Respiratory Management and Outcome of Preterm Infants

Transcription

1 Respiratory Management and Outcome of Preterm Infants 6 th Annual Care Of The Sick Newborn Conference Shu Wu, MD. Department of Pediatrics Division of Neonatology University of Miami School of Medicine Prematurity and Pulmonary Morbidity 3,950,000 live birth in the USA in 2011 ~58,855 infants with birth weight <1,500g (VLBW) ~28,835 infants with birth weight <1,000g (ELBW) ELBW infants are at the highest risk for respiratory distress syndrome, bronchopulmonary dysplasia (BPD), and long-term pulmonary complications Bronchopulmonary Dysplasia (BPD) Bronchopulmonary Dysplasia (O 2 at 36 wks PMA), Years , NICHD BPD is the most common chronic lung disease of premature infants O 2 requirement >28 days at 36 weeks PMA Original BPD was first described in 1967 Moderately premature infants Pre-surfactant era, severe respiratory distress High pressure/volume MV and high levels of supplemental O 2 New BPD was introduced in 1999 ELBW infants <28 weeks GA Post-surfactant era, milder respiratory distress Increasing O 2 and MV needs over the first several weeks of life Prolonged O 2 need beyond 36 wk PMA UM NICU Admissions of Preterm Infants Birth Weight <1500g Survival to Discharge

2 O 2 dependent >36 wks CGA (% among survivors) 5/18/2015 O 2 Dependent 36 Weeks PMA BPD and Lung Developmental Stage < BW (grams) Embryonic Weeks Pseudoglandular Canalicular Saccular Alveolar Years Forming conducting airway -Birth of the acinus Preterm Birth at risk for BPD -Forming acinus -Epithelial differentiation -Airspace expansion -Secondary septation -Forming air-blood barrier -Producing surfactant -Capillary remodeling Lung Immaturity: Key in BPD 38 wk GA Intra-uterine 26 wk GA Normal alveoli Risk and Protective Factors for BPD Saccular??? Extra-uterine 38 wk PMA BPD Risk factors Protective factors Modified, Yodar et al, Neoreviews 2008, 9:e447 Strategies to Protect the Immature Lung Gentle ventilation: Patient triggered ventilation Adequate tidal volume/volume target Permissive hypercapnia Avoid invasive ventilation: CPAP, NIMV Avoid high inspired oxygen concentrations Pharmacological Approaches to Prevent and Treat BPD Acceleration of lung maturation: Antenatal steroids Treating RDS: Surfactant replacement Prevent and treat infection: Azithromycin Anti-inflammation: Postnatal steroids Treating apnea: Caffeine Decrease pulmonary edema: Diuretics Bronchodilators: Albuterol, Atrovent Pulmonary vasodilators: ino, sildenafil Nutritional supplements: Vitamin A 2

3 Antenatal Steroids First discovered in 1969 in animal studies to enhance lung maturation First RCT was conducted in 1972 to prevent RDS in preterm deliveries Large RCTs in preterm delivery have shown: Reduction of mortality and RDS Reduction of IVH and NEC Does not increase the risk of sepsis Long-term Effects of Antenatal Steroids Outcome Number of birth (n) 23 weeks GA ANS No ANS OR 95% CI Survival to discharge * (%) Survival w/o O 2 at 36 wks (%) Survival to F/U (%) Survival w/o NDI (%) * * * NICHD Neonatal Research Network, Carlo W et al, Ped Res, weeks GA ANS No ANS OR 95% CI * * * * P<0.001 Surfactant Replacement Was established as an effective and safe therapy for immaturity-related surfactant deficiency by early 1990s Surfactant Preparations and Recommended Doses Generic name Trade Name Source Dose Bovactant Alveofact Bovine 50 mg/kg/dose Improves survival of preterm infants Bovine lipid extract surfactant BLES Bovine 135 mg/kg/dose Reduces incidence and severity of RDS Reduces incidence of pneumothorax Additive effect with antenatal steroids Poractant alfa Curosurf Porcine 200 mg/kg/dose Calfactant Infasurf Bovine 105 mg/kg/dose Surfactant-TA Surfacten Bovine 100 mg/kg/dose Beractant Survanta Bovine 100 mg/kg/dose Colfoseril palmitate Exosurf Synthetic 64 mg/kg/dose Use of Azithromycin for the Prevention of BPD Outcome Azithromycin (n=111) Placebo (n=109) Birth weight (g) 803± ±188 Gestational age 25.7±1.5 26±1.6 Incidence of Ureaplasma 31% 40% P value Days of MV 28±26 26± Days of O 2 65±40 64± Ureaplasma positive BPD or death 73% (19/26) 94% (33/35) 0.03 Postnatal Corticosteroids in Preterm Infants Have been used since the 1970s to ameliorate lung inflammation in ventilated preterm infants In the middle of 1990s, 25-50% of all very low birth weight infants received postnatal steroids: Facilitates extubation and improves lung compliance No effect on duration of supplemental O 2, duration of hospitalization or mortality In 2001, meta-analyses highlighted the association between postnatal steroids and impaired neurodevelopment Ballard HO, et al, Pediatric Pulmonology, 46:111,

