Adrenal insufficiency

Study objectives: To examine the incidence and response to treatment of adrenal insufficiency (AI) in high-risk postoperative patients.

Design: Prospective observational case series.

Setting: Large urban tertiary-care surgical ICU (SICU).

Participants: Adults [is greater than] 55 years of age who required vasopressor therapy after adequate volume resuscitation in the immediate postoperative period.

Interventions: Each patient underwent a cosyntropin (ACTH) stimulation test; at the discretion of the clinical team, some patients were empirically given hydrocortisone (100 mg IV q8h for three doses) before serum cortisol values became available.

Measurements: Adrenal dysfunction (AD), defined as serum cortisol [is less than] 20 [micro]g/dL at all time points, with [Delta]cortisol (60 min post-ACTH minus baseline) of [is less than or equal to] 9 [micro]g/dL; functional hypoadrenalism (FH), defined as serum cortisol [is less than] 30 [micro]g/dL at all time points or [Delta]cortisol (60 min post-ACTH minus baseline) [is less than or equal to] 9 [micro]g/dL; and AI, as the presence of either AD or FH.

Results: One hundred four patients were enrolled with a mean age (SD) of 65.2 [+ or -] 16.9 years. AI (AD plus FH) was found in 34 of 104 patients (32.7%): AD was found in 9 patients (8.7%), FH in 25 patients (24%), and normal adrenal function in 70 patients (67.3%). The absolute eosinophil count was significantly higher in the combined AD and FH groups compared with the group with normal adrenal function (p [is less than] 0.05). Forty-six of 104 patients (44.2%) received hydrocortisone; 29 (63%) could be weaned from treatment with vasopressors within 24 h. This beneficial effect of hydrocortisone reached statistical significance in the FH group when compared with untreated patients (p [is less than] 0.031); a similar trend was seen in the AD group (p = 0.083). Mortality was also lower in the hydrocortisone-treated AI patients (5 of 23 [21%] vs 5 of 11 [45%] in those not receiving hydrocortisone; p [is less than] 0.01).

Conclusion: There is a high incidence of AI among SICU patients [is greater than] 55 years of age with postoperative hypotension requiring vasopressors. There is also a significant association between hydrocortisone replacement therapy, resolution of vasopressor requirements, and improved survival.

(CHEST 2001; 119:889-896)

Key words: adrenal disorders; adrenal dysfunction; adrenal gland; adrenal insufficiency; critically ill; eosinophilia; functional hypoadrenalism: postoperative period: sepsis; septic shock; surgical patient; systemic inflammatory response syndrome

Abbreviations: ACTH = corticotropin; AD = adrenal dysfunction; AI = adrenal insufficiency; FH = functional hypoadrenalism; SICU = surgical ICU

Adrenal insufficiency (AI) is overall rare, with an incidence of [is less than] 0.01% in the general population.[1] However, up to 28% of seriously ill patients are often found to have occult or unrecognized AI.[2-4] It has been hypothesized that the postoperative surgical phase represents a significant risk factor for AI. This is thought to result from marked stimulation of the neurohumoral hypothalamic-pituitary-adrenal axis, which may fail to respond to the combination of underlying disease, surgical procedure, and postoperative homeostatic adaptation.

In the setting of critical illness, the failure of an appropriate neurohumoral response with insufficient cortisol release can lead to the clinical picture of vasopressor-dependent refractory hypotension. This is characterized by elevated cardiac output and decreased systemic vascular resistance.[3-5] An additional risk factor for AI in the surgical ICU (SICU) is represented by age, inasmuch as the incidence among patients [is greater than] 55 years old is 2.5 times that of their younger counterpart.[6]

It is possible that the outcome of postoperative patients could be improved if the effect of a single factor, namely AI, were isolated for evaluation. To that end, this study examined the incidence and outcome of diagnosis and treatment of AI in a high-risk population of postoperative vasopressor-dependent patients with age [is greater than] 55 years.

MATERIALS AND METHODS

Study Design

This study was approved by the Henry Ford Health Systems Institutional Review Board for Human Research. This was a prospective, nonoutcome, observational convenieuce case study of adult patients in a large, urban, tertiary-care SICU during a 2-year period (from 1995 to 1997).

