Respiratory distress syndrome

This slideshow focuses on identification and management of respiratory distress syndrome in preterm babies,especially focussing on surfactant therapy.

1. Respiratory Distress Syndrome By: Dr. Nivedita Mishra Pediatric Resident (1 st year) Tribhuvan University T eaching H ospital

2. OBJECTIVES To define and assess respiratory distress. To discuss the incidence and risk factors associated with the common conditions causing respiratory distress. To recognise the important conditions leading to respiratory distress by clinical features, pathophysiology & radiological features. To identify the complications related to these diseases. To discuss the management with emphasis on role of surfactant therapy.

3. Definition of Respiratory Distress Presence of any 2 of the following features:* R.R > 60/min Subcostal / intercostal Recessions Expiratory G runt /Groaning Signs should be assessed in context of Spo2, colour, activity of the baby. * NNPD Report 2002-2003.NNPD Network,ICMR;p67

4. Incidence 5.8% of live born infants have respiratory morbidities. NNPD Data 2002-03 Respiratory D istress occurs in : 2.2% of all newborns. Rubaltelli FF,Dani C,Reali MF.et al.Acute neonatal Respiratory Distress in Italy: a one year prospective study,Acta Paediatr;1998;87:1261-68 60% of infants below 1000g (ELBW): RDS(50.8%) > TTN(4.3%) > Pneumonia/Sepsis(1.9%) In higher birth weight preterm & term babies TTN is more common.(68%) Contributes 30-40% of admissions in NICU. Mathai SS,Raju U,Kanitkar M,et al.Management of Respiratory D istress in the Newborn.MJAFI 2007;63:269-72r

5. Causes of Respiratory Distress (Data from Rubaltelli FF,Dani C,Reali MF.et al.Acute neonatal Respiratory Distress in Italy: a one year prospective study,Acta Paediatr;1998;87:1261-68) Incidence Respiratory Distress Syndrome 46% TTN 37% Pneumonia/Sepsis 5% Meconium Aspiration Syndrome 2% Congenital Cardiac Malformation 2% Chromosomal Disorders /Multiple Congenital Anomalies 1.4% Spontaneous Pneumothorax 1.2% Perinatal Asphyxia 1.1% Pulmonary Haemorrhage 1% Persistent Pulmonary Hypertension 0.8% Diaphragmatic Hernia 0.8% Apnoea of Prematurity 0.6% Pulmonary Hypoplasia 0.3% Pulmonary Dysplasia 0.2% Hydrothorax 0.2% Post-surgical Diaphragmatic Palsy 0.2%

6. Assessment of Respiratory Distress Initial assessment: to find out life threatening conditions requiring immediate management Inadequate/Obstructed Airway: Gasping , Choking,Stridor . Circulatory collapse: Bradycardia,Hypotension,poor perfusion. Intervention: Bag-Mask ventilation/intubation

7. Silverman score FEATURE 1 2 UPPER CHEST MOVEMENT Synchronus with abdomen Inspiratory lag See-saw respiration LOWER CHEST MOVEMENT no minimal marked XIPHOID RETRACTIONS no minimal marked NASAL FLARING no minimal marked GRUNTING no Audible with steth Audible without steth Downe’s score FEATURE 1 2 CYANOSIS No In room air/ 40% Fio2 In 40%Fio2 RETRACTIONS No Mild Mod- Severe GRUNTING No Audible with steth Audible without steth AIR ENTRY Normal Decr . Barely audible RESPIRATORY RATE <60 60-80 >80 / apnoea Score > 4 = clinical respiratory distress Score > 7 = impending respiratory faliure

8. Assessment of Respiratory Distress L ook for Clues to E tiology : Nasal stuffiness,drooling Presence of Meconium staining of nails, umbilical stump. Birth trauma Dysmorphic features – Pierre Robin syndrome, Beckwith- Wiedmann syndrome, Moebius syndrome. Anomalies- Hydrocephalus, Arnold- Chiari malformation, Choanal atresia , Neck masses, Cleft palate, Chest wall deformities, Scaphoid Abdomen.

