Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival

Relative adrenal insufficiency is frequent in patients with severe sepsis and is associated with hemodynamic instability, renal failure, and increased mortality. This study prospectively evaluated the effects of steroids on shock resolution and hospital survival in a series of 25 consecutive patients with cirrhosis and septic shock (group 1). Adrenal function was evaluated by the short corticotropin test within the first 24 hours of admission. Patients with adrenal insufficiency were treated with stress doses of intravenous hydrocortisone (50 mg/6 h). Data were compared to those obtained from the last 50 consecutive patients with cirrhosis and septic shock admitted to the same intensive care unit in whom adrenal function was not investigated and who did not receive treatment with steroids (group 2). Incidence of adrenal insufficiency in group 1 was 68% (17 patients). Adrenal dysfunction was frequent in patients with advanced cirrhosis (Child C: 76% vs. Child B: 25%, P = .08). Resolution of septic shock (96% vs. 58%, P = .001), survival in the intensive care unit (68% vs. 38%, P = .03), and hospital survival (64% vs. 32%, P = .003) were significantly higher in group 1. The main causes of death in group 1 were hepatorenal syndrome or liver failure (7 of 9 patients). In contrast, refractory shock caused most of the deaths in group 2 (20 of 34 patients). In conclusion, relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock. Hydrocortisone administration in these patients is associated with a high frequency of shock resolution and high survival rate.     

Diagnosis of adrenal insufficiency in severe sepsis and septic shock

RATIONALE: Diagnosis of adrenal insufficiency in critically ill patients has relied on random or cosyntropin-stimulated cortisol levels, and has not been corroborated by a more accurate diagnostic standard. OBJECTIVE: We used the overnight metyrapone stimulation test to investigate the diagnostic value of the standard cosyntropin stimulation test, and the prevalence of sepsis-associated adrenal insufficiency. METHODS: This was an inception cohort study. MEASUREMENTS AND RESULTS: In two consecutive septic cohorts (n = 61 and n = 40), in 44 patients without sepsis and in 32 healthy volunteers, we measured (1) serum cortisol before and after cosyntropin stimulation, albumin, and corticosteroid-binding globulin levels, and (2) serum corticotropin, cortisol, and 11beta-deoxycortisol levels before and after an overnight metyrapone stimulation. Adrenal insufficiency was defined by postmetyrapone serum 11beta-deoxycortisol levels below 7 microg/dl. More patients with sepsis (31/61 [59% of original cohort with sepsis] and 24/40 [60% of validation cohort with sepsis]) met criteria for adrenal insufficiency than patients without sepsis (3/44; 7%) (p < 0.001 for both comparisons). Baseline cortisol (< 10 microg/dl), Delta cortisol (< 9 microg/dl), and free cortisol (< 2 microg/dl) had a positive likelihood ratio equal to infinity, 8.46 (95% confidence interval, 1.19-60.25), and 9.50 (95% confidence interval, 1.05-9.54), respectively. The best predictor of adrenal insufficiency (as defined by metyrapone testing) was baseline cortisol of 10 microg/dl or less or Delta cortisol of less than 9 microg/dl. The best predictors of normal adrenal response were cosyntropin-stimulated cortisol of 44 microg/dl or greater and Delta cortisol of 16.8 microg/dl or greater. CONCLUSIONS: In sepsis, adrenal insufficiency is likely when baseline cortisol levels are less than 10 microg/dl or delta cortisol is less than 9 microg/dl, and unlikely when cosyntropin-stimulated cortisol level is 44 microg/dl or greater or Delta cortisol is 16.8 microg/dl or greater.     

Adrenocortical dysfunction in liver disease: a systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.     