4 Meta-analyses Assessing the Timing of Postnatal Steroids Administration Age Effect Outcome Evidence < 7 days Short-term Long-term Short-term Ventilation Mortality CLD Cerebral palsy Ventilation Extubation rate No change Reduced risk Increased risk Extubation rate OR 0.75 ( ) OR 1 ( ) OR 0.76 ( ) OR 1.45 ( ) OR 0.62 ( ) Caffeine Is one of the most commonly used medication in NICU for apnea of prematurity Can enhance central respiratory drive 7-14 days Long-term Mortality CLD Cerebral palsy No change Reduced risk No difference OR 0.66 ( ) OR 0.62 ( ) OR 0.83 ( ) Can improve minute ventilation, pulmonary mechanics and respiratory muscle contractility >21 days Short-term Long-term Ventilation Mortality CLD Cerebral palsy Yates HL, Arch Di Child Fetal neonatal ED, 97:F299, 2012 Extubation rate No change Reduced risk No difference OR 0.69 ( ) OR 1.03 ( ) OR 0.76 (0.58-1) OR 1.2 ( ) Prevent lung inflammation? Caffeine Therapy for Apnea of Prematurity (CAP Trial) Short Term Outcome CAP Trial-Long Term Outcome Outcome Caffeine (n=1006) Placebo (n=1000) Birth weight (g) 964± ±181 OR (95% CI) Death 5.2% 5.5% 0.93 ( ) NEC 6.3% 6.7% 0.93 ( ) Brain injury by US 13% 14.3% 0.97 ( ) Weight gain -23g (-32 to -13) BPD at 36 weeks PMA 36.3% 46.9% 0.64 ( ) PDA/drug therapy 29.3% 38.1% 0.67 ( ) PDA/surgical closure 4.5% 12.6% 0.29 ( ) At 18 months corrected age Caffeine (n=833) Placebo (n=807) P value Death 6.8% 6.9% 0.99 Cerebral palsy 4.3% 7.7% MDI < % 36.6% 0.03 MDI < % 16.2% 0.02 At 5 years corrected age Death/at least 1 impairment 21.1% 24.8% 0.09 Full scale IQ< % 19.4% 0.44 Schmidt B. NEJM, 354: , 2006 Schmidt B, JAMA 307:3, 2012 Diuretic Therapy in Preterm Infants Commonly used loop diuretics: Furosemide, Thiazide ± Spironolactone Rationale: Lung edema, PDA, renal insufficiency Potential benefits: Improvement in lung function Risks: Electrolyte imbalance, ototoxicity, renal Ca + No evidence of benefit on clinical outcomes: Mortality, duration of ventilation and O 2, BPD No evidence to support routine use Bronchodilators Albuterol (Inhaled b 2 -agonist): Used in BPD with reversible bronchospasm Short-term improvements in pulmonary resistance and compliance Long-term efficacy has not been established May develop tolerance with prolonged use Atrovent (Ipratropium bromide): A muscarinic antagonist Clinical trials did not show efficacy in BPD progression or long-term respiratory status Consider to be used if wheezing and not responding to albuterol 4

5 Inhaled Nitric Oxide (ino) Is a selective pulmonary vasodilator Is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants Prevent or treat BPD in preterm infant? INO in Preterm Infants Meta-analysis (Askie LM, Pediatrics 2011;128:729) In preterm infants <34 wk gestation: 14 trials were conducted 11 trials were analyzed from 1997 to 2010 Total 3298 infants NIH consensus: evidence does not support use of ino in the care of preterm infants <34 wk GA Primary Outcome Secondary Outcome Askie LM, Pediatrics 2011;128:729 Askie LM, Pediatrics 2011;128:729 Sildenafil Is a selective type 5 phosphodiesterase inhibitor that increases cgmp and causes vasodilation Can be given orally, and over long periods of time with apparent low toxicity Reported increased mortality in older children with high doses Using off-label for the treatment of pulmonary hypertension caused by BPD Vitamin A Vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells Preterm infants have low vitamin A status at birth, and this has been associated with increased risk of developing chronic lung disease Recommend does: 5000 IU/dose, im, 3/week 5

