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Prophylactic surfactant therapy has been shown to decrease the incidence and

severity of RDS, mortality, pneumothorax, and PIE, compared with rescue

treatment.

11 However, these findings were reported in studies that were conducted

prior to routine clinical use of CPAP for the management of RDS. In studies that

utilized routine CPAP as initial management of RDS, a significantly lower incidence

of BPD or death was seen in the CPAP group when compared with prophylactic

surfactant therapy without CPAP.

11

In contrast, when comparing early versus late

rescue therapy (regardless of routine initial use of CPAP), infants treated in the early

group had significant decreases in the incidence of mortality, air leak, BPD, and the

combined variable of BPD or death.

11 Thus, CPAP should be utilized initially, with

selective early rescue surfactant administration in infants in whom symptoms of RDS

persist.

Surfactant should be administered by qualified physicians with the presence of

nursing and respiratory therapy personnel.

14

(For a video on surfactant

administration, go to http://www.youtube.com/watch?

v=hkUdH01sLmA&feature=related.) Surfactants can be administered through a

disconnected endotracheal tube (ETT) via 5F catheter or through a side port of ETT

adapter via ventilator, depending on the product (see Table 105-2). Both

administrative techniques are effective and are not significantly different with regard

to clinical outcomes.

11 Several alternative methods of surfactant administration have

been utilized in an effort to avoid mechanical ventilation. The “INSURE” (INtubate–

SURfactant–Extubate) technique is a strategy that administers surfactant during a

brief intubation followed by immediate extubation to nasal CPAP. This technique

was associated with a reduced need for mechanical ventilation and subsequent

BPD.

11

Because surfactant works better if given earlier in the course of RDS, it is

important to determine who is at highest risk for RDS. Unfortunately, the exact

criteria to clinically determine high-risk newborns are still unclear. Surfactant

treatment should be administered as soon as clinical signs of RDS appear. The

administration of CPAP after birth with subsequent selective surfactant therapy

should be the preferred alternative to prophylactic surfactant therapy. Early therapy

avoids progression of the disease and the potential for decreased surfactant

effectiveness; therefore, it should be considered in preterm infants born at <30

weeks’ gestation who need mechanical ventilation because of severe RDS. Because

L.D. has clinical, laboratory, and radiographic findings consistent with RDS, a dose

of 2.5 mL/kg (200 mg/kg phospholipid) of poractant alfa should be administered to

L.D. intratracheally immediately within 1 hour of age with subsequent extubation to

CPAP as soon as possible.

CASE 105-1, QUESTION 5: Within 1 hour of poractant alfa administration, L.D.’s oxygenation improved,

and the FIO2 was weaned from 60% to 40%. Ten hours later, the ABGs revealed the following:

pH, 7.30

PCO2

, 45 mm Hg

PO2

, 50 mm Hg

Base deficit, 2

O2

saturation, 90% on the following ventilator settings: FIO2

, 0.40; intermittent mechanical ventilation (IMV),

30; PIP, 18; positive end-expiratory pressure (PEEP), +5

Should another dose of poractant alfa be administered?

The response to a single dose of surfactant usually is transient; thus, more than one

dose may be needed. Response to surfactant therapy can be variable, especially in

preterm newborns or in those who require high oxygen and ventilatory pressures.

3

Reasons for lack of response include surfactant inhibition by proteins that have

leaked into the alveolar spaces, inactivation of surfactant by inflammatory mediators

(free oxygen radicals, proteases), presence of conditions that can decrease surfactant

effectiveness (e.g., pulmonary edema), or poor delivery of surfactant to the alveoli

(owing to atelectasis).

3 The degree of responsiveness to surfactant also decreases

with increasing postnatal age.

10

Although the indications for subsequent doses of surfactant vary, persistence of

respiratory failure is the major clinical indicator for retreatment. In practice, most

infants require only one dose of surfactant. This may be related to advances in

neonatal and perinatal management and an increased use of antenatal steroids.

However, there are neonates who may be more likely to require more than one dose;

these include those who were not exposed to antenatal steroids and/or those with

extreme prematurity (<26 weeks’ gestation). A second dose of poractant alfa should

be given to L.D. because he still requires mechanical ventilation with relatively high

inspiratory pressures and supplemental oxygen (FIO2 ≥ 0.3) to maintain an arterial

PO2 of at least 50 mm Hg and oxygen saturation of 90%.

