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. 2004 Mar;89(2):F119–F126. doi: 10.1136/adc.2002.021972

Transient adrenocortical insufficiency of prematurity and systemic hypotension in very low birthweight infants

P Ng, C Lee, C Lam, K Ma, T Fok, I Chan, E Wong
PMCID: PMC1756043  PMID: 14977894

Abstract

Objectives: A proportion of preterm, very low birthweight (VLBW, < 1500 g) infants may show inadequate adrenal response to stress in the immediate postnatal period. The human corticotrophin releasing hormone (hCRH) stimulation test was used to: (a) determine the relation between pituitary-adrenal response and systemic blood pressure in these infants; (b) characterise the endocrinological features of transient adrenocortical insufficiency of prematurity (TAP).

Study design: A total of 226 hCRH tests were performed on 137 VLBW infants on day 7 and 14 of life in a tertiary neonatal centre.

Results: Basal, peak, and incremental rise in serum cortisol (ΔCort0–30) on day 7 were associated significantly with the lowest systolic, mean, and diastolic blood pressures recorded during the first two weeks of life (r > 0.25, p < 0.005). These cortisol concentrations also correlated significantly but negatively with the maximum and total cumulative dose of dopamine (r > -0.22, p < 0.02), dobutamine (r > -0.18, p < 0.04), and adrenaline (r > -0.26, p < 0.004), total volume of crystalloid (r > -0.22, p < 0.02), and duration of inotrope treatment (r > -0.25, p < 0.006). Multivariate regression analysis of significant factors showed that the lowest systolic, mean, and diastolic blood pressures remained independently associated with serum cortisol (basal, peak, and ΔCort0–30) on day 7. Hypotensive infants requiring inotropes (group 2) were significantly less mature and more sick than infants with normal blood pressure (group 1). The areas under the ACTH response curves were significantly greater in group 2 than in group 1, on both day 7 (p = 0.004) and day 14 (p = 0.004). In contrast, the area under the cortisol response curve was significantly greater in group 1 than in group 2 on day 7 (p = 0.001), but there was no significant difference between the two groups on day 14. In addition, serum cortisol at the 50th centile in hypotensive infants had high specificity and positive predictive value (0.80–0.93 and 0.81–0.89 respectively) for predicting early neonatal hypotension.

Conclusions: This study characterises the fundamental endocrinological features of TAP: normal or exaggerated pituitary response; adrenocortical insufficiency; good recovery of adrenal function by day 14 of postnatal life. The results also provide the centiles of serum cortisol for hypotensive patients and infants with normal blood pressure, and show a significant relation between serum cortisol and blood pressure in VLBW infants.

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Figure 1 .

Figure 1

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Patient recruitment process of the study. NEC, Necrotising enterocolitis.

Figure 2 .

Figure 2

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Adrenocorticotrophin (ACTH) response of the human corticotrophin releasing hormone test on days 7 and 14 in very low birthweight infants with relatively normal blood pressure (group 1) and in hypotensive infants requiring inotropic support (group 2). The values are mean (SEM). The area under the curve (AUC) is significantly greater in group 2 than in group 1, on both day 7 (p = 0.004) and 14 (p = 0.004).

Figure 3 .

