Pamela A.

Harris-Haman, DNP, CRNP, NNP-BC, and Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editors

Clinical Issues in Neonatal Care

Impact of Diuretic Therapy in the Treatment

of Bronchopulmonary Dysplasia and Acute
Kidney Injury in the Neonatal Population
Alexandra Kesler Johnson, APRN, MSN, NNP-BC; Natalie Lynch, APRN, MSN, NNP-BC;
Desi Newberry, APRN, DNP, NNP-BC; Amy J. Jnah, APRN, DNP, NNP-BC

ABSTRACT
Background: Diuretics are among the most frequently prescribed medications in the neonatal intensive care unit (NICU),
despite minimal data regarding the safety and efficacy of their use in the neonatal population. Off-label diuretic therapy
is used in preterm and full-term infants to both optimize kidney function and improve respiratory status.
Purpose: This article examines the literature specific to the impact of diuretic therapy in the NICU and compares the
benefits versus risks of utilization as they pertain to the prevention and treatment of renal and pulmonary dysfunction in
this population.
Methods/Search Strategy: A comprehensive literature search of online databases was performed, utilizing: CINAHL via
EBSCO, PubMed, and ProQuest. Full-text, peer-reviewed, clinical trials, and review articles published in the English lan-
guage between 2005 and 2015 were searched.
Findings/Results: Diuretics rank as the seventh most frequently prescribed medication in the NICU. More than 8% of
all NICU patients and 37% of infants born at less than 32 gestational weeks and weighing less than 1500 g are exposed
to diuretics. Benefits include lung fluid resorption acceleration, improved urine output, fluid retention counteraction, and
augmentation of physiologic weight loss.
Implications for Practice: Diuretics are currently utilized in the NICU at an alarming rate, without adequate clinical trials
regarding their safety and efficacy of use.
Implications for Research: Updated studies are needed regarding short- and long-term outcomes of diuretic use, as well
as overall general outcome data regarding the impact and evaluation of diuretic usage in the NICU population.
Key Words: acute kidney injury, bronchopulmonary dysplasia, chronic lung disease, diuretic, failure to thrive, infant, linear
growth restriction, neonate, renal disease

iuretic therapy is a controversial manage- There is a lack of Food and Drug Administration

D ment strategy with a wide range of accep-

tance, application, and results across
neonatal intensive care units (NICU). Diuretics
remain one of the most frequently prescribed medi-
cations in the NICU, despite minimal data regard-
ing the safety, efficacy, and long-term implications
associated with their use.1 The off-label use of
diuretics within the preterm and full-term infant
population primarily focuses upon optimizing kid-
ney function and improving respiratory status.
Various conditions are associated with use that
include but are not limited to renal dysfunction,
pulmonary disease, sepsis with resultant increased
capillary permeability, oliguric acute kidney injury
(AKI), congestive heart failure, and postoperative
fluid retention management.2,3
Author Affiliations: NNP Program, East Carolina University College of
Nursing, Greenville, North Carolina.
No conflicts of interest or funding to disclose.
Correspondence: Alexandra Kesler Johnson, APRN, MSN, NNP-BC;
NNP Program, East Carolina University College of Nursing, Greenville,
NC (kesleral05@ecualumni.ecu.edu).
Copyright © 2017 by The National Association of Neonatal Nurses
DOI: 10.1097/ANC.0000000000000427
approval to support diuretic use in neonates.1
Despite the paucity of evidence regarding safety and
efficacy, current research describes that approxi-
mately 8% of all infants and approximately 37% of
infants less than 32 weeks’ gestation and less than
1500-g birth weight are prescribed diuretics at least
once during their birth hospitalization.1,4 Furosemide
was noted to be the most commonly used diuretic,
with greater than 93% of infants receiving at least
1 dose during their treatment course.1 A survey of
400 neonatologists throughout the United States
was conducted, and of the 400 participants, 156
(39%) reported using diuretics as a therapeutic
modality for clinical management of bronchopul-
monary dysplasia (BPD).4 In a similar study, a ques-
tionnaire was sent to 96 tertiary NICUs in Japan
regarding pharmacotherapy use related to BPD
treatment and prevention, which yielded an over-
whelming high percentage of use for furosemide and
spironolactone; 84% of units surveyed utilized these
oral diuretics for BPD treatment.5 Diuretics are pre-
scribed to manage common pulmonary and renal
comorbidities; however, those prescriptive decisions
are often not grounded in scientific evidence.

