In High adherence to therapy, use of nasal steroids, and low or normal BMI were associated with higher likelihood of HPA axis dysfunction. Hypothalamic—pituitary—adrenal axis suppression in asthmatic school children. Pediatrics doi Download references. You can also search for this author in PubMed Google Scholar. Reprints and Permissions.
High prevalence of HPA axis suppression in children taking corticosteroids. Nat Rev Endocrinol 9, 64 Download citation. Published : 04 December Issue Date : February Advanced search. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.
Skip to main content Thank you for visiting nature. Indeed, the absolute risk of adrenal crisis after cessation of oral and inhaled corticosteroids might be considered rare based on the literature, but is likely to be substantially underreported in clinical practice [ 15 ]. Importantly, the manifestation and the severity of clinical signs depend on the presence of stress with its resulting increased cortisol demand.
Upon major stress, even a mild adrenal insufficiency can be hazardous leading to hemodynamic instability, vasoactive-refractory shock and ultimatively death [ 3 , 15 , 18 ]. Consequently, in adrenal insufficiency administration of systemic corticosteroids preferably hydrocortisone is mandatory and potentially lifesaving.
Unfortunately, symptoms of adrenal insufficiency are highly variable and only occur if the patient is experiencing more or less severe stress. Therefore, predicting or excluding the risk for adrenal insufficiency from clinical parameters, as often falsely done, is delicate and potentially dangerous.
Illustratively, typical symptoms of adrenal insufficiency e. This should be kept in mind before an absence of adrenal insufficiency is postulated based on the absence of signs and symptoms by the treating physician.
Based on our data and supported by the literature, basal cortisol levels are helpful to diagnose adrenal insufficiency in a subset of patients, i. Measurement of basal ACTH concentration did not improve the diagnostic accuracy. This is not surprising because of the pulsatile secretion of ACTH. In asthmatic patients, the various adverse effects of oral and even inhaled corticosteroids on the HPA axis, including adrenal crisis, have been well recognized [ 18 , 19 ]. In patients receiving systemic corticosteroids for acute exacerbation of COPD, the frequency and duration of adrenal suppression has not prospectively been investigated.
Surprisingly, in common practice, a so called "short-term" 14 days course of systemic corticosteroids is generally considered safe and the potential consequences of adrenal suppression are often neglected [ 16 ]. In our patients, adrenal stimulation tests revealed a suppressed adrenal response to corticotropin in 7 out of 9 patients after only one day of treatment and in 8 out of 9 patients after the 2 weeks course. Similar proportions have been reported from studies on longer-term glucocorticoid treatment [ 20 ].
The observed gradual recovery of the suppressed adrenal response to the low-dose corticotropin test was heterogeneous among the patients lasting from a few days to up to 3 weeks after withdrawal. In individual patients, it is not possible to predict the duration of the HPA axis recovery, though, careful instruction and observation of these patients and examination for potential adrenal insufficiency should be recommended.
This study has limitations. Firstly, we have only included a small, but well defined number of patients to assess the adrenal response after steroid treatment for AECOPD. The number of performed tests is too small to recommend definitive cut-off levels for peak cortisol concentrations during acute illnesses. Secondly, our population varied in respect to the use of inhaled corticosteroids on admission, which is a known risk factor for adrenal insufficiency.
Still, the impact of inhaled corticosteroids can not be addressed with this study. Thirdly, we did not directly assess free cortisol values or albumin or cortisol binding globulin concentrations to calculate free cortisol levels. Depending on the severity and kinetic of acute disease, total and free cortisol levels may show discordant results and total cortisol levels may not adequately anticipate the free cortisol levels needed during severe peracute stress [ 21 ].
In conclusion, short-term, low-dose systemic steroid treatment for AECOPD exposes the patients to the risk of adrenal insufficiency. During the period of recovery the function of the adrenal response to stress may still be impaired. In a minority of patients the adrenal response even remained suppressed for several weeks. If patients are exposed to stress after such treatment, adrenal function should be assessed. N Engl J Med. Niewoehner DE: The role of systemic corticosteroids in acute exacerbation of chronic obstructive pulmonary disease.
