Chronic Lung Disease: Bronchopulmonary Dysplasia Your Name Here Date

Chronic Lung Disease:
Bronchopulmonary Dysplasia
Your Name Here
Date
Objectives
• Patient Presentation
• Disease State Overview
• Current treatments
▫ Preventative
▫ Treatment alternatives
▫ Current recommendations
• Patient Course
• Summary
Patient Presentation
• LHS is a premature female infant
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DOB: 7/14/08
25 week gestation
765 g at birth
APGAR : 1/1/1 at 1/5/10 minutes
• LHS was born at home and immediately transported
to Lexington ER
• In the ER LHS required Epi x 3 doses for
bradycardia and was intubated
• LHS transferred to PHR after intubation and stable
heart rate obtained
Physical Exam and Vitals upon Admit
Physical Exam (nml except)
Vitals
• General: preterm infant
in moderate respiratory
distress
• Chest: breath sounds
equal but ↓ bilaterally
• Neuro: responds to
stimulation but with ↓
activity
• Skin & extremities:
bruising on trunk, head,
and extremities
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Temp: 95.3
HR: 171 bpm
RR: 30/3↓
BP: 37/20↓
Admission Labs
CBC & BMP
ABG
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WBC: 16.4
Hct: 50.5
PLT: 185
Glucose: 94
Na: 144
K: 4.3
Cl: 116 ↑
CO2: 24
SCr: 0.7
Ca: 7.8
Bilirubin: 5.4↑
pH: 7.25↓
pCO2: 52↑
pO2: 59↓
HCO3: 22
Differential Dx on Admission
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Hyperbilirubinemia
Respiratory Distress Syndrome
Sepsis
Risk for IVH
Progressive Dx throughout course..
• Added diagnoses:
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PDA- moderate left to right shunting
PHTN – 40 mmHg
Pulmonary Interstitial Emphysema
Chronic Lung Disease
Cardiovascular
Grade 4 IVH
Hypotension
Anemia
Renal insufficiency
Nasal septum erosion
Medications
On Admission..
Hospital Course..
• Ampicillin 78mg q12 hours
(100mg/kg)
• Gentamicin 3.9mg q48 hours
(5mg/kg)
• Mycostatin swab q6 hours
• Survanta x 1 dose
• Cefotaxime 48mg q12 hours
(48mg/kg)
• Nitroglycerin paste 0.25% q8 hours
• Neoprofen 9mg x 1 dose (9mg/kg),
5mg x 1 dose(5mg/kg)
• Dopamine (20mcg/kg/min)
• Furosemide 1 mg q12 hours
(1mg/kg)
• Hydrocortisone 1 mg q6 hours
(1mg/kg/dose)
• Bacitracin q6 hours
• Lotrisone/ Lotrimin q6 hours to
diaper area
• Morphine 0.1mg q2 hours
• Midazolam 0.1mg q2 hours
Chronic Lung Disease.. What does it
mean?
• Depends on who you ask!
▫ Need for assisted ventilation or
supplemental O2 at 36 weeks post
conceptual age
▫ Respiratory failure in the 1st week
of life requiring assisted
ventilation for minimum of 3 days
▫ Persistent respiratory symptoms
(tachypnea, rales, etc) and O2
dependence at 28 days
postnatally
▫ CXR findings consistent with CLD
aka BPD
Who develops CLD?