Advances in Neonatal Care • Vol. 00, No. 00 • pp. 1-10 1

Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
2 Johnson et al
Much of the research that guides current practice
is greater than 10 years old and, therefore, must be
considered outdated. For this literature review, a
comprehensive search was conducted from 2005 to
2015 to evaluate what current research exists, with
the goal to validate or disprove current practice
standards with up-to-date research. The search
yielded 1 randomized controlled trial, 6 retrospec-
tive cohort studies that examined the use of diuretic
therapy for pulmonary or renal management, and
multiple review articles that focused on studies that
were conducted prior to 2005.3 Many of these stud-
ies referenced by recent literature reviews are now
outdated, due to the routine use of antenatal ste-
roids, and increasing surfactant use over the past
10 years. However, these older studies are still
regarded as the foundation by which diuretic use is
justified in the NICU population today. The purpose
of this article is to examine the impact of diuretic
therapy on the NICU population and compare the
benefits versus risks of utilization, specifically as it
pertains to the prevention and treatment of renal
and pulmonary dysfunction as a means to inform
the current prescriptive practices of advanced prac-
tice clinicians as well as clinical staff in the NICU.
FIGURE 1
Diuretics and renal physiology.
Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
RENAL PHYSIOLOGY
In utero, the fetal kidneys need to play only a minor
part in the regulation of salt and water balance; how-
ever, in postnatal life, the kidneys go through a pro-
gressive maturation that parallels the neonate’s own
needs for optimal growth and development.6 After
birth, the kidneys are responsible not only for the
regulation of salt and water balance but also for waste
extraction, concentration and dilution of urine, and
assistance in the regulation of blood pressure and cal-
cium homeostasis through hormonal regulation.6 The
nephron is the functional unit of the kidney, which
houses the glomerulus within the Bowman capsule,
proximal convoluted tubule, loop of Henle, distal
convoluted tubule, and collecting duct (Figure 1). The
proximal tubule is the main site of reabsorption for
sodium; however, water, bicarbonate, chloride, and
potassium are also reabsorbed here and hydrogen ions
are secreted (Figure 1). The loop of Henle is the major
site of water reabsorption, which also absorbs multi-
ple electrolytes including sodium, chloride, potas-
sium, magnesium, and calcium (Figure 1). After the
kidney filtrate has passed through the loop of Henle,
it also drives past the interstitium where there is free
www.advancesinneonatalcare.org

