Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Relative adrenal insufficiency in the preterm and term infant

Journal of Perinatology volume 29, pages S44–S49 (2009)Cite this article

Abstract

Cortisol release in the face of illness or stress is vital for survival. Relative adrenal insufficiency occurs when a patient's cortisol response is inadequate for the degree of illness or stress. Numerous studies have documented the existence of relative adrenal insufficiency in critically ill adults, and its association with increased morbidity and mortality. There is increasing evidence that relative adrenal insufficiency may be an etiology for hemodynamic instability and hypotension in the critically ill newborn, but compared with the adult population, there is still a paucity of data in this population. Randomized controlled trials are needed to evaluate the efficacy and safety of glucocorticoids for the treatment of cardiovascular insufficiency due to relative adrenal insufficiency in ill preterm and term newborn infants.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Annane D, Sebille V, Troche G, Raphael J, Gajdos P, Bellissant E . A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotrophin. JAMA 2000; 283: 1038–1045.

    Article  CAS  PubMed  Google Scholar 

  2. Cooper MS, Stewart PM . Corticosteroid insufficiency in acutely ill patients. N Engl J Med 2003; 348: 727–734.

    Article  CAS  PubMed  Google Scholar 

  3. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y . Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004; 329: 480–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Arafah BM . Hypothalamic pituitary adrenal function during critical illness: limitation of current assessment methods. J Clin Endocrinol Metab 2006; 91: 3725–3745.

    Article  CAS  PubMed  Google Scholar 

  5. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862–871.

    Article  CAS  PubMed  Google Scholar 

  6. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S et al. Imunologic and hemodynamic effects of ‘low-dose’ hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 2003; 167: 512–520.

    Article  PubMed  Google Scholar 

  7. Briegel J, Kellermann W, Forst H, Haller M, Bittle M, Hoffmann GE et al. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. Clin Investig 1994; 72: 782–787.

    Article  CAS  PubMed  Google Scholar 

  8. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al., CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358: 111–124.

    Article  CAS  PubMed  Google Scholar 

  9. Cooper MS, Stewart PM . Adrenal insufficiency in critical illness. J Intensive Care Med 2007; 22: 348–362.

    Article  PubMed  Google Scholar 

  10. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M . Multiple actions of steroid hormones—a focus on rapid, nongenomic effects. Pharmacol Rev 2000; 52: 513–555.

    CAS  PubMed  Google Scholar 

  11. Chrousos GP . The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332: 1351–1362.

    Article  CAS  PubMed  Google Scholar 

  12. Prigent H, Maxime V, Annane D . Clinical review: corticotherapy in sepsis. Crit Care 2004; 8: 122–129.

    Article  PubMed  Google Scholar 

  13. Swingle WW, Pfiffner JJ, Vars HM, Bott PA, Parkins WM . The function of the adrenal cortical hormone and the cause of death from adrenal insufficiency. Science 1933; 77: 58–64.

    Article  CAS  PubMed  Google Scholar 

  14. Swingle WW, DaVanzo JP, Crossfield HC, Glenister D, Osborn M, Rowan R et al. Glucocorticoids and maintenance of blood pressure and plasma volume of adrenalectomized dogs subjected to stress. Proc Soc Exp Biol Med 1959; 100: 617–622.

    Article  CAS  PubMed  Google Scholar 

  15. Udelsman R, Ramp J, Gallucci WT, Gordon A, Lipford E, Norton JA et al. Adaption during surgical stress: a reevaluation of the role of glucocorticoids. J Clin Invest 1986; 77: 1377–1381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. deJong FH, Mallios C, Jansen C, Scheck PAE, Lamberts SWJ . Etomidate suppresses adrenocortical function by inhibition of 11B-hydroxylation. J Clin Endocrinol Metab 1984; 59: 1143–1147.

    Article  CAS  Google Scholar 

  17. Lamberts SWJ, Bruining HA, deJong FH . Corticosteroid therapy in severe illness. N Engl J Med 1997; 337: 1285–1292.

    Article  CAS  PubMed  Google Scholar 

  18. de Kleijn ED, Joosten FM, Van Rijn B, Westerterp M, De Groot R, Hokken-Koelega ACS et al. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J 2002; 21: 330–336.

    Article  PubMed  Google Scholar 

  19. den Brinker M, Koen FM, Joosten FM, Liem O, de Jong FH, Hop WCJ et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005; 90: 5110–5117.