Patient Selection

Consecutive postoperative patients [is greater than] 55 years of age who experienced hypotension requiring vasopressor therapy after adequate volume resuscitation within 24 h of SICU admission were enrolled in this study. All patients initially underwent a fluid challenge that consisted of a 500-mL bolus infusion of crystalloid solution given IV for 5 min. Cardiac output and pulmonary capillary, wedge pressure were measured before and at 5 min and 10 min after fluid challenge. A rise in cardiac output of [is greater than] 20% was taken to indicate hypovolemia, a fall [is greater than] 20% indicated hypervolemia, and changes of [is less than] 20% indicated euvolemia. Patients were considered vasopressor dependent if these agents were required to maintain the mean arterial pressure at levels [is greater than] 65 to 70 mm Hg. The vasopressor agents and corresponding dose ranges were norepinephrine (3 to 40 [micro]g/min), phenylephrine (30 to 300 [micro]g/min), epinephrine (2 to 100 [micro]g/min), or dopamine (6 to 30 [micro]g/kg/min). Criteria for exclusion from the study were HIV infection, known preexisting adrenal disease or adrenalectomy, administration of etomidate, administration of steroids during surgery, or administration of steroids within the 3 months previous to admission.[7,8]

Study Protocol

A corticotropin (ACTH or cosyntropin) stimulation test (Cortrosyn; Organon Pharmaceuticals; West Orange, NJ) was performed in all patients.[9,10] Immediately after collection of baseline serum cortisol, ACTH, 0.25 mg, was administered as an IV bolus for 2 min. Blood for serum cortisol determination was obtained again at 30 and 60 min after ACTH injection. Blood was collected in sterile siliconized glass tubes containing ethylenediaminetetra-acetic acid and sent to the immunoassay ligand laboratory for processing. Sera were separated and frozen at -20 [degrees] C until assayed. Cortisol was determined with a commercially available chemiluminescent immunoassay kit (Access Immunoassay System; Sanofi Diagnostics Pasteur, Inc; Chaska, MN). In normal subjects, serum cortisol concentrations range from 5 to 20 [micro]g/dL (138 to 552 nmol/L), being higher at 7 AM to 9 AM. The response to ACTH stimulation in nonstressed healthy subjects is an increase of [is greater than or equal to] 50% in serum cortisol concentration or a rise of [is greater than or equal to] 9 [micro]g/dL by 60 min after ACTH injection. Patients were treated at the discretion of the clinical management team before cortisol measurements were available with hydrocortisone (100 mg IV q8h for three doses) administered immediately after the ACTH test.

Outcome Measurements

In critically ill patients, adrenal dysfunction (AD) has been defined as the presence of random serum cortisol [is less than] 20 [micro]g/dL ([is less than] 552 mnol/L).[4,6,9-13] An additional category, functional hypo-adrenalism (FH) has been defined as the combination of random serum cortisol [is greater than or equal to] 20 [micro]g/dL, and a serum cortisol level at 60 min after ACTH stimulation of [is less than] 30 [micro]g/dL or [Delta]cortisol (60-min concentration minus baseline) of [is less than or equal to] 9 [micro]g/dL.[14-19] In the present investigation, AD was defined as the finding of serum cortisol [is less than] 20 [micro]g/dL in any of the blood samples (before and after ACTH) plus a [Delta]cortisol after ACTH of [is less than or equal to] 9 [micro]g/dL. FH was defined by a cortisol level [is less than] 30 [micro]g/dL in any of the blood samples (before and after ACTH) or [Delta]cortisol [is less than or equal to] 9 [micro]g/dL. AI was defined as the presence of either AD or FH. A positive hemodynamic response was defined as cessation of the need for vasopressor therapy to maintain a mean arterial pressure [is greater than] 65 to 70 mm Hg within 24 h of the first hydrocortisone dose or within 24 h of the ACTH stimulation test in patients not treated with hydrocortisone.

Statistical Methods

Continuous variables were compared using a Student's two-sample t test unless variances were unequal; in the latter case, Welch's two-sample t test was used. Categorical variables were analyzed with the [chi square] test. Cell counts were compared with the Fisher's Exact Test. Analysis of variance was performed with Tukey's method of multiple comparisons. The Kruskal-Wallis test and the Wilcoxon nonparametric test were used to identify differences in the ranks of data among the three groups studied. Statistical significance was defined as a p [is less than] 0.05 and an [Alpha] of 0.017. All results are presented as the mean [+ or -] SD.

