Background. Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks’ postmenstrual age, particularly in infants exposed to histologic chorioamnionitis.
Methods. Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks’ postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation ≥90%).
Results. Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect.
Conclusions. Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.
Comments
Hydrocortisone and the neonate. How bad is it?
Varsha Bhatt-Mehta, Pharm.D., FCCP 1,2, Schumacher RE, MD2, Barks JDE, MD2 College of Pharmacy1 and Department of Pediatrics and Communicable Diseases2 University of Michigan Ann Arbor, MI 48109
Financial Disclosures from all authors:
No financial disclosures to make from any of the authors.
Correspondence: Varsha Bhatt-Mehta, Pharm.D., FCCP
F5790, 1500 E. Medical Center Dr Ann Arbor, MI 48109 Tel: (734)-936-8985 Fax: (734)-763-7728 [email protected]
In 2004, Watterberg et al1 published the results of a randomized, placebo controlled, multi center trial of prophylactic intravenous (IV) hydrocortisone to prevent BPD in the very low birth weight (VLBW) neonate, at highest risk for developing BPD. This study was based on an earlier pilot study where early prophylaxis with low-dose hydrocortisone increased the likelihood of survival without chronic lung disease in extremely low birth weight infants. This pilot study was based on the notion that the development of chronic lung disease (CLD) is associated with relative adrenal insufficiency (RAI).2 The multi center trial was discontinued prematurely due to increased incidence of spontaneous gastrointestinal perforations in the treatment group receiving IV hydrocortisone and prophylactic indomethacin compared with placebo group that received prophylactic indomethacin and placebo. There were two other groups that received either IV hydrocortisone or placebo alone. This review is focused on the spontaneous gastrointestinal perforations effects of treatment. The results of this multi center study have greater implications in the practice of neonatology since the use of IV hydrocortisone for suspected RAI for various indications (e.g. pressor resistant hypotension) in premature (and sometimes full term) infants is becoming increasingly common.3 While data for this indication of IV hydrocortisone are scarce in neonates, presence of RAI in the sick neonate is well-recognized.4,5 The multi center study reported a significant risk for development of spontaneous gastrointestinal (GI) perforations (overall unadjusted OR 4.59, p=0.01) but “excess risk” due to hydrocortisone treatment was not evaluated in this high-risk population that has many other reasons for developing gastrointestinal bleeds and perforations including the use of concomitant medication such as indomethacin.6 Calculation of “ excess risk” (Attributable Risk (AR)) provides a better measure of the actual impact of hydrocortisone on GI perforations
In this study, 139 infants in the treatment group and 136 infants in the placebo group (76% of the total subjects enrolled) received indomethacin along with hydrocortisone or placebo during the treatment period. The incidence of GI perforations without apparent necrotizing enterocolitis (NEC) was 12% in the hydrocortisone plus indomethacin group and 1% in the placebo plus indomethacin group.
Table 1. Attributable Risk in infants who received Indomethacin and Hydrocortisone (Treatment) or Indomethacin and Placebo (Placebo)
GI Perforations No GI Perforations Total Treatment* 16 (12% of 139)+ 123 139 Placebo** 2 (1% of 136)† + 134 136
*Exposure=Hydrocortisone, Indomethacin **Unexposed= Placebo, Indomethacin + Numbers are rounded to the nearest whole number
† (2/139 for comparison between equal #s. Due to rounding this number remains unaffected)
AR=(16 -2) =14 per 139 OR 10 cases of GI perforations per 100 infants. Thus, 10 cases out of 100, of spontaneous GI perforations in the group exposed to hydrocortisone and indomethacin could be attributed to this exposure compared with the group exposed to indomethacin and placebo.