    Article  CAS  PubMed  Google Scholar 

  20. Finlay WE, McKee Jl . Serum cortisol levels in severely stressed patients. Lancet 1982; 1: 1414–1415.

    Article  CAS  PubMed  Google Scholar 

  21. McKee JI, Finlay WE . Cortisol replacement in severely stressed patients. Lancet 1983; 1: 484.

    Article  CAS  PubMed  Google Scholar 

  22. Mesiano S, Jaffe RB . Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997; 18: 378–403.

    CAS  PubMed  Google Scholar 

  23. Donaldson A, Nicolini U, Symes EK, Rodeck CH, Tannirandorn Y . Changes in concentrations of cortisol, dehydroepiandrosterone sulphate and progesterone in fetal and maternal serum during pregnancy. Clin Endocrinol (Oxf) 1991; 35: 447–451.

    Article  CAS  Google Scholar 

  24. Ward RM, Kimura RE, Rich-Denson C . Addisonian crisis in extremely premature neonates. Clin Res 1991; 39: 11A.

    Google Scholar 

  25. Colasurdo MA, Hanna CE, Gilhooly JT, Reynolds JW . Hydrocortisone replacement in extremely premature neonates with cortisol insufficiency. Clin Res 1989; 37: 180A.

    Google Scholar 

  26. Scott SM, Watterberg KL . Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants. Pediatr Res 1995; 37: 112–116.

    Article  CAS  PubMed  Google Scholar 

  27. Hanna CE, Jett PL, Laird MR, Mandel SH, LaFranchi SH, Reynolds JW . Corticosteroid binding globulin, total serum cortisol, and stress in extremely low-birth weight infants. Am J Perinatol 1997; 14: 201–204.

    Article  CAS  PubMed  Google Scholar 

  28. Huysman MWA, Hokken-Koelega ACS, De Ridder MAJ, Sauer PJJ . Adrenal function in sick very preterm infants. Pediatr Res 2000; 48: 629–633.

    Article  CAS  PubMed  Google Scholar 

  29. Karlsson R, Kallio J, Irjala K, Ekblad S, Toppari J, Kero P . Adrenocorticotropin and corticotropin-releasing hormone tests in preterm infants. J Clin Endocrinol Metab 2000; 85: 4592–4595.

    CAS  PubMed  Google Scholar 

  30. Ng P, Wong G, Lam CWK, Lee CH, Wong M, Fok T et al. The pituitary–adrenal response to exogenous human corticotropin-releasing hormone in preterm, very low birth weight infants. J Clin Endocrinol Metab 1997; 82: 797–799.

    Article  CAS  PubMed  Google Scholar 

  31. Watterberg KL, Scott SM . Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia. Pediatrics 1995; 95: 120–125.

    CAS  PubMed  Google Scholar 

  32. Watterberg KL, Scott SM, Backstrom C, Gifford KL, Cook KL . Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus. Pediatrics 2000; 105: 320–324.

    Article  CAS  PubMed  Google Scholar 

  33. Watterberg KL, Gerdes JS, Cole CH, Aucott SW, Thilo EH, Mammel MC et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics 2004; 114: 1649–1657.

    Article  PubMed  Google Scholar 

  34. Banks BA, Stouffer N, Cnaan A, Ning Y, Merrill JD, Ballard RA et al., North American Thyrotropin-Releasing Hormone Trial Collaborators. Association of plasma cortisol and chronic lung disease in preterm infants. Pediatrics 2001; 107: 494–498.

    Article  CAS  PubMed  Google Scholar 

  35. Ng PC, Lam CW, Fok TF, Lee CH, Ma KC, Chan IH et al. Refractory hypotension in preterm infants with adrenocortical insufficiency. Arch Dis Child Fetal Neonatal Ed 2001; 84: F122–F124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arnold JD, Bonacruz G, Leslie GI, Veldhuis JD, Milmlow D, Silink M . Antenatal glucocorticoids modulate the amplitude of pulsatile cortisol secretion in premature neonates. Pediatr Res 1998; 44: 876–881.

    Article  CAS  PubMed  Google Scholar 

  37. Yoder B, Martin H, McCurnin DC, Coalson JJ . Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons. Pediatr Res 2002; 51: 426–432.

    Article  CAS  PubMed  Google Scholar 

  38. Gertsmann D, Minton S, Stoddard R, Lang L, Burnham E, Auxier P . Capillary leak syndrome in ventilated neonates needing cardiovascular support (CVS)-response to hydrocortisone. J Invest Med 1997; 45: 166A.

