IU Health Riley NICU Guideline for Diuretic and Fluid ... · IU Health Riley NICU Guideline for Diuretic and Fluid Management for Bronchopulmonary Dysplasia in Preterm Infants Born

IU Health Riley NICU Guideline for Diuretic and Fluid Management for

Bronchopulmonary Dysplasia in Preterm Infants Born Less than 32 Weeks’ Gestation Alejandra Valladolid MD, William A. Engle MD, Scott C Denne MD, Rebecca Rose MD, Diane Lorant MD, Michael Trautman

MD, Brenda Poindexter MD, Autumn Kiefer MD, Marya Strand MD, Elizabeth Wetzel MD, Zeynep Salih MD, William Buss

PharmD, Katherine Malloy PharmD, Mitzi Boilanger RN, Mary Beth Koch NNP, Daniel Davenport NNP, Mary Fox, NNP,

Tammy Losh RT

Reaffirmed March 16, 2018

Summary Conclusions and Recommendations:

Fluid restriction and diuretic use for preterm infants at risk for or with BPD are common practices with

evidence limited by studies with small numbers of patients, significant heterogeneity, and bias that were

performed during the epoch of the “classic BPD” (surfactant 1990, antenatal corticosteroids 1995) . Therefore,

the following recommendations are predominately based on the principle of reducing variation to improve

outcomes.

Fluid restriction may reduce the risk of BPD and has few associated risks. Furosemide may acutely change

pulmonary mechanics but no evidence for improvements in important long term outcomes is currently

available, though important long term risks are known. Chronic treatment of BPD with furosemide is not

recommended. Furosemide treatment of acute pulmonary edema complicating a BPD crisis may have short

term benefit. Chronic use of distal tubule diuretics (a thiazide and spironolactone) may reduce mortality but

the evidence is weak and treatment is associated with important morbidities. Distal tubule diuretics are not

recommended for routine use because of limited supportive data and associated electrolyte imbalances. If

diuretics are used to treat BPD, a thiazide diuretic alone is suggested because the addition of spironolactone

does not appear to reduce the need for salt supplementation or improve outcomes; careful monitoring for

complications of treatment is indicated. Therefore, the recommendations for use of fluid restriction and

diuretics in preterm infants at risk for or with BPD include:

Recommendation #1:

Fluid restriction for infants less than 32 weeks’ gestation at birth is recommended for 4 weeks after birth to

prevent and thereafter to treat established BPD as long as growth is supported and fluid losses are not

excessive because of polyuria or other fluid losses (e.g. insensible, chylothorax, third space).

Quality of evidence: moderate

Strength of recommendation: strong

DISCLAIMER: THIS GUIDELINE IS PROVIDED FOR INFORMATIONAL AND EDUCATIONAL USE

ONLY. THE INFORMATION AND OPINIONS IN THIS GUIDELINE ARE THOSE OF THE AUTHORS

AND NOT THE AMERICAN ACADEMY OF PEDIATRICS. THE RECOMMENDATIONS DO NOT

INDICATE AN EXCLUSIVE COURSE OF TREATMENT OR SERVE AS A STANDARD OF MEDICAL

CARE. VARIATIONS IN APPLICATION OF THESE GUIDELINES THAT TAKE INTO ACCOUNT

INDIVIDUAL CIRCUMSTANCES IS EXPECTED.

Recommendation #2:

If fluid administration has not previously been restricted to 130 to 140 ml/kg per day, a 7 to 10 day course of

fluid restriction prior to initiating a trial of diuretics for BPD is recommended because of the risks associated

with diuretic use (see below).

Quality of Evidence: weak

Strength of Recommendation: strong

Recommendation #3:

Chronic use of furosemide is not recommended for prevention or treatment of BPD in preterm infants.

Level of Evidence: moderate


Recommendation #4:

A short (< 3 day) course of furosemide may help treat pulmonary edema during a BPD crisis.


Strength of recommendation: moderate

Recommendation #5:

Electrolyte imbalance, osteopenia, nephrocalcinosis, hearing loss, patent ductus arteriosus and other potential

complications should be monitored if treatment with furosemide or other loop diuretics is initiated.