flow of water between the tubules and the interstitium
itself in route to the distal convoluted tubule. Within
the distal tubule, aldosterone influences movement in
the distal tubule causing more sodium and water reab-
sorption, and there is also secretion of hydrogen ions,
ammonia, and potassium (Figure 1). Antidiuretic hor-
mone also acts on the collecting tubule to make it
more permeable to water; therefore, with sufficient
antidiuretic hormone, the kidney filtrate loses water
into the interstitium which the body reabsorbs and
this in effect results in the concentration of urine.
The fraction of cardiac output and absolute renal
blood flow that are directly sent to the kidneys both
increase with increasing gestational age.6 Therefore, the
glomerular filtration rate (GFR) as well progressively
increases with increasing gestational age, with GFR
reaching adult values by approximately 2 years of age;
however, this can be severely delayed in very preterm
infants.6 Renal development is functionally immature
and incomplete in infants born less than 34 weeks’ ges-
tation, with new nephron formation continuing until
approximately 36 weeks’ gestation.3,7 As such, low
nephron mass and decreased GFR are common in pre-
mature infants managed within the confines of
NICUs.3,7,8 Low nephron mass increases workload
within the glomeruli.9 Persistent increased workload
can lead to glomerular hypertrophy, capillary wall dam-
age, and AKI.9 High plasma renin activity, decreased
proximal tubular sodium reabsorption, decreased inter-
cortical perfusion, and immature vasoregulation are
also observed among premature infants.8 Thus, prema-
ture infants are at risk for hypoperfusion of their already
underdeveloped and overworked kidneys.
RENAL PATHOPHYSIOLOGY
Acute Kidney Injury
There is no current and universally accepted defini-
tion for AKI.8,9 Acute kidney injury is described as
the abrupt deterioration of renal function over a
period of days to hours, which results in failed excre-
tion of urine, leading to nitrogenous waste retention
and failure to maintain electrolyte and fluid homeo-
stasis.7,8 Acute kidney injury is observed in 3.2% to
24% of infants admitted to the NICU, with critically
ill premature and term infants representing a popu-
lation among those with the highest incidence of
AKI.8,10 Risk factors for AKI encompass both criti-
cally ill and preterm infants including extremely low
and very low birth-weight populations.7,8 Additional
risk factors include hypotension, hypovolemia,
hypoxia, elevated mean airway pressure, clinically
significant patent ductus arteriosus, and exposure to
nephrotoxic drugs including gentamicin, cephalo-
sporins, or non–steroidal anti-inflammatory drugs.7,8
Premature infants represent the most at-risk pop-
ulation, with up to 79% of very low birth-weight
infants diagnosed with AKI during the birth
Advances in Neonatal Care • Vol. 00, No. 00
Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
Impact of Diuretic Therapy 3
hospitalization.10 Preterm infants are at higher risk
for the development of AKI due to prenatal distress
and multiple risk factor exposure including intra-
uterine growth restriction, maternal medications
(primarily non–steroidal anti-inflammatory drugs
and antibiotics), infections, and placental insuffi-
ciency.8 The postnatal treatment course of preterm
infants additionally compounds their risk for AKI
due to associated complications including mechani-
cal ventilation, sepsis, hypoxia, acidosis, catabolism,
hypotension, and the need for cardiopulmonary
resuscitation.7,8 These infants are at great risk due to
their frequent exposure to nephrotoxic drugs, infec-
tions, and overall propensity for multiorgan failure.9
Premature infants have an AKI incidence range
between 3.2% and 24%, which carries a mortality
rate of 10% to 61%.8,10
The kidneys of preterm infants are both structur-
ally and functionally immature, with either incom-
plete or impaired glomerulogenesis and thus a low
GFR.2 As such, these underdeveloped, premature
kidneys are subject to greater physiologic challenges
than those of their fully developed, term counter-
parts.2 Altered kidney function leads to fluid reten-
tion, a common and pathologic problem among hos-
pitalized premature and critically ill term neonates,
often associated with both renal and pulmonary
disease states.2 Volume overload is observed because
of low nephron mass and reduced filtration rates,
frequently observed in cases of AKI.9 Diuretic ther-
apy is often used to convert oliguric AKI into nonoli-
guric AKI.7 Progressive AKI can further increase
pulmonary edema, secondary to the excessive fluid
retention.9 A strong foundation of knowledge of the
pathophysiology of AKI is essential to inform clini-
cal and prescriptive practices within the NICU.
Acute kidney injury is classified according to the
degree of urinary function (anuric, oliguric, or nono-
liguric) and type of renal failure (prerenal, intrinsic,
or postrenal).10 Anuria is defined as the absence of
urine output. Oliguria is defined as an hourly urine
output of less than 1 mL/kg/h.8 Oliguric AKI carries
a much higher mortality rate, 81% versus 25% in
nonoliguric AKI.8 Nonoliguric AKI is defined as AKI
associated with urine output that is adequate in vol-
ume but poor in quality due to inadequate reabsorp-
tion of sodium and bicarb in the renal tubules.7
These 3 states of urinary function contribute to the
risk for 3 types of renal failure.
Prerenal failure is the most common reversible
cause for AKI, caused by decreased perfusion and is
often a consequence of hypotension and hypovole-
mia with or without hypoxia.7 The pathophysiology
behind prerenal failure is related to either poor car-
diac output with decreased perfusion to the kidneys
or inadequate intravascular volume.7 Unfortunately,
conditions leading to prerenal failure often afflict
the neonatal population, especially the preterm
4 Johnson et al
neonate, and include dehydration (thin, friable
immature skin with high degree of insensible water
loss), blood loss (high volume of iatrogenic losses as
well as intracranial hemorrhages), third spacing
edema and gastrointestinal losses, as well as hypo-
tension, sepsis, patent ductus arteriosus, and hypoxia
or ischemia.7
Intrinsic renal failure, the ominous and irrevers-
ible type of AKI, is characterized by internal damage
to the kidneys including and/or resulting from acute
tubular necrosis (caused by ischemia, hypoxia,
nephrotoxic drugs, and toxins), vascular thrombo-
ses, and congenital parenchymal abnormalities
including polycystic and multicystic kidney dis-
eases.7 Intrinsic renal failure is primarily associated
with prenatal asphyxia and end organ damage,
which leads to hypoxia and ischemia, resulting in
acute tubular necrosis.11
Postrenal failure is often classified as obstructive
in nature.7 Postrenal failure can be due to ureteric or
urethral obstructions, bladder issues (neuropathic
bladder), or bilateral obstructions such as fungal
balls.7 Relief of the obstruction often leads to
improvement in symptoms including an improve-
ment in both GFR and urine output; however,
chronic kidney dysfunction may ensue because of
the underlying associated renal dysplasia.6 A thor-
ough understanding of renal function in the prema-
ture infant born at less than 34 weeks’ gestation and
an understanding of the various types of renal fail-
ure are essential to identify, evaluate, and prevent
irreversible damage.
Acute kidney injury represents the deterioration
of renal function often afflicting the neonatal popu-
lation, which results in absent or decreased urine
excretion, fluid and electrolyte imbalances, and
nitrogenous waste retention.7,8 Acute kidney injury,
therefore, results in rising urea concentrations and
inadequate water excretion, in addition to impaired
tubular resorption of bicarbonate and sodium,
which manifest as systemic or pulmonary edema.7
Acute kidney injury also not only causes pulmonary
edema secondary to volume overload but also con-
tributes a proinflammatory process with elevated
levels of interleukins, free radicals, granulocyte
colony-stimulating factor, endothelial growth fac-
tors, neutrophils, and tumor necrosis factor α, which
have all shown links to the pathophysiology of
BPD.9 While little remains known about the link
between the interactions of the lungs and kidneys of
preterm infants and their impact on BPD,9 their
pathophysiological link is undeniable.
PULMONARY PATHOPHYSIOLOGY
Respiratory distress syndrome is the most common
respiratory disorder affecting premature infants,
occurring in up to 93% of all premature infants born
Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
less than 28 weeks’ gestation.12 Bronchopulmonary
dysplasia is a chronic lung disease that commonly
manifests in premature infants who require pro-
longed mechanical ventilation and oxygen therapy
for respiratory distress syndrome.13,14 Preterm
infants requiring supplemental oxygen and mechani-
cal ventilation represent the population with the
highest incidence and risk for the development of
BPD.14,15 Preterm infants are at increased risk due to
their underdeveloped and immature lungs, low anti-
oxidant levels, and common need for respiratory
support.15 A recent study, conducted in the postsur-
factant era of pulmonary management, found that
an absence of physiologic weight loss in the initial
postnatal period combined with elevated total fluid
intake during the first 10 days of age was positively
correlated with an increased risk for acquired BPD
in extremely low birth-weight infants (P < .001).16
Infants affected by fetal growth restriction are also
at increased risk for the development of BPD due to
theorized decreased lung growth, as well as infants
with poor postnatal growth rates specifically per-
taining to linear growth due to suboptimal organ
growth and development.17 An understanding of the
pathophysiology of BPD is essential for NICU clini-
cians to enable the provision of informed clinical
and prescriptive decisions.
Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia is a chronic lung dis-
ease of pulmonary dysfunction, which is the cumula-
tive result of premature birth, immature lungs, and
damaged lung tissue.13,14 There is a lack of consensus
on the definition and diagnostic criteria of BPD in
the literature. Over the past 50 years, both the diag-
nosis and the definition of BPD have evolved. In the
1960s, what is now commonly referred to as the
“old” BPD was most often seen in larger preterm
infants and was classically identified by histopatho-
logic findings including interstitial and alveolar
edema, severe airway injury, and extensive small air-
way disease in conjunction with overinflation and
fibrosis.14 In contrast, “new” BPD is seen more often
in extremely premature infants, with both modest
ventilation and supplemental oxygen needs.14,15 In
relation to histological classification, disruption in
the growth of the distal lung and arrested alveolar-
ization largely describes the currently accepted ver-
sion of “new” BPD.14,15,18
The pivotal point in neonatal medicine that revo-
lutionized the care of preterm neonates and shifted
the classification of “old” to “new” BPD was the
introduction of both antenatal steroids and surfac-
tant replacement therapy.14 These interventions for
prenatal and postnatal lung development are now
considered to be current standards of care in mater-
nal and fetal health as well as neonatology, respec-
tively. Because of the shift from “old” to “new”
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 Impact of Diuretic Therapy 5

