PEDIATRICS Vol. 117 No. 2 February 2006, pp. 516-518 (doi:10.1542/peds.2005-2057)
COMMENTARY |
Hydrocortisone and Vasopressor-Resistant Shock in Preterm Neonates
USC Division of Neonatal Medicine, Childrens Hospital Los Angeles and Women's and Children's Hospital, LAC/USC Medical Center, Los Angeles, California; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California
Abbreviations: VLBW—very low birth weight
Because systemic hypotension and significant fluctuations in blood pressure in the immediate postnatal period are associated with increased mortality and major adverse outcomes in preterm neonates, most neonatologists attempt to maintain blood pressure in the perceived gestational- and postnatal-age–dependent "normal" range. Many very low birth weight (VLBW) neonates respond to medium-to-high doses of dopamine, epinephrine, and/or dobutamine and are able to wean off the medications within a few days. However, more than half of them become dependent on medium-to-high–dose vasopressor/inotrope support beyond the first few postnatal days or do not respond at all. Findings of a few observational and retrospective studies have suggested that these neonates respond to relatively low doses of hydrocortisone, with normalization of their cardiovascular status and decreasing vasopressor/inotrope requirement.1–3 Despite the limited information provided by these publications on safety and efficacy and despite the lack of appropriately designed prospective clinical trials, hydrocortisone has now become the choice of treatment of preterm neonates with vasopressor-resistant hypotension. The study by Ng et al,4 published in this issue of Pediatrics, is indeed the first prospective randomized clinical trial that assessed the effectiveness of relatively low doses of hydrocortisone in the treatment of refractory hypotension of VLBW neonates during the immediate postnatal period.
The findings of this prospective, double-blind, randomized, controlled trial indicate that a 5-day course of 3 mg/kg per day of hydrocortisone started on the first postnatal day decreases the cumulative doses of vasopressors/inotropes and volume expanders as well as the number of patients who require vasopressor/inotrope support by 72 hours of the drug administration. In addition, mean arterial blood pressure was significantly and consistently higher in the hydrocortisone-treated group. These beneficial cardiovascular effects were not accompanied by apparent adverse effects such as an increased incidence of hyperglycemia, systemic infections, or intestinal perforation.
These findings are important and confirm the observations of the retrospective studies1–3 on the effectiveness of hydrocortisone in reversing vasopressor resistance in the VLBW neonate. However, several important points need to be addressed before hydrocortisone can become the generally accepted treatment modality for hypotension and vasopressor resistance in the VLBW neonate especially during the immediate postnatal period.
One needs to examine the rationale for the use of hydrocortisone in this most vulnerable patient population because, in most cases and after some time, cardiovascular stability will be achieved by the use of vasopressors and/or inotropes alone. The first argument for the early use of hydrocortisone could be that the sooner one normalizes blood pressure during the immediate postnatal period in the VLBW neonate, the better the outcome. However, because the gestational- and postnatal-age–dependent normal blood pressure range is not known, because "normal" blood pressure in the first 24 hours may not guarantee normal cerebral perfusion and there is more direct evidence for an association than a causation between hypotension and adverse outcomes in the VLBW neonate, stabilization of the cardiovascular status with little blood pressure fluctuation and with little to no vasopressor/inotrope support remains an intuitively desirable goal but one without much direct evidence to support it.
The second argument for the early use of hydrocortisone is that the drug specifically addresses the underlying etiology of the cardiovascular instability in this patient population, and thus it is the logical choice of treatment. Indeed, findings of cardiovascular cellular physiology and developmental endocrinology and some clinical data support a role for hydrocortisone use in critically ill hypotensive extremely low birth weight neonates. In critical illness, desensitization of the cardiovascular system to catecholamines occurs through the downregulation of adrenergic receptors and second messenger systems.5 This process is attenuated or prevented by the regulatory actions of glucocorticoids on the expression of cardiovascular adrenergic receptors and second messenger systems5 and by the mineralocorticoid-induced direct increase in myocardial and vascular smooth muscle cell contractility.6 In addition, as summarized recently,3 corticosteroids contribute to the maintenance of capillary integrity, inhibit catecholamine metabolism and reuptake of norepinephrine into sympathetic nerve endings, increase the expression of angiotensin type 2 receptors in the myocardium, and inhibit prostacyclin production and the induction of inducible nitric-oxide synthase. Each of these complex actions of corticosteroids aids in sustaining the sensitivity of the cardiovascular system to catecholamines in response to acute stress or critical illness.
