Respiratory Distress Syndrome(RDS) in neonates

A comprehensive ppt on pathophysiology and management of Respiratory Distress Syndrome..

1. RDS-Pathophysiology and Management R K Shwetabh Moderator- Dr Abhishek Paul

2. SPECIFIC LEARNING OBJECTIVES Introduction Pathophysiology Diagnosis Prevention Treatment

3. INTRODUCTION Leading cause of respiratory morbidity and mortality in preterm neonates Also known as Hyaline Membrane Disease Incidence-1% of total live births(USA)*.2.42% In India # Deficiency/inactivation of surfactant Respiratory distress at birth/within 6 HOL. Fanaroff and Martin-10 th Edition Neonatal Respiratory Distress Syndrome: Tackling A Worldwide Problem,Janet Dayer 2019 Incidence and etiology of respiratory distress-K Nagendra

4. TERMINOLOGY RDS- Diagnosis established pathologically/biochemical documentation of surfactant deficiency Most series- Clinical features+Radiological evidence. Respiratory insufficiency of prematurity-Need of oxygen+ventilation in absence of typical radiological findings. Respiratory Instability of prematurity-VLBW infants+some respiratory support. May have some contributing factors –inconsistent central respiratory drive. Fanaroff and Martin-10 th Edition

5. INCIDENCE Avery’s Disease of the Newborn-11 th Edition

6. INCIDENCE Gestation Percentage 22-24 week 95-98% <28 week 60-80% 28-32 week 25-50% 32-36 week 15-30% >37 week 1-3% Fanaroff and Martin-10 th Edition

7. INCIDENCE Avery’s Disease of the Newborn-11 th Edition

8. RISK FACTORS Risk Factor Possible Explaination Prematurity Lack of surfactant Lack of antenatal steroids Male sex Fetal androgen inhibit production of surfactant phospholipid Maternal Diabetes Fetal insulin inhibit production of surfactant phospholipid LSCS Normal Labour->Endogenous glucocorticoid->E- NaC channel->Fluid clearance Preterm labour(selected cases) Infection->Downregulate production of surfactant components African race(lower risk) Increased presence of protective genetic polymorphism

9. RISK FACTORS Risk factors Possible Explaination Mutation in surfactant related protein B,ABCA 3 RDS in Term neonates,Dysfuctional ; protein,limited production Perinatal asphyxia Hypoxia Acute lung injury->Decreased production/activity of surfactant Sepsis Inflamaation Decrease production/activity of surfactant Hypothermia Low surfactant release

10. PATHOPHYSIOLOGY

11. SURFACTANT Alveolar Type 2 pneumocytes Production starts by 20 week of gestation Appears in amniotic fluid by 28-32 week Mature level -35 week Decreases surface tension

12. COMPONENTS Avery’s Disease of the Newborn-11 th Edition

13. PRODUCTION Synthesized,packaged and secreted by Type 2 alveolar cells. Storage-Lamellar body(lysosomal derived memebrane bound organelle) Secretion-Stimuli like stretch Surfactant phospholipid transition through extracellular storage form/tubular myelin Released at air-lipid monolayer Can be recycled or engulfed and degraded by alveolar macrophage

14. PRODUCTION

15. PRODUCTION

16. COMPONENTS Predominant- DPCC(Dipalmitoyl phosphatidylcholine) Only surface active component-Can lower surface tension to zero Unsaturated phospholipid & cholesterol-Maintain monolayer to remain liquid at body temperature Glucocorticoid & agent increasing c AMP promote DPCC. Beta adrenergic agonist-Increase DPCC

17. PROTEINS SP-A,SP-B,SP-C and SP-D SP B & SP C-Hydrophobic SP A & SP D-Hydrophilic Hydrophobic- Surface active properties Hydrophilic-Host defence,immunomodulation , surfactant clearance and metabolism.

18. PROTEIN H ydrophobic proteins facilitate a) mobilization of surfactant phospholipid from tubular myelin to the surface monolayer b) promote spreading of phospholipids in the surfactant film c)assist in film stability at the end of expiration. SP-B is essential for the process of lamellar body formation Inherited deficiency of SP-B->normal surfactant phospholipid profile but poor surface tension

19. FACTORS AFFECTING SURFACTANT PRODUCTION Corticosteroid-Increased gene expression->Protein and lipid component Thyroxine- Prostaglandin Catecholamine Stimualatory effect on type 2 pneumocyte

20. SURFACE TENSION Tend to collapse the alveoli P = T/r More pressure required as radius decreases

21. SURFACE TENSION Surfactant deficiency collpases the alveoli Alveoli collapse during expiration More force required to open collapsed alveoli(like a balloon) Surfactant prevents the collapse

22. SURFACE TENSION

23. CLINICAL FEATURES Set of physiologic maneuvers Establish functional residual capacity (FRC) and optimize gas exchange R esult in characteristic signs/symptoms of RDS Onset within first 6 hours of life

24. CLINICAL FEATURES Clinical feature Explaination Tachypnea Minute volume=RR*Tidal volume Retraction Blocked airway->High negative intrathoracic pressure->Retraction Grunting Exhalation against closed glottis Flaring of alae nasi To reduce the resistance to air flow Hypoxia,Cyanosis Decreased oxygenation Lethargy Refusal to feed

25. CLINICAL FEATURES

26. PATHOGENESIS Textbook of Clinical Neonatology,IAP

27. DIAGNOSIS

28. ANTENATAL DIAGNOSIS Assess lung maturity Amniotic fluid assessment by amniocentesis A)Lamellar body count: Done in amniotic fluid to determine fetal lung maturity Lamellar body –packet of phospholipids >50000 lamellar bodies/microliter Indirectly by optical density of amniotic fluid Cloherty Manual of Neonatal Care-7 th Edition