RESULTS

A total of 104 patients were enrolled in the study; the mean age was 65.2 [+ or -] 16.9 years, and surgical diagnoses are listed in Table 1. Adrenal function was abnormal in 34 of 104 of all patients (30.7%); 9 patients (8.7%) had AD and 25 (24%) had FH (Table 2). All patients enrolled fulfilled criteria for the systemic inflammatory response syndrome and were classified as having severe sepsis or septic shock.[20] Seventy patients (67.3%) exhibited normal baseline serum cortisol ([is greater than] 20 [micro]g/dL) and response to the ACTH stimulation test. There were no significant differences between groups for any of the following variables: age, sex, temperature, heart rate, BP, central venous pressure, pulmonary capillary wedge pressure, and cardiac index (Table 3). The amount of fluid given before the administration of vasopressor therapy was similar in all groups.

[TABULAR DATA 2-3 NOT REPRODUCIBLE IN ASCII]

Laboratory data also showed lack of significant differences among groups in sodium, potassium, chloride, glucose, calcium, magnesium, and phosphorous (Table 4). Leukocytosis with a left shift (increased bands) was represented equally in all groups, and the number of lymphocytes did not differ among groups. However, the number of eosinophils, relative and absolute, was significantly higher in the AD and FH groups compared with normal ACTH responders (Table 4).

[TABULAR DATA 4 NOT REPRODUCIBLE IN ASCII]

Forty-six of 104 patients (44.9.%) received hydrocortisone at a dose representing physiologic replacement in this setting. Twenty-nine of the treated patients (63%) could be weaned off of vasopressor therapy within 24 h of the first hydrocortisone dose. Comparison of the effect of hydrocortisone within each group shows that in the FH group, hydrocortisone therapy was associated with significantly higher rate of success in the withdrawal of vasopressor therapy (p [is less than] 0.031; Table 5). A similar trend was noted in the AD group, but because of the small number of patients, the difference did not reach statistical significance (p = 0.083; Table 5). Of note, among the hydrocortisone-treated, normal ACTH responders, those who could be weaned from vasopressor therapy within 24 h had significantly lower baseline serum cortisol levels as compared with those who continued requiring vasopressor agents (p [is less than] 0.001; Table 6), although the post-ACTH 30-min and 60-min serum cortisol levels were similar (Table 6).

Table 5--Response to Vasopressor Therapy Withdrawal in Hypotensive SICU Patients(*)

(*) Values are expressed as No./total (%) unless otherwise indicated; a positive response indicates not vasopressor dependent within 24 h. Received hydrocortisone (HC), 100 mg IV bolus q8h for three doses.

Table 6--Serum Cortisol Concentrations in Hydrocortisone-Treated SICU Patients With a Normal Response to ACTH

(*) Significant difference (p < 0.01)

Overall mortality in the entire patient population was 40% (42 of 104 patients). Among the patients with AI, the mortality rate was 29% (10 of 34). Mortality was significantly lower in the hydrocortisone-treated group, 5 of 23 patients (21%), than in the untreated group, 5 of 11 patients (45%; p [is less than] 0.01).

DISCUSSION

Cortisol is a major stress response hormone that has metabolic, catabolic, anti-inflammatory, and vasoactive properties on cardiac muscle and the peripheral vasculature. Thus, cortisol mediates maintenance of peripheral vasomotor tone by facilitating catecholamine-induced vasoconstriction and has a permissive effect on the synthesis of catecholamines and vasoactive peptides.[21,22] Cortisol also has inotropic effects and modulates free water distribution within the vascular compartment.[5] In response to external or internal stress, the neuronally stimulated release of corticotropin-releasing factor from the hypothalamus induces an increase in ACTH secretion by the anterior pituitary gland, overriding the normal diurnal pattern of ACTH and cortisol secretion. The adrenal cortex responds to ACTH by increasing cortisol secretion, but prolonged elevation of serum cortisol triggers a negative feedback inhibition loop that results in subsequent decreases in ACTH and cortisol release.[23] Previous studies have defined criteria for normal adrenal function at rest, as well as in the stressed state, allowing the identification of patients at risk for the development of adrenal crisis.[24,25] When conducted on ambulatory healthy subjects, such studies have concluded that a normal response is an ACTH-stimulated serum cortisol level [is greater than or equal to] 20 [micro]g/dL.[14,24,26,27] Patients with normal hypothalamic-pituitary-adrenal axis function are found to consistently have elevated circulating cortisol concentrations during periods of stress or serious illness.[28-31] Total serum cortisol is increased, from 2 to 10 times the upper limit of normal, and there is a loss of diurnal variation.[32-65] The failure to reach these levels in the stressed state has lead to the diagnosis of AI.