Figure 3

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Cortisol response of the human corticotrophin releasing hormone test on day 7 and 14 in very low birthweight infants with relatively normal blood pressure (group 1) and in hypotensive infants requiring inotropic support (group 2). The values are mean (SEM). The area under the curve (AUC) is significantly greater in group 1 than in group 2 on day 7 (p = 0.001).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ballard J. L., Khoury J. C., Wedig K., Wang L., Eilers-Walsman B. L., Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr. 1991 Sep;119(3):417–423. doi: 10.1016/s0022-3476(05)82056-6. [DOI] [PubMed] [Google Scholar]
  2. Bauer K., Linderkamp O., Versmold H. T. Systolic blood pressure and blood volume in preterm infants. Arch Dis Child. 1993 Nov;69(5 Spec No):521–522. doi: 10.1136/adc.69.5_spec_no.521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bourchier D., Weston P. J. Randomised trial of dopamine compared with hydrocortisone for the treatment of hypotensive very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1997 May;76(3):F174–F178. doi: 10.1136/fn.76.3.f174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brodde O. E., Michel M. C., Gordon E. P., Sandoval A., Gilbert E. M., Bristow M. R. Beta-adrenoceptor regulation in the human heart: can it be monitored in circulating lymphocytes? Eur Heart J. 1989 Jun;10 (Suppl B):2–10. doi: 10.1093/eurheartj/10.suppl_b.2. [DOI] [PubMed] [Google Scholar]
  5. Davies A. O., Lefkowitz R. J. Corticosteroid-induced differential regulation of beta-adrenergic receptors in circulating human polymorphonuclear leukocytes and mononuclear leukocytes. J Clin Endocrinol Metab. 1980 Sep;51(3):599–605. doi: 10.1210/jcem-51-3-599. [DOI] [PubMed] [Google Scholar]
  6. 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 Apr;152(4):354–356. doi: 10.1007/BF01956753. [DOI] [PubMed] [Google Scholar]
  7. Gaissmaier R. E., Pohlandt F. Single-dose dexamethasone treatment of hypotension in preterm infants. J Pediatr. 1999 Jun;134(6):701–705. doi: 10.1016/s0022-3476(99)70284-2. [DOI] [PubMed] [Google Scholar]
  8. Gill A. B., Weindling A. M. Echocardiographic assessment of cardiac function in shocked very low birthweight infants. Arch Dis Child. 1993 Jan;68(1 Spec No):17–21. doi: 10.1136/adc.68.1_spec_no.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goldstein R. F., Thompson R. J., Jr, Oehler J. M., Brazy J. E. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics. 1995 Feb;95(2):238–243. [PubMed] [Google Scholar]
  10. Greenough A. Use and misuse of albumin infusions in neonatal care. Eur J Pediatr. 1998 Sep;157(9):699–702. doi: 10.1007/s004310050917. [DOI] [PubMed] [Google Scholar]
  11. Heckmann M., Wudy S. A., Haack D., Pohlandt F. Reference range for serum cortisol in well preterm infants. Arch Dis Child Fetal Neonatal Ed. 1999 Nov;81(3):F171–F174. doi: 10.1136/fn.81.3.f171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Heckmann M., Wudy S. A., Haack D., Pohlandt F. Serum cortisol concentrations in ill preterm infants less than 30 weeks gestational age. Acta Paediatr. 2000 Sep;89(9):1098–1103. doi: 10.1080/713794576. [DOI] [PubMed] [Google Scholar]
  13. Helbock H. J., Insoft R. M., Conte F. A. Glucocorticoid-responsive hypotension in extremely low birth weight newborns. Pediatrics. 1993 Nov;92(5):715–717. [PubMed] [Google Scholar]
  14. Hingre R. V., Gross S. J., Hingre K. S., Mayes D. M., Richman R. A. Adrenal steroidogenesis in very low birth weight preterm infants. J Clin Endocrinol Metab. 1994 Feb;78(2):266–270. doi: 10.1210/jcem.78.2.8106610. [DOI] [PubMed] [Google Scholar]
  15. Hui K. K., Conolly M. E., Tashkin D. P. Reversal of human lymphocyte beta-adrenoceptor desensitization by glucocorticoids. Clin Pharmacol Ther. 1982 Nov;32(5):566–571. doi: 10.1038/clpt.1982.204. [DOI] [PubMed] [Google Scholar]
  16. Huysman M. W., Hokken-Koelega A. C., De Ridder M. A., Sauer P. J. Adrenal function in sick very preterm infants. Pediatr Res. 2000 Nov;48(5):629–633. doi: 10.1203/00006450-200011000-00013. [DOI] [PubMed] [Google Scholar]
  17. 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 Dec;85(12):4592–4595. doi: 10.1210/jcem.85.12.7032. [DOI] [PubMed] [Google Scholar]
  18. Klarr J. M., Faix R. G., Pryce C. J., Bhatt-Mehta V. Randomized, blind trial of dopamine versus dobutamine for treatment of hypotension in preterm infants with respiratory distress syndrome. J Pediatr. 1994 Jul;125(1):117–122. doi: 10.1016/s0022-3476(94)70137-7. [DOI] [PubMed] [Google Scholar]
  19. Korte C., Styne D., Merritt T. A., Mayes D., Wertz A., Helbock H. J. Adrenocortical function in the very low birth weight infant: improved testing sensitivity and association with neonatal outcome. J Pediatr. 1996 Feb;128(2):257–263. doi: 10.1016/s0022-3476(96)70404-3. [DOI] [PubMed] [Google Scholar]
