Evidence-based approach to diuretic therapy in the neonate

Introduction

Diuretics are commonly used in the neonatal population to treat infants with bronchopulmonary dysplasia (BPD), cardiac disease associated with congestive heart failure, and acute kidney injury (AKI). The relatively high frequency of diuretic use has been documented by several large retrospective cohorts. Laughon et al. utilized the Pediatrix Medical Group data warehouse (1997–2011) to identify that 37% of almost 40,000 infants <32 weeks’ gestation and <1500 g birth weight were exposed to at least one diuretic, with 93% of these infants receiving at least a single dose of furosemide. Using this same database, Clark et al. reported that furosemide was the seventh most commonly reported medication in the neonatal intensive care unit (NICU), with over 8% of all NICU patients being exposed to the agent. This widespread use of diuretics occurs despite the lack of evidence demonstrating a beneficial effect of long-term diuretic therapy on clinical outcomes in infants with BPD and other medical conditions. A survey of US neonatologists involving hypothetical clinical scenarios suggests diuretic therapy for very low birth weight infants in the first 28 days of life is commonly used, despite limited evidence of benefit from randomized trials. A majority of respondents expected sustained improvements in pulmonary mechanics, decreased days on mechanical ventilation, and decreased length of stay, despite the lack of evidence in current literature. Finally, although the list of potential complications from diuretic therapy is extensive, including electrolyte abnormalities, bone demineralization, and growth failure, these appear to have limited influence on the decision-making process. This disparity underscores the reasons for both furosemide and hydrochlorothiazide being included on the 2020–2021 Best Pharmaceuticals for Children Act (BPCA) Priority list of needs in pediatric therapeutics.

A rational, patient-centered approach to diuretic therapy in neonates requires a basic understanding of developmental renal physiology and function, knowledge of the mechanisms of action of diuretics, evidence of their efficacy relative to specific disease states, and familiarity with the potential adverse effects. This chapter seeks to fulfill these needs of the clinician with a particular focus on the use of diuretics in neonates with lung disease, congenital heart disease, and AKI.

Developmental renal physiology and function

During the last trimester of gestation, the fetal kidneys receive only 2%–4% of the combined ventricular blood output. Following birth there is a decrease in renal vascular resistance associated with a rise in arterial pressure, both contributing to an increase in renal blood flow during the weeks following birth such that the newborn kidney receives 8%–10% of cardiac output at the end of the first week of life and 15%–18% by a few months of age. In comparison, 25% of cardiac output is distributed to the kidneys in the normal adult. Accompanying postnatal changes in blood flow are marked increases in the glomerular filtration rate (GFR) and sodium reabsorption. In a longitudinal study of preterm infants whose gestational ages at birth ranged from 27 to 31 weeks, Vieux et al. identified that GFR, as measured by creatinine clearance, increased from 18.5 ± 12.6 (day 7) to 26.2 ± 19.6 mL/min per 1.73 m ² (day 28). GFR was approximately two times higher in 31-week gestation infants compared with 27-week gestation infants throughout this period. It is estimated that GFR increases at least 50% during the first day of life in the term infant and doubles by 2 weeks of age. Studies in animal models suggest anatomical and neurohumoral factors, including the renin-angiotensin system, nitric oxide, and prostaglandins, contribute to these developmental changes that have important implications regarding the pharmacokinetics of diuretics in neonates.

Sodium is the principal cation in the extracellular water compartment and is instrumental in maintaining the size of the extracellular space, including intravascular volume. Because preservation of extracellular and intravascular volume is essential for life, the mature kidney displays redundant sodium transport systems that allow for a high degree of renal tubular sodium reabsorption. In contrast, the developing kidney exhibits obligate urine sodium loss because of immaturity of renal tubular sodium transport. In utero, urinary fractional excretion of sodium (FENa) is remarkably high, averaging 10%–15%. Urine sodium losses remain high in preterm infants 22–32 weeks’ gestation (FENa 5%–10% during first few days of life) and slowly decrease with advancing postnatal age, typically achieving an FENa of 0.5%–1% by 36 weeks postmenstrual age. ^, In full-term infants, FENa decreases to 2%–4% in the first few hours after birth and to lower values in the subsequent 48 hours. Changes in renal sodium excretion appear to be related to changes in renal blood flow distribution, proximal tubule length, expression and activity of sodium-potassium ATPase and luminal membrane sodium-hydrogen exchanger, and response to hormones.

Sodium reabsorption in the kidney

The majority of sodium filtered by the glomerulus is reabsorbed along the renal tubule by a variety of ion pumps and transport proteins. The primary site of sodium reabsorption is within the proximal tubule (50%–70% of total renal sodium reabsorption), with lesser amounts reabsorbed in the loop of Henle (25%–30%), the distal tubule (5%), and the collecting duct (3%). The basolateral sodium-potassium ATPase (Na ⁺ -K ⁺ -ATPase) provides the electrochemical driving force for sodium reabsorption along the nephron tubule, decreasing intracellular sodium concentration and generating a negative cellular potential difference. With the proximal tubule, sodium is reabsorbed along with organic solutes, via the Na-H exchanger in the apical membrane, and passively across tight junctions. Within the thick ascending loop of Henle, the Na ⁺ -K ⁺ -2Cl ⁻ cotransporter in the apical membrane is primarily responsible for sodium reabsorption. This is the transporter that is inhibited by loop diuretics, such as furosemide. Sodium transport in the distal convoluted tubule occurs via the Na-Cl transporter (NCC), which is inhibited by thiazide diuretics, while the collecting tubule primarily utilizes the epithelial sodium channel (ENaC) on principal cells and a Na ⁺ -dependent Cl ⁻ /HCO ₃ exchanger on intercalated cells. Different classes of diuretics, described later, target these different, apically located transporters to block sodium, chloride, and ultimately water reabsorption in the kidney, leading to various degrees of natriuresis, chloruresis, and diuresis.

Diuretic classes based upon mechanisms of action

Diuretics are designed to reduce sodium and chloride reabsorption within the renal tubules and in doing so reduce the luminal-to-cellular osmotic gradient, which in turn limits water reabsorption and increases urine production (i.e., water loss). Diuretics are typically classified by their sites and mechanisms of action. The two most common types of diuretics used in the neonatal population, loop diuretics (acting in the thick ascending limb) and thiazide diuretics (acting in the distal convoluted tubule), are described herein. Potassium-sparing diuretics, which represent a third class of diuretics and act in the aldosterone-sensitive distal nephron, are less commonly used and then typically in combination with thiazides. Diuretics with limited use or pharmacologic/pharmacokinetic data in the neonatal population will only briefly be mentioned.