• Risk factors for development of CLD:
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Very low birth weight <1500g
Gestational age <32 weeks
Severe initial respiratory distress
Prolonged mechanical ventilation or exposure to high
O2 concentrations
PDA, pneumothorax, pulmonary interstitial
emphysema
Fluid overload
Infections
White ethnicity
Male gender
Incidence and Mortality
• Incidence:
▫ Increasing over the past 20 years
due to increased survival rates,
increased number of live births,
substantial increase in number of
VLBW infants
▫ 5-20% of neonates on mechanical
ventilation
▫ 40% of VLBW infants
▫ Only 1% in term infants
• Mortality:
▫ 30-40% prior to current
preventative meds
▫ Associated with approximately
5,000 infants deaths/year
Pathophysiology
• Fetal lung development progresses through 4 stages
during gestation
▫ The 4th and final stage occurs at 24 weeks-term and is the
most important stage in lung development
▫ Stage 4- lung tissue remodeling, bronchiole division,
decrease connective tissue, capillary budding, surfactant
production
 26 weeks- gas exchange possible
 32 weeks- alveoli form
• Babies born prematurely fail to progress through all of
stage 4
▫ Surfactant deficiencies- surfactant is needed to decrease the
surface tension within the alveoli and prevent the collapse of
alveoli; deficiency leads to increase work of breathing due to
baby having to reinflate collapsed lung with each breath
Pathophysiology cont…
• Low antioxidant levels
▫ Low levels of alpha1 antitrypsin, vitamin A, catalase,
glutathione
▫ Inability of the lungs to protect themselves from
oxidizing agents and enzymes (eg. A1AT protects lungs
from elastase which destroys lungs elastin fibers)
▫ Exposure to high levels of O2 radicals via mechanical
ventilation cause damage to lungs (oxygen toxicity)
▫ These injuries initiate inflammatory processes within
the lungs with large influx of neutrophils and other
inflammatory mediators, causing further insult
▫ Vicious cycle
Morbidities associated with CLD
• Pulmonary
▫ Permanent lung damage- inability to wean from ventilator
▫ Early onset COPD as adult
• Anemia
• Cor pulmonale
• Metabolic
▫ Electrolyte abnormalities
▫ Acidosis
• Neurologic
▫ Developmental delays
▫ Cerebral tissue damage
• Medication adverse effects
Treatment Options.. The good, the
bad, and the ugly….
• Preventative treatments
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Antenatal steroids
Surfactant- prophylaxis
PDA closure
Vitamin A & E
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Oxygen
iNO
Corticosteroids(systemic vs. inhaled)
Diuretics
Beta agonists
Anticholinergics
• Treatments
Antenatal Steroids
• Betamethasone (Celestone) and Dexamethasone (Decadron)
• Dose:
▫ 2 doses of Betamethasone 12 mg given 24 hours apart
▫ 4 doses of Dexamethasone 6mg given 12 hours apart
• Given to mother’s between 24-34 weeks gestation who are expected
to go into labor within the next 7 days; if labor does not occur within
7 days, do not repeat!
▫ Most effective 24 hours after initial dose and up to 24 hours after last
dose
• MOA in CLD prevention: speed up the development of the fetus’s
lungs and increase surfactant production in the fetus; reduce
alveolar wall thickness and facilitate gas exchange
• Side effects: rare for short exposure to steroids but may include
maternal hypertension or hyperglycemia
• Decreases the infants risk of: Respiratory Distress Syndrome,
Intraventricular Hemorrhage, Necrotizing enterocolitis, and death
Surfactants
• Types of surfactants:
▫ Natural Human Surfactant
▫ Biologic Surfactant
 Bovine
 Porcine
▫ Synthetic Surfactant
• MOA in CLD: Surfactant decreases the surface tension in the
airways, which leads to increased lung compliance and
decreased lung atelectasis
• Advantages: Reduces both neonatal mortality and air leaks by
50% with an overall reduction of infant mortality in the US of
6%
▫ Also have beneficial effects in MAS and ECMO
• Side effects: bradycardia, hypotension, cyanosis(calfactant)
Surfactants cont…
• Biologic:
▫ Beractant (Survanta) – bovine; 100mg/kg (4ml/kg) up to 4
doses within 48 hours at least 6 hours apart
▫ Poractant alfa (Curasurf)- porcine; initial 200mg/kg/dose
(2.5ml/kg) and may repeat at 12 hour intervals with
100mg/kg/dose(1.25ml/kg) up to 2 additional times
(max 5ml)
▫ Calfactant (Infasurf)- bovine; 105mg/kg (3ml/kg) every 12
hours up to 3 doses
• Synthetic
▫ Lucinactant (Surfaxin)- phase 3 clinical trials; 175mg/kg
(5.8ml/kg)
▫ Colfosceril palmitate (Exosurf)- 1st synthetic surfactant; no
longer used in US
Surfactants cont..