The clinical importance of adrenal insufficiency in acute hepatic dysfunction

Acute liver failure and septic shock share many clinical features, including hyperdynamic cardiovascular collapse. Adrenal insufficiency may result in a similar cardiovascular syndrome. In septic shock, adrenal insufficiency, defined using the short synacthen test (SST), is associated with hemodynamic instability and poor outcome. We examined the SST, a dynamic test of adrenal function, in 45 patients with acute hepatic dysfunction (AHD) and determined the association of these results with hemodynamic profile, severity of illness, and outcomes. Abnormal SSTs were common, occurring in 62% of patients. Those who required noradrenaline (NA) for blood pressure support had a significantly lower increment (median, 161 vs. 540 nmol/L; P <.001) following synacthen compared with patients who did not. Increment and peak were lower in patients who required ventilation for the management of encephalopathy (increment, 254 vs. 616 nmol/L, P <.01; peak, 533 vs. 1,002 nmol/L, P <.01). Increment was significantly lower in those who fulfilled liver transplant criteria compared with those who did not (121 vs. 356 nmol/L; P <.01). Patients who died or underwent liver transplantation had a lower increment (148 vs. 419 nmol/L) and peak (438 vs. 764 nmol/L) than those who survived (P <.01). There was an inverse correlation between increment and severity of illness (Sequential Organ Failure Assessment, r = -0.63; P <.01). In conclusion, adrenal dysfunction assessed by the SST is common in AHD and may contribute to hemodynamic instability and mortality. It is more frequent in those with severe liver disease and correlates with severity of illness.     

Update on adrenal insufficiency in patients with liver cirrhosis

Liver cirrhosis is a major cause of mortality worldwide,often with severe sepsis as the terminal event.Over the last two decades,several studies have reported that in septic patients the adrenal glands respond inappropriately to stimulation,and that the treatment with corticosteroids decreases mortality in such patients.Both cirrhosis and septic shock share many hemodynamic abnormalities such as hyperdynamic circulatory failure,decreased peripheral vascular resistance,increased cardiac output,hypo-responsiveness to vasopressors,increased levels of proinflammatory cytokines [interleukine(IL)-1,IL-6,tumor necrosis factor-alpha] and it has,consequently,been reported that adrenal insufficiency(AI) is common in critically ill cirrhotic patients.AI may also be present in patients with stable cirrhosis without sepsis and in those undergoing liver transplantation.The term hepato-adrenal syndrome defines AI in patients with advanced liver disease with sepsis and/or other complications,and it suggests that it could be a feature of liver disease per se,with a dif-ferent pathogenesis from that of septic shock.Relative AI is the term given to inadequate cortisol response to stress.More recently,another term is used,namely "critical illness related corticosteroid insufficiency" to define "an inadequate cellular corticosteroid activity for the severity of the patient’s illness".The mechanisms of AI in liver cirrhosis are not completely understood,although decreased levels of high-density lipoprotein cholesterol and high levels of proinflammatory cytokines and circulatory endotoxin have been suggested.The prevalence of AI in cirrhotic patients varies widely according to the stage of the liver disease(compensated or decompensated,with or without sepsis),the diagnostic criteria defining AI and the methodology used.The effects of corticosteroid therapy on cirrhotic patients with septic shock and AI are controversial.This review aims to summarize the existing published information regarding AI in patients with liver cirrhosis.     