29. Lecithin/sphingomyelin ratio Performed by thin layer chromatography Normal >2 Exceptions- IDM,Erythroblastosis fetalis Exceptios-IUGR,abruptio placenta,hydrops fetalis Contaminant –blood and meconium affect the value Cloherty Manual of Neonatal Care-7 th Edition

30. ANTENATAL DIAGNOSIS C) TDx -FLM II( Fetal Lung Maturity) Surfactant:albumin ratio Polarization light >55 D)Presence of phosphatidylglycerol Not affected by contamination Low sensitivity E)Foam stability index Cloherty Manual of Neonatal Care-7 th Edition

31. GASTRIC ASPIRATE SHAKE TEST Bedside test 0.5 ml gastric aspirate(within 1 hour of birth)+0.5 ml 95% ethyl alcohol(4 ml glass tube of 82*10.25 mm). Tube corked and shaken(15 second)->Left to stand for 15 minute->Stability of bubble Entire rim of bubble-Positive test Absence of bubble-negative Incomplete rim-Intermediate High specificity,70% sensitivity AIIMS NICU Protocol-2 nd Edition

32. Chest XRAY X ray finding Explaination Diffuse reticulogranular pattern Small airways open(black) surrounded by collapsed alveoli/fluid Air bronchogram Beyond 2 nd /3 rd gen due to collapse White out/ground glass Diffuse alveolar collapse Low lung volume Diaphragm at 8 th rib level(low FRC,Diffuse alveolar collapse)

33. Xray grading Grade 1- Symmetrical reticulogranular pattern Decrease in transparency of lung No certain difference to normal finding

34. XRAY GRADING Grade 2 Soft decrease in transparency with an aerobronchogram,which overlaps the heart

35. XRAY GRADING Grade 3 Greater decrease in transparency+blurry diaphragm and heart

36. XRAY GRADING Grade 4 White out lung Practically homogenic lung opacity

37. CHEST XRAY

38. LUNG USG Lung consolidation(Most important indicator)+ air bronchogram Thickend pleural line Absent A lines Pleural effusion-15-20% Lack of lung sliding (grade IV RDS) Pulmonary consolidation+pleural abnormality+diffuse white out lung/absent A line-Sensitivity 90%

39. LUNG USG LUNG CONSOLIDATION IN RDS Most important Most common site-Posterior part Generally bilateral but can be unilateral also Prominent air bronchograms+ D/d-Pneumonia and collapse/consolidation to airway obstruction

40. LUNG USG AIS & WHITE OUT LUNG Bilateral AIS/White out lung-Common feature AIS+ spared area –Useful in diagnosis PLEURAL LINE ABNORMALITIES Rough,fuzzy (irregular) pleural line/ pelural thickness>0.5 mm Also present in – Pneumonia,TTN and pulmonary hemorrhage High sensitivity Point of Care LUNG USG-Dr Pradeep Suryavanshi

41. LUNG USG PREDICTING NEED FOR SURFACTANT THERAPY Single USG accurately predicts-need for surfactant therapy-one/two More accurate in preterm babies White out lung may not change even after surfactant

42. LUNG USG:RDS

43. LUNG USG :RDS

44. LUNG USG FOR PREDICTING SURFACTANT REPLACEMENT 2023 Meta analysis 7 prospective studies,697 infants Oxygen requirement,clinical and radiological signs used Result-Pooled estimates of sensitivity, specificity, diagnostic odds ratio, negative predictive value, and positive predictive value for LUS predicting the first surfactant dose were 0.89 (0.82-0.95), 0.86 (0.78-0.95), 3.78 (3.05-4.50), 0.92 (0.87-0.97), 0.79 (0.65-0.92). Conclusion- Lung ultrasound is highly predictive of the need for early surfactant replacement. This evidence was derived from studies with homogeneous patient characteristics and low risk of bias. -

45. Lung usg & surfactant? 2015 JAMA Prospective study 130 neonates Lung USG done within 1 st hour of life Surfactant given according to 2013 EUROPEAN guidelines

46. Result:  The LUS score predicted the need for surfactant better in preterm babies with a GA less than 34 weeks (area under the curve = 0.93; 95% CI, 0.86-0.99;  P  < .001) than in term and late-preterm neonates with a GA of 34 weeks or greater (area under the curve = 0.71; 95% CI, 0.54-0.90;  P  = .02); the areas under the curve for these 2 GA subgroups are significantly different ( P  = .02). In babies with a GA less than 34 weeks, a LUS score cutoff of 4 predicted surfactant administration with 100% sensitivity and 61% specificity, yielding a posttest probability of 72%. Conclusion:  The LUS score is well correlated with oxygenation status in both term and preterm neonates, and it shows good reliability to predict surfactant administration in preterm babies with a GA less than 34 weeks under continuous positive airway pressure.

