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Prospective Evaluation of Postnatal Steroid Administration: A 1-Year Experience From the California Perinatal Quality Care Collaborative

^a Department of Neonatology, University of California San Diego Medical Center, San Diego, California
^b Department of Neonatology, Childrens Hospital and Research Center, Oakland, California
^c Department of Neonatal and Developmental Pediatrics, California Perinatal Quality Care Collaborative, Stanford University, Stanford, California
^d Perinatal Quality Improvement Panel, California Perinatal Quality Care Collaborative, Southern California Permanente Medical Group, Los Angeles, California

	ABSTRACT

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OBJECTIVE. Postnatal steroids (PNSs) are used frequently to prevent or treat chronic lung disease (CLD) in the very low birth weight (VLBW) infant, and their use continues despite concerns regarding an increased incidence of longer-term neurodevelopmental abnormalities in such infants. More recently, there has been a suggestion that corticosteroids may be a useful alternative therapy for hypotension in VLBW infants, but there have been no prospective reports of such use for a current cohort of VLBW infants.

METHODS. The California Perinatal Quality Care Collaborative (CPQCC) requested members to supplement their routine Vermont Oxford Network data collection with additional information on any VLBW infant treated during their hospital course with PNS, for any indication. The indication, actual agent used, total initial daily dose, age at treatment, type of respiratory support, mean airway pressure, fraction of inspired oxygen, and duration of first dosing were recorded.

RESULTS. From April 2002 to March 2003 in California, 22 of the 62 CPQCC hospitals reported supplemental data, if applicable, from a cohort of 1401 VLBW infants (expanded data group [EDG]), representing 33.2% of the VLBW infants registered with the CPQCC during the 12-month period. PNSs for CLD were administered to 8.2% of all VLBW infants in 2003, 8.6% of infants in the 42 hospitals that did not submit supplemental data (routine data-set group, compared with 7.6% in EDG hospitals). Of the 1401 VLBW infants in the EDG, 19.3% received PNSs; 3.6% received PNSs for only CLD, 11.8% for only non-CLD indications, and 4.0% for both indications. At all birth weight categories, non-CLD use was significantly greater than CLD use. The most common non-CLD indication was hypotension, followed by extubation stridor, for which 36 (16.3%) infants were treated. For hypotension, medications used were hydrocortisone followed by dexamethasone. Infants treated with PNSs exclusively for hypotension had a significantly higher incidence of intraventricular hemorrhage, periventricular leukomalacia, and death when compared with infants treated only for CLD or those who did not receive PNSs.

CONCLUSIONS. The common early use of hydrocortisone for hypotension and the high morbidity and mortality in children receiving such treatment has not been recognized previously and prospective trials evaluating the short- and long-term risk/benefit of such treatment are urgently required.

Key Words: chronic lung disease • hydrocortisone • hypotension • preterm infant

Abbreviations: PNS—postnatal steroid • RDS—respiratory distress syndrome • IVH—intraventricular hemorrhage • CLD—chronic lung disease • ELBW—extremely low birth weight • CPQCC—California Perinatal Quality Care Collaborative • VON—Vermont Oxford Network • VLBW—very low birth weight • IQR—interquartile range • BPD—bronchopulmonary dysplasia • FIO₂—fraction of inspired oxygen • EDG—expanded data group • RDG—routine data group • PVL—periventricular leukomalacia

THE FIRST STUDIES of postnatal steroid (PNS) use for the preterm infant with respiratory distress were published 16 years before the initial reports of prenatal steroids. The first study evaluated corticosteroids in 32 infants of diabetic mothers and reported that there was no significant reduction in the incidence and severity of respiratory distress syndrome (RDS).¹ Altman² suggested a benefit for such treatment in infants with moderate to severe distress in 1965, but the first controlled evaluation was performed by Baden et al³ in 1972. This study was a blinded comparison of 12.5 mg/kg of hydrocortisone versus placebo given at admission and 12 hours later in 44 premature infants with RDS and reported no significant benefit to steroid administration. In the same year, Ewerbech and Helwig⁴ reported on the outcome of 10 infants with severe RDS who were treated with prednisolone, of whom 5 died, 3 of whom had autopsies with evidence of massive intraventricular hemorrhage (IVH).