Adrenal function during coronary artery bypass grafting

OBJECTIVE: To assess adrenal function in patients undergoing coronary artery bypass grafting (CABG) by means of the low-dose (1 microg) ACTH test, and to correlate the adrenal function with clinical outcome. METHODS: During a 5-Month period we prospectively included 45 patients undergoing elective CABG with cardiopulmonary bypass and without symptoms of endocrine disease. Low-dose (1 microg) ACTH tests were performed on the day before surgery (day -1), immediately after the operation (day 0), on the two subsequent days in the intensive care unit (day 1 and day 2), and on the day of discharge from the hospital. A number of clinical, hemodynamic and laboratory parameters were monitored throughout. RESULTS: On day -1, 75% of the study patients had normal stimulated plasma cortisol concentrations. Eleven patients (25%) had an impaired adrenal response to 1 microg ACTH. The stimulated plasma cortisol concentrations in patients who had an inadequate adrenal response on day -1 remained significantly reduced on day 1 (756+/-205 vs 949+/-259 nmol/l, P=0.03) (mean+/-s.d.), day 2 (644 (580-793) vs 885 (713-1087), P=0.03) (median (interquartile range)), and on the day of discharge (698+/-201 vs 854+/-186, P=0.05). In patients with a normal adrenal response in the preoperative setting peak cortisol concentrations were reached on day 1, in patients with a blunted adrenal response they were reached on day 2. There were significant correlations between the stimulated plasma cortisol concentrations and the blood loss (r=-0.50, P=0.002) and Volume balance (r=0.41, P=0.015). CONCLUSIONS: Occult (partial) adrenal insufficiency is common in patients undergoing CABG who are otherwise asymptomatic as regards endocrine disease. The adrenal function in these patients differs both in the magnitude of cortisol response to ACTH and in the time course, with significantly delayed peak cortisol concentrations. Adequate regulation of Volume balance and the amount of blood loss seem to correlate with adequacy of adrenal function.     

Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests

OBJECTIVES: Patients with organic growth hormone deficiency (GHD) or with structural hypothalamic-pituitary abnormalities may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis (HPA) is essential in these patients because, although clinically asymptomatic, their HPA cannot appropriately react to stressful stimuli with potentially life-threatening consequences. DESIGN AND METHODS: In this study we evaluated the integrity of the HPA in 24 patients (age 4.2-31 years at the time of the study) with an established diagnosis of GHD and compared the reliability of the insulin tolerance test (ITT), short synacthen test (SST), low-dose SST (LDSST), and corticotropin releasing hormone (CRH) test in the diagnosis of adrenal insufficiency. RESULTS: At a cortisol cut-off for a normal response of 550 nmol/l (20 microg/dl), the response to ITT was subnormal in 11 subjects, 6 with congenital and 5 with acquired GHD. Four patients had overt adrenal insufficiency, with morning cortisol concentrations ranging between 66.2-135.2 nmol/l (2.4-4.9 microg/dl) and typical clinical symptoms and laboratory findings. In all these patients, a subnormal cortisol response to ITT was confirmed by LDSST and by CRH tests. SST failed to identify one of the patients as adrenal insufficient. In the seven asymptomatic patients with a subnormal cortisol response to ITT, the diagnosis of adrenal insufficiency was confirmed in one by LDSST, in none by SST, and in five by CRH tests. The five patients with a normal cortisol response to ITT exhibited a normal response also after LDSST and SST. Only two of them had a normal response after a CRH test. In the seven patients with asymptomatic adrenal insufficiency mean morning cortisol concentration was significantly higher than in the patients with overt adrenal insufficiency. ITT was contraindicated in eight patients, and none of them had clinical symptoms of overt adrenal insufficiency. One of these patients had a subnormal cortisol response to LDSST, SST, and CRH, and three exhibited a subnormal response to CRH but normal responses to LDSST and to SST. CONCLUSION: We conclude that none of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency. Consequently, clinical judgment remains one of the most important issues for deciding which patients need assessment or re-assessment of adrenal function.     

Impact of gastroenterology consultation on the outcomes of patients admitted to the hospital with decompensated cirrhosis.

Managed care has strongly discouraged generalists from referring patients to specialists in an effort to reduce the costs of health care. The aim of this study was to compare patient outcomes when generalists work together with gastroenterologists or alone in the management of patients admitted to the hospital with decompensated cirrhosis. Consecutive patients admitted to the hospital with decompensated cirrhosis over a 1-year period were identified. We compared the length of stay, cost of hospitalization, incidence of hospital readmission, and mortality for patients who did and those who did not have a gastroenterology (GI) consultation. A GI consultation was requested for 107 of the 197 patients (54.3%). Patients who had a GI consultation had a significantly shorter length of stay (5.6 +/- 3.5 vs. 10.1 +/- 5.8 days, P <.001) and a lower cost of hospitalization ($6,004 +/- $4,994 vs. $10,006 +/- $6,183, P <.001) than those patients who were managed by generalists alone. The 30-day incidence of readmission (13.3% vs. 27.8%, P =.01) and mortality (7.5% vs. 16.7%, P =.045) were significantly lower in the GI consultation group. During a median follow-up of 618 days (range, 2-970), patients who had a GI consultation during hospitalization had a significantly longer time to hospital readmission (P <.001) and improved survival (P =.02) compared with those who were managed by generalists alone. In conclusion, for patients admitted to the hospital with decompensated cirrhosis, individuals who were managed by generalists in conjunction with gastroenterologists had better outcomes than those who were managed by generalists alone.     