47. DIFFERENTIAL DIAGNOSIS Differential Diagnosis Specific differentiating feature Pneumonia(Group B streptococcus) Sepsis screen +,Fulminant rapid progressive course TTN Term,LSCS delivered.Resolve within hours Obstructed TAPVC No response to surfactant,normal volume lung,ECHO Genetic disorder of surfactant system Term babies.Family history.No response to surfactant, Disordered lung development Term/Near term.No response to surfactant Eg -alveolar capillary dysplasia with malalignemnt of pulmonary veins,congenital alveolar dysplasia,brain heart lung disease

48. ANTENATAL CORTICOSTEROIDS

49. H ISTORY 1969 , New Zealand Howie and Liggins observed that , Lambs who received glucocorticoids and delivered prematurely had lungs that remained partially expanded 1970s -->Liggins and Howie performed a landmark RCT, Betamethasone 282 mothers  decreased RDS and mortality

50. MECHANISM OF ACTION

51. DRUGS                BETAMETHASONE  1 ml of Betamethasone= 3mg Betamethasone sodium phosphate(fast and short acting,India ) + 3mg of Betamethasone acetate(long acting) Absorbability : Phosphate>acetate Half life: 72hours  One hour after injection : drug conc.  in cord blood is 20% of the total maternal serum levels.  DEXAMETHASONE  Available as Dexamethasone sodium phosphate  Rapid onset and shorter duration of action  Half life-60 hours Shorter dosing frequency  Less costly and More widely available

52. Dose & Route of DRUGS Betamethasone  two doses of 12 mg given intramuscularly 24 hours apart. OR   Dexamethasone  four doses of 6 mg given intramuscularly 12 hours apart. A nonsulfite -containing preparation should be used as the sulfite preservative commonly used in dexamethasone preparations may be directly neurotoxic in newborns American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 171: management of preterm labor . Obstet Gynecol 2016;128(4):e155–64.

53. WHY ONLY THESE TWO DRUGS Beta and Dexa are most widely studied Identical biologic activity, and readily cross the placenta. Devoid of mineralocorticoid activity. Relatively weak immunosuppressive actions. Longer duration of action in comparison with cortisol and methylprednisolone.( Betacode trial) Less extensively metabolized by the placental enzyme 11-beta hydroxysteroid dehydrogenase type 2 If beta/ dexa are unavailable, hydrocortisone 500 mg iv every 12 hours for 4 doses can be given as a last resort

54. DEXA IN INDIA,WHY? Preferred agent is Betamethasone acetate- Not easily available Dexamethasone is easily available and less expensive and stable at high temperature as compared to betamethasone phosphate  Therefore Dexamethasone is preferred Dose: 6mg each 12 hours apart for 48 hours as I.M. injection 

55. TRIALS AND STUDIES

56. The Antenatal Steroids for Term Caesarean Section (ASTECS) TRIAL

57. ASTECS TRIAL Objective:  To test whether steroids reduce respiratory distress in babies born by elective caesarean section at term. Design:  Multicentre pragmatic randomised trial. Setting:  10 maternity units. Participants:  998 consenting women randomised at decision to deliver by elective caesarean section; 503 randomised to treatment group. Interventions:  The treatment group received two intramuscular doses of 12 mg betamethasone in the 48 hours before delivery. The control group received treatment as usual. Outcome measures:  The primary outcome was admission to special care baby unit with respiratory distress. Secondary outcomes were severity of respiratory distress and level of care in response. Results:  Sex, birth weight, and gestation were not different between the two groups. Of the 35 babies admitted to special baby units with respiratory distress, 24 were in the control group and 11 in the intervention group (P = 0.02). The incidence of admission with respiratory distress was 0.051 in the control group and 0.024 in the treatment group (relative risk 0.46, 95% confidence interval 0.23 to 0.93). The incidence of transient tachypnoea of the newborn was 0.040 in the control group and 0.021 in the treatment group (0.54, 0.26 to 1.12). The incidence of respiratory distress syndrome was 0.011 in the control group and 0.002 in the treatment group (0.21, 0.03 to 1.32). Conclusions:  Antenatal betamethasone and delaying delivery until 39 weeks both reduce admissions to special care baby units with respiratory distress after elective caesarean section at term.

58. ALPS(Antenatal late preterm stEroid ) TRIAL 2015 AJOG Double blinded placebo controlled,RCT at 17 tertiary medical centre 2831 subjects(1402-placebo,1429-Betamethasone group) INCLUSION CRITERIA-Women with a singleton gestation, who were at high risk for preterm birth between 34 0/7 and 36 6/5 weeks’ gestation

59. ALPS TRIAL Administration of Betamethasone led to significant decrease in the primary outcome, the need for respiratory support within the first 72 hours of life (14.4% vs 11.6%; RR, 0.80; 95% CI, 0.66–0.97). Rates of severe respiratory morbidity, Bronchopulmonary dysplasia, Transient tachypnea of the newborn, Need for resuscitation at birth, Postnatal surfactant No increased risk of clinical chorioamniotis , endometritis, or cesarean delivery Neonates treated with betamethasone did have an increased risk of hypoglycemia (24% vs 14.9%; RR, 1.61; 95% CI, 1.38–1.88),

60. All randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour ), regardless of other co-morbidity, for inclusion in this review. 2017,30 studies (7774 women and 8158 infants).