There have been a plethora of studies evaluating the effects of PNSs for the prevention or treatment of chronic lung disease (CLD).⁵,⁶ Metaanalyses of early (<96 hours of age)⁷ and later use of PNSs to reduce CLD⁸,⁹ demonstrated significant benefits with regard to earlier extubation and decreased risks of CLD at both 28 days and 36 weeks, death, or CLD at 28 days and 36 weeks, but there was a disturbing tendency toward an increase in neurodevelopmental impairment consistent with previous animal experiments, which had shown that glucocorticoids administered during critical periods of brain development may impair myelinization, brain cell division, and longer-term behavioral effects.¹⁰–¹⁶ The American Academy of Pediatrics Committee on the Fetus and Newborn cautioned that PNS use outside of randomized trials should be reserved for "exceptional clinical circumstances."¹⁷

The use of PNSs for the prevention or treatment of CLD remains common, especially for the extremely low birth weight infant (ELBW) whose birth weight is <1000 g, and information from the Vermont Oxford Network (VON), of which the California Perinatal Quality Care Collaborative (CPQCC) is a contributing member, indicates that for the year 2001, 38% of ELBW infants (22–65%) received PNSs.¹⁸ In California, the use of PNSs for the very low birth weight (VLBW) infant was 14.3%, with an interquartile range (IQR) of 4.7 to 40.8 in 2000 and 11.8% (2.1% to 28.1%) in 2001.

There is now substantial emerging evidence that PNSs are associated with both increased short-term neonatal complications and long-term adverse effects. At least 2 large prospective trials of PNSs have been terminated because of short-term toxicity, including gastrointestinal hemorrhage and intestinal perforation requiring surgery.¹⁹,²⁰ Other prospective trials have also reported a high incidence of other adverse effects, including an increase in nosocomial sepsis, meningitis, and hyperglycemia²¹,²²; hypertriglyceridemia; increased free fatty acid levels²³; increased protein catabolism and poorer somatic growth²⁴–²⁶; and pituitary-adrenal suppression,²⁷ which can last for 1 month after therapy.²⁸,²⁹

None of the published trials evaluating PNSs were powered to evaluate long-term follow-up. A number of reports, many describing follow-up studies of infants enrolled in randomized, controlled trials of PNSs to prevent or ameliorate bronchopulmonary dysplasia (BPD), noted that such use was associated with a significantly increased occurrence of neurodevelopmental impairment, especially if the risk of the development of CLD was <35% in the control infants.³⁰–³²

Low blood pressure is frequently seen in the ELBW infant, and it has been postulated that this may be a reflection of adrenal insufficiency. As a result, corticosteroids have been used to treat hypotension in such infants and have been found to be equivalent to dopamine in 1 prospective randomized trial.³³,³⁴ These observations have led to an increased use of early PNSs to treat such hypotension. To date, there has not been any prospective study evaluating the overall use of corticosteroids, including the treatment of low blood pressure in a population of VLBW infants and the resultant neonatal outcomes. In an effort to further delineate the current indications and use of PNSs in VLBW infants, including the use of early PNSs for the treatment of low blood pressure, we developed a prospective expanded data set for use within the CPQCC for a full calendar year.

	METHODS

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The CPQCC data set is identical to the VON data set for infants 1500 g at birth. The CPQCC requested that all of its members submit, for calendar year 2003, a single additional supplemental data form for all infants who received any PNS during their hospital stay (see Appendix). These additional data provided information about the age of the infant in days at the first dose of PNS, its indication, the mean airway pressure and fraction of inspired oxygen (FIO₂), and the type of ventilation for infants treated for CLD, the initial daily dose, and the total duration of steroids given. The cohort of infants from those hospitals voluntarily contributing supplemental data on PNS use constitute the expanded data group (EDG). The cohort of infants from those hospitals choosing not to contribute data constitute the routine data group (RDG). After completion of data collection for 2003, the incidence of the use of PNSs for CLD as reported in the CPQCC data were calculated for the overall population and the infants <1000 g and 750 g at birth. We calculated the number and percentage of infants for whom the supplemental data were submitted. The means, medians, SDs, and IQRs were calculated. Comparisons between cohorts were done with ² or Student’s t test as appropriate. A P value of <.05 was considered significant.

View larger version (83K): [in this window] [in a new window]   APPENDIX

	RESULTS

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View larger version (19K): [in this window] [in a new window]   FIGURE 1 PNS use for CLD according to birth weight comparing the CPQCC, EDG, and RDG. , CPQCC; , RDG group; , EDG group.

View larger version (16K): [in this window] [in a new window]   FIGURE 2 PNS use according to birth weight and indication for the EDG infants. , CLD; , non-CLD; , both indications.

