Screening for hypothalamo-pituitary-adrenal axis suppression in asthmatics taking high dose inhaled corticosteroids

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 micrograms; range 1200-2650 micrograms) beclomethasone dipropionate (n = 69) or budesonide (n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol less than 190 nmol l-1; urine free cortisol less than 80 nmol 24 h-1; rise in cortisol in response to tetracosactrin or hypoglycaemia less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1. HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol (rs = 0.84; P = 0.001) and post-tetracosactrin cortisol (r = 0.75; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

大剂量吸入糖皮质激素的安全性

吸入性糖皮质激素因其有效的抗炎作用广泛应用于多种呼吸系统疾病治疗中。长期大剂量吸入糖皮质激素的安全性正引起广泛重视,这也成为近年来研究的焦点。本文就大剂量吸入糖皮质激素的安全性（全身反应及局部反应）作一综述。     

Hypothalamo-pituitary-adrenal axis sensitization after chronic salt loading

Hypothalamic parvocellular vasopressin (VP) and corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) are major secretagogues of corticotropin (ACTH), and central plasticity including their alteration is closely related to hypothalamic-pituitary-adrenal (HPA) axis modulation. Chronic hyperosmotic stress caused by 2% salt loading has been known to alter VP and CRH expression. We recently reported that rehydration, a recovery stage from salt loading, induced a prolonged increase in parvocellular VP mRNA expression and suggested that rehydration can modulate HPA axis function without obvious external stress. In the present study, we examined hypothalamic VP and CRH mRNA expression and their responsiveness to acute immobilization stress in control, salt-loaded and rehydrated animals, in order to clarify the precise mechanism of HPA axis regulation during rehydration. The results were further compared with plasma corticosterone and ACTH levels. Plasma corticosterone decreased during salt loading, whereas it increased during rehydration at 1 week. Basal ACTH concentration increased in 1-week-rehydrated animals, with enhanced responsiveness to the acute immobilization stress. In the hypothalamic parvocellular PVN, basal CRH mRNA levels also decreased during salt loading and increased during rehydration. Basal VP mRNA was up-regulated during both salt loading and rehydration. VP mRNA responded to additional acute stress during salt loading and rehydration, but CRH mRNA did not. These results indicate that the HPA axis activity of parvocellular neurons is still altered at 1 week of rehydration and that VP plays a dominant role in regulating ACTH release in response to acute stress. This rehydration stage may thus be a good model for analysis of post-stress sensitization of the HPA axis.     

Hypothalamo-pituitary-adrenal axis and growth hormone axis in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disease and is associated with cytokines (IL-1, IL-6, TNF-alpha) production. There is little information on hypothalamo-pituitary-adrenal (HPA) axis and growth hormone (GH) axis in the patients with RA. We have, therefore, investigated these systems in twenty patients with confirmed RA. Ten of the patients had active and 10 patients remitted RA. Serum cortisol, ACTH and GH levels were measured in the basal state and after insulin induced hypoglycaemia. Cortisol, adrenocorticotropic hormone (ACTH) and GH responses were impaired in 65%, 85% and 30% of the patients, respectively. The basal and peak hormone levels were similar between the patients with active RA and the patients in remission. These findings indicate that there is an impairment in HPA and GH axis in patients with active and remitted RA. The site of this impairment is probably hypothalamus and/or pituitary gland.     

Mummification of the infarcted myocardium by high dose corticosteroids

There is evidence that glucocorticoids reduce infarct size but their use in myocardial infarction remains controversial because of their potential adverse effects on healing of the infarct. To investigate the healing process, rats received either four parenteral doses of 50 mg/kg of methylprednisolone (MP) or saline 5 min, 3,6 and 24 hr after coronary occlusion and their hearts were examined by light and electron microscopy 48 hr and seven days after occlusion. At 48 hr, in five untreated rats, only 12 +/- 7% of injured myocytes showed the persistence of striations and a relatively intact sarcolemma despite loss of nuclei and hence appeared "mummified" whereas in six MP-treated rats 72 +/- 8% of myocytes exhibited this appearance (P less than 0.001). In treated rats there were fewer phagocytes than in controls. At seven days, in seven MP-rats, mummified cells were still more prominent than in five untreated rats and there were fewer phagocytes and less collagen. In conclusion, high dose of MP delays the inflammatory process and retards the disintegration of necrotic myocytes, resulting in impaired healing.     

