ACTH Stimulation Test in Pediatrics

Patient Group	ACTH Dose	Cortisol Measurement Timepoints	Administration Route
Newborns (microdose)	1 microgram (1 mcg) of synthetic ACTH	0 minutes (Baseline), 30 minutes, 60 minutes	Intravenous (IV) or Intramuscular (IM)
Newborns (Neonates)	0.125 milligrams (125 micrograms) of synthetic ACTH	0 minutes (Baseline), 30 minutes, 60 minutes	Intravenous (IV) or Intramuscular (IM)
Infants and Older Children	0.25 milligrams (250 micrograms) of synthetic ACTH	0 minutes (Baseline), 30 minutes, 60 minutes	Intravenous (IV) or Intramuscular (IM)

Cortisol Measurement and Interpretation

Timing	Normal Response	Indication of Adrenal Insufficiency
Baseline (0 minutes)	Varies with age and time of day; generally >5 mcg/dL	Low (<5 mcg/dL) could indicate adrenal insufficiency
30 minutes after ACTH	>18-20 mcg/dL (500-550 nmol/L)	<18 mcg/dL suggests possible adrenal insufficiency
60 minutes after ACTH	>18-20 mcg/dL (500-550 nmol/L)	<18 mcg/dL confirms likely adrenal insufficiency Introduction

The ACTH (adrenocorticotropic hormone) stimulation test is a critical diagnostic tool used to evaluate adrenal gland function in pediatric patients, including newborns, infants, and older children. This test helps determine if the adrenal glands are capable of producing sufficient cortisol in response to ACTH stimulation, thereby assessing the presence of adrenal insufficiency. Given the importance of cortisol in various physiological processes, including stress response, metabolism, and immune function, it is essential to accurately diagnose and manage adrenal insufficiency in children.

Why Perform the ACTH Stimulation Test?

Cortisol is a vital hormone produced by the adrenal cortex, playing a crucial role in maintaining homeostasis, especially during stress. Insufficient cortisol production can lead to adrenal insufficiency, a condition that, if untreated, can be life-threatening. The ACTH stimulation test helps differentiate between primary adrenal insufficiency (where the problem lies within the adrenal glands themselves) and secondary or tertiary adrenal insufficiency (where the issue is related to the pituitary or hypothalamus). The test is particularly important in pediatric populations where timely diagnosis can significantly impact long-term outcomes.

Indications for the ACTH Stimulation Test:

• Suspected Adrenal Insufficiency: Symptoms such as chronic fatigue, weakness, hypotension, unexplained weight loss, and hypoglycemia.

• Congenital Adrenal Hyperplasia (CAH): To monitor adrenal function in known cases or to diagnose this condition.

• Hypopituitarism: To evaluate secondary adrenal insufficiency due to pituitary dysfunction.

• Critical Illness: When adrenal insufficiency is suspected in critically ill children.
  

Procedure for the ACTH Stimulation Test in Pediatrics

1. Baseline Cortisol Measurement:

• Rationale: The test begins with measuring the baseline serum cortisol level, which provides a reference point for evaluating the adrenal glands' response to ACTH.

• Procedure: A blood sample is drawn before administering ACTH to measure the baseline cortisol level.

2. Administration of Synthetic ACTH (Cosyntropin):

• Dosage:

  • Newborns (Neonates): Administer 0.125 mg (125 micrograms) of synthetic ACTH either intravenously or intramuscularly.

  • Infants and Older Children: Administer 0.25 mg (250 micrograms) of synthetic ACTH intravenously or intramuscularly.

• Rationale: The standardized dosage is based on ensuring a sufficient stimulus to the adrenal glands, regardless of body weight, to elicit a maximal cortisol response.

3. Post-ACTH Cortisol Level Measurement:

• Timepoints: Cortisol levels are measured at 30 minutes and 60 minutes after ACTH administration.

• Rationale: These timepoints are critical for assessing the peak adrenal response to ACTH, with the expectation that cortisol levels should significantly rise from the baseline.

4. Interpretation of Results:

• Normal Response: A significant increase in cortisol levels, typically greater than 18-20 micrograms/dL (500-550 nmol/L), indicates normal adrenal function.

• Impaired Response:

  • Primary Adrenal Insufficiency: Characterized by a low baseline cortisol level and an inadequate response to ACTH stimulation, suggesting adrenal gland dysfunction.

  • Secondary or Tertiary Adrenal Insufficiency: Indicated by a low cortisol response due to insufficient ACTH production from the pituitary or hypothalamus.
    

Clinical Implications

The results of the ACTH stimulation test guide the clinical management of adrenal insufficiency in pediatric patients:

• Normal Response: Excludes significant adrenal insufficiency and often requires no further immediate intervention.

