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(Chest. 2003;124:57-62.)
© 2003 American College of Chest Physicians

Lack of Long-term Adverse Adrenal Effects From Inhaled Triamcinolone*

Lung Health Study II

Michael S. Eichenhorn, MD, FCCP; Robert A. Wise, MD, FCCP; Thelma C. Madhok, PhD; Lynn B. Gerald, PhD, MSPH; William C. Bailey, MD, FCCP; Donald P. Tashkin, MD, FCCP and Paul D. Scanlon, MD; and the Lung Health Study Research Group{dagger}

* From Henry Ford Hospital (Dr. Eichenhorn), Detroit, MI; Johns Hopkins University School of Medicine (Dr. Wise), Baltimore, MD; University of Minnesota (Dr. Madhok), Minneapolis, MN; University of Alabama at Birmingham (Drs. Gerald and Bailey), Birmingham, AL; University of California, Los Angeles (Dr. Tashkin), Los Angeles, CA; and Mayo Clinic (Dr. Scanlon), Rochester, MN. {dagger} A complete list of LHS participants is given in the Appendix.

Correspondence to: John E. Connett, PhD, University of Minnesota, Division of Biostatistics, 2221 University Ave SE, #200 Minneapolis, MN 55414-3080; e-mail: john-c{at}ccbr.umn.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Study objectives: Inhaled corticosteroids (ICS) are widely used in the treatment of COPD. One of the potential adverse effects of their use is the development of adrenal suppression. Our study aimed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD.

Methods: Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were randomized to receive either triamcinolone, 1,200 µg, or placebo daily. Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation.

Results: Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period. There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup.

Conclusion: Use of inhaled triamcinolone, 1,200 µg/d, over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation.

Key Words: adrenal function • COPD • inhaled corticosteroids • stimulated cortisol response


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Appendix
 References
 
Inhaled corticosteroids (ICS) are widely used in the management of symptomatic obstructive airways disease. In asthma, treatment is intended to reduce airways inflammation, leading to improvement in lung function by reducing airways reactivity, improving symptom control, and preventing exacerbations. In COPD, despite a different mechanism of inflammation and controversy over their efficacy, the use of inhaled steroids is widespread and has been demonstrated to be effective in diminishing exacerbations.1 2 3 4

The adverse effects of ICS are generally considered to be minimal and acceptable.5 6 Increasing recognition of dose-related systemic adverse effects has led to the recommendation that achieving the minimal maintenance dose associated with optimal asthma control is an important therapeutic goal.7 Potential side effects of ICS include adrenal suppression, accelerated loss of bone mineral density, easy bruisability, oral thrush, posterior subcapsular cataract formation, and glaucoma. There is no certainty as to whether persons who have used ICS for a prolonged period require steroid supplementation for acute stresses, such as surgery or infections because of blunted adrenal responsiveness. Most studies addressing the adverse effects of ICS on adrenal function have involved periods of administration from 2 weeks to 12 months and have been conducted in asthmatics in whom the intermittent use of oral steroids may have confounded the results. Furthermore, previous studies in asthmatics have involved mainly children and young adults. Thus, the effect of ICS on adrenal function in older adults is unknown.

The Lung Health Study (LHS) II8 was a placebo-controlled clinical trial of the effects of inhaled triamcinolone, 1,200 µg/d, on the annual age related decline in pulmonary function in patients with COPD. While the primary intent of the study was to determine the impact of ICS on the course of COPD over 4.5 years, using a randomized, multicenter, masked, placebo-controlled trial design, potential side effects of thrush, bruisability, adrenal suppression, bone demineralization, and the development of cataracts and glaucoma were also studied. Although inhaled triamcinolone is a widely prescribed corticosteroid aerosol, relatively few published studies of its effects on adrenal suppression are available, and these were all performed in young asthmatic patients.7 9 The intent of this report is to describe the long-term effects of a moderate dose of inhaled triamcinolone on adrenal function in older individuals with COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Appendix
 References
 
In LHS II, 1,116 participants at 10 clinical centers in North America were recruited. Individuals participating (n = 1,018) and screened (n = 98) in the first LHS10 and who were smoking or had recently quit (less than 2 years) comprised the study group. Other inclusion criteria included age between 40 years and 69 years and the presence of obstruction as defined by an FEV1/FVC ratio < 0.70 and an FEV1 between 30% and 90% of predicted. Candidates were excluded if they had used an inhaled or oral corticosteroid within the last 6 months or if they had other coexistent medical conditions that might interfere with participation in the study over its 4.5-year duration. Those who met entry criteria and were willing to participate provided informed consent and were randomized to receive either triamcinolone acetonide, 1,200 µg/d (six puffs bid), or an identical appearing placebo. Participants in the main study were recruited for inclusion in three separate safety studies involving serial bone densitometry, tests of adrenal suppression, and examination for possible ocular complications.

