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Chronic Lung Disease:

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.

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Chronic Lung Disease:

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  1. Chronic Lung Disease: Bronchopulmonary Dysplasia Your Name Here Date

  2. Objectives • Patient Presentation • Disease State Overview • Current treatments • Preventative • Treatment alternatives • Current recommendations • Patient Course • Summary

  3. 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

  4. 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↓

  5. 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↓ • pCO2: 52↑ • pO2: 59↓ • HCO3: 22

  6. Differential Dx on Admission • Hyperbilirubinemia • Respiratory Distress Syndrome • Sepsis • Risk for IVH

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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)

  18. 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

  19. 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

  20. 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

  21. 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)

  22. 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 O2 radicals to H2O • No benefit seen • N-Acetylcysteine • Precursor for glutathione an antioxidant • No effect seen

  23. 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

  24. 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

  25. 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

  26. 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 hyper-responsiveness in CLD • Immediate changes in lung compliance are noted but no meaningful outcomes for CLD have been demonstrated

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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 derHeide-Jalving M et al. Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?. ActaPaediatrica. 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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