Quality of evidence: high


Recommendation #6:

It is not recommended to routinely use distal tubule diuretics for treatment of infants with established BPD

because of limitations in available data and complications of diuretic use.

Quality of evidence: low


Recommendation #7:

If diuretics are used for treatment of established BPD, thiazides alone are suggested; the addition of

spironolactone does not appear to reduce the need for salt supplementation. (See Table 5 for recommended

dosing and costs.)



Recommendation #8:

If a thiazide diuretic is used to treat BPD, a 7 to 10 day trial is recommended to establish effectiveness and

safety in individual patients prior to continuing long term administration. The randomized trials began

treatment at 7 to 12 weeks of chronologic age. Other inclusion criteria are having received at least 4 weeks of

mechanical respiratory support (e.g. ventilation, CPAP, HFNC > 2 lpm), ongoing supplemental oxygen greater

than 30%, and radiographic evidence of BPD.

Benefit is evidenced by a clinically important reduction in duration or amount of positive pressure

ventilation or other respiratory supporta, supplemental oxygen requirementa, and clinical signs of

respiratory distress; such improvement should be documented in the physician’s note.

Chronic use of distal tubule diuretics is not indicated without evidence of benefit or if clinically

important complications in electrolyte, pH, calcium and glucose homeostasis occur.

Supplementation with sodium, potassium and other replacement salts should be reserved for short

term correction of electrolyte complications and not used to counter the imbalances caused by

continued use of thiazide diuretics.



Recommendation #9:

Electrolyte imbalance, osteopenia, hypercalcemia, hyperglycemia, and other potential complications should be

monitored if treatment with distal tubule diuretics is initiated.

Thiazide diuretics should be discontinued in the presence of clinically important disturbances in

electrolyte, pH balance, calcium and glucose homeostasis or other significant complications.

Quality of evidence: strong

Background

Bronchopulmonary dysplasia (BPD), or chronic lung disease of the neonate, is associated with inflammatory

pulmonary edema. This edema may be exacerbated by the presence of pulmonary hyperperfusion through a

patent ductus arteriosus or, in the presence of cor pulmonale, pulmonary congestion. Diuretic treatment

and/or fluid restriction to reduce interstitial edema within the lung are, therefore, theoretically rational and

frequently recommended for infants with BPD. Diuretics may effect this change in interstitial lung fluid by

reducing extracellular fluid volume (e.g. thiazide diuretics, furosemide) or diuresis-independent lung fluid

absorption (e.g. furosemide).

Chronic diuretic use is limited by tolerance, in which both hormonal and renal adaptation to overcome acute

fluid and electrolyte changes impede long-term effectiveness; electrolyte imbalances; metabolic alkalosis;

hypovolemia; osteopenia/hyperphosphaturia; nephrocalcinosis (e.g. furosemide) ; hyperuricemia; and agent-

specific complications (e.g. furosemide – patent ductus arteriosus, neurosensory hearing loss, cholelithiasis;

thiazides – severe hyponatremia, hypercalcemia, glucose intolerance). Of note, the hypocalciuric effect of

thiazides, a presumed benefit, is impeded by sodium supplementation (Brickman 1972, Campfield 1997,

Mensenkamp 2006); hypercalciuria and nephrocalcinosis have not been reported during treatment with

thiazides and sodium supplementation.

Diuretic treatment for BPD with and without pulmonary hypertension, though frequently used, has little

support in the published literature. Importantly, there is a paucity of evidence for diuretic use in the era of the

“new BPD” which is most characterized pathologically by an arrest of alveolarization and associated with

exposure to antenatal corticosteroids and exogenous surfactant treatment of respiratory distress syndrome.

