Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit? If So, How Should It Be Managed?

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Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit? If So, How Should It Be Managed? Luminita Eid, Yoram G. Weiss

Physiologic and pathophysiologic perturbations initiate a well-coordinated response to maintain homeostasis.1 Adaption is in part characterized by alterations in cardiovascular function, metabolic activity, and inflammation.2 This response involves activation and secretion of hormones from the adrenal cortex. However, during the course of the intense and potentially prolonged response that accompanies critical illness, acute adrenal insufficiency (AI) may develop.3 This deficit may increase the mortality of critically ill or injured patients.4

NORMAL PHYSIOLOGY OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTION In healthy subjects, cortisol secretion by the adrenal gland is tightly controlled by the hypothalamic-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) produced in the hypothalamus in response to a variety of signals (cold, fever, infection, trauma, emotional distress, burns, inflammatory agents, pain, hypotension, exercise, hemorrhage) is transferred through the hypothalamicpituitary portal system to the anterior pituitary gland. The CRH acts on specialized cells that produce and release adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates adrenal cortical cells to produce steroid hormones, including cortisol. Negative feedback, which reduces the secretion of both CRH and ACTH, is exerted by secreted cortisol at the level of both the hypothalamus and the pituitary. This ensures a tightly regulated system.5 Cortisol normally is secreted in a diurnal pattern, with a maximal circulatory level early in the morning, followed by a steady decrease throughout the day. The serum cortisol response to ACTH stimulation also is circadian. Therefore, afternoon responsiveness is greater owing to the decreased cortisol level. In addition, cortisol secretion is pulsatile and not continuous. These factors become important when interpreting random cortisol levels.6 Under normal conditions, the adrenal glands release 20 to 30 mg of cortisol each day. When under physiologic

stress, a normal adrenal gland can secrete about 10 to 12 times that amount.5 Ninety-five percent of the cortisol circulating in the blood is carried by cortisol-binding globulin (CBG; transcortin), albumin, or both. Five percent is unbound and thus physiologically active. It is this free cortisol that is regulated to maintain homeostasis.5 Cleavage of CBG by elastase secreted from activated neutrophils results in a 10-fold decrease in its affinity for cortisol. This has been proposed as a mechanism for cortisol delivery and release to sites of inflammation.7 Free cortisol levels are significantly affected by changes in CBG and albumin and affect measured cortisol levels.8

MOLECULAR ACTIONS OF GLUCOCORTICOIDS Glucocorticoids regulate gene transcription in every cell of the body. These effects are summarized in Table 73-1.9–17

ALTERATIONS IN HYPOTHALAMICPITUITARY-ADRENAL AXIS FUNCTIONING DURING CRITICAL ILLNESS The classic regulators of the axis continue to be operable in critically ill patients but with significant alterations.

Cytokines and the HPA Axis Sepsis mediators alter the HPA axis. During inflammatory processes, cytokines such as interleukin-1a (IL-1a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a) can activate the HPA axis at the level of the hypothalamus, pituitary, and adrenal cortex.18–23 This increases levels of CRH, ACTH, and glucocorticoids.24–26 These concentrations also may reflect impaired glucocorticoid clearance, especially in patients with impaired hepatocellular function, decreased hepatic blood flow, and depressed renal or thyroid function.27 In addition, cytokines alter glucocorticoid receptor

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Table 73-1 Effects of Cortisol on Organ System Function System

Acute

Long-Term

Host defense

Protection from the potentially harmful inflammatory mediators9

Anti-inflammatory and immunosuppressive effects, influencing lymphocytes, NK cells, monocytes, macrophages, eosinophils, neutrophils, basophils, and macrophages.9 Decrease the accumulation and function of these cells at inflammatory sites, stabilize lysosomal membranes, decrease release of inflammatory mediators, impair antigen processing and antibody formation by B lymphocytes.10 Poor tissue repair and wound healing, immunosuppression and vulnerability to infection

Metabolism

Mobilization of energy stores: increase glycogen stores, increase blood glucose, decrease peripheral glucose uptake and metabolism, increase lipolysis, increase protein catabolism

Insulin-resistant “steroid” diabetes mellitus

Increase hepatic gluconeogenesis, inhibit adipose tissue glucose uptake, stimulate free fatty acid release from adipose tissue and amino acid release from body proteins, in order to facilitate substrate and energy supply to the cells during stress11

Centripetal obesity, moon face Protein depletion in muscle, connective and other tissues

Musculoskeletal

Protein catabolism: alter calcium homeostasis, lower serum calcium levels by inhibition of calcium absorption from the gut, decrease renal calcium reabsorption and promotion of the shift of calcium from extracellular to intracellular compartment9

Impaired growth, muscle wasting, loss of connecting tissue, osteoporosis, and disturbed calcium homeostasis

Central nervous system

Improved cognitive function

Mood changes (depression and psychotic episodes), neurodegeneration9

Cardiovascular

Salt and water retention: inhibition of the production of vasoactive inflammatory mediators Required for normal reactivity to angiotensin II, epinephrine, and norepinephrine contributing to the maintenance of cardiac contractility, vascular tone, and blood pressure as well as for synthesis of NAþ-Kþ ATPase,12 catecholamines, and catecholamine receptors13,14 Decrease the production of nitric oxide15–17

Hypertension and other cardiovascular disease

Reproductive

Inhibition of hypothalamic-pituitary-gonadal function

Menstrual irregularities, male and female infertility

Gastrointestinal tract

Reduced bicarbonate and mucus production Inhibit gastric and intestinal motility9