Am J Respir Med. Clin Endocrinol Oxf. Thaler LM, Blevins LS: The low dose 1-microg adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab. Abdu TA, Elhadd TA, Neary R, Clayton RN: Comparison of the low dose short synacthen test 1 microg , the conventional dose short synacthen test microg , and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease.
Ann Intern Med. CAS Google Scholar. Clayton RN: Short Synacthen test versus insulin stress test for assessment of the hypothalamo [correction of hypothalmo]-pituitary — adrenal axis: controversy revisited. Vondracek SF, Hemstreet BA: Is there an optimal corticosteroid regimen for the management of an acute exacerbation of chronic obstructive pulmonary disease?.
Krasner AS: Glucocorticoid-induced adrenal insufficiency. Arch Dis Child. Side effects with inhaled steroids should not be forgotten. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P: The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. Download references. The authors would like to thank Fausta Chiaverio for her great contribution and support of the research team and the staff from the emergency room of the University Hospital in Basel for their support during the recruitment phase of the study.
You can also search for this author in PubMed Google Scholar. Correspondence to Philipp Schuetz. PS analyzed the data and wrote the first report. This article is published under license to BioMed Central Ltd.
Reprints and Permissions. Schuetz, P. Effect of a day course of systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis in patients with acute exacerbation of chronic obstructive pulmonary disease. BMC Pulm Med 8, 1 Download citation. Received : 20 August Accepted : 26 January Published : 26 January Skip to main content.
Growth impairment has been reported in an infant treated with betamethasone valerate 0. Turpeinen et al. Prolonged use of topical steroids on the eyelid can induce open-angle glaucoma and cataract from transpalpebraltarsal penetration. Death due to disseminated cytomegalovirus infection in two infants is the dreaded complication reported yet.
In both the cases, clobetasol propionate was the culprit agent. A systematic compilation of systemic side effects of topical corticosteroids to increase awareness among dermatologists. Source of Support: Nil. Conflict of Interest: Nil. National Center for Biotechnology Information , U. Journal List Indian J Dermatol v. Indian J Dermatol. Author information Article notes Copyright and License information Disclaimer. Address for correspondence: Dr.
E-mail: moc. Received May; Accepted May. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC. Abstract With the introduction of topical corticosteroids, a milestone has been achieved in dermatologic therapy; owing to its potent anti-inflammatory and ant proliferative effects, it became possible to treat some hitherto resistant dermatoses.
Keywords: Adverse effects , hypothalamus-pituitary-adrenal axis , infants and children , percutaneous absorption , topical corticosteroids. What was known? Topical steroids can be absorbed through the skin Even small doses of potent topical steroids can produce systemic side effects particularly in children and the elderly Diseased skin has impaired barrier function resulting in enhanced percutaneous absorption and systemic side effects.
Introduction Topical corticosteroids are one of the most commonly used topical medicines in dermatology. Percutaneous Absorption of Topical Steroids Percutaneous absorption involves passage of the drug through epidermis, dermis, and into the circulation. These factors are: Age of the patient: Young children have greater surface area to volume ratio and are less able to metabolize the drug quickly and adequately Body site and area treated: Penetration of the drug correlates inversely with the thickness of the stratum corneum; drug penetration is highest through mucous membrane and scrotal skin and least through palmo-plantar skin Amount of topical steroid used: Absorption is directly proportional to the mass or concentration of topical steroid applied to the skin up to a critical point Structure and Potency of the drug: Higher the potency, increased is the chance of systemic side effects.
It also affects the biotransformation of the active molecule Vehicle of the drug: Vehicle is one of the factors which determine the partition co-efficient, Km and hence percutaneous transport. Duration of therapy Use of occlusion: Occlusion via any means increases the hydration and temperature of stratum corneum and thus enhances drug penetration.
