Adrenal Reserve Research Articles

Association between Adrenal Insufficiency and Ventilator Weaning

Adrenal insufficiency is a common disorder in critically ill patients with mechanical ventilation and is usually associated with higher mortality and poor clinical outcome. To determine whether stress dose corticosteroid supplementation can improve ventilator weaning and clinical outcome in patients with adrenal insufficiency. A prospective, randomized, placebo controlled, double-blinded study was conducted in the intensive care unit of a tertiary teaching hospital. A total of 93 mechanically ventilated patients were enrolled in the ventilator weaning trial. Adrenal function was assessed in all patients. Patients with adrenal insufficiency were randomized to the treatment group (50 mg intravenous hydrocortisone every 6 h) and the placebo group. The successful ventilator weaning percentage was significantly higher in the adequate adrenal reserve group (88.4%) and in the stress dose hydrocortisone treatment group (91.4%) than in the placebo group (68.6%). The weaning period was shorter in the hydrocortisone treatment group than in the placebo group. No significant adverse effects were observed in the corticosteroid treatment group. For patients with respiratory failure, early identification of adrenal insufficiency and appropriate supplementation with stress dose hydrocortisone increase the success of ventilator weaning and shortens the weaning period.

Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock*

To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock. Prospective, randomized, double-blind, single-center study. Medical intensive care unit of a university hospital. Forty-one consecutive patients with early hyperdynamic septic shock. After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score. Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p < .02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group. Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.

Relative adrenal insufficiency in patients with septic shock: Comparison of low-dose and conventional corticotropin tests*

To compare a low-dose (1 microg) corticotropin stimulation test with the more standard (250 microg) test for the diagnosis of relative adrenal insufficiency. Diagnostic study. Thirty-one-bed mixed medico-surgical department of intensive care. Forty-six consecutive patients with septic shock. Corticotropin stimulation tests (low-dose test, 1 microg, and standard 250-microg test), performed consecutively at an interval >4 hrs. In each test, serum cortisol levels were measured before (T0) and 30 (T30), 60 (T60), and 90 (T90) mins after corticotropin injection. The maximal increase in cortisol (Deltamax) was calculated as the difference between T0 and the highest cortisol value at T30, T60, or T90 and considered as adequate if >9 microg/dL (250 nmol/L). Nonresponders to the low-dose test had a lower survival rate than responders to both tests (27 vs. 47%, p = .06; Kaplan Meier curves). Interestingly, nonresponders to high-dose test received hydrocortisone treatment and had a similar survival to responders. Multivariable logistic regression disclosed that the response to the combined low-dose test and high-dose test was an independent predictor of survival (odds ratio 28.91, 95% confidence interval 1.81-462.70, p = .017), whereas basal or maximal cortisol levels in both tests were not. The low-dose test identified a subgroup of patients in septic shock with inadequate adrenal reserve who had a worse outcome and would have been missed by the high-dose test. These patients may also benefit from glucocorticoid replacement therapy.

Adrenal Angiotensin: Origin and Site of Generation

Circulating angiotensin (Ang) II accumulates in adrenal tissue via binding to Ang II type 1 (AT1) receptors, reaching levels that are 15 to 20 times higher than in blood. Adrenal tissue contains a second renin transcript that gives rise to a truncated prorenin representing a cytosolic form of renin. Here we investigated what percentage of adrenal Ang II originates at adrenal tissue sites, and whether intracellular renin contributes to adrenal angiotensin production. Concentrations of endogenous and iodine-125 (125I)-labeled Ang I and II were measured in adrenal tissue and blood from pigs after 125I-Ang I infusion. In the adrenal tissue in all animals, 125I-Ang I was undetectable. In untreated pigs, adrenal 125I-Ang II was 17 +/- 1 times arterial 125I-Ang II, and tissue Ang I and II were 5 +/- 1 and 388 +/- 40 times higher than plasma Ang I and II. The AT1 receptor antagonist eprosartan reduced adrenal 125I-Ang II accumulation by 80%, and increased plasma Ang II to a greater degree than tissue Ang II. As a consequence, eprosartan equally reduced the tissue/plasma concentration ratios of both Ang II and 125I-Ang II. Captopril did not alter 125I-Ang II accumulation, and acutely, but not chronically, reduced the adrenal Ang II/I ratio. More than 90% of adrenal Ang II originates at adrenal tissue sites. Local adrenal Ang II generation occurs extracellularly and is followed by internalization via AT1 receptor-mediated endocytosis. Enhanced angiotensin generation, combined with incomplete AT1 receptor blockade and the large adrenal AT1 receptor reserve, explains why eprosartan increased rather than decreased adrenal Ang II. Our data do not support angiotensin generation by truncated prorenin.

Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic–pituitary–adrenal axis

Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary-adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 mug of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1alpha stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1alpha administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.

Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening

Plasma assay for very long-chain fatty acids has made it possible to perform large-scale screening of at-risk individuals to identify asymptomatic patients with X-linked adrenoleukodystrophy (X-ALD). We evaluated the burden of undiagnosed adrenal insufficiency in 49 such patients (age, 4.5 +/- 3.5 years). Serum adrenocorticotropic hormone (ACTH) and standard-dose ACTH stimulation test were performed at the baseline and followed prospectively until initiation of adrenal replacement therapy (follow-up, 2 +/- 1.7 years). At baseline, 39 (80%) patients had impaired adrenal function, serum ACTH levels were elevated in 34 (69%) patients, and ACTH stimulation test was abnormal in 21(43%) patients. There was a moderate association between Serum ACTH and age at baseline, ( r = 0.32, P = .05). By the end of follow-up, 86% of patients had borderline or overt adrenal insufficiency (age of onset, 4.8 +/- 3.7 years). We detected a high prevalence of unrecognized adrenocortical insufficiency in asymptomatic boys with X-ALD. It is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early identification of impaired adrenal reserve, and timely initiation of therapy. It manifests early and before onset of neurologic symptoms, suggesting X-ALD as a candidate disorder for neonatal screening.

Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation.

The postresuscitation phase after out-of-hospital circulatory arrest shares similarities with severe sepsis. Corticosteroid replacement is beneficial in patients with septic shock and adrenal dysfunction. The goal of this study was to assess baseline cortisol and adrenal reserve of out-of-hospital circulatory arrest patients after recovery of spontaneous circulation. Thirty-three consecutive patients successfully resuscitated after cardiac arrest were prospectively included between March 2002 and June 2003. A serum cortisol assay and a corticotropin test (250 microg i.v.) were done 6 to 36 h after circulatory arrest. A cortisol increase smaller than 9 microg/dL after corticotropin (nonresponders) defined adrenal reserve insufficiency. Response status was compared in the three outcome groups: survival with full neurologic recovery (n = 4), early death from refractory shock (n = 10), or later death from neurologic dysfunction (n = 19). Patients who died of early refractory shock had lower baseline cortisol levels than patients who died of neurologic dysfunction (27 microg/dL [15-47] vs. 52 microg/dL [28-73], respectively; P < 0.01), suggesting an inadequate adrenal response to severe systemic inflammation. Corticotropin response status was not associated with standard severity markers and seemed uninfluenced by therapeutic hypothermia. In conclusion, patients who die of early refractory shock after cardiopulmonary resuscitation may have an inadequate adrenal response to the stress associated with this condition. Thresholds for cortisol levels at baseline and after corticotropin need to be determined in this clinical setting.

The effect of a steroid “burst” and long-term, inhaled fluticasone propionate on adrenal reserve

