Wednesday, May 5, 2021

Endocrinopathies in the ICU Patient Case File

Posted By: Medical Group - 5/05/2021 Post Author : Medical Group Post Date : Wednesday, May 5, 2021 Post Time : 5/05/2021
Endocrinopathies in the ICU Patient Case File
Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH

Case 34
A 63-year-old man underwent a surgical appendectomy and colostomy formation for a ruptured appendicitis with abscess and devitalized cecum. At the time of the operation, he was noted to have necrosis and perforation of the cecum with fecal peritonitis. On postoperative day 8,  the patient remains on the ventilator with PAO2/FIO2 = 260. Over the past 48 hours, he has developed worsening oliguria with urine output of <300 mL over the past 18 hours. The patient is becoming visibly jaundiced. A CT scan of the abdomen reveals no intrahepatic ductal dilatation, moderate amount of postoperative inflammatory changes throughout the peritoneal  cavity,  and no signs of active intrabdominal infections. 

⯈ What is the most likely diagnosis?
⯈ What are the causes of the patient's current condition?
⯈ How would you monitor and quantify the patient's organ dysfunction?
⯈ What are your therapeutic strategies and goals for this patient?


ANSWER TO CASE

Endocrinopathies in the ICU Patient

Summary: A 69-year-old man is recovering from sepsis due to peritonitis from a GI process; the patient is noted now to have altered mental status and tachycardia. A normal CT scan of the brain suggests that anatomic causes are unlikely to be responsible for his current condition.
  • Potential causes of patient's current picture: The cardiovascular and neurological abnormalities observed in critically ill patients can have a variety of possible causes, including hypoxia from pulmonary pathology, analgesics and sedation medication-related changes, and critical illness-induced endocrinopathies.
  • Manifestations of endocrine disorders associated with critical illnesses: Endocrine-related changes following critical illnesses may include behavioral changes (psychomotor, cognitive, and sleep disorders), cardiovascular changes (vasadilatory shock, multiple organ dysfunction syndrome), metabolic changes (defects in glucose metabolism, protein-wasting), and immunologic changes ( increased susceptibility to infections caused by increased immune suppression related to the shift of TH1/TH2 balances toward an excess of TH2 cells).
ANALYSIS

Objectives
  1. To learn the cardiovascular, metabolic, behavioral, and immune disorders that may be produced by endocrine changes associated with critical illnesses.
  2. To learn to recognize the manifestations of endocrinopathies in the ICU.
  3. To learn the medications that may contribute to endocrinopathies.
Considerations
This patient has been critically ill in the ICU and has had a prolonged ICU course following intra-abdominal infection and sepsis. Even though he has taken steps toward improvement, his persistent tachycardia and mental status change now requires that we further investigate for the causes. At this point, complete blood count, chemistries, arterial blood gas, chest x-ray, electrocardiogram, and cardiac enzymes may be useful in identifying cardiopulmonary causes. Potential new sources of infections may be evaluated with a thorough physical examination, appropriate cultures, and imaging studies. In addition, anatomic causes should be evaluated with a brain CT.

The possibility of endocrinopathies should also be entertained when a patient with critical illness develops cardiovascular, metabolic, and neuropsychiatric derangements, as critical illness can affect the homeostatic processes in several organ systems. A severe septic insult can initially overwhelm the body's innate stress responses primarily regulated by the sympathetic nervous system and hypothalamus- pituitary-adrenal (HPA) axis, leading to early hemodynamic instability that is often associated with mental status changes. Subsequent to these initial responses, critically ill individuals may enter into a state of hypercatabolism, which could be produced by thyroid dysfunction and manifest clinically as tachycardia, atrial fibrillation, or agitation. In older individuals, hyperthyroidism may also manifest as lethargy. Elevated metabolic activity secondary to hyperthyroidism can be evaluated by thyroid function studies. Delirium and cognitive impairment occur quite frequently among individuals following recovery from ARDS, where significant cognitive dysfunction, anxiety, and depression are often reported. The exact causes of these neuropsychiatric changes have not been determined; however, it has been theorized that intense inflammatory mediator and cytokine responses may alter neurohormonal homeostasis and lead to neuropsychiatric dysfunctions.