Diseases with impaired barrier function like atopic dermatitis or Netherton syndrome have been associated with enhanced penetration Coexistent hepatic and renal disease: The glucocorticoids are metabolized mainly in the liver by CYP 3A4 and excreted through kidneys. Investigation Protocol Evaluation of patients suspected to have secondary adrenal failure or HPA axis suppression and Cushing's syndrome may consist of the following tests.
Basal cortisol level measurement An early morning 8 a. Midnight or nocturnal salivary cortisol level This is an excellent diagnostic tool. ACTH stimulation test This is the preferred method of detecting adrenal suppression. Insulin tolerance test ITT This test evaluates the entire HPA axis and is capable of assessing partial and recent onset adrenal suppression.
Metyrapone test This provocative test also examines the status of the entire HPA axis. Other tests that can be done for screening with less definitive results are: Random serum cortisol Serum ACTH levels hour urinary free cortisol. Systemic Side Effects In addition to local side effects, prolonged use of topical steroids can cause systemic side effects which are less common than those due to systemic corticosteroids.
The documented adverse effects are: Suppression of the hypothalamic-pituitary-adrenal axis Iatrogenic Cushing's syndrome Growth retardation in infants and children Ocular: Glaucoma and loss of vision Avascular necrosis of femoral head Severe disseminated cytomegalovirus infection resulting in death in infants. A systematic compilation of systemic side effects of topical corticosteroids to increase awareness among dermatologists Some rare systemic side effects have been discussed.
References 1. The effect of topically applied compound F in selected dermatoses. J Invest Dermatol. In vivo percutaneous absorption of hydrocortisone in psoriatic patients and normal volunteers. J Am Acad Dermatol. Riegelman S. Pharmacokinetic factors affecting epidermal penetration and percutaneous absorption. Clin Pharmacol Ther. Increased skin permeability in preterm infants. J Pediatr. In vivo percutaneous penetration. Washington DC: Hemisphere Publishing; Principles of topical therapy.
Fitzpatrick's Dermatology in General Medicine. New York: Mc Graw-Hill; Regional variation in percutaneous penetration of 14C cortisol in man. Trommer H, Neubert RH. Overcoming the stratum corneum: The modulation of skin penetration. A review. Skin Pharmacol Physiol. Franz TJ. Kinetics of cutaneous drug penetration. Int J Dermatol. Wolverton SE. Philadelphia: Elsevier Inc; Comprehensive Dermatologic Drug Therapy; pp.
Mailbach HI. In vivo percutaneous penetration of corticoids in man and unresolved problems in their efficacy. Brisson P. Percutaneous absorption. Can Med Assoc J. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab. Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders. Clin Biochem. Diagnosis of secondary adrenal insufficiency: Unstimulated early morning cortisol in saliva and serum in comparison with the insulin tolerance test.
Horm Metab Res. Assessment of adrenal function in cirrhotic patients using concentration of serum-free and salivary cortisol. Liver Int. Assessment of adrenal function in cirrhotic patients: Salivary cortisol should be preferred. J Hepatol. Clinical review Laboratory assessment of adrenal insufficiency.
Hypothalamus-pituitary-adrenal axis evaluation in patients with hypothalamo-pituitary disorders: Comparison of different provocative tests. Clin Endocrinol Oxf ; 68 — The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol Oxf ; 56 —9. Magnotti M, Shimshi M. Diagnosing adrenal insufficiency: Which test is best-the 1-microg or the microg cosyntropin stimulation test?
Endocr Pract. Exogenous Cushing's syndrome due to topical corticosteroid application: Case report and review literature. Adverse effects of topical glucocorticosteroids. Adverse effects of topical corticosteroids. Cushing's syndrome and pituitary-adrenal suppression due to clobetasol propionate.
Br Med J. Effect on adrenal function of topically applied clobetasol propionate Dermovate Br Med J. Adrenal suppression following low-dose topical clobetasol propionate. J R Soc Med. Comprehensive Dermatologic Drug Therapy; p. Meynadier J, Guillot B. Pituitary-adrenal function after topical steroids. Lehner T, Lyne C. Adrenal function during topical oral corticosteroid treatment. Scoggins RB, Kliman B. Percutaneous absorption of corticosteroids: Systemic effects.
