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
varsham@umich.edu
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:
1. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early
adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter
trial. Pediatrics. 2004;114:1649-1657.
2. Watterberg KL, Gerdes JS, Gifford KL, et al. Prophylaxis against
early adrenal insufficiency to prevent chronic lung disease in premature
infants. Pediatrics. 1999;104:1258-1263.
3. Baker CF, SchumacherRE, Barks JD, Vazquez DM, Bhatt-Mehta V.
Evaluation of Hydrocortisone in Neonates with Pressor Resistant
Hypotension. (Abstract) Pediatric Academic Societies’ 2005 Annual
Meeting. Washington DC. May 2005
4. Huysman MWA, Hokken-Koelega ACS, DeRidder MAJ, et al. Adrenal
function in sick very preterm infants. Pediatr Res. 2000;48:629-633.
5. 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. 6.
6. Hwang H, Murphy JJ, Gow KW, et al. Are localized intestinal
perforations distinct from necrotizing enterocolitis? J Pediatr Surg.
2003;38:763-767.
7. Shorter NA, Liu JY, Mooney DP, et al. Indomethacin-associated
bowel perforations: a study of possible risk factors. J Pediatr Surg.
1999;34:442-444.
8. Tanaka A, Hase S, Miyazawa T, et al. Role of cyclooxygenase(COX)-
1 and COX2 inhibition in nonsetroidal anti-inflammatory drug-induced
intestinal damage in rats:relation to various pathogenic events. J
Pharmacol Exp Ther. 2002;303:1248-1254. 9.
9. Filaretova L, Tanaka A, Miyazawa T, et al. Mechanisms by which
endogenous glucocoticoid protects against indomethacin induced gastric
injury in rats. Am J Physiol Gatsrointest Liver Physiol. 2002;283:G1082-
G1089.
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
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