PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1070-1074

Cardiovascular Effects of Hydrocortisone in Preterm Infants With Pressor-Resistant Hypotension

Istvan Seri, MD, PhD, Rosemarie Tan, MD, PhD, and Jaquelyn Evans, MD

From the Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.

	ABSTRACT

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Objective.  To study the cardiovascular effects of hydrocortisone in preterm infants with hypotension unresponsive to volume and pressor administration.

Study Design.  Retrospective review of the cardiovascular response to 23 courses of hydrocortisone administration during the first day of treatment in 21 preterm infants (gestational age: 26.9 ± 3.9 weeks; postnatal age: 11.3 ± 13.1 days). Hydrocortisone (2 mg/kg/d in 16 patients and 3-6 mg/kg/d in 5 patients) was administered when dopamine (22.2 ± 11 µg/kg/min, range: 8-60) alone (n = 16) or in combination with dobutamine (8.4 ± 4.9 µg/kg/min, range: 5-20, n = 7) and/or epinephrine (0.38 ± 0.56 µg/kg/min, range: 0.01-1.2, n = 4) failed to normalize blood pressure.

Results.  Mean blood pressure increased from 29.3 ± 4.1 to 34.1 ± 5.2, 38.0 ± 8.0, and 41.8 ± 6.6 mm Hg by 2, 4, and 6 hours of hydrocortisone administration, respectively, and remained stable thereafter. Urine output increased despite a decrease in fluid administration during the first day of hydrocortisone treatment. The dose of dopamine and the number of patients receiving dobutamine and/or epinephrine also decreased during the same period. Eighteen of the 21 patients survived.

Conclusions.  Preterm infants with volume- and pressor-resistant hypotension respond to hydrocortisone with rapid normalization of the cardiovascular status and sustained decreases in volume and pressor requirement.  Key words:  blood pressure, dopamine, hydrocortisone, hypotension, preterm infant.

Severe and prolonged hypotension, defined as systemic mean blood pressure below the 10th percentile of the empiric blood pressure norms,^1,2 is associated with increased mortality and central nervous system morbidity in preterm infants.^3-5 Therefore, interventions leading to increases in blood pressure and stabilization of the cardiovascular system may affect mortality and short- and long-term central nervous system morbidity in this patient population. In most hypotensive preterm infants, cautious and limited volume administration and the early use of dopamine are effective in improving the cardiovascular status and renal function.^1,6 However, a subgroup of hypotensive preterm infants does not respond even when treatment is escalated and aggressive volume resuscitation and dopamine doses well beyond the conventional (2-20 µg/kg/min) dose range are used.^1,7 In these patients with volume- and pressor-resistant hypotension, several therapeutic approaches have been attempted including additional escalation of dopamine treatment,⁸ addition of epinephrine^9,10 or norepinephrine,¹¹ and more recently, initiation of steroid administration.^7,12-15

Although steroid administration may be effective in improving blood pressure and stabilizing cardiovascular status,^7,12-15 the number of patients in the peer-reviewed literature that comprise the population reported to benefit from steroid treatment of hypotension is small.^7,12,13,15 In addition, the time course of the improvement in blood pressure in response to steroid treatment has not been systematically investigated. Therefore, in the present study, we report the changes in mean arterial blood pressure, heart rate, urine output, and fluid intake after the initiation of hydrocortisone (HC) treatment, with special attention to the timing of the cardiovascular changes in response to steroid administration in 21 preterm infants with volume- and pressor-resistant hypotension.