The clinical use of corticosteroids aims to decrease inflammation in the lungs by reducing lymphocyte count, promoting anti-inflammatory cytokines, and suppressing pro-inflammatory cytokines by genomic modification [ 4 ]. Due to their anti-inflammatory properties, corticosteroids, such as dexamethasone and hydrocortisone, are used to prevent and manage BPD.
We will also recommend steroid management strategies based on the available evidence, using caution for when the evidence is less robust. The evidence available regarding the routine use of inhaled corticosteroids ICS for BPD treatment suggests it is not recommended currently; therefore, ICS will have limited discussion in this review. Finally, a major challenge in using steroids for neonatal lung disease is the concern for adrenal suppression and risk of adrenal insufficiency if glucocorticoids are stopped too rapidly.
Since there are limited data available providing such guidance, we provide our shared clinical experience in managing adrenal suppression as well as counseling families, follow-up with the caregiver, and monitoring, if needed, once the patient is discharged from the hospital. Corticosteroids exert their anti-inflammatory and immunosuppressive effects through genomic mechanisms [ 5 ]. They diffuse across cell membranes and bind to receptors, inducing a conformational change of the receptor and formation of the receptor-corticosteroid complex [ 2 , 4 , 6 ].
The receptor-corticosteroid complex enters the cell nucleus. For glucocorticoids, the complex binds to DNA at a glucocorticoid response element GRE motif resulting in transactivation upregulation of anti-inflammatory mediator expression and transrepression inhibition of pro-inflammatory mediator expression. Other effects of corticosteroids include inhibition of phospholipase A2 which is also responsible for the production of pro-inflammatory mediators and inhibition of genes responsible for the expression of cyclooxygenase-2 [ 4 ].
After a glucocorticoid crosses the cell membrane it forms a glucocorticoid-glucocorticoid receptor GR complex. This complex is then able to enter the cell nucleus and exert genomic effects that either increase or decrease gene transcription. This complex may also have non-genomic effects by increasing synthesis of annexin A1 or interacting with cell membrane.
A similar mechanism occurs with synthetic corticosteroids, although the percentage bound to protein varies for each drug [ 5 ]. At higher steroid concentrations, CBG may become saturated, leading to an increase in unbound steroid available to access the cell [ 9 ].
Of note, CBG levels are lower in premature and sick infants, increasing the amount of unbound steroid [ 10 , 11 ]. A cortisol level measures the total cortisol level bound and free. Therefore, cortisol measurements in these infants may overestimate the need for a replacement since it may not accurately reflect the free cortisol level. Glucocorticoids undergo hepatic metabolism through phase 1 oxidation and reduction reactions followed by phase II conjugation.
The phase II reactions involved in corticosteroid metabolism include sulfation or glucuronidation. Natural steroids possess both glucocorticoid and mineralocorticoid activity to some degree [ 12 ]. Cortisol is the endogenous glucocorticoid produced by the adrenal gland via cholesterol metabolism.
Aldosterone is the primary mineralocorticoid produced by the zona glomerulosa of the adrenal gland, with secretion regulated by the renin-angiotensin system [ 4 ]. The mineralocorticoid effect occurs primarily in the renal epithelial cells and is mediated by intracellular mineralocorticoid receptors which regulate transcription of sodium channels. This pathway enhances sodium absorption and potassium excretion in the nephrons with subsequent passive water reabsorption leading to increased intravascular volume and blood pressure [ 13 ].
Synthetically derived corticosteroid analogs have intrinsic properties to mimic and increase glucocorticoid or mineralocorticoid activity and potency. Synthetic structural modifications Fig. The basic structure of cortisol includes four basic rings A—D and several features important for both glucocorticoid and mineralocorticoid activity.
