Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

doi:10.1016/j.jpeds.2014.01.058

The Journal of Pediatrics

Volume 164, Issue 6, June 2014, Pages 1449-1455.e1

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https://doi.org/10.1016/j.jpeds.2014.01.058 Get rights and content

Objective

To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation.

Study design

We performed a multicenter study of infants born at <32 weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0 μg/kg) stimulation test (performed before the ligation), and at 10-12 hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1 × dopamine [μg/kg/min] + 1 × dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15.

Results

Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P = .006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension.

Conclusion

Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Section snippets

Methods

Between May 2009 and February 2012, 95 infants were enrolled at 12 sites with institutional review board approval and parental consent. Infants were eligible for the study if they were: (1) delivered between 23^1/7 and 31^6/7 weeks' gestation; and (2) scheduled for PDA ligation. The criteria to determine the need for ligation were not standardized between the centers. The decision to perform the ligation was made by the clinical care teams. Infants were excluded from the trial if they had: (1)

Results

Ninety-five infants were enrolled in the study before PDA ligation; 52 infants were normotensive throughout the postoperative period, and 43 infants developed hypotension: 14 infants had minimal hypotension (ie, were treated with volume boluses alone [18 ± 6 mL/kg]); 29 also received catecholamines (dopamine-alone, 72%; dobutamine-alone, 7%; dopamine and dobutamine, 21%). Six infants had mild, 9 moderate, and 14 severe/catecholamine-resistant hypotension. Twelve of the 14 infants with

Discussion

We hypothesized that an immature or impaired adrenal response to stress (with low levels of cortisol and high levels of cortisol precursors) might be responsible for the postoperative hypotension that often follows PDA ligation. Our findings do not support this hypothesis. In fact cortisol concentrations in infants who developed postoperative hypotension (responsive to catecholamine or volume resuscitation) were significantly greater than cortisol concentrations measured in normotensive infants