BPD, a uniform clinical definition of BPD was pro-
posed by the National Institute of Child Health and
Human Development Workshop in 2000 and refined
in 2001 to include the need for supplemental oxygen
for 28 days or greater.12,19-21 The differentiation
between mild, moderate, and severe BPD is deter-
mined by gestational age at birth and degree of oxy-
gen requirement at the time of discharge.12,14,20,21 The
National Institutes of Health outlines severity-based
diagnostic criteria for mild, moderate, and severe
BPD in children born at gestational age of less than
32 gestational weeks, which is summarized in
Table 1. Respectively, the diagnostic criteria for
infants born 32 gestational weeks or greater are
summarized in Table 2. Even with the use of prena-
tal steroids and surfactant administration, the inci-
dence of BPD has remained relatively unchanged.
This may be due in part to the increased survival rate
of earlier preterm infants.15 Bronchopulmonary dys-
plasia is more strongly correlated with decreasing
birth weight, with an average of 30% of infants born
less than 1000 g developing BPD.15,22 In addition,
97% of patients with BPD have a recorded birth
weight of less than 1250 g.15,22
The pathophysiology behind BPD is multisys-
temic in origin.23 Bronchopulmonary dysplasia is
thought to be caused by oxygen-free radicals,
ventilator-induced lung injury, and the release of
inflammatory cytokines.13,14 The release of cytokines
as a result to oxygen-free radicals overwhelms the
antioxidant defense mechanism, leading to lung
injury and the inhibition of surfactant synthesis.15
Lung injury during the early stages of development
leads to arrested alveolar and pulmonary growth,
resulting in larger alveoli with fewer capillaries and
small airway scarring.13 The pulmonary edema, both
alveolar and interstitial in nature, that follows is due
to increased pulmonary capillary permeability and
fluid overload.24 Edema further impairs pulmonary
function through increasing airway resistance and
reducing lung compliance.24
Premature infants have low levels of antioxidants,
increasing their vulnerability to oxygen toxicity.15
Oxygen toxicity, ventilator-associated barotrauma,
and the subsequent inflammatory reaction that often
accompanies necessary mechanical ventilation all
place the preterm infant at increased risk for the
development of BPD.18 Unfortunately, longitudinal
studies regarding pulmonary function into adult-
hood in patients with a history of BPD do not exist.15
The prevention and treatment of BPD is also multi-
factorial and begins during the antenatal period.18
Current postnatal management strategies include
judicious ventilator management, fluid and nutri-
tional augmentation, and pharmacological strate-
gies including the use of diuretics that are largely
based upon research that is becoming increasingly
less relevant to the current NICU population.
Although short-term gains are often associated
with diuretic use, long-term risks and benefits have
yet to be adequately defined. An example is the
impact that diuretics and fluid restriction have on
nutrition, which negatively effects linear growth and
weight gain.17 This may also negatively impact lung
growth, thus increasing the risk for BPD develop-
ment.17 The scarcity of clinical trials and prospective
longitudinal studies on the use of diuretics, paired
with the prevalence of BPD in the NICU population,
surrounding these treatment and prevention modali-
ties is alarming and highlights the overall absence of
evidence-based care guidelines that are vital to yield-
ing optimal outcomes.1,5,25
MEDICATION CATEGORY: DIURETICS
Diuretics are often regarded as a necessary adjunct
to the clinical management of premature or critically
ill late premature or term infants. Medications may
be classified by their therapeutic use or pharmaco-
logic profile (chemical structure, mechanism of
action, and potency). The 3 main types of diuretics
commonly used in the NICU include the loop diuret-
ics, thiazide diuretics, and potassium-sparing diuret-
ics.13,23 All 3 diuretic types have different mecha-
nisms of action, as well as different benefits and risks
associated with their use.
Diuretic Classification: Loop Diuretics
Loop diuretics are considered the most powerful of
diuretics, as they can induce the excretion of up to
25% of the filtered sodium load. Loop diuretics are
characterized by a quick onset of action, primarily