Increased susceptibility to ulcers

Renal

Bind to mineralocorticoid receptors and increase sodium reabsorption and excretion of potassium and hydrogen ions, while increasing free water excretion by inhibition of antidiuretic hormone release9

(GR) number and activity.28,29 Cytokines also, however, suppress the HPA axis and GR function.18–20,28,29 Indeed, several studies have reported inappropriately low ACTH levels in patients with the systemic inflammatory response (SIRS) and severe sepsis.30,31

Cortisol Response to Critical Illness Critical illness activates the HPA axis through different mechanisms. Pain, fever, hypovolemia, hypotension, and tissue damage all may increase corticotropin and cortisol secretion with a loss of normal diurnal variation in these

hormones.32 However, the activity of the HPA axis during critical illness is biphasic. In the initial, acute phase of illness, the HPA axis is activated primarily by an increase in CRH secretion and cytokine production. Therefore, plasma ACTH and cortisol are elevated. Teleologically, this response should provide energy and protect the body by increasing gluconeogenesis, maintaining intravascular volume, and inhibiting acute inflammation.32 During prolonged critical illnesses, the response differs, highlighting a wide range of cortisol levels among patients with sepsis.33 Plasma ACTH concentrations decrease despite persistent hypercortisolism. This suggests that

Chapter 73 Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit? cortisol secretion is regulated through alternative pathways.34 The persistence of hypercortisolism may contribute to long-term complications, including hyperglycemia, myopathy, poor wound healing, and psychiatric alterations.35 However, prolonged critical illness also may present with low cortisol levels.33

DEFINITION AND INCIDENCE OF RELATIVE ADRENAL INSUFFICIENCY Definition Several studies have shown that patients with sepsis and normal or high baseline cortisol levels develop a syndrome of relative AI. This is typified by a depressed cortisol response to the ACTH stimulation test.36 This sepsis-associated AI is associated with increased mortality.36 It has been proposed that an unstimulated cortisol level of less than 15 mg/dL (414 nmol/L) represents relative AI.37–40 Some investigators believe that the rapid corticotropin stimulation test is useful in evaluating adrenocortical function in these cases.35 Postcorticotropin cortisol concentrations should be greater than 20 mg/dL (550 nmol/L) or increase more than 9 mg/dL (248 nmol/L).35,41 The absence of an increase of at least 9 mg/dL is hypothesized to define relative AI. Importantly, however, these data are not experimentally verifiable, and thus the appropriate cortisol concentration and increase to ACTH stimulation in sepsis and septic shock are not known.

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Table 73-2 Causes of Adrenal Insufficiency in Critically Ill Patients REVERSIBLE DYSFUNCTION OF THE HPA AXIS • Sepsis, systemic inflammatory response syndrome • Drugs (corticosteroids, etomidate, rifampin, phenytoin, ketoconazole) • Hypothermia

PRIMARY ADRENAL INSUFFICIENCY • • • • • • • •

Autoimmune Human immunodeficiency virus (infection, drugs) Cytomegalovirus infection Antiphospholipid syndrome Metastatic carcinoma (lung, breast, kidney) Systemic fungal infections Tuberculosis Hemorrhage (disseminated intravascular coagulation, anticoagulation, meningococcemia)

SECONDARY ADRENAL INSUFFICIENCY • • • • • •

Pituitary (tumors, metastasis, surgery, or radiation) Empty sella syndrome Craniopharyngioma Sarcoidosis, histiocytosis Postpartum pituitary necrosis Head trauma

Primary AI is rare, with an incidence of less than 0.015 in the general population.42 The reported incidence of AI in intensive care unit (ICU) settings varies. In the most recent study, 46.7% of patients did not have an appropriate response to corticotropin.43

ketoconazole or etomidate, depress glucocorticoid synthesis, secretion, or both.43,50 Several infectious agents are associated with AI. Tuberculosis, the main cause of AI in the past, has been replaced by cytomegalovirus, histoplasma, cryptococcus, or toxoplasma infections in modern ICUs. These tend to occur in HIVpositive or immunosuppressed patients.51 Tumor (primary or metastatic) infiltration of the adrenal and intra-adrenal hemorrhage are additional possible but rare causes of AI.51

CAUSES OF ACUTE ADRENAL INSUFFICIENCY IN THE CRITICALLY ILL

CLINICAL FEATURES OF HYPOTHALAMICPITUITARY-ADRENAL AXIS FAILURE

Several factors have been associated with AI in critically ill patients (Table 73-2). An inflammatory state such as sepsis is accompanied by both primary and secondary AI.44 This may result from circulating cytokines.45 It is important to recognize these patients because of the high mortality of this disorder if untreated.22 As many as 30% of patients with septic shock44 and up to 25% of critically ill patients with human immunodeficiency virus (HIV)46 may acquire AI that is associated with resistance to ACTH. Both human and animal studies have shown that sepsis is associated with either a decrease in the number of GR47 or decreased GR function and affinity for glucocorticoids.48,49 Several investigators observed higher cortisol levels among patients recovering from septic shock relative to levels expected in healthy adults. In addition, survivors have a more robust response to ACTH stimulation than nonsurvivors.33 Several drugs used in the ICU setting may induce AI. These include cytochrome P-450 inducers (rifampin, phenytoin) that increase cortisol metabolism. Others, like

Clinical diagnosis of HPA failure in critically ill patients may be due to the combination of AI and the underlying disease. Therefore, it often is difficult to diagnose. Thus, there should be a high index of suspicion in critically ill patients requiring vasopressor support.52 Laboratory assessment can help identifying patients at risk. The presence of eosinophilia may be an additional sign of AI. Clinical signs associated with AI are presented in Table 73-3.

