Stress Doses Of Glucocorticoids Research Articles

Adrenal suppression from vamorolone and prednisone in Duchenne muscular dystrophy: results from the phase 2b clinical trial.

Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD). To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD, and to assess cortisol thresholds using a monoclonal antibody immunoassay. Post-hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500nmol/L ("historical threshold") and <400nmol/L ("revised threshold"). Mean age at enrolment was 5.41±0.86 years (N=118). At Week 24, proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day=100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day=95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day=84.2% (16/19) and 47.5% (9/19); and placebo=20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48=0.83). AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.

SAT290 Course of SARS-CoV-2 Infection In Patients With Congenital Adrenal Hyperplasia

Abstract Disclosure: R. Javaid: None. S. Kollender: None. A. Moon: None. D.P. Merke: Research Investigator; Self; Diurnal, Neurocrine Biosciences. Patients with primary adrenal insufficiency (PAI) are at risk for life-threatening adrenal crises, most often triggered by illness. Prior studies suggest possible inefficient immune response in PAI, especially in patients with autoimmune Addison’s disease. Starting in December 2019, the pandemic due to the novel SARS-CoV-2 coronavirus created many challenges in patient management. Data regarding COVID-19,risk of severe illness, and proper prevention of adrenal crisis in patients with PAI due to congenital adrenal hyperplasia (CAH) are lacking.Objective:To describe the experience of patients with PAI due to CAH who acquired COVID-19 in a large cohort study.Methods:Questionnaires and retrospective chart reviews were performed for all patients enrolled in a Natural History Study at the National institute of Health (NCT00250159) who reported COVID-19 infection from March 2019 until November 2022.Results:42 patients with CAH (25 salt-wasting 21OHD, 13 simple virilizing 21OHD, 1 nonclassic 21OHD, 3 P450 SCC deficiency) reported 46 episodes of COVID-19 infections (12 pediatric, 34 adult), 16 were before nationwide vaccine distribution. Of the 30 responses post vaccine, 23 were vaccinated and 7 were unvaccinated. Patients were instructed to stress dose according to standard guidelines for general illnesses. In 21 episodes, patients did not stress dose; in 25 episodes, patients stress dosed orally (1 to 15days); in 6 episodes, patients received intramuscular Solucortef injections. Two patients (8 y.o., 63 y.o.) were hospitalized. One patient with salt-wasting CAH and asthma developed long COVID following 2COVID-19 episodes. Patient risk factors for COVID-19 included: 6 obese (BMI &amp;gt; 30), 2 tobacco users, 1 with concomitant type 1 diabetes mellitus. COVID-related symptomatology was similar to national trends. Early in the pandemic, patients were more likely to have loss of taste and smell, as well as GI symptoms, and later in the pandemic, patients were more likely to experience cough, sore throat, tiredness, and body aches. Data analysis underway.Conclusion:Patients with PAI due to CAH do not appear to be at greater risk of acquiring COVID-19 and do not have higher risk of complications triggered by COVID-19 infection than the general population. Standard glucocorticoid stress dosing guidelines are appropriate in the setting of COVID-19. Glucocorticoid stress dosing is not recommended if the patient is without fever or gastrointestinal symptoms. Presentation: Saturday, June 17, 2023

OR26-4 Glucocorticoid Receptor Expression and Signaling During Critical Illness, in Relation to the Duration of Illness and the Systemic Glucocorticoid Availability: A Prospective, Observational, Cross-Sectional Human and a Translational Mouse Study