61. 30 studies (7774 women and 8158 infants). Limitations: 1.Highly heterogeneous/highly selected population of women included 2.No trial is independently powered for neonatal mortality Poor generalisability to LMIC-India

62. Antenatal Corticosteroids for Improving Outcomes in preterm Newborns – ACTION ACTION 2 – 34-36 weeks ACTION 1- 26- <34 weeks WHO 2 concurrent trials Dexamethasone Sodium phosphate 5 countries: Bangladesh, Nigeria, Pakistan, Kenya, India Maternal & neonatal outcomes

63. J ACTION 1- 26- <34 weeks WHO Maternal & neonatal outcomes

64. ACTION II Trial 2022 4 hospitals of India 26/12/17-21/5/2020 Inclusion criteria- pregnant women at risk of iminnent preterm birth between 34 week-36 week Double blinded,RCT Course of 6mg im Dexa vs Placebo

65. ACTION II TRIAL 782 women, 391 to each arm. Result: Neonatal death occurred in 11 of 412 liveborn babies (2.7%) in the dexamethasone group and 12 of 425 liveborn babies (2.8%) in the placebo group (RR 0.95; 95% CI 0.42–2.12). Any baby death occurred in 16 of 417 infants (3.8%) in the dexamethasone group and 19 of 432 infants (4.4%) in the placebo group (RR 0.87; 95% CI 0.45–1.67). Severe neonatal respiratory distress was infrequent in both groups (0.8% vs 0.5%; RR 1.56; 95% CI 0.26–9.29). Possible maternal bacterial infection did not differ between groups (2.3% vs. 3.8%, RR 0.60; 95% CI 0.27–1.35). Fewer neonates in the dexamethasone group required resuscitation at birth (RR 0.38, CI 0.15–0.97). Other secondary outcomes were similar in the two arms. Conclusion: Antenatal dexamethasone did not result in a reduction in neonatal death, stillbirth or neonatal death, or severe neonatal respiratory distress in this trial.

66. ACTION III TRIAL A multi-country, multi- centre , three-arm, parallel group, double-blind, placebocontrolled , randomized trial of two doses of antenatal corticosteroids for women with a high probability of birth in the late preterm period in hospitals in low-resource countries to improve newborn outcomes AIM: To assess the benefits and possible harms of two regimens of antenatal corticosteroids, dexamethasone phosphate 4x6mg IM q12h and betamethasone phosphate(LOW DOSE) 4x2mg IM q12h, compared to placebo, when given to pregnant women in the late preterm period (gestation age of 34+0 to 36+5 weeks) when they are at risk of preterm birth. Countries:India,Bagladesh,Pakistan,Nigeria,Kenya

67. All identified published and unpublished RCT or quasi- randomised control trials comparing any 2 corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta) Brownfoot FC, 2013

68. Type- Multicentric,double blind RCT 1346 pregnant women from 14 maternity hospitals in Australia and New Zealand at risk of preterm birth before 34 weeks of gestation included 679-Dexa,667-Betamethasone Similar incidence of death or neurosensory disability in the dexamethasone (198 [33%] of 603 infants) and betamethasone groups (192 [32%] of 591 infants; adjusted relative risk [ adjRR ] 0·97, 95% CI 0·83 to 1·13; p=0·66). 18 (3%) of 679 women in the dexamethasone group and 28 of 667 (4%) women in the betamethasone group reported side-effects. Discomfort at the injection site, the most frequent side-effect, was less likely in the dexamethasone group than in the betamethasone group (six [1%] women vs 17 [3%] women; p=0·02). Interpretation The incidence of survival without neurosensory disability at age 2 years did not differ between 2 groups. Study period-Jan 28, 2009, and Feb 1, 2013

69. Dexamethasone vs Betamethasone Children exposed to dexamethasone were less likely to be hypertensive at age 2 years No significant difference in severe IVH/PVL/ROP Use of betamethasone requires few injections 2 inj , 24 hours apart Either antenatal corticosteroid can be given to women before preterm birth to improve infant and child health LANCET, 2019

70. ROUTE Intravenous administration  – The clinical efficacy has not been studied in human pregnancy. Intravenous administration results in rapid peaks and troughs in maternal and fetal steroid concentrations. Less sustained fetal exposure to corticosteroid stimulation ->not be as effective as intramuscular administration. Oral administration of  dexamethasone Absence of adequate data establishing the safety and efficacy of oral dexamethasone therapy for fetal maturation Increase the risk of sepsis rates Recommend to use only intramuscular therapy

71. TIMING Risk of preterm delivery within 7 days ACOG 2017 RCOG 23 0/7-23 6/7 week Considered(based on family decision) Y N 24 0/7-33 6/7 week Recommended Y Y 34 0/7-36 6/7 week Recommended(not received before) Y Y Repeat course Once <34 week,received not more tham1 week before,still at risk of preterm birth in 7 days Y N LSCS <39 week - Y(May be considered)

72. TIMING

73. SUMMARY Gestation Repeat Dose ACOG(2017) 24-36 week Consider 23 week If last dose >2 weeks and <34 weeks gestation RCOG(2022) 24-34 (+ 6) weeks Consider 23 weeks Consider <39 -LSCS Not recommended WHO 24-34 weeks If last dose >1 week and <34 weeks gestation Government of India(2014) 24-34 weeks Not recommended

74. TREATMENT(Based on European consensus guidelines on management OF RDS-2022 UPDATE)

75. Evolution of European consensus on RDS

76. PRENATAL CARE Mothers at high risk of preterm birth <28–30 weeks of gestation should be transferred to perinatal centres with experience in management of RDS (B1). In women with a singleton pregnancy and a short cervix in mid-pregnancy or previous preterm birth, vaginal progesterone treatment should be used to increase gestational age at delivery and reduce perinatal mortality and morbidity (A1). In women with symptoms of preterm labour , cervical length and accurate biomarker measurements should be considered to prevent unnecessary use of tocolytic drugs and/or antenatal steroids (B2). Clinicians should o ffe r a single course of prenatal corticosteroids to all women at high risk of preterm delivery, from when pregnancy is considered potentially viable up to 34 completed weeks of gestation, ideally at least 24 h before birth (A1).