Incidence

DIAGNOSIS OF HYPOTHALAMICPITUITARY-ADRENAL AXIS FAILURE Several tests have been proposed for the diagnosis of AI.

Measurement of Random Serum Cortisol Levels A number of investigators have suggested that a random low serum cortisol level is indicative of HPA failure.53,54

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Table 73-3 Signs Suggestive of Adrenal Insufficiency in Critically Ill Patients • • • • • • • • • • • • • •

Sepsis, with hypotension resistant to volume resuscitation Vasopressor dependence Hyperdynamic circulation Weakness, fatigue Anorexia, weight loss Nausea, vomiting, diarrhea Anemia Eosinophilia Metabolic acidosis Hyponatremia and hyperkalemia Hypoglycemia Mental status changes Hyperpigmentation, vitiligo Fever

High-Dose Adrenocorticotropic Hormone Test This approach is designed to measure the integrity of the HPA axis. It is performed by administering 250 mg of corticotropin intravenously. Serum cortisol levels are measured at 30 and 60 minutes.62 In ambulatory healthy subjects, an increase in serum cortisol levels to 18 to 20 mg/dL is considered normal.62,63 Similarly, a level less than 18 to 20 mg/dL or an increase of less than 9 mg/dL is considered abnormal.64 The threshold of 18 mg/dL may be inappropriately low in critically ill patients.65 Importantly, 250 mg of corticotropin may be sufficient to override adrenal resistance to ACTH and result in a normal cortisol response even though the patient may fail to respond to stress.44

Low-Dose Adrenocorticotropic Hormone Test They postulate that the central nervous system–HPA axis is maximally activated in severely stressed patients. This results in a fixed response and loss of diurnal variation.32 Thus, a random cortisol level provides adequate information about the integrity of the entire axis.3 This approach is problematic for several reasons. First, the cortisol level that indicates failure is unknown. Values ranging from 10 to 34 mg/dL have been proposed. Current thinking is that unstimulated cortisol levels less than 15 mg/dL (414 nmol/L) should be used as a cutoff for the diagnosis of relative adrenal insufficiency.16 A second problem involves the high degree to which cortisol is bound to CBG and albumin. Therefore, low levels may reflect nothing more than hypoalbuminemia or redirected hepatic protein synthesis.16 Finally, data correlating levels with mortality are confusing because both low (suggesting insufficient response to stress) and high (reflecting more severe stress) cortisol levels have been associated with increased mortality.41,53,55–58

Free Plasma Cortisol Measurement Measurement of free plasma cortisol has been suggested. This avoids the problems associated with changes in the plasma concentrations of proteins that bind cortisol. Free cortisol may be calculated using the Coolens equation.59,60 A number of studies suggest that free plasma cortisol is likely to provide a more accurate reflection of circulating glucocorticoid activity than total plasma cortisol.61 This approach is supported by several important findings: (1) ACTH markedly stimulated free cortisol increments whereas total cortisol increments are nearly undetectable; (2) basal free cortisol levels are more elevated than total cortisol in septic patients; (3) after resolution of septic shock, basal free cortisol levels fell promptly, but total cortisol levels remained elevated; and (4) there is less overlap between relative AI and nonrelative AI patients when basal free cortisol levels, rather than basal total cortisol levels, were used to make the diagnosis.61 Despite the logic of this approach, there are no data that directly support the use of free cortisol measurements.

Some clinicians have argued that a corticotropin dose of only 1 mg is more sensitive and specific for primary and secondary adrenal insufficiency.44 This eliminates concern that a large dose will elicit a response even when responses in the HPA axis are suppressed. However, this approach becomes problematic when the HPA axis is maximally stimulated. In this setting, the stressed patient may be secreting all the cortisol possible, and that amount may be appropriate. Failure to respond to stimulation would not be indicative of insufficiency. Other tests have been proposed but are unexplored in critically ill patients.

DIAGNOSIS OF RELATIVE ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTS The prognostic importance of adrenal insufficiency in septic shock is well described. However, it is important to systematically evaluate the value of routine testing of adrenal function and the effect of steroid replacement in the critically ill. Several randomized clinical trials (RCTs) have addressed this issue. The recently published CORTICUS study,43 the largest RCT in the field, evaluated (1) the reliability of the short corticotropin test for the diagnosis of relative AI, and (2) the effect of cortisol replacement in patients with refractory hypotension.66 To reduce heterogeneity in the determination of cortisol levels, all samples were measured blindly and serially before interim and final analyses in a central laboratory using the Elecsys cortisol assay (Roche Diagnostics). The authors concluded that the short corticotropin test was not useful for determining the advisability of corticosteroid treatment in patients with septic shock. These results also raise concerns regarding the accepted definition of relative adrenal insufficiency. Indeed, the measured cortisol level was not consistent between different assays. Other studies have described the poor relationship between measurement methods.66 There also is concern about the dose, timing, and type of corticotropin.43

Chapter 73 Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit? Based on these findings, the guidelines regarding management of severe sepsis and septic shock presented in the 2008 Surviving Sepsis guidelines were modified so that an ACTH test was not used to identify the subset of adults with septic shock who needed steroids.66

THERAPEUTIC APPROACH TO PATIENTS WITH PRESUMED ADRENAL INSUFFICIENCY Most of the published data on the use of steroids in critically ill patients have come from subjects with severe sepsis or septic shock. The rationale for their use in these settings is multifactorial: potent anti-inflammatory properties, inhibition of cytokine production, inhibition of migration of inflammatory cells into tissues, increase in vasoactive tone, enhancement of responsiveness to catecholamine, prevention of desensitization, or downregulation of b-adrenergic receptors. However, clinical trials of glucocorticoid therapy in septic patients have yielded conflicting results. Tables 73-4 and 73-5 summarize the most important meta-analyses and randomized controlled trials regarding steroid use in sepsis. It is important to emphasize that in most of the studies that contributed data to meta-analyses, pretreatment serum cortisol levels were significantly elevated relative

