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In addition, MDIs

are less expensive than nebulization. Therefore, the use of MDIs with an appropriate

spacing device is preferred for most infants.

Corticosteroids

Corticosteroids, particularly dexamethasone, have been used extensively for the

prevention and treatment of BPD. Mechanisms of action of corticosteroids include

(a) reduction of polymorphonuclear leukocyte migration to the lung, (b) reduction of

lung inflammation, (c) inhibition of prostaglandin, leukotriene, tumor necrosis factor,

and interleukin synthesis, (d) reduction of elastase production, (e) stimulation of

surfactant synthesis, (f) reduction of vascular permeability and pulmonary edema, (g)

enhancement of β-adrenergic receptor activity, (h) reduction of pulmonary fibronectin

(which can reduce the risk of interstitial fibrosis), and (i) stimulation of serum retinol

concentrations.

2,26

Systemic dexamethasone is associated with many serious short-term adverse

effects, including hyperglycemia, increased BP, hypertrophic cardiomyopathy, GI

bleeding, intestinal perforation, pituitary–adrenal suppression, bone

demineralization, poor weight gain, and increased risk of infection.

2,24 Serious longterm adverse effects such as cerebral palsy (CP) and neurosensory disability have

also been identified in preterm infants who receive systemic corticosteroids.

23,24,27

Early (within the first week of life) and late (administered after 1 week of life) use

of dexamethasone was associated with significant decreases in the incidences of

BPD and the combined outcome of death or BPD at 28 days’ postnatal age (PNA)

and at 36 weeks’ PMA.

37,38 Additionally, infants in the late group had a significantly

lower incidence of mortality at 28 days’ PNA. However, the risk for CP and the

combined outcome of death or CP were significantly increased in the early group.

38

Although none of the studies were powered to detect long-term neurologic adverse

events, the authors concluded that the benefits of early dexamethasone use do not

outweigh the adverse effects and cannot be currently recommended.

38 The use of late

dexamethasone should be reserved for infants who are unable to be weaned off the

ventilator, and the dose and duration of treatment should be minimized.

37 Recent

trials evaluating the adverse long-term neurodevelopmental outcomes associated

with dexamethasone reported that low-dose dexamethasone (0.15 mg/kg/day)

appeared to be safe and did not increase the risk of CP, whereas high-dose

dexamethasone (0.5 mg/kg/day) was associated with significantly increased risk of

CP.

39

Although studies have reported that hydrocortisone may be safer than

dexamethasone, a meta-analysis found no effect of hydrocortisone on survival

without BPD or mortality.

23,27,40

In addition, an increase in spontaneous GI

perforation was found in the hydrocortisone-treated group in the largest trial,

resulting in an early termination of three studies.

23,27,39,40 The incidence of GI

perforation may have been increased as a result of concomitant treatment with

indomethacin. In contrast to studies of high-dose dexamethasone, long-term adverse

effects (e.g., CP, neurodevelopmental impairment) of hydrocortisone in patients

assessed at 2 to 8 years of age have been reported to be similar to placebo or

untreated groups.

39,40 The doses of hydrocortisone used in most of these studies (1

mg/kg/day) were lower than the doses of dexamethasone used in clinical trials. Most

infants treated with dexamethasone received a dose of 0.2 to 0.5 mg/kg/day, which is

equivalent to hydrocortisone 5 to 15 mg/kg/day. Furthermore, all of these studies

initiated hydrocortisone within the first week of life. Currently, there are no trials

evaluating the use of hydrocortisone after 1 week of life in infants with established,

ventilator-dependent BPD.

Based on these clinical findings, a policy statement from the American Academy

of Pediatrics (AAP) does not recommend high-dose dexamethasone (0.5 mg/kg/day

or greater) owing to the absence of improved short- and long-term outcomes from

randomized trials.

39

It also does not recommend low-dose dexamethasone (<0.2

mg/kg/day) or high-dose hydrocortisone (3–6 mg/kg/day) owing to insufficient

evidence. Early low-dose hydrocortisone (1 mg/kg/day) given within the first 2

weeks of life may benefit a specific patient population. Clinicians must weigh the

potential risks of BPD with the potential adverse effects associated with

glucocorticoids; therapy should be considered in VLBW infants at high risk for

experiencing BPD (e.g., those still on mechanical ventilation after 1–2 weeks of age).