Although widely used, the effects of steroid "bursts" on the hypothalamic-pituitary-adrenal axis, especially with long-term, concomitant topical steroids use, have not been studied. To examine the effect of a prednisone burst, long-term intranasal steroids, and inhaled fluticasone propionate on the suppression and recovery of adrenal function. Adult patients taking long-term intranasal steroids, either moderate-dose (440 microg/d) or high-dose (880 microg/d) inhaled fluticasone propionate, underwent a low-dose cosyntropin stimulation test (LDCST) before and 2 days after a prednisone burst. Suppressed adrenal responses were monitored with a weekly LDCST. Persistent abnormal LDCST results were confirmed by 8-hour cosyntropin infusion. Inhaled fluticasone dosages were decreased; adrenal recovery was evaluated by a monthly LDCST. Adverse effects of steroids were monitored by questionnaires. Sixty-three patients participated in the study. Three of 31 patients not taking inhaled steroids and 1 of 13 patients taking moderate-dose fluticasone had abnormal LDCST results on day 2 after the prednisone burst, which normalized by the second week. In the high-dose fluticasone group, 14 of 19 patients had suppressed LDCST responses on day 2 and adrenal function recovered in 10 of 19 patients by the fourth week. These patients complained significantly of decreased libido (P = 0.02), listlessness (P = 0.03), and weight loss (P = 0.05). High-dose fluticasone (r = 0.66, P < 0.001) and duration of use (r = 0.32, P = 0.01) were statistically correlated with adrenal impairment. Of the 4 patients with persistent adrenal impairment, 3 patients successfully reduced dosages of inhaled fluticasone and adrenal function recovered in 2 to 10 months. Prednisone bursts induce brief adrenal impairment. Intranasal steroids and moderate-dose fluticasone had no effect on adrenal function. High-dose, inhaled fluticasone caused mild-to-significant adrenal suppression and delayed the recovery after a steroid burst. Avoiding or limiting the duration of high-dose inhaled steroids would minimize systemic adverse effects.

Adrenal cortex function in asthmatic patients following the discontinuation of chronic therapy with systemic glucocorticosteroids.

To estimate the time it takes for adrenal cortex function in asthmatic patients to return to normal after discontinuation of chronic therapy with systemic glucocorticosteroids (GCs) and to assess the relationship between the duration of the disease, chronic therapy, and the return of the normal adrenal cortex functioning. The study involved 58 asthmatic patients and 31 healthy volunteers (aged 20-69 years). Adrenal cortex function was evaluated with the Synacthen short test, and determining serum and urinary free cortisol levels after 1, 3, 6, 12, 18, and 21 months following the discontinuation of systemic therapy with GCs. A decreased adrenal reserve was observed 1 month after withdrawal of GCs in 50% of the chronically treated patients. Adrenal cortex function returned to normal in 55% of patients within 6 months, in 24% within 12 months, and in 14% within 15 months of discontinuation of systemic GCs administration. A significant positive correlation between the time taken for return to normal adrenal cortex function and duration of the disease and of GCs therapy was found. Symptoms of adrenal failure may develop in about 50% of asthmatic patients. In the majority of patients treated long term with systemic GCs, adrenal cortex function returns to normal within 6 months following discontinuation of GCs. The time of such return depends on the duration of the disease and of therapy with systemic GCs.

Assessment of Cortisol Response With Low-Dose and High-Dose ACTH in Patients With Chronic Fatigue Syndrome and Healthy Comparison Subjects

A reduced secretion of cortisol has been proposed as a possible explanation of the symptoms in chronic fatigue syndrome. However, the evidence of hypocortisolism in chronic fatigue syndrome is conflicting. In order to simultaneously assess possible alterations in adrenocortical sensitivity and secretory adrenal reserve, the authors administered both low-dose and high-dose ACTH to a group of 18 chronic fatigue syndrome patients and 18 age- and gender-matched healthy comparison subjects. No response differences for salivary and plasma cortisol were detectable after administration of either low-dose or high-dose ACTH, indicating that primary adrenal insufficiency is unlikely to play a significant role in the etiology of chronic fatigue syndrome.

Adrenal gland volume after spinal cord injury.

