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COMMENTARY |
Department of Pediatrics, University of Oulu, Oulu, Finland
Abbreviations: BPD, bronchopulmonary dysplasia • PDA, patent ductus arteriosus • BW, birth weight
Hydrocortisone at doses corresponding or exceeding the endogenous corticosteroid secretion during stress has been studied in randomized trials since the early 1970s.1 Lately, the aim has been to stabilize very low blood pressure or decrease the risk of bronchopulmonary dysplasia (BPD).2,3
According to experimental studies, the beneficial hemodynamic effects are largely a result of an increase in myocardial smooth muscle contractility.4 Corticosteroids increase cardiovascular adrenergic receptors and enhance the microvascular endothelial barrier function, and hydrocortisone has a mineralocorticoid-mediated effect on cardiac muscle. Closure of patent ductus arteriosus (PDA) is promoted by corticosteroid, which also decreases the synthesis of prostaglandins and endothelial nitric-oxide synthetase.5 The blood pressure is just one function that, together with perfusion resistance and oxygen carrying capacity of the blood, determine the oxygen delivery to the tissue. The pressure-passive cerebral perfusion evident in some very preterm infants argues for interventions that increase and stabilize the perfusion pressures.
Beneficial hemodynamic effects of hydrocortisone have been observed in randomized, placebo-controlled trials. In a single-center randomized trial of 48 preterm infants (mean gestational age: 26.6 weeks; birth weight [BW]: <1500 g [mean: 920 g]), hydrocortisone was given at 3 mg/kg per day, divided into 3 intravenous injections for 4 days, starting during the first week (a mean of 11 hours after birth) for treatment of refractory hypotension.3 Despite an increase in mean blood pressure, there was a decrease in the requirement for dopamine, dobutamine, and saline infusions and no detectable effects on PDA or other outcomes. In 3 randomized trials in which the influence of early neonatal hydrocortisone on survival without BPD was studied, the acute hemodynamic changes were studied as secondary outcomes. In a 3-center study starting before 24 hours of age and involving 52 infants with significant respiratory distress (mean gestational age: 26.6 weeks; BW: <1250 g [mean: 890 g]), hydrocortisone was given at 2 mg/kg for 2 days and then 1.5 mg/kg for 2 days followed by a 6-day taper.6 No significant effect was reported on either the blood pressure or vasopressor requirements, but the risk of PDA decreased.6,7 In a 2-center randomized study by Watterberg et al,2 40 preterm infants (mean gestational age: 25.3 weeks; BW: 500–999 g [mean: 750 g]) were treated with hydrocortisone within 48 hours after birth at 1 mg/kg per day for 9 days followed by a 3-day taper. This study revealed no significant differences in hemodynamic parameters. In a similar multicenter study by Watterberg et al8 (360 infants with BWs of 500–999 g [mean: 735 g]; mean gestational age: 25.3 weeks) revealed that the hydrocortisone treatment increased mean blood pressure, whereas no difference in requirements of vasopressors, fluid intake, or in the incidence of PDA was evident. The variable treatment results of these mostly small trials may reflect the differences in the indications, the dosage of hydrocortisone, and differences in other treatment practices. For instance, Ng et al3 used saline infusions for treatment of hypotension, whereas Peltoniemi et al6 used liberal transfusion guidelines for red blood cells,9 which were given by slow infusion in small volumes.