77. PRENATAL CARE A single repeat course of steroids may be given in threatened preterm birth before 32 weeks of gestation if the first course was administered at least 1–2 weeks earlier (A2). MgSO 4 should be administered to women with imminent delivery before 32 weeks of gestation (A1)-Reduces incidence of CP at 2 years Clinicians should consider short-term use of tocolytic drugs in very preterm pregnancies to allow completion of a course of prenatal corticosteroids and/or in utero transfer to a perinatal centre (B1).

78. FETAL BIOMARKERS Fetal Fibronectin - 1) Extracellular matrix glycoprotein 2) Normally very low levels in cervicovaginal secretions 3) Levels > 50 ng/ml one of the best predictors of preterm labour PAMG 1- Placental Alpha macroglobulin 1

79. DELIVERY ROOM STABILISATION If clinical condition allows, defer clamping the umbilical cord for at least 60 s (A1). Only when DCC is not feasible, consider umbilical cord milking in infants with GA >28 weeks (B2) T-piece devices should be used rather than bag and mask (B1)   Spontaneously breathing preterm infants should be stabilised using CPAP (A1). If apnoeic or bradycardic, start giving ventilation breaths. Expert consensus is to start with CPAP pressure at least 6 cm H 2 O and peak inspiratory pressures 20–25 cm H 2 O (D2)

80. DELIVERY ROOM STABILISATION Oxygen for resuscitation should be controlled using a blender. Use an initial FiO 2 of 0.30 for babies <28 weeks of gestation and 0.21–0.30 for those 28–31 weeks, 0.21 for 32 weeks of gestation and above. FiO 2 adjustments up or down should be guided by pulse oximetry (B2). SpO 2 of 80% or more (and heart rate >100/min) should be achieved within 5 min (C2). Intubation should be reserved for babies not responding to positive pressure ventilation via face mask or nasal prongs (A1). Plastic bags or occlusive wrapping under radiant warmers and humidified gas should be used during stabilisation for babies <32 weeks of gestation to reduce the risk of hypothermia. Hyperthermia should also be avoided (A1).

81. SUPPORTIVE CARE Core temperature should be maintained between 36.5°C and 37.5°C at all times (C1).   Most babies should be started on intravenous fluids of 70–80 mL/kg/day in a humidified incubator, although some very immature babies may need more (C2). Fluids must be tailored individually according to serum sodium levels, urine output, and weight loss (D1). Parenteral nutrition should be started from birth. Amino acids 1.5–2 g/kg/d should be started from day 1 and quickly built up to 2.5–3.5 g/kg/d (B2). Lipids 1–2 g/kg/d should be started from day 1 and quickly built up to 4.0 g/kg/day as tolerated (C2).

82. SUPPORTIVE CARE En t eral feed i ng w it h mo t her’s m il k shou l d be s t ar t ed from t he first day i f t he baby i s hemodynamically stable (B2).   In infants with RDS, antibiotics should be used judiciously and stopped early when sepsis is ruled out (D1). Treatment of hypotension is recommended when there is evidence of poor tissue perfusion such as oliguria, acidosis, and poor capillary refill (C2). Treatment will depend on the cause.

83. SUPPORTIVE CARE When a decision is made to attempt pharmacologic closure of hemodynamically significant PDA, indomethacin, ibuprofen, or paracetamol can be used with a similar efficacy (A2). Paracetamol is preferred when there is thrombocytopaenia or concerns about renal function (B2). Thresholds for red blood cell transfusion in infants can be set at 12 g/dL (HCT 36%) for those with severe cardiorespiratory disease, 11 g/dL (HCT 30%) for those who are oxygen dependent, and 7 g/dL (HCT 25%) for stable infants beyond 2 weeks of age (A2). In preterm babies receiving oxygen, the saturation target should be between 90 and 94% (B2). Alarm limits should be set to 89% and 95% (D2)

84. SPECIFIC TREATMENT:CPAP CPAP(Continuous Positive Airway Pressure) -Positive pressure to the airway of spontaneously breathing neonate throughout respiratory cycle. How does it help? Prevent collapse of alveoli Recruitment of alveoli Stabilise airway Decrease work of breathing Maintain FRC

85. CPAP:Practical guidelines Heated and humified oxygen used Flow of 5-10 litres needed to prevent rebreathing and hypercarbia Indication Silverman Anderson score 3 or more CPAP prophylaxis Discussed later Modality Under water CPAP,Ventilator /Variable flow

86. CPAP Initiating CPAP a)Pressure b)FiO2 6 cm H20 0.4-0.5 If no improvement a)Pressure b)FiO2 Increase in steps of 1-2 cm.maxm 7-8 cm H20 Increase in steps of 0.05( maxm 0.6) Monitoring and goal Target saturation-90-95% Adequate chest expansion 8-9 ribs Clinical no/minimal respiratory distress Gradual reduction in Fio2 21% Failure of CPAP Worsening of Respiratory distress as indicated by worsening a) Silvermann Anderson Score and/or b)PaO2<50 or PaCO2>60 Despite PEEP-7-8 cm H20 and FiO2-0.5/0.6

87. WEANING FROM CPAP When to wean? No respiratory distress Normal Sp02/VBG How to wean? Reduce FiO2 in step of 5% to 40% then decrease pressure in steps of 1-2 cm to 3-4 cm H20 Weaning of support should initially focus on reduction of supplemental oxygen until O 2 requirements are at least <30%, preferably <25%. For the preterm infant >32 weeks of gestation, discontinuation of CPAP can be considered at CPAP 4 to 5 and <25% O 2. For infants born at <32 weeks of gestation, poor chest wall compliance alone can lead to progressive atelectasis,

88. CONTRAINDICATION Apnea Air leaks Congenital malformation of airway-Choanal atresia,cleft palate,TEF,CDH Severe cardiovascular instability Poor respiratory drive

89. Complications Overdistention : Administration of surfactant  Recruitment of atelectic regions Rapid changes in lung compliance lead to overdistention of airspaces. In turn, this can result in inadequate tidal volumes leading to hypercarbia ; tamponade of the alveolar capillary bed, with ventilation-perfusion mismatch leading to hypercarbia and hypoxemia; poor venous return sufficient to reduce cardiac output. Air leak Overdistention Most often due to large changes in airway pressures at the level of the respiratory bronchiole where airways lose their supporting structure  leading to disruption of the airway wall. This may occur in the context of an infant struggling to breathe or crying against CPAP.