Studies of diuretics, both loop (furosemide, bumetanide) and distal tubule (thiazides, spironolactone)

medications, were completed in the years between 1970 and 2000. These studies are also hampered by a

focus on the impact of diuretics on lung mechanics, small sample sizes (significant heterogeneity that limits

meta-analysis, bias (blinding inconsistently documented) and limited or no information about important

clinical outcomes (such as mortality, length of hospital stay, duration of oxygen or ventilator days,

rehospitalization rates, and neurodevelopment). Such limitations force clinicians to make individualized

decisions on use of fluid restriction and diuretic treatment that was purposed for infants with “old BPD”, has

not been supported by clinical trials, and may be associated with important complications.

In the Riley NICU, clinicians frequently use diuretics to treat infants at high risk for or with BPD. During 2010

and 2011, 10.8% of 129 surviving infants born weighing less than 1000 grams were discharged on

hydrochlorothiazide/spironolactone and 1.6% on furosemide. During the same interval, 170 total patients less

than 1000 grams were admitted and 41 died. Of the 170 patients, 69 received aldactazide (41%) and 81 (48%)

received furosemide at some time during the hospitalization.

The purpose of this guideline is to review the evidence and make recommendations for use of fluid restriction

and diuretics in the management of infants with or developing BPD. Recommendations are largely based on

the principle of improving outcomes by reducing variation in practice because of the weak data available.

This guideline is not intended for management of congestive heart failure, fluid overload, renal failure or other

conditions that may be responsive to diuretic treatment. Furthermore, the guideline is intended to provide

general principles on which to individualize treatment; it is not possible to prescribe treatment for every

clinical scenario.

Literature Search

Pubmed and OVID were searched on 02.2013 with key words [bronchopulmonary dysplasia or chronic lung

disease], [diuretics exploded], [thiazides], [spironolactone], [furosemide] and limited to newborns and infants.

References were also obtained from ancestry searches of the bibliographies of key review articles and

textbook chapters pertaining to bronchopulmonary dysplasia and treatment.

A revision of literature was done March 2018 using Pubmed with key words [bronchopulmonary dysplasia or

chronic lung disease] [Diuretics] [fluid restriction] and limited to newborns and infants. It is determined that

there continues to be insufficient evidence to support routine diuretics for prophylaxis or therapy in BPD

management. The current recommendation are thereby reaffirmed.

Critical Appraisal

Systematic reviews have been performed for fluid restriction and diuretic use to prevent or treat BPD,

although the quality of the data is low to moderate. Table 1 The quality of data was assessed using the Grade

system [Balshem 2011]. Grade provides a transparent way to evaluate the evidence and then build practice

recommendations [Guyatt 2008]. Grade also allows for other criteria, such as cost, incidence of the outcome

in question, and the setting in which the recommendation will be applied, to influence the final strength of the

recommendation.

Table 1. GRADE and Quality Rating of Data

Quality Rating Interpretation of Quality Rating

High Quality Further research is very unlikely to change our confidence in the estimate of effect

Moderate Quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

Low Quality Further research is very likely to have and important impact on our confidence in the estimate of effect and is likely to change the estimate

Very Low Quality Any estimate of effect is very uncertain

Fluid Restriction

Fluid restriction is a common intervention to prevent and/or treat BPD. Oh and colleagues (2005) reported a

relationship with higher fluid intake and lack of weight loss postnatally with risk of death or BPD (p< 0.001 and

0.006, respectively) in a cohort of 1382 extremely preterm infants from a randomized, controlled trial to assess

parenteral glutamine supplementation and late onset sepsis. For infants born weighing less than 1000 grams;

total fluid intakes per day were about 20 ml/kg per day less in those who did not develop BPD (P<.001). Table

2. This difference in fluid intakes persisted when red blood cell transfusions were removed from the

calculations. Weight loss nadir in both groups occurred at 5 days of age with an average weight loss of 8.1% of

birth weight in the BPD or death group and 9.0% in the BPD-free group. Note that these total daily fluid

intakes were determined retrospectively; they do not reflect the initial fluid intakes prescribed.