Spinal cord injury in adult men may result in hypothalamic-pituitary-adrenal axis dysfunction. Atrophy of adrenal glands was speculated in these patients. This study was undertaken to clarify the functional-anatomic correlation between adrenal volume and body surface area in subjects with spinal cord injury with impaired adrenal reserve. Twenty male subjects with chronic spinal cord injury with impaired adrenal reserve were identified by adrenocorticotropic hormone stimulation test from a group of 42 subjects. All subjects with spinal cord injury and healthy volunteers underwent computed tomographic imaging with contiguous 3-mm section over adrenal glands for volumetric measurements. Ten pairs of subjects with spinal cord injury and controls with matched height and weight were included in the statistical analysis. Significantly increased relative adrenal volumes were noted among subjects with chronic spinal cord injury and impaired adrenal reserve as compared with the body weight-matched and height-matched control group. Increased relative adrenal volumes were found after chronic spinal cord injury. Hyperplasia of the zona glomerulosa may be the cause of increased relative adrenal volume after chronic spinal cord injury.

Adrenal function in the human immunodeficiency virus-infected patient.

Although clinical manifestations of adrenal dysfunction are uncommon in patients infected with human immunodeficiency virus (HIV), subclinical functional abnormalities of the hypothalamic-pituitary-adrenal axis are frequent. Patients infected with HIV usually have higher basal serum cortisol and lower serum dehydroepiandrosterone concentrations than HIV-seronegative individuals. This imbalance has been related to progression of the infection by inducing a shift from T(H)1 to T(H)2 immunologic responses. Although, adrenal reserve may be marginal in HIV-infected patients, clinically evident adrenal insufficiency is uncommon and, when present, it is observed in advanced stages of the infection. Hypocortisolemia should be treated regardless of the existence of associated symptoms. On the contrary, hypercortisolemia in the absence of features of Cushing syndrome is common and should not promote treatment nor specific studies. The possible influence that alterations of the adrenal function could have on the patients' immune status and the eventual effect of antiretrovirals on these alterations merit further investigation.

Adrenal function in pediatric critical illness.

OBJECTIVES: Adrenal dysfunction has been documented in critically ill adult populations and in children with septic shock and may have serious consequences if undiagnosed. However, there is no information available on adrenal function in critically ill children with various underlying conditions. DESIGN: A prospective, descriptive study was carried out to investigate the occurrence of adrenal dysfunction in pediatric critical illness. PATIENTS: Thirteen patients were consecutively recruited from a pediatric critical care unit with Pediatric Risk of Mortality Scores (PRISM; illness severity scores) >/=10 and hemodynamic instability as defined by the need for inotropes and/or >20 mL/kg fluid in a 24-hr period. INTERVENTIONS: Baseline cortisol and adrenocorticotropic hormone (ACTH) levels were measured followed by post-ACTH stimulation test cortisol levels to determine adrenal reserve. MEASUREMENTS AND MAIN RESULTS: Baseline cortisol levels ranged from 0.10 to 37.4 &mgr;g/dL (mean, 12.2 +/- 9.6). Adrenal dysfunction as defined by a baseline cortisol level of <7 &mgr;g/dL (am cortisol) or a post-ACTH stimulation level of <18 &mgr;g/dL was observed in four of the 13 patients (31%; 95% confidence interval, 5.7%,55.9%). All three of the patients with baseline cortisol levels of <7 &mgr;g/dL had low-normal ACTH levels. There was no difference in baseline PRISM scores (14.7 +/- 4.11, 12.7 +/- 2.65; p =.37) or admitting diagnoses for those with and without adrenal dysfunction. CONCLUSIONS: We conclude that some critically ill children do no mount adequate basal cortisol levels in the face of severe physiologic stress but do respond to external ACTH stimulation to better delineate the hypothalamic-pituitary-adrenal axis in critically ill children and to determine the clinical consequences of these biochemical abnormalities.

