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• Compliance with inhaled corticosteroids is important when considering adrenal suppression
  Malcolm Brodlie
  Published on: 9 January 2022
• High-Dose Inhaled Fluticasone, Asthma, and Adrenal Insufficiency
  geoffrey todd
  Published on: 9 January 2022
• Diagnostically, the low dose short synacthen test and the high dose test can complement each other
  oscar,m jolobe
  Published on: 9 January 2022

• Published on: 9 January 2022

  Compliance with inhaled corticosteroids is important when considering adrenal suppression

  • Malcolm Brodlie, SpR Paediatrics
  • Other Contributors:
    • Steve Cunningham

  Dear Editor,

  We read with interest the article by Paton and colleagues[1] reporting the results of low dose Synacthen tests in children prescribed fluticasone proprionate (FP). The finding of flat adrenal responses in 2.8% of children tested (all prescribed greater than or equal to 1,000 micrograms of FP per day) provides further evidence of the potential dangers of high doses.

  We recently published the...

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  Dear Editor,

  We read with interest the article by Paton and colleagues[1] reporting the results of low dose Synacthen tests in children prescribed fluticasone proprionate (FP). The finding of flat adrenal responses in 2.8% of children tested (all prescribed greater than or equal to 1,000 micrograms of FP per day) provides further evidence of the potential dangers of high doses.

  We recently published the results of standard dose Synacthen tests in children recommended greater than or equal to 1,000 micrograms per day of FP. Three of the 29 children tested were found to have complete adrenal suppression.[2] In his editorial Russell[3] highlights compliance with therapy as likely to be important given the fact that not all patients on high dose FP suffer adrenal failure. In our study, the first of its kind to our knowledge in this context, we examined compliance in terms of the actual amount of FP prescribed over the last year in primary care relative to that recommended by the hospital specialist. The three children with adrenal suppression had actually only been prescribed a median of 493 micrograms of FP per day over the last year, compared to a median of 433 micrograms in the normal group. Overall, there was an inverse correlation between actual prescribed daily FP dose and peak cortisol response to Synacthen (rs –0.44, P =0.03).[2]

  Our study was relatively small in size and used a pragmatic measure of compliance however the results suggest that compliance with therapy should be considered and that in reality children with adrenal suppression may be receiving smaller doses of FP than we think.

  References:

  [1] Paton J, Jardine E, McNeil E, et al. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled fluticasone. Arch Dis Child 2006;91:808-813.

  [2] Brodlie M, McMurray A, Crofton PM, et al. Strategies to screen for adrenal suppression in children with asthma should take account of compliance with inhaled corticosteroids. Eur J Pediatr 2006 Oct 7; [Epub ahead of print].

  [3] Russell G. Very high dose inhaled corticosteroids: panacea or poison? Arch Dis Child 2006;91:802-803.

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  Conflict of Interest:
  None declared.

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• Published on: 9 January 2022

  High-Dose Inhaled Fluticasone, Asthma, and Adrenal Insufficiency

  • geoffrey todd, chest physician

  Dear Editor,

  Paton et al (1) described varying degrees of adrenal insufficiency in children treated with high-dose inhaled Fluticasone Propionate (FP) for asthma. They state “The attempts to reduce FP in the other children with flat responses resulted in unacceptable worsening of asthma symptoms, reflecting the value of high-dose FP in children with more severe asthma”. However, is it not the case that high-dose FP...

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  Dear Editor,

  Paton et al (1) described varying degrees of adrenal insufficiency in children treated with high-dose inhaled Fluticasone Propionate (FP) for asthma. They state “The attempts to reduce FP in the other children with flat responses resulted in unacceptable worsening of asthma symptoms, reflecting the value of high-dose FP in children with more severe asthma”. However, is it not the case that high-dose FP is behaving exactly in the same way as oral prednisolone, ie making asthma better but also causing severe adrenal suppression? Remember the systemic effect of 1000 mg/day of FP has been estimated as equivalent to 11 mgs of oral prednisolone (2). Further, in a study for the National Heart, Lung and Blood Institute’s Asthma Clinical Research Network, using plasma cortisol AUC, a dosage of FP of only 352 mg/day produced 50% adrenal suppression, a significantly greater degree than the equipotent dosage of beclometasone, leaving the authors to conclude that “increasing the dose beyond this point of maximum efficacy … resulted in increase in systemic effect, especially with fluticasone metered dose inhaler with its CFC propellant” (3).

  Surely the only reason why high-dose FP appears to help severe asthma is its systemic effect which isn’t often measured using a sensitive method, eg plasma cortisol AUC or the low dose ACTH test? Paediatricians need to realise that giving high-dose FP or, indeed, high equipotent doses of Beclometasone or Budesonide, is just an expensive way of prescribing oral steroids.

  Yours sincerely

  DR G R G TODD
  CONSULTANT CHEST PHYSICIAN

  Conflict of Interest

  Dr Todd has not received any funding from any pharmaceutical company in the past 5 years.

  References:

  1. Paton J, Jardine E, McNeill E, Beaton S, Galloway P, Young P, Donaldson M. Adrenal responses to low dose synthetic ACTH (Synacthen) in children receiving high dose inhaled Fluticasone. Arch Dis Child 2006; 91: 808-813.

  2. Tan KS, McFarlane LC, Lipworth BJ. Effects of oraland inhaled corticosteroid on lymphocyte beta2-adrenoceptor function in asthmatic patients. Br J Clin Pharmacol 1997;44:565-568.

  3. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Dolovich M, Drazen JM, Fagan JK, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410-418.

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  Conflict of Interest:
  None declared.

