Hydrocortisone for Hypotension and Vasopressor Dependence in Preterm Neonates
Hydrocortisone for Hypotension and Vasopressor Dependence in Preterm Neonates
Background: A full consensus has not been reached about the hemodynamic efficacy of hydrocortisone administration in hypotensive and vasopressor-dependent preterm neonates.
Objective: To examine the efficacy of hydrocortisone for treatment of hypotension and reduction of vasopressor requirements in preterm infants.
Method: Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels.
Result: Random effects meta-analysis showed that hydrocortisone increases blood pressure (seven studies; N=144; r=0.71, 95%CI=0.18 to 0.92) and reduces vasopressor requirement (five studies; N=93; r=0.74, 95%CI=0.0084 to 0.96). The number of new or unretrieved studies averaging null results required to increase the overall p to 0.05 is k=78 for blood pressure increase and k=47 for vasopressor requirement reduction.
Conclusion: The effects of hydrocortisone on increasing blood pressure and decreasing vasopressor requirements in preterm infants are robust with a large tolerance for future null results. Actual clinical benefits of increasing blood pressure and decreasing vasopressor requirements, however, remain unknown. Long-term sequelae of hydrocortisone administration have yet to be fully elucidated.
Preterm infants, especially very low birth weight infants (birth weight <1500 g), account for a significant percentage of all neonatal mortality.
Although a causal relationship has yet to be established, one variable associated with increased mortality in the preterm infant is systemic hypotension. In addition to increased mortality, systemic hypotension has also been associated with other adverse events, such as intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental morbidity.
Although the normal gestational and postnatal age-dependent blood pressure range is not known, systemic hypotension is commonly defined in one of two ways in clinical research examining this patient population. According to the more frequently used definition of systemic hypotension in clinical research, a neonate is considered as hypotensive if his/her mean blood pressure is below the fifth or tenth percentile of the normative data for the infant's gestational and postnatal age and weight. The less frequently used definition of hypotension is a mean blood pressure less than or equal in numbers to the patient's gestational age in weeks. This definition is mostly used for the first postnatal day(s) and more so in clinical practice than in research studies.
The standard empiric treatment for systemic hypotension includes the use of volume expanders, vasopressor/inotropes (for example dopamine, epinephrine), and/or inotropes (for example dobutamine). However, a significant proportion of preterm infants do not respond to these treatments and presents with ongoing hypotension or become dependent on vasopressor/inotrope administration to maintain blood pressure at the perceived minimally acceptable levels.
The etiology of the ongoing hypotension and vasopressor dependence is thought to be due, at least in part, to the relative adrenal insufficiency of the preterm infant. In addition, downregulation of the cardiovascular adrenergic receptors because of chronic stimulation and critical illness has also been implicated as a cause of ongoing hypotension and vasopressor dependence. As one of the genomic actions of corticosteroids is the upregulation of cardiovascular adrenergic receptor expression, receptor downregulation is thought to be enhanced in patients with relative adrenal insufficiency. Therefore, the use of corticosteroids to treat vasopressor-resistant hypotension addresses both the relative adrenal insufficiency and receptor downregulation.
Hydrocortisone is the corticosteroid most frequently used for the treatment of vasopressor-resistant hypotension in the preterm neonate in the clinical practice because of its perceived effectiveness and lack of evidence for neurodevelopmental side effects. Although hydrocortisone has been shown to increase blood pressure and reduce vasopressor dependence in preterm infants, the sample sizes used in studies examining these relationships have been relatively small, limiting the certainty and generalizability of results.
The purpose of this study is to provide a quantitative review of research examining the relationship between hydrocortisone administration, hypotension, and vasopressor requirements through the use of meta-analytic techniques.
We tested the following three specific hypotheses:
Abstract and Introduction
Abstract
Background: A full consensus has not been reached about the hemodynamic efficacy of hydrocortisone administration in hypotensive and vasopressor-dependent preterm neonates.