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Patent Ductus Arteriosus in the Preterm Infant
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In full-term infants, obliteration of the ductus arteriosus (DA) takes place through a process of vasoconstriction and anatomic remodeling after birth. In contrast, preterm newborn infants frequently fail to close their DA. Factors that play a prominent role in DA regulation involve those that promote constriction of the ductus (e.g., oxygen, endothelin, Ca²⁺ channels, catecholamines, and Rho kinase), those that oppose it (e.g., intraluminal pressure, prostaglandins, nitric oxide, carbon monoxide, potassium channels, and cyclic adenosine monophosphate [AMP] and cyclic guanosine monophosphate [GMP]), and those that regulate ductus smooth muscle hypoxia, neointimal mound formation, and smooth muscle cell death. The relative importance of each of these factors depends on the intrauterine and extrauterine environment, the degree of ductus maturation, and the genetic background and species being studied. The clinical consequences of a patent ductus arteriosus (PDA) are related to the magnitude of the left-to-right shunt through the PDA, the cardiac and vascular responses to the shunt, and the associated changes in blood flow to the lungs, kidneys, intestine, and brain. Controlled clinical trials demonstrate that a moderate-to-large PDA increases the incidence of severe pulmonary hemorrhage and systemic hypotension during the first week as well as the need for higher levels of ventilator support at the end of the first week. However, controversy exists about the consequences of exposure to a persistent moderate-to-large PDA shunt for greater than 1 week. Further investigations will be needed to determine which infants are likely to benefit from early PDA treatment and which infants might best be left untreated while awaiting spontaneous ductus closure.
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Surgical management of a patent ductus arteriosus: Is this still an option?
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The evolution of neonatal intensive care over the past decade has seen the role of surgical patent ductus arteriosus (PDA) ligation in preterm infants both decrease in scope and become laden with uncertainty. Associations of ligation with adverse neonatal and neurodevelopmental outcomes have rendered the ligation decision more challenging for clinicians and have been associated with a decline in surgical treatment, but these findings may be due to bias from confounding by indication in observational studies rather than a causal detrimental effect of ligation. Accordingly, ligation may still be indicated for infants with large ductal shunts and moderate–severe respiratory insufficiency in whom the prospect of timely spontaneous closure appears low. Ultimately a randomized trial of surgical ligation versus conservative management is necessary to assess the efficacy of this invasive intervention in a population of extremely preterm infants with large ductal shunts. Simultaneously, the transcatheter approach to ductal closure in the very immature infant represents an exciting therapeutic alternative but which is still in its infancy. Insights into the pathophysiology of postoperative cardiorespiratory deterioration, including the importance of left ventricular afterload, may help clinicians avoid instability and mitigate a potentially injurious aspect of surgical treatment. This review examines the evidence regarding the benefits and risks of PDA surgery in preterm neonates and provides a pathophysiology-based management paradigm to guide perioperative care in high-risk infants.
Changing patterns of patent ductus arteriosus surgical ligation in the United States
2018, Seminars in Perinatology
Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids’ Inpatient Database (2000–2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500 g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000 g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2–3.9%); however, mortality decreased (12.4–6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Patent ductus arteriosus, its treatments, and the risks of pulmonary morbidity
2018, Seminars in Perinatology
A persistent left-to-right shunt through a patent ductus arteriosus (PDA) increases the rate of hydrostatic fluid filtration into the lung’s interstitium, impairs pulmonary mechanics, and prolongs the need for mechanical ventilation. In preclinical trials, pharmacologic PDA closure leads to improved alveolarization and minimizes the impaired postnatal alveolar development that is the pathologic hallmark of bronchopulmonary dysplasia (BPD). Although routine prophylactic treatment of a PDA on the day of birth does not appear to offer any more protection against BPD than delaying treatment for 2–3 days, recent evidence from quality improvement trials suggests that early pharmacologic treatment decreases the incidence of BPD compared with a treatment approach that exposes infants to a moderate-to-large PDA shunt for the first 7–10 days after birth. After the first week, routine pharmacologic treatment (compared with continued PDA exposure) no longer appears to alter the course of BPD development. Evidence from epidemiologic, preclinical, and randomized controlled trials demonstrate that early ductus ligation is an independent risk factor for the development of BPD.
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There is growing controversy in the field of neonatal hemodynamics about the diagnosis and treatment of neonatal cardiovascular compromise in the very preterm infant. Accordingly, fundamental questions such as the timely recognition of the subpopulation of neonates at high risk for the development of hemodynamic compromise in the transitional period, the definition of individual patient-dependent blood pressure (BP) thresholds associated with inadequate tissue oxygen delivery (DO₂), the role of physiologic cord clamping, the recognition of the hemodynamic antecedents of peri-intraventricular hemorrhage, and other related issues are yet to be answered. In the absence of such information, applying the principles of developmental cardiovascular physiology and pathophysiology can help in establishing the diagnosis and determining the optimal management of neonatal circulatory compromise.
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Therefore this chapter first reviews the principles of fetal, transitional, and posttransitional hemodynamics, with an emphasis on the principles of developmental cardiovascular physiology. Building on the physiologic principles reviewed, the second part of the chapter then discusses the etiology and pathophysiology of neonatal cardiovascular compromise. The major goals of this chapter are to help the reader to appreciate the impact of immaturity and/or pathologic events on the physiology of neonatal cardiovascular transition and understand the primary factors leading to cardiovascular compromise in the preterm and term neonate. Using this knowledge, along with carefully selected and relevant information from clinical trials, the clinician can best assess and manage hemodynamic disturbance in the immediate transitional period and beyond and potentially reduce the end-organ damage caused by decreased DO₂ to the organs, especially the immature brain in affected neonates.

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: Supported by the Thrasher Research Fund, National Institutes of Health National Heart, Lung, and Blood Institute (HL109199), and National Center for Research Resources (CTSI UL 1 TR000004 through the University of California, San Francisco), and the Jamie and Bobby Gates Foundation. Mass spectrometry was supported by the Michigan Nutrition Obesity Center (DK089503) and Michigan Regional Comprehensive Metabolomics Research Core (U24DK097153). The authors declare no conflicts of interest.

^∗: A list of members of the PDA Ligation/Hypotension Trial Investigators is available at www.jpeds.com (Appendix).

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Original ArticleHypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

Objective

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

J Pediatr

J Thorac Cardiovasc Surg

J Pediatr

Metabolism

J Pediatr

Early Hum Dev

Crit Care Resusc

Risk factors predicting vasopressor use after patent ductus arteriosus ligation

Am J Perinatol

Acute hemodynamic decompensation following patent ductus arteriosus ligation in premature infants

J Invest Surg

Postoperative cardiorespiratory instability following ligation of the preterm ductus arteriosus is related to early need for intervention

J Perinatol

Do intra-operative fluids influence the need for post-operative cardiotropic support after a PDA ligation?

Zhongguo Dang Dai Er Ke Za Zhi

Adrenal function in preterm infants undergoing patent ductus arteriosus ligation

Neonatology

Do cortisol concentrations predict short-term outcomes in extremely low birth weight infants?

Pediatrics

Response to ACTH in the newborn

Arch Dis Child

Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia

Pediatrics

Serum cortisol concentrations in ill preterm infants less than 30 weeks gestational age

Acta Paediatr

Original Article
Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones