTH-stimulated 11-deoxycortisol and androstenedione, and decreased basal and ACTH-stimulated androstenedione/cortisol and DHEAS/cortisol ratios. Our data suggest that a shift away from androgen synthesis toward the glucocorticoid pathway occurs in acute illness.     

Glucose absorption and gastric emptying in critical illness

Introduction

Gallstones are the most common cause of acute pancreatitis worldwide. Patients with severe acute biliary pancreatitis (SABP) constitute a subgroup of severe acute pancreatitis (SAP) patients in whom systemic inflammation may be triggered and perpetuated by different mechanisms. The aim of this prospective investigation was to examine the adrenal response to corticotropin and the relationship between adrenal function and outcome in patients with SABP.

Methods

Thirty-two patients with SABP were enrolled in this study. A short corticotropin (250 μg) stimulation test (SST) was performed within the first 24 hours of admission to the ICU. Critical illness related corticosteroid insufficiency (CIRCI) was defined as follows: baseline value less than 10 μg/dL, or cortisol response less than 9 μg/dL.

Results

CIRCI occurred in 34.4% of patients. The patients with CIRCI were more severely ill as evidenced by higher APACHE II and SOFA scores and numbers of organ system dysfunction on the day of SST. The in-hospital mortality for the entire group was 21.9%. The CIRCI group had a higher hospital mortality rate compared to those with normal adrenal function (45.5% vs. 9.5%, P = 0.032). The hospital survivors had a higher cortisol response to corticotropin (17.4 (8.3–27.1) vs. 7.2 (1.7–12) μg/dL, P = 0.019). The cortisol response to corticotropin inversely correlated with SOFA score and the number of organ dysfunction on the day of SST. The rates of pancreatic necrosis and bacteremia were significantly higher in the CIRCI group (100% vs 42.9%, P = 0.002; 81.8% vs 23.8%, P = 0.003, respectively).

Conclusions

CIRCI is common in patients with SABP. It is associated with bacteremia, multiple organ dysfunction and increased mortality.     

Simultaneous measurement of eight corticosteroids by liquid chromatography, and application of the procedure to diagnosis of congenital adrenal hyperplasia

We describe a liquid-chromatographic procedure for simultaneously determining eight steroids in serum. We used a Zorbax ODS column and a mobile phase of methanol/isopropanol/water (44/10/46, by vol), which well resolves the steroids cortisone, cortisol, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, androstenedione, 17-hydroxyprogesterone, and progesterone, but not 11-deoxycorticosterone and androstenedione. Analytical recoveries of the steroids ranged from 89.27% to 99.58%. CVs were less than 10%. Prednisone and dexamethasone do not interfere. Using this method, we studied the serum steroid profiles of six patients with congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase or 17-hydroxylase. Not only could we make a clearcut diagnosis and distinguish the subtle types of CAH, but also we could investigate clinical and biochemical variants of CAH. For example, we confirmed 17-hydroxylase deficiency in a patient who was normotensive with primary amenorrhea and streak gonads.     

Serum cortisol/cortisone ratio after Synacthen stimulation

OBJECTIVES: 11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes interconvert active cortisol and inactive cortisone. There is growing evidence that local tissue concentrations of cortisol are generally modulated by site specific different 11beta-HSD actions. While 11beta-HSD type 2 unidirectionally inactivates cortisol, type 1 isoform acts bidirectionally. 11beta-HSD type 1 is mainly localized in the liver and may thus restore circulating biologically inactive cortisone to active cortisol thereby modulating systemic glucocorticoid action; such a mechanism might be of importance in stressful situations. To study this hypothesis we investigated the influence of exogenous ACTH on serum cortisol/cortisone ratio. DESIGN AND METHODS: Paired serum samples that were submitted for routine analysis of cortisol before and 1 h after stimulation with 250 microg ACTH (1-24) (Synacthen) were collected prospectively if the routine tests indicated normal adrenal function; 40 patients were included in the study, 29 patients were female, 11 male, median age was 31 yr (range 14-70). Serum cortisol and cortisone were determined using LC-ESI/MS/MS with an online sample extraction system and tri-deuterated cortisol as the internal standard. RESULTS: While mean serum cortisol increased by 109% (mean basal concentration 373 nmol/L (SD 151 nmol/L), stimulated 781 nmol/L (SD 194 nmol/L)), mean serum cortisone significantly decreased after ACTH administration by 31% (p < 0.001, paired t-test for differences). Mean serum cortisone was 70 nmol/L (SD 16 nmol/L) before and 48 nmol (SD 16 nmol/L) after ACTH administration; decrease in serum cortisone was observed in 34 (85%) of the patients. The ratio of serum cortisol/cortisone increased in all subjects (mean 5.4 (SD 1.9) before ACTH, and 16.2 (SD 6.2) after ACTH; p < 0.001). CONCLUSIONS: The data of our observational study suggest a modulation of peripheral metabolism of cortisol by ACTH with a stimulation of systemic 11beta-HSD type 1 activity, leading to restoration of inactive cortisone to biologically active cortisol.     