Abstract Critically ill patients are thought to develop maladaptive glucocorticoid-resistance which convinces many clinicians to administer stress doses of glucocorticoids to overcome this state of glucocorticoid-resistance. However, supportive data arises mainly from whole blood cells. It is currently not known if the observed changes in regulators and markers of glucocorticoid signaling and activity are also present in other cell and tissue types with a role in critical illness. We quantified regulators and markers of glucocorticoid signaling and activity in several cell and tissue types in critically ill humans and animals and in healthy controls. We found that throughout critical illness, glucocorticoid activity appeared suppressed in neutrophils, but upregulated in monocytes and skeletal muscle. Also in vital tissues GRα-signaling was altered in a tissue-specific, largely time-independent manner. Increasing systemic glucocorticoid availability increased glucocorticoid activity in adipose tissue, diaphragm and lung, whereas in immune cells and other tissues regulatory pathways counteracted. These data argue against glucocorticoid-treatable generalized glucocorticoid resistance and rather point towards an adaptive response in each specific cell or tissue type to optimally guide the beneficial actions of glucocorticoids to the tissues that need it while protecting collateral undesirable effects in tissue that are harmed by elevated systemic glucocorticoid availability. Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.

Emergency card, emergency medication, and information leaflet for the prevention and treatment of adrenal crisis (Addison crisis): an Austrian consensus document

Ein wichtiges Ziel bei der Behandlung der Nebenniereninsuffizienz ist die Prävention der Nebennierenkrise (auch akute Nebenniereninsuffizienz oder Addison-Krise genannt). Um in Österreich eine bessere Implementierung sowie Harmonisierung der Maßnahmen zur Prävention und Therapie der Nebennierenkrise zu erreichen, wurde dieses Konsensusdokument erarbeitet. Folgende Maßnahmen werden grundsätzlich für alle Patient*innen mit Nebenniereninsuffizienz empfohlen und in diesem Manuskript ausführlich erörtert: 1. Versorgung mit einer Notfallkarte („steroid emergency card“) sowie evtl. auch mit einem Armband oder einer Halskette (oder Ähnlichem) mit medizinischem Alarmhinweis „Nebenniereninsuffizienz, benötigt Glukokortikoide“. 2. Versorgung mit einem Hydrocortison-Notfallkit zur Injektion (alternativ auch Suppositorien/Zäpfchen zur Notfallapplikation) sowie ausreichenden oralen Glukokortikoiddosen für Stresssituationen/Erkrankungen. 3. Schulung von Patient*innen und Angehörigen zur Steigerung der Glukokortikoidtherapie in Stresssituationen bzw. bei Erkrankungen („sick day rules“) und zur Selbstinjektion von Hydrocortison. 4. Versorgung mit einer Behandlungsleitlinie (Informationszettel) zur Prävention und Therapie der Nebennierenkrise, welche bei Bedarf auch dem Gesundheitspersonal gezeigt werden soll. 5. Versorgung mit einer Notfall-Telefonnummer des behandelnden endokrinologischen Teams und/oder medizinisch geschulter Betreuungspersonen bzw. Angehöriger. 6. Regelmäßige (vorzugsweise jährliche) Wiederholung der Schulungsmaßnahmen. Dieses Konsensusdokument beinhaltet auch ausführliche Empfehlungen für die perioperative Glukokortikoidtherapie sowie für diverse andere Stresssituationen.

Management of Acute Adrenal Insufficiency-Related Adverse Events in Children with Congenital Adrenal Hyperplasia: Results of an International Survey of Specialist Centres.