TABLE 1. Diagnostic Criteria of Bronchopulmonary Dysplasia Less Than 32 Gestational

Weeks20,21
Need for supplemental oxygen >21% for at least 28 d, and
Mild BPD No supplemental oxygen at 36-wk PMA or discharge home; whichever comes first
Moderate BPD Need for <30% supplemental oxygen at 36-wk PMA or discharge home; whichever comes first
Severe BPD Need for ≥30% supplemental oxygen and/or the need for PPV at 36-wk PMA or discharge
home; whichever comes first
Abbreviations: BPD, bronchopulmonary dysplasia; PMA, postmenstrual age; PPV, positive pressure ventilation.

Advances in Neonatal Care • Vol. 00, No. 00

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6 Johnson et al

TABLE 2. Diagnostic Criteria of Bronchopulmonary Dysplasia Greater Than 32 Gestational

Weeks20,21
Need for supplemental oxygen >21% for at least 28 d, and
Mild BPD No supplemental oxygen by 56 d of life or discharge home; whichever comes first
Moderate BPD Need for <30% supplemental oxygen at 56 d of life or discharge home, whichever comes first
Severe BPD Need for ≥30% supplemental oxygen and/or PPV at 56 d of life or discharge home; whichever
comes first
Abbreviations: BPD, bronchopulmonary dysplasia; PPV, positive pressure ventilation.

exerting their effects on the thick ascending limb of
the loop of Henle by blocking the Na+: K+: 2Cl−
luminal transporter system, which affects the dilu-
tion and concentration of urine.3,13,26 Loop diuretics,
such as bumetanide and furosemide, compete for
chloride binding sites, inhibiting chloride reabsorp-
tion and leading to an active reabsorption of
sodium,23 resulting in a negative fluid balance.2,13
Bumetanide, the most potent loop diuretic, is
reported to be approximately 20 to 40 times more
potent than its more commonly utilized loop diuretic
counterpart, furosemide.11 Bumetanide is highly
lipid-soluble; therefore, it more easily diffuses into
the tubular lumen and thus is less dependent on
active tubular secretion.11 Bumetanide has been
studied for its use with BPD, fluid overload, and car-
diac failure.11 However, it has not been studied as a
treatment option for oliguric AKI in preterm
infants.11 Bumetanide has been shown to displace
bilirubin from albumin to a lesser extent than furo-
semide.2 While hyperbilirubinemia is as risk factor
with both bumetanide and furosemide use, in com-
parison, infants treated with bumetanide are at
decreased risk (Table 3).2 Although bumetanide is
less ototoxic than furosemide, it can cause signifi-
cant electrolyte disturbances including losses via the
urine and has not been fully studied for use in the
neonatal population (Table 3).23
Furosemide, a sulfonamide, is the second-most
potent loop diuretic. It acts to increase intraluminal
osmolality while decreasing medullary interstitial
osmolality, thus resulting in increased water and salt
excretion.30 Furosemide also acts to accelerate lung
fluid reabsorption via a 2-part mechanism: diuresis-
independent and diuresis-dependent responses.13,24
The diuresis-independent response has immediate
onset and enhances fluid reabsorption from the
lungs through systemic vasodilation leading to
decreased pulmonary blood flow, as well as pulmo-
nary vasodilation causing increased transpulmonary
fluid absorption (Table 4 ). 13,24 The diuresis-
dependent response to furosemide reduces extracel-
lular volume, via increasing urine output (Table 4).13
Risks associated with the use of furosemide include
electrolyte disturbances in the form of hypokalemia,
hypochloremia, hyponatremia, metabolic alkalosis,
and hyperuricemia (Table 3).24 Since loop diuretics
are so highly protein bound, there is increased con-
cern for both albumin displacement and hyperbiliru-
binemia (Table 3).3,7,11 Furosemide is 95% to 98%
protein bound, and, therefore, only a small amount of
the medication is filtered by the glomerulus.3,7 Addi-
tional side effects of furosemide use include hypovo-
lemia and hemodynamic instability, resulting from
decreased plasma volume following prompt diuresis
(Table 3).3,24 Furosemide treatment is also associated
with hypercalciuria and nephrocalcinosis; exposure
cumulative of greater than 10 mg/kg was found
through multivariate analysis to be the greatest inde-
pendent risk factor for nephrocalcinosis (Table 3).2,3,24