9. Assessment of Respiratory Distress History ANTENATAL INTRANATAL POSTNATAL Diabetes mellitus, Epilepsy PPROM/PROM Gestational age Fever,UTI Intrapartum fever / Chorioamnionitis Shake test POLY/OLIGOHYDRAMNIOS Sedative use , Onset/course of respiratory distress Antenatal steroids status Meconium stained liquor Radiological features Rh Isoimmunisation Abnormal fetal monitoring Inborn errors of metabolism Narcotic use Instrumental delivery /Birth trauma Teratogenic drug use Need for Bag-Mask ventilation

10. Respiratory Distress Syndrome A D isease typical of preterm infants that arises d/t insufficient pulmonary surfactant in the alveoli. Results in high Surface Tension and Atelectasis . Alveolar type 2 cells do not develop until early in the third trimester. Their number & capacity to produce surfactant increases throughout third trimester.

11. Incidence of RDS Incidence is inversely proportional to gestational age & birth weight. Worldwide data: Indian data: <28 WOG – 60 to 80% 58% in <30 wog 32-36WOG- 15 TO 30% 32% b/w 30-32 wog 10% b/w 33-34 wog 37 WOG- Term – 5% 500-750 gm-54% (NICHD Neonatal Research Network,Fanaroff et.al) 751-1000gm- 36% 1251-1500gm-22% 6.8 to 14.1% of preterm live births in India 1.2% of all live births (NATIONAL NEONATAL PERINATAL DATA 2013 report)

12. Development of Lungs 5 STAGES : Embryonic (3.5 to 7 wog) Pseudoglandular (5-17 wog) Canalicular (16-26 wog)-epithelial differentiation,accumulation of glycogen for lipid synthesis. Saccular (24-38 wog)-thinning of pulmonary mesenchyme,vascularisation of peripheral airspaces. Alveolar (32 wog – 2yrs)- type 2 pneumocytes formed by differentiation of epithelial cells with lamellar body inclusions (storage granule for surfactant) Microvascular maturation (birth-3yrs)

13. 4 TH WOG: ventral endodermal pouch of foregut Pri lung buds Pri . Bronchi Lt main bronchus-2 sec. Bronchi Rt main bronchus-3 sec. Bronchi Each sec.bronchus grows into a lobe

14. Lung maturation Lung maturity determines the newborn’s preparedness for air breathing. By 24 WOG sufficient structural lung development is present to allow for gas exchange across lung epithelial and endothelial cells but insufficient no.of type 2 pneumocytes to generate surfactant. Surfactant production depends on: Normal perfusion,Temp,Ph . Mature levels of pulmonary surfactant after 35 wks. ( normal L/S Ratio = 2:1). low risk of RDS if L/S ratio>2 Bedside test to detect lung maturation- Shake test on Gastric aspirate (- ve in RDS)

15. Lung maturation Production of lecithin is developmentally regulated.also present in cell membranes necessitating correction for presence of contaminants like blood,meconium etc. TDx -FLM II- corrects presence of albumin in amniotic fluid sample.low risk of RDS if >55mg lecithin/gm of Albumin. Invasive testing( Amniocentesis )- CDH,CHD.For Precise timing of delivery of a near term infant. 1.Presence of >50,000 lamellar bodies / microliter of amniotic fluid is correlated with lung maturity. 2. Optical density of amniotic fluid (proxy for presence of lamellar bodies)

16. Risk factors for RDS Prematurity - Developmental immaturity of Type II PNEUMOCYTES Male fetus - more androgens,reduces surf.phospholipids . White race Maternal diabetes - more fetal insulin,reduces surf.proteins . Lack of labour -no endogenous maternal glucocorticoids,excess fetal lung fluid d/t delivery without labour. No antenatal steroid administration. Perinatal asphyxia,Hypothermia Pulmonary infection- inflammatory cytokines. Mutation in surfactant protein B, ABCA3 transporter - asso.with ILD. Benefit by lung transplant.