90. COMPLICATIONS Under distention : Failure to establish FRC will result in persistent need for oxygen supplementation persistent atelect rauma of poorly supported airspaces. This is often due to difficulty with the patient-device interface and/or an open mouth that presents a path for release of distending pressure. Repositioning patients in a side-lying or prone position to prop the jaw closed, or use of soft chin straps, can be useful. Nasal septum trauma

91. COMPLICATIONS Decreased cardiac output Increased pulmonary blood flow resistance Gastric distension/CPAP belly syndrome

92. CPAP:IS IT EFFECTIVE? 2020 5 studies,322 neonates In preterm infants with respiratory distress, the application of CPAP is associated with reduced respiratory failure, use of mechanical ventilation and mortality and an increased rate of pneumothorax compared to spontaneous breathing with supplemental oxygen as necessary.

93. PROPHYLACTIC CPAP Seven trials 3123 babies were included in the meta-analysis .Four trials recruiting 765 babies compared CPAP with supportive care and three trials (2364 infants) compared CPAP with mechanical ventilation. CPAP resulted in a small but clinically significant reduction in the incidence of BPD at 36 weeks, (typical RR 0.89, 95% CI 0.79 to 0.99; typical RD -0.04, 95% CI -0.08 to 0.00; 3 studies, 772 infants, moderate-quality evidence); and death or BPD (typical RR 0.89, 95% CI 0.81 to 0.97; typical RD -0.05, 95% CI -0.09 to 0.01; 3 studies, 1042 infants, moderate-quality evidence). There was also a clinically important reduction in the need for mechanical ventilation (typical RR 0.50, 95% CI 0.42 to 0.59; typical RD -0.49, 95% CI -0.59 to -0.39; 2 studies, 760 infants, moderate-quality evidence); and the use of surfactant in the CPAP group (typical RR 0.54, 95% CI 0.40 to 0.73; typical RD -0.41, 95% CI -0.54 to -0.28; 3 studies, 1744 infants, moderate-quality evidence). Authors' conclusions:  There is insufficient evidence to evaluate prophylactic CPAP compared to oxygen therapy and other supportive care. However when compared to mechanical ventilation prophylactic nasal CPAP in very preterm infants reduces the need for mechanical ventilation and surfactant and also reduces the incidence of BPD and death or BPD.

94. CPAP VS DUOPAP 2021 BMC,RCT 148 neonates (with gestational age of 28 to 34 weeks) with respiratory distress syndrome 74 neonates were assigned to duo positive airway pressure (NDUOPAP) group and 74 neonates to nasal continuous positive airway pressure (NCPAP) group. The primary outcome in this study was failure of N-DUOPAP and NCPAP treatments within the first 72 h after birth and secondary outcomes included treatment complications. Results: there was not significant difference between DUOPAP (4.1 %) and NCPAP (8.1 %) in treatment failure at the first 72 h of birth (p = 0.494), but non-invasive ventilation time was less in the DUOPAP group (p = 0.004). There were not significant differences in the frequency of patent ductus arteriosus (PDA), pneumothorax, intraventricular hemorrhage (IVH) and bronchopulmonary dysplasia (BPD), apnea and mortality between the two groups. Need for repeated doses of surfactant (p = 0.042) in the NDUOPAP group was significantly lower than that of the NCPAP group. The duration of oxygen therapy in the NDUOPAP group was significantly lower than that of the NCPAP group (p = 0.034). Also, the duration of hospitalization in the NDUOPAP group was shorter than that of the NCPAP group (p = 0.002).

95. CPAP VS DUOPAP Conclusions: DUOPAP compared to NCPAP did not reduce the need for mechanical ventilation during the first 72 h of birth, but the duration of non-invasive ventilation and oxygen demand, the need for multiple doses of surfactant and length of stay in the DUOPAP group were less than those in the CPAP group

96. Bubble cpap vs ventilator cpap RCT KEM 124 neonates(57 each group) In all, 47 of 57 (82.5%) neonates from BCPAP group and 36 of 57 (63.2%) neonates from the VCPAP group completed CPAP successfully. Conclusion: BCPAP has higher success rate than VCPAP for managing preterm neonates with early onset respiratory distress, with comparable safety.

97. HFNC Flow 2-8 L/min HFNC broadly observed equivalent to CPAP for babies >28 weeks coming o f MV E ase of use and less nasal trauma L ess evidence for smaller babies. In a large-scale non-inferiority RCT, HFNC more often resulted in treatment failure compared to CPAP, but the need for MV was similar and inferiority related to this predefined primary outcome should not necessarily be equated with futility R ecent meta-analysis of HFNC trials recommends HFNC use as a firs t - li ne op ti on for resp i ra t ory support i n c e n t res c a pab l e of offer i ng CPAP and/or NIPPV as a backup.