TABLE 3. Risks Associated With Diuretic Use

Bumetanide • Albumin displacement (to a lesser extent than furosemide).2
• Electrolyte disturbances.23
• Ototoxicity (to a lesser extent than furosemide)
Furosemide • Electrolyte disturbances (hypokalemia, hypochloremia, hyponatremia, metabolic alkalosis,
and hyperuricemia).24
• Albumin displacement and hyperbilirubinemia.3,8,24
• Hypovolemia and hemodynamic instability.3,24
• Osteopenia of prematurity.10,27
• Ototoxicity, increased risk in infants with impaired clearance.3
Thiazide • Hypokalemia.24
• Hyponatremia in the VLBW infant.28
Spironolactone • Hypercalciuria, when used in combination with thiazide diuretics.29
Abbreviation: VLBW, very low birth-weight.

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Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
 Impact of Diuretic Therapy 7

TABLE 4. Mechanism of Action of Diuretics Commonly Used in the Neonatal Intensive Care
Unit
Loop diuretics • Enhance fluid reabsorption from the lungs due to systemic vasodilation.13,31
• Increase pulmonary vasodilation as a result of increased prostaglandins.31
• Prostaglandin-induced vasodilatory renal response increases urine output.8,9
• Reduce lung edema.26
• Reduce bronchoconstriction.26
• Reduce extracellular volume, thereby increasing urine output.13
Thiazide • Inhibits the reabsorption of sodium and chloride, leading to increased excretion of sodium in
the urine.13,24
• Increases excretion of water
• Increases urine output
Spironolactone • Acute administration: decreases lung congestion and decreases lung fluid.28
• Chronic administration: decreases lung fibrosis and increases lung diffusion and
compliance.28
• Encourages the excretion of sodium, water, and chloride, while sparing potassium losses,
increasing urine output.3,24

Loop diuretics have also been identified as a risk fac-
tor for osteopenia of prematurity or metabolic bone
disease and are correlated with a decrease in linear
growth due in part to an inhibition of magnesium and
calcium resorption (Table 3).11,27
Ototoxicity represents another historically docu-
mented, yet controversial, adverse effect of furose-
mide exposure (Table 3).3 Debate continues regard-
ing the validity of this association, and the limited
data have motivated scientists to further investigate
this phenomenon. Recent research has concluded
that exclusive exposure to loop diuretics was not sig-
nificantly associated with congenital or delayed-
onset hearing loss, nor considered a significant risk
factor thereof (odds ratio: 3.9, 95% confidence inter-
val: 2.4-6.2, P < .05).32 Furosemide administration,
in addition to all diuretics, should be subject to close
and consistent scrutiny by healthcare professionals.2
Additional research is indicated, using a diverse pop-
ulation of infants versus those from a single academic
center, to conclude that furosemide administration
should, in fact, be removed as a risk indicator for
congenital and delayed onset hearing loss.
Diuretic Classification: Thiazides
Thiazide diuretics, such as chlorothiazide, cause
diuresis via the distal convoluted tubules.13 These
diuretics work by binding to the chloride site of the
electroneutral sodium chloride channel and inhibit-
ing reabsorption of both sodium and chloride.13
Thiazides exert their effect on the potassium-
independent Na+/Cl− transporter, thereby inhibit-
ing Na+/Cl− cotransport.13,24 As a result, sodium
excretion in the urine is increased, causing up to 5%
to 8% of filtered sodium to be excreted via the urine,
which can result in hyponatremia (Tables 3 and 4).3,23
This excretion of sodium is accompanied by simul-
taneous loss of bicarbonate and potassium, which
can result in severe hypokalemia.24 Despite the risk
for hypokalemia, thiazide diuretics are often pre-
ferred over loop diuretics for chronic use, since they
are less potent and carry decreased risk profile for
overall electrolyte imbalance in comparison with
loop diuretics (Table 3).13,29 To minimize the hypo-
kalemic effect, thiazides are often used in conjunc-
tion with a potassium-sparing diuretic.24
Diuretic Classification: Potassium-Sparing
Diuretics
Potassium-sparing diuretics, such as spironolactone,
inhibit the effects of aldosterone on the distal tubules
by acting as a competitive aldosterone receptor
antagonist,23 acting exclusively on the Na+:K+/
Hydrogen ion exchange pump in the distal tubules
and collecting duct.13 Acting primarily on the distal
tubule, potassium-sparing diuretics are far less
potent than loop diuretics and may potentially result
in fewer electrolyte abnormalities.29 Potassium-
sparing diuretics encourage the excretion of sodium,
water, and chloride, while sparing urinary potassium
losses (Table 4).3,24 These diuretics are most often
used in the neonatal population because of their
potassium-sparing effects and are often utilized in
conjunction with thiazide diuretics to maximize
diuresis.3,29 A limited number of controlled trials
have examined the use of spironolactone and thia-
zide diuretics in conjunction for BPD; mixed results
revealed an overall increase in urine output, which
was not uniformly associated with pulmonary
improvement.33 Associated risks of spironolactone
use include hypercalciuria when the medication is
used in combination with thiazide diuretics
(Table 3).29
DIURETIC USAGE WITH AKI
The goal of diuretic therapy in the prevention of AKI
is to maintain fluid and electrolyte homeostasis as