Approach To:
Endocrinopathies in the ICU Patient

CLINICAL APPROACH

Sepsis in the Critically Ill Patient
A systematic guideline as delineated by the Surviving Sepsis campaign provides a multidisciplinary approach to optimize treatment of septic patients. In the initial management, fluid resuscitation begins with isotonic crystalloid for the goals of mean arterial pressure (MAP) >65 mm Hg, central venous pressure 8 to 12, and urine output >0.5 mL/kg/h. Vasoactive agents such as norepinephrine or dopamine are started when patients are unable to maintain MAP >65 mm Hg despite adequate fluid administration. Transfusion of packed red blood cells may also be initiated for a general hemoglobin goal of 7 to 9 g/dL; however, for patients with lactic acidosis, hemorrhage, or coronary ischemia, the hemoglobin goal should be 10 g/dL. Source control with broad-spectrum antibiotics should be started immediately, with subsequent narrowing of coverage as soon as culture results are available. In managing critical illness, physicians should remain vigilant in considering endocrine derangements such as adrenal insufficiency, hyper-or hypoglycemia, vasopressin deficiency, and thyroid dysfunction.

Endocrine Response to Critical Illness
Two physiologic pathways are activated during periods of acute stress: the sympathetic nervous system and the endocrine system. The sympathetic nervous system is activated via secretion of catecholamines from the adrenal medulla, leading to changes in the cardiovascular, metabolic, immunologic, and endocrine systems. In the acute phase of illness, the endocrine system is responsible for an adaptive response to maintain organ perfusion, decrease anabolism, and up-regulate the immune response. In the chronic phase of illness, the endocrine system may play a role in the development of persistent hypercatabolism and contribute to organ dysfunction.

Sympathetic Nervous System and Arginine Vasopressin
The "fight or flight" response from the sympathomimetic system is produced by norepinephrine, epinephrine, and dopamine release from the adrenal medulla. These hormones produce complex adaptive responses throughout the body, leading to increased alertness, skin vasoconstriction, vasodilation of skeletal and coronary arteries, bronchodilatation, tachycardia, tachypnea, pupillary dilatation, and glycogenolysis. Catecholamines are also released from mesenteric organs during stress, which contribute to a significant percentage of total levels in the body. Catecholamine release from
a typical SIRS reaction typically decreases within 3 to 5 days, which may be inadequate in periods of severe stress such as in septic shock. Three major pathways are theorized to contribute to development of vasodilatory shock: (1) overproduction of nitric oxide (NO), (2) hyperpolarization of vascular smooth muscle membranes, and (3) relative deficiency of vasopressin.

Some patients with sepsis have insufficient host catecholamine responses and therefore, may benefit from exogenous administration of vasoactive medication to maintain end-organ perfusion. Dopamine or norepinephrine is often given as a first line agent when septic shock patients are refractory to appropriate fluid management. Arginine vasopressin is a neurohypophyseal hormone that acts on V1 vascular smooth muscle cell receptors and V2 renal tubular cell receptors to cause hemostasis, arterial vasoconstriction, and antidiuresis. With sepsis, some patients may develop relative vasopressin deficiency with down-regulation of V1 receptors, and may benefit from low-dose exogenous vasopressin. Thus, patients with septic shock that is refractory to fluid management and high-dose conventional vasopressors may be candidates for vasopressin.

Hypothalamic-Pituitary-Adrenal Axis
Acute stress also activates the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for survival. Initiation of this pathway begins with the increased secretion of corticotrophin-releasing hormone from the paraventricular nucleus of the hypothalamus, which in turn stimulates the anterior pituitary to produce ACTH. ACTH then signals for the adrenal cortex to produce cortisol. Cortisol has several important physiologic actions on metabolism, including stimulatory effects on the cardiovascular and immune system. During stress, cortisol increases blood glucose concentration by activating hepatic gluconeogenesis and inhibiting glucose uptake by peripheral tissues. Cortisol also activates lipolysis in adipose tissue to increase free fatty acid release. Cortisol increases blood pressure by sensitizing vascular smooth muscle to catecholamines. Immunologically, cortisol produces anti-inflammatory effects by reducing the number and function of T and B lymphocytes, monocytes, neutrophils, and eosinophils at the site of inflammation.