The design of LHS II has been described in greater detail elsewhere.8 Of the 1,116 participants in 10 centers, 221 participants in 5 centers participated in the ancillary study on adrenal function. Additional exclusion criteria for this ancillary study included pregnancy, lack of baseline testing, previous allergic reaction to cosyntropin, and known adrenal or pituitary disorders. Premenopausal women were required to have a negative pregnancy test result within 7 days of study entry.

At study entry, all participants had basal serum cortisol determinations on venous blood obtained before 10 AM, followed by bolus IV or IM administration of 0.25 mg of cosyntropin, with repeat measures of serum cortisol 30 min and 60 min later. Basal and stimulated cortisol measurements were repeated 1 year and 3 years later. Samples were centrifuged and then frozen within 30 min of centrifugation and shipped to a central laboratory for cortisol determinations (Mayo Medical Laboratories, Rochester, MN). Samples were stored at - 70°C and then analyzed in batches, using an enzymatic immunoassay kit. Neither instrumentation nor methodology changed during the 3 years of study.

Analysis of the results obtained was conducted by the Data Collection Center at the University of Minnesota. Descriptive statistics (means, SDs, and percentage) were used to examine differences between randomized treatment groups, both in baseline characteristics and in prestimulation and poststimulation levels of plasma cortisol in response to cosyntropin. Figures showing cortisol levels at each follow-up period were based on observed mean values. Comparisons between the ICS group and the placebo group on baseline characteristics were evaluated using either t tests for continuous values or {chi}2 tests for categorical variables.

Intent-to-treat analyses of differences between the ICS and placebo groups in cortisol levels (prestimulation, and 30 min and 60 min following cosyntropin injection) at study entry prior to receiving study drug, and at 1 year and 3 years after randomization, were performed using t tests. Analyses were performed for men and women separately and for both genders combined. No adjustments were made in such analyses for multiple comparisons. Differences in subsets defined by the participant’s level of adherence with their assigned medication were examined using t tests. Separate analyses were performed for all subjects, as well as a cohort analysis for the 173 participants completing all three sets of determinations.

Normal baseline function was defined as a serum cortisol level > 5 µg/dL. Normal response to cosyntropin was defined as an increment in cortisol level of at least 7 µg/dL at 30 min or 60 min poststimulation or a peak level at 30 min or 60 min poststimulation >= 18 µg/dL.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Appendix
 References
 
Two hundred twenty-one participants entered the ancillary study of adrenal function, with 106 assigned to the active drug, and 115 assigned to placebo. Both treatment groups were similar with regard to age, gender, race, and baseline pulmonary function. Of the enrolled participants who had baseline measurements of adrenal function prior to initiation of treatment with ICS, 89% underwent repeat testing at year 1 and 85% at year 3 (Table 1 ). Baseline characteristics of both the enrolled participants and those who completed all adrenal function studies were similar to the entire LHS II population as a whole.


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  		Table 1.. Baseline Characteristics of Adrenal Function Study Participants*

 
No meaningful differences were noted between the placebo and active treatments groups in basal morning cortisol or the response to cosyntropin stimulation 30 min or 60 min after stimulation at baseline (before initiation of study drug) or at year 1 and year 3. When only those patients completing all three sets of measurements (baseline, year 1, and year 3) were separately analyzed, basal cortisol levels at baseline as well as year 1 and year 3 were slightly higher in the placebo group, although values for both groups were within the normal range, and no significant decline in basal cortisol levels were noted with either group. In fact, basal cortisol levels increased in both groups over the 3 years of observation. In addition, 30-min and 60-min poststimulation values were similar in both groups at baseline and year 3, but slightly higher in the placebo group for year 1 (Figs 1 2 3 ). These trends were evident for the treatment groups as a whole and for those participants with good compliance. Given the similarities between both groups and the normal values in each category, no likely biological significance can be attributed to the differences at baseline or the lesser rise in the ICS group. No gender differences in adrenal function were identified (Table 2 ).



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  		Figure 1.. Representation of prestimulus cortisol levels by time and treatment, and prestimulation cortisol levels in 84 participants in the ICS group and the 89 participants in the placebo group having measurements at all three study points.

 


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  		Figure 2.. Representation of poststimulus cortisol levels by time and treatment for the 84 participants in the ICS group and the 89 participants in the placebo (Pla) group with adrenal responsiveness measured at all three study points, and the cortisol levels noted 30 min and 60 min after cosyntropin stimulation.

 


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  		Figure 3.. Representation of poststimulus cortisol level change by time and treatment for the 84 participants in the ICS group and the 89 participants in the placebo group with adrenal responsiveness measured at all three study points, and the change in cortisol levels 30 min and 60 min after cosyntropin stimulation. See Figure 2 legend for expansion of abbreviation.