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Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
8 Johnson et al
well as to improve urine output.7,11 It has been
hypothesized that patients who respond well to
diuretic therapy may exhibit less severe AKI.8 Unfor-
tunately, there are no existing clinical trials that
focus on the use of diuretics with AKI in the neona-
tal population that were conducted within the last
10 years.
The use of furosemide as a preventative strategy
for AKI has been reported in the literature; however,
the basis for its use is greatly influenced by its mech-
anism of action.30 Loop diuretics may limit and pre-
vent volume overload secondary to daily nutrition,
total fluid, and intravenous medication manage-
ment.10 This strategy encourages an energy require-
ment reduction due to blockade of cotransporter
activity, renal blood flow preservation due to
prostaglandin-mediated vasodilation, and mainte-
nance of urine output as well as luminal water and
salt flow, which clears tubular debris.3,30 Careful
attention must be paid to the correction of signifi-
cant acidosis and hypotension prior to the use of
furosemide for AKI, as well as to the maintenance of
fluid balance prior to the use of furosemide for oli-
guric AKI as it can potentiate these issues if they are
preexisting.7
Bumetanide is utilized as a second-line treatment
strategy with the treatment of AKI due to its
increased potency.11 A study of bumetanide therapy
reported increased urine output from 0.6 ± 0.6 mL/
kg/h to 3.0 ± 2.1 mL/kg/h within 24 to 48 hours of
initiation of therapy (P < .005).11 Further research
and randomized controlled trials are needed to
determine efficacy and safety of the use of bumetanide
versus furosemide for AKI treatment in preterm
infants. Not only is there a lack of clinical evidence
regarding the use of diuretics, discrepancy exists
regarding specific diuretic of choice for various clini-
cal scenarios.11
DIURETIC USAGE WITH BPD
Pulmonary edema is a common clinical manifesta-
tion of BPD. Diuretic therapy is often utilized to
counteract fluid retention as well as to augment
physiologic weight loss, in efforts to reduce the inci-
dence of BPD.1 The goal of diuretic therapy in the
management of patients with BPD is to assist the
reabsorption of excessive interstitial edema from the
lungs, which otherwise results in physiologic changes
in lung compliance.18 Diuresis improves pulmonary
function because it promotes reabsorption via the
pulmonary capillaries as a result of lower hydro-
static pressure and higher oncotic pressure.13 Diure-
sis decreases pulmonary interstitial fluid, which acts
to improve pulmonary function, increase gas
exchange, and thereby decrease respiratory support
requirements.1 Thereby diuresis leads to less baro-
trauma and volutrauma of the lung tissue.1 Multiple
Copyright © 2017 National Association of Neonatal Nurses. Unauthorized reproduction of this article is prohibited.
medication therapies are utilized in the management
and prevention of BPD, including both singular and
combination pharmacotherapies; however, there is a
scarcity of evidence to support their use.33 No singu-
lar medication thus far has been proven to have a
significant impact on the prevalence or severity of
BPD.33 Although the mechanisms behind loop
diuretic therapy for the management of pulmonary
function sound promising, it must be balanced with
the common side effects associated with use.24,26,29
Despite the fact that diuretics have been shown to
improve lung function and decrease pulmonary
edema, there are no data which support that the use
of diuretics decreases the incidence or associated
mortality risk with BPD.18
A systematic review of the use of loop diuretics in
preterm infants with respiratory distress syndrome
demonstrated that the benefits of furosemide admin-
istration including transient oxygenation improve-
ment and decreased risk of extubation failure did
not outweigh associated risks.31 The authors con-
cluded that furosemide administration had no long-
term benefits.31 In addition, it was concluded that
although there was a decrease in the duration of
mechanical ventilation, furosemide administration
exhibited no change in the risk for developing BPD.31
Furthermore, due to the small sample sizes of exist-
ing studies, correlation of furosemide use and
increased risk of mortality could not be excluded.31
Of the few existing studies, a trend was concluded
connecting the use of furosemide with increased
mortality and an increased risk for hemodynamic
instability.31
A recent literature review from 2011 on the use of
diuretics acting on the distal renal tubules for pre-
term infants with or developing chronic lung disease
was conducted.28 The authors concluded that in
infants greater than 3 weeks of age with chronic lung
disease or developing chronic lung disease, routine
administration of a combination of thiazide and spi-
ronolactone improved lung compliance and pulmo-
nary mechanics and reduced the need for loop-
diuretic therapy.28 However, the authors cautioned
against positive interpretation of these results due to
small sample size and surprisingly few studies to
support this finding.28 Therefore, the authors did not
find enough evidence to support the routine use of
diuretics acting on the distal renal tubule, such as
thiazides and spironolactone, in preterm infants
with BPD.28 Furthermore, the reviewers found a
decrease in both mortality and extubation failure
rates following chronic therapy with distal tubule
diuretics; however, there were no data to support the
use of diuretics in nonintubated patients.28
The use of antenatal steroids and postnatal surfac-
tant was found to reduce the incidence of neonatal
death (95% confidence interval), but it did not result
in a decreased risk of developing BPD.15,18,34 It is
www.advancesinneonatalcare.org
 Impact of Diuretic Therapy 9