Thyrotoxic Storm

Thyrotoxic storm is a syndrome of exaggerated thyrotoxicosis with systemic decompensation seen in 1-2% of hospital admissions for thyrotoxicosis. The diagnosis is based on recognition of typical cardinal manifestations, but even when diagnosed and treated, mortality rates are high. Results of thyroid function tests may be no more abnormal than those seen in uncomplicated thyrotoxicosis. Often, there is a history of partially treated thyrotoxicosis, and/or decompensation related to a precipitating event such as infection, stroke, pulmonary embolism, or radioiodine therapy. Treatment must be aggressive and includes volume repletion with i.v. glucose and saline, and pressor agents may be needed. Patients belong in an intensive care unit, with a cooling blanket for hyperpyrexia. Appropriate cardiac medications are employed to control ventricular rate in those with atrial fibrillation. The thyroid is blocked by large doses of antithyroid agent. In patients unable to swallow, tablets can be crushed and given by nasogastric tube or per rectum. After antithyroid drugs are started, stable iodine as Lugol's solution is given to block further hormone release from the gland. Sodium ipodate can be used instead of iodine and has the advantage of inhibiting conversion of T4 to T3. In severe cases, thyroid hormone may be removed from the circulation by peritoneal dialysis or plasmapheresis, and cholestyramine resin may be used to bind T4 and T3 within the gastrointestinal tract. β-adrenergic antagonists such as propranolol are given, or the very short-acting β-adrenergic blocker, esmolol, has also been used with success. A Swan-Ganz catheter is used to monitor central hemodynamics, especially in patients receiving high-dose propranolol, pressors, digoxin, diuretics, and fluids. Large doses of dexamethasone have been given based on presumed increased glucocorticoid requirements in thyrotoxicosis and because adrenal reserve may be reduced. Therapy must be continued until a normal metabolic state is achieved, at which time iodine is progressively withdrawn and plans made for definitive treatment.

Thyrotoxic Storm

Thyrotoxic storm is a syndrome of exaggerated thyrotoxicosis with systemic decompensation seen in 1-2% of hospital admissions for thyrotoxicosis. The diagnosis is based on recognition of typical cardinal manifestations, but even when diagnosed and treated, mortality rates are high. Results of thyroid function tests may be no more abnormal than those seen in uncomplicated thyrotoxicosis. Often, there is a history of partially treated thyrotoxicosis, and/or decompensation related to a precipitating event such as infection, stroke, pulmonary embolism, or radioiodine therapy. Treatment must be aggressive and includes volume repletion with i.v. glucose and saline, and pressor agents may be needed. Patients belong in an intensive care unit, with a cooling blanket for hyperpyrexia. Appropriate cardiac medications are employed to control ventricular rate in those with atrial fibrillation. The thyroid is blocked by large doses of antithyroid agent. In patients unable to swallow, tablets can be crushed and given by nasogastric tube or per rectum. After antithyroid drugs are started, stable iodine as Lugol's solution is given to block further hormone release from the gland. Sodium ipodate can be used instead of iodine and has the advantage of inhibiting conversion of T4 to T3. In severe cases, thyroid hormone may be removed from the circulation by peritoneal dialysis or plasmapheresis, and cholestyramine resin may be used to bind T4 and T3 within the gastrointestinal tract. β-adrenergic antagonists such as propranolol are given, or the very short-acting β-adrenergic blocker, esmolol, has also been used with success. A Swan-Ganz catheter is used to monitor central hemodynamics, especially in patients receiving high-dose propranolol, pressors, digoxin, diuretics, and fluids. Large doses of dexamethasone have been given based on presumed increased glucocorticoid requirements in thyrotoxicosis and because adrenal reserve may be reduced. Therapy must be continued until a normal metabolic state is achieved, at which time iodine is progressively withdrawn and plans made for definitive treatment.

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

IntroductionDehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic–pituitary–adrenal axis.Materials and methodThis was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-α and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death.ResultsOn admission, DHEAS was extremely low in septic shock (1.2 ± 0.8 mol/l) in comparison with multiple trauma patients (2.4 ± 0.5 μmol/l; P < 0.05) and control patients (4.2 ± 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 ± 0.3 μmol/l) than did survivors (1.7 ± 1.1 μmol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points.ConclusionWe identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.

Adrenocorticotropic hormone and cortisol levels in relation to inflammatory response and disease severity in children with meningococcal disease.