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to accepted norms.41 Additionally, even treatment with “low-dose” steroids (150 to 200 mg hydrocortisone per day) resulted in both free and total serum cortisol levels that were much higher than those noted in any group of critically ill patients.67 This increases the potential for adverse effects (e.g., secondary infection with resistant organisms, myopathy, hyperglycemia, hypokalemia) when steroids are administered.68 Two large randomized controlled studies have addressed current therapy of AI in critically ill patients. In a French study, the authors used an ACTH stimulation test to divide their septic patients into responders (increase of >9 mg/dL in serum cortisol) and nonresponders (increase of <9 mg/dL). These investigators noted a benefit from steroid therapy in patients labeled as nonresponders.41 However, the recently published CORTICUS study was unable to demonstrate a statistically significant mortality difference between patients who did not respond to corticotropin and those who did.43 Indeed, hydrocortisone did not alter mortality in either group but was associated with an increased rate of resistant infection. Several differences in the design of these two studies may explain these contradictory findings (Table 73-6). These include entry window, duration of hypotension needed for inclusion, the use of fludrocortisone in addition to hydrocortisone, treatment duration, and the corticosteroid weaning

Table 73-4 Summary of Meta-Analyses on Steroid Use in Sepsis Study

No. of Trials

No. of Subjects

Intervention

Control

Outcomes

Lefering & Neugebauer, 199569

10

1329

Clinical evidence and treatment effects of low- vs. high-dose or type of corticosteroid used in proven gram-positive or gram-negative sepsis

Placebo or supportive treatment alone

No beneficial effect of corticosteroids in septic shock was observed; there is some evidence for a positive effect in patients with gramnegative septicemia.

Cronin et al, 199570

9

1232

Effect of corticosteroid therapy on morbidity and mortality in sepsis

Placebo or supportive treatment alone

No support for the use of corticosteroids in patients with sepsis or septic shock, and suggests that their use may be harmful

Minneci et al, 200471

5

875

Effects of glucocorticoids on survival or vasopressor requirements

Placebo or supportive treatment alone

Short courses of high-dose glucocorticoids decrease survival during sepsis. A 5- to 7-day course of physiologic hydrocortisone doses increases survival and shock reversal in patients with vasopressor-dependent septic shock.

Keh & Sprung, 200472

13

811

Impact of a low or a high dose of corticosteroids in severe sepsis and septic shock

Placebo or supportive treatment alone

Low doses of corticosteroids are recommended in vasopressor-dependent septic shock. High-dose corticosteroids are not recommended in sepsis. Addition of oral fludrocortisone is considered an optional approach.

Annane et al, 200473

16

2063

Effects of corticosteroids in severe sepsis and septic shock

Placebo or supportive treatment alone

Corticosteroid use did not significantly affect mortality in septic shock. Long courses of low doses of corticosteroids decreased 28-day and hospital mortality.

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Table 73-5 Summary of Randomized Controlled Trials on Steroid Use in Sepsis* Study Design

Intervention

Control

Outcomes

Wagner et al, 195574

Two parallel groups, 2 centers, 113 adults with pneumococcal pneumonia; shock present in only 3

Quasi-randomized

Hydrocortisone (orally 80 mg on admission followed by 60 mg 3 times on day 1, then 40 mg 4 times on day 2, 20 mg 4 times on day 3, 10 mg 4 times on day 4, and 10 mg twice on day 5)

Standard therapy (first 85 patients); placebo (last 28 patients)

Fever; pleuritic pains; patient’s well-being

Cooperative Study Group, 196375

Two parallel groups, 5 centers, 194 adults and 135 children with vasopressor-dependent septic shock

Quasi-randomized

Hydrocortisone (intravenous infusion of 300 mg for 24 hr, then 250 mg for 24 hr, followed by 200 mg orally on day 3, then tapered off in steps of 50 mg/ day—i.e., total duration of treatment 6 days)

Placebo

Primary: hospital mortality Secondary: safety

Bennett et al, 196376

96 patients

Double-blind

Hydrocortisone, 300 mg  1, then decrease by 50 mg/day

Standard treatment

Hospital mortality, complications of treatment

Klastersky et al, 197177

Two parallel groups, 1 center, 85 adults with disseminated cancer and life-threatening infection

Double-blind

Betamethasone (1 mg/kg/day in 2 intravenous doses for 3 consecutive days)

Placebo

30-day mortality; rate of adverse events

Schumer, 197678

Three parallel groups, 1 center, 172 adults with septic shock with positive blood cultures

Double-blind

Dexamethasone (3 mg/kg as a single intravenous bolus); methylprednisolone (30 mg/kg as a single intravenous bolus). Treatments might have been repeated once after 4 hr and had to be initiated at time of diagnosis.

Placebo

Primary: 28-day mortality Secondary: complication rates

Thompson et al, 197679

28 patients

Double-blind

Methylprednisolone, 30 mg/kg  1 and then repeat up to 3 times within 24 hr if in shock

Standard treatment

Hospital mortality, toxicities of treatment

Sprung et al, 198480

Three parallel groups, 2 centers, 59 adults with vasopressor-dependent septic shock

Open-label

Dexamethasone (6 mg/kg as a single intravenous 10- to 15min infusion); methylprednisolone (30 mg/kg as a single intravenous dose 10to 15-min infusion). Treatments might have been repeated once after 4 hr if shock persisted and had to be initiated at time of diagnosis.