Both low systemic blood pressure and PDA with significant left-to-right shunting are surrogate outcomes associated with adverse outcomes such as death, poor neurodevelopment, or BPD in some studies. The antiinflammatory corticosteroid additionally protects the lungs by maintaining the integrity of the alveolar capillary barrier, increasing surfactant secretion, and inducing ion transport across alveolar epithelium and other defense functions. On the other hand, a high dose of glucocorticoid causes poor lung growth and alveolization, characteristic of BPD, whereas cortisol at a low level may promote lung growth.10
Neurodevelopmental delay and cerebral palsy in children exposed to dexamethasone in early life have not been observed in a trial involving hydrocortisone11 or in a prospective study of infants exposed to hydrocortisone after the first week.12 These observations are promising. A mechanism proposed in the pathogenesis of abnormal neurologic outcome after dexamethasone treatment is excessive activation of glucocorticoid receptors, which induces apoptosis and neuronal death. The preferential binding of hydrocortisone to the mineralocorticoid receptor may not result in a similar detrimental effect. Early administration of hydrocortisone as used in current trials cannot yet be declared free from adverse neurologic sequelae. Despite insufficient evidence, administration of hydrocortisone to very low birth weight infants soon after birth has become a common practice in many centers.13
Recent trials using hydrocortisone for prevention of BPD were discontinued because of an increased risk of intestinal perforation.6,8 This complication coincided with administration of nonsteroidal antiinflammatory drugs, which are known to decrease intestinal perfusion. According to retrospective reports, administration of indomethacin may be associated with intestinal perforation. Corticosteroid administration accelerates normal intestinal mucosal development, producing mucosal hypertrophy and smooth muscle thinning. In addition, a proinflammatory cytokine inactivates the rate-limiting enzyme of cortisol catabolism in intestinal epithelium.14 Local increase in corticosteroids and decrease in prostaglandins may predispose a patient for the perforation. This and other potential complications (hypertension, hyperglycemia, gastric hemorrhage, increased risk of infections) must be balanced against the benefits of hydrocortisone. In the trials thus far, the starting dose and duration of hydrocortisone treatment have been variable. Also, the dosage has not been adjusted on the basis of the individual's characteristics with respect to the ability of the hypothalamic-adrenal axis to recognize the stress. After all, the transient or relative adrenal deficiency evident in some very preterm infants may require pharmacologic intervention.
In the Ng et al study,3 hydrocortisone had neither detectable influence on the risk of BPD nor adverse effects. On the basis of the posthoc analysis, Peltoniemi et al6 found that the pretreatment serum cortisol levels were associated with treatment effects. Infants with low endogenous cortisol levels and with low cortisol stress response to corticotropin (below the medians) had a high risk of BPD. In this group, hydrocortisone treatment decreased the risk of BPD without spontaneous intestinal perforations. On the other hand, the infants with higher-than-median cortisol levels at birth tended to have a low baseline risk of BPD, and hydrocortisone given to these infants was associated with intestinal perforations. Of the population with low pretreatment cortisol levels, 19% were from confirmed chorioamnionitis pregnancies and 34% were from preeclampsia pregnancies, whereas of those with high pretreatment cortisol levels, 64% were from chorioamnionitis pregnancies and 4% were from preeclampsia pregnancies.6 On the other hand, Watterberg et al8 found that hydrocortisone supplementation decreased the risk of BPD in those from pregnancies with chorioamnionitis, whereas the rest of the population had no benefit. According a subgroup analysis, low pretreatment corticotropin-induced cortisol predicted BPD, whereas the infants with spontaneous intestinal perforations tended to have high cortisol values.
In individual trials the beneficial effects of hydrocortisone were variable and generally smaller than those found initially. Local intestinal perforation is a serious adverse effect that clouds attempts to introduce hydrocortisone in early neonatal management. Perhaps we are approaching the limits of current treatment practices to improve the early adaptation of the most immature infants. It is also possible that we need to modify the dosage, limit the drug-drug interactions, and scrutinize patient selection. In the past, assessment of lung immaturity was proposed before antenatal glucocorticoid or surfactant treatment at birth. However, these therapies proved to be cost-effective and safe to extremely preterm infants. We cannot always be so lucky. Laboratory analysis of very high-risk fetuses and newborn infants may be critical in choosing an acute neonatal treatment. At birth or shortly thereafter, vital functions of very low birth weight infants are closely monitored. Undesirable symptoms are often treated acutely and aggressively in an attempt to prevent their progression. Although this strategy is mostly successful, the underlying defect remains undefined. Respiratory distress and low blood pressure are frequent symptoms in early life despite high endogenous steroid levels. Here we propose that in corticosteroid trials on very high-risk infants in early life, there is a need to incorporate measurements of cortisol in clinical practice.
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FOOTNOTES |
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Address correspondence to Mikko Hallman, MD, PhD, Department of Pediatrics, University of Oulu, PO Box 5000, University of Oulu, FIN-90014 Oulu, Finland. E-mail: mikko.hallman{at}oulu.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
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  K J Rademaker, L S de Vries, C S P M Uiterwaal, F Groenendaal, D E Grobbee, and F van Bel Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2008; 93(1): F58 - F63. [Abstract] [Full Text] [PDF]
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