CASE 105-1, QUESTION 6: On rounds, the medical resident asks you about the complications of surfactant

treatment in premature infants. Describe the information on adverse effects and their frequency that you would

provide for the medical team.

The most common adverse effects of surfactant therapy are related to the method of

administration.

11 During administration, L.D. may experience bradycardia and oxygen

desaturation

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secondary to vagal stimulation and airway obstruction.

6–9 These adverse events

might require temporary discontinuation of surfactant administration and increased

ventilator support.

The risk of pulmonary hemorrhage, which usually occurs within the first 72 hours

of life, can be found in up to 6% of neonates receiving surfactant therapy.

3 However,

pulmonary hemorrhage has not been consistently reported in recent studies; thus, the

association between surfactant therapy and this disorder is questionable.

3

Furthermore, the benefits of surfactant therapy far outweigh the potential risk of

pulmonary hemorrhage.

BRONCHOPULMONARY DYSPLASIA

CASE 105-2

QUESTION 1: J.T. is a 12-week-old, 2-kg female who was born at 25 weeks’ gestation. Her medical history

includes RDS, episodes of sepsis and pneumonia, and 5 weeks of parenteral nutrition. J.T. has also failed

extubation numerous times and is currently requiring mechanical ventilation with an FIO2

of 0.5. Current vital

signs are as follows:

RR, 60 breaths/minute

HR, 150 beats/minute

BP, 80/55 mm Hg

O2

saturation, 90%

On physical examination, J.T. has intercostal and subcostal retractions, shallow breathing, and an expiratory

wheeze. Bilateral diffuse haziness with lung hyperinflation, focal emphysema, atelectasis, and irregular fibrous

streaks are seen on chest radiograph. J.T. is currently receiving enteral feedings with a preterm 20-cal/ounce

formula at 40 mL every 3 hours. Based on these findings, the diagnosis of BPD is made. What is the

pathogenesis of BPD? What risk factors for BPD does J.T. have? What clinical signs and laboratory evidence

of BPD are apparent in J.T.?

BPD (also known as chronic lung disease) is the most common form of chronic

pulmonary disease in infants. The disease develops in newborns that require

supplemental oxygen and positive-pressure ventilation for RDS or other primary lung

disorders. A severity-based definition of BPD has been developed by the National

Institute of Child Health and Human Development.

21 For infants born at less than 32

weeks’ gestational age, assessment of BPD is performed at 36 weeks’ PMA or at the

time of discharge. Mild BPD is defined as a need for supplemental O2

in excess of

21% for at least 28 days but not at 36 weeks’ PMA or discharge; moderate BPD as a

need for supplemental O2

for at least 28 days plus treatment with less than 30% O2 at

36 weeks’ PMA or discharge; and severe BPD as a need for supplemental O2

for at

least 28 days plus treatment with at least 30% O2 or positive-pressure ventilation at

36 weeks’ PMA or discharge. For infants born at 32 weeks’ gestational age or older,

the above definitions are different only in that assessments are conducted at 56 days

of life rather than 36 weeks’ PMA.

21 BPD is a significant cause of infant morbidity

and mortality. BPD affects 10,000 to 15,000 infants in the United States each year.

21

The incidence and severity of BPD are inversely related to gestational age and birth

weight. Infants born at 23 weeks’ gestation have a 73% incidence of BPD compared

with a 23% incidence in infants born at 28 weeks’ gestation.

21 Similarly, 56% of

infants born at 23 weeks’ gestation develop severe disease compared with 8% in

infants born at 28 weeks’ gestation.

21 Overall, from 1993 to 2006, the incidence of

BPD has decreased; however, length of hospital stay has increased significantly. This

may be due to a change in the definition of BPD and/or an increase in the use of

CPAP.

22

Pathogenesis and Clinical Manifestations

The cause of BPD seems to be multifactorial. Lung immaturity, surfactant deficiency,

oxygen toxicity, barotrauma or volutrauma, and inflammation all play important roles.