Parents should be fully informed about the short- and long-term adverse effects of

systemic corticosteroids.

39 Despite the AAP recommendation, some clinicians would

still consider administering a short course of low-dose systemic corticosteroid to

help facilitate extubation. This practice may be supported by a meta-regression

analysis demonstrating that the impact of postnatal steroids on the combined outcome

of death or CP was modified by the risk of BPD.

24 When postnatal steroids were

used in infants with a low risk for BPD (<35%), there was a significant increase in

the risk of death or CP. However, when used in infants with a higher risk for BPD

(>65%), a significant reduction in the risk of death or CP was found. Overall, infants

with a >50% predicted risk of BPD had less harm associated with steroids than those

at lower risk of BPD.

24 Dexamethasone 0.2 mg/kg/day in two divided doses (tapered

for 5–7 days) may be considered for J.T., even though she is now 13 weeks old.

Throughout therapy, J.T. should

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be monitored for hyperglycemia, hypertension, GI bleeding, and intestinal

perforation.

Inhaled steroids such as beclomethasone dipropionate, flunisolide, fluticasone, and

budesonide have also been used for the treatment and prevention of BPD.

30,41 When

compared to placebo, inhaled corticosteroids have not been shown to decrease the

incidence of death or BPD, the combined outcome of death or BPD, and duration of

mechanical ventilation and oxygen therapy; however, the use of systemic steroid may

be decreased.

30,41 When compared to systemic steroids, no significant differences in

mortality or the incidence of BPD were found.

31,32 The use of early inhaled steroids

(i.e., prevention) was associated with increased duration of mechanical ventilation

and oxygenation. None of these studies evaluated long-term neurodevelopmental

outcomes associated with inhaled steroids. Adverse effects of inhaled steroids are

less common than with systemic steroids; these include mild adrenal suppression,

bronchospasm, tongue hypertrophy, and oral candidiasis.

30–32,41

Inhaled steroids may

suppress the pituitary–adrenal axis; however, studies have reported conflicting

results. Suppression may vary depending on the type of inhaled steroids, dosing

regimen, and other factors such as prematurity.

33 The infant’s mouth should be

cleaned after each use of inhaled steroid to minimize complications such as oral

thrush. As with inhaled bronchodilators, administration is a therapeutic problem with

these medications. Further studies evaluating the optimal dose, duration of therapy,

time of initiation, delivery technique, most appropriate preparation, and long-term

adverse effects (including neurodevelopmental outcome) of corticosteroids are

needed before inhaled steroids can be routinely recommended.

Long-Term Sequelae

CASE 105-2, QUESTION 4: Five months have passed, and J.T. is now 4.5 months old (corrected age),

weighs 5 kg, and is ready for discharge. During the past several months, ventilation requirements slowly

decreased, and J.T. was eventually extubated. However, she still requires supplemental oxygen at an FIO2

of

30%, 0.25 L/minute via nasal cannula, to maintain an oxygen saturation of 90% to 95%. What are the long-term

complications of BPD that can be expected in J.T.?

Infants with BPD have little pulmonary reserve and, therefore, are at higher risk

for experiencing frequent respiratory exacerbations. BPD places J.T. at risk for

recurrent infections of the lower respiratory tract, and she may require frequent

hospitalizations during the first year for bronchiolitis and pneumonia. Approximately

50% of all children with BPD require hospitalization for respiratory exacerbations

during early childhood.

21 Respiratory syncytial virus is a common cause of

respiratory distress and recurrent atelectasis. With time, most preterm survivors with

BPD have an improvement in pulmonary function owing to lung growth; however,

many continue to have airway hyper-reactivity. Infants with severe BPD can also

experience pulmonary hypertension, cor pulmonale, systemic hypertension, and left

ventricular hypertrophy.

In addition, J.T. may be at risk for experiencing bone demineralization and rickets.

VLBW infants are born with inadequate stores of vitamin D. In general, these

premature infants may not receive an adequate intake of vitamin D, either

parenterally or through their diet. Most VLBW infants require prolonged parenteral

nutrition, which may cause cholestasis or hepatic failure. Prolonged cholestasis or

chronic hepatic congestion owing to heart failure may cause malabsorption of

calcium and vitamin D. In addition, furosemide may exacerbate calcium deficiencies

by causing hypercalciuria. These combined factors may result in bone

demineralization and rickets. Infants with BPD usually have a high catabolism and

increased oxygen consumption as a result of an increased work of breathing and

chronic hypoxia. Inadequate nutritional support may negatively affect weight gain,

growth, and long-term outcome of BPD.

