chronic lung disease2

8/10/2019 Chronic Lung Disease2

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Chronic Lung Disease:Bronchopulmonary Dysplasia

Your Name Here

Date


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Objectives

Patient Presentation

Disease State Overview

Current treatments

Preventative

Treatment alternatives

Current recommendations Patient Course

Summary


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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 forbradycardia and was intubated

LHS transferred to PHR after intubation and stableheart rate obtained


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Physical Exam and Vitals upon Admit

Physical Exam (nml except) Vitals

General: preterm infant

in moderate respiratorydistress

Chest: breath soundsequal but bilaterally

Neuro: responds tostimulation but with activity

Skin & extremities:bruising on trunk, head,

and extremities

Temp: 95.3

HR: 171 bpm

RR: 30/3

BP: 37/20


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Admission LabsCBC & 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

pCO2: 52 pO2: 59

HCO3: 22


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Differential Dx on Admission

Hyperbilirubinemia

Respiratory Distress Syndrome

Sepsis

Risk for IVH


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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


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MedicationsOn 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 todiaper area

Morphine 0.1mg q2 hours

Midazolam 0.1mg q2 hours


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Chronic Lung Disease.. What does itmean? Depends on who you ask!

Need for assisted ventilation orsupplemental O2 at 36 weeks postconceptual age

Respiratory failure in the 1stweekof life requiring assisted

ventilation for minimum of 3 days

Persistent respiratory symptoms

(tachypnea, rales, etc) and O2dependence at 28 dayspostnatally

CXR findings consistent with CLDaka BPD


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Who develops CLD? Risk factors for development of CLD:

Very low birth weight


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Incidence and Mortality Incidence:

Increasing over the past 20 yearsdue to increased survival rates,

increased number of live births,substantial increase in number ofVLBW infants

5-20% of neonates on mechanicalventilation

40% of VLBW infants

Only 1% in term infants Mortality:

30-40% prior to currentpreventative meds

Associated with approximately5,000 infants deaths/year


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Pathophysiology Fetal lung development progresses through 4 stages

during gestation The 4thand 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, surfactantproduction 26 weeks- gas exchange possible 32 weeks- alveoli form

Babies born prematurely fail to progress through all ofstage 4 Surfactant deficiencies- surfactant is needed to decrease the

surface tension within the alveoli and prevent the collapse ofalveoli; deficiency leads to increase work of breathing due tobaby having to reinflate collapsed lung with each breath


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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 lungsfrom 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 otherinflammatory mediators, causing further insult

Vicious cycle


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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


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Treatment Options.. The good, thebad, 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


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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 mothers between 24-34 weeks gestation who are expectedto go into labor within the next 7 days; if labor does not occur within7 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 fetuss

lungs and increase surfactant production in the fetus; reducealveolar wall thickness and facilitate gas exchange

Side effects: rare for short exposure to steroids but may includematernal hypertension or hyperglycemia

Decreases the infants risk of: Respiratory Distress Syndrome,Intraventricular Hemorrhage, Necrotizing enterocolitis, and death


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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 anddecreased lung atelectasis

Advantages: Reduces both neonatal mortality and air leaks by50% with an overall reduction of infant mortality in the US of6% Also have beneficial effects in MAS and ECMO

Side effects: bradycardia, hypotension, cyanosis(calfactant)


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Surfactants cont Biologic:

Beractant (Survanta) bovine; 100mg/kg (4ml/kg) up to 4doseswithin 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 with100mg/kg/dose(1.25ml/kg) up to 2 additional times(max 5ml)

Calfactant (Infasurf)- bovine; 105mg/kg (3ml/kg) every 12hours up to 3 doses

Synthetic Lucinactant (Surfaxin)- phase 3 clinical trials; 175mg/kg

(5.8ml/kg) Colfosceril palmitate (Exosurf)- 1stsynthetic surfactant; no

longer used in US


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Surfactants cont.. Administration

All are refrigerated and slowly warmed to

room temperature manually Can be returned to the refrigerator one time afterbeing 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 infantsrequiring mechanical ventilation

Pt is rotated to different positions throughoutadministration to equally distribute over lungs


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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 onvent with poractant; no difference in mortality or CLD

Lucinactant vs. natural noninferior to poractant;fewer RDS development at 14 days vs. beractant


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PDA Closure

PDA is a risk factor for the development ofchronic lung disease

Many believed that medications used to close thePDA would therefore reduce CLD

RCTs have not shown any significant reduction

in CLD in infants that undergo treatment toclose PDA

Indomethacin (0.2mg/kg, 0.1mg/kg, 0.1mg/kg)or Neoprofen (10mg/kg, 5mg/kg, 5mg/kg)


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Antioxidants and VitaminsVitamin A Vitamin E & Other Antioxidants

Many preterm infants Vit Adeficient

Involved in the regulation andpromotion of growth anddifferentiation of many cells-increases alveoli number

Maintains the integrity ofrespiratory tract cells- improves

lung healing RCT showed that in infants


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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 recognizedpharmacologic principles; since it has certain toxiceffects and is not completely harmless (as believed bymany) 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