In 1855 Thomas Addison first described a syndrome of "languor, debility and remarkable feebleness of the heart" caused by "failure of the suprarenal glands" that is now recognized as AI.[36] It can be either primary (failure of adrenal gland) or secondary (failure of hypothalamic or pituitary stimulation of the adrenal gland) and is defined as a relative or absolute deficiency in glucocorticoid and mineralocorticoid availability.[7,37,38] The classic signs and symptoms of AI are hypotension, hyponatremia, hyperkalemia, hypercalcemia, hypoglycemia, metabolic acidosis, and eosinophilia.[30] Such classic findings were not a distinguishing feature in this study, perhaps because of the combination of underlying disease and prior therapeutic intervention that obscured the clinical picture. However, although the clinical diagnosis of AI could not be entertained in this population, the study did, nevertheless, confirm previous findings of eosinophilia as a marker of AI.[39,40]

The incidence of AI is low in the general population ([is less than] 0.01%),[1,41,42] but as occult or unrecognized AI it has higher prevalence among seriously ill patients (0.1 to 28%).[2-4,13,28] Because of the wide range of prevalence in the latter population, routine screening of all ICU patients becomes impractical.[34,43] Nevertheless, selected groups, such as post-operative surgical patients, may be at significantly higher risk for AI because of the combined burden represented by the initial pathologic insult, surgical procedure, and course in the postoperative ICU. Age has been shown to be an additional risk factor for AI, inasmuch as patients [is greater than] 55 years old have a threefold increase in the risk for AI in the SICU compared with younger patients.[6,44] Moreover, the clinical picture of vasopressor-dependent refractory hypotension with elevated cardiac output and decreased systemic vascular resistance that is frequently observed in the SICU has also been reported in AI.[3,5] Thus, the risk factors for the postoperative period of advanced age and persistent hypotension after adequate volume resuscitation, provide the rationale for defining the patients included in this study as being at high risk for development of AD.

The pathogenesis of AI in the high-risk patient is complex, and concepts on this area continue to evolve. In the absence of ACTH levels to confirm the diagnosis, the inability of the AD group to increase cortisol levels after ACTH suggests primary adrenal insufficiency. Likewise, the partial response in the FH group suggests secondary AI. Regarding the patients who had a normal response to ACTH and who received hydrocortisone with positive hemodynamic response, the initial baseline cortisol levels were actually low for a stressed state. The ability of patients in this latter group to increase relatively low baseline concentrations (20 [+ or-] 4 [micro]g/dL) to levels consistent with a normal response to ACTH also supports a secondary adrenal disorder.

This syndrome of "transient ACTH deficiency in critical illness or secondary AI" has been previously described.[2,3] Patients in that category exhibit responses to ACTH that are remarkably similar to those of the current study patients, with similar restoration of hemodynamic stability after replacement therapy with hydrocortisone.[2,3] The mechanism for the production of this postoperative disorder is complex. The systemic inflammatory response syndrome, which frequently accompanies the postoperative course, results in the release of cytokines such as tumor necrosis factor-[Alpha],[45] which in vitro suppresses the pituitary response to the hypothalamic corticotropin-releasing hormone[46] and the release of cortisol from ACTH-stimulated adrenal cells.[47,48] Because the systemic inflammatory response is frequently transient in the postsurgical phase,[49] it would explain at least partly the temporary nature of the adrenal disorders in this patient population.[2,44]