The other supporting notion for a specific role of hydrocortisone in preterm neonates with critical cardiovascular compromise is based on the accumulating evidence that VLBW neonates have impaired cortisol production in response to stress or endogenous or exogenous corticotropin.7,8 In addition, VLBW neonates may also have a blunted hypothalamic sensitivity to recognize stress. In this context, it is of interest that both the hydrocortisone-treated and control VLBW neonates enrolled in the study by Ng et al4 exhibited relatively low baseline serum cortisol levels in the range of 1.4 to 6.9 µg/dL. One caveat in the endocrinologic characterization of the "transient or relative adrenal insufficiency of prematurity" is the lack of the systematic evaluation of the association between the concentrations of total and free serum cortisol and serum protein in the critically ill VLBW neonate.9
Finally, in discussing the rationale of hydrocortisone administration in hypotensive VLBW neonates with vasopressor resistance, one needs to examine the potential risks of the drug and weigh them against those of vasopressors/inotropes. At present, it is unclear whether low-to-moderate doses of hydrocortisone interfere with neurodevelopment. Because there is overwhelming evidence that early and/or medium-to-high cumulative doses of dexamethasone have detrimental effects on the developing brain,10 it is of utmost importance that this question be addressed before the routine use of hydrocortisone to support cardiovascular stability in this extremely vulnerable patient population can be recommended. The findings of a recent study on structural and functional brain development at an age of 8 years suggest that hydrocortisone, used for the treatment of bronchopulmonary dysplasia in ventilator-dependent preterm neonates at a median age of 18 days and at cumulative doses of >50 mg, does not interfere with brain development.11 Because the cumulative dose of hydrocortisone that is used to combat cardiovascular compromise1–4 is much less, these results may be reassuring. However, there are several points that invite caution when interpreting these findings. First, the study on the effect of hydrocortisone on neurodevelopment is not appropriately powered to detect small but important differences between hydrocortisone-treated and control VLBW neonates.11 Second, only a limited number of preterm neonates born at 24 to 26 weeks' gestation were included in this study. Thus, the most vulnerable patient population that is most likely to develop vasopressor-resistant hypotension and neurodevelopmental handicaps was significantly underrepresented. Third, we still have no information on the neurodevelopmental effects of early hydrocortisone administration. This is another important point, because hydrocortisone has been used during the first 1 to 2 postnatal weeks to improve survival without bronchopulmonary dysplasia8 and to treat vasopressor-resistant hypotension.1–4 The findings that dexamethasone is more neurotoxic when administered during the first postnatal days10 deepen the concerns related to the timing of steroid administration.
The other major issue with the early use of hydrocortisone in VLBW neonates relates to the increased risk of intestinal perforations, especially when it is used concurrently with indomethacin.8 It is interesting to note that, although in the present study by Ng et al4 79% of the patients were exposed to both indomethacin and hydrocortisone, gastrointestinal complications including ileal perforations were not different between the treated and control groups. The authors speculated that this observation might relate to the routine use of a proton-pump inhibitor in their patients but acknowledged that there are no data to support this hypothesis. It also is interesting to note that findings of a recent study suggest that VLBW neonates with low baseline serum cortisol levels may be at less risk for developing ileal perforations when treated with low-dose hydrocortisone and a cyclooxygenase inhibitor during the first postnatal days.12 However, until more information is available on the relationship of low basal serum cortisol levels and the safety of the use of early hydrocortisone and indomethacin in VLBW neonates, it seems prudent to avoid concurrent administration of the 2 medications.
Another potential adverse effect of hydrocortisone administration is that the drug may primarily enhance the vasoconstrictive effects of dopamine or epinephrine; thus, despite normalization of the blood pressure, tissue perfusion could remain or become compromised. However, recent preliminary data suggest that all aspects of myocardial function (including tissue perfusion) improve in response to hydrocortisone administration.13
In summary, the findings of Ng et al4 demonstrate that relatively low-dose hydrocortisone administration improves cardiovascular stability and decreases the need for vasopressor support in hypotensive VLBW neonates. However, it remains to be seen whether this treatment modality improves mortality and/or long-term outcomes. Based on the available information, it is reasonable to consider the use of low-dose hydrocortisone in VLBW neonates who remain hypotensive despite medium-to-high–dose vasopressor support or cannot be weaned off vasopressors. The most appropriate daily dose, the dosing frequency, the length of hydrocortisone administration, and the vasopressor dose triggering hydrocortisone use remain to be determined and, at present, have to be carefully considered by the clinician. Finally, despite the lack of a difference in the incidence of intestinal perforations between the indomethacin-exposed hydrocortisone-treated and control groups in this study,4 the concurrent use of indomethacin and hydrocortisone cannot not be recommended at this time.
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FOOTNOTES |
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Accepted Aug 22, 2005.
Address correspondence to Istvan Seri, MD, PhD, Childrens Hospital Los Angeles, 4650 Sunset Blvd, MS 31, Los Angeles, CA 90027. E-mail: iseri{at}chla.usc.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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