• Administration
▫ All are refrigerated and slowly warmed to
room temperature manually
 Can be returned to the refrigerator one time after
being warmed and within 24 hours (8 for beractant)
▫ Prophylaxis- all administered intratracheally
within 10-15 minutes of birth
▫ Rescue- within 6-24 hours of life in infants
requiring mechanical ventilation
▫ Pt is rotated to different positions throughout
administration to equally distribute over lungs
Surfactants cont..
• Comparisons between different surfactants:
▫ Advantages of synthetic surfactant (lucinactant)
 ↓risk of infection and immunologic response; production
of large quantities with consistent quality
▫ Advantages of natural surfactants
 Faster onset of action; cheaper; many trials
▫ Beractant vs. Calfactant- studies have shown ↓mean
airway pressure, FiO2 and # of doses for calfactant
 Long term- no difference in CLD or mortality
▫ Beractant vs. Poractant- ↓O2 req., MAP, and days on
vent with poractant; no difference in mortality or CLD
▫ Lucinactant vs. natural – noninferior to poractant;
fewer RDS development at 14 days vs. beractant
PDA Closure
• PDA is a risk factor for the development of
chronic lung disease
• Many believed that medications used to close the
PDA would therefore reduce CLD
• RCT’s have not shown any significant reduction
in CLD in infants that undergo treatment to
close PDA
• Indomethacin (0.2mg/kg, 0.1mg/kg, 0.1mg/kg)
or Neoprofen (10mg/kg, 5mg/kg, 5mg/kg)
Antioxidants and Vitamins
Vitamin A
Vitamin E & Other Antioxidants
• Many preterm infants Vit A
deficient
• Involved in the regulation and
promotion of growth and
differentiation of many cellsincreases alveoli number
• Maintains the integrity of
respiratory tract cells- improves
lung healing
• RCT showed that in infants <1kg
that a large dose of IM Vit A
given 3 times a week for 4 weeks
slightly decreased risk of CLD
• Oral Vitamin A doesn’t provide
same benefit
• Vitamin E
▫ Antioxidant activity
▫ Scavenges free radicals, like
O2, which leads to much of
the lung trauma associated
with CLD
▫ No benefit has been seen yet
• Superoxide Dismutase
▫ Endogenous antioxidant
▫ Converts O2 radicals to H2O
▫ No benefit seen
• N-Acetylcysteine
▫ Precursor for glutathione an
antioxidant
▫ No effect seen
Oxygen therapy
• Most commonly used therapy
• Goal is to achieve adequate tissue oxygenation without
creating oxygen toxicity and oxidative stress
• “The clinician must bear in mind the oxygen is a drug
and must be used in accordance with well recognized
pharmacologic principles; since it has certain toxic
effects and is not completely harmless (as believed by
many) it should be given only in the lowest dosage or
concentration required by the particular patient.” –
Julius Comroe 1945
• Too high oxygen levels increase risk for grade 3-4 ROP
and lung damage
• Protocol for specific ranges have not been identified
Inhaled Nitric Oxide
• Dose= ≤20ppm for 7 days
• Selective pulmonary vasodilatation without lowering
systemic blood pressure due to very short half-life in
body (2-4 sec)
• May improve lung oxygenation in atelectasis, reduce
lung inflammation, improve surfactant function, and
promote lung growth
• Benefit in PHTN clearly demonstrated
• Benefit in CLD is still up the air- some studies say clear
↓in CLD, others see only short-term or no benefit
• Cost:benefit ratio for treatment not in favor of treating
CLD patients
Diuretics
• Lung edema often accompanies CLD and may complicate it’s
presentation
• Furosemide is the most common diuretic used in neonatal period
▫ MOA: inhibits Na and Cl absorption in the Loop of Henle leading to
excretion of water, Na, Cl, K, Mg, and Ca
▫ Dose: 1-2 mg/kg/dose q 12-24 hours
• Another common diuretic combination in CLD is Aldactazide
(Spironolactone/HCTZ)
▫ MOA: spironolactone is a K-sparing diuretic that inhibits aldosterone
leading to Na and water excretion and K retention; HCTZ is a thiazide
diuretic that works in the distal tubules to cause water and Na excretion
▫ Dose: 1.5-3 mg/kg/day in 2-4 doses