Dexamethasone was used for 41.5% of EDG infants treated for CLD, followed by inhaled steroids, which were used for 38.7% of such infants. Before their first dose of PNSs for CLD, administered at a median of 34 days (IQR: 23.5–45.5 days), 59 (55.7%) of 106 infants were receiving conventional ventilation, and 41 (38.7%) were receiving high-frequency ventilation, with a median FIO₂ of 0.53 and a median mean airway pressure of 10 cm H₂O. There were 2 infants receiving continuous positive airway pressure and 2 on nasal cannula. Twelve (11.3%) of the infants treated with PNSs for CLD had pulmonary interstitial emphysema, 77 (72.6%) were receiving diuretics, and 7 (6.6%) were receiving bronchodilators. The median number of courses was 1 (IQR: 1–2) both for infants treated only for CLD (50) and those treated for both CLD and another indication (56). However, the total days of treatment was longer in infants treated for both CLD and another indication (median: 27 days; IQR: 8–56) than in infants who received PNSs only for CLD (median: 14.5 days; IQR: 5–35). For both groups, the 25% who constituted the upper quartiles were exposed to PNS treatment for >35 days in the CLD-only infants and for >56 days in the dual indication group.

Table 2 shows the treatment profiles by indication and steroid preparation. The longest average exposure to PNSs was 51.8 days, seen in infants treated with inhaled steroids for CLD. The shortest average exposure was 4.1 days, seen in infants treated with hydrocortisone for weaning from the respirator. Infants treated for hypotension with hydrocortisone averaged 9 days, and those treated with dexamethasone averaged 8.4 days of administration (Table 2).

	DISCUSSION

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The American Academy of Pediatrics Committee on the Fetus and Newborn cautioned neonatologists in March 2002 that PNS use, outside of clinical trials, should be reserved only for "exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support)."¹⁷ We describe the actual use of PNSs for the observed calendar year of 2003, 8 to 20 months after the Committee of the Fetus and Newborn statement and the CPQCC’s efforts to bring this recommendation to the attention of California’s neonatology community through the development of a toolkit designed to inform about the evidence for PNS use in preterm infants.³⁸ The use of PNSs for CLD has fallen in California from 11.8% in 2001 to 7.9% in 2003. This recent trend has also been described for the VON, the National Institute of Child Health and Human Development Neonatal Research Network, and the Canadian Neonatal Network, with an indication that, currently, 7% of VLBW infants continue to receive PNSs to prevent or treat CLD.³⁹ Our study indicates that there is a significant and unreported use of PNSs for managing hypotension, and because we do not have any antecedent information on the use of PNSs for hypotension, we cannot comment on whether this use is increasing.

There is evidence that the very premature infant has an incomplete adrenal hormone response after birth, which may result in an exaggerated inflammatory response and an increased incidence of BPD at 36 weeks, an observation that has been recently refuted.⁴⁰,⁴¹ Watterberg et al evaluated the use of hydrocortisone given for the first 12 days of life in such infants and noted a reduction in BPD without associated morbidity.⁴² A subsequent multicenter study by the same investigators was stopped because of evidence of bowel perforation, and, to date, there has not been any report of the long-term outcome of infants treated in these 2 trials.⁴³ Antenatal maternal steroid has been shown to improve blood pressure in the VLBW infant.⁴⁴ Animal models have confirmed this effect.⁴⁵ More recently, Ng et al⁴⁶ demonstrated that basal, peak, and incremental rise in serum cortisol on day 7 were associated significantly with the lowest systolic, mean, and diastolic blood pressures recorded during the first 2 weeks of life (r > 0.25; P < .005). They also reported that the 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.

Hypotension occurs in 20% of VLBW infants and may be associated with subsequent brain injury, and its treatment is problematic.⁴⁷ Hypotension requiring vasoactive drug treatment occurred in the first 24 hours of life in 40% of the infants enrolled in the Watterberg et al trial and up to 33% of the infants of <750 g birth weight in the Hall et al study.⁴⁴,⁴⁸ Dopamine is the agent most frequently used for the treatment of low blood pressure in the VLBW infant. However, recent studies by Osborn et al⁴⁹ have demonstrated that dopamine may not increase cardiac output. Others have developed a technique to measure superior vena cava flow using ultrasound Doppler studies⁵⁰,⁵¹ and reported that low superior vena cava flow, not blood pressure, was the only independent risk factor for late IVH in both cohorts (1995–1996 adjusted odds ratio: 20.39; 1998–1999 adjusted odds ratio: 5.16).⁵²

