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ARTICLE: Kristi L. Watterberg, Jeffrey S. Gerdes, Kathleen L. Gifford, and Hung-Mo Lin Prophylaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants Pediatrics 1999; 104: 1258-1263 [Abstract] [Full text] [PDF]

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Beth Durrance   (31 January 2000)

Prophylaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants

Stephen Wardle   (3 February 2000)

Author's reply

Kristi L Watterberg   (7 February 2000)

Authors reply to Dr. Wardle's P3R

KL Watterberg   (15 February 2000)

Untitled 31 January 2000
Beth Durrance, Consultant Send letter to journal: Re: this article beth.durrance{at}parexel.com Beth Durrance	What dosage forms were used for treatment? Is this dosage form standard for this treatment? Are there any alternatives?
Prophylaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants 3 February 2000
Stephen Wardle, Lecturer in Neonatal Medicine Send letter to journal: Re: Prophylaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants s.p.wardle{at}liverpool.ac.uk Stephen Wardle	I read the paper by Watterberg et al with interest (1). I was surprised to find that hypotension and inotropic support were not reported in more detail. Hydrocortisone is used with increasing frequency as a treatment for hypotension when conventional therapies fail (2-4) and these authors had suggested that hypotension is the commonest manifestation of adrenal insufficiency in the preterm infant (5). If this is the case one might have expected that prophylactic treatment given in the way described by Watterberg might have been expected to decrease the incidence of hypotension if commenced early enough. The incidence of hypotension is not reported. The number of days of inotrope use is reported but with no statistical analysis. Although the number of infants with a mean blood pressure above 50 mmHg is reported the proportion with a low blood pressure is not. Detailed information regarding the time of commencement of therapy, the incidence of hypotension and the median number of days of inotropic or other therapy would have been interesting. Hypotension is known to be associated with an adverse outcome both in terms of mortality and morbidity (periventricular haemorrhage). If hypotension could be prevented with hydrocortisone therapy then it is interesting to speculate whether this could affect these other outcomes. I suspect that in order to do this prophylactic therapy would need to be commenced soon after birth rather than at 48 hours as in this study. Antenatal therapy with corticosteroids decreases the incidence of both death and periventricular haemorrhage (6) and it may also decrease the incidence of hypotension and the need for blood pressure support (7) but trials of postnatal steroids have so far not been as successful and indeed may be associated with a higher incidence of adverse neurological outcome (7). Therefore timing of the intervention and the dose are extremely important. The authors also report that infants with chronic lung disease (CLD) have lower basal and stimulated cortisol concentrations. Unfortunately the infants with CLD were smaller and less mature although we are not told by what extent. Gestational age undoubtedly affects cortisol concentration (8) therefore this difference may have simply been related to differences between the groups. Finally the measured cortisol concentrations in the two groups did not differ significantly. This is surprising as one would have expected the hydrocortisone given to the study group to have been detected in the cortisol assay. Was their assay able to differentiate endogenous cortisol from exogenous hydrocortisone? Or did the exogenous cortisol suppress cortisol production? References 1. Waterberg KL, et al Prophyllaxis Against Early Adrenal Insufficiency to Prevent Chronic Lung Disease in Premature Infants. Pediatrics 104:1258- 1263, 1999 2. 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 152:354-356, 1993. 3. Helbock HJ, Insoft RM, Conte FA. Glucocorticoid-responsive hypotension in extremely low birth weight newborns. Pediatrics 5:715-717, 1993. 4. Bourchier D, Weston PJ. Randomised trial of dopamine compared with hydrocotisone for the treatment of hypotensive very low birthweight infants. Arch Dis Child 76 (3):174-178, 1997. 5. Scott SM, Watterberg KL. Effect of gestational age, and illness on plasma cortisol concentrations in premature infants. Pediatr Res 37:112- 116, 1995. 6. Watkins AM, West CR, Cooke RWI. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Human Development 19:103-110, 1989. 7. Moise AA, Wearden ME, Kozinetz CA, Gest AL, Welty SE, Hansen TN. Antenatal steroids are associated with less need for blood pressure support in extremely premature infants. Pediatrics 95(6):845-850, 1995. 8. Heckmann M, Wudy SA, Haack D, Pohlandt F. Reference Range for Serum Cortisol in Well Preterm Infants. Arch Dis Child 1999;81:F171-F174
Author's reply 7 February 2000
Kristi L Watterberg Send letter to journal: Re: Author's reply klw9{at}psu.edu Kristi L Watterberg	As stated in Methods, the dosage form used was hydrocortisone sodium succinate (Solu-Cortef 100 mg plain, Upjohn), reconstituted as directed by the manufacturer. This is one of many standard hydrocortisone preparations available; we chose this particular preparation specifically because it contains no preservative. There is no ‘standard’ for this treatment, as this was a clinical trial of a new therapy. Many alternative preparations of hydrocortisone are available, as listed in the Physician’s Desk Reference.
Authors reply to Dr. Wardle's P3R 15 February 2000
KL Watterberg Send letter to journal: Re: Authors reply to Dr. Wardle's P3R klw9{at}psu.edu KL Watterberg	Dr. Wardle (P3R, February 3, 2000) comments that he was surprised that hypotension and inotropic support were not reported in more detail in our article. We appreciate the opportunity to discuss this subject further since, as Dr. Wardle points out, we have suggested that hypotension can be one manifestation of adrenal insufficiency in the premature infant. We did report that the treated infants received fewer days of inotropic therapy; however, the difference was not statistically significant. On every day after the second day of therapy, mean blood pressure values were higher in the infants treated with hydrocortisone and fewer treated infants received inotropic support; again, however, these differences were not statistically significant. We plan to continue to monitor measures of cardiovascular function in a larger, multicenter trial. We agree that if the goal of hydrocortisone therapy were to ameliorate hypotension in these infants, initiation of treatment immediately after birth would likely prove more efficacious. The primary objective of this study, however, was to reduce chronic lung disease. We chose to defer the initiation of therapy for at least 12 hours to avoid unnecessarily treating infants who were quickly extubated and therefore at lower risk for CLD. Therapy was initiated at a median age of about 31 hours of life. Dr. Wardle questions whether the lower basal and stimulated cortisol concentrations in infants developing CLD could be related to gestational age. As we stated in the paper, gestational age was included in these analyses. Further, as discussed in Dr. Wardle’s references 5 and 8, we and others have reported that cortisol values early in life show an inverse correlation with gestational age, and thus might be expected to be higher, rather than lower, in smaller, more immature infants. Finally, Dr. Wardle expresses surprise that cortisol concentrations did not differ significantly between the treatment and placebo groups. As stated in Study Procedures, these values were obtained at least three days after completion of hydrocortisone therapy (day of life 15 – 19, as stated in the Figure legend). Therefore, we did not anticipate that the hydrocortisone-treated infants should have significantly higher values. Instead, we were pleased to find that hydrocortisone therapy did not appear to suppress either basal or stimulated cortisol values.