Table 2. Total daily fluid intake in the Death or BPD group versus the BPD-free group. (mL/kg)

Age (day) Death or BPD BPD-free

Mean SD Range Mean SD Range

2 136 42 46-332 118 32 66-297

3 158 51 48-466 134 34 55-309

4 170 46 60-390 147 33 51-326

5 171 40 67-329 154 31 63-294

The differences for fluid intake, suggest that close attention to fluid management may have significant impact

on the outcome of BPD or death. Oh’s report from the Neonatal Research Network is important because

subjects were similar to populations at high risk for the “new BPD” today: extremely preterm (Gestation age

at birth about 26 weeks), antenatal steroids exposure (about 80%) and surfactant treatment were common.

Bell and Acarregui (2010) performed a Cochrane review of restricted versus liberal water intake for preventing

morbidity and mortality in preterm infants. Five studies were randomized but all differed in timing and

duration of treatment; four studies assessed BPD as an outcome. Fluid restriction was protocol driven in all

studies and all resulted in significant differences between the restricted and liberal groups; the fluid volume in

the restricted group often began at 50-60 ml/kg per day on day 1 and reached 140 to 150 ml/kg on day 5; the

liberal group received 20-50 ml/kg per day more. Three studies limited the onset and duration to the first 3 to

7 days after birth and 2 studies extended duration of fluid restriction through 28 – 30 days.

BPD was a secondary outcome assessed in this meta-analysis and was not found to be different between the

restricted and liberal fluid groups (RR 0.85, 95% CI 0.63, 1.14, n = 526, 21.7% vs 25.5%). Table 3.

Table 3. Restricted versus liberal water intake, outcome bronchopulmonary dysplasia

Study Restricted

n/N

Liberal

n/N

Weight Risk Ratio

M-H, Fixed, 95%CI

Bell 1980 5/85 8/85 11.9% 0.63 (0.21, 1.83)

Kavvadia 2000 21/84 22/84 32.8% 0.95 (0.57, 1.60)

Lorenz 1982 10/44 12/44 17.9% 0.83 (0.40, 1.73)

Tammela

1992

21/50 25/50 37.3% 0.84 (0.55, 1.29)

TOTAL 57/263

21.7%

67/263

25.5%

100% 0.85 (0.63, 1.14)

Heterogeneity Chi2 = 0.51, df = 3 (P= 0.92); I2 = 0.0%

Although none of the studies found a significant difference in incidence of BPD, the trend in all the studies was

for a lower risk suggesting that additional data would be helpful to clarify the effect of fluid status on BPD.

These studies were also heterogeneous but included a moderately large total number of patients (526). Of

interest, postnatal weight loss was greater and the incidence of necrotizing enterocolitis (NEC, RR 0.43, 95% CI

0.21, 0.87, n=526, 3.8% vs 9.1%) and patent ductus arteriosus (PDA, RR 0.52, 95% CI 0.37, 0.73, n=526, 15.6%

vs 30.0%) were both significantly less frequent with fluid restriction. Adverse outcomes with fluid restriction

through the first month after birth were not increased in a randomized trial of 168 ventilated infants with a

median gestational age of 27 weeks. (Kavvadia 2000) Furthermore, it is common practice by clinicians in the

Riley NICU and recommended by experts (Bancalari and Walsh 2011, Binwale and Ehrenkranz 2006) to restrict

fluids “to the minimum required to provide the calories necessary for metabolic needs and growth” for infants

with BPD to minimize fluid overload and pulmonary edema as long as growth is not jeopardized. There are no

published studies that address whether fluid restriction after BPD is established is effective or harmful.

Recommendation #1:

Fluid restriction for infants less than 32 weeks’ gestation at birth is recommended for 4 weeks after birth to

prevent and thereafter to treat established BPD as long as growth is supported and fluid losses are not

excessive because of polyuria or other fluid losses (e.g. insensible, chylothorax, third space). Careful attention

to fluid balance is important during the first days to weeks after birth especially in extremely preterm infants.

Initial fluid volumes of 100 ml/kg per day (< 750 gram birth weight) and 80 ml/kg per day (≥ 750 gram birth

weight) are recommended on the first day after birth and then titrated based on assessment of fluid status

(e.g. weight, urine output, sodium, chloride, blood urea nitrogen, creatinine, estimated insensible losses, net

fluid balance, blood pressure*, heart rate, perfusion) to target weight loss of about 2% per day to a nadir of 9%

at 5 days of age.