No treatment, placebo

Primary: hospital mortality; shock reversal Secondary: complications of septic shock; treatment safety

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No. of Subjects

Section IX

Study

Continued

Two parallel groups, 19 centers, 382 adults with severe sepsis (n ¼ 234) or septic shock (n ¼ 148)

Double-blind

Methylprednisolone (30 mg/kg 20 min intravenous infusion, every 6 hr for 24 hr). Treatments had to be initiated 2 hr from time entry criteria were met.

Placebo

Primary: 14-day development of shock for severe sepsis; shock reversal for septic shock; 14-day mortality and safety

Veterans Administration Systemic Sepsis Cooperative Study Group, 198782

Two parallel groups, 10 centers, 223 adults with severe sepsis or septic shock (n ¼ 100)

Double-blind

Methylprednisolone (30 mg/kg as a single intravenous 10-15 min infusion, followed by a constant infusion of 5 mg/kg/hr for 9 hr). Treatments had to be initiated within 2 hr.

Placebo

Primary: 14-day mortality Secondary: complications

Lucas & Ledgerwood, 198483

Two parallel groups, 1 center, 48 adults with septic shock

Open-label

Dexamethasone (2 mg/kg as a single intravenous bolus followed by a maintenance infusion of 2 mg/kg/24 hr for 2 days)

Standard treatment

Primary: 14-day mortality (unclear) Secondary: improvement in hemodynamics; improvement in pulmonary function; safety

Luce et al, 198884

Two parallel groups, 1 center, 75 adults with septic shock

Double-blind

Methylprednisolone (30 mg/kg 15 min intravenous infusion, every 6 hr for 24 hr); placebo

Placebo

Primary: 28-day mortality Secondary: complication rates

Slusher et al, 199685

Two parallel groups, 2 centers, 72 African children aged 1 to 16 yr with severe sepsis or septic shock

Double-blind

Dexamethasone (0.20 mg/kg every 8 hr for 2 days) Treatments might have been repeated once after 4 hr if shock persisted and had to be initiated 5-10 min before first dose of antibiotic.

Placebo

Primary: hospital mortality (unclear) Secondary: hemodynamic stability at 48 hr; complications

Bollaert et al, 199886

Two parallel groups, 2 centers, 41 adults with vasopressor- and ventilator-dependent septic shock

Double-blind

Hydrocortisone (100 mg intravenous bolus every 8 hr for 5 days, then tapered over 6 days) Treatments had to be initiated after 48 hr or more from shock onset.

Placebo

Primary: shock reversal Secondary: 28-day mortality; improvement in hemodynamics; safety

Briegel et al, 199987

Two parallel groups, 1 center, 40 adults with vasopressor- and ventilator-dependent septic shock

Prospective randomized double-blind, singlecenter

Hydrocortisone (100 mg 30-min intravenous infusion followed by 0.18 mg/kg/hr continuous infusion until shock reversal and then tapered off) Treatments had to be initiated within 72 hr from shock onset.

Placebo

Primary: shock reversal Secondary: 28-day mortality; improvement in hemodynamics; organ system failure; safety

Chapter 73 Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit?

Bone et al, 198781

Continued

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Table 73-5

Summary of Randomized Controlled Trials on Steroid Use in Sepsis*—Cont’d Study Design

Intervention

Control

Outcomes

Chawla et al, 199988

Two parallel groups, 1 center, 44 adults with vasopressor-dependent septic shock

Double-blind

Hydrocortisone (100 mg intravenous bolus every 8 hr for 3 days, then tapered over 4 days) Treatments had to be initiated after 72 hr or more from shock onset.

Placebo

Primary: shock reversal Secondary: 28-day mortality; improvement in hemodynamics; safety

Annane et al, 200241

Two parallel groups, 19 centers, 300 adults with vasopressor- and ventilator-dependent septic shock

Double-blind

Hydrocortisone (50 mg intravenous bolus every 6 hr for 7 days þ fludrocortisone 50 g taken orally every 24 hr for 7 days) Treatments initiated within 8 hr from shock onset

Respective placebos

Primary: 28-day mortality in nonresponders Secondary: 28-day mortality in responders and all patients; intensive care unit mortality; hospital mortality; 1-year mortality; shock reversal; organ system failure-free days; safety

Yildiz et al, 200289

Two parallel groups, 1 center, 40 adults with sepsis (n ¼ 14), severe sepsis (n ¼ 17), and septic shock (n ¼ 9)

Double-blind

Prednisolone (2 intravenous bolus, 5 mg at 6 am and 2.5 mg at 8 pm for 10 days)

Placebo

Primary: 28-day mortality Secondary: complications

Keh et al, 200368

40 adults with vasopressor-dependent septic shock

Double- blind crossover design

Hydrocortisone (100 mg 30-min intravenous infusion followed by 10 mg/hr continuous infusion for 3 days) All patients received hydrocortisone for 3 days

Preceded or followed by placebo for 3 days

Primary: immune response Secondary: improvement in hemodynamics and organ system failure; safety

Oppert et al, 200590

Single-center study, 48 patients

Prospective randomized double-blind

Patients were randomized to receive low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg/hr)

Placebo

Time to cessation of vasopressor support (primary end point) Secondary end points were cytokine response, 28-day survival, and the Sequential Organ Failure Assessment (SOFA) score Continued

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No. of Subjects

Section IX

Study

6 centers, 46 patients

Randomized double-blind

Patients with clinical and radiographic evidence of pneumonia were randomly assigned in a 1:1 manner to receive hydrocortisone infusion (intravenous 200-mg loading bolus) followed by an infusion (hydrocortisone 240 mg in 500 mL 0.9% saline) at a rate of 10 mg/hr for 7 days)

Placebo

Primary end points: improvement in PaO2/ FiO2 and multiple-organ dysfunction syndrome, and development of delayed septic shock Secondary end points: duration of mechanical ventilation, length of intensive care and hospital stay, survival to hospital discharge and to 60 days

Sprung et al, 200843

52 intensive care units, 499 patients

Randomized double-blind

Patients received either 50 mg of intravenous hydrocortisone or placebo every 6 hr for 5 days; the dose was then tapered during a 6-day period.

