Chronic Lung Disease:

shawlaskewvilleUrban and Civil

Nov 29, 2013 (3 years and 4 months ago)

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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


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




Temp:
95.3


HR: 171 bpm


RR:
30/3



BP:
37/20


Admission Labs

CBC & BMP

ABG


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



pCO
2
:
52



pO
2
:
59



HCO
3
: 22

Differential Dx on Admission


Hyperbilirubinemia


Respiratory Distress Syndrome


Sepsis


Risk for IVH


Progressive Dx throughout course..


Added diagnoses:


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 1
st

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:


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 4
th

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 alpha
1
antitrypsin, vitamin A, catalase,
glutathione


Inability of the lungs to protect themselves from
oxidizing agents and enzymes (eg. A
1
AT 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


Antenatal steroids


Surfactant
-

prophylaxis


PDA closure


Vitamin A & E


Treatments


Oxygen


iNO


Corticosteroids(systemic vs. inhaled)


Diuretics


Beta agonists


Anticholinergics




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)
-

1
st

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 cells
-

increases 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 O
2

radicals to H
2
O


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

Beta
2

Agonists


Beta Agonists (Albuterol)


MOA: stimulates B2 receptors and relaxes
bronchial smooth muscle with little effect on heart


Assisted ventilation may add to bronchial hyper
-
responsiveness 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:


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


Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7
-
14 days) postnatal corticosteroids for
preventing chronic lung disease in preterm infants (Review).
The Cochrane Library
. 2008; 3:1
-
34.


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

dysplasia.
Seminars in Neonatology
. 2003; 8:83
-
91.


Tin W,
Wiswell

TE. Adjunctive therapies in chronic lung disease: Examining the evidence.
Seminars in
Fetal and Neonatal Medicine
. 2008; 13:44
-
52.


Truog

WE. Chronic Lung
Dease

and Randomized Interventional Trials : Status in 2005.
NeoReviews
.
2005; 6:e278
-
e288.


Halliday HL. Postnatal steroids in chronic lung disease in the newborn.
Paediatric

Respiratory Reviews
.
2004; 5:S245
-
S248.


Ghodrat

M. Lung Surfactants.
Am J Health
-
Syst

Pharm
. 2006; 63:1504
-
1521.


Gianni LM, El
-
Chaar

G. Neonatal Bronchopulmonary Dysplasia.
Pharmacist
. 2000; HS 33
-

HS42.


Pauly

TH, Kuhn RJ. The Use of Exogenous Lung Surfactant for Neonatal Respiratory Distress Syndrome:
A Review. Neonatal Pharmacology Quarterly 1993; 2:15
-
23.


Malloy CA. A Prospective, Randomized, Double
-
masked Trial Comparing Low Dose to Conventional Dose
Dexamethasone is Neonatal Chronic Lung Disease.
Internet Journal of Pediatrics and Neonatology
.
2005: 5:10
-
22.