Premature infants, especially those at less than 26 weeks’ gestation, are at a higher

risk for BPD owing to lung immaturity.

21 Surfactant deficiency and the immature

parenchymal structure of the lung and chest wall contribute to the development of

BPD. Oxygen therapy, which causes a release of free oxygen radicals, is directly

associated with the pathogenesis of BPD. Prolonged exposure to high oxygen

concentrations and free oxygen radicals causes tissue damage, alveolar–capillary

leaks, and atelectasis with resultant impaired gas exchange and pulmonary

edema.

21,23,24 This may lead to the chronic pulmonary fibrotic changes seen in infants

with BPD. In term infants, the lungs contain antioxidant enzymes that help to protect

the lung from damage produced by free oxygen radicals. However, in preterm infants,

the concentration of antioxidant enzymes may be low or absent. Therefore, premature

infants are more susceptible to develop BPD than term infants.

Barotrauma secondary to positive-pressure ventilation is also a major factor in the

pathogenesis of BPD, independent of oxygen toxicity.

21,23 Barotrauma is caused by

repetitive distension of the terminal airways during mechanical ventilation. This

results in disruption of the epithelium and an increase in capillary permeability to

proteinaceous fluid. The severity of lung injury is related to the amount of positive

peak pressure used. Volutrauma is also involved in the pathogenesis of BPD and is

caused by high tidal volume ventilation and overdistension. The combined iatrogenic

insults of oxygen toxicity and barotrauma or volutrauma, both inflicted on an

immature lung for an extended time, can worsen lung damage.

The inflammatory process in the lung is activated by oxygen toxicity, barotrauma

or volutrauma, or other injury. This results in the attraction and activation of

leukocytes (e.g., neutrophils, macrophages), which may cause further release of

inflammatory mediators, elastase, and collagenase.

24 Elevated levels of elastase and

collagenase can destroy the elastin and collagen framework of the lung. α1

-Proteinase

inhibitor, a major defense against elastase activity, may be inactivated by free oxygen

radicals. Therefore, the combined elevated levels of elastase and the decreased

activity of α1

-proteinase inhibitor may enhance lung injury and lead to the

development of BPD.

Infants who exhibit BPD also have elevated levels of cytokines such as plateletactivating factor, leukotrienes, tumor necrosis factor, and fibronectin.

24 These agents,

combined with the activated leukocytes, cause significant lung damage with

breakdown of capillary endothelial integrity and capillary leakage. Furthermore, the

increased fibronectin levels found in tracheal aspirate samples of infants with early

BPD may predispose them to exhibit pulmonary fibrosis.

24

Infection and nutrient deficiency may also play a role in the pathogenesis of BPD.

The presence of chorioamnionitis may increase the infants’ risk for BPD, although

recent studies failed to report similar findings. Pathogens such as Ureaplasma,

Chlamydia, or cytomegalovirus may cause chronic infection and contribute to the

development of BPD.

21,23,24 A recent meta-analysis has shown direct correlations

between Ureaplasma colonization and the presence of BPD, regardless of gestational

age.

25 Deficiencies in nutrients such as vitamin A (retinol) or trace elements such as

zinc, copper, and selenium (which are integral components of the antioxidant enzyme

structure) may also play a role in the pathogenesis of BPD.

J.T. has two of the most important risk factors for BPD, low birth weight, and

decreased gestational age. She is also at risk for

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BPD owing to mechanical ventilation, oxygen toxicity, and fluid excess (160

mL/kg/day). Other risk factors include male sex, white ethnicity, and persistent

PDA.

21,24

BPD is characterized by tachypnea with shallow breathing, intercostal and

subcostal retractions, and expiratory wheezing as demonstrated in J.T. Other signs

and symptoms include rales, rhonchi, cough, airflow obstruction, airway hyperreactivity, increased mucus production, hypoxemia, and hypercarbia.

24 J.T.’s chest

radiograph shows evidence of BPD, including focal emphysema, atelectasis,

bilateral diffuse haziness (interstitial thickening) with increased expansion of the

lungs, and irregular fibrous streaks. Mucous plugging, sepsis, and pneumonia can

also develop in BPD infants on chronic mechanical ventilation. Infants with severe

BPD eventually experience cardiovascular complications such as pulmonary

hypertension, cor pulmonale, systemic hypertension, and left ventricular hypertrophy.