Recommendation #2:

If fluid administration has not previously been restricted to 130 to 140 ml/kg per day, a 7 to 10 day course of

fluid restriction prior to initiating a trial of diuretics for BPD is recommended because of the risks associated

with diuretic use (see below).

Quality of Evidence: weak

Strength of Recommendation: strong

*Blood pressure alone is often used to determine need for volume resuscitation. It is important to know

expected changes in blood pressures in the first days to weeks after birth in neonates and consider the vital

signs, urine output, chemistries, other indicators of fluid status and limitations of devices for blood pressure

measurement before administering fluid for volume replacement.

Furosemide (Loop diuretic) and Bronchopulmonary Dysplasia

The use of loops diuretics, primarily furosemide, for treatment of infants with evolving or established BPD has

been the subject of more than 27 investigations, six of which were randomized controlled trials that assessed

outcomes of interest such as short term improvements in oxygen or ventilator support/pulmonary mechanics.

These six randomized controlled trials were performed between 1982 and 1998 (era of “old BPD, limited

antenatal steroid exposure, some with surfactant use); they were subjected to meta-analysis using Cochrane

Review methodology (Stewart and Brion, 2011). The infants in this meta-analysis were less than 37 weeks’

gestation at birth and required supplemental oxygen or mechanical ventilation after 5 days of age. The mean

postnatal age for inclusion in the meta-analysis was three weeks. Potential complications of treatment such as

hypovolemia, alkalosis, hyponatremia, hypochloremia, osteopenia, nephrocalcinosis, cholelithiasis, and

neurosensory hearing loss were also assessed if data was available.

Five of the six studies in the meta-analysis included a placebo control and four of the six included infants

whose average postnatal age was greater than 3 weeks and average gestational age at birth ranged from 27 to

30 weeks; these latter four studies were performed in 1983 (2 studies), 1985 (1 study) and 1990 (1 study).

Cross-over designs were used following either a single dose of furosemide or repeated doses for up to 8 days;

one study evaluated a parallel and cross-over design of treatment for 7 days followed by a washout period

before the cross-over. Bias was evident because of lack of blind (1 study) and attrition (1 study). The number

of patients assessed for specific outcomes such as change in alveolar-arterial oxygen gradient and

supplemental oxygen, percent extubated within 1 week, change in ventilator peak pressure and ventilator

frequency and changes in pulmonary mechanics is very limited (8 to 59 patients). Importantly, these studies

assessed pathophysiologic outcomes (pulmonary mechanics); none assessed important short (duration of O2

administration, incidence of BPD, BPD at 36 weeks’ postmenstrual age) or long term outcomes. Complications

of furosemide treatment, like the important short and long term outcomes, were insufficiently assessed in

these studies.

The short term pathophysiologic and pulmonary mechanics changes associated with short term furosemide

are listed according to duration of treatment:

• After 1 day :

o Decreased alveolar-arterial oxygen gradient (not sustained)

o Increased compliance (following single dose)

o Decreased airway resistance (following single dose, not sustained)

• After 7-8 days:

o Lowered supplemental oxygen concentration

o Increased compliance

o Improved minute ventilation

o Decrease in average weight gain

•

These studies suggest that single dose or short course of less than 3 days of furosemide treatment may

have beneficial physiologic effects and, in the presence of acute pulmonary edema during a BPD crisis,

may provide short term physiologic improvement. Chronic treatment with furosemide is complicated by a

number of well known side effects: hypovolemia, alkalosis, hyponatremia, hypochloremia, osteopenia,

nephrocalcinosis, cholelithiasis, and neurosensory hearing loss. Jensen et al. in a retrospective cohort

from 2010-2012 found that the probability of severe metabolic bone disease increased by 1.4% for every 2

weeks of furosemide treatment. Therefore,benefits of furosemide treatment for 7 -8 days or more must

be weighed against the known risks of chronic use, reduction in weight gain and lack of long term

outcome efficacy.