Structural components that are critical for both glucocorticoid and mineralocorticoid activity include the 3-ketone group and the 4,5 double bond on ring A. The presence of the hydroxyl group contributes to both the glucocorticoid function and potency. The hydroxyl group is also needed for glucocorticoid activity. The hydroxyl group is needed for glucocorticoid, but not mineralocorticoid activity. The primary corticosteroids utilized for the anti-inflammatory effects in infants with BPD include hydrocortisone, dexamethasone, prednisolone, and methylprednisolone.
The glucocorticoid and mineralocorticoid activity of these corticosteroids are described relative to hydrocortisone, the synthetic analog of cortisol Table 1. Hydrocortisone primarily possesses glucocorticoid activity, although it exhibits mineralocorticoid activity at supraphysiologic doses. The higher doses of hydrocortisone are necessary to alter the dysregulated immune response that contributes to BPD.
While supraphysiologic doses of hydrocortisone could have mineralocorticoid effect, the doses used in treating these infants do not reach the pharmacologic threshold to induce significant sodium retention or hypertension. Pharmacologic doses for BPD prevention or treatment can range from slightly above physiologic doses to greater than recommended stress dosing, and therefore may or may not induce a mineralocorticoid effect such as hypertension depending on the dose and duration [ 14 , 17 ].
Due to its rapid oral absorption and short-acting duration, hydrocortisone is appropriate for physiologic cortisol replacement in the setting of hypothalamic-pituitary-adrenal HPA axis suppression that occurs with supraphysiologic doses of glucocorticoids Table 1 [ 4 , 16 ]. Dexamethasone is a long-acting glucocorticoid agonist that is about 25 times more potent than hydrocortisone. The potency of dexamethasone is attributed to its relative stability due to the halogenated structure carbon 9 and the additional double bond found between carbons 1 and 2 Fig.
Unlike other glucocorticoids e. In fact, dexamethasone does not require activation to exert effects on glucocorticoid receptors, and does not bind to mineralocorticoid receptors [ 18 ]. Prednisolone and methylprednisolone are synthetic glucocorticoids with similar potency and are used interchangeably in practice.
Methylprednisolone, a corticosteroid containing glucocorticoid potency similar to prednisolone, is sometimes used in place of prednisolone when an intravenous formulation is desired. Historically, these corticosteroids have been safely used for other pulmonary diseases, primarily within the pediatric asthma population [ 19 , 20 , 21 ]. Early use of postnatal corticosteroids birth to 7 days of age targets relative cortisol insufficiency and mediates inflammatory injury in the perinatal period such as chorioamnionitis, surfactant insufficiency, and early invasive mechanical ventilation [ 24 , 25 ].
Dexamethasone has been studied most extensively in randomized controlled trials RCT. However, these pulmonary benefits are outweighed by the associated short-term adverse effect of gastrointestinal perforation, specifically in conjunction with indomethacin, and long-term neurodevelopmental adverse effects [ 22 ]. Specifically, early dexamethasone increases risk for neuromotor impairment and cerebral palsy CP , even considering treatment courses as short as 3 days [ 26 , 27 ].
In contrast, emerging data may support the role of early hydrocortisone use for the prevention of BPD. Administration of ICS may decrease pulmonary inflammation while minimizing systemic exposure. The trial showed a reduction of BPD for the inhaled budesonide group compared to placebo However, this benefit was offset by a non-significant increase in mortality with budesonide compared with placebo Although the rate of neurodevelopmental disability did not differ between the groups, the difference in mortality at 2 years of age follow-up was higher for the treatment group Based on these findings, early administration of ICS cannot be recommended at this time.
One of the limitations of ICS in preterm infants is poor pulmonary deposition due to intrinsically low lung volumes and inspiratory pressures [ 33 , 34 ]. To overcome this limitation, corticosteroids can be instilled into the lungs using surfactant as a vehicle. Two single-center trials evaluated this approach [ 35 , 36 ]. There were no differences in growth parameters or NDI between the intervention and control group at 2 to 3 years of age [ 36 ].