Neurologic and developmental abnormalities such as learning disabilities, speech

delays, vision and hearing impairment, and poor attention span can also occur in

infants with BPD.

21 BPD itself is not an independent risk factor for neurologic

abnormality; related factors include birth weight, gestational age, and socioeconomic

status.

21 Long-term follow-up evaluations at 1 to 15 years of age in infants previously

treated with high-dose dexamethasone revealed an increase in neurodevelopmental

abnormalities such as CP and decreased school performance in some studies.

39

However, it is not known whether these abnormalities were attributable to an

adverse effect of dexamethasone on brain development or to an improved survival of

infants who may already be at risk for experiencing these abnormalities.

Mortality rates for infants with BPD range from 30% to 40%.

28 Approximately

80% of deaths associated with BPD occur during initial hospitalization and are

attributable to respiratory failure, sepsis, pneumonia, cor pulmonale, and congestive

heart failure.

28

Prevention

CASE 105-2, QUESTION 5: What preventive measures could have been used to decrease the likelihood of

the development of BPD in J.T.?

Prevention of prematurity and other etiologic factors of RDS is the most effective

means of preventing BPD. Although both antenatal steroids and exogenous surfactant

therapy have been shown to reduce the incidence of RDS, the incidence of BPD has

not been affected.

23 One of the causes of BPD can be vitamin A deficiency, which can

predispose infants to BPD owing to impaired lung healing, increased susceptibility to

infection and loss of cilia, and decreased number of alveoli.

23 Premature infants,

especially VLBW infants, are at greatest risk owing to low body stores, inadequate

intake during feedings, and decreased enteral absorption of vitamin A. Intramuscular

(IM) vitamin A has been shown to significantly reduce the combined outcome of

mortality or BPD; however, no difference was found with mortality, ROP, or

sepsis.

23

In contrast, administration of oral vitamin A 5,000 international units/day

did not decrease the incidence of BPD, perhaps because of inadequate dose or poor

oral absorption.

42 Vitamin A seems to be a relatively safe drug; the incidence of

adverse effects was similar between treated and control groups.

23 Although evidence

appears to support IM vitamin A in infants with birth weight less than 1,000 g, further

studies evaluating the efficacy, safety, and optimal dosage regimen of vitamin A for

the prevention of BPD are needed.

Ureaplasma urealyticum colonization of the respiratory tract of premature infants

is a significant risk factor for BPD. Several studies evaluated the use of macrolide

antibiotics for eradication of Ureaplasma in premature infants at risk for BPD.

23,43

Although erythromycin has not been shown to reduce the incidence of BPD or death,

studies evaluating azithromycin and clarithromycin reported variable efficacy results.

Azithromycin and clarithromycin have shown to decrease the incidence of BPD, but

only in infants positive for Ureaplasma.

43 However, prolonged antibiotic exposure

has been linked to an increased rate of NEC or sepsis. Furthermore, erythromycin use

has been associated with infantile hypertrophic pyloric stenosis.

2 Therefore, due to

these adverse findings as well as conflicting clinical efficacy, routine use of

macrolide antibiotics is not recommended.

Optimization of nutritional support may also help to prevent the development of

BPD because proper nutrition helps to promote

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lung maturation, growth, and repair. Excessive fluid administration should be

avoided because it may lead to BPD. Fluid restriction decreases both the incidence

of BPD and mortality.

24 The early use of caffeine (initiated before 3 days of life) to

treat apnea of prematurity in infants with birth weights of 500 to 1,250 g has been

shown to decrease the incidence of neurodevelopmental impairment, including CP. In

addition, the incidence of BPD was significantly decreased in the caffeine-treated

infants, although BPD was one of their secondary outcomes.

23,44 Fluid restriction, the

early use of caffeine citrate, and IM vitamin A could have been recommended for

J.T. in the early course of her hospitalization to help decrease the likelihood of her

experiencing BPD.