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• Published on: 9 January 2022

  Diagnostically, the low dose short synacthen test and the high dose test can complement each other

  • oscar,m jolobe, retired geriatrician

  Dear Editor,

  The concept utilised in this study,namely, that the low-dose short synacthen test(LDT)is more sensitive than the conventional high dose test(HDT)(1), should not rule out the use of the HDT, given the fact that the two tests can complement each other in the context of suspected secondary hypoadrenalism, depending on the pre-test probability of this disorder(2). The rationale is that the superior sensiti...

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  Dear Editor,

  The concept utilised in this study,namely, that the low-dose short synacthen test(LDT)is more sensitive than the conventional high dose test(HDT)(1), should not rule out the use of the HDT, given the fact that the two tests can complement each other in the context of suspected secondary hypoadrenalism, depending on the pre-test probability of this disorder(2). The rationale is that the superior sensitivity of the LDT(though disputed by others)(3) comes about at the expense of a lower degree of specificity. Consequently a negative result from the HDT is less reliable than a corresponding result from the LDT, and a positive result(ie subnormal cortisol resonse)from the LDT is less reliable than a correspondingly positive result from the HDT(2). Accordingly,in the estimation of one author, where the pretest probability of secondary hypoadrenalism is modest(for example, of the order of 50%)the post test probability of this disorder, following a normal cortisol response, would be of the order of 12% under the LDT, and 28% under the HDT. Conversely a subnormal cortisol response would generate a post test probability of disease of the order of 81% under the LDT and 91% under the HDT. When, on the other hand, the pretest probability is as low as 10% a subnormal cortisol response under the LDT generates a post test probability of the order of 32% whilst the HDT generates the post test probability of the order of 54%(2). Specificity might be enhanced by having different post synacthen serum cortisol cut-off levels for the two tests, namely, 500 nmol/l, for the HDT(3), and a lower cut-off level, namely 400 nmol/l for the LDT(4). In the event that a patient with high pre-test probability for secondary hypoadrenalism should stimulate to a serum cortisol level of > 500 nmol/l under the HDT, subsequent testing should then be undertaken using the LDT at the lower serum cortisol cut-off level. The rationale for the lower cut-off level is that even in normal subjects peak cortisol responses are lower after the LDT than after the HDT(5),and a lower cut-off level would enhance specificity without too much loss of sensitivity(4) Short of the insulin tolerance test and the metayrapone test, alternative testing strategies include the corticotropin releasing hormone(CRH) test which, however, is too cumbersome and costly. Furthermore, neither the LDT, HDT, nor the CRH have proved to be completely reliable in establishing or excluding the presence of secondary or tertiary hypoadrenalism, and clinical judgment remains a crucial factor in deciding which patients need assessment or reassessment of adrenal function(6). In the context of drug-related secondary hypoadrenalism, evaluation of pre- test probability of disease should include a recognition that a subnormal cortisol response to synacthen would only come about if exposure to medication had been of sufficient duration to result in adrenal atrophy(3). Shortcomings of dynamic tets themselves are attributable partly to inherently patient-specific factors(7) and partly to assay- specific factors(8). Patient-specific confounders probably include the inherent variability in the set point for the HPA axis, now acknowledged to be a fact of life in the work up of Cushing's disease(7). The important assay-specific confounder is inter-assay variability, exemplified by 30 minute post synacthen serum cortisol levels ranging from 510 to 626 nmol/l in normal subjects, depending on the assay, and differences in peak cortisol time points, also depending on the assay(8). The authors of the latter study speculated that inter-assay variability might be attributable to the release of steroids other than cortisol in resonse to synacthen, and that these "other" steroids might cross react with some assays to a greater degree than with others, or might displace cortisol from cortisol binding globulin(CBG)(8). CBG levels may themselves be abnormally high, as in diabetes mellitus, or abnormally low, as in obesity(9). To counter the problem of CBG-related variations in serum cortisol the latest variation in the LDT is to measure salivary instead of serum cortisol following parenteral administration of synacthen(9).

  References:

  (1) Paton J., Jardine E., McNeill E., et al Adrenal response to low-dose synthetic ACTH(synacthen) in children receiving high dose inhaled fluticasone Archives of Disease in Childhood 2006:91:808-13

  (2)Nieman LK Dynamic evaluation of adrenal hypofunction Journal of Endocrinological Investigation 2003:26(Suppl.to no.7):74-82

  (3)Dorin RI., Qualls CR., Crapo LM Diagnosis of adrenal insufficiency Annals of Internal Medicine 2003:139:194-204

  (4) Doi SAR., Lasheen I., Al-Humood K., Al-Shoumer AS Relationship between cortisol increment and basal cortisol: Implications for the low-dose short adrenocorticotropic hormone stimulation test Clinical Chemistry 2006:52:746-9

  (5)Soule S., Van Zyl Smit C., Parolis G., et al The low-dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism Clinicall Endocrinology(Oxford)2000:53:221-7

  (6) Maghnie M., Uga E., Temporini F., et al Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests European Journal of Endocrinology 2005:152:735-41

  (7)Findling JW., Raff H Screening and diagnosis of Cushing's syndrome Endocrinology and Metabolism Clinics of North America 2005:34:385-402

  (8) Clark PM., Neylon I., Raggatt PR., Sheppard MC., Stewart PM Defining the normal cortisol response to the short synacthen test: implications for the investigation of hypothalamic-pituitary disorders Clinical Endocrinology 1998:49:287-92

  (9) Marcus-Perlman Y., Tordjman K., Greenman Y., et al Low-dose ACTH(1 mcg) salivary test: a poetential alternative to the classical blood test Clinical Endocrinology 2006:64:215-8

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  Conflict of Interest:
  None declared.

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