Placebo

Primary outcome: 28-day mortality among patients who did not have a response to corticotropin test

*No meta-analyses available.

Chapter 73 Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit?

Confalonieri et al, 200591

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Table 73-6 Comparison between the French and CORTICUS Studies French Study (Annane et al, 200241)

CORTICUS Study (Sprung et al, 200843)

Entry window

8 hr

72 hr

SBP < 90 mm Hg

>1 hr

<1 hr

Additional prescription

Fludrocortisone

None

Treatment duration

7 days

11 days

Hydrocortisone weaning

No

Yes

1. For minor surgery, a dose of 25 mg hydrocortisone daily3 2. For moderate surgical stress, a dose of 50 to 75 mg hydrocortisone for 1 to 2 days3 3. For major procedures, 100 to 150 mg hydrocortisone for 2 to 3 days3 It has been recommended that doses be increased to maximal stress dose (300 mg/day) in patients who remain hypotensive or deteriorate during recovery from surgery.3 However, this recommendation is unsupported by data.

AUTHORS’ RECOMMENDATIONS

SAPS II

59  21

49  17

Nonresponders

76.6%

47%

Resistant infection

No

Increased

SAPS, Simplified Acute Physiology Score; SBP, systolic blood pressure.

procedure. These differences may have affected the severity of patients recruited to either study (see Table 73-6). The contrasting findings in these two large randomized controlled studies are reflected in recently published guidelines regarding the management of severe sepsis and septic shock.66 It is important to note that some of these recommendations are based on common practice with little evidence to support them. The Surviving Sepsis Campaign recommends the following: 1. Intravenous hydrocortisone is administered only for adult septic shock patients with blood pressure that is poorly responsive to fluid resuscitation and vasopressor therapy. Although corticosteroids promote reversal of shock, they fail to reduce sepsis-related mortality. 2. Corticosteroids should not be given to septic patients in the absence of shock. However, there is no contraindication to continuing steroid therapy if the patient’s history or endocrine status warrants. 3. Doses of corticosteroids for septic shock should be not higher than 300 mg per day. 4. In patients with septic shock, hydrocortisone is preferable to dexamethasone because it may lead to immediate and prolonged suppression of the HPA axis. 5. Fludrocortisone should be considered if hydrocortisone, which has some mineralocorticoid activity, is not available. 6. Weaning from steroid therapy occurs when vasopressors are no longer required. Tapering the dose is recommended because there may be an increase in proinflammatory mediators and hemodynamic deterioration after abrupt cessation of corticosteroids.43 Patients with inadequate adrenal reserve and those receiving chronic steroid therapy should receive sufficient steroid during severe stress or critical illness. Although not supported by data, the accepted practice is to provide glucocorticoid therapy based on type of surgery. Recommendations are as follows:

• The response of the HPA axis is altered by critical illness. This in part reflects the ability of cytokines to activate responses. • Despite disagreement regarding definitions and diagnosis, AI may develop during critical illness. • AI in critically ill patients is associated with poor outcome. • Randomized clinical trials are at odds regarding the use of corticosteroids in critically ill patients. The differences may reflect study design or the replacement regimen used. • Virtually all trials show that corticosteroid administration improves hemodynamics in critically ill patients. • The ACTH stimulation test gives inconsistent results and should not be the basis for starting corticosteroids. • In hemodynamically compromised patients who are not responsive to fluid or vasopressor and inotropic therapy, a trial of corticosteroids is warranted.

REFERENCES 1. Pacak K, Palkovits M. Stressor specificity of central neuroendocrine responses: Implications for stress-related disorders. Endocr Rev. 2001;22:502–548. 2. Tsigos C, Chrousos GP. Hypothalamic-pituitary adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53: 865–887. 3. Marik PE, Zaloga GP. Adrenal insufficiency in the critically ill: A new look at an older problem. Chest. 2002;122:1784–1796. 4. Jurney TH, Cockrell Jr JL, Lindberg JS, et al. Spectrum of serum cortisol response to ACTH in ICU patients: Correlation with degree of illness and mortality. Chest. 1987;92:292–295. 5. Habib KE, Gold PW, Chrousos GP. Neuroendocrinology of stress. Endocrinol Metab Clin. 2001;30:695–728. 6. Miller DB, O’Callaghan JP. Neuroendocrine aspects of the response to stress. Metabolism. 2002;51:S5–S10. 7. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo conformational change in inflammation. Nature. 1988;336:257–258. 8. Hammond GL, Smith CL, Paterson NAM, Sibbald WJ. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab. 1990;71:34–39. 9. Munck A, Naray-Fejes-Toth A. Glucocorticoids and stress: Permissive and suppressive actions. Ann N Y Acad Sci. 1994;746: 115–130. 10. Auphan N, Didonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: Inhibition of NF-kB activity through induction of IkB synthesis. Science. 1995;270:286–290. 11. Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885–909. 12. Orlowski J, Lingrel JB. Thyroid and glucocorticoid hormones regulate the expression of multiple Na,K-ATPase genes in cultured neonatal rat cardiac myocytes. J Biol Chem. 1990;265:3462–3470.