Objective: To examine the efficacy of hydrocortisone for treatment of hypotension and reduction of vasopressor requirements in preterm infants.
Method: Standard meta-analytic techniques, including random and fixed effects models, were used to calculate combined effect size correlations and significance levels.
Result: Random effects meta-analysis showed that hydrocortisone increases blood pressure (seven studies; N=144; r=0.71, 95%CI=0.18 to 0.92) and reduces vasopressor requirement (five studies; N=93; r=0.74, 95%CI=0.0084 to 0.96). The number of new or unretrieved studies averaging null results required to increase the overall p to 0.05 is k=78 for blood pressure increase and k=47 for vasopressor requirement reduction.
Conclusion: The effects of hydrocortisone on increasing blood pressure and decreasing vasopressor requirements in preterm infants are robust with a large tolerance for future null results. Actual clinical benefits of increasing blood pressure and decreasing vasopressor requirements, however, remain unknown. Long-term sequelae of hydrocortisone administration have yet to be fully elucidated.
Introduction
Preterm infants, especially very low birth weight infants (birth weight <1500 g), account for a significant percentage of all neonatal mortality.
Although a causal relationship has yet to be established, one variable associated with increased mortality in the preterm infant is systemic hypotension. In addition to increased mortality, systemic hypotension has also been associated with other adverse events, such as intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental morbidity.
Although the normal gestational and postnatal age-dependent blood pressure range is not known, systemic hypotension is commonly defined in one of two ways in clinical research examining this patient population. According to the more frequently used definition of systemic hypotension in clinical research, a neonate is considered as hypotensive if his/her mean blood pressure is below the fifth or tenth percentile of the normative data for the infant's gestational and postnatal age and weight. The less frequently used definition of hypotension is a mean blood pressure less than or equal in numbers to the patient's gestational age in weeks. This definition is mostly used for the first postnatal day(s) and more so in clinical practice than in research studies.
The standard empiric treatment for systemic hypotension includes the use of volume expanders, vasopressor/inotropes (for example dopamine, epinephrine), and/or inotropes (for example dobutamine). However, a significant proportion of preterm infants do not respond to these treatments and presents with ongoing hypotension or become dependent on vasopressor/inotrope administration to maintain blood pressure at the perceived minimally acceptable levels.
The etiology of the ongoing hypotension and vasopressor dependence is thought to be due, at least in part, to the relative adrenal insufficiency of the preterm infant. In addition, downregulation of the cardiovascular adrenergic receptors because of chronic stimulation and critical illness has also been implicated as a cause of ongoing hypotension and vasopressor dependence. As one of the genomic actions of corticosteroids is the upregulation of cardiovascular adrenergic receptor expression, receptor downregulation is thought to be enhanced in patients with relative adrenal insufficiency. Therefore, the use of corticosteroids to treat vasopressor-resistant hypotension addresses both the relative adrenal insufficiency and receptor downregulation.
Hydrocortisone is the corticosteroid most frequently used for the treatment of vasopressor-resistant hypotension in the preterm neonate in the clinical practice because of its perceived effectiveness and lack of evidence for neurodevelopmental side effects. Although hydrocortisone has been shown to increase blood pressure and reduce vasopressor dependence in preterm infants, the sample sizes used in studies examining these relationships have been relatively small, limiting the certainty and generalizability of results.
The purpose of this study is to provide a quantitative review of research examining the relationship between hydrocortisone administration, hypotension, and vasopressor requirements through the use of meta-analytic techniques.
We tested the following three specific hypotheses:
Hydrocortisone administration will significantly increase blood pressure in hypotensive preterm infants.
Hydrocortisone administration will significantly increase blood pressure in vasopressor-dependent preterm infants.
Among preterm infants with vasopressor-dependent hypotension, hydrocortisone administration will significantly reduce the dose of vasopressors required to maintain blood pressure in the perceived normal range.
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