In addition to chronic respiratory and cardiovascular complications, infants with

BPD have significant growth, nutritional, and neurodevelopmental problems.

21,24

Management

CASE 105-2, QUESTION 2: What nonpharmacologic and therapeutic agents should be used to manage

BPD in J.T.?

The medical management of infants with BPD includes supplemental oxygen

therapy, mechanical ventilation, fluid restriction, nutritional management, and various

pharmacologic interventions. Supplemental oxygen administered via mechanical

ventilation, CPAP, or nasal cannula should be provided to maintain an oxygen

saturation of 90% to 95% and prevent hypoxemia.

23,24 Fluids should be restricted to

120–130 mL/kg/day to prevent congestive heart disease and pulmonary edema.

Because infants with BPD have a 25% increase in caloric expenditure, hypercaloric

formulas (e.g., 24 or 27 cal/ounce) may be used to optimize calories while restricting

fluid intake.

23,26

If this increased energy is not provided, infants are at risk for

undergoing a catabolic state that places them at higher risk of experiencing more

severe BPD (inadequate nutrition may potentiate the toxic effects of oxygen toxicity

and barotrauma). The goal of nutritional therapy is to produce weight gains of 10 to

30 g/day, which can usually be accomplished by providing 140 to 160 kcal/kg/day.

26

If infants do not tolerate enteral feedings, parenteral nutrition should be substituted

until the gastrointestinal (GI) tract becomes more functional. Because J.T. is on a 20-

cal/ounce formula, switching her to a hypercaloric formula would help to optimize

her weight gain. Her fluids should be restricted to 120–130 mL/kg/day.

PHARMACOLOGIC THERAPY

The treatment of BPD consists of multiple-drug therapy, which includes diuretics,

bronchodilators, and corticosteroids.

2,27–32 Despite the advancement of drug therapy,

none of these drugs have been shown to reverse pulmonary damage in infants with

BPD. Instead, they are used primarily to reduce clinical symptoms and to improve

lung function.

Diuretics

Infants with BPD are particularly prone to pulmonary edema from cardiogenic and

noncardiogenic factors. Left ventricular failure may worsen the already existing right

ventricular failure. Pulmonary vascular permeability is increased because of the

disruption of the alveolar–capillary unit and causes an increased amount of fluid in

the interstitium. Although the precise mechanism in the treatment of BPD is unknown,

diuretics help to reduce interstitial lung water.

24,27

In addition, diuretics lower

pulmonary vascular resistance and improve gas exchange, thereby reducing oxygen

requirements. The most commonly used diuretics are furosemide, thiazides, and

spironolactone. Furosemide is the drug of choice because of its potent diuretic effect.

In addition, it increases lymphatic flow and plasma oncotic pressure and decreases

pulmonary interstitial edema. The use of furosemide in infants with BPD was

associated with short-term improvement in lung compliance and oxygenation,

decreased total pulmonary resistance, and facilitation in ventilator weaning.

27,29

However, a meta-analysis did not support all of these findings. Tolerance to

furosemide may develop after a few days of therapy; this may be a result of the

contraction in extracellular volume, which can lead to a compensatory increase in

water and sodium reabsorption in the renal tubules. Furosemide can have significant

adverse effects including hypochloremia, hypokalemia, and hyponatremia.

Furthermore, volume depletion, hypercalciuria, nephrocalcinosis, osteopenia, and

ototoxicity may also occur.

24,29 Excessive fluid loss or hypochloremia may result in

metabolic alkalosis and worsen respiratory acidosis. Some of these adverse effects

may be reduced by using alternate-day furosemide therapy or nebulized furosemide.

27

Neither of these regimens were associated with electrolyte imbalances, and both

were shown to significantly increase lung compliance and decrease pulmonary

resistance.

29

Thiazide diuretics (e.g., hydrochlorothiazide) in combination with a potassiumsparing diuretic (e.g., spironolactone) can improve lung function and decrease

oxygen requirements with increased diuresis.