PATENT DUCTUS ARTERIOSUS

The fetus has three unique circulatory structures that differ from the adult circulation:

(a) the ductus venosus, which permits blood to bypass the liver; (b) the foramen

ovale, which allows blood to pass from the right atrium into the left atrium; and (c)

the ductus arteriosus, the structure that connects the pulmonary artery to the

descending aorta and allows blood to bypass the lungs (Fig. 105-1).

45

In addition to

these structural differences, vascular resistance and pressure play important roles in

determining the pathway of the fetal circulation. For example, the relative hypoxia

that occurs in utero causes pulmonary vasoconstriction. Pulmonary vasoconstriction,

along with compression of pulmonary blood vessels by unexpanded fetal lung mass,

results in a high pulmonary vascular resistance and decreased pulmonary blood flow.

This decreased pulmonary blood flow is acceptable in utero because the lungs

essentially are nonfunctional. Large amounts of blood, however, must be pumped

through the placenta where gas exchange occurs.

Maximally oxygenated blood (PO2

, 30–35 mm Hg) flows from the placenta to the

fetus through the umbilical vein (Fig. 105-1). Approximately 50% of the umbilical

venous blood is shunted away from the liver through the ductus venosus and directed

into the inferior vena cava. Blood from the inferior vena cava and superior vena cava

then enters the right atrium. Most of the blood from the inferior vena cava, which is

well oxygenated, is directed in a straight pathway across the right atrium through the

foramen ovale directly into the left atrium. It then enters the left ventricle through the

mitral valve and is pumped through the ascending aorta and into the vessels of the

head and forelimbs. Thus, the fetal brain is preferentially perfused with blood

containing a higher amount of oxygen. Deoxygenated blood returning from the head

region via the superior vena cava enters the right atrium and is directed through the

tricuspid valve into the right ventricle, where it then is pumped into the pulmonary

artery. Most of this blood is diverted through the ductus arteriosus into the

descending aorta and then through the two umbilical arteries to the placenta. A small

percentage of the blood flows to the lower extremities and then is returned to the

heart via the inferior vena cava.

45

Figure 105-1 Fetal circulation. (Adapted with permission from Sandra MN, The Lippincott Manual of Nursing

Practice. 7th ed. Lippincott Williams & Wilkins; 2001.)

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Changes at Birth

At birth, major circulatory changes result from umbilical cord clamping, aeration and

expansion of the lungs, and an increase in arterial PO2

. These changes are important

in the transition from a fetal to an adult circulation. When the umbilical cord is

clamped, blood flow decreases through the ductus venosus. Clamping of the

umbilical cord also results in a twofold increase in systemic vascular resistance.

This increase in systemic vascular resistance increases aortic, left ventricular, and

left atrial pressures and cardiac output. Pulmonary pressures and blood flow also

change. After the neonate’s first breath, the lungs expand, oxygenation improves, and

pulmonary vascular resistance immediately drops. This increases pulmonary blood

flow, causing a decrease in pulmonary arterial, right ventricular, and right atrial

pressures.

45,46

Closure of the Foramen Ovale

Because of the decreased right atrial pressure and increased left atrial pressure that

occur after birth, blood attempts to flow down the pressure gradient from the left

atrium through the foramen ovale into the right atrium. This is in the opposite

direction from what occurs in fetal life. The small, valve like flap that lies over the

foramen ovale on the left side of the atrial septum closes over the foramen ovale

opening when the pressure in the left atrium exceeds the pressure in the right atrium.

Closure of this flap prevents further flow through the foramen ovale. As long as the

pressure in the left atrium is higher than that in the right atrium, the foramen ovale

remains functionally closed, until it closes anatomically.

Closure of the Ductus Arteriosus

Closure of the ductus arteriosus is more complex and depends on many factors. In

utero, patency of the ductus arteriosus is maintained through the combined

vasodilatory effects of a low PO2 and high concentrations of prostanoids, particularly

prostaglandin E2

(PGE2

) and prostacyclin.

47 After birth, the smooth muscles of the

ductus arteriosus constrict as arterial oxygenation increases and concentrations of

placentally derived prostaglandins, particularly PGE2

, decrease.