 

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  		Table 2.. Comparison Between Placebo and ICS Groups on Plasma Cortisol Levels, Prestimulation

 
Moreover, all participants completing the study maintained normal adrenal responsiveness to stimulation over 3 years with the following exceptions. Two participants each in the placebo and active treatment groups had depressed basal adrenal function at the end of 3 years. One of those, in the placebo group, also had blunted responsiveness. Two participants in the ICS group and one in the placebo group had depressed basal function at baseline. The possibility that these participants may have received systemic steroids unbeknownst to the investigator cannot be excluded, but is not considered likely.

Because of concerns that poor adherence with the study drug may have obscured the effect of active treatment, a subanalysis was conducted based on drug adherence, with adherence based on the weight of returned canisters. Participants were considered to have good adherence with the medication if canister weight indicated use of six or more puffs or >= 600 µg of triamcinolone daily. This subgroup was similar to the participants as a whole (Table 1) . Basal and poststimulation cortisol levels were not affected by the level of adherence with the study drug (Table 3 ). As found in the overall group, participants with good adherence on active drug had higher cortisol levels at all points of measurement, including baseline, compared to the placebo group.


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  		Table 3.. Comparison Between Placebo and ICS Groups on Plasma Cortisol Levels, Based on Adherence, Prestimulation*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Appendix
 References
 
Systemic side effects have been variably reported from the use of inhaled corticosteroids in asthma and COPD. Differences in doses employed, potency, and effectiveness of respiratory delivery between the various formulations of inhaled corticosteroids and in duration of use have contributed to this variability in reported systemic toxicity. LHS II provided an opportunity to study the systemic effects of a moderate dose of inhaled triamcinolone in patients with COPD in whom adherence to a prescribed program was carefully and objectively monitored. LHS II reported no change in the rate of decline in pulmonary function with the use of triamcinolone, although airways reactivity was reduced.8 Easy bruising was noted approximately twice as frequently in adherent LHS II participants receiving ICS as compared to placebo, and a lower bone mineral density in the lumbar spine and the hip was seen in the active treatment group compared to the placebo group (Paul Scanlon, MD; unpublished data; December 1998).8 Despite these findings suggesting systemic steroid effect in LHS II participants, we found no adverse effect on adrenal function during 3 years of use either in basal adrenal function or responsiveness to stimulation by exogenous cosyntropin.

The observed rise in cortisol levels in treated and untreated subjects over time is not explained by methodologic change, as neither assay kits nor times of venous sampling changed during the study. There were no changes in the manufacture or handling of the kits nor in the reference standards employed in the laboratory analysis. There was no variation in levels recorded between centers. Unfortunately, the reference laboratory was not able to retrospectively review all cortisol levels performed outside the LHS over the same period of time to determine whether this rise was generic or limited to the study population. COPD progression might lead to increased steroid levels as a result of added inflammation or other stresses, but the degree of disease progression was quite minor and this supposition is entirely speculative. Whatever the explanation, similar effects were observed in both treatment groups, so we are confident that these trends are not the effect of active treatment with inhaled triamcinolone. As noted, the placebo group had higher basal levels of plasma cortisol at all three visits compared to the triamcinolone group. As both values were within the normal range, we believe this represents a failure of randomization to match this characteristic precisely, rather than an effect of the drug, since it was noted prior to drug administration.

Since the measures of hypothalamic-pituitary-adrenal (HPA) axis suppression used in this study (basal morning cortisol and responsiveness to stimulation by superphysiologic doses of cosyntropin) are less sensitive to subtle HPA suppression than 24-h urinary free cortisol or 24-h integrated plasma cortisol levels,7 it is possible that our methods were too insensitive to detect a true, albeit minor, degree of adrenal suppression.

Prior studies on inhaled triamcinolone have suggested either no effect11 or a limited biochemical effect9 12 on HPA function. A meta-analysis7 using more sensitive measures of HPA function does suggest a modest alteration in adrenal function following use of triamcinolone. Skin bruising has been shown by others to correlate with adrenal suppression,7 but this was not the case in the present study, in that skin bruisability was higher in treated subjects whose adrenal function was not demonstrably impaired. We cannot exclude a small adrenal suppressive effect, which might be statistically detectable if more sensitive measures of HPA function had been employed. The clinical relevance of this minor degree of adrenal suppression would be debatable.

In summary, we found no clear evidence that the long-term use of inhaled triamcinolone, 1,200 µg/d, suppresses either basal or stimulated adrenal function in older patients with COPD, although evidence of other systemic effects was noted. The maintained response to exogenous stimulation suggests there is no concern regarding stress responses in these patients, whether exogenous or endogenous. Based on the present study, we would not recommend the use of systemic corticosteroids in stress doses for patients receiving moderate doses of ICS. Since other doses and formulations of ICS have different patterns of absorption and metabolism, we cannot confidently extend this recommendation to patients receiving other inhaled steroids or who have received repeated doses of oral corticosteroids.