    Google Scholar 

  39. Helbock HJ, Insoft RM, Conte FA . Glucocorticoid-responsive hypotension in extremely low birth weight newborns. Pediatrics 1993; 92: 715–717.

    CAS  PubMed  Google Scholar 

  40. Gaissmaier RE, Pohlandt F . Single-dose dexamethasone treatment of hypotension in preterm infants. J Pediatr 1999; 134: 701–705.

    Article  CAS  PubMed  Google Scholar 

  41. Fauser A, Pohlandt F, Bartmann P, Gortner L . Rapid increase of blood pressure in extremely low birth weight infants after a single dose of dexamethasone. Eur J Pediatr 1993; 152: 354–356.

    Article  CAS  PubMed  Google Scholar 

  42. Seri I, Tan R, Evans J . Cardiovascular effects of hydrocortisone in preterm infants with pressor-resistant hypotension. Pediatrics 2001; 107: 1070–1074.

    Article  CAS  PubMed  Google Scholar 

  43. Kopelman AE, Moise AA, Holbert D, Hegemier SE . A single very early dexamethasone dose improves respiratory and cardiovascular adaptation in preterm infants. J Pediatr 1999; 135: 345–350.

    Article  CAS  PubMed  Google Scholar 

  44. Noori S, Friedlich P, Wong P, Ebrahimi M, Siassi B, Seri I . Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated preterm and term neonates. Pediatrics 2006; 118: 1456–1466.

    Article  PubMed  Google Scholar 

  45. Ng PC, Lee CH, Bnur FL, Chan IH, Lee AW, Wong E et al. A double-blind, randomized, controlled study of a ‘stress dose’ of hydrocortisone for rescue treatment of refractory hypotension in preterm infants. Pediatrics 2006; 117: 367–375.

    Article  PubMed  Google Scholar 

  46. Bonsante F, Latorre G, Iacobelli S, Forziati V, Laforgia N, Esposito L et al. Early low-dose hydrocortisone in very preterm infants: a randomized, placebo-controlled trial. Neonatology 2007; 91: 217–221.

    Article  CAS  PubMed  Google Scholar 

  47. Efird MM, Heerens AT, Gordon PV, Bose CL, Young DA . A randomized-controlled trial of prophylactic hydrocortisone supplementation for the prevention of hypotension in extremely low birth weight infants. J Perinatol 2005; 25: 119–124.

    Article  CAS  PubMed  Google Scholar 

  48. Watterberg KL . Adrenocortical function and dysfunction in the fetus and neonate. Semin Neonatol 2004; 9: 13–21.

    Article  PubMed  Google Scholar 

  49. Goland RS, Wardlaw SL, Blum M, Tropper PJ, Stark RI . Biologically active corticotrophin-releasing hormone in maternal and fetal plasma during pregnancy. Am J Obstet Gynecol 1988; 159: 884–890.

    Article  CAS  PubMed  Google Scholar 

  50. McLean M, Smith R . Corticotrophin-releasing hormone and human parturition. Reproduction 2001; 121: 493–501.

    Article  CAS  PubMed  Google Scholar 

  51. Anand KJ, Hansen DD, Hickey PR . Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology 1990; 73: 661–670.

    Article  CAS  PubMed  Google Scholar 

  52. Naito Y, Fukata J, Tamai S, Seo N, Nakai Y, Mori K et al. Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab 1991; 73: 111–117.

    Article  CAS  PubMed  Google Scholar 

  53. Anand KJ, Aynsley-Green A . Measuring the severity of surgical stress in newborn infants. J Pediatr Surg 1988; 23: 297–305.

    Article  CAS  PubMed  Google Scholar 

  54. Thomas S, Murphy JF, Dyas J, Ryalls M, Hughes IA . Response to ACTH in the newborn. Arch Dis Child 1986; 61: 57–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pittinger TP, Sawin RS . Adrenocortical insufficiency in infants with congenital diaphragmatic hernia: a pilot study. J Pediatr Surg 2000; 35: 223–226.

    Article  CAS  PubMed  Google Scholar 

  56. Tantavit P, Subramanian N, Garg M, Ramanathan R, deLemos RA . Low serum cortisol in term newborns with refractory hypotension. J Perinatol 1999; 19: 352–357.