47

In utero, the PO2 of

the ductal blood is 18 to 22 mm Hg, whereas after birth in a term neonate, it is

approximately 100 mm Hg. Normally, the ductus arteriosus of a term neonate

functionally closes within the first few days of life (i.e., in 82% of infants within 48

hours of life and in 100% of infants within 96 hours of life). Anatomic closure of the

ductus occurs within 2 to 3 weeks of life. When the ductus arteriosus fails to close, it

is called patent ductus arteriosus (PDA). In a term neonate, a PDA beyond the first

few days of life generally is permanent. It usually is secondary to an anatomic defect

in the wall of the ductus arteriosus and requires surgical ligation. In contrast, a PDA

in a preterm neonate may persist for weeks and still close spontaneously.

When a PDA is present, the direction and amount of shunting through this opening

are determined by the pressure gradient between the systemic and pulmonary

circulations. Usually, blood flows from the aorta into the pulmonary circulation.

Because systemic vascular resistance and aortic pressure are increased, and

pulmonary vascular resistance and pulmonary arterial pressure are decreased after

birth, blood pumped from the left ventricle into the aorta flows from the aorta (a

high-pressure area) through the PDA and into the pulmonary artery (a lower-pressure

area). This flow is called left-to-right shunting and is in contrast to the right-to-left

shunting that occurs through the PDA during fetal life.

Clinical Presentation

CASE 105-3

QUESTION 1: T.S. is a 750-g female who was born at 25 weeks’ gestational age to a 22-year-old gravida 2

para 1 woman. One hour after birth, T.S. exhibited symptoms of RDS, and two doses of beractant were given

within the first 24 hours of life. After the second dose of beractant, T.S.’s respiratory function greatly improved,

and no further doses of beractant were required. On the third day of life, the nurse noticed that T.S. had

tachycardia, a systolic murmur, a hyperactive precordium, and a widened pulse pressure. Her lungs sounded

“wet.” In addition, the nurse noted that T.S.’s combined IV fluid rates total 160 mL/kg/day instead of the

desired fluid intake of 120 mL/kg/day. Current vitalsigns and ABGs are as follows:

HR, 190 beats/minute

RR, 65 breaths/minute

BP, 55/23 mm Hg

O2

saturation, 89%

pH, 7.22

PCO2

, 55 mm Hg

PO2

, 77 mm Hg

Base deficit, 10

Ventilator support is increased to compensate for T.S.’s deteriorating respiratory status. Echocardiography is

performed and shows a moderate-size PDA with significant left-to-right shunting. The chest radiograph shows

pulmonary edema and an enlarged heart. What risk factors for PDA does T.S. have?

T.S. has two major risk factors for developing a symptomatic PDA: prematurity

and RDS. The occurrence of a PDA is inversely proportional to gestational age and

birth weight. The incidence of PDA is approximately 45% in premature infants with

a birth weight of less than 1,750 g, but can be as high as 80% in premature infants

with a birth weight of less than 1,200 g.

48

In contrast, the incidence of PDA in term

infants is only 0.06%.

48 Preterm neonates are at a higher risk for PDA than term

newborns because the smooth muscle of the immature ductus is more sensitive to the

dilatory effects of prostaglandins and less sensitive to the constrictive effects of

increased oxygen tension. In addition, circulating concentrations of PGE2 are often

elevated in premature infants owing to the decreased pulmonary metabolism of

prostaglandins. These factors contribute to the delayed closure of the ductus

arteriosus in premature infants. With advanced gestation, the ductus is less

responsive to the relaxant effects of prostaglandins and is more sensitive to the

constricting effects of oxygen.

49

RDS also increases the risk for PDA. Exogenous surfactant also may increase the

risk and lead to an earlier clinical presentation of symptomatic PDA.

49,50 PDA can

further complicate the course of RDS.

49,51 T.S.’s course is typical of a preterm

neonate with resolving RDS. T.S.’s pulmonary function improved after surfactant

administration. Consequently, pulmonary vascular resistance decreased and the

degree of left-to-right shunting across the ductus arteriosus increased, causing a

deterioration in respiratory status. In addition, the excess fluid that T.S. received is

an iatrogenic factor that may have increased the shunting across the PDA, aggravating

the degree of pulmonary congestion.

49

CASE 105-3, QUESTION 2: How is T.S.’s presentation consistent with that of PDA?