However, when the excess risk is calculated for infants who did not receive concomitant indomethacin, the results are quite different. In this cohort, the reported incidence of GI perforations was higher in the placebo arm (5%) than the hydrocortisone arm (2%) (Table 2)
Table 2. Attributable Risk in infants who received hydrocortisone alone or placebo alone
GI Perforations No GI Perforations Total Treatment* 1(2% of 41)+ 40 41 Placebo** 2(5% of 44)+ 42 44
*Exposure=Hydrocortisone **Unexposed= Placebo + Numbers are rounded to the nearest whole number
Here, AR= (2-1) =1 per 44 or 3 cases of GI perforations per 100 infants exposed to hydrocortisone were prevented by exposure to hydrocortisone.
While this difference is not statistically significant it may have clinical importance since there is an inherent propensity for spontaneous GI perforations in the very low birth weight infants (Placebo group) that may be reduced by administration of hydrocortisone, i.e. the anti- inflammatory activity of hydrocortisone may confer some protection against such spontaneous GI perforations. Indomethacin is known to be associated with gastrointestinal perforations.
A variety of mechanism is proposed for this adverse effect including inhibition of prostaglandins synthesis, reduced intestinal contraction and direct mucosal damage 7,8. As the authors point out, physiologic concentrations of glucocorticoids may protect against indomethcin induced damage 9. The increased incidence of spontaneous GI perforation was seen in infants with high concentrations of cortisol at the initiation of treatment with hydrocortisone. Cortisol levels in the chorioamnionitis group were reported as being higher compared with infants not exposed to chorioamnionitis prior to starting hydrocortisone treatment. The time lapsed between antenatal steroids and initiation of hydrocortisone treatment is not available in the article but it is plausible that these infants had high endogenous cortisol or total glucocorticoid concentrations in the first 48 hours after birth as well when the hydrocortisone prophylaxis was initiated. These high glucocorticoid concentrations along with indomethacin may have resulted in a drug interaction leading to spontaneous GI bleeds.
Roberts10 and Gordon11 also raise some important issues regarding this study. We would like to add to these issues by raising the question of the correct dose of hydrocortisone as well as identification of the VLBW infant that may most benefit from physiologic replacement of cortisol. Cortisol (and exogenous hydrocortisone) are extensively protein bound. It is extremely important to correctly identify true endogenous deficiency of cortisol by determining baseline concentration of free cortisol. This is a difficult task since most clinical laboratories use the rapid Radioimmunoassay techniques that measure total serum cortisol, but measuring free cortisol serum concentrations may be an important issue since administration of low dose steroids in true RAI may actually prevent long term morbidity and mortality in this population. Animal data suggest that hydrocortisone may not suppress HPA axis to the same extent as dexamethsone12. This fact may make hydrocortisone a valuable steroidal agent in the limited armamentarium of drugs used in neonates.
It seems prudent to avoid blanket prophylaxis with hydrocortisone in all VLBW infants for prevention of BPD, hypotension, respiratory distress or any other condition that is suspected to be a result of RAI. Yet, our analysis would indicate the “excess” risk of spontaneous GI perforations due to hydrocortisone is small. Limiting the administration of “low dose’ hydrocortisone to cautiously and carefully selected patients with “low endogenous levels” could provide a very useful therapeutic alternative when concomitant use of indomethacin is avoided. Peltoniemi et al14 have recently proposed such an approach recently. Larger studies are needed to confirm this approach to use of IV hydrocortisone.
References:
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10. Roberts RS. Early closure of Watterberg trial. (Commentary) Pediatrics. 2004;114:1670-1671.
11. Gordon PV. Weighing statistical certainty against ethical , clinical, and biologic expediency: the contributions of the Watterberg trial tip the scales in the right direction. Letter to the Editor. Pediatrics. 2005;115:1446-1447.
12. Bhatt-Mehta, V , Neal CR Jr, Vazquez D. Effect of Early Life Glucocorticoid Administration on the Limbic-Hypothalamic-Pituitary-Adrenal Axis (LHPA) Stress Response. (Abstract) Pediatric Academic Societies’ 2006 Annual Meeting. San Francisco, CA April-May 2006
13. Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 2001;344:95-101.
14. Peltoniemi O, Kari A, Heinonen K, et al. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr 2005;146:632-7
Conflict of Interest:
None declared