98. HFNC VS CPAP Study Design:  Prospective observational cohort study Setting :  Tertiary care level III neonatal intensive care unit Participants :  88 preterm infants between 28 to 34 weeks of gestation with mild to moderate respiratory distress within 6 hours of birth. Intervention:  Eligible infants were treated either with Heated Humidified High Flow Nasal Cannula ( n =46) or Nasal Continuous Positive Airway Pressure ( n =42). Primary outcome :  Need for mechanical ventilation within 72 hrs of initiating support. Results:  Baseline demographic characteristics were comparable between the two groups. There was no difference in the requirement of mechanical ventilation between Heated Humidified High Flow Nasal Cannula (19.5%) and Nasal Continuous Positive Airway Pressure (26.2%) groups [RD – 0.74 (95% CI 0.34-1.62;  P  =0.46)]. Moderate or severe nasal trauma occurred less frequently with Heated Humidified High Flow Nasal Cannula (10.9%) in comparison to Nasal Continuous Positive Airway Pressure (40.5%) ( P = 0.004). Conclusion:  Heated Humidified High Flow Nasal Cannula was comparable to Nasal Continuous Positive Airway Pressure as a primary respiratory support for preterm infants with respiratory distress, with lesser incidence of nasal trauma.

99. Result: The use of HHHFNC was noninferior to nCPAP with regard to the primary outcome.Significant between-group differences in secondary outcomes were not found between the HHHFNC and nCPAP /BiPAP groups, including duration of respiratory support , need for surfactant, air leaks and bronchopulmonary dysplasia. Conclusion:HHHFNC showed efficacy and safety similar to those of nCPAP /BiPAP when applied as a primary approach to mild to moderate RDS in preterm infants older than 28 weeks’ GA. Unblinded,RCT 2015 29 week-36 week 6 days Mild to moderate RDS Criteria –for starting support-SA>5 or Fio2>30% for target saturation 88-93% Randomized to either nCPAP /BIPAP or HFNC 316 infants-158 each group

100.   564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. Results:  Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events. Conclusions:  When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP.

101. OTHER MODALITY Nasal HFO- Regional ventilation similar End expiratory lung volume may be higher 4 RCT-n HFO decreases intubation rate(lack of clarity of methodology) NAVA( Neurally Adjusted Ventialatory Assist) May be effective No conclusive evidence

102. recommendations CPAP or (s)NIPPV should be started from birth in all babies at risk of RDS, such as those <30 weeks of gestation who do not need intubation for stabilisation (A1).   NIV with early rescue surfactant by LISA technique is considered optimal management for babies with RDS (A1). The system delivering CPAP is of little importance; however, the interface should be short binasal prongs or mask with a starting pressure of about 6–8 cm H 2 O (A2). Ability to escalate to NIPPV will reduce the need for invasive MV in some infants (A1). BIPAP devices confer no advantage over CPAP alone (A2). However, synchronised NIPPV, if delivered through a ventilator, can reduce need for ventilation or need for re- ventilation following extubation and may reduce BPD (A2). HFNC can be used as an alternative to CPAP for some babies, with the advantage of less nasal trauma, provided centres have access to CPAP or NIPPV for those failing this mode (B2).

103. SURFACTANT THERAPY Term neonates-100 mg/kg Preterm neonates-4-5 mg/kg

104. SURFACTANT

105. SURFACTANT THERAPY Prophylactic- Within 15-30 min of birth Early rescue-With in 2 hours Late rescue-After 2 hours

106. SURFACTANT Methods LISA(Less Invasive Surfactant Therapy) MIST(Minimally invasive Surfactant therapy) Through LMA Nebulised surfactant delivery InSurE Side effects Pulmonary hemorrhage Hypoxia Bradycardia

107. SURFACTANT THERAPY If a preterm baby <30 weeks of gestation requires intubation for stabilisation , they should be given surfactant (A2). Babies with RDS needing treatment should be given an animal-derived surfactant preparation (A1). LISA is the preferred method of surfactant administration for spontaneously breathing babies on CPAP (A1). Laryngeal mask surfactant may be used for more mature infants >1.0 kg (B2).   An initial dose of 200 mg/kg of poractant alfa is better than 100 mg/kg of poractant alfa or 100 mg/kg beractant for rescue therapy (A1).

108. SURFACTANT THERAPY Rescue surfactant should be given early in the course of the disease (A1). Suggested protocol would be to treat worsening babies with RDS when FiO 2 > 0.30 on CPAP pressure ≥6 cm H 2 O or if lung ultrasound suggests surfactant need (B2). A second and occasionally a third dose of surfactant should be given if there is ongoing evidence of RDS such as persistent high oxygen requirement and other problems have been excluded (A1).

109. MECHANICAL VENTILATION 50% of babies on NIV<28 week require MV Indication Fatigue V/Q mismatch->Increased FiO2 and CPAP inadequate to maintain gas exchange Goal To provide lowest level of ventilatory support to provide adequate oxygenation and ventilation Acceptable ABG at optimal lung volume Avoiding over distension and atelectasia

110. MECHANICAL VENTILATION Volume Targeted Ventilation Advantage-Reduce hypocarbia PIP- 20 cm H20(European guidelines-25-30 cm H20) Tidal volume- 5ml/kg Rate-30-40/min PEEP-Usually 5-6 cm H20.Adjusted by finding a point where FiO2 is at its lowest with hemodynamically stability and acceptable ABG.