   Appendix
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
References
 
The principal investigators and senior staff of the clinical and coordinating centers, the National Heart, Lung, and Blood Institute, and members of the Safety and Data Monitoring Board are as follows: Case Western Reserve University, Cleveland, OH (M.D. Altose, MD, Principal Investigator; S. Redline, MD, Co-Principal Investigator; C.D. Deitz, PhD; K.J. Quinlan); Henry Ford Hospital, Detroit, MI (M.S. Eichenhorn, MD, Principal Investigator; W.A. Conway, Jr., MD, Co-Principal Investigator; R.L. Jentons, MA; K. Braden; M. Ketchum); Johns Hopkins University School of Medicine, Baltimore, MD (R.A. Wise, MD, Principal Investigator; S. Permutt, MD, Co-Principal Investigator; C.S. Rand, PhD, Co-Principal Investigator; M. Daniel; V. Santopietro; K. Schiller, PhD); Mayo Clinic, Rochester, MN (P.D. Scanlon, MD, Principal Investigator; A.M. Patel, MD, Co-Principal Investigator; J.P. Utz, MD, Co-Principal Investigator; D.E. Williams, MD, Co-Principal Investigator; G.M. Caron; K.S. Mieras; L. Walters); Oregon Health Sciences University, Portland, OR (A.S. Buist, MD, Principal Investigator; L.R. Johnson, PhD, LHS Pulmonary Function Coordinator; V.J. Bortz; S.L. Persons; H.A. Schueler); University of Alabama at Birmingham, Birmingham, AL (W.C. Bailey, MD, Principal Investigator; C.M. Brooks, EdD, Co-Principal Investigator; L.B. Gerald; PhD, MSPH; L. Montiel); University of California, Los Angeles, Los Angeles, CA (D.P. Tashkin, MD, Principal Investigator; A.H. Coulson, PhD, Co-Principal Investigator; E.C. Kleerup, MD, Co-Principal Investigator; V.C. Li, PhD, MPH, Co-Principal Investigator; M.A. Nides, PhD; I.P. Zuniga; Y.E. Lee); University of Manitoba, Winnipeg, MN (N.R. Anthonisen, MD, Principal Investigator, Steering Committee Chair; J. Manfreda, MD, Co-Principal Investigator; R.P. Murray, PhD, Co-Principal Investigator; S.C. Rempel-Rossum; J.M. Stoyko); University of Minnesota Coordinating Center, Minneapolis, MN (J.E. Connett, PhD, Principal Investigator; M.O. Kjelsberg, PhD, Co-Principal Investigator; M.T. Bollenbeck, MS; K.J. Kurnow, MS; P.G. Lindgren, MS; T.C. Madhok, PhD; M.A. Skeans, MS; H.T. Voelker); University of Pittsburgh, Pittsburgh, PA (R.M. Rogers, MD, Principal Investigator; G.R. Owens, MD [former Principal Investigator, deceased]; F.M. Vitale, MA; M.E. Pusateri); University of Utah, Salt Lake City, UT (R.E. Kanner, MD, Principal Investigator; G.M. Villegas; C. Esplin; R.S. Stayner); Safety and Data Monitoring Board (R. Bascom, MD; J.R. Landis, PhD; J.R. Maurer, MD; Y. Phillips, MD; S.I. Rennard, MD; J.K. Stoller, MD; I. Tager, MD; A. Thomas, Jr., MD); National Heart, Lung, and Blood Institute, Bethesda, MD (S.S. Hurd, PhD, Former Director, Division of Lung Diseases; G. Weinmann, MD, Project Officer, and Director, Airway Biology and Disease Program; M.C. Wu, PhD, Division of Epidemiology and Clinical Applications).


   Footnotes
 
Abbreviations: HPA = hypothalamic-pituitary-adrenal; ICS = inhaled corticosteroids; LHS = Lung Health Study

Supported under a cooperative agreement with the National Institutes of Health (NHLBI-5U01-HL50267-05). Triamcinolone and placebo, as well as support for the ancillary safety studies on bone density and adrenal function, were provided by Rhône-Poulenc Rorer (now Aventis).

Dr. Bailey is participating in an Aventis drug study in progress, a phase III double-blind, parallel-group, multicenter, placebo-controlled study to determine the effectiveness of ciclesonide to reduce oral corticosteroid use in patients with severe persistent asthma.

Dr. Scanlon is currently providing research support for institutional review board-approved protocols (some investigator initiated, some company initiated) from various companies, including Aventis.

Dr. Wise consulted for Aventis regarding new drug development in September and October of 2000 and received $2,000 compensation.

Received for publication August 1, 2002. Accepted for publication December 2, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Appendix
 References
 

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