  20. Lee J., Rajadurai V. S., Tan K. W. Blood pressure standards for very low birthweight infants during the first day of life. Arch Dis Child Fetal Neonatal Ed. 1999 Nov;81(3):F168–F170. doi: 10.1136/fn.81.3.f168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lee M. M., Rajagopalan L., Berg G. J., Moshang T., Jr Serum adrenal steroid concentrations in premature infants. J Clin Endocrinol Metab. 1989 Dec;69(6):1133–1136. doi: 10.1210/jcem-69-6-1133. [DOI] [PubMed] [Google Scholar]
  22. Mano K., Akbarzadeh A., Townley R. G. Effect of hydrocortisone on beta-adrenergic receptors in lung membranes. Life Sci. 1979 Nov 26;25(22):1925–1930. doi: 10.1016/0024-3205(79)90614-3. [DOI] [PubMed] [Google Scholar]
  23. Ment L. R., Oh W., Ehrenkranz R. A., Philip A. G., Vohr B., Allan W., Duncan C. C., Scott D. T., Taylor K. J., Katz K. H. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994 Apr;93(4):543–550. [PubMed] [Google Scholar]
  24. Miall-Allen V. M., de Vries L. S., Dubowitz L. M., Whitelaw A. G. Blood pressure fluctuation and intraventricular hemorrhage in the preterm infant of less than 31 weeks' gestation. Pediatrics. 1989 May;83(5):657–661. [PubMed] [Google Scholar]
  25. Murphy D. J., Hope P. L., Johnson A. Neonatal risk factors for cerebral palsy in very preterm babies: case-control study. BMJ. 1997 Feb 8;314(7078):404–408. doi: 10.1136/bmj.314.7078.404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ng P. C., Lam C. W. K., Lee C. H., Ma K. C., Fok T. F., Chan I. H. S., Wong E. Reference ranges and factors affecting the human corticotropin-releasing hormone test in preterm, very low birth weight infants. J Clin Endocrinol Metab. 2002 Oct;87(10):4621–4628. doi: 10.1210/jc.2001-011620. [DOI] [PubMed] [Google Scholar]
  27. Ng P. C., Lam C. W., Fok T. F., Lee C. H., Ma K. C., Chan I. H., Wong E. Refractory hypotension in preterm infants with adrenocortical insufficiency. Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F122–F124. doi: 10.1136/fn.84.2.F122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ng P. C. The fetal and neonatal hypothalamic-pituitary-adrenal axis. Arch Dis Child Fetal Neonatal Ed. 2000 May;82(3):F250–F254. doi: 10.1136/fn.82.3.F250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ng P. C., Wong G. W., Lam C. W., Lee C. H., Wong M. Y., Fok T. F., Wong W., Chan D. C. Pituitary-adrenal response in preterm very low birth weight infants after treatment with antenatal corticosteroids. J Clin Endocrinol Metab. 1997 Nov;82(11):3548–3552. doi: 10.1210/jcem.82.11.4392. [DOI] [PubMed] [Google Scholar]
  30. Ng P. C., Wong G. W., Lam C. W., Lee C. H., Wong M. Y., Fok T. F., Wong W., Chan D. C. The pituitary-adrenal responses to exogenous human corticotropin-releasing hormone in preterm, very low birth weight infants. J Clin Endocrinol Metab. 1997 Mar;82(3):797–799. doi: 10.1210/jcem.82.3.3832. [DOI] [PubMed] [Google Scholar]
  31. Pladys P., Wodey E., Bétrémieux P., Beuchée A., Ecoffey C. Effects of volume expansion on cardiac output in the preterm infant. Acta Paediatr. 1997 Nov;86(11):1241–1245. doi: 10.1111/j.1651-2227.1997.tb14854.x. [DOI] [PubMed] [Google Scholar]
  32. Sapolsky R. M., Meaney M. J. Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res. 1986 Mar;396(1):64–76. doi: 10.1016/s0006-8993(86)80190-1. [DOI] [PubMed] [Google Scholar]
  33. Scott S. M., Watterberg K. L. Effect of gestational age, postnatal age, and illness on plasma cortisol concentrations in premature infants. Pediatr Res. 1995 Jan;37(1):112–116. doi: 10.1203/00006450-199501000-00021. [DOI] [PubMed] [Google Scholar]
  34. Segar J. L., Bedell K., Page W. V., Mazursky J. E., Nuyt A. M., Robillard J. E. Effect of cortisol on gene expression of the renin-angiotensin system in fetal sheep. Pediatr Res. 1995 Jun;37(6):741–746. doi: 10.1203/00006450-199506000-00012. [DOI] [PubMed] [Google Scholar]
  35. So K. W., Fok T. F., Ng P. C., Wong W. W., Cheung K. L. Randomised controlled trial of colloid or crystalloid in hypotensive preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997 Jan;76(1):F43–F46. doi: 10.1136/fn.76.1.f43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Watterberg K. L., Gerdes J. S., Cook K. L. Impaired glucocorticoid synthesis in premature infants developing chronic lung disease. Pediatr Res. 2001 Aug;50(2):190–195. doi: 10.1203/00006450-200108000-00005. [DOI] [PubMed] [Google Scholar]
  37. Wittekind C. A., Arnold J. D., Leslie G. I., Luttrell B., Jones M. P. Longitudinal study of plasma ACTH and cortisol in very low birth weight infants in the first 8 weeks of life. Early Hum Dev. 1993 Jul;33(3):191–200. doi: 10.1016/0378-3782(93)90145-k. [DOI] [PubMed] [Google Scholar]
  38. Yoder BradleyA, Martin Helen, McCurnin Donald C., Coalson Jacqueline J. Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons. Pediatr Res. 2002 Apr;51(4):426–432. doi: 10.1203/00006450-200204000-00006. [DOI] [PubMed] [Google Scholar]
  39. al Saedi S., Dean H., Dent W., Cronin C. Reference ranges for serum cortisol and 17-hydroxyprogesterone levels in preterm infants. J Pediatr. 1995 Jun;126(6):985–987. doi: 10.1016/s0022-3476(95)70229-6. [DOI] [PubMed] [Google Scholar]

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