Recommendation #3:

Chronic use of furosemide is not recommended for prevention or treatment of BPD in preterm infants.



Recommendation #4:

Short term (i.e. less than 3 days) administration of furosemide may be used in acute treatment of pulmonary

edema during a BPD crisis.



Recommendation #5:

Electrolyte imbalance, osteopenia, nephrocalcinosis, hearing loss, patent ductus arteriosus and other potential

complications should be monitored if treatment with furosemide or other loop diuretics is initiated.

Quality of evidence: high


Thiazide and Spironolactone (Distal tubule diuretics) and Bronchopulmonary Dysplasia

Thiazide diuretics, chlorothiazide and hydrochlorothiazide, are frequently used in combination with

spironolactone, a potassium sparing but weak diuretic. Stewart and colleagues (2011) performed a Cochrane

review of diuretics acting on the distal renal tubule for preterm infants with BPD or evolving BPD (i.e. over 5

days old at initiation of diuretics). The principle four studies were performed before antenatal steroids and

surfactant were consistently used ( Albersheim 1989, Englehardt 1989, Kao 1984, Kao 1994). Subjects in the

studies were more than 4 weeks old, received mechanical ventilation for at least 4 weeks, required

supplemental oxygen (usually greater than 30%) and had radiographic evidence of moderate to severe classic

bronchopulmonary dysplasia. Most studies began diuretics at 7 to 12 weeks of age and included an average

gestational age that ranged between 26 and 29 weeks’ gestation. Only 6 studies met the criteria for being

randomized, controlled and had outcomes of interest, short-term improvements in pulmonary mechanics or

important clinical outcomes. Although conclusions from these studies are limited for reasons noted above,

mortality was significantly decreased with chronic treatment with a thiazide-spironolactone combination

(Relative risk 0.30, 95% Confidence interval 0.09 – 0.93, risk difference -17, n = 77). Table 4. Mortality was not

different in subjects who were not intubated at the time of study (n=43, Kao 1994) but was significantly

different in subjects who were intubated at the time of study [(Relative risk 0.30, 95% Confidence interval

0.09-0.93)(n=34, Albersheim 1989)]. It is important to recognize that the evidence for a reduction in mortality

using thiazide and spironolactone diuretics is weak because it is based on a small number of patients (77) from

two studies without benefit of antenatal corticosteroids and, in some infants, surfactant treatment; additional

research involving large numbers of patients exposed to antenatal corticosteroids and exogenous surfactant in

randomized, controlled clinical trials is needed to demonstrate the efficacy and safety of distal tubule diuretics

for treatment of BPD.

Other significant improvements associated with chronic thiazide and spironolactone treatment included less

need for furosemide (at least 10-12 doses) and increased compliance after 20 weeks when off O2 and off

randomized medication in non-intubated cases. Table 4. Compliance consistently improved at 4 weeks after

treatment initiation in non-intubated and intubated cases but there was no effect at 8 to 10 weeks. Transient

improvements in airway resistance after 1 week of thiazide/spironolactone treatment was noted but no

change in oxygen requirement after 4 weeks of treatment was found; no assessments of requirement for

mechanical ventilation or reduction in mechanical ventilation settings were reported.

Rehospitalizations for respiratory deterioration during the 1st year after birth were increased in the

thiazide/spironolactone group. Also, the need for sodium and potassium supplementation was increased.

There was no statistically significant difference for calcium excretion, nephrocalcinosis, hearing loss, weight at

1 year and length at 1 year.

Table 4. Thiazide and Spironolactone versus Control: Outcomes and Effect Sizes for Treatment of Preterm Infants with Bronchopulmonary Dysplasia

Outcome # Studies

N Treatment vs Control

Statistic Effect size

PHYSIOLOGIC AND CLINICAL OUTCOMES

Death before discharge* Non intubated Intubated

2

1 1

77

43 34

7.3% vs 22.2%

0% vs 0% 15.8% vs

53.3%

RR (95% CI) 0.30 0.09, 0.93)*

0.0 (0.0, 0.0) 0.30 (0.09, 0.93)