However, an increased risk of CP has been associated with late high-dose dexamethasone therapy, although aggregate data analysis has shown no increase in NDI [ 38 , 39 , 40 ]. The negative findings were primarily due to the traditional higher and longer dosing courses 21—day tapering courses of dexamethasone. Recent data demonstrate that delaying exposure to corticosteroids until after 7 days of age while utilizing shorter courses and lower doses may favorably shift the risk:benefit ratio [ 23 , 38 ].
To address both the efficacy and safety of late low-dose, short-course dexamethasone, Dexamethasone: A Randomized Trial DART studied a cumulative dose of 0. This pivotal trial was hampered by slow recruitment, owing to the widespread backlash against dexamethasone therapy among clinicians and parents concerned about potential neurodevelopmental harm [ 42 ]. The median age at which dexamethasone was initiated in this trial was 23 days, but the trial was halted well before achieving the desired sample size.
However, the lack of statistical power renders these findings inconclusive [ 43 ]. Preterm infants between 7 and 14 days of age who were ventilator dependent and at high risk for developing BPD were randomized to either high-dose hydrocortisone or placebo Table 2 [ 44 ]. Outstanding questions regarding both the relative efficacy and neurologic impact of dexamethasone and hydrocortisone highlight the urgent need for direct comparison of relatively high-dose hydrocortisone to low-dose dexamethasone in randomized trials [ 46 , 47 ].
A specific meta-analysis of trials for both early and late corticosteroids demonstrates a strong correlation between baseline risk of BPD in the study population and risk of the composite outcome of death or CP [ 48 ]. In this context, many clinicians utilize corticosteroids either low-dose dexamethasone or high-dose hydrocortisone in infants who require persistent invasive mechanical ventilation in the early evolving phase of BPD. One way to identify high-risk infants who can be considered for corticosteroid use is with the Neonatal BPD Outcome Estimator [ 49 ].
Therefore, centers must individualize a treatment threshold that stratifies outcomes e. Further studies in this time period could help guide clinicians on the timing and effectiveness of corticosteroids to facilitate extubation, reduce the severity of BPD, and assess improvements in morbidities e.
Bhandari et al. A retrospective study by Linafelter et al. The investigators noted a significant decrease in respiratory support after one week of prednisolone therapy and noted no further benefits from the prolongation of therapy and significant linear growth impairment by week 4.
Both the Bhandari and Linafelter studies indicated a potential benefit for improving the respiratory status of infants with established BPD. However, both studies concluded that the benefits of prednisolone therapies may not be seen with a prolonged course or multiple courses. Likewise, benefits must be carefully measured against adverse effects. ICS, such as beclomethasone, budesonide, and fluticasone, are also commonly used to treat evolving or established BPD [ 52 ].
ICS use is inversely related to GA and directly related to duration of mechanical ventilation exposure [ 56 ]. Yuskel et al. Dugas et al. The study concluded that fluticasone does not reduce invasive mechanical ventilation duration or the need for supplemental oxygen use [ 59 ]. A prolonged 1-year course of fluticasone or placebo was also evaluated by Beresford et al.
This study reported no difference in respiratory symptoms, duration of supplemental oxygen use, respiratory illnesses, or need for hospitalization [ 60 ]. At this moment, although there is limited supporting evidence for the use of ICS, clinicians have few therapeutic options for managing ongoing pulmonary inflammation in preterm infants.
In examining the highlighted trials above, we note that as postnatal age and PMA increase, the treatment regimens used both increased initial doses and cumulative doses Fig. The cumulative steroid dose can be very high, particularly if infants are exposed to more than one regimen or stall in their glucocorticoid weaning due to failure to meet clinical outcomes, depending on the cumulative exposure and duration of the corticosteroid course s Fig.
Infants are at risk for secondary adrenal insufficiency if the infant has been given supraphysiologic glucocorticoid doses for more than 14 days [ 61 ]. Exogenous supraphysiologic glucocorticoids cause secondary adrenal insufficiency through a myriad of effects on the HPA axis, the physiologic regulator of endogenous glucocorticoid production Fig.