111. MECHANICAL VENTILATION WEANING- Fio2 and PIP/Vt weaned initially Extubation successful a)Rate 25-30/ mim b)PIP-14-16 cm H20 To deliver desired Vt SIMV is also safe

112. HFO V ery small gas volume delivery at fast rates to an optimally inflated lung, using a continuous distending pressure (CDP) Paucity of data from contemporary trials, comparing HFOV to VTV Determining the optimal distending pressure clinically involves finding the pressure at which oxygenation deteriorates during a stepwise reduction from full lung inflation and aiming for 1–2 cm H 2 O above . Volume targeting in HFOV reduces CO 2 variability and allows e!ect i ve ven til a ti on w it h very sma l l ti dal vo l umes, wh i ch may be l ung pro t ect i ve.

113. HF0 SETTINGS Parameters Settings MAP Initial MAP-2-5 cm higher than conventional ventilator Titrated-According to Fio2 and adequate lung expansion Frequency 10-15 Hz(smaller babies),Lower frequency-Big babies Inspiratory time 0.33 Amplitude To provide adequate chest espansion (clinically and ABG parameters) Weaning Fio2 weaned first MAP (Once FiO2 < 0.6) Ampliude adjusted by chest vibration and ABG Frequency-Last

114. RECOMMENDATION MV should be used in babies with RDS when other methods of respiratory support have failed (A1). Duration of MV should be minimised (B2). Lung-protective modes such as VTV or high-frequency oscillation ventilation should be the first choice for babies with RDS who require MV (A1). When weaning from MV, it is reasonable to tolerate a modest degree of hypercarbia, provided the pH remains above 7.22 (B2). Avoid pCO 2 < 4.7 kPa (35 mm Hg) when on MV to reduce brain injury (C1).

115. OTHER DRUGS INO in preterm babies should be limited to a therapeutic trial for those in whom there is documented pulmonary hypertension with severe respiratory distress and stopped if there is no response (D2). Ca ff e i ne (20 mg / kg l oad i ng, 5– 1 mg / kg ma i n t enanc e ) shou l d be used t o faci lit a t e wean i ng from MV (A1). Ear l y caffe i ne c a n be c o ns i dered for bab i es at h i gh r i sk of need i ng MV such as preterm babies on NIV (C1). Opioids should be used selectively when indicated by clinical judgement and evaluation of pain indicators (D1). The routine use of morphine or midazolam infusions in ventilated preterm infants is not recommended (A1).

116. PERMISSIVE HYPERCAPNIA Hypocapnia in preterm infants being associated with increased risk of periventricular leukomalacia. S evere hypercapnia linked with IVH, NEC, BPD, and ROP . Permissive hypercapnia->reduced tidal volumes and facilitate extubation . No definitive evidence Tolerating modest degrees of hypercarbia is reasonable, provided the pH is acceptable.

117. Postnatal steroids Mechanical ventilation related lung injury DART regimen Inhaled budesonide-Higher mortality A short tapering course of low-dose dexamethasone should be considered to facilitate extubation in babies who remain on MV after 1–2 weeks (A2).

118. INEFFECTIVE/POTENTIALLY HARMFUL THERAPIES Sustained lung inflation Diuretics Restricted fluids Digoxin

119. COMPLICATIONS Pneumothorax Pneumo-mediastinum Subcutaneous emphysema IVH PDA CLD Nosocomial sepsis

120. OUTCOME Presurfactant era, RDS resolved at 2 to 4 days of age, preceded by spontaneous diuresis. With widespread use of antenatal glucocorticoids, early use of nCPAP , availability of exogenous surfactant, Time course of RDS difficult to define. Frequent association of preterm birth with chorioamnionitis or latent inflammation affect time to resolution. RDS in infants born at ≥32 weeks' gestational age and without other complications  resolve fully with no long-term pulmonary sequelae. Infants <32 weeks‘ gestational age are at risk for BPD; risk increases with decreasing gestational age

121. TAKE HOME MESSAGE RDS is most common cause of morbidity and mortality in preterm population A course of steroid is simple,low cost and effective intervention to reduce RDS. CPAP is respiratory support modality of choice. Surfactant therapy is standard of care. For optimizing outcomes anticipation of problems,asepsis,meticulous supportive care,nutrition and team work are keys.

122. REFERENCES Avery’s Disease of the Newborn-10 th Edition Fanaroff & Martin-10 th Edition AIIMS NICU Protocol-2 nd Edition Cloherty & Stark;s Manual of Neonatal Care-10 th Edition European consensus guidelines on management OF RDS-2022 UPDATE Point of care Lung USG-Dr Pradeep Suryavanshi

123. THANK YOU

124. OVERVIEW

125. Thank you

126. SUMMARY

127. ACS in low resource settings Cluster- randomized trial of a multifaceted intervention to increase the use of antenatal corticosteroids at all levels of care (community, health centre , district hospitals) in LMIC ACT -ANTENATAL CORTICOSTEROIDS TRIAL 2015 LANCET 6 countries: Argentina, Zambia, Guatemala, Belgaum (India), Nagpur (India ), Pakistan, and Kenya Primary outcome- • 28-day neonatal mortality among infants less than the 5th percentile for BW • Less-than-5th-percentile BW group (referred to as less-than-5 th percentile infants) was a proxy for preterm birth Others outcomes: stillbirth, suspected maternal infections Excluded from the Cochrane Review update : • Not a test of the safety and efficacy of steroids. • it was an evaluation of a strategy to scale-up steroid treatment

128. ACT Conclusions Increased perinatal mortality among all births ACT -ANTENATAL CORTICOSTEROIDS TRIAL 2015 LANCET Increased risk of suspected maternal infection in women with births less than 5 th percentile & overall For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred Secondary analysis

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