吸入性皮质激素治疗259例支气管哮喘的疗效分析

目的 观察吸入性皮质激素治疗支气管哮喘的疗效。方法 我院259例中、重度支气管哮喘住院患者根据治疗方法分为两组，133例(未用吸入性皮质激素)与126例(用吸入性皮质激素的)治疗效果相比较得出结论。结果 长期、规律、小剂量应用吸入性皮质激素能有效地控制哮喘急性发作及其相关症状和降低住院率，无明显的副作用。结论 吸入性皮质激素可较长期应用于支气管哮喘患者。     

全球哮喘防治创议推荐糖皮质激素的半量吸入分级治疗支气管哮喘患者的疗效分析

目的为减轻支气管哮喘(简称哮喘)患者的经济负担,探讨中国控制哮喘最小吸入糖皮质激素(ICS)剂量。方法86例患者随机分为:(1)G组42例:应用全球哮喘防治创议(GINA)推荐高限剂量,中度患者每次250μg,每天2次;重度患者每次375μg,每天2次;(2)H组44例:应用G组剂量半量,中度患者每次125μg,每天2次;重度患者早晨125μg、晚上250μg,每天各1次。采用随机、对照、平行分组、多中心临床研究,筛选期1周仅按需吸入沙丁胺醇。治疗期共24周。结果治疗后G和H组日间症状评分:重度哮喘G组为(0.7±0.8)分,H组为(0.4±0.6)分,中度G组为(0.4±0.5)分,H组为(0.3±0.5)分;第一秒用力呼气容积(FEV1):重度G组为(1.5±0.5)L,H组为(1.8±0.6)L,中度G组为(2.3±0.6)L,H组为(2.3±0.8)L;第一秒用力呼气容积占预计值百分比(FEV1占预计值%):重度G组为(54±17)%,H组为(59±19)%,中度G组为(79±14)%,H组为(79±15)%;晨间最大呼气流量(PEF)增加值:中、重度G组分别为45、67L/min,中、重度H组分别为56、65L/min;夜间憋醒天数:重度G、H组分别为81、69d;无症状天数:重度G、H组分别为88、98d;合并用沙丁胺醇剂量(重度G、H组分别为5.0、3.4喷/d)等32项(次)比较差异均无统计学意义(P均>0.05)。G组中度哮喘患者首次加重3例,H组为11例,两组比较差异有统计学意义(χ2=4.74,P<0.05);G组中度哮喘控制例数为18例,H组为12例,两组比较差异有统计学意义(χ2=4.97,P<0.05);而G组中度哮喘患者夜间症状评分为(0.30±0.22)分,H组为(0.13±0.33)分,两组比较差异有统计学意义(t=-2.06,P<0.05)、重度哮喘加重天数G组为11d,H组为6d,两组比较差异有统计学意义(U=31.00,P<0.05)。结论大多数中国哮喘患者应用GINA推荐的ICS高限剂量与其半量分级治疗,可取得相似的疗效。     

Clinical evaluation of anaphylactic reactions to intravenous corticosteroids in adult asthmatics