27 Although less potent than furosemide,

the combination of these two diuretics can reduce the incidence of hypokalemia

commonly associated with loop or thiazide diuretics. Adverse effects commonly seen

with this combination include hyponatremia, hyperkalemia or hypokalemia,

hypercalciuria, hyperuricemia, hyperglycemia, azotemia, and hypomagnesia.

2

In

summary, despite insufficient evidence of long-term efficacy (e.g., decreased oxygen

requirement, need for mechanical ventilation, death, severity of BPD) and the

potential for adverse effects, diuretics are often used in the management of BPD to

provide short-term improvement in pulmonary edema and reduce the need for

ventilatory support.

Generally, infants with BPD are treated with furosemide, but are changed to a

combination diuretic if long-term treatment is needed to avoid adverse effects.

Suggested indications for initiating furosemide therapy include (a) 1-week-old

infants with early BPD and ventilator dependency, (b) infants with stable BPD who

significantly worsen owing to fluid overload, (c) infants with chronic BPD who do

not improve, and (d) infants requiring an increased fluid intake to provide adequate

calories.

26 Because J.T. has chronic BPD and is not improving (i.e., she has not been

able to be weaned off the ventilator), furosemide 2 mg/kg given every 12 hours

enterally may be considered. J.T. should be monitored and treated for electrolyte

disturbances while on furosemide.

CASE 105-2, QUESTION 3: One week after starting furosemide, J.T. still requires high ventilatory settings

and is unable to be weaned from the ventilator. What other therapeutic agents may be considered to treat J.T.’s

BPD?

Inhaled Bronchodilators

Infants in the early stages of BPD generally have airway hyperactivity and smooth

muscle hypertrophy. They are also at higher risk for bronchoconstriction owing to

increased airway resistance secondary to hypoxia. Therefore, the use of

bronchodilators may be helpful in these infants. β2

-Agonists such as albuterol have

been shown to provide short-term improvements (4 hours) in lung compliance and

pulmonary resistance owing to bronchial smooth muscle relaxation.

17,33 However,

inhaled bronchodilators are not effective in all infants with BPD. Infants in the late

stages of BPD may have severe pulmonary damage and fibrotic changes.

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Only half of these infants demonstrate a decrease in pulmonary resistance after

albuterol therapy.

34

In addition, tolerance may develop with prolonged

administration.

27 Therefore, inhaled bronchodilators should be reserved for infants

who clearly demonstrate improvements during therapy. Currently, there are no welldesigned studies evaluating the chronic use or long-term outcome of using inhaled

bronchodilators in BPD infants. Despite the lack of meaningful long-term clinical

outcomes associated with β2

-agonists and the variable results, their use continues to

be very common in preterm infants with BPD. Further studies evaluating the efficacy

and safety of long-term inhaled bronchodilator therapy are needed.

Inhaled anticholinergics (e.g., ipratropium bromide) have produced short-term

benefits (approximately 4 hours) in infants with BPD by improving pulmonary

function.

27

Inhaled anticholinergics, which relax bronchial smooth muscle and

decrease mucus secretion, are generally reserved for infants who fail or are

intolerant to albuterol, or as an adjunct to albuterol if clinical improvement is not

seen.

27 The combined therapy of albuterol and ipratropium may be more effective

than either drug alone.

27 The adverse effect profile of ipratropium is minimal because

the drug is poorly absorbed.

A major problem with inhaled bronchodilators is their method of administration

and drug delivery. Inhaled bronchodilators can be given by jet or ultrasonic

nebulization or via a metered-dose inhaler (MDI).

29 For ventilator-dependent infants

receiving MDIs, the MDI is connected to an adapter that is attached to the ventilator

circuit and ETT. MDIs can also be given through bag ventilation via the ETT. For

nonventilated infants, the MDI can be given using a valved holding chamber device

and a face mask.

Compared with MDIs, nebulization has several disadvantages including loss or

inefficient delivery of drug and cooling of the inspired oxygen mixture. In several

neonatal studies, MDIs with a spacer provided more efficient delivery of inhaled

bronchodilators and greater improvements in oxygenation and ventilation; smaller

doses and a shorter treatment time were also used.

35,36 Furthermore, when comparing

the three different devices, the MDI with spacer and the ultrasonic nebulizer are more

efficient in delivering aerosols to neonates than the jet nebulizer.

29