Approximately 10% to 20% of critically ill patients may exhibit some adrenal insufficiency, with the incidence reported as high as 60% among patients with septic shock. Glucocorticoid resistance is a phenomenon described in septic patients. Observations suggest that mediators released in patients with critical illness, and sepsis in particular, may either stimulate or impair the synthesis and activation of cortisol via actions on the HPA axis and the glucocorticoid receptor signaling system.

Three laboratory assays are applied for the detection of adrenal insufficiency. The first is serum cortisol level, which reflects total hormone concentration. The disadvantage of analyzing serum cortisol level is that free cortisol, rather than the protein-bound fraction is actually responsible for the physiologic activities of the hormone. In most critically ill patients, corticosteroid-binding globulin levels

are decreased. Furthermore, with acute stimulation of the adrenal gland, free cortisol increase is substantially more pronounced than the increase of total cortisol concentrations. Consequently, the total serum cortisol level may not accurately reflect free cortisol levels and adrenal functions in critically ill patients. Free cortisol level measurements would be preferable; however, this assay is not widely available. The cosyntropin stimulation test is a measurement of change (increase) in serum cortisol following the administration of 250 μg dose of synthetic ACTH. An increase <9 μg/dL within 60 minutes is indicative of an inability for the adrenal glands to appropriately respond to ACTH stimulation. However, this test has its limitations, as it does not assess the integrity of the HPA axis, the response of the HPA axis to other stresses such as hypotension or hypoglycemia, or the adequacy of stress cortisol levels.

In a multicenter, randomized controlled trial, Annane and colleagues reported improved survival in catecholamine-dependent patients with septic shock that was unresponsive to cosyntropin who were given a 7 -day course of steroids. In another randomized control trial reported in 2008 (The Corticus Trial), no difference in mortality was found with steroid administration in septic patients with or without appropriate responses to cosyntropin stimulation. This study did find a shorter duration for shock reversal in the steroid-treated patients when compared to patients receiving placebos. These apparently conflicting results may be explained by the sicker patients in the Annane study. In 2008, based on a meta-analysis of 6 randomized control trials, the American College of Critical Care Medicine issued a consensus statement that hydrocortisone should be considered in the management of patients with septic shock, particularly those patients who have responded poorly to fluid resuscitation and vasopressor agents. The decision to treat septic patients with corticosteroids should be based on clinical criteria and not on results of cosyntropin stimulation test or other adrenal function testing.

Insulin
Critical illness and sepsis frequently cause hyperglycemia in patients with or without a history of diabetes mellitus. The causes of critical illness-induced hyperglycemia include catecholamine-mediated inhibition of insulin release, glucocorticoid and proinflammatory cytokine induced glucose synthesis and release. In addition, pancreatic β-cell dysfunction, hepatic glucose production dysfunction, and peripheral insulin resistance are other factors that contribute to the hyperglycemia. In critically ill patients, hyperglycemia contributes to increased morbidity and mortality through a variety of mechanisms, including augmentation of oxidative burden, activation of stress-signaling pathways, and impairment of neutrophil function. Furthermore, hyperglycemia is associated with the increase in risk for myocardial infarction, impairment of wound healing, and increased mortality in patients following surgery, trauma, or neurotrauma.

Intensive insulin therapy was found to have reduced mortality benefits in a randomized control trial involving mechanically ventilated cardiac surgical patients. These benefits were observed in patients with and without known diabetes, and the benefits appeared to be most significant among patients with sepsis-induced multipleorgan failure, and an ICU stay of >5 days. Target glucose values of 80 to 110 mg/dL were originally suggested as being most beneficial for ICU patients based o n the above-mentioned study; however, more recent evidence suggest that target value of 140 to 180 are more appropriate and produce fewer hypoglycemiarelated complications when compared to target glucose values of 80 to 110 mg/dL.

Hypothalamic-Pituitary-Thyroid Axis
Thyroid hormones produced by the thyroid gland are regulated by thyrotropinreleasing hormone (TRH) and thyroid-stimulating hormone (TSH) released by the hypothalamus and anterior pituitary, respectively. Thyroid hormones act to increase the basal metabolic rate, affect protein synthesis, and increase the sensitivity of tissues to catecholamines. Thyroxine (T4) is the principal hormone produced by the thyroid and can be subsequently deiodinated to the active form, triiodothyronine (T3) in extrathyroidal tissues. Approximately 99% of all T3 and T4 are bound to thyroxine-binding globulins and other plasma proteins; its physiologically active form is unbound, the level of which can be measured via laboratory testing.