17. Pathophysiology of RDS RDS manifests histologically as HYALINE MEMBRANE DISEASE. -During breathing( spont /assisted),shear stresses in the alveoli cause damage to lung architecture : 1.Repetitive reopening of collapsed alveoli 2.Overdistension of open alveoli. -Leakage of proteinaceous debris into airways (HYALINE MEMBRANES) -Debris impairs function of surfactant. -Insufficient/Dysfunctional Surfactant -> generalised atelectasis -> V/P Mismatch-> hypoxia -> acidosis -> decr . surfactant production -Respiratory Faliure .

18. 1. PINK MEMBRANE LINING ALVEOLI AND ALVEOLAR DUCTS. 2. PULMONARY ARTERIOLES WITH THICK MUSCULAR COAT,SMALL LUMEN. 3. DISTENDED LYMPHATICS

19. Course of RDS REPAIR PHASE : Begins during 2 nd day after birth (appearance of macrophages,PMNs -> debris is phagocytosed -> epithelium regenerated) DIURETIC PHASE : edema fluid in the interstitium mobilised to lymphatics -> High urine output. In uncomplicated RDS improvement by end of 1 st week after birth. In infants < 1250 gm,larger newborns need high O2 conc. & PPV- Inflammation,inappropriate repair -> Emphysema, Fibrosis Tends to get worse over first 1-3 days after birth before improving.Pneumocytes regenerate.O2 requirement reduces. Death is rare on 1 st day of illness.occurs by 2 nd to 7 th day d/t alveolar air leaks,pul.haemorrhage,IVH .

20. Clinical signs of RDS Tachypnoea - to increase Co2-O2 exchange Grunting – partial closure of glottis during expiration to maintain end expiratory pressure. Retractions - to generate high - ve intrathoracic pressure at inspiration. Cyanosis - intrapulmonary shunting of blood past atelectatic lung tissues. Murmur - poorly inflated lungs have widespread collapse of pulmonary vessels PAH Lt to Rt shunting across PDA. Pallor - From acidosis d/t poor elimination of Co2 Lethargy - D/t incr. WOB Poor feeding Apnoea

21. Investigations Lab features: ABG- initially only hypoxemia,later hypercarbia and then acidosis manifest. GRBS CBC Blood c/s Gastric aspirate for shake test. Radiographic features: Reticulogranular (Ground glass) pattern Air bronchograms -crisp black lines Homogenously & diffusely dense lung fields. Low lung vol.- diaphragm at 8 th rib level or higher. d/d : TTN= Normal / High lung vol.+ prominent interstitial fluid pattern.( coarse white lines radiating from the hilum )

22. Prevention of RDS Antenatal steroids: causes thinning of alveolar mesenchyme for proper gas exchange. ANC DOSES given from 24 to 34 wog : Betamethasone @ 12mg I.M/24hrly for 2 doses. Or, Dexamethasone @ 6mg I.M/12hrly for 4 doses. Benefit max. If given 24 hrs before delivery. Evidenced by significant reduction in NND by 31%,RDS by 34%,IVH by 46% ( dexa ),NEC by 54%. (ROBERTS & DALZIEL Meta analysis in 2006 of 21 published trials ) Prevention of asphyxia: delivery by C-section of at risk babies CPAP: to prevent end expiratory alveolar collapse,reduce WOB,better match ventilation to perfusion. COIN TRIAL compared the outcomes of Early nasal CPAP vs prophylactic intubation in 25-28 wog newborns. 46% of CPAP group eventually required intubation during first 5 days with pneumothorax in 9% compared to only 3% in intubated group. Immediate extubation to CPAP after surfactant dosing can be done to avoid complications from ETT e.g. Excessive tidal vol,airway inflammation. Exogenous surfactant.

23. Role of Surfactants Water beads up on a clean surface. Surface tension opposes spreading. Lipids form a monolayer at the air water interface. Surface tension decreases as monolayer is compressed.

24. Laplace’s Law :P = 2T/r P : pressure required to inflate the bubble T: surface tension R: radius of bubble More pressure required for overcoming surface tension to keep open a bubble as its radius decreases. With surfactant,surface tension falls to zero as its radius decreases so negligible pressure required.