Need for furosemide (at least 10-12 doses)*

1 43 2.4% vs 27.8% RR (95% CI) 0.12 (0.02, 0.65)*

Rehospitalizations for respiratory deterioration*

1 43 63.6% vs 28.6%

RR (95% CI) 2.23 (1.06, 4.70)*

Compliance change after 20 weeks when off O2 and Off medication, non-intubated cases*

1 43 11% vs -14% RR (95% CI) 0.25 (0.02, 0.48)*

Compliance after 4 weeks treatment*

1 22 Mean Difference (95% CI)

0.16 (0.03, 0.29)*

Compliance after 8 weeks treatment

1 13 Mean Difference (95% CI)

0.05 (-0.15, 0.25)

Airway resistance after 4 weeks treatment*

1 43 Mean Difference (95%)

-25.7 (-41.2, -10.3)*

Airway resistance after 10 weeks treatment


-2.2 (-18.2, 13.9)

Length of hospitalization


-3.0 (-32.01, 26.01)

Duration of O2 1 43 Mean Difference (95%)

-12.00 (-51.58, 23.58)

COMPLICATIONS

Need for Na or K supplementataion*

1 34 89.5% vs 46.7%

RR (95% CI) 1.92 (1.09, 3.37)*

Calcium excretion 1 20 Mean Difference (95% CI)

-1.70 (-5.27, 1.87)

Nephrocalcinosis 1 43 31.8% vs 23.8%

RR (95% CI) 1.34 (0.50, 3.56)

Hearing loss

1 43 9.1% vs 4.8% RR (95% CI) 1.91 (0.19, 19.52)

Weight @ 1 year PMA 1 43 Mean Difference (95% CI)

0.20 (-0.61, 1.01)

Length @ 1 year PMA 1 43 Mean Difference (95% CI)

-0.30 (-2.81, 2.21)

* and Bold indicate statistically significant findings. Note that the confidence intervals in the Effect

Size column do not include 1.

The efficacy of adding spironolactone, an aldosterone antagonist, to a thiazide diuretic has been questioned.

In a double-blind, randomized trial of 33 infants started on diuretic treatment for BPD at a postmenstrual age

of 26 to 36 weeks, Hoffman and colleagues (2000) found that spironolactone failed to decrease the need for

electrolyte supplementation (sodium and potassium chloride), the primary outcome, or improve pulmonary

mechanics or electrolyte balance.

Recommendation #6:

It is not recommended to routinely use distal tubule diuretics for treatment of infants with established BPD

because of limitations in available data and complications of diuretic use.

Quality of evidence: low


Recommendation #7:

If diuretics are used for treatment of established BPD, thiazides alone are suggested; the addition of

spironolactone does not appear to reduce the need for salt supplementation. (See Table 5 for recommended

dosing and costs.)



Recommendation #8:

If a thiazide diuretic is used to treat BPD, a 7 to 10 day trial is recommended to establish effectiveness and

safety in individual patients prior to continuing long term administration. The randomized trials began

treatment at 7 to 12 weeks of chronologic age. Other inclusion criteria are having received at least 4 weeks of

mechanical respiratory support (e.g. ventilation, CPAP, HFNC > 2 lpm), ongoing supplemental oxygen greater

than 30%, and radiographic evidence of BPD.

Benefit is evidenced by a clinically important reduction in duration or amount of positive pressure ventilation

or other respiratory supporta, supplemental oxygen requirementa, and clinical signs of respiratory distress;

such improvement should be documented in the physician’s note.

Chronic use of distal tubule diuretics is not indicated without evidence of benefit or if clinically important

complications in electrolyte, pH, calcium and glucose homeostasis occur.

Supplementation with sodium, potassium and other replacement salts should be reserved for short term

correction of electrolyte complications and not used to counter the imbalances caused by continued use of

thiazide diuretics.



Recommendation #9:

Electrolyte imbalance, osteopenia, hypercalcemia, hyperglycemia, and other potential complications should be

monitored if treatment with distal tubule diuretics is initiated.