• Monitoring: must monitor all electrolytes for abnormalities, and
furosemide may cause ototoxicity
• Overall benefit in CLD may be minimal but there is established
benefit in decreasing lung edema which can exacerbate CLD
Beta2 Agonists
• Beta Agonists (Albuterol)
▫ MOA: stimulates B2 receptors and relaxes
bronchial smooth muscle with little effect on heart
▫ Assisted ventilation may add to bronchial hyperresponsiveness in CLD
▫ Immediate changes in lung compliance are noted
but no meaningful outcomes for CLD have been
demonstrated
Anticholinergics
• Anticholinergics (Ipratropium bromide)
▫ MOA: Blocks the actions of Ach at muscarinic sites
leading to bronchial dilation and decreased
respiratory secretions
▫ Similarly to Beta agonist therapy, short term
benefit is documented with increased lung
compliance
▫ No evidence from RCT to be able to recommend
for treatment of CLD
Corticosteroids
• Corticosteroid use in the prevention and treatment of CLD
▫ Many different regimens have been implicated in a majority of
different trials
▫ Differing in the time of initiation, duration of treatment, tapering
regimen, and starting doses
▫ Dexamethasone is primary corticosteroid used, but recent
findings are leading to increased research into Hydrocortisone
and inhaled corticosteroids
▫ Long and short term side effects severely limit use
• MOA in CLD: corticosteroids act at the gluccocorticoid
receptors which alter the transcription of many genes;
decreases the expression of several pro-inflammatory
proteins(neutrophils, elastase, prostaglandins) and increase
expression of anti-inflammatory proteins; decrease pulmonary
inflammation and fibrosis
• Used in the hopes of weaning patient from mechanical
ventilation
Corticosteroids
• The side effects:
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Hyperglycemia
Hypertension
Left ventricular hypertrophy
Infection
Decreased weight gain and decreased head circumference
Gastrointestinal bleeding
Long term neurodevelopmental delays- including cerebral
palsy, abnormal neurologic exams, developmental delays
 MOA: direct toxic effects on neurons in the brain causing
neuronal degeneration, reduced expression of nerve growth
factor, delayed myelination of nerves, reduced brain growth
Corticosteroid Regimens
• Dexamethasone
▫ Initiation: ranging from 1-42 days after birth
 Early treatment: <96 hours after birth
 Moderately early: 7-14 days after birth
 Delayed treatment: >3 weeks after birth
▫ Duration of treatment: ranging from 3-42 days
 Most commonly 3 days, 7 days, 14 days, 18 days, 21 days,
42 days
▫ Dosage:
 Most common starting dose is 0.5mg/kg/day divided
every 12 hours
 Recent studies start with as low as 0.08mg/kg/day
Which regimen is best? Good Question!
• Initiation
▫ Better outcomes on CLD are seen with the early and
moderately-early groups
 Significant reduction in mortality at 28 days of life and a
significant reduction in oxygen dependence at 36 weeks
 Delayed treatment regimen showed no significant decrease in
mortality associated with CLD and weak effect on CLD at 36
weeks
▫ But significantly more adverse effects in the early and
moderately early regimen including higher rates of
neurodevelopmental delays (including CP)
 Review article cites that in the early treated group for every 100
babies treated, CLD would be prevented in 10, with additional 6
with GI bleed, 12 with CP, and 14 more with abnormal neurologic
exam
 Delayed regimen not associated with increased adverse effects
(except hypertension), specifically no increased
neurodevelopmental delays
Regimens cont..
• Duration of treatment:
▫ Shorter treatment regimens (1-3 days) have shown an
increased need for steroids later in hospital stay
 Shorter regimens have shown decreased short term side effects
but increased need for supplemental O2
▫ Longer treatment regimens (42 days) have shown reduced
mechanical ventilation, O2 requirement, and length of stay
but possible increased short term side effects
▫ Shoot for the middle!