T.S.’s clinical presentation is related to the increased pulmonary blood flow,

decreased systemic perfusion, and left ventricular volume overload that resulted from

the shunting of left ventricular cardiac output through the PDA into the lungs. To

compensate

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for the inadequate peripheral perfusion, HR increases. This results in an increase

in cardiac output and a greater left-to-right shunt through the PDA, creating a vicious

cycle. The widened pulse pressure (the difference between systolic and diastolic

pressures, 32 mm Hg) is a result of diversion of aortic blood flow through the PDA,

which is causing the bounding pulses. The systolic murmur, which is not always

present, is the result of turbulent blood flow through the ductus arteriosus occurring

because the pulmonary vascular resistance decreases. Tachycardia, hyperactive

precordium, and a continuous murmur are results of the left-to-right shunting through

the ductus arteriosus during systole.

52

CASE 105-3, QUESTION 3: What are the potential complications of this hemodynamically significant PDA

in T.S.?

The increased pulmonary blood flow and resultant pulmonary edema will worsen

T.S.’s respiratory disease and increase the need for ventilatory support. The higher

ventilatory settings (increase in MAP and FIO2

) place T.S. at risk for having BPD. If

the PDA is left untreated, T.S. may experience congestive heart failure secondary to

an increased left ventricular end-diastolic volume. A hemodynamically significant

PDA also places T.S. at risk for IVH and NEC.

49

Treatment

CASE 105-3, QUESTION 4: How should T.S.’s PDA be managed?

The initial medical management for T.S.’s symptomatic PDA is supportive care,

which includes fluid management (e.g., fluid restriction and diuretic therapy),

correction of anemia, and treatment of hypoxia and acidosis. Although excessive

fluid administration may increase the risk of PDA, fluid restriction alone is unlikely

to result in ductal closure. T.S.’s fluid intake should be restricted to 100–120

mL/kg/day (approximately 80% of total fluid maintenance requirements) to avoid

worsening of her pulmonary edema and to prevent congestive heart failure.

49

Furosemide 1 mg/kg IV push should also be given to T.S. immediately to treat her

pulmonary edema. In addition to fluid management, correction of anemia is important.

Low concentrations of hemoglobin result in an increased cardiac output, which may

worsen the infant’s cardiac function. Anemia not only increases the demand of left

ventricular output to ensure adequate oxygen delivery to the tissues, but may also

increase the magnitude of the left-to-right shunt by decreasing the resistance of blood

flow through the pulmonary vascular bed.

49 Maintaining a hematocrit level of more

than 40% to 45% is often recommended. Because of T.S.’s gestational age, birth

weight, and size of PDA, it is unlikely that she will respond to these general

measures alone. Therefore, T.S. requires pharmacologic treatment with indomethacin

or ibuprofen.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Both indomethacin and ibuprofen are available in injectable form for the treatment of

PDA. These drugs nonspecifically inhibit prostaglandin synthesis, thereby

eliminating the vasodilator effects of the PGE series on the ductus arteriosus,

allowing the ductus to close. Indomethacin has been used clinically for more than 30

years for the treatment of PDA. However, because of its adverse effects, other

prostaglandin inhibitors, such as ibuprofen, have been studied for PDA closure.

Results indicate that ibuprofen is as effective as indomethacin in closing the ductus

and causes significantly less of a decrease in renal, mesenteric, and cerebral blood

flow. In a recent meta-analysis comparing ibuprofen with indomethacin, ibuprofen

reduced the risks of NEC and transient adverse effects on renal function (e.g.,

oliguria, elevations of serum creatinine [SCr]).

53 However, the incidence of

mortality, BPD, and IVH were similar for both drugs. Unfortunately, no long-term

follow-up studies of ibuprofen exist. These studies are needed to determine whether

ibuprofen or indomethacin is the drug of choice for PDA closure.

53 Based on the

studies currently available, ibuprofen may be preferred in patients who have or are at

risk for decreased renal function. The initial dose of ibuprofen lysine is 10 mg/kg

followed by two doses of 5 mg/kg given at 24-hour intervals. If urinary output

decreases to less than 0.6 mL/kg/hour, the second or third doses should be held.

2

Unfortunately, not every infant treated with a nonsteroidal anti-inflammatory drug

(NSAID) responds with constriction of the ductus arteriosus; therefore, surgical

ligation of the PDA may be required. Ligation generally is reserved for neonates who

do not respond to pharmacologic therapy or those in whom drug therapy is

contraindicated.