BACKGROUND: Corticosteroids form an important component of the treatment of acute asthma. Systemic anaphylactic reactions to intravenous corticosteroids have been reported, although their incidence is extremely rare. OBJECTIVES: To determine the clinical features and underlying mechanisms of anaphylactic reactions to intravenous corticosteroids in adult asthmatics. SUBJECTS AND METHODS: The clinical features of 7 adult asthmatics (4 males, 3 females, mean age 39.4 +/- 16.9 years), who had developed systemic anaphylactic reactions to intravenous administration of corticosteroids for the treatment of acute asthma, were studied retrospectively on the basis of their medical records. Skin tests using various injectable steroid preparations were performed in 3 cases to determine the mechanism of this reaction. RESULTS: Systemic anaphylactic reactions to intravenous administration of corticosteroids occurred in severe atopic asthmatics with previous exposure to parenteral corticosteroids, irrespective of age and gender. Aspirin-intolerant asthma was identified in only 3 subjects. In all cases, anaphylactic reactions were induced following intravenous administration of succinate-containing corticosteroid preparations, i.e. hydrocortisone and methylprednisolone. Administration of phosphate-containing corticosteroids, i.e. dexamethasone and betamethasone, was safe and resulted in a resolution of anaphylactic symptoms. Immunological examination with skin tests suggested that anaphylactic reactions were an IgE-mediated hypersensitivity. CONCLUSIONS: Intravenous injection of succinate-containing corticosteroids in high-risk asthmatics should be performed slowly by drip injection under continuous monitoring. Once anaphylactic reactions occur, it is important to stop the injection immediately and to use conventional medication for anaphylaxis.     

Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy

These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n = 37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.     

Suppression of pituitary-adrenal axis by triamcinolone acetonide in asthmatics]

To assess the inhibitory effect of triamcinolone acetonide on pituitary-adrenal axis, we measured plasma cortisol, plasma ACTH and performed short ACTH stimulation test before and after injection of 40 mg of triamcinolone acetonide intramuscularly in 34 asthmatic patients. At the same time salivary cortisol levels had been followed up for four weeks in ten of the 34 patients. Maximum adrenal suppression was found in two to three days after the administration. The suppression rates of salivary cortisol, plasma cortisol, plasma ACTH and ACTH stimulation test were 81.5%, 53.2%, 70% and 45.6% respectively. Such suppression lasted for two weeks. Afterwards the secretion of pituitary and adrenal glands recovered gradually. The secretion of plasma ACTH and salivary cortisol returned to normal in four weeks and that of plasma cortisol in five weeks. Triamcinolone acetonide, 40 mg monthly, is comparable with prednisone 10 mg daily, or oral dexamethasone 0.75 mg daily. The inhibitory effect of the steroids on pituitary-adrenal axis was in the order of dexamethasone, triamcinolone acetonide and prednisone.     

Effect of high dose inhaled corticosteroids on cell mediated immunity in patients with asthma

BackgroundCell mediated immunity is suppressed by systemic corticosteroids. Inhaled corticosteroids have been shown to affect parameters including bone metabolism, hypothalamus–pituitary adrenal axis, linear growth, and lead to the development of cataracts. However, it is unclear if high dose inhaled corticosteroid therapy affects cell mediated immunity.Study objectivesTo evaluate if asthma patients taking high dose inhaled corticosteroids chronically have reduced cell mediated immunity compared to asthma patients not taking inhaled corticosteroids.MethodsEighteen asthmatic subjects participated in this cross-sectional study. Cell mediated immunity was evaluated in nine patients who had been taking high dose inhaled corticosteroids for >6 months and nine patients not taking inhaled corticosteroids. Cell mediated immunity was evaluated by delayed type hypersensitivity (DTH) skin testing with intradermal placement of candida and tetanus antigens.ResultsThere was no significant difference in DTH skin test results between the high dose inhaled corticosteroid and no corticosteroid treated asthma group.ConclusionPatients with asthma taking high dose inhaled corticosteroids chronically (>6 months) did not have significantly greater impaired cell mediated immunity than patients not taking inhaled corticosteroids in this study.     