In a retrospective review of 21 preterm infants with hypotension unresponsive to volume and dopamine alone or in combination with other agents including dobutamine or epinephrine, Seri et al⁵³ reported rapid normalization of the cardiovascular status and sustained decreases in volume and pressor requirement with hydrocortisone treatment. Another group reported similar results using a single dose of dexamethasone in hypotensive infants unresponsive to dopamine and epinephrine.⁵⁴ It is postulated that steroids exert their effects on dopaminergic receptors, as well as through direct cardiac effects. There is reason to believe that dopamine may lead to increased splanchnic vasoconstriction, and, thus, its use may aggravate any bowel ischemia and possibly increase the occurrence of necrotizing enterocolitis.⁵⁵ Volume alone is seldom effective in treating low blood pressure in VLBW infants, and a low blood pressure is not predictive of a low blood volume in the preterm infant.⁵⁶,⁵⁷ In addition, volume administration may increase left to right ductal shunting and is less effective than dopamine in increasing blood pressure.⁵⁸,⁵⁹ There was also a recent suggestion that volume administration to preterm hypoxic animals may impair cerebral oxygen delivery.⁶⁰

These observations may be encouraging the use of alternate pharmacological approaches for the hypotensive VLBW infant. For the EDG units surveyed in this study, >15% of VLBW infants received hydrocortisone for hypotension confirming the high incidence of hypotension in this population. Before the present study, there has not been any report describing the extent of the use of hydrocortisone, dexamethasone, or any other steroid preparation for the treatment of early hypotension in the VLBW infant. All of the previous reports described small numbers of infants, and none have reported any clinical short- or longer-term outcomes in infants treated with any steroid preparation for low blood pressure. We believed that there was a substantial use of PNSs for hypotension involving the use of single or repeated doses of hydrocortisone for VLBW infants. The current study represents the largest series of infants reported for whom early PNSs were prescribed for the treatment of low blood pressure.

Our prospective survey has confirmed that the use of hydrocortisone for hypotension has become a common practice, being used almost twice as often as PNSs for CLD and that although it would appear that the use of PNSs for CLD has fallen, the overall use of PNSs may have actually increased in California. The infants who received PNSs for CLD in the EDG were typically 35 days old, ventilated on a mean airway pressure of 10 cm H₂O and a FIO₂ of .53. All of the previous information on the use of PNSs in the VLBW infant comes from prospective randomized trials in which the use of the PNSs followed a protocol for the prevention or treatment of CLD. Current PNS use differs from previous randomized trials, even in those where therapy began at >21 days of age, in that treatment was begun later and was not uniformly initiated for study indications. In many of the previous studies of PNSs for CLD, the infants were treated early with criteria that were felt to predict CLD. The delay observed in our survey for treating infants with PNSs for CLD may reflect the concern that earlier use may be associated with greater longer-term neuromorbidity and the use of other respiratory approaches, including early continuous positive airway pressure,⁶¹ early intubation for surfactant followed by extubation,⁶² and noninvasive ventilation support.⁶³

A major shortcoming of our study is that only 22 of 62 units voluntarily submitted supplemental data, with these units contributing information for 33% of all infants for whom data were collected through the CPQCC in 2003. The groups differed only in the higher percentage of inborn infants and slightly lower birth weight seen in the EDG units. It is difficult to be certain if the results obtained are reflective of all of the CPQCC units, and, indeed, one may speculate that the units that completed the supplemental forms for their infants believed that they were not frequent users of PNSs. The overall results suggested that for PNS use for CLD, this was true but not significantly different from the RDG units, and we do not have a contemporary comparison group for the non-CLD use of PNSs.

At the present time, our observations suggest that there is significant use of PNSs for the treatment of low blood pressure in the VLBW infant and that, overall, 19% of VLBW infants in California receive PNSs, the majority for indications other than CLD, specifically, hypotension. Such infants experience high mortality and significantly greater morbidities, most likely secondary to the hypotension; however, this is not a proven relationship, and caution is required regarding the possible contributing role of early PNSs. We would suggest that there is an urgent need for large, well-designed trials to evaluate the safety and efficacy of PNSs to treat hypotension in the VLBW infant and to evaluate both short- and longer-term neurodevelopmental outcomes in such infants before this practice gains increased use.

	FOOTNOTES

 
Accepted Jul 13, 2005.

Address correspondence to Neil N. Finer, MD, FRCP, Division of Neonatology, University of California San Diego Medical Center, 401 Dickenson St, San Diego, CA 92103-8774. E-mail: nfiner{at}ucsd.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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