Adrenal insufficiency in the critically ill: a new look at an old problem

Stress from many sources, including pain, fever, and hypotension, activates the hypothalamic-pituitary-adrenal (HPA) axis with the sustained secretion of corticotropin and cortisol. Increased glucocorticoid action is an essential component of the stress response, and even minor degrees of adrenal insufficiency can be fatal in the stressed host. HPA dysfunction is a common and underdiagnosed disorder in the critically ill. We review the risk factors, pathophysiology, diagnostic approach, and management of HPA dysfunction in the critically ill.     

The long-term predictive accuracy of the short synacthen (corticotropin) stimulation test for assessment of the hypothalamic-pituitary-adrenal axis

CONTEXT: The high-dose short Synacthen (corticotropin) test (SST) is widely used to investigate suspected secondary adrenal insufficiency, but concern remains about falsely reassuring results. OBJECTIVE: Our objective was to evaluate the long-term safety of the SST. METHOD: We retrospectively evaluated the clinical outcome in 178 patients who achieved 30-min cortisol values in the lowest 15th percentile of normal healthy responses. Thirty patients were later excluded because of missing case notes (20 patients) or unsubstantiated pituitary pathology (10 patients). The remaining 148 patients were divided into two groups: group 1, patients with cortisol response between the 5th and 15th percentiles of normal response (551-635 nmol/liter, 98 patients); and group 2, patients with borderline response between the 2.5th and 5th percentiles (510-550 nmol/liter, 50 patients). Patients did not receive routine glucocorticoid therapy, but those in group 2 were advised to take hydrocortisone in case of intercurrent illness. RESULTS: The median follow-up period from the initial SST was 4.2 yr (range, 4 months to 7 yr). A total of 137 patients showed no clinical or biochemical evidence of adrenal insufficiency during follow-up. Of the remaining 11 patients, seven became hypoadrenal after subsequent pituitary surgery or radiotherapy, one patient in group 1 developed adrenal insufficiency at 2 yr, and one patient in group 2 developed adrenal insufficiency at 6 months. The other two patients who were in group 2 had clinical diagnostic uncertainty. CONCLUSION: The high-dose SST is safe for the purpose of excluding clinically significant secondary adrenal insufficiency and is indicated as the first line of investigation for this purpose.     

Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality

Recent reports suggest adrenal insufficiency in critically ill patients is common. We found only one case of de novo adrenal insufficiency using admission ACTH injection in 70 selected intensive care unit (ICU) patients. Random serum cortisol levels correlated positively with illness severity in ICU patients using proven methods for assessing illness severity. Those with the highest random serum cortisol levels (greater than 60 micrograms/dl) had the greatest mortality, while those with lower random cortisol levels which stimulated to more than 18 micrograms/dl after ACTH injection had improved outcomes. Based on our results, routine screening for adrenal insufficiency in ICU patients is not warranted. If it is suspected, the cosyntropin test should be performed since low random cortisol levels (even to 5 micrograms/dl) are not diagnostic of adrenal insufficiency.     