6 Vitamin A Supplementation for Extremely Low Birth Weight Infants Long-term Lung Function in BPD and Full-term Infants Outcome Vitamin A Placebo P value (n=405) (n=402) Birth wt (g) 770± ±138 Death 17% 16% 0.96 CLD at 36 wks 47% 56% 0.03 Tyson JE, NICHD Neonatal Research Newtwork, NEJM, 340:25, 1999 Seminars in Fetal & Neonatal Med 2013;1-7 Chronic Respiratory Morbidity Needing supplementary oxygen at home Recurrent respiratory symptoms: Coughing, wheezing, asthma, pneumonia Re-hospitalization Abnormal lung function: Lower lung volumes, airway obstruction Lower forced expiratory flows, reduced diffusing capacities Pulmonary abnormalities on imaging: Persistent up to young adulthood Pulmonary hypertension: Abnormal echocardiogram Confirmation by cardiac catheterization Increasing mortality One-Year Respiratory Outcomes of Preterm Infants in the Nitric Oxide to Prevent Chronic Lung Disease Trial Total 455 infants Birth weight (g) 765 ± 156 Gestational age (wks) 25.8 ± 1.4 Any home O 2 (%) 44 Persistent home O 2 (%) 6.2 Bronchodilator use (%) 47.1 Inhaled steroid use (%) 26.1 Systemic steroid use (%) 14.4 Diuretic use (%) 23.5 Any hospitalization (%) 48.5 Respiratory hospitalization (%) 22.3 J Pediatr 2008;153:525-9 Respiratory Symptoms and Lung Function at 11 Years in Children Born Extremely Preterm (The EPICure Study) Lung Function after Preterm Birth: Development from Mid-Childhood to Adulthood All EP Classmates (C) EP C Δ (95% CI) n Gestational age at birth, wks 25.0 (0.7) 36 Age, years 10.9 (0.38) 10.9 (0.55) 0.0 ( 0.1; 0.1) Current asthma 42 (25%) 20 (13%) 12% (4; 21%), P<0.01 Asthma medication 41 (25%) 16 (11%) 14% (6; 22%), P<0.01 Seen by respiratory specialist 14 (8%) 4 (3%) 6% (1; 11%), P<0.05 Exercise-induced wheeze 34 (21%) 13 (9%) 12% (4; 19%), P<0.01 Nocturnal cough 33 (20%) 16 (11%) 9% (1; 17%), P<0.05 zfev1-1.4 (1.2) 0.0 (1.0) -1.5 (-.17; -1.2), P<0.001 Am J Respir Crit Care Med, 2010;182: Thorax, 2013;68:

7 CXR and Chest CT of BPD Contrast Tracheobronchogram of BPD CXR from a 4 month old boy (ex-24 week) with severe BPD Chest CT from a 2 year old boy (ex-24 week) with severe BPD Contrast tracheobronchogram from an ex 24 week preterm infant with a persistent CPAP requirement. Inspiratory (A) and expiratory (B) images demonstrating marked reduction in calibre of both left and right sided large airways on expiration. Andrew C. Wilson, Pediatric Respiratory Reviews, Volume 11, Issue 3, 2010, Andrew C. Wilson, Pediatric Respiratory Reviews, Volume 11, Issue 3, 2010, Chest CT Findings in BPD Chest CT Findings in BPD and Correlation with Lung Function Hyperlucence and linear opacities Triangular subpleural opacities Arch Dis Child Fetal Neonatal Ed 2007;92:F Total 41 patients Birth weight (g), mean (SD) 914 (37) Gestation age (weeks), mean (SD) 27.2 (0.2) Duration of O 2 supplement (days), mean (SD) 68 (6) PMA at end O 2 supplement (weeks), mean (SD) 37 (0.7) CT, months of age Hyperlucent areas, n (%) 36 (88%) Linear opacities, n (%) 39 (95%) Triangular subpleural opacities, n (%) 26 (63%) Mahut etal, Arch Dis Child Fetal Neonatal Ed 2007;92:F Chest CT Findings in BPD and Correlation with Lung Function Chest CT Findings in BPD and Correlation with Lung Function P < 0.05 P < 0.05 P < 0.02 r = , P < 0.02 r = , P < 0.02 Arch Dis Child Fetal Neonatal Ed 2007;92:F Arch Dis Child Fetal Neonatal Ed 2007;92:F

8 Pulmonary Hypertension in BPD: Clinical Findings, Cardiovascular Anomalies and Outcomes Total 29 patients Median diagnosis of PH (months) 4.5 ( ) Echo RVP/SP (%) 70 (60-80) Cardiac catheterization (n) 14 Aortopulmonary collaterals (n) Pulmonary vein stenosis (n) ASD (n) PDA (n) Median fellow up (months) 35 (21-91) Spontaneous resolved PH (n) PH medications (n) Shunt closure (n) Death (n) Cerro etal Pediatric Pulmonology, 2013;49:49-59 Pulmonary Hypertension in BPD A and B: Pulmonary wedge angiographies of patients showing variable degrees of vascular hypoplasia. septum (IVS) morphology on echocardiography C and D: Lung perfusion before scintigraphy and CT scans and after the specific PH showing drug stenosis treatment. of the left b: pulmonary veins and Pulmonary hypertension (PH) hypoperfusion outcome of the left lung. after treatment. E: Aortogram at 12 months old. F: Aortogram at 4 years old. Showing filling of the lower lobe pulmonary arteries from aortic collaterals.. Pediatric Pulmonology, 2013;49:49-59 BPD with Pulmonary Hypertension: Mortality Take Home Message! Preterm birth is a significant global heath problem The incidence of BPD is not decreasing There is no effective therapy for BPD Long-term pulmonary morbidities of BPD survivors are concerning It is imperative that lung function of these patients be closely monitored Pediatric Pulmonology, 2013;49:49-59 Thank You! 8