There is wide variation in reported rates of acute adrenal insufficiency (AI)-related adverse events (sick day episodes and adrenal crises) between centres. This study aimed to evaluate the level of consensus on criteria considered essential for defining and managing these events in children with Congenital Adrenal Hyperplasia. Active users of the International Congenital Adrenal Hyperplasia and International Disorders of Sex Development (I-CAH/I-DSD) Registries (n = 66), non-active users of I-CAH/I-DSD (n = 35), and the EuRRECa e-Reporting Registry (n = 10) were approached to complete an online survey. Fifty-six centres from 27 countries responded to the survey; the response rates for the three groups were 42 (65%), 11 (31%), and 3 (30%), respectively. Steroid management plans, one to one patient education, and contact details of health care staff were provided by over 90% of centres in high-income countries. All 56 centres advised glucocorticoid stress dosing in the event of fever. Less common indications for sick day dosing included vaccination and mild afebrile intercurrent illness, recommended by 17 (30%) and 9 (16%) centres, respectively. The most frequently reported stress dosing regimens were tripling the total daily dose of hydrocortisone and administering 3 times daily and doubling or tripling the largest daily hydrocortisone dose depending on the nature of the trigger and administering 3 times daily, recommended by 24 (43%) and 21 (38%) centres, respectively. Vomiting was the most common indication for intramuscular hydrocortisone injection, reported by 34 (61%) centres. Over 50% of respondents indicated that essential clinical criteria for adrenal crisis should include fatigue and nausea or vomiting and over 60% indicated that hypotension, hyponatraemia, hyperkalaemia, and clinical improvement following parenteral glucocorticoids were essential criteria. In the event of an adrenal crisis, 47 (84%) reported that the majority of patients were admitted to hospital. For the management of an adrenal crisis, a bolus parenteral injection of hydrocortisone was the most frequently administered medication, reported by 50 (89%) centres. Although there is variation in the definition and management of AI-related adverse events in children amongst centres, there is also a good level of consensus on specific aspects that can lead to greater benchmarking of care.

The effect of patient-managed stress dosing on electrolytes and blood pressure in acute illness in children with adrenal insufficiency.

Adrenal crises (AC) are acute episodes of adrenal insufficiency (AI). Manifestations include hypotension and electrolyte disturbances. Glucocorticoid stress dosing (SD) can prevent AC progression, but its effect on physiological parameters has not been assessed in a 'real world setting'. To assess the effect of prior self-managed glucocorticoid dose escalation on physiological markers in children with congenital adrenal hyperplasia (CAH) presenting to hospital for an acute illness. An audit of records of all children with CAH presenting to paediatric referral hospital between 2000 and 2015. Potassium, sodium and glucose levels, and hypotension were compared between children who had and had not used SD. There were 321 attendances by patients with CAH and an acute illness during the study period. Any form of SD was used by 64.2% (n=206); intramuscular (IM) hydrocortisone was used by 22.1% (n=71) and oral only by 41.7% (n=134). Use of SD (oral and/or IM) was associated with a significantly lower mean potassium level (4.02±0.71 vs. 4.27±0.79mmol/l, P<.05). Linear regression analysis showed that age (beta: -0.04years (95% CI -0.06, -0.02)), diarrhoea (beta: -0.41 (95% CI -0.06, -0.02)) and any form of stress dosing (oral, IM or both) (beta: -0.29 (95% CI -0.55, -0.04)) were each independently and significantly associated with potassium levels. SD was not significantly associated with sodium or glucose concentrations or with estimates of hypotension. Patient-initiated SD resulted in a significant reduction in hyperkalaemia and lowered mean potassium levels in paediatric patients with CAH but did not alter significantly sodium and glucose concentrations or incidences of hypotension.