Euthyroid sick syndrome, also known as low T3 to T4 syndrome or nonthyroidal illness syndrome, is commonly identified in critically ill patients. This is characterized by an acute decrease in T3 followed by a decrease in T4 within 24 to 48 hours. This caused by inhibition in T4 to T3 conversion, leading to an increase in reverse-T3 (rT3). TSH often increases briefly at onset, but usually remains within the low-normal range without a circadian rhythm. Although this may reflect an adaptive mechanism aimed at reducing hypercatabolism, this disease process is associated with an increased mortality despite a lack of overt hyper-or hypothyroid symptoms. A small randomized control trial found no mortality benefit in exogenous administration of T4 versus placebo in critically ill patients with this disorder. Another nonrandomized cohort study showed no clinical outcome difference in patients undergoing continuous thyrotropin-releasing hormone infusion. Current recommendations call for no intervention to correct the thyroid hormone levels in euthyroid sick syndrome.

Somatotropic Axis
Growth hormone (GH) is secreted by the anterior pituitary in a pulsatile fashion and has anabolic effects in the body, increasing lipolysis, protein synthesis, and reducing glucose uptake in hepatocytes. Its activity is mediated by insulin like growth factor 1 (IGF-1), which is bound by IGF-binding proteins (IGFBP), thereby reducing its bioavailability but prolonging its half-life. The acute phase of critical illness is characterized by a reduced pulsatile release of GH, high basal GH levels, and low levels of IGF-1 and IGFBP. Cytokine release during stress causes a widespread GH resistance with the down-regulation of GH receptors, causing reduced anabolic activity, and providing metabolic energy while wasting muscle protein. This has deleterious effects in critically ill patients, including delaying wound healing, depressed immune function, and respiratory muscle dysfunction. Two large clinical trials investigating whether exogenous GH would reverse hypercatabolism found no benefit, and in fact, an increased risk of infection and death. Currently, there is no evidence to show that pharmacologic agents acting on the somatotropic axis has any benefit on clinical outcome in critically patients.

Hypothalamic-Pituitary-Gonadal Axis
Gonadal hormones, which interact with androgen and estrogen receptors, are mediated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) released by the anterior pituitary; LH and FSH in turn are regulated by gonadotropinreleasing hormone secreted by the hypothalamus. In males, a low level of testosterone is associated with acute and chronic critical illness and is directly associated with mortality. Female patients may experience the "hypothalamic amenorrhea of stress." Although estrogen supplementation has been shown to be beneficial in critically ill patients, current recommendations do not endorse routine use of sex hormone replacement. Furthermore, estrogen use can increase the risk of venous thromboembolism.

Sleep Disturbances in the ICU
Sleep disturbances in the ICU are common, and these disturbances may include decreased nocturnal sleep, reduced or absence of deep sleep, and disrupted circadian patterns. In addition, ICU patients commonly report anxiety, fear, and nightmares associated with sleep during and after their ICU stays. The normal sleep-wake cycle is controlled by complex interactions between neurotransmitters such as catecholamines, glutamate, histamine, melatonin, and acetylcholine. Melatonin production by the pineal gland follows a diurnal variation pattern and is responsible in promoting nocturnal sleep. Septic patients have been found to have a continuous, nonfluctuating secretion of melatonin. Altered melatonin production is believed to be beneficial during sepsis, as it possesses antioxidant properties. ICU patients may also have sleep disruption due to disturbances in the HPA axis activity, which modulates cortisol release following stress. Cortisol is known to inhibit sleep. Because of these endogenous changes as well as the external stimuli, 60% of all ICU patients report sleep disturbances.