This prospective observational study investigated the relationship of the hypothalamic-pituitary-adrenal axis to inflammatory markers and to disease severity in children with meningococcal disease. In total, 32 children were studied: 10 with distinct meningococcal meningitis (MM), 10 with MM and septic shock, and 12 with fulminant meningococcal septicemia (FMS). Levels of adrenocorticotropic hormone (ACTH) and interleukin (IL)-6, IL-8, and IL-10 were lowest in the MM group and dramatically elevated in the FMS group. Cortisol and C-reactive protein levels were highest in the MM group and relatively low in the FMS group. Levels of ACTH and inflammatory markers decreased within the first 24 h of admission, but cortisol levels did not fluctuate. Cortisol was significantly inversely correlated with IL-6, IL-8, and IL-10 (P < or =.04). These results suggest that the adrenal reserve in children is insufficient to handle the extreme conditions and stress associated with severe meningococcal disease.

(229) Serum Cortisol Concentrations and Adrenal Reserve May Be Altered by Severe Chronic Pain

(229) Serum Cortisol Concentrations and Adrenal Reserve May Be Altered by Severe Chronic Pain

Presymptomatic diagnosis of X-linked adrenal hypoplasia congenita by analysis of DAX1

A novel DAX1 mutation (L381H) was discovered in the asymptomatic 8-month-old brother of a boy with primary adrenal failure. The infant had impaired adrenal reserve despite normal basal adrenal steroid concentrations. This case highlights the value of genetic testing in children at risk of the development of X-linked adrenal hypoplasia congenita before the onset of a potentially life-threatening adrenal crisis. (J Pediatr 2000;137:878-81)

Cortisol and adrenocorticotropic hormone response to surgical stress (splenectomy) in thalassemic patients

Many vital organs, including the endocrine glands, are affected by iron deposition in thalassemic (Thal.) patients. Involvement of the adrenal gland, although not uncommon, is usually not clinically evident, especially in non-stressful situations. Although the pituitary-adrenal axis (PAA) has been evaluated by several investigators, the impact of surgical stress has not yet been assessed. Do Thal. patients have an adequate adrenocorticotropic hormone (ACTH) cortisol response upon surgical insult? The PAA of 27 (8 female, 19 male) Thal. patients aged 4-15 years (mean 8.96) admitted during 1996-1997 for splenectomy was evaluated before and after surgical stress. Blood samples for measurement of ACTH and cortisol were taken 1 day before and about 2 h after the surgical insult. For comparison, 22 (9 female, 13 male) non-thalassemic (N. Thal.) patients aged 3.5-14 years (mean 7.95) admitted for elective laparotomy who had no evidence of chronic disease or malnutrition served as controls. Timing of blood sampling was similar to that of the study group. The cortisol response after surgical stress was significantly higher than baseline for both the Thal. (17.4 +/- 6.3 vs 30.81 +/- 11.49 microg/dl; P < 0.001) and N. Thal. groups (20.65 +/- 9.1 vs 36.87 +/- 11.08 microg/dl; P < 0.001). N. Thal. patients showed significant elevation of ACTH upon surgical stress (72.5 +/- 39.5 vs 129.09 +/- 67.9 pg/ml; P < 0.001), while the difference between pre- and post-stress was not statistically remarkable in Thal. patients (104.15 +/- 60.74 vs 186.8 +/- 246.24 pg/ml; P = 0.123). However, ACTH before operation in Thal. was significantly higher than that of N. Thal. patients (104.15 +/- 60.74 vs 72.5 +/- 39.5 pg/ml; P < 0.042), with no remarkable difference after surgical stress between both groups (186.8 +/- 246.24 vs 129.09 +/- 67.9; P = 0.261). The serum ferritin in 8 of 13 young Thal. patients (4-8 years old) was < 2,000 ng/ml and 2,000-3,000 in the remaining 5, while in the 14 older patients (9-15 years) it was < 2,000 in 5, 2,000-3,000 in 7, and more than 3,000 ng/ml in the oldest 2 (13 and 15 years). The PAA is usually intact and responsive in Thal. patients. However, the underlying cause of the significantly increased preoperative ACTH concentrations may be a decreased adrenal reserve, presumably related to age and iron load. For this reason, the possibility of primary partial or early adrenal insufficiency in spite of adequate but probably less than expected cortisol synthesis before and after surgical stress should be considered in every prepubertal or older Thal. patient.