SUN-164 Adrenal Crisis in Early Pregnancy

Nausea and vomiting are common symptoms in pregnancy, ranging from occasional nausea to fulminant and intractable vomiting. Many underlying metabolic disorders can mimic this, primary adrenal insufficiency (PAI) being one of them. Here, we present a case of adrenal insufficiency early in pregnancy.A 28 year old lady G1P0 at 8 weeks of gestations, with a past medical history of Grave’s Disease, presented to our hospital on 3 occasions over one week with severe intractable nausea and vomiting. On prior visits, she had received intravenous fluids and discharged home. Laboratory work-up was ordered on the third visit and she was found to have severe hyponatremia with level of 111mMol/L. TSH and FT4 levels were both within the reference range. AM cortisol level was low at 2.3mcg/dL. ACTH and renin were both significantly elevated confirming diagnosis of PAI. Intravenous hydrocortisone was commenced immediately with rapid resolution of her symptoms and correction of her hyponatremia. She was followed at the endocrinology clinic, with appropriate up-titration of glucocorticoid and mineralocorticoid doses throughout her pregnancy.Diagnosis of PAI is usually established prior to pregnancy. Presentation during pregnancy is not common, but it should be considered as a differential diagnosis when symptoms are out of proportion to the gestational status. Normal pregnancy is accompanied by progressive increase in circulating CRH and ACTH, increasing the levels of free cortisol as early as 7 weeks of gestation, rising up to 20-fold by the end of pregnancy. These physiologic changes could explain early presentation of adrenal crisis given insufficient glucocorticoid production. A delay in diagnosis and treatment increases the risk of maternal and fetal morbidity and mortality significantly.Management of PAI during pregnancy can be challenging as there are no established guidelines and they have mainly been based on observational studies (1). The appropriate selection and dose of the glucocorticoid is important for the treatment of PAI to minimize adverse effects on mother and baby (2). At the time of active labor and delivery, stress doses of glucocorticoids need to be administered to prevent adrenal crisis (3).In conclusion, early diagnosis and appropriate management of PAI during pregnancy is necessary to sustain a healthy pregnancy.Bibliography1 Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow‐up of patients with primary adrenal insufficiency. J Intern Med 2014; 275: 104– 15.2 Bandoli G, Palmsten K, Forbess C, et al. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum Dis Clin North Am. 2017; 43(3): 489–5023 Chen K, Powrie R. Approach to the use of Glucocorticoids in Pregnancy for Nonobstetric Indications. de Swiet’s Medical Disorders in Obstetric Practice: Fifth Edition. 736-741.

SUN-167 Treatment Considerations for a Healthy Pregnancy in Women with Classical Congenital Adrenal Hyperplasia (CAH)

Background:CAH is caused by an enzyme deficiency involved in cortisol synthesis leading to an increase in ACTH. Increased ACTH causes elevated levels of steroid hormone precursors & chronic stimulation of the adrenal glands resulting in hyperplasia. The most common form of CAH is due to 21OH deficiency (21OHD) with the classic, salt-wasting form causing glucocorticoid & mineralocorticoid deficiency & androgen excess.Poorly controlled CAH causes increased production of androgens & progesterone & decreased fertility. Fertility in woman with 21OHD can be challenging due to decreased sexual interest & anatomical abnormalities. Despite these challenges, the pregnancy rate is not significantly lower in women with well controlled 21OHD. However, as these patients are uncommon recommendations for pregnancy can be challenging for endocrinologists.Clinical Case:A 27-year old G0P0 female with classic, salt losing CAH presented to discuss pregnancy. Her medications were hydrocortisone 10mg qAM & 5mg qHS & fludrocortisone 0.1mg daily. She denied symptoms of dehydration, nausea, vomiting, dizziness, or fatigue.She was diagnosed with CAH while in-utero & started on steroid therapy after birth. She did not require any surgical genital reconstruction. Menarche occurred at age 11 and she had regular menses every 35-40 days, with no evidence of excessive androgen exposure including excess body hair, deepening of her voice, or cliteromegaly.On physical exam she was normotensive & had no evidence of virilization or cushingoid features. She exhibited minor darkening of the palmar creases. Her labs were significant for free testosterone of 9.1 pg/ml (0.2-5.0 pg/ml), total testosterone of 115 ng/dl (2-45 ng/dl), ACTH of 780 pg/ml (6-50 pg/ml), androstenedione of 636 ng/dl (41-262 ng/dl), & 17 OHP of 1560 ng/dl (15-290 ng/dl).Her hydrocortisone dose was increased to 20 mg qAM & 10 mg qHS & fludrocortisone 0.1mg daily was continued. Our objectives were to normalize the androgen level & suppress serum progesterone to less than 2 nmol/L. If the objectives were not reached she would be converted to prednisone BID.Conclusion:Endocrine providers are the primary resource for fertility recommendations for 21OHD patients & must understand the challenges in this very rare group of patients. Collaboration with the perinatologist is crucial for success.The goals of preconception endocrine assessment in a patient with classic CAH are to adjust hormone therapy to ensure optimal endocrine milieu for conception & risk assessment of having a child affected with 21OHD. The patient will need a higher dose of fludrocortisone during the later part of pregnancy. Counseling that stress doses of glucocorticoids for intercurrent illness and during labor and delivery are required for both the patient and the obstetrician.