Drug-Induced Endocrine Disorders
Drug-Induced Pituitary-Adrenal Axis Dysfunction Etomidate is often used for rapid sequence
induction during intubation. Continuous infusion of etomidate had been utilized during the 1980s, but this practice was discontinued when it was found to be associated with increased mortality due to adrenal dysfunction. Single dose etomidate has been reported to contribute to adrenal dysfunction; however, its uncommon occurrence suggests that the risk is minimal. The patients in which single-dose etomidate may produce clinically significant adrenal insufficiency are the septic patients, in whom any level of adrenal dysfunction could contribute to worse clinical outcomes; therefore, the current recommendations suggest that ketamine may be a more appropriate agent for rapid-sequence induction in the septic patient population. The etomidate effect on adrenal dysfunction is believed to be due to a dose-dependent blockade of the enzyme involved in the final conversion of cholesterol to cortisol.

Chronic glucocorticoid therapy is common in ICU patients. Patients with a history of chronic glucocorticoid therapy are at risk for the development of adrenal insufficiency during stress states; however, the dose and duration of prior steroid use do not predict the likelihood of insufficiency. It is recommended that patients in shock and with history of chronic steroid use receive steroid repletion, and patients without shock should b e closely monitored for signs of insufficiency rather than receiving
empiric replacement.

Drugs causing up-regulation of cytochrome P-450 (CYP-450) activity may increase cortisol metabolism (breakdown) and contribute to adrenal insufficiency. Examples of this class of agents are rifampin, phenobarbital, and phenytoin. The medication effects can be observed within 7 days of therapy initiation and require close monitoring of clinical effects.

Antifungal agents causing CYP-450 inhibition may produce adrenal insufficiency by suppressing CYP-450-dependent steroidogenesis. Ketoconazole is the most well documented antifungal agent associated with adrenal insufficiency. Fluconazole and itraconazole are agents that produce adrenal insufficiency much less frequently in comparison to ketoconazole. Due to the potential of causing clinically significant adrenal insufficiency, patients receiving antifugal therapy should be closely monitored.

Drug-Induced Thyroid Dysfunction Dopamine infusion is associated with the occurrence of nonthyroidal illness syndrome. This effect is related to the reduction of TSH concentration and reduction in thyroxine production. Dopamine effects on thyroid functions can be observed within 24 hours after the initiation of dopamine infusion, and these effects are completely reversed within 24 hours following termination of dopamine infusion.

Lithium is concentrated in the thyroid and may cause a decrease in thyroxine release. Hypothyroidism and goiter formation may occur in individuals with prolonged lithium intake; hypothyroidism is reported in approximately 20% of individuals taking lithium for 10 years or longer.

Amiodarone is frequently prescribed for the management of atrial or ventricular arrhythmias. By weight, 37% of amiodarone is made up of iodine, and this medication is structurally similar to thyroxine. Long-term and short-term administration of amiodarone have the potential of producing thyrotoxicosis. Amiodarone induced thyrotoxicosis 1 (AIT-I) describes the amiodarone-induced thyrotoxicosis that occurs in individuals with preexisting thyroid diseases. This problem is treated with anti thyroid medications such as methimazole or propylthiouracil. ATI-II is an amiodarone- induced thyroiditis causing destruction of the gland and release of thyroid hormone; this condition is best treated with glucocorticoids. Due to the long half­ life of amiodarone (50-100 days), ATI diseases may occur long after discontinuation of the medication.

Interestingly, amiodarone can also cause hypothyroidism; however, the mechanisms that cause amiodarone-induced hypothyroidism are undetermined at this time. Women and those with a history of Hashimoto thyroiditis are at increased risk for amiodarone-induced hypothyroidism. Most cases of hypothyroidism are mild and can be managed with thyroxine replacement or the discontinuation of amiodarone.

CLINICAL CASE CORRELATION
  • See also Case 15 (Cardiac Arrthythmias), Case 19 (Sepsis), and Case 33 (Multiorgan Dysfunction).

COMPREHENSION QUESTIONS

34.1  A 44-year-old man is hospitalized for septic shock due to pneumonia, and he has received crystalloid resuscitation to achieve a CVP of 18 mm Hg. Thereafter, a norepinephrine drip was initiated. Despite these measures, his mean arterial pressures remained below 65 mm Hg. Vasopressin drip at 0.03 U/min was initiated without improvement. He is believed to be on the appropriate antimicrobial regimen for his infection. Which of the following is the most appropriate management in this patient?
A. Proceed with a cosyntropin stimulation test and give hydrocortisone if the patient is demonstrated to have insufficient adrenal response.
B. Give 100 μg of thyroxine.
C. Measure plasma vasopressin level.
D. Administer cortisol 100 μg intravenously.
E. Transfuse 2 U of pack red blood cells.