	MATERIALS AND METHODS

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The data were obtained by review of the charts and flowsheets of hypotensive preterm infants who received HC per the guidelines on the use of steroids in preterm infants with volume- and pressor-resistant hypotension developed by the Division of Neonatology at the Children's Hospital of Philadelphia and the University of Pennsylvania. The records of all preterm infants who were treated during a 2-year period according to these guidelines in the Newborn Infant Center at the Children's Hospital of Philadelphia and in the Neonatal Intensive Care Unit at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, were reviewed for this study. According to divisional guidelines, a trial of HC administration may be considered by the attending neonatologist if the mean blood pressure remains at or below the 10th percentile for gestational and postnatal age-dependent norms² despite volume administration and high-dose pressor/inotrope support. High-dose pressor/inotrope support is arbitrarily defined in the guidelines as the administration of dopamine at doses >20 µg/kg/min or the combined use of dopamine (10-15 µg/kg/min) with dobutamine and/or epinephrine. Although the dose of HC may vary according to the underlying pathology and previous steroid administration, in patients with no evidence for severe capillary leak or previous steroid administration, the guidelines recommend 1 mg/kg/dose of HC twice daily for 1 to 3 days. Accordingly, 16 patients in the study received HC at 1 mg/kg/dose twice daily for 1 to 3 days for a total of 17 treatment courses, while the 5 preterm infants with severe capillary leak syndrome and/or previous steroid treatment received 3 to 6 mg/kg/d of HC divided twice daily or four times daily for 2 to 3 days for a total of 6 treatment courses.

Chart reviews were performed when patients met the following criteria: gestational age 36 weeks by early prenatal ultrasonography, physical examination, or both; postnatal age 36 weeks of adjusted gestational age; hypotension resistant to volume resuscitation and pressor and inotrope support; HC administration as per the above-described divisional guidelines to stabilize the cardiovascular status in preterm infants with volume- and pressor-resistant hypotension; and appropriate documentation of the timing and doses of pressor, inotrope, and HC administration, fluid intake, cardiovascular parameters, and urine output. Patients were excluded from evaluation if changes in pressor and inotrope support coincided with the initiation of HC treatment. Data on heart rate, blood pressure, urine output, and pressor and inotrope support were reviewed for the last 12 hours before and for the first two 12-hour periods after the initiation of HC administration.

Heart rate and systolic, diastolic, and mean blood pressure values were recorded on the flow sheet every 15 to 60 minutes depending on the instability of the cardiovascular status of the patient. Blood pressure data were obtained from an umbilical or peripheral arterial catheter connected to a pressure transducer and displayed on a monitor (Marquette Electronic Ink, Milwaukee, WI) and/or from oscillometric blood pressure measurements (Criticon, Johnson & Johnson, Arlington, TX). The blood pressure values presented in this study represent the average of 2 to 4 blood pressure recordings. Dopamine, dobutamine, and epinephrine were infused into a peripheral or central vein by calibrated infusion pumps, and the values represent the average dose administered for the given time periods. HC was administered over 20 minutes into a peripheral vein. Urine output was recorded on the flowsheets from data obtained from either continuous urine collection from a bladder catheter or from diaper weights. Data on fluid administration and blood sugar evaluation (OneTouch or SureStepPro, Lifescan, Milpitas, CA) were also obtained from the records on the flowsheets as charted by nursing as required by nursing guidelines. In patients receiving HC, blood sugar evaluations were routinely performed every 2 to 4 hours.

The chart review was performed by 2 of the authors (R.T. and J.E.), whereas the data analysis was accomplished by the third author (I.S.) in an effort to enhance the objectivity of this retrospective study by separating data collection from data analysis. Finally, the institutional review board granted the study an expedited approval with a waiver of informed consent.

Statistical Analysis

Data collected are given as means ± standard deviation (SD) unless indicated otherwise. Paired t test (2-tailed), unpaired t test (2-tailed), and 1 factor analysis of variance (Fisher's PLSD [protected least square difference] test) were used for data analysis where applicable. A P < .05 was considered significant.