• Adrenal Insufficiency Diagnosis:

  • Primary Adrenal Insufficiency: Requires lifelong corticosteroid replacement therapy. In cases like Addison's disease or Congenital Adrenal Hyperplasia (CAH), mineralocorticoid replacement may also be necessary.

  • Secondary/Tertiary Adrenal Insufficiency: Often managed with glucocorticoid replacement, with attention to the underlying cause, such as pituitary adenomas or hypothalamic disorders.

Long-term Management:

• Ongoing Monitoring: Regular follow-up is essential to adjust medication dosages, especially during periods of illness or stress, where cortisol demand increases.

• Patient and Family Education: It is crucial to educate families about the condition, including recognizing signs of adrenal crisis and the importance of stress dosing during illness or surgery.
  

Conclusion

The ACTH stimulation test remains a cornerstone in the evaluation of adrenal function in pediatric patients. By providing a structured and accurate assessment of adrenal insufficiency, this test allows for timely and effective management, ensuring better outcomes for children with this potentially life-threatening condition. Regular follow-up and patient education are critical components of ongoing care for those diagnosed with adrenal insufficiency.

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Cortisol Levels and Cutoff Values for the ACTH Stimulation Test in Pediatrics

The interpretation of cortisol levels in response to the ACTH stimulation test can vary depending on the gestational age (GA), the dose of ACTH administered, and the timing of the cortisol measurements. Below is a summary of the expected cortisol values and the cutoff points for diagnosing adrenal insufficiency.

Cortisol Measurement and Interpretation

Timing	Normal Response	Indication of Adrenal Insufficiency
Baseline (0 minutes)	Varies with age and time of day; generally >5 mcg/dL	Low (<5 mcg/dL) could indicate adrenal insufficiency
30 minutes after ACTH	>18-20 mcg/dL (500-550 nmol/L)	<18 mcg/dL suggests possible adrenal insufficiency
60 minutes after ACTH	>18-20 mcg/dL (500-550 nmol/L)	<18 mcg/dL confirms likely adrenal insufficiency

Cortisol Response Based on GA and ACTH Dose

1. 1 mcg ACTH Dose in Newborns (Neonates)

   • Gestational Age (GA): Preterm (<37 weeks) vs. Full-term (≥37 weeks)

   • Baseline (0 min):

     • Preterm: Cortisol levels may be slightly lower; typically >5 mcg/dL is expected.

     • Full-term: Generally >5 mcg/dL.

   • 30 and 60 min after ACTH:

     • Normal Response: >18 mcg/dL at 30 or 60 minutes.

     • Adrenal Insufficiency: <18 mcg/dL at 30 or 60 minutes.

2. 125 mcg ACTH Dose in Newborns (Neonates)

   • Baseline (0 min):

     • Typically >5 mcg/dL.

   • 30 and 60 min after ACTH:

     • Normal Response: >18-20 mcg/dL at 30 or 60 minutes.

     • Adrenal Insufficiency: <18 mcg/dL at 30 or 60 minutes.

3. 250 mcg ACTH Dose in Infants and Older Children

   • Baseline (0 min):

     • Typically >5 mcg/dL; consider age and clinical context.

   • 30 and 60 min after ACTH:

     • Normal Response: >18-20 mcg/dL at 30 or 60 minutes.

     • Adrenal Insufficiency: <18 mcg/dL at 30 or 60 minutes.
       

Gestational Age and Adrenal Response

• Preterm Infants:

  • May have lower baseline cortisol levels due to immature adrenal glands.

  • Normal response after ACTH stimulation may still reach the >18 mcg/dL threshold, but slightly lower cutoffs may sometimes be considered based on clinical context.

• Full-term Infants and Older Children:

  • Expected to have baseline cortisol levels around or above 5 mcg/dL.

  • A strong response (>18-20 mcg/dL) to ACTH stimulation is expected at both 30 and 60 minutes.
    

Cutoff Values for Adrenal Insufficiency Diagnosis

• Baseline Cortisol:

  • <5 mcg/dL: May suggest adrenal insufficiency, especially if symptoms are present.

• Post-ACTH Cortisol (30 or 60 min):

  • <18 mcg/dL: Indicates likely adrenal insufficiency, necessitating further evaluation and possibly initiating corticosteroid therapy.
    

Summary

• Normal Cortisol Response: A rise to >18-20 mcg/dL at 30 or 60 minutes post-ACTH indicates normal adrenal function.

• Adrenal Insufficiency: Failure to reach 18 mcg/dL after ACTH administration suggests adrenal insufficiency, with the specific cutoff being consistent across different gestational ages and doses.
  

Clinical Application

• Preterm Neonates: More cautious interpretation may be required due to lower baseline levels.

• Full-term and Older Children: More standardized cutoff values apply, with clear differentiation between normal and impaired responses.