49

CASE 105-3, QUESTION 5: Due to lower risks of adverse effects on renal function, the attending physician

would like to treat T.S. with ibuprofen for closure of her PDA. You explain to the medical team that there is a

temporary shortage of ibuprofen, and therefore, T.S. should be treated with indomethacin. The medical team

then asks the following: What is the dose of indomethacin for T.S.? and What route should be used for its

administration?

The medical team should be told the following information. The route of choice for

indomethacin is IV; enteral indomethacin is less effective. This reduced effectiveness

may be related to the formulation of the suspension and decreased, erratic enteral

absorption. In addition, the use of enteral indomethacin has been associated with

NEC.

54

A large interpatient variability of indomethacin pharmacokinetics occurs in

preterm neonates. Serum concentrations do not correlate consistently with therapeutic

or adverse effects. Furthermore, the optimal therapeutic serum concentration is not

yet defined.

55 Although many dosage regimens have been reported, dosing guidelines

from the National Collaborative Study are commonly used.

51 Three indomethacin

doses are given in 12- to 24-hour intervals, with the first dose equal to 0.2 mg/kg IV

in all neonates. Because indomethacin clearance is directly proportional to postnatal

age, the second and third doses are determined by postnatal age at initiation of

indomethacin therapy. If onset of treatment was at less than 2 days’ PNA, neonates

receive 0.1 mg/kg/dose; if initiation of therapy occurred at 2 to 7 days’ PNA,

neonates receive 0.2 mg/kg/dose; if therapy began at more than 7 days’ PNA,

neonates receive 0.25 mg/kg/dose. Second and third doses are administered at 12- to

24-hour intervals. No specific guidelines exist regarding which patients receive

every-12-hour versus every-24-hour dosing; however, the individual dosing interval

generally is determined by the neonate’s urine output. If urine output remains greater

than 1 mL/kg/hour after an indomethacin dose, then the next dose may be given in 12

hours. If urine output is less than 1 mL/kg/hour but greater than 0.6 mL/kg/hour, then

the dosing interval may be extended to 24 hours. Doses should be held if urine output

is less than 0.6 mL/kg/hour. T.S. should receive three doses of indomethacin 0.15 mg

(0.2 mg/kg/dose) given every 12 hours, as long as her urine output remains greater

than 1 mL/kg/hour. If T.S.’s urine output decreases, then the dosing interval should be

adjusted as outlined above.

Other indomethacin dosing regimens have been evaluated more recently for the

treatment of PDA in preterm infants. An initial dose of 0.2 mg/kg followed by either

0.1 or 0.2 mg/kg for two doses at 12- to 24-hour intervals has been used. In a study

measuring serum concentrations, higher doses of indomethacin were required in

older neonates (>10 days’ PNA).

56 This may be owing to an increased indomethacin

clearance in these infants.

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Because rapid IV administration of indomethacin can decrease cerebral,

mesenteric, and renal blood flow, longer infusion rates of 20 to 30 minutes are

recommended.

57

Response to NSAID therapy can be determined by assessing the clinical signs of

PDA such as tachycardia, widened pulse pressure, bounding pulses, heart murmur,

and the ability to wean from ventilator support. In certain cases, echocardiography

may be performed to confirm closure of a PDA.

CASE 105-3, QUESTION 6: What clinical and laboratory data should be monitored during T.S.’s

indomethacin therapy?

Before initiating indomethacin therapy, T.S. should receive an echocardiogram to

rule out ductal-dependent congenital heart disease and to confirm the presence of a

PDA. In addition, an SCr and blood urea nitrogen (BUN) should be obtained from

T.S. before indomethacin therapy because nephrotoxicity is the most common

adverse effect. Infants receiving indomethacin can experience transient oliguria with

increased SCr. This occurs as a result of indomethacin-induced decreases in renal

blood flow and glomerular filtration rate.

51 Dilutional hyponatremia may occur

secondary to either decreased urine output or decreased free water diuresis owing to

increased antidiuretic hormone activity. Treatment of hyponatremia should be aimed

at decreasing free water intake through fluid restriction rather than by sodium

supplementation. Typically, renal function normalizes within 72 hours after the last

dose of indomethacin. In general, indomethacin therapy is contraindicated in neonates

with renal failure, urine output less than 0.6 mL/kg/hour, or an SCr of 1.8 mg/dL or

greater.

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