• Starting doses:
▫ An arbitrary number of 0.5mg/kg/day was established in
1985; this dose is 10-15x basal cortisol secretion and 2-3x
higher than typical anti-inflammatory doses used in peds
▫ Studies have shown that doses as low as 0.08mg/kg/day
have had similar pulmonary benefits to 0.5mg/kg/day with
significantly less short term and long term adverse effects
Hydrocortisone
• Potential alternative to dexamethasone with less short and
long term effects (including neurodevelopmental)
• Hydrocortisone is natural steroid compared to dex which is
synthetic
▫ Dex has 25-30x higher anti-inflammatory action
▫ Dex interacts with GCC receptors while HC interacts with
mineralocorticoid receptors
 GCC receptor involved in adverse neural effects causing apoptosis
of cells; MCC stimulation is actually protective against apoptosis
▫ Half life of Dex is 36-72 hours compared to HC half life of 8-12
hours leading to less accumulation of HC
• Fewer studies with HC but evidence so far is demonstrating
similar results in treating CLD compared to Dex with a less
severe adverse effect profile
• Dose: 1-5mg/kg/dose tapered over 10-22 days
Inhaled Corticosteroids
• Can be used early (<2 weeks) or late (>2 weeks)
• Early: 5 trials have been conducted in compare inhaled to
systemic steroid used in early treatment
▫ The only outcome affected by inhaled steroids was a reduction in
the needs for later systemic steroid use
▫ There was a trend toward decrease mortality but didn’t reach
statistical significance
• Late: 4 trials of inhaled steroids used as late treatment
▫ Increased incidence of extubation
▫ One trial showed reduced airway resistance; another trial showed
respirator rate and inspired O2 concentration could be reduced
faster
• Trials have looked at Budesonide, Beclomethasone,
Fluticasone
• Can be given via nebulization or MDI
• No adverse effects found- Local action in lungs with little to no
systemic effects
Steroid Recommendations
• American Academy of Pediatrics and Canadian Pediatric
Society joint statement:
▫ Routine use of systemic corticosteroids is not
recommended for prevention or treatment of CLD in VLBW
infants
▫ Postnatal use of dexamethasone should be limited to
carefully designed trials
▫ Long term neurodevelopmental assessment of infants who
are, or have been subject to dexamethasone is encouraged
▫ Clinical trials involving the use of other anti-inflammatory
steroids are needed before additional recommendations can
be made
▫ Outside clinical trials the use of steroids should be limited
to very extreme clinical circumstances
Back to LHS..
• Wrap-up of hospital course
▫ Pt developed significant morbidities over hospital course as
outlined in the previous slide of diagnoses accumulated over
hospital course; but related to the CLD…
▫ Day 3: CXR confirms RDS and PIE and pt with worsening acidosis
 Pt intubated on HFOV
▫ Day 12: CXR shows chronic changes beginning in lungs and
evidence of atelectasis
▫ Day 20: worsening CBG’s with ↑respiratory acidosis
 Pt septic with hypotension requiring Dopamine and anuria requiring
multiple Lasix boluses
▫ Day 22: diagnosed with chronic lung disease and started
hydrocortisone (1mg/kg/dose q6 hours)
▫ Day 25: extubated! Switched to non-invasive ventilation with nasal
cannulas
▫ Day 28: weaned HC to 1mg/kg/dose q8 hours with plan to D/C HC
by day 39 (day 33-0.5mg q12h x 4 doses, 0.25mg q12h x2 doses, 0.1
mg q12 x2 doses, 0.1 mg qd x 1 day) – length of HC 17 days
Summary
• CLD can be a very complex and dangerous disease
state for neonates
• There are many treatment options for CLD but not
much evidence out there to support many of the
therapies
• Many treatment options are based on precedents set
at facility and not EBM
• Much more research needed in CLD to provide
concrete evidence on effective and safe therapies
• Best to abide by AAP statement and avoid steroid
use unless child likely to die without treatment until
further evidence is provided
References
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Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days) postnatal corticosteroids for
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Rademaker KJ et al. Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn
and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed. 2008; 93:F58-F63.
Van der Heide-Jalving M et al. Short- and long-term effects of neonatal glucocorticoid therapy: is
hydrocortisone an alternative to dexamethasone?. Acta Paediatrica. 2003; 92:827-35.
Grier DG, Halliday HL. Corticosteroids in the prevention and management of bronchopulmonary
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