	RESULTS

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A total of 23 treatment courses of HC therapy in 21 preterm infants were evaluated. Gestational age, birth weight, and postnatal age were 26.9 ± 3.9 weeks (range: 23-36), 952 ± 607 g (range: 478-2450), and 11.3 ± 13.1 days (0-40), respectively. Nine patients had culture-proven sepsis; the remaining diagnoses were prematurity with severe respiratory distress syndrome (n = 7), asphyxia (n = 2), premature delivery 3 to 4 weeks after intrauterine tracheal ligation for severe congenital diaphragmatic hernia (n = 2), and omphalocele with pulmonary hypertension (n = 1). All patients required mechanical ventilation, had severe arterial hypotension, and were started on HC when, in conjunction with aggressive volume resuscitation, dopamine alone (19.1 ± 8 µg/kg/min, range: 8-40 µg/kg/min; n = 13) or in combination with dobutamine (8.4 ± 4.9 µg/kg/min; range: 5-20 µg/kg/min; n = 7) and/or epinephrine (0.38 ± 0.56 µg/kg/min; range: 0.01-1.2 µg/kg/min; n = 4) failed to normalize blood pressure. At the start of HC administration, the dose of dopamine for all of the 23 treatment courses was 22.2 ± 11 µg/kg/min (range: 8-60 µg/kg/min; n = 23).

Mean blood pressure increased by 2 hours of HC treatment from the preHC value of 29.3 ± 4.1 to 34.1 ± 5.2 mm Hg (P < .05, Fig 1 and Fig 2A) and was higher in 20 out of the 23 individual treatment courses (Fig 1). By 4 hours of HC treatment, blood pressure increased to 38.0 ± 8.0 mm Hg and, at this time, was higher in all but 1 of the patients compared with the preHC blood pressure value (P < .05, Fig 1 and Fig 2A). The increases in blood pressure occurred despite unchanged pressor and inotrope support during this period of time (Fig 2B). At 6 hours after the first dose of HC, blood pressure increased to 41.8 ± 6.6 mm Hg (P < .05 vs HC [4 hours]), and remained close to this level during the first 24 hours of HC administration (Fig 2A). The sustained increase in the blood pressure occurred despite the decrease in the dose of dopamine (Fig 2B) and the decrease in the number of patients on additional epinephrine or dobutamine infusion by 12 and 24 hours of HC treatment, and despite the decrease in volume administration during this period (Fig 3A). In association with the improvement in the cardiovascular status and the decrease in pressor and inotrope requirement, heart rate decreased by 12 and 24 hours of HC treatment from a preHC value of 175 ± 20 beats per minute to 161 ± 13 and 158 ± 12 beats per minute, respectively (P > .05, analysis of variance, Fisher's PLSD). Finally, there was no difference in the cardiovascular response between the patients in the higher (n = 6) and lower (n = 17) HC dosing groups (data not shown).

View larger version (23K): [in this window] [in a new window]   Fig. 1.   Individual and average mean blood pressure values immediately before (preHC) and 2 (HC [2 h]) and 4 (HC [4 h]) hours after the first dose of hydrocortisone in 23 courses of hydrocortisone treatment in 21 preterm infants (* P < .05 vs preHC; analysis of variance, Fisher's PLSD).

View larger version (35K): [in this window] [in a new window]   Fig. 2.   Mean blood pressure (mean ± SD; Fig 2A) and dopamine requirement (mean ± SD; Fig 2B) during 12 hours before and the first 24 hours after the first dose of hydrocortisone. Before hydrocortisone administration, blood pressure remained low (Fig 2A), despite significantly increased dopamine doses (Fig 2B;  = P < .05 vs baseline [0 hours]). However, mean blood pressure increased significantly by 2 hours after the first dose of hydrocortisone (Fig 2A; * = P < .05 vs baseline [0 hours]) and continued to rise until 6 hours of hydrocortisone therapy remaining stable thereafter (Fig 2A * = P < .05 vs baseline [0 hours];  = P < .05 vs HC [2 hours]). Additionally, the dose of dopamine significantly decreased by 12 and 24 hours of hydrocortisone therapy (Fig 2B; * = P < .05 vs baseline [0 hours]).

View larger version (34K): [in this window] [in a new window]   Fig. 3.   Changes in individual and mean fluid intake (A) and urine output (B) during 12 hours before (preHC) and the first two 12-hour periods after the first dose of hydrocortisone (HC[0-12 hours] and HC-1[2-24 hours], respectively) in 23 courses of hydrocortisone treatment in 21 preterm infants (* = P < .05 vs PreHC; analysis of variance, Fisher's PLSD). Fluid intake decreased (A), whereas urine output increased (B) after the initiation of hydrocortisone therapy.