25. Surfactant Composition

26. Endogenous Surfactant Constitutents : DPPC/Lecithin: In gel form at body temp.Unsaturated Fatty Acids & cholesterol make it fluid. ( Minigarro et al,2008) Phosphatidylcholine : Marker of lung maturation.Assembled in Lamellar Bodies inside type 2 Pneumocytes in bilayered membrane. SP-B (hydrophobic), SP-C: Helps transition from bilayer to monolayer.Absence causes “Fatal Neonatal Respiratory Faliure .” SP-A , SP-D ( hydrophillic ): role in immune defense.SP -A is involved in reuptake and reuse of secreted surfactant.

27. Exogenous Surfactant : Historical summary YEAR CONTRIBUTOR DISCOVERY/ EVENT 1929 Von Neergaard Surface tension contributes to lung recoil. 1947 Greunwald Lungs of stillborn infants have high surface tension. 1955 Prattle Hypothesised that absence of surfactant material contributes to RDS. 1957 Clement Demonstrated surfactant dysfunction in experimental animals. 1959 Avery & Mead Demonstrated that RDS in human infants is due to surfactant deficiency. 1963 US President J.F.Kennedy’s son(34 wog) dies of RDS. Increased research interest and funding for RDS. 1972 Enhorning & Robertson Used natural surfactants to delay progression of RDS in preterm Rabbits. 1980 Fujiwara et.al 1 st successful use of surfactant in human infants. 1990 Exogenous surfactant widely used throughout the developed world.

28. a.Non protein synthetic surfactants: 1.Adsurf = pumactant =DPPC,PG 2. EXOSURF= Colfoseril palmitate = DPPC b.Protein containing Animal Surfactants: 1.Curosurf (porcine lung tissue)= poractant alfa 2.Alveofact = SF-RI 1 3.BLES (bovine lipid extract Surfactant) 4.Infasurf (calf lung extract) = calactant 5.Survanta (bovine lung tissue)= Beractant 6.Surfacten c.Peptide containing synthetic surfactants: 1.Venticute= rSP -C surfactant= DPPC,POPG,PA,rSP -C 2.Surfaxin= Lucinactant =DPPC,POPG,PA,KL4 Natural surfactants are faster acting but Expensive, immunologic & infectious complications, inconsistent content.

29. Surfactant Selection Compared to standard therapy without surfactant, a Meta-analysis of 13 RCTs suggested that Animal derived exogenous surfactant reduces the risk of pneumothorax by 58%, pulmonary interstitial pneumonia by 55%, mortality by 32% & combined outcome of BPD or death by 17% ( Seger & Soll,2009) Meta-analysis of 11 RCTs showed that Natural surfactants were faster acting than artificial surfactants with lower incidence of pneumothorax and mortality .( Soll & Blanco,2001) Clinical trials comparing the available natural surfactants have been inconclusive.

30. Surfactant Selection Curosurf vs Survanta - Curosurf is less costly because of fewer doses,quicker oxygen weaning (d/t large amount of phospholipid in each dose) but no clinical difference in outcome. ( Ramanathan et al.,2004) Lucinactant superior to older synthetic surfactants ( Sinha et al,2005) ,but its superiority to animal surfactants has not been conclusively proven ( Moya et al,2005) Compared to 1 st gen synthetic surfactants,current studies strongly support the use of natural surfactants because of reduced air leak & more rapid response to treatment.( Cochrane Review Article 2007)

31. Timing of Surfactant administration When to give 1 st dose of surfactant ? Which populations to consider? Prophylactically , within 15 min after birth. (CUROSURF @ 200mg/kg) <26 WOG 26-30 WOG if: a. no Antenatal steroids given to mother. b. Baby needs intubation anyway. Early rescue , in 1 st 60 min after birth. <30 WOG at first signs of RDS. Treatment of established RDS, within 12hrs after birth. All babies with RDS, regardless of gestational age if they need ventilator and atleast 30-40% FiO2. Repeat doses: if infant requires ventilatory support and has Fio2 req.>30%. Min 6 hrs duration is needed b/W 2 doses. Surfactant not usually contd. Beyond 3 DOL.