The hypothalamus releases corticotropin releasing hormone CRH from neurons in the paraventricular nucleus. CRH then stimulates transcription of pro-opiomelanocortin from the anterior pituitary gland corticotropes. A series of proteolytic cleavages leads to the production of adrenocorticotropic hormone ACTH. ACTH then stimulates the adrenal gland to produce cortisol.
ACTH upregulates cortisol production acutely by increasing the available cholesterol substrate pool and stimulating the synthesis of the steroidogenic acute regulatory protein responsible for transporting cholesterol into the mitochondria for steroidogenesis to occur. Often antenatal steroid exposure is not considered. BPD bronchopulmonary dysplasia, BP blood pressure. Cortisol exerts negative feedback on both the hypothalamus and anterior pituitary, leading to decrease in both corticotropin releasing factor CRF and adrenocorticotropic hormone ACTH predominantly through action on the glucocorticoid receptor GR.
When cortisol levels drop or there is a physiologic need for cortisol release, CRF and ACTH levels rise, stimulating the secretion and production of cortisol by the adrenal gland. Mineralocorticoid receptors MR are expressed at low levels in the hypothalamus and anterior pituitary. Prolonged exposure to glucocorticoids affects all levels of the HPA axis. In addition, glucocorticoid therapy suppresses both pro-opiomelanocortin production and storage of ACTH.
With long-term chronic suppression of ACTH release, there is a diminished transcription of enzymes involved in the biosynthesis of glucocorticoids. The adrenal reserve is lost, leading to the risk of an adrenal crisis after exogenous glucocorticoid treatment is discontinued.
Recovery of the HPA axis after glucocorticoid exposure is dependent on multiple factors, including the total dose, potency, and length of glucocorticoid exposure. Studies in VLBW premature infants treated with a 3-week course of dexamethasone demonstrated differential recovery of the axis, with the hypothalamic-pituitary signaling measured by CRH testing recovering earlier than adrenal gland function measured by ACTH stimulation testing [ 64 , 65 ]. This indicates that infants are at risk for an adrenal crisis following glucocorticoid therapy and will require stress dose steroids during critical illness, with or without fever, and for surgical procedures [ 61 , 63 ].
This strategy is part of the regimens used in most postnatal corticosteroid studies Table 2. While there are no specific guidelines for glucocorticoid weaning, we propose a protocol Table 3. It should be noted that methylprednisolone, prednisolone, and dexamethasone are 4x, 5x, and 25x more potent than hydrocortisone, respectively Table 1 [ 5 ]. For infants who have been on a steroid course for 10—14 days including taper time , glucocorticoids can be discontinued once the steroid course is completed Table 3.
These infants generally do not require follow-up with pediatric endocrinologists. However, they should be monitored closely for signs and symptoms of adrenal insufficiency, including hypoglycemia, hypotension, and hyponatremia, as well as lethargy, poor feeding, and listlessness. Glucocorticoids are essential for free water excretion; thus, patients with central adrenal insufficiency may develop fluid retention and hyponatremia [ 66 , 67 ].
If the infant is discharged within 14 days of the steroid treatment, pediatrician evaluation post-discharge is prudent to ensure adequate feeding, growth, and developmental progress Table 4 [ 68 ]. A similar practice has been used for over a decade at the University at Buffalo. In our experience, the protocol is safe and adaptable for inpatient use. At that point, convert over to hydrocortisone administered as twice-daily dosing for 3 days. During this time, especially with twice-daily dosing and lower exogenous HC levels, the HPA axis has an opportunity to initiate endogenous cortisol production.
If the infant has any evidence of adrenal insufficiency during the weaning process, the dose can be increased to the previously tolerated dose, and the frequency of dosing weans can be extended by an additional 3—6 days. Once the steroid wean is complete, the infant should be monitored closely for signs of adrenal insufficiency. The team also needs to determine if and when the infant should undergo provocative stimulation of the adrenal gland to evaluate the recovery of the HPA axis [ 61 , 63 ].
Based on our collective experience and recommendations, Table 4 guides management with respect to the involvement of a pediatric endocrinologist and the need for a stimulation test. The length of steroid exposure and the anticipated observation period in the hospital after the steroid wean are considered when making this decision. Although obtaining cortisol levels in infants after being weaned to maintenance or off hydrocortisone might decrease the number of ACTH stimulation tests, our collective recommendation is that obtaining a pre-8 a.