At the time of the initiation of HC treatment, in addition to dopamine administration, 7 and 4 patients received dobutamine and epinephrine, respectively, with 1 preterm infant receiving all 3 medications. However, by the end of the first 24 hours of HC administration, the number of patients on dobutamine and epinephrine decreased to 3 and 2, respectively.

Fluid intake during the 12-hour period before the first dose of HC was 9.1 ± 2.6 mL/kg/hour and decreased significantly during the first two 12-hour periods of HC treatment to 7.32 ± 2.5 and 6.88 ± 1.6 mL/kg/hour, respectively (P < .05, analysis of variance, Fisher's PLSD; Fig 3A), attributable to decreased administration of normal saline and/or blood products. Despite the decrease in fluid intake, urine output increased from 3.2 ± 2.9 mL/kg/hour in the 12-hour period before HC administration to 5.1 ± 2.4 mL/kg/hour during the first 24 hours of HC treatment (P < .05, paired t test). Evaluation of the urine output in two 12-hour periods during the first day of HC treatment revealed that the increase in urine output reached statistical significance only during the first 12 hours (Fig 3B).

Blood glucose values during the last two 6-hour periods before HC administration were 129 ± 50 and 131 ± 62 mg/dL, respectively. Blood glucose remained stable during the first 24 hours of HC treatment at 138 ± 52, 133 ± 56, 130 ± 40, and 125 ± 52 mg/dL at 2, 6, 12, and 24 hours, respectively (P > .05, analysis of variance, Fisher's PLSD). In addition, there was no difference in maximum blood glucose values and glucose administration before and during HC treatment (data not shown). Eighteen of the 21 patients survived.

	DISCUSSION

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The cardiovascular effects of steroid treatment of preterm infants with refractory hypotension have been described only in a few peer-reviewed studies and on a relatively small number of patients.^7,12,13,15 In addition, the time course of the improvement in blood pressure in response to steroid treatment has not been systematically investigated. Although the present study is retrospective in its data-collection design, the findings have been obtained from a patient population treated prospectively according to predefined clinical guidelines. In agreement with earlier findings,^7,11-15 our study demonstrates that preterm infants with volume- and pressor-resistant hypotension respond to steroid administration with an improvement in the cardiovascular status and decreases in volume and pressor requirement. However, in addition to strengthening the notion that preterm neonates with refractory hypotension may benefit from a short steroid treatment, our data also reveal that the improvement in blood pressure occurs within the first 2 hours of HC administration. A previous randomized trial in preterm infants with nonpressor-resistant hypotension also found a beneficial blood pressure response to 2.5 mg/kg/dose of HC by 2 hours after the first dose of the drug.¹⁶ If confirmed in preterm infants with pressor-resistant hypotension, this finding has important clinical implications because the rapid and sustained stabilization of the cardiovascular status in critically ill preterm infants may have beneficial short- and long-term consequences.^3-5

Although the pathophysiology of the pressor-resistant hypotension has not been fully clarified, downregulation of the adrenergic receptors in cases of critical illness and exogenous catecholamine administration^17,18 and a relative or absolute adrenal insufficiency^19-21 have recently emerged as probable causative factors.

There is accumulating evidence that the attenuated cardiovascular responsiveness to catecholamines in severe disease states and/or after prolonged pressor treatment is, at least in part, caused by the down-regulation of the cardiovascular adrenergic receptors and second messengers systems.^17,18 Because of the lysosomal destruction of adrenergic receptors during the process of downregulation,^17,18 reversal of this process requires new protein synthesis. Because expression of the cardiovascular adrenergic receptors and some components of their second messenger systems is inducible by glucocorticoids,^22,23 steroid administration offers a powerful tool to reverse adrenergic receptor downregulation. These genomic effects of steroids resulting in the synthesis and membrane-assembly of new receptor proteins require at least several hours to take place.