32. Method of Surfactant Dosing Warm surfactant prior to administration. ( 8 min if held b/w palms, 20 min at room temp) Vial should not be heated or shaken. Strict aspsis to be observed during procedure. Can be given via ETT OR LMA. Surfactant distribution is better when administered as a bolus ( 4 aliquots ) rather than by infusing slowly over several minutes (Fernandez et al,1998) Should be given as quickly as tolerated with least disruptive infant positioning. Auscultate for b/l equal air entry,monitor spo2. Ventilate carefully till saturation and H.R stabilises before administering next aliquot. Avoid suctioning for atleast 2hrs after administration. InSurE = INTUBATE-SURFACTANT-EXTUBATE to CPAP. Repeat dosing : if Fio2 >/=0.35, MAP >7 cm H2O to maintain PaO2 of 50-70 mm Hg, PaCo2 at 50 mm Hg. Recommended interval b/w doses is 6 hrs.

33. Care after Dosing Immediately lower Fio2 while monitoring Spo2. When Tidal volume (evidenced by chest wall rise/ventilator reading) increases, lower inspiratory pressure to avoid air leak syndrome, Pul.haemorrhage . Poor response if lung hypoplasia , pneumonia, pulmonary oedema (avoid excessive i.v.f administration), cong.heart ds (low b.p ),poor distribution of surfactant,inadequate dose. Rapid improvement in lung compliance after dosing-> excessive pul.blood flow-> Lt to Rt shunting via PDA-> Pul.haemorrage .

34. Complications of RDS ACUTE : Air leak ETT/ nasal cannulation complications Infections Intracranial haemorrhage PDA LONG TERM: 1. BPD,PPHN 2. ROP 3. PVL,IVH 4.AKI (d/t acidosis)

35. Differential diagnosis of RDS Extremely elevated PaCo2 within minutes of birth. = Pulmonary hypoplasia / Tension pneumothorax / Cong.Diaphragmatic Hernia. Tachypnoeic , Cyanotic baby with low PaCo2 = TTN/ Cong. cyanotic Heart dis.(TAPVC) Pneumonia/ sepsis on blood c/s Hypoglycemia (GRBS < 40) Symptomatic Polycythemia (PCV > 65)

36. Transient tachypnoea of Newborn Results from delayed clearance of fetal lung fluid.(transient pulmonary oedema) Benign,Self limited, RR=60-120/min , persisting for 12-72 hrs Late preterm/term. INCIDENCE: 0.3- 0.6% of term & 1% of preterm deliveries.

37. PATHOPHYSIOLOGY: Switch from secretory mode to absorptive mode facilitated by changes in the feto -maternal mileu d/t surge in glucocorticoids and catecholamines near the end of pregnancy and during spontaneous labour. Amiloride sensitive Na+ channels on apical membrane of alveolar epithelium( ENaC activated by Na+/ K+ATPase ) ALVEOLI- TYPE 2 PNEUMOCYTES- INTERSTITIUM-LYMPHATIC Accumulation of fluid in the interstitium ->airway compression->air trapping,V /Q mismatch,reduced FRC.

38. CXR: Perihilar markings( sunburst pattern ), Fluid in fissure , Hyperinflation(palpable liver & spleen), Cardiomegaly (distinguishes it from TAPVR) .

39. Risk factors: Prematurity, 2. C-sec delivery without preceeding labour, 3. Male baby, 4. F/H/O Asthma esp.in mother(altered sensitivity of beta-adrenergic Rs to catecholamines ), 5. Macrosomia , 6. Maternal diabetes, 7. Multiple gestations, 8. Excessive maternal sedation, 9. Vol.of Maternal i.v fluids

40. NO RELIABLE DIAGNOSTIC TESTS FOR TTN. Rapid resolution distinguishes it from Pneumonia, MAS. USG helps to differentiate TTN from RDS. A controlled trial of furosemide & epinephrine administration to accelerate clearance of lung fluid showed no benefit. ( Wisewell et.al 1985) Newborns with TTN are at mildly increased risk for later development of Asthma ( Birnkrant et.al,1996;Liem et al,2007;Schaubel et al,2006) ANC have a PROTECTIVE EFFECT. Supportive t/t: Delay oral feeding till tachypnoea settles. Requires FiO2 <0.40.

41. Pneumonia/Sepsis INCIDENCE: 5% overall Birth wt. 1500-2500gm =0.28%, <1000gm = 1.9% Causative organisms: E.coli (44%), Grp.B Streptococcus (11%), CONS (11%), H.Influenzae , S.viridans (8%), Listeria,Citrobacter,Candida (2%) Presents before 72hol as EONNS as Newborns are unable to localise Pul . Infections.

42. Pneumonia/Sepsis Risk factors: Maternal fever, Chorioamnionitis , Uterine tenderness, PROM(>18hrs), Multiple/single unclean vaginal exams, Prematurity. Marked by Leucopenia , incr.CRP T/t: empirically Ampicillin + Gentamycin for 48 hrs while awaiting blood c/s reports. If c/s – ve,mother has been on Abx give for 5-7 days

43. Meconium Aspiration Syndrome Incidence: 10-15% overall.Low incidence in preterms.High incidence in post mature & SGA babies. >37 wog = 0.4% to 1.8 % ( Dargaville & Copnell,2006;Singh et al,2009), >39wog =50% ( Gouyon et al,2008) Approx 3-4% of infants born through MSAF develop MAS ( meconium found below vocal cords) 30-50% of MAS cases require mech.ventilation /CPAP. Mortality b/w 4-12% (Gordon & Avery,2009)

44. Meconium Aspiration Syndrome MSAF results from a post-term fetus with rising motilin levels & normal G.I function,vagal stimulation d/t cord or head compression or in-utero fetal stress,Decr. Anal sphincter tone. FETAL ACIDEMIA- > Incr. PERISTALSIS-> passage of meconium-> fetal gasping-> meconium inhaled->chemical pneumonitis, ball- valve obstruction-> Hypoxia + Air Trapping+Air Leak. Meconium inactivates surfactants. Leads to PPHN. Thin meconium is more notorius.

45. CXR: diffuse fluffy infiltrates

46. Clinical signs of MAS vary with timing , volume , consistency of aspirated meconium . Tachypnoea,cyanosis,WOB Metabolic acidosis Hypotension, Postductal desaturation ( Rt -Lt shunt via PDA) indicating PPHN Pneumothorax Severity grading of MAS : Mild - <40% O2 for <48 hrs Moderate - >40% O2 for >48 hrs Severe – ventilation for >48 hrs

47. C-sec for Utero -placental insufficiency d/t: Chr. respiratory ds ./ cvd Heavy smokers Pre eclampsia /HTN IUGR Big baby Amnioinfusion -relieves cord compression in TMSL in labour SUCTIONING: 80-100 mmHg No2 improves oxygenation Mech.ventilation : High freq.device -> high risk of hyperinflation-> PPHTN Slower rate better gas exchange. ECMO if respiratory faliure : 94-97% survival range ANTIBIOTICS: Intrauterine infection may be the Cause of initial passage of meconium . Meconium may itself promote the growth of bacteria in the lungs. ANTIOXIDANTS: N-acetyl cysteine Surfactants Corticosteroids

48. References Avery’s Diseases of the Newborn. 9 TH EDN. Chap.42,43,44,46. Cloherty and Stark’ Manual of Neonatal care. 8 TH EDN. Chap 32,33,35. AIIMS Protocols in Neonatology. Respiratory Distress Syndrome – Dilemmas in management; Journal of neonatology;P.N Rao.2007;21(2):92-8 Surfactant replacement therapy. Journal of neonatology;S.Kalra,D.Singh 23(2):163-8 Respiratory Distress in Newborn/pedsinreview.aappublications.org

49. THANK YOU.