Adrenocortical function in patients with macrometastases of the adrenal gland

OBJECTIVE: Metastases of the adrenal gland are a frequent finding in patients with malignant tumors like bronchogenic carcinoma or breast cancer. Only limited and conflicting data on adrenocortical function in these patients are available. DESIGN: Cross-sectional study. METHODS: We investigated the impact of adrenal macrometastases on adrenocortical function in a series of 28 tumor patients using the ACTH(1-24) stimulation test and dexamethasone suppression test. Seven normal controls (Con), eleven patients without adrenal metastases (No Met), eight patients with unilateral (Uni Met) and nine patients with bilateral adrenal metastases (Bil Met) were investigated. RESULTS: The prevalence of adrenal insufficiency was low in our study population, with only two of nine patients with bilateral metastases having subclinical adrenocortical insufficiency. In the remaining patients with uni- or bilateral metastases, baseline and stimulated cortisol concentrations were higher than in controls and cancer patients without metastases (baseline cortisol (in nmol/l): Con: 307+/-33.2 vs Uni Met: 440+/-53.5, and Bil Met: 637.6+/-92.1, P=0.04 by ANOVA; cortisol 60 min after ACTH(1-24): Con: 794.6+/-41.2 vs Uni Met: 990.8+/-92.9, and Bil Met: 1151.4+/-155.5, P=0.03 by ANOVA). Simultaneously, baseline and stimulated serum aldosterone concentrations were significantly blunted in the tumor groups. CONCLUSIONS: Adrenal insufficiency is infrequent and develops only in patients with bilateral metastases. However, the majority of patients have activation of the hypothalamic-pituitary-adrenal axis despite adrenal metastases with strongly elevated cortisol concentrations.     

Relative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome)

AimRelative adrenal insufficiency (RAI) has been reported in critically ill patients with cirrhosis. We evaluated the prevalence of RAI and its relationship to clinical course in non-septic cirrhosis patients with ascites.MethodsThe study included 66 consecutive non-septic cirrhosis patients with ascites. RAI was defined by a delta cortisol lower than 9 μg/dL and/or a peak cortisol lower than 18 μg/dL.ResultsSixty-six patients with cirrhosis and ascites were studied. The mean Child-Turcotte-Pugh (CTP) and model for end stage liver disease (MELD) scores were 10.6 ± 1.9 and 21.5 ± 7.3, respectively. The prevalence of RAI in patients with cirrhosis and ascites was 47% (31/66). The prevalence of RAI in patients with and without spontaneous bacterial peritonitis, renal failure and type 1 hepatorenal syndrome (HRS) was comparable. Baseline hyponatremia was common in RAI (42% versus 17%, p = 0.026). There was a significant correlation of prevalence of RAI with prothrombin time, international normalized ratio, MELD scores and CTP class. During follow-up, there was no association between RAI and the risk to develop new infections, severe sepsis, type 1 HRS and death.ConclusionsRAI is common in non-septic cirrhotic patients with ascites and its prevalence increases with severity of liver disease. However, it does not affect the short-term outcome in these patients.     

Relative adrenal insufficiency in the non-critically ill patient with cirrhosis: A systematic review and meta-analysis

Background & Aims

Characterization of relative adrenal insufficiency (RAI) in cirrhosis is heterogeneous with regard to studied patient populations and diagnostic methodology. We aimed to describe the prevalence and prognostic importance of RAI in non-critically ill patients with cirrhosis.

Methods

A systematic review and meta-analysis was performed using MeSH terms and Boolean operators to search five large databases (Ovid-MEDLINE, ScienceDirect, Web of Science, Cochrane Library and ClinicalTrials.gov ). The population of interest was patients with cirrhosis and without critical illness. The primary outcome was the pooled prevalence of RAI as defined by a peak total cortisol level <18 μg/dl, delta total cortisol <9 μg/dl or composite of the two thresholds in response either a standard-dose or low-dose short synacthen test. Odds ratios and standardized mean differences from random-effects models estimated important clinical outcomes and patient characteristics by adrenal functional status.