Alternatives for measuring endogenous adrenocortical activity in asthmatics treated with inhaled corticosteroids

We compared a 12-hour, hourly integrated plasma cortisol profile in asthmatics treated with a corticosteroids with a variety of modified methods based on less frequent blood sampling. Excellent agreement with the reference was observed for sampling at 10 p.m. and 8 a.m. (correlation coefficient of 0.97; 95 % confidence interval 0.97, 0.98); at 9 p.m. and 7 a.m. (r = 0. 95; 0. 94, 0.96); at 11 p.m. and 7 a.m. (r = 0.94; 0.93, 0.95); every 2 hours (r = 0. 96; 0.96, 0.97); and every 3 hours (r = 0. 91, 0.91, 0.93). The two-sample alternatives (10 p.m/8 a.m. and 9 p.m/7 a.m.) are accurate, as well as more convenient, economical, and practical.     

Hypothalamo-pituitary-adrenal axis dysregulation in patients with rheumatoid arthritis after the dexamethasone/corticotrophin releasing factor test

A defective hypothalamo-pituitary-adrenal axis response to inflammatory cytokines may contribute to the pathophysiology of rheumatoid arthritis (RA). The purpose of this study was to define further the mechanisms responsible for this dysregulation. Six normal individuals and seven patients with active RA were recruited and given an oral dose of dexamethasone at 2300 h the evening before the study. The next day, an i.v. catheter was fitted at 1300 h. Blood samples were collected between 1400 h and 1700 h before and after infusion (at 1500 h) of corticotrophin releasing factor (CRF). Plasma was separated and stored at-20 degrees C before radioimmunoassay for ACTH, cortisol and dihydroepiandrosterone (DHEA). Before the CRF challenge, ACTH and cortisol were significantly increased and DHEA significantly decreased in the patients with RA compared with the controls. Neither ACTH nor DHEA was significantly altered after CRF infusion. Control individuals did not mount a cortisol response to infusion of CRF. Similarly, four of the patients with RA did not respond to CRF. However, in contrast to the controls, three of the patients mounted an immediate and sustained cortisol response after receiving CRF. These data reveal that three of the seven patients with RA were able to escape from dexamethasone suppression and mount a cortisol response to CRF challenge. This suggests that there may be a subpopulation of patients with RA who have impaired glucocorticoid feedback. The implications of this alteration for disease progression remain to be determined.     

Effect of intermittent high dose parenteral corticosteroids on the alveolitis of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder in which chronic accumulation of neutrophils within the alveolar structures occurs. These cells with their large stores of preformed mediators likely play a major role in subsequent lung derangement. To evaluate the adjunctive use of intermittent high dose "pulse" corticosteroid therapy as a means of inhibiting neutrophil accumulation in the IPF lung, 5 patients were treated in a single blind random fashion with "high dose" corticosteroids (2 g methylprednisolone given intravenously once a week plus 0.25 mg/kg prednisone given orally daily) and 8 patients were treated with "low dose" corticosteroids only (0.25 mg/kg prednisone given orally daily). All patients had biopsy-proved disease in midcourse, and the 2 groups were matched for clinical and physiologic criteria. To evaluate the effect of these therapies on the quantity of neutrophils in the lungs of these patients, both groups underwent bronchoalveolar lavage and 67Ga scanning at the beginning and end of the 6-month study period; both methods gave an estimate of the intensity of the neutrophil alveolitis in these patients. Low dose corticosteroids had little effect on neutrophil accumulation (% neutrophils in lavage, - 5 +/- 8% change from baseline; 67Ga uptake, + 27 +/- 14% change from baseline), whereas high dose corticosteroids significantly reduced neutrophil accumulation (% neutrophils in lavage, - 46 +/- 8% change from baseline, p less than 0.02 compared with that in the low dose group; 67 Ga uptake, - 23 +/- 11% change from baseline, p less than 0.05 compared with that in the low dose group). In addition, 2 patients in the high dose group were reevaluated 6 months after cessation of the intermittent high dose pulse corticosteroids. Both had marked increases in lavage neutrophils compared with when they were receiving the high dose therapy (10 to 22% and 18 to 52%, respectively). These findings suggest that massive doses of intermittent intravenously administered corticosteroids may help to suppress the neutrophil component of the alveolitis of IPF.