This is because infants, particularly those in an intensive care setting, have not established a diurnal rhythm for cortisol production [ 71 , 72 ]. The pediatric endocrinology team can assist with the interpretation of adrenal function testing, can provide stress dose counseling to families as needed, and plan outpatient follow up as needed.
Even with the recommended glucocorticoid weans, some neonates will have either confirmed or presumed ongoing secondary adrenal insufficiency at the time of discharge. For these patients, a discharge plan should be developed with pediatric endocrinology colleagues. Hydrocortisone is commercially available as a tablet, which may be crushed and mixed with a small amount of formula.
Oral suspensions are also commonly used and can be requested from a compounding pharmacy. Regardless of the formulation used, parents should be taught when and how much hydrocortisone should be administered, and instructed to monitor the expiration date of the formulation.
This letter also guides future medical professionals to provide appropriate care for an infant during the recovery phase of secondary adrenal insufficiency. Infants discharged from the NICU with an ongoing diagnosis of secondary adrenal insufficiency should be scheduled for outpatient follow-up with pediatric endocrinology.
The endocrinology team will adjust hydrocortisone stress doses for growth, reinforce stress dosing issues, assess recovery of the HPA axis and answer guardian or caretaker questions. The previous recommendations are based on a protocol developed collaboratively between neonatology and endocrinology in Buffalo in , which avoids routine cortisol measurements.
Anecdotally this protocol has worked well and been safe for over a decade. The development of BPD is multidimensional. The imbalance of pro-inflammatory and anti-inflammatory pathways contributing to the lung injury can be attributed to different settings: prenatal e. Systemic corticosteroids have anti-inflammatory properties and provide clinicians with options to prevent, treat, or mitigate the lung injury.
Dexamethasone and inhaled budesonide are not recommended for use before 7 days of age. Similarly, although inhaled budesonide decreases the risk of BPD, it has been shown to increase mortality. If early hydrocortisone is used, concurrent treatment with NSAIDs must be avoided to reduce the risk of gastrointestinal perforation. Infants with either evolving or established BPD may benefit from late postnatal corticosteroids.
However, a consensus approach balancing the benefits and risks of corticosteroid treatment in early evolving BPD does not exist. There are also no prospective trials comparing dexamethasone to hydrocortisone directly. The relative benefits timing of extubation, prevention of BPD, and late pulmonary complications and risks long-term NDI of high-dose hydrocortisone compared to low-dose dexamethasone remain a research priority. After 21 days of age, based on clear efficacy in this window of lung disease, dexamethasone can be used with less concern for neurologic harm.
In this period, the evidence for BPD management with corticosteroids is minimal. In our practice, we continue to utilize the DART regimen in this period. For infants with established severe BPD, prednisolone may be used, but data are based only on retrospective analyses. In our practice, we tend to utilize the shorter Bhandari et al. When prolonged prednisolone courses in the Linafelter et al. Likewise, monitoring for adverse effects, including growth failure, should be assessed regularly as a multidisciplinary team.
Iatrogenic adrenal insufficiency is a side effect of this glucocorticoid treatment and must be managed appropriately. By recognizing the different potencies of glucocorticoids and using rational weaning protocols, recovery of the HPA axis is possible in the hospital. If this is not an option, families should be educated on recognizing and treating adrenal insufficiency in order to decrease the risk of morbidity. The neonatal care team plays a definitive role in the recognition and management of secondary adrenal insufficiency while providing reassurance to caregivers that this condition generally resolves as their child matures.
Since systemic steroids are used commonly in premature infants in various circumstances, including in the management of BPD, we need to be strategic in how we safely support the recovery of the HPA axis for these babies. Jobe AH. Postnatal corticosteroids for bronchopulmonary dysplasia.
Clin Perinatol. Inflammatory mediators in the immunobiology of bronchopulmonary dysplasia.