Hypothalamo-pituitary-adrenal axis activity after intracranial catastrophies: what is enough?

This commentary on a paper by Bendel and colleagues in the previous issue of Critical Care describes the difficulty in assessing the sufficiency of adrenal responses to endogenous, stress-induced adrenocorticotropic hormone (ACTH) release by the pituitary or to exogenous ACTH administration in the critically ill patient in general, and after subarachnoid hemorrhage in particular. It is argued that comparisons with responses under circumstances of equal stress as well as assessments of severity of disease are necessary to judge the sufficiency of cortisol responses to endogenous and exogenous ACTH before treatment is considered. There are no universally applicable cutoff values for cortisol levels – and increases in cortisol levels with increasing levels of ACTH – for the diagnosis of relative adrenal insufficiency (or as it is now commonly termed, critical illnes-related corticosteroid insufficiency) following, for example, subarachnoid hemorrhage or other intracranial catastrophes. The paper by Bendel and colleagues is critically discussed in view of these concepts.     

Cortisol levels and adrenal response in severe community-acquired pneumonia: A systematic review of the literature

Objectives

Our aim was to review the literature on the prevalence and impact of critical-illness related corticosteroid insufficiency (CIRCI) on the outcomes of patients with severe community-acquired pneumonia (CAP).

Methods

We reviewed Cochrane, Medline, and CINAHL databases (through July 2008) to identify studies evaluating the adrenal function in severe CAP. Main data collected were prevalence of CIRCI and its mortality.

Results

We screened 152 articles and identified 7 valid studies. Evaluation of adrenal function varied, and most studies used baseline total cortisol levels. The prevalence of CIRCI in severe CAP ranged from 0% to 48%. Among 533 patients, 56 (10.7%) had cortisol levels of 10 μg/dL or less and 121 patients (21.2%) had cortisol levels of 15 μg/dL or less. In a raw analysis, there was no significant difference in mortality when patients with cortisol levels less than 10 μg/dL (8.6 vs 15.5%; P = .55) or less than 15 μg/dL (12.4 vs 16%; P = .38) were compared with those with cortisol above these levels. In the meta-analysis, relative risk for mortality were 0.81 (confidence interval, 0.39-1.7; P = .59; χ² = 1.04) for cortisol levels less than 10 μg/dL and relative risk was 0.67 (confidence interval, 0.4-1.14; P = .84; χ² = 1.4) for cortisol levels less than 15 μg/dL.

Conclusions

A significant proportion of patients with severe CAP fulfilled criteria for CIRCI. However, CIRCI does not seem to affect the outcomes. Noteworthy, the presence of elevated cortisol levels is associated with increased mortality and may be useful as a prognostic marker in patients with severe CAP.     

A Prospective Observational Study of the Effect of Etomidate on Septic Patient Mortality and Length of Stay

Objectives: Etomidate is known to cause adrenal suppression after single‐bolus administration. Some studies suggest that when etomidate is used as an induction agent for intubation of septic patients in the emergency department (ED), this adrenal suppression leads to increased mortality, vasopressor requirements, and length of hospital stay. The authors sought to determine differences in the in‐hospital mortality and hospital length of stay (LOS) between septic patients given etomidate and patients given alternative or no induction agents for rapid‐sequence intubation in our ED. Methods: This was a nonrandomized, prospective observational study of all patients meeting sepsis criteria who were intubated in an ED over a 9‐month period. Times of patient presentation, intubation, admission, discharge, and/or death were recorded, as well as the intubation agent used, if any, and corticosteroid use. The authors also recorded relevant laboratory and demographic variables to determine severity of illness using the Mortality in Emergency Department Sepsis (MEDS) score. Mortality and survivor LOS between the patients given etomidate and those given alternative or no induction agents were compared. Results: A total of 106 patients with sepsis were intubated over the study period. Of these, 74 patients received etomidate, while 32 patients received ketamine, benzodiazepines, propofol, or no induction agents. Age in years (median = 78; interquartile range [IQR] = 67 to 83), gender (45% male), MEDS score (median = 13; IQR = 10 to 15), and receipt of supplemental corticosteroids (56%) were statistically similar between the two groups. In‐hospital mortality of patients given etomidate (38%; 95% confidence interval [CI] = 28% to 49%) was similar to those receiving alternatives (44%; 95% CI = 28% to 61%). Surviving patients had a median hospital LOS after receiving etomidate of 10 days compared to those receiving alternatives (7.5 days; p = 0.08). Conclusions: No statistically significant increase in hospital LOS or mortality in patients given etomidate for rapid‐sequence intubation was found. Suggestions that the use of etomidate for intubation in the ED be abandoned are not supported by these data.