Chapter 73 Can Acute Adrenal Insufficiency Be Diagnosed in the Intensive Care Unit? 13. Sakaue M, Hoffman BB. Glucocorticoids induce transcription and expression of the a1B adrenergic receptor gene in DTT1 MF-2 smooth muscle cells. J Clin Invest. 1991;88:385–389. 14. Collins S, Caron MG, Lefkowitz RJ. b-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids. J Biol Chem. 1988;263:9067–9070. 15. Matsumura M, Kakishita H, Suzuki M, et al. Dexamethasone suppresses iNOS gene expression by inhibiting NF-kB in vascular smooth muscle cells. Life Sci. 2001;69:1067–1077. 16. Redington AE, Meng QH, Springall DR, et al. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax. 2001;56:351–357. 17. Fujii E, Yoshioka T, Ishida H, et al. Evaluation of iNOS dependent and independent mechanisms of the microvascular permeability change induced by lipopolysaccharide. Br J Pharmacol. 2000;130:90–94. 18. Catalano RD, Parameswaran V, Ramachandran J, et al. Mechanisms of adrenocortical depression during Escherichia coli shock. Arch Surg. 1984;119:145–150. 19. Keri G, Parameswaran V, Trunkey DD, et al. Effects of septic shock plasma on adrenocortical cell function. Life Sci. 1981;28:1917–1923. 20. Melby JC, Egdahl RH, Spink WW. Secretion and metabolism of cortisol after injection of endotoxin. J Lab Clin Med. 1960;56:50–62. 21. Jaattela M, Ilvesmaki V, Voutilainen R, et al. Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology. 1998;128:623–629. 22. Schroeder S, Wichers M, Klingmuller D, et al. The hypothalamicpituitary adrenal axis of patients with severe sepsis: Altered response to corticotropin-releasing hormone. Crit Care Med. 2001;29:310–316. 23. Natarajan R, Ploszay S, Horton R, et al. Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin II induced aldosterone synthesis. Endocrinology. 1989;125:3084–3089. 24. Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 1993;77:1690–1694. 25. Bateman A, Singh A, Kral T, et al. The immune-hypothalamicpituitary-adrenal axis. Endocr Rev. 1989;10:92–112. 26. Gaillard RC, Turnill D, Sappino P, et al. Tumor necrosis factor-a inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology. 1990;127:101–106. 27. Melby JC, Spink WW. Comparative studies on adrenal cortical function in healthy adults and in patients with shock due to infection. J Clin Invest. 1958;37:1791–1798. 28. Pariante CM, Pearce BD, Pisell TL, et al. The proinflammatory cytokine, interleukin-1a, reduces glucocorticoid receptor translocation and function. Endocrinology. 1999;140:4359–4366. 29. Melby JC, Spink WW. Comparative studies of adrenal cortisol function and cortisol metabolism in healthy adults and in patients with septic shock due to infection. J Clin Invest. 1958; 37:1791–1798. 30. Jaattela M, Carpen O, Stenman UH, et al. Regulation of ACTHinduced steroidogenesis in human fetal adrenals by rTNF-a. Mol Cell Endocrinol. 1990;68:R31–R36. 31. Zhu Q, Solomon S. Isolation and mode of action of rabbit corticostatic (antiadrenocorticotropin) peptides. Endocrinology. 1992; 130:1413–1423. 32. Naito Y, Fukata J, Tamai S, et al. Biphasic changes in hypothalamicpituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab. 1991; 73:111–117. 33. Goodman SI, Sprung CL, Ziegler D, Weiss YG. Cortisol changes among patients with septic shock and the relationship to ICU and hospital stay. Intensive Care Med. 2005;31:1362–1369. 34. Barton RN, Stoner HB, Watson SM. Relationship among plasma cortisol adrenocorticotropin and severity of injury in recently injured patients. J Trauma. 1987;27:384–392. 35. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000;283:1038–1045. 36. Aygen B, Inan M, Doganay M, Kelestimur F. Adrenal function in patients with sepsis. Exp Clin Endocrinol Diabetes. 1997;105: 182–186.