34.2  A 55 -year-old woman with a history of goiter develops fever, tachycardia, and anxiety 12 hours following the initiation of amiodarone drip for ventricular arrhythmias. Her serum TSH is noted to be <0.01. Which of the following statement best describe her current condition?
A. This patient is experiencing amiodarone-induced hypothyroidism.
B. This condition is best treated by corticosteroid administration.
C. This patient is experiencing amiodarone-induced thyroiditis.
D. This patient's condition is best treated with propylthiouracil.
E. This condition is best treated with iodine administration.

34.3  Which of the following statements best describe the current recommended approach to glycemic control in the ICU?
A. Strict glucose control targeting glucose levels of 80 to 110 is strongly recommended for postoperative patients.
B. Glucose control targeting glucose levels of 140 to 180 is associated with lower morbidity and mortality than glucose target levels of 80 to 110.
C. Glycemic control in the ICU has not been shown to provide clinical benefits.
D. Hyperglycemia is generally not a problem unless individuals are receiving total parenteral nutrition.
E. Serum glucose levels >180 is associated with improved neurological outcomes following head injury.


ANSWERS TO QUESTIONS

34.1  D. This patient has persistent septic shock despite sufficient fluid resuscitation to restore intravascular volume. He remains refractory to norepinephrine and low-dose vasopressin infusions. Based on the meta-analysis findings of 6 randomized control trial and the American College of Critical Care Medicine consensus recommendations, hydrocortisone should be considered in this individual. Thyroxine replacement and blood transfusions do not play a role in the treatment of vasopressor-refractory septic shock. Measurement of serum vasopressin levels does not play a significant role in clinical decision-making in this setting.

34.2  D. This patient has clinical and biochemical evidence of hyperthyroidism. The condition may or may not be the result of amiodarone-induced hyperthyroidism. In either case, the appropriate treatment is anti thyroid medications such as propylthiouracil. Amiodarone can also produce hyperthyroidism by causing an autoimmune thyroiditis; however, this process generally takes more than 12 hours to appear.

34.3  B. Current evidence suggest that glycemic control targeting glucose levels of 140 to 180 mg/dL rather than 80 to 110 mg/dL is associated with fewer occurrences of hypoglycemia-associated complications.


CLINICAL PEARLS

 Dopamine and norepinephrine are first-line agents to maintain end ­organ perfusion in septic shock after patients have been adequately volume resuscitated. 
 Arginine vasopressin may be indicated in patients who are  refractory to high dose vasopressors in critically ill patients who are suspected to have relative vasopressin deficiency. 
 Hydrocortisone should be considered in septic shock when hypotension is refractory to fluid and vasopressor agents, and the patient has clinical evidence of adrenal insufficiency. 
 Treatment of septic patients with corticosteroids should be a clinical decision and should not be determined on the basis of adrenal function test­ing results. 
 Insulin therapy with target glucose levels of 140 to 180 mg/dL is beneficial in critically ill patients. 
 Nonthyroidal illness syndrome may occur in critically ill patients; how­ever, no intervention is currently recommended to restore normal thyroid levels. 
 Gonadal steroids have a  linear relationship with mortality in critically ill patients; however, current  literature does not support exogenous replacement.

References

Annane D. Effect of treatment with low doses of hydrocortisone and fludrocortisones on mortality in patients with septic shock. ]AMA. 2002;288:862. 

Bello G, Paliani MG, Pontecorvi A, Antonelli M. Treating nonthyroidal illness syndrome in the criti­cally ill patients: still a matter of controversy. Curr Drug Ta rgets . 2009; 10:778-787. 

Bougle A, Annane D. Endocrinopathy. In: Gabrielli A, Layon AJ, Yu M, eds. Civetta, Ta ylor, and Kirby's Critical Care. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:2411-2427. 

Marik PE, Pastore SM, Annane D, et al. Recommendations for the diagnosis and management of cor­ticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937-1949. 

Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl] Med. 2008;358:111- 124. 

Thomas Z, Bandali F, McCowen K, Malhotra A. Drug-induced endocrine disorders in the intensive care unit. Crit Care Med. 2010;38(6):821 9-8230.

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