Interestingly, 10 of 23 empirically treated patients with a normal baseline cortisol and ACTH test showed a positive hemodynamic response. The mechanism for this beneficial therapeutic response is unclear, but could represent a masked form of AI from diagnostic limitations. The total measured plasma cortisol represents the sum of cortisol bound to cortisol-binding globulin and albumin, and free cortisol. It is the latter fraction that is physiologically active, and free cortisol levels are significantly affected by changes in cortisol-binding globulin and albumin. The concentration of these proteins could fluctuate as a result of endogenous and exogenous hormones, organ dysfunction (such as liver disease), or changes in the volume of distribution secondary to fluid resuscitation. These alterations, which frequently accompany the postoperative surgical phase, would explain, at least partly, why some patients may respond to cortisol replacement in spite of having appropriate total cortisol levels.[5] In addition, a deranged interaction between catecholamines, adrenergic receptors, and corticosteroids would lead to adrenergic hyporesponsiveness. This desensitization or down-regulation of [Alpha]- and [Beta]-adrenergic receptors may result in vascular hyporesponsiveness and myocardial depression,[50,51] at appropriate total cortisol levels. Such conditions would reverse with physiologic doses of hydrocortisone.[52,53]

There are few outcome studies regarding the effect of glucocorticoid replacement therapy in patients with AI in this setting, although it is known that the disorder may have life-threatening consequences.[38] In the present study, the overall mortality rate of abnormal responders was significantly lower among those receiving hydrocortisone (21%) than in untreated patients (45%). A number of case series studies have described hemodynamic improvement after cortisol replacement therapy that followed diagnosis of AI.[3,11,28,54] Bollaert et al[55] showed reversal of severe late septic shock (improved hemodynamics) and a beneficial effect on mortality with hydrocortisone therapy. As confirmed in this study, an important therapeutic benefit of early diagnosis and treatment is the potential to decrease the need for administering high doses of vasopressor therapy with its possible negative consequences.[56]

Limitations

The present study provides evidence for the existence of glucocorticoid-responsive shock states in the severely ill ICU patient, and it also confirms that the standard criteria for abnormal adrenal response may not be appropriate in this population; however, questions still remain unanswered. The first, and most clinically relevant, is whether diagnosis and treatment of these disorders has an effect on mortality. Although mortality was not a primary outcome of this study, post hoc analysis of mortality data suggests survival benefit in diagnosing and treating this disorder. That impression notwithstanding, it must be stated again that this study was not designed with mortality as a primary outcome, and this post hoc analysis reflects only crude mortality data with no determination of attributable causes. Future studies are needed to determine survival benefits of treatment. Secondly, as plasma ACTH levels were not obtained, we cannot clearly delineate whether our findings represent a primary or secondary AI.

CONCLUSION

Although the incidence of AI is higher than normal in critically ill patients, the incidence in surgical ICU patients is even higher when restricting the evaluation to patients with the risk factors of age [is greater than] 55 years and postoperative hypotension requiring vasopressors after adequate volume resuscitation. In that setting, the laboratory examination and hemodynamic profile do not assist in the diagnosis of AI, except for the presence of eosinophilia. Administration of hydrocortisone replacement therapy in those patients is significantly associated with resolution of vasopressor dependency within 24 h; hydrocortisone treatment was also associated with a trend toward improved survival among patients with AI.

ACKNOWLEDGMENT: The authors thank Julie Massura, MS, and Gary Chase, PhD, for their biostatistical expertise and Alexandna Muzzin and Julie Ressler for their contributions to the article.

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(*) From the Departments of Surgery (Drs. Rivers, Gaspari, and Horst) and Pharmacy (Dr. Mlynarek), Henry Ford Hospital, Case Western Reserve University, Detroit, MI; Wayne State University (Dr. Fath), Grace Hospital, Detroit, MI; Department of Medicine (Dr. Wortsman), Southern Illinois University, Springfield, IL; and American University of Beirut (Dr. Saad), Beirut, Lebanon.

Manuscript received July 1, 1999; revision accepted August 14, 2000.

Correspondence to: Emanuel P. Rivers, MD, MPH, FCCP, Henry Ford Hospital, Department of Surgery, 2799 W. Grand Blvd, Detroit, MI 48202; e-mail: erivers1@hfhs.org

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