Thiazide diuretics should be discontinued in the presence of clinically important disturbances in electrolyte, pH

balance, calcium and glucose homeostasis or other significant complications.

Quality of evidence: strong


Table 5. Dosing, Concentration of Formulations, and Costs of Thiazide Diuretics at IU Health

Thiazide Diuretic Hydrochlorothiazide Chlorothiazide (Diuril)

Enteral Dose 2-4mg/kg/day

in two divided doses

(10mg/mL)

20-40mg/kg/day

in two divided doses

(50mg/mL)

IV Dose* N/A *

Enteral Patient Charge $10.20 per dose $10.30 per dose

IV Patient Charge N/A *

*Furosemide is recommended over chlorothiazide as the intravenous diuretic of choice because there is

limited pharmacologic data in neonates for chlorothiazide and it has a high cost. There is insufficient neonatal

data to recommend a dose or interval for intravenous chlorothiazide. If temporary transition from an oral

thiazide to a parenteral diuretic is needed, furosemide is preferred.

Recent evidence of extreme variation in diuretic use for BPD in US hospitals.

Several studies have described marked variation in use of diuretics in NICUs. Slaughter et al. in a retrospective

cohort from 2007-2011 in 35 US hospitals demonstrated a mean proportion of days that infants received

diuretics during their NICU stay ranged from 5.1% to 61.9% across hospitals. (Figure 1).

Figure 1

Similarly, Cuevas G et al. found diuretic use varied across 8 NICUs from 28% to 87% (p = 0.018). Laughon et al.

in large retrospective cohort from the Pediatrix database from 1997-2011 also found significant variation in

diuretic use amongst NICUs (0% to 75% (Figure 2) Furthermore, in this same Pediatrix database during an era

of frequent antenatal corticosteroid and surfactant use, diuretic use in increased from 29% to 39%.. Such large

variation in diuretic use in NICUs speaks to the fact that data supporting safety and efficacy are limited.

Importantly, to determine risk:benefit, additional large randomized trials are needed in the current era of

frequent antenatal corticosteroid and surfactant use and the “new” bronchopulmonary dysplasia.

Figure 2

Use of Lasix and Thiazide Diuretics Since Institution of Guideline in 2013

Trends in use of diuretics in preterm infants show a decline beginning in 2011 to 2013. In 2013 after

implementing the initial guideline, the use of thiazide diuretics , the predominate diuretic used in the Riley

NICU for bronchopulmonary dysplasia, decreased from about 18% to 4%. (Figures 3 and 4)This low usage has

been maintained indicative of a change in treatment culture following implementation of the guideline.

Figure 3. Lasix Use in the Riley NICU 2008 – 2016.

Figure 4. Thiazide Diuretic Use in Riley NICU 2008 – 2016.

Primary References

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Slaughter JL, Stenger MR, Reagan PB. Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics. 2013;131(4):716-23 Stewart A, Brion LP. Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease (Review). Cochrane Database Syst Rev 2011;9:CD001453 Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev 2011;9:CD001817 Van Marter LJ, Leviton A, Allred EN, Pagano M, Kuban Karl CK. Hydrations during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants. J Pediatr 1990;116:942-949

REAFFIRMATION COMMENTS

This guideline was updated on March 16, 2018. A literature search for this topic from 2012 to March

2018 was completed. No additional information was uncovered that changes the recommendations

in this guideline. The guideline was updated to include recent references and reaffirmed. New data

from several large case series have shown large variability in use of diuretics amongst Neonatal

Intensive Care Units, as well as a recent multicenter observational cohort who failed to support

improved respiratory outcomes in infants who received diuretic therapy. Such variability, lack of

clear benefit in infants with bronchopulmonary dysplasia and known risks support current

recommendations that routine diuretics for infants with BPD be avoided. In addition, diuretic use,

especially the thiazide diuretics, has declined substantially since this guideline was instituted,

indicative of a culture change in prescribing practices.

Documents

IU Health Riley NICU Guideline for Diuretic and Fluid ... · IU Health Riley NICU Guideline for Diuretic and Fluid Management for Bronchopulmonary Dysplasia in Preterm Infants Born