Summary of Recommendations for Practice and Research

What we know:
What needs to be studied:
What we can do today:
Abbreviations: AKI, acute kidney injury; BPD, bronchopulmonary dysplasia; FDA, Food and Drug Administration; NICU, neonatal
intensive care unit.
• Diuretics are among the most frequently prescribed NICU medications, de-
spite lack of FDA approval.1
• Minimal studies are available, limited to the lack of participation consent.1
• Off-label diuretic therapy in the NICU is used to optimize renal and pulmo-
nary function.3
• The use of diuretics in the conversion of oliguric AKI to nonoliguric AKI.
• Diuretic use in preterm infants for the management of BPD in the current set-
ting of routine surfactant replacement and antenatal steroid use.
• Long-term effects of the chronic use of diuretics in the preterm infant, in rela-
tion to morbidity and mortality.
• Limit chronic use of diuretics in the preterm infant until further studies are
conducted on long-term use.
• Use diuretics with caution, weighing benefits against potential side effects.2
• Actively participate in research studies and outcome data collection regard-
ing diuretic use.

possible that the incidence of lung edema formerly
treated with diuretic therapy has decreased because
of the recent developments in management of this
patient population in the last decade.28 Updated stud-
ies are needed to determine the efficacy and safety of
routine administration of diuretics for the treatment
and prevention of BPD, since the majority of studies
regarding the role of diuretics in this capacity were
conducted prior to routine use of antenatal steroids
and surfactant becoming the standard of care.
CONCLUSION
The field of neonatal pharmacology represents a
research frontier that is highly understudied due in
part to the struggle of obtaining parental consent for
study participation.1 Because of ethical implications
confounding the research of vulnerable populations
such as infants, there has long been a struggle to
obtain specific relevant data for research endeavors
surrounding preterm and high-risk infants. Yet, phar-
macological therapies without adequate clinical trials
are currently prescribed at an alarming rate because
of their transient beneficial effects as well as the lack
of alternative approved therapies. The current litera-
ture regarding the use of diuretics in the NICU popu-
lation represents outdated studies that were con-
ducted prior to the routine use of current interventional
therapies such as prenatal steroids and surfactant
replacement. Despite the lack of relevant, current
research with this population, diuretics remain
among the most commonly prescribed medications in
neonatology. Diuretics are utilized to both treat and
prevent fluid retention states, as well as their sequelae,
yet significant variations in practice exist throughout
neonatology. Variations in practice include when and
how to utilize diuretics as well as which diuretics to
choose, the dose to prescribe, and the duration of
their course. In addition, a deficiency of multicenter
studies regarding both the indications for use of
diuretics and the timing of use should also be taken
into consideration as this emphasizes potentially
additional variation in use among centers.25
In summary, this review of the current literature
concludes that diuretics should be used with caution
in this population and their benefits should be
weighed against the risks. It is important to recog-
nize that along with the lack of literature concerning
diuretic use with neonates, there comes a concurrent
deficiency of guidelines regarding the management
of the side effect profile related to this medication
class. Research funding specific to pharmaceutical
clinical trials of diuretic therapy in the neonatal
population, and prospective longitudinal studies
that describe the life span implications associated
with diuretic use, is urgently needed to inform pre-
scriptive practices in the NICU. This type of research
is long overdue and yet, without a funding priority
the neonatal population will continue to be cared
for in an environment that is based more on previ-
ous habit (the way we have always done it) than on
evidence.
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