However, in addition to their genomic effects, steroids exert certain nongenomic actions, which affect the cardiovascular system without delay. Glucocorticoids inhibit the catechol-0-methyltransferase, the rate-limiting enzyme in catecholamine metabolism, and decrease the reuptake of norepinephrine by the sympathetic nerve endings, leading to increases in the plasma concentration of catecholamines.²⁴ Physiologic doses of mineralocorticoids and, to a lesser degree, pharmacologic doses of glucocorticoids also instantly increase cytosolic calcium availability in myocardial and vascular smooth muscle cells acting via putative cell membrane-bound specific steroid receptors.^24,25 In addition, steroids inhibit prostacyclin production and the induction of nitric oxide synthase,²⁶ limiting the pathologic vasodilation associated with the nonspecific or specific inflammatory response in the critically ill preterm infant. Finally, by improving capillary integrity,²⁷ steroid administration may also increase the effective circulating blood volume in patients with capillary leak.

Besides adrenergic receptor downregulation, adrenal insufficiency may play a role in the development of pressor/inotrope resistance.^19-21 Adrenal insufficiency primarily occurs in preterm infants with a history of previous severe illness and/or long-term steroid treatment for chronic lung disease. However, it may also be present in extremely immature preterm infants during the first week of life.^19,21 In addition, especially during periods of critical illness, even a relative adrenal insufficiency may cause a disruption in the balance between adrenergic receptor destruction and synthesis leading to decreased sensitivity of the cardiovascular system to endogenous and exogenous catecholamines. In these infants, steroid administration may serve as hormone replacement therapy and may be necessary for several days (rarely weeks) to achieve a sustained improvement in the cardiovascular function.^1,7

No adverse effects have been reported in the previous studies using brief HC or dexamethasone therapy in preterm infants with volume- and pressor-resistant hypotension.^7,11-15 However, the results of a case-control study suggested that there might be an association between disseminated candidal infection and prolonged and high-dose HC treatment in extremely low birth weight infants during the first 35 days of life.²⁸ Although our study was not designed to investigate the side effects of short-term HC administration, we also did not find evidence for adverse occurrences including changes in glucose homeostasis or an increased rate of candidal infection. It is important to note that we administered HC at significantly lower doses and shorter duration than most of the previous studies, and that we used HC because of the theoretical benefits of the combination of its mostly mineralocorticoid-mediated nongenomic and glucocorticoid-mediated genomic cardiovascular actions.²⁴ However, although the findings of the present and previous^7,12,15 studies are encouraging, randomized studies on large patient populations are needed to establish the lowest effective dose of HC and to investigate the drug's effects on cardiovascular and renal function, organ blood flows, and tissue perfusion. Finally, the potential for short- and long-term adverse neurologic effects of steroid use for refractory hypotension in preterm infants also needs to be carefully evaluated.

	CONCLUSION

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The findings of the present study strengthen the notion that brief HC administration may restore cardiovascular stability in preterm infants with volume- and pressor-resistant hypotension. In addition, this study has demonstrated a rapid increase in blood pressure within 2 hours of the first HC dose followed by a sustained improvement in the cardiovascular status and urine output in this patient population. Based on these findings, we speculate that the nongenomic actions of HC may be responsible for the observed rapid cardiovascular response whereas the genomic actions contribute to the sustained normalization of the blood pressure and the decrease in pressor and inotrope requirement.

	FOOTNOTES

Received for publication May 10, 2000; accepted Aug 25, 2000.

This paper was presented in part at the Annual Meeting of the APS-SPR in San Francisco, California, May 1999, and published in abstract form (Pediatr Res. 1999;45:224A).

Reprint requests to (I.S.) Children's Hospital of Philadelphia, University of Pennsylvania, 34th Street and Civic Center Blvd, Philadelphia, PA 19104. E-mail: seri{at}email.chop.edu

	ABBREVIATIONS

HC, hydrocortisone; SD, standard deviation; PLSD, protected least square difference.

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