Screening for Nonclassic Congenital Adrenal Hyperplasia in the Era of Liquid Chromatography-Tandem Mass Spectrometry.

ContextScreening for and diagnosing non classic congenital adrenal hyperplasia (NCCAH) uses serum 17-hydroxyprogesterone (17OHP) thresholds established from immunoassay data; however, a new liquid-chromatography tandem mass spectrometry (LC-MS/MS) method results in lower 17OHP values. The evolution of immunoassays is also challenging our diagnostic cut-off for glucocorticoid insufficiency and few data re-evaluate the utility of testing for glucocorticoid insufficiency in NCCAH.Objective(1) Evaluate the 17OHP threshold that predicts NCCAH in children using LC-MS/MS, and (2) determine the prevalence of glucocorticoid insufficiency in NCCAH.MethodsA retrospective chart review of pediatric patients who underwent ACTH stimulation tests with cortisol and 17OHP measurements from 2011 to 2018 for assessment of NCCAH. Other adrenal pathologies were excluded. A cortisol < 415 nmol/L defined glucocorticoid insufficiency. Published correlation data determined a 17OHP of 3.3 nmol/L by LC-MS/MS was equivalent to 6 nmol/L by immunoassay. Data analysis was by measures of diagnostic accuracy.ResultsOf 188 patients included, 23 (12%) had NCCAH (21/23 had genetic confirmation); the remaining 2 had peak 17OHP > 30 nmol/L. Baseline 17OHP ≥ 6 nmol/L most accurately screened for NCCAH—sensitivity and specificity 96%. Almost all genetically confirmed NCCAH (20/21) had peak 17OHP > 30 nmol/L; all subjects with other diagnoses peaked < 30 nmol/L. Glucocorticoid insufficiency was present in 55% with NCCAH.ConclusionsDespite the increased specificity of LC-MS/MS, a baseline 17OHP ≥ 6 nmol/L most accurately screened for NCCAH; this supports current practice guidelines. This threshold identified all with glucocorticoid insufficiency, notably prevalent in our cohort and for whom glucocorticoid stress dosing should be considered.

Longitudinal assessment of illnesses, stress dosing and illness sequelae in patients with congenital adrenal hyperplasia

Context Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises. Objective We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education. Methods Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations. Results A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P ≤ 0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03). Conclusions Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children.

Longitudinal Assessment of Illnesses, Stress Dosing, and Illness Sequelae in Patients With Congenital Adrenal Hyperplasia.

Patients with congenital adrenal hyperplasia (CAH) are at risk for life-threatening adrenal crises. Management of illness episodes aims to prevent adrenal crises. We evaluated rates of illnesses and associated factors in patients with CAH followed prospectively and receiving repeated glucocorticoid stress dosing education. Longitudinal analysis of 156 patients with CAH followed at the National Institutes of Health Clinical Center over 23 years was performed. The rates of illnesses and stress-dose days, emergency room (ER) visits, hospitalizations, and adrenal crises were analyzed in relation to phenotype, age, sex, treatment, and hormonal evaluations. A total of 2298 visits were evaluated. Patients were followed for 9.3 ± 6.0 years. During childhood, there were more illness episodes and stress dosing than adulthood (P < 0.001); however, more ER visits and hospitalizations occurred during adulthood (P ≤ 0.03). The most robust predictors of stress dosing were young age, low hydrocortisone and high fludrocortisone dose during childhood, and female sex during adulthood. Gastrointestinal and upper respiratory tract infections (URIs) were the two most common precipitating events for adrenal crises and hospitalizations across all ages. Adrenal crisis with probable hypoglycemia occurred in 11 pediatric patients (ages 1.1 to 11.3 years). Undetectable epinephrine was associated with ER visits during childhood (P = 0.03) and illness episodes during adulthood (P = 0.03). Repeated stress-related glucocorticoid dosing teaching is essential, but revised age-appropriate guidelines for the management of infectious illnesses are needed for patients with adrenal insufficiency that aim to reduce adrenal crises and prevent hypoglycemia, particularly in children.