    Article  Google Scholar 

  57. Soliman AT, Taman KH, Rizk MM, Nasr IS, AIRimawy H, Hamido MS . Circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations in normal, appropriate−for−gestational−age newborns versus those with sepsis and respiratory distress: cortisol response to low-dose and standard-dose ACTH tests. Metabolism 2004; 53: 209–214.

    Article  CAS  PubMed  Google Scholar 

  58. Fernandez EF, Watterberg KL . Prevalence of low cortisol values in term and near-term infants with vasopressor-resistant hypotension. J Perinatol 2005; 25: 114–118.

    Article  CAS  PubMed  Google Scholar 

  59. Fernandez EF, Montman R, Watterberg KL . ACTH and cortisol response to critical illness in term and late preterm newborns. J Perinatol 2008; 28: 797–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Reincke M, Allolio B, Wurth G, Winkelmann W . The hypothalamic–pituitary–adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. J Clin Edocrinol Metab 1993; 77: 151–156.

    CAS  Google Scholar 

  61. Joosten KFM, De Kleijn ED, Westerterp M, De Hoog M, Eijck FCV, Hop WCJ et al. Endocrine and metabolic responses in children with meningococcal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000; 85: 3746–3753.

    Article  CAS  PubMed  Google Scholar 

  62. Mial-Allen VM, DeVries LS, Whitelaw AGL . Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child 1987; 62: 1068–1069.

    Article  Google Scholar 

  63. Watterberg KL, Gerdes JS, Cook KL . Impaired glucocorticoid synthesis in premature infants developing chronic lung disease. Pediatr Res 2001; 50: 190–195.

    Article  CAS  PubMed  Google Scholar 

  64. Mial-Allen VM, DeVries LS, Dubowitz LMS, Whitelaw AGL . Blood pressure fluctuation and intraventricular hemorrhage in the preterm infant of less than 31 weeks gestation. Pediatrics 1989; 83: 657–661.

    Google Scholar 

  65. Kopelman AE . Blood pressure and cerebral ischemia in very low birth weight infants. J Pediatr 1990; 116: 1000–1002.

    Article  CAS  PubMed  Google Scholar 

  66. Goldstein RF, Thompson Jr RJ, Oehler JM, Brazy JE . Influence of acidosis, hypoxemia and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995; 95: 238–243.

    CAS  PubMed  Google Scholar 

  67. Murphy DJ, Hope PL, Johnson A . Neonatal risk factors for cerebral palsy in very preterm babies: case–control study. BMJ 1997; 314: 404–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Peltoniemi O, Kari MA, Heinonen K, Saarela T, Nikolajev K, Andersson S et al. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005; 146: 632–637.

    Article  CAS  PubMed  Google Scholar 

  69. Rademaker KJ, Uiterwaal CS, Groenendaal F, Venema MM, van Bel F, Beek FJ et al. Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children. J Pediatr 2007; 150: 351–357.

    Article  CAS  PubMed  Google Scholar 

  70. Watterberg KL, Shaffer ML, Mishefske MJ, Leach CL, Mammel MC, Couser RJ et al. Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics 2007; 120: 40–48.

    Article  PubMed  Google Scholar 

  71. Watterberg KL, Shaffer ML, for The PROPHET Study Group. Cortisol concentrations and apparent serum half-life during hydrocortisone therapy in extremely low birth weight infants. PAS 2005; 57: 1501.

    Google Scholar 

  72. Gordon PV, Price WA, Stiles AD, Rutledge JC . Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants. Pediatr Dev Pathol 2001; 4: 532–537.

    Article  CAS  PubMed  Google Scholar 

  73. Reynolds JW, Colle E, Ulstrom RA . Adrenocortical steroid metabolism in newborn infants. V. Physiologic disposition of exogenous cortisol loads in the early neonatal period. J Clin Endocrinol Metab 1962; 22: 245–254.

    Article  CAS  PubMed  Google Scholar 

  74. Ng PC, Lee CH, Lam CW, Ma KC, Chan IH, Wong E et al. Early pituitary–adrenal response and respiratory outcomes in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004; 89: F127–F130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, USA

    E F Fernandez & K L Watterberg

Authors
  1. E F Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K L Watterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E F Fernandez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernandez, E., Watterberg, K. Relative adrenal insufficiency in the preterm and term infant. J Perinatol 29 (Suppl 2), S44–S49 (2009). https://doi.org/10.1038/jp.2009.24

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jp.2009.24

Keywords

This article is cited by

Search

Advanced search

Quick links