Conservative management

Natural evolution of the patent ductus arteriosus in the extremely premature newborn and respiratory outcomes

Early Bubble CPAP Protocol Implementation and Rates of Death or Severe BPD

A few words on diuretics

In our approach, we do not use diuretics in the context of a left to right ductus in premature infants. However, we start considering diuretics in infants who have reached maturity (36 weeks post-menstrual age and beyond - and not before) when they have a significant left to right patent ductus arteriosus increasing Qp:Qs. Physiologically, it is thought that diuretics mitigate the hemodynamic burden of a large PDA by reducing intravascular volume and left ventricular preload, which lowers left atrial and pulmonary venous pressures. This decrease in pulmonary capillary hydrostatic pressure resolves interstitial edema, thereby improving pulmonary compliance, gas exchange, and cardiopulmonary coupling while alleviating ventricular volume overload. Regarding viscosity, diuretics can increase blood viscosity through hemoconcentration (loss of plasma volume). Physiologically, this increased viscosity elevates pulmonary vascular resistance, which can theoretically reduce the magnitude of the left-to-right shunt by increasing the impedance to pulmonary blood flow. In our practice, when infants have reached 36 weeks’ postmenstrual age and demonstrate a hemodynamically significant left-to-right PDA and/or echocardiographic signs of pulmonary hypertension on screening studies, we initiate diuretic therapy with hydrochlorothiazide 1 mg/kg/day in combination with spironolactone 1 mg/kg/day. Patients are reassessed approximately two weeks later, at which point the need to discontinue or continue therapy is reviewed, with decisions guided by clinical status and close echocardiographic follow-up.

• By reducing circulating volume, diuretics may lower preload and help relieve signs of congestive heart failure, but in very preterm infants with significant ductal steal this may further compromise systemic perfusion (gut, kidneys, brain), particularly if combined with aggressive fluid restriction. Thus, while they can improve pulmonary status, they may exacerbate post‑ductal hypoperfusion and contribute to renal dysfunction or intestinal ischemia if used without careful hemodynamic assessment. For these reasons, we do not recommend their use before acheiving a certain level of maturity and be beyond the window of vulnerability that could precipitate hypoperfusion. See Cochrane Review here.

• Hydrochlorothiazide (HCTZ) combined with spironolactone in a near-term or term-corrected infant with a large left-to-right PDA primarily promotes diuresis to alleviate congestive heart failure symptoms without the suspected prostaglandin-stimulating effects previously described with loop diuretics like furosemide (although this has been challenged as well).

  • HCTZ inhibits the Na-Cl cotransporter in the distal convoluted tubule, increasing sodium and water excretion while risking hypokalemia, hyponatremia, and hypovolemia. Spironolactone blocks aldosterone receptors in the collecting duct, providing potassium-sparing natriuresis with milder diuretic potency. Together, they synergistically enhance urine output, reduce edema, and prevent potassium loss compared to HCTZ alone.

  • Unlike furosemide, which is thought to increase renal PGE2 synthesis (although controversial) and can prolong ductal patency, neither HCTZ nor spironolactone significantly alters prostaglandin production or ductal tone, so they are unlikely to directly impact PDA closure or persistence in term infants. In left-to-right shunting, they reduce preload and pulmonary venous congestion, potentially improving respiratory status, hepatomegaly, and weight gain while awaiting spontaneous closure (common in term infants) or definitive therapy. This combination has shown clinical benefits in infants <1 year with congenital heart disease CHF, hastening symptom relief when added to digoxin and thiazides. See reference (Hobbins SM, Fowler RS, Rowe RD, Korey AG. Spironolactone therapy in infants with congestive heart failure secondary to congenital heart disease. Arch Dis Child. 1981 Dec;56(12):934-8. doi: 10.1136/adc.56.12.934. PMID: 7036914; PMCID: PMC1627485.)

    • A retrospective study of 64 extremely premature infants (≤27 weeks GA) with large PDA compared furosemide-exposed (for pulmonary edema) versus non-exposed during NSAID therapy. Contrary to expectations, furosemide did not reduce PDA closure rates (RR 0.88, 95% CI 0.28–2.75) or increase surgical needs (RR 1.53, 95% CI 0.37–3.55). Authors conclude it appears safe as adjunct therapy for large PDA with fluid overload, despite PGE2 concerns. ​ 

    • Corroborating Study (Kuo et al., 2024): In 105 very low birth weight infants, furosemide exposure did not affect PDA closure likelihood or timing (p=0.384 for probability; similar PMA to closure ~35 weeks). 

  • Electrolyte imbalances (e.g., hyperkalemia from spironolactone, hyponatremia from HCTZ) require close monitoring, especially in infants with immature renal function or on other CHF meds. Excessive diuresis may worsen systemic steal from the large PDA, reducing cardiac output or perfusion to gut/kidneys/brain; echo-guided use is ideal. No direct PDA-specific trials in term infants exist, but data from preterm BPD/CHD supports cautious symptomatic use. The use of diuretics should be carefully weighed against the risk of growth and weight gain impairment, as well as electrolyte abnormalities.

    • See reference: https://pubmed.ncbi.nlm.nih.gov/2926575/ No pulmonary benefit.

    • See reference: https://pubmed.ncbi.nlm.nih.gov/6377221/ Some potential but debated mild improvements. 

    • See reference: https://pubmed.ncbi.nlm.nih.gov/32227546/ 

    • See reference of FDA on spironolactone and hydrochlorothiazide tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/012616s081lbl.pdf 

  • Litterature of Ventricular Septal Defect: Diuretics like furosemide are commonly used in infants with left-to-right shunts from ventricular septal defects (VSD) to manage congestive heart failure (CHF) symptoms, primarily by reducing pulmonary congestion and edema. In left-to-right VSD shunts, excess pulmonary blood flow causes pulmonary venous hypertension and edema, leading to tachypnea, retractions, hepatomegaly, and poor growth. Diuretics are thought to alleviate this by promoting natriuresis, reducing preload, extracellular fluid volume, and pulmonary edema without directly affecting shunt volume. One prospective study of 126 infants <2 months with left-to-right shunts (mostly VSD/ASD) used oral furosemide (0.5–3 mg/kg/day) plus spironolactone for CHF symptoms (tachypnea, retractions, etc.). No direct shunt reduction was measured, but electrolyte monitoring was key due to risks like hyponatremia (32%) and hypokalemia (22%). Evidence is mostly observational or from broader CHF cohorts; no large RCTs quantify VSD-specific shunt reduction. Risks include electrolyte imbalances, ototoxicity, nephrocalcinosis in preterms, and potential PDA effects (not VSD). Use with afterload reducers (e.g., ACE inhibitors) and monitor closely.

    • See reference: Pacifici GM. Clinical pharmacology of furosemide in neonates: a review. Pharmaceuticals (Basel). 2013 Sep 5;6(9):1094-129. doi: 10.3390/ph6091094. PMID: 24276421; PMCID: PMC3818833.

    • The American Heart Association states that diuretics are a key component in treating symptoms of fluid overload in patients with congenital heart disease and heart failure, including those with VSD, with loop diuretics being the preferred agents. Thiazide diuretics may be added to enhance the effect of loop diuretics in cases of diuretic resistance or to mitigate calcinuria and nephrocalcinosis associated with long-term loop diuretic use.

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