Stress doses of glucocorticoids cannot prevent progression of all adrenal crises.

Adrenal crises (ACs) sometimes progress rapidly and can be fatal. The aims of the present study were to reveal whether stress doses of glucocorticoids (SDGs) can prevent progression of severe ACs and to suggest a method of prevention, through analysis of its clinical features. We studied 24 severe ACs (nine patients) that occurred after diagnosis of primary or secondary adrenal insufficiency, retrospectively. The following information was analyzed: 1) whether SDGs were given orally and/or sc; 2) duration from the time when some symptoms started to the time when the patient came to the hospital; and 3) presence of hypoglycemia and electrolyte disturbance (hyponatremia, hyperkalemia). Eleven crises occurred after taking SDGs. Ten crises progressed within 3 h. Six of these ten crises progressed to severe ACs despite the fact that the patients took SDGs. Six crises were observed in association with hypoglycemia, and five of these six crises occurred in patients under 5 yr of age. Three of the six crises in association with hypoglycemia progressed to ACs within 3 h. Two of the three crises progressed to severe status within 3 h despite the fact that the patients took SDGs. Electrolyte disturbance was observed in only one crisis. In conclusion, SDGs cannot prevent progression of all ACs. Progression can be associated with hypoglycemia, particularly in patients under 5 yr of age. Patients should be given guidance on an ongoing basis on how to prevent ACs and hypoglycemia.

Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal-recessive disease causing cortisol deficiency, aldosterone deficiency and hyperandrogenism. Diagnosis of 21-OHD is confirmed by steroid analysis in newborn screening or later on. Standard medical treatment consists of oral glucocorticoid and mineralocorticoid administration in order to suppress adrenal androgens and to compensate for adrenal steroid deficiencies. However, available treatment is far from ideal, and not much is known about the long-term outcome in CAH as trials in patients in adulthood or old age are rare. Here we briefly describe the pathophysiology, clinical picture, genetics and epidemiology of 21-OHD. This is followed by a comprehensive review of the recent advances in diagnosis, treatment and outcome. Novel insights have been gained in the fields of newborn screening, specific steroid measurement utilizing mass spectrometry, genetics, glucocorticoid stress dosing, additive medical therapy, prenatal treatment, side-effects of medical treatment, adrenomedullary involvement, metabolic morbidity, fertility and gender identity. However, many issues are still unresolved, and novel questions, which will have to be answered in the future, arise with every new finding.

Endocrine complications in intensive care unit patients

Summary This review addressed end organ endocrine dysfunction or failure associated with diabetes, thyrid abnormalities, adrenal insufficiency, pheochromocytoma, and pituitary dysfunction, as well as the issue of corticosteroid replacement or pharmacologic application in the critically ill. Diabetes is a common cause that precipitates ICU admission or is a secondary factor in the routine care of the stressed and critically ill medical or surgical patient. Early identification of hypoglycemia is crucial to avoid potentially devastating neurologic sequale. Increasing data on the deleterious effects on immune function, wound healing, and recovery from ischemia has prompted the use of regular insulin infusions in acute and critically ill patients in an attempt to maintain euglycemia. 58 The large Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction trial reported the acute and long-term benefits of initial infusions of glucose, insulin, and potassium combined with tighter glycemic control in diabetics with acute myocardial infaretion. 15 DKA and NKHC share several common features and represent severe endpoints of abnormal glucose and fat metabolism. These entities require timely diagnosis and therapy and rapid identification of the inciting cause to limit morbidity and mortality. Cerebral edema is a relatively uncommon development in DKA, occurring most often in children and resulting in severe neurologic sequalae in many patients. Asymptomatic thyroid disease is fairly prevalant in the United States. Extremes of dysfunction may result in thyroid storm or myxedema coma, both requiring rapid identification and therapy. Thyroid hormone synthesis and peripheral metabllism and function are markedly altered in acute illness. The differentiation of thyroid activity has been markedly improved over the past several decades with the wide application of increasingly sensitive tests, such as the TSH, free T4, and free T3. The euthyroid sick syndrome is recognized as a “normal” physiologic response to critical illness. Supplementation with exogenous thyroid hormone in patients with euthyroid sick syndrome is not indicated and may be deleterious. Adrenal homeostasis is crucial for adequate response to life-threatening trauma or critical illness. The body is normally able to increase glucocorticoid release by a factor of roughly 10-fold. As the population ages and the use of corticosteroids increases, AI should be considered in any hemodynamically unstable patient. Relative AI is being recognized more commonly, particularly as a process in sepsis and septic shock. Recent preliminary data from an ongoing multicenter trial supports the short-term administration of physiologic, stress doses of glucocorticoids in such patients. Patients with pheochromocytoma, and uncommon chromaffin cell tumor, present to the ICU on occasion for acute diagnosis and initiation of therapy or for postoperative management. These tumors are most commonly adrenal in origin, secrete excessive norepinephrine, and may be associated with familial endocrinopathies. Alpha blockade is the mainstay of initial therapy followed by intravascular fluid expansion and judicious use of β blockade and calcium channel blockade in select patients. Pituitary pathology should be considered in patients with a period of significant shock; those who have undergone frontal craniotomy or pituitary resection; those who sustained head injury; or those with cerebral thrombosis who develop polyuria, hypothermia, electrolyte abnormalities, or hyperosmolarity. On occasion, nephrogenic DI develops in patients with renal pathology or secondary to medications, such as lithium or amphotericin B. Patients with central DI should be treated with fluids, have their serum sodium corrected, and receive DDAVP. Patients with suspected or known panhypopituitarism should be treated with appropriate doses of adrenal and thyroid hormone replacement.

Treatment of adrenocortical insufficiency.

1. Gilbert P. August, MD* 1. 2. *Chairman, Department of Endocrinology & Metabolism, Children’s National Medical Center; Professor of Pediatrics, George Washington University School of Medicine, Washington, DC. The adrenal cortex secretes three types of hormones: mineralocorticoids, glucocorticoids, and androgens. Acute or chronic deficiencies of aldosterone, the primary mineralocorticoid, or of cortisol (hydrocortisone), the primary glucocorticoid, can rapidly become life-threatening. Adrenocortical insufficiency can be primary or secondary (Table 1⇓ ). The most common causes of adrenocortical insufficiency today are congenital adrenal hyperplasia in the newborn and failure to provide adequate stress doses of glucocorticoids to patients receiving long-term treatment with these agents. View this table: Table 1. Etiology of Adrenocortical Insufficiency The symptoms of adrenocortical insufficiency depend on whether cortisol or both cortisol and aldosterone are deficient (Table 2⇓ ). Pure aldosterone deficiency is rare, but does occur in children who have a defect in the enzyme complex corticosterone methyl oxidase. Pseudohypoaldosteronism produces similar symptoms but presumably is due to a defect in the aldosterone receptor. Hyporeninemic hypoaldosteronism is even rarer. Patients who have acquired immunodeficiency syndrome (AIDS) can develop a mineralocorticoid deficiency without concurrent cortisol deficiency. View this table: Table 2. Signs and Symptoms of Adrenocortical Insufficiency Hyperpigmentation, a sign of cortisol deficiency, develops over time and is seen most easily on the backs of the hands, elbows, and knees; in the creases of the hands; and on the buccal …

Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels

In patients with septic shock, to (1) determine the incidence of adrenal insufficiency (AI), (2) observe the effects of glucocorticoid therapy on outcome in those with impaired adrenal function, and (3) investigate a possible correlation between adrenal function and peripheral cytokine levels. Twenty-one patients admitted to the medical and surgical intensive care unit with septic shock and 11 healthy volunteers were studied. Cortisol, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels were measured before and after infusion of low (1 microgram) and standard doses (250 micrograms) of adrenocorticotropic hormone (ACTH) within 24 hours of the diagnosis of septic shock. Patients with subnormal adrenal responses to ACTH were treated with stress doses of steroids. Hormone, cytokine, and survival data in patients with normal response were compared to those with subnormal adrenal function. Five patients (23.8%) exhibited AI by ACTH stimulation testing. Three of them received steroid supplementation with rapid improvement in hemodynamic parameters. Autopsies of 2 patients with AI revealed intact adrenal cortices. Sixteen patients had adequate adrenal responses (AAR) to the standard-dose ACTH infusion. TNF-alpha levels were inversely correlated with mean arterial pressure (MAP) (r = -.52, P = 0.038) in AAR but not AI. There was no difference in mean peripheral TNF-alpha levels between AAR and AI. There was no correlation between TNF-alpha levels and mortality or adrenal function in those with septic shock. A trend toward lower IL-6 levels in AI suggests a link between reduced IL-6 levels and understimulation of the pituitary-adrenal axis in this group. Mortality in patients with AI was 80% at 4 weeks as compared with 43.8% in the group with normal adrenal response. Adrenal hyporesponsiveness is a feature of septic shock in some patients. Its etiology is probably complex. Steroid supplementation appeared to improve short-term survival when AI occurred, although these patients' overall mortality was worse than that of patients with septic shock and AAR. The standard-dose (250 micrograms) rapid ACTH infusion test was adequate for detecting AI. Adrenal insufficiency should be suspected in patients with septic shock who do not respond to conventional treatment. Performing the ACTH infusion test and initiating a trial of stress doses of glucocorticoids pending the results is a reasonable strategy in this situation.

ADRENAL SUPPRESSION AND STEROID SUPPLEMENTATION IN RENAL TRANSPLANT RECIPIENTS

The use of increased dosages of glucocorticoids during periods of physiologic stress in allograft recipients represents a clinical dilemma in that the short-term exogenous therapy required may significantly impair wound healing and immunocompetence. To investigate whether "stress steroids" are actually necessary, a prospective study was conducted in 40 renal allograft recipients admitted with significant physiologic stress. Stress categories included sepsis, metabolic abnormalities, and surgery. These patients received only their baseline prednisone immunosuppression (5-10 mg/day) and no supraphysiologic or stress doses of glucocorticoids. The clinical course of the patients revealed no evidence of adrenal insufficiency. There was no mortality, increase in hospital stay, or eosinophilia. Five episodes of hyponatremia and seven instances of hypotension were attributed to primary disease processes and responded promptly to specific treatment without steroid supplementation. Biochemical evaluation during stress revealed suppression of ACTH levels in 74.5% of episodes, elevation of urinary free cortisol levels in 79.1% of episodes, and elevation of isolated serum cortisol levels in 55.9% of episodes. This suggested that these patients had physiologically adequate adrenal function. The cosyntropin stimulation test overestimated the incidence and degree of clinically significant adrenal dysfunction (63% of patients) and was not a useful indication of a requirement for additional glucocorticoids. We conclude that functional adrenal suppression is uncommon in renal allograft recipients receiving baseline prednisone immunosuppression (5-10 mg/day) and that the demands of physiologic stress are met by a combination of endogenous adrenal function plus exogenous, baseline, immunosuppressive doses of glucocorticoids. Supra-physiologic or high doses of so-called "stress steroids" are not required. The cosyntropin stimulation test has significant clinical limitations and did not serve to alter clinical care.