Results

Twenty-two studies were included in final analysis, comprising 1991 patients with cirrhosis. The pooled prevalence of RAI was 37% (95% CI 33–42%). The prevalence of RAI varied by Child–Pugh classification, type of stimulation test used, specific diagnostic threshold and by severity of illness. Ninety-day mortality was significantly higher in patients with RAI (OR 2.88, 95% CI 1.69–4.92, I2 = 15%, p < 0.001).

Conclusions

Relative adrenal insufficiency is highly prevalent in non-critically ill patients with cirrhosis and associated with increased mortality. Despite the proposed multifactorial pathogenesis, no studies to date have investigated therapeutic interventions in this specific population.     

High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate

INTRODUCTION: Megestrol acetate (MA) is a progestational agent used for palliation of breast and endometrial cancer. The drug promotes weight gain via appetite stimulation. This property has led to widespread use in patients with wasting illnesses. Increasing numbers of reports suggest glucocorticoid activity. OBJECTIVE: Unrecognized adrenal suppression may result from MA use. This is the first study to examine the prevalence of adrenal suppression in hospitalized patients treated with MA. SUBJECTS AND DESIGN: This is a cross-sectional study of hospitalized patients receiving MA compared to control subjects. Morning cortisol levels, endocrine signs and symptoms, and duration of MA therapy were evaluated in 28 hospitalized medical patients treated with MA, and 21 control patients admitted to the same hospital service during the study period. RESULTS: Median cortisol levels were significantly lower in patients using MA vs controls (160 vs 386 nmol/l, p=0.003). Forty-three percent of subjects on MA demonstrated morning cortisol levels below the normal range (138-690 nmol/l), compared with 10% of controls (p=0.013). Ninety-three percent of subjects taking MA had morning cortisol levels below the level that excludes adrenal insufficiency in hospitalized patients (497 nmol/l) vs 71% of controls (p=0.06). CONCLUSIONS: MA use is associated with significant adrenal suppression in acutely ill individuals. This should alert physicians to the possibility of adrenal insufficiency and the need to assess for signs or symptoms of adrenal insufficiency, and mandates a low threshold for testing adrenal function in hospitalized patients taking MA.     

Adrenal androgens and illness

We have studied the adrenal androgen status of medically ill patients, patients before and after cholecystectomy and during recovery from burns injury. In patients ill for less than 2 weeks, serum androstenedione concentrations (mean +/- SEM) were raised (7.94 +/- 0.98 nmol/l) as compared with a control group (4.83 +/- 0.38 nmol/l, P less than 0.005) or with patients ill for more than 2 weeks (5.21 +/- 0.46 nmol/l, P less than 0.02); serum dehydroepiandrosterone sulphate (DHAS) levels were lower in patients ill for more than 2 weeks (1.21 +/- 0.42 mumol/l) than in either the acutely ill group (5.98 +/- 1.06 mumol/l, P less than 0.001) or the control ill group (5.56 +/- 0.59 mumol/l, P less than 0.001). In post-operative patients serum DHAS levels fell to below pre-operative levels reaching a nadir at day 8 (0.54 +/- 0.19 vs 1.66 +/- 0.56 mumol/l, P less than 0.02). In burned patients serum cortisol levels were increased on admission (661 +/- 91 vs 359 +/- 30 nmol/l, P less than 0.005) and remained high over the study period. Serum androstenedione concentrations were also high on admission (7.5 +/- 1.0 vs 3.9 +/- 0.3 nmol/l, P less than 0.02). Serum DHAS concentrations were similar to control values on admission (6.8 +/- 1.2 vs 5.2 +/- 0.7 mumol/l), fell to low levels thereafter reaching a nadir during week 3 (1.6 +/- 0.6 mumol/l, P less than 0.001). Steroid synthesis in times of chronic illness may be diverted from adrenal androgen to corticosteroid pathways ensuring maintained secretion of cortisol, which is essential to the health of ill patients.     

Myocardial injury in critically ill patients: relation to increased cardiac troponin I and hospital mortality

OBJECTIVE: To examine the relationship between myocardial injury, assessed by cardiac troponin I (cTnI) levels, and outcome in selected critically ill patients without acute coronary syndromes or cardiac dysfunction. DESIGN AND SETTING: Prospective, observational study in the emergency ICU of a university teaching hospital. POPULATION: Over a 6-month period, 217 consecutive patients admitted to the ICU were studied. METHODS AND RESULTS: cTnI assays were performed in all patients on admission to the ICU. The incidence of myocardial injury, defined by cTnI level > 0.1 ng/mL, was 32% (69 of 217 patients). Overall mortality was 27% (58 of 217 patients). Patients with myocardial injury had a mortality rate of 51%, compared with only 16% mortality for those without myocardial injury (p < 0.001). The hospital mortality rate was highest among older patients (71 +/- 14% vs 58.5 +/- 20%, p < 0.0001) and patients with higher simplified acute physiology scale (SAPS) II score (62 +/- 25% vs 37 +/- 17%, p < 0.0001). Mechanical ventilation was associated with higher in-hospital death (50% vs 31%, for patients who died in the hospital vs those who were discharged alive; p = 0.03). Elevated blood levels of cTnI were found to be independently associated with hospital mortality, regardless of the presence of SAPS II score and mechanical ventilation, in the logistic regression analysis (odds ratio, 2.09; 95% confidence interval, 1.06 to 4.11; p = 0.01). CONCLUSIONS: This study demonstrates the high frequency of myocardial injury (32%) in critically ill patients without acute coronary syndromes or cardiac dysfunction on admission to ICU. Myocardial injury is an independent determinant of hospital mortality. Assessment of myocardial injury on admission to ICU would make it possible to identify patients at increased risk of death.     

The Effect of Adrenal Replacement Therapy on Rates of Fungal Colonization and Mortality in Critically Ill Patients Awaiting Liver Transplantation

Background

The effect of adrenal replacement therapy (ART) with hydrocortisone on critical endpoints such as infection and mortality in critically ill patients with cirrhosis remains unclear. We evaluated our indications for ART in patients with cirrhosis with clinical symptoms of adrenal insufficiency (AI), and examined the rate of peri-transplant fungal colonization and mortality associated with ART.

Methods

Seventy-eight patients with cirrhosis admitted to our institution''s surgical intensive care unit (ICU) over a 4-year period met criteria for AI by vasopressor requirement and baseline cortisol levels. Outcomes included disposition at 90-days, fungal colonization, and fungal infection in the presence or absence of ART.

Results

In total, 56 patients received hydrocortisone (HC+) while 22 did not (HC−). The HC+ and HC− groups had comparable median Model for End-stage Liver Disease (MELD) scores (26.5 vs. 25, respectively; p=0.93), median ICU lengths of stay (23 vs. 20 days, respectively; p=0.54) and median cortisol levels (18 μg/dL for both, p=0.87). Fungal cultures (FC) from blood, urine or bronchoalveolar lavage/sputum were positive for 44% of HC+, and 40.9% of HC− (p=0.77) had mortality rates between HC+ and HC− groups that were not significantly different (60.7% vs. 50%, respectively; p=0.39; α=0.05). The 90-day outcomes for HC+ vs. HC− (39.3% vs. 50% discharged, respectively; p=0.39; α=0.05) and those surviving to transplant (17.9% vs. 36.4%, respectively; p=0.08; α=0.05) were not significantly different between the two groups.

Conclusion

In this small single-center series, we found that steroid administration for AI does not affect the rate of fungal colonization/infection or mortality. Further prospective studies are required to determine the utility of ART and factors affecting the rate of FC and mortality in these patients.     