519

37. Jacobs HS, Nabarro JD. Plasma 11-hydroxycorticosteroid and growth hormone levels in acute medical illnesses. BMJ. 1969;2:595–598. 38. Barquist E, Kirton O. Adrenal insufficiency in the surgical intensive care unit patient. J Trauma. 1997;42:27–31. 39. Kidess AI, Caplan RH, Reynertson RH, et al. Transient corticotropin deficiency in critical illness. Mayo Clin Proc. 1993;68:435–441. 40. Bouachour G, Tirot P, Varache N, et al. Hemodynamic changes in acute adrenal insufficiency. Intensive Care Med. 1994;20:138–141. 41. Annane D, Se´bille V, Charpentier C, Bollaert P-E, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisones on mortality in patients with septic shock. JAMA. 2002;288:862–871. 42. Kidess AI, Caplan RH, Reynertson RH, et al. Transient corticotrophin deficiency in critical illness. Mayo Clin Proc. 1993;68:435–441. 43. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–124. 44. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med. 2003;31:141–145. 45. Briegel J, Scheelling G, Haller M, et al. A comparison of the adrenocortical response during septic shock and after complete recovery. Intensive Care Med. 1996;22:894–899. 46. Marik PE, Kiminyo K, Zaloga GP. Adrenal insufficiency in critically ill HIV infected patients. Crit Care Med. 2002;30:1267–1273. 47. Ali M, Allen HR, Vedeckis WV, et al. Depletion of rat liver glucocorticoid receptor hormone-binding and its mRNA in sepsis. Life Sci. 1991;48:603–611. 48. Molijn GJ, Koper JW, van Uffelen CJ, et al. Temperature induced down-regulation of the glucocorticoid receptor in peripheral blood mononuclear leukocytes in patients with sepsis and septic shock. Clin Endocrinol. 1995;43:197–203. 49. Norbiato G, Bevilacqua M, Vago T, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74:608–613. 50. Malerba G, Romano-Girard F, Cravoisy A, et al. Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med. 2005;31:388–392. 51. Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med. 1994;154:949–973. 52. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996; 335: 1206–1212. 53. Sibbald WJ, Short A, Cohen MP, et al. Variations in adrenocortical responsiveness during severe bacterial infections: Unrecognized adrenocortical insufficiency in severe bacterial infections. Ann Surg. 1977;186:29–33. 54. Dennhardt R, Gramm HJ, Meinhold K, et al. Patterns of endocrine secretion during sepsis. Prog Clin Biol Res. 1989;308:751–756. 55. Jurney TH, Cockrell Jr JL, Lindberg JS, et al. Spectrum of serum cortisol response to ACTH in ICU patients: Correlation with degree of illness and mortality. Chest. 1987;92:292–295. 56. Bernard F, Outtrim J, Menon DK, Matta BF. Incidence of adrenal insufficiency after severe traumatic brain injury varies according to definition used: Clinical implications. Br J Anaesth. 2006; 96:72–76. 57. Finlay WEI, McKee JI. Serum cortisol levels in severely stressed patients. Lancet. 1982;1:1414–1415. 58. Sam S, Corbridge TC, Mokhlesi B, et al. Cortisol levels and mortality in severe sepsis. Clin Endocrinol. 2004;60:29–35. 59. Vogeser M, Felbinger TW, Kilger E, et al. Corticosteroid-binding globulin and free cortisol in the early postoperative period after cardiac surgery. Clin Biochem. 1999;32:213–216. 60. Lewis JG, Bagley CJ, Elder PA, et al. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin Chim Acta. 2005;359:189–194. 61. Ho JT, Al-Musalhi H, Chapman MJ, et al. Septic shock and sepsis: A comparison of total and free plasma cortisol levels. J Clin Endocrinol Metab. 2006;91:105–114. 62. Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med. 1971;128:761–763. 63. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotrophin and survival in septic shock. Lancet. 1991;337:582–583. 64. Clark PM, Neylon I, Raggatt PR, et al. Defining the normal cortisol response to the short Synacthen test: Implications for the investigation of hypothalamic-pituitary disorders. Clin Endocrinol. 1998;49:287–292.

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ENDOCRINE CRITICAL CARE

65. Dorin RI, Kearns PJ. High output circulatory failure in acute adrenal insufficiency. Crit Care Med. 1988;16:296–297. 66. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2008. Intensive Care Med. 2008;34:17–60. 67. Oppert M, Reinicke A, Graf KJ, et al. Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock. Intensive Care Med. 2000;26:1747–1755. 68. Keh D, Boehnke T, Weber-Carstens S, et al. Immunologic and hemodynamic effects of “low dose” hydrocortisone in septic shock: A double-blind, randomized placebo controlled cross over study. Am J Respir Crit Care Med. 2003;167:512–520. 69. Lefering R, Neugebauer EAM. Steroid controversy in sepsis and septic shock: A meta-analysis. Crit Care Med. 1995;23:1294–1303. 70. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23:1430–1439. 71. Minneci PC, Deans KJ, Banks SM, et al. Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141:47–56. 72. Keh D, Sprung C. Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review. Crit Care Med. 2004;32(suppl):S527–S533. 73. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for severe sepsis and septic shock: A systematic review and metaanalysis. BMJ. 2004;329:480–489. 74. Wagner HN, Bennett IL, Lasagna L, et al. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp. 1955;98:197–215. 75. Cooperative Study Group. The effectiveness of hydrocortisone in the management of severe infections. JAMA. 1963;183:462–465. 76. Bennett IL, Finland M, Hamburger M, et al. The effectiveness of hydrocortisone in the management of severe infection. JAMA. 1963;183:462–465. 77. Klastersky J, Cappel R, Debusscher L. Effectiveness of betamethasone in management of severe infections: A double-blind study. N Engl J Med. 1971;284:1248–1250. 78. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976;184:333–341.

79. Thompson WL, Gurley HT, Lutz BA, et al. Inefficacy of glucocorticoids in shock (double-blind study). Clin Res. 1976;24:258A. 80. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock: A prospective, controlled study. N Engl J Med. 1984;311:1137–1143. 81. Bone RG, Fisher CJ, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653–658. 82. Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987;317:659–665. 83. Lucas C, Ledgerwood A. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Arch Surg. 1984;119:537–541. 84. Luce JM, Montgomery AB, Marks JD, et al. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis. 1988;138:62–68. 85. Slusher T, Gbadero D, Howard C, et al. Randomized, placebocontrolled, double blinded trial of dexamethasone in African children with sepsis. Pediatr Infect Dis J. 1996;15:579–583. 86. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645–650. 87. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27: 723–732. 88. Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory septic shock. Crit Care Med. 1999;27:A33. 89. Yildiz O, Doganay M, Aygen B, et al. Physiologic-dose steroid therapy in sepsis. Crit Care. 2002;6:251–259. 90. Oppert M, Schindler R, Husung C, et al. Low dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med. 2005;33:2457–2464. 91. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: A preliminary randomized study. Am J Respir Crit Care Med. 2005; 171:242–248.