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Inhaled Nitric Oxide Dose= 20ppm for 7 days Selective pulmonary vasodilatation without lowering

systemic blood pressure due to very short half-life inbody (2-4 sec) May improve lung oxygenation in atelectasis, reduce

lung inflammation, improve surfactant function, andpromote lung growth

Benefit in PHTN clearly demonstrated Benefit in CLD is still up the air- some studies say clearin CLD, others see only short-term or no benefit

Cost:benefit ratio for treatment not in favor of treatingCLD patients


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Diuretics Lung edema often accompanies CLD and may complicate its

presentation Furosemide is the most common diuretic used in neonatal period

MOA: inhibits Na and Cl absorption in the Loop of Henle leading toexcretion 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, andfurosemide may cause ototoxicity

Overall benefit in CLD may be minimal but there is establishedbenefit in decreasing lung edema which can exacerbate CLD


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Beta2Agonists

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 notedbut no meaningful outcomes for CLD have beendemonstrated


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Anticholinergics

Anticholinergics (Ipratropium bromide)

MOA: Blocks the actions of Ach at muscarinic sites

leading to bronchial dilation and decreasedrespiratory secretions

Similarly to Beta agonist therapy, short termbenefit is documented with increased lung

compliance

No evidence from RCT to be able to recommendfor treatment of CLD


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Corticosteroids Corticosteroid use in the prevention and treatment of CLD

Many different regimens have been implicated in a majority ofdifferent 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 Hydrocortisoneand 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-inflammatoryproteins(neutrophils, elastase, prostaglandins) and increaseexpression of anti-inflammatory proteins; decrease pulmonaryinflammation and fibrosis

Used in the hopes of weaning patient from mechanicalventilation


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Corticosteroids The side effects:

Hyperglycemia

Hypertension Left ventricular hypertrophy

Infection

Decreased weight gain and decreased head circumference Gastrointestinal bleeding

Long term neurodevelopmental delays- including cerebralpalsy, abnormal neurologic exams, developmental delays MOA: direct toxic effects on neurons in the brain causing

neuronal degeneration, reduced expression of nerve growthfactor, delayed myelination of nerves, reduced brain growth


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Corticosteroid Regimens Dexamethasone

Initiation: ranging from 1-42 days after birth

Early 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 dividedevery 12 hours

Recent studies start with as low as 0.08mg/kg/day


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Which regimen is best? Good Question! Initiation

Better outcomes on CLD are seen with the early andmoderately-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 36weeks

But significantly more adverse effects in the early andmoderately 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 6with GI bleed, 12 with CP, and 14 more with abnormal neurologicexam

Delayed regimen not associated with increased adverse effects

(except hypertension), specifically no increasedneurodevelopmental delays


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Regimens cont.. Duration of treatment:

Shorter treatment regimens (1-3 days) have shown anincreased 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 staybut possible increased short term side effects

Shoot for the middle!

Starting doses: An arbitrary number of 0.5mg/kg/day was established in1985; this dose is 10-15x basal cortisol secretion and 2-3xhigher than typical anti-inflammatory doses used in peds

Studies have shown that doses as low as 0.08mg/kg/dayhave had similar pulmonary benefits to 0.5mg/kg/day with

significantly less short term and long term adverse effects


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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 8-12hours 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 lesssevere adverse effect profile

Dose: 1-5mg/kg/dose tapered over 10-22 days


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Inhaled Corticosteroids Can be used early (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 didnt 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 reducedfaster

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 nosystemic effects


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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 VLBWinfants

Postnatal use of dexamethasone should be limited tocarefully designed trials

Long term neurodevelopmental assessment of infants whoare, or have been subject to dexamethasone is encouraged

Clinical trials involving the use of other anti-inflammatorysteroids are needed before additional recommendations canbe made

Outside clinical trials the use of steroids should be limitedto very extreme clinical circumstances


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Back to LHS.. Wrap-up of hospital course

Pt developed significant morbidities over hospital course asoutlined in the previous slide of diagnoses accumulated overhospital 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 andevidence of atelectasis

Day 20: worsening CBGs withrespiratory acidosis Pt septic with hypotension requiring Dopamine and anuria requiring

multiple Lasix boluses

Day 22: diagnosed with chronic lung disease and startedhydrocortisone (1mg/kg/dose q6 hours)

Day 25: extubated! Switched to non-invasive ventilation with nasalcannulas

Day 28: weaned HC to 1mg/kg/dose q8 hours with plan to D/C HCby day 39 (day 33-0.5mg q12h x 4 doses, 0.25mg q12h x2 doses, 0.1mg q12 x2 doses, 0.1 mg qd x 1 day) length of HC 17 days


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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 thetherapies

Many treatment options are based on precedents setat facility and not EBM

Much more research needed in CLD to provideconcrete evidence on effective and safe therapies Best to abide by AAP statement and avoid steroid

use unless child likely to die without treatment untilfurther evidence is provided


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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.

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