Adipokine levels and cardiovascular risk in patients with adrenal incidentaloma

Adrenal incidentalomas (AIs) have been associated with an increased incidence of several cardiovascular risk factors, similar to overt Cushing syndrome. Data about the involvement of the adipokines in the development of insulin resistance and atherosclerosis in AI are completely lacking. The aim of the present study was to evaluate plasma interleukin 6 (IL-6), adiponectin, resistin, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1 (MCP-1) levels in patients with AI. Plasma IL-6, adiponectin, resistin, TNF-alpha, and MCP-1 levels were measured in 20 healthy subjects (6 males; 14 females; age, 58.5 +/- 2.2 years; body mass index, 28.1 +/- 0.9 kg/m(2)) and in 20 patients (5 males; 15 females; age, 57.9 +/- 2.0 years; body mass index, 28.0 +/- 0.8 kg/m(2)) with AI and typical computed tomographic features of cortical adenoma, who were not affected by diabetes mellitus, hypertension, or other relevant diseases. All patients underwent anthropometric measurements and determination of basal corticotropin, cortisol, and urinary free cortisol excretion. Overnight dexamethasone test and 250-microg corticotropin test were performed in all cases. A subclinical Cushing syndrome was found in 3 patients, whereas the others had apparently nonfunctioning masses. Plasma IL-6, adiponectin, resistin, TNF-alpha, and MCP-1 levels were higher in patients than in controls (64.4 +/- 2.8 vs 5.5 +/- 0.6 pg/mL, 13.7 +/- 1.3 vs 3.6 +/- 0.5 microg/mL, 12.5 +/- 1.9 vs 5.1 +/- 0.2 ng/mL, 27.0 +/- 1.5 vs 22.2 +/- 1.5 pg/mL, 172.5 +/- 20.0 vs 104.4 +/- 19.5 pg/mL, respectively; P < .05) and apparently not affected by the presence of visceral obesity. Plasma IL-6 levels were negatively correlated with urinary free cortisol (r = -0.461, P < .05), and TNF-alpha levels were positively correlated with cortisol after the administration of 1 mg dexamethasone (r = 0.636, P < .01). In conclusion, patients with AI may show increased levels of adipokines (apparently not related to the presence of diabetes, hypertension, or obesity), which may be affected by the presence of the adrenal adenoma. For some adipokines, a direct production from the adrenal gland may be hypothesized even if other studies are needed to better investigate the role of adipokines in states of altered cortisol secretion.     

The dissociation of renin and aldosterone during critical illness

A syndrome of elevated PRA accompanied by inappropriately low plasma aldosterone (ALDO) levels has been identified in some critically ill patients. To determine whether this phenomenon is due to a disturbance in factors that stimulate ALDO, we measured PRA, angiotensin II (AII), potassium (K+), and ACTH levels in 83 patients admitted to an intensive care unit. In 59 patients, PRA was greater than 2.0 ng/ml X h. Of these, 24 had an ALDO to PRA ratio (ALDO/PRA) below 2 (group I), and 35 had an ALDO/PRA ratio of 2 or more (group II). An ALDO/PRA ratio below 2 was deemed inappropriately low. Despite markedly elevated PRA [34 +/- 12 (+/- SE) ng/ml X h], the group I patients had inappropriately low ALDO levels (19 +/- 5 ng/dL). Patients in group II had significantly higher ALDO levels (48 +/- 6 ng/dL) despite lower PRA (9 +/- 1 ng/ml X h). AII levels were appropriately elevated in group I (39 +/- 26 pg/mL) and significantly greater (P less than 0.5) than those in group II. PRA correlated well with AII in both groups. There were no differences in plasma ACTH or K+ in these 2 groups, and plasma cortisol levels were similarly elevated in both groups of patients. Of 66 consecutively studied patients, 14 (21%) had inappropriate ALDO (group I). Mortality was significantly greater in group I (75%) than in group II (46%; P less than 0.001). In summary, a significant subset (21%) of seriously ill patients have inappropriately low ALDO levels despite elevated PRA. This dissociation is not due to an impairment of AII production or changes in plasma ACTH or K+. This phenomenon is associated with a higher mortality during critical illness. In light of evidence of decreased adrenal androgen secretion during severe illness, this dissociation of renin and aldosterone may represent an additional adrenal adaptation designed to promote cortisol production in critically ill patients.