RDS

Respiratory distress syndrome : 

Respiratory distress syndrome Mikko Hallman Childrens’ Hospital and Biocenter Oulu, University of Oulu

Neonatal respiratory distress : 

Neonatal respiratory distress Etiology and pathogenesis Risk factors and prevention Treatment practices and outcome New horizons

Definition of RDS in the newborn : 

Definition of RDS in the newborn Severe respiratory distress from birth lasting for >48 hours or rapid response to surfactant Typical chest X-ray findings Typical course or autopsy findings

Surfactant and the Risk of RDS : 

Surfactant and the Risk of RDS Lung surfactant not present in immature lung Surfactant secreted into amniotic fluid Large variation in surfactant in given gestation Surfactant predicts the risk of RDS before birth Surfactant in AF L/S ratio, others Gestation weeks 24 32 40 Incidence of RDS 100 0 Md SPC Disaturated Phosphatidylcholine PG Phosphatidylglycerol

Functions of surfactant – roles of surfactant proteins (SP) : 

Functions of surfactant – roles of surfactant proteins (SP) Fast surface adsorption and concentration to surface during tidal ventilation (anti-atelectasis, -edema) DPC, PG, SP-B, SP-C in particular Multiple functions in immuninity: all surfactant proteins and even phospholipids SP-A and SP-D: - soluble receptors to bacteria, viruses and fungi - promote phagocytosis - serve as anti- or proinflammatory agents depending on the aggregate size of SP 3. Multiple interactions with macrophages, cytokines, and receptors (CD91, TLR, CD14, SIRPa)

Synthesis, intracellular transport and storage, secretion, function, clearance, recycling of surfactant : 

Synthesis, intracellular transport and storage, secretion, function, clearance, recycling of surfactant Synthesis & intracellular transport rate limiting in RDS

Airway Branching as a Function of Fetal Age : 

Airway Branching as a Function of Fetal Age

Predisposing factors to RDS: heterogenous, multifactorial disease : 

Predisposing factors to RDS: heterogenous, multifactorial disease Very preterm infants compliant chest cage, tendency to apnea saccular terminal air spaces high alveolar – capillary permeability inflammatory cytokines tend to upregulate surfactant immature innate immune responsiveness genetic risk factors not refined in evolution Preterm - near term infants stiff chest cage small-sized developing alveoli inflammatory cytokines tend downregulate surfactant host reponses resemble those in term infants genetic factors refined in evolution

Risk factors for RDS and factors protecting from RDS : 

Risk factors for RDS and factors protecting from RDS

Gestation-Dependent Risk of RDSData from Finnish Birth Cohort 1987-2000* : 

Gestation-Dependent Risk of RDSData from Finnish Birth Cohort 1987-2000* Finnish birth register 1987 to 2000 873 684 births, 23 278 twin births 9 725 twin preterm births Marttila et al Am J Obstet Gynecol 2004 1st < 2nd born: p <0.0001 Singleton < twin <30 w: p <0.001 Singleton > twin >30 w: p <0.0001

RDS as a target of genetic studies : 

RDS as a target of genetic studies Prior to neonatal intensive care RDS was fatal disease regardless of gestation small preterm died regardless of RDS many near term or preterm infants survived when no RDS ? RDS in near term or preterm infants is an important selection factor in evolution, but not in VLBW infants Twin studies: 30-60% of susceptibility determined by genetic factors Studies complicated by the fact that presenting twin has an environment protecting against RDS

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RDS Disease cathgories Inherent factors Environment Genetic variation Other genes Surfactant protein genes Antenatal factors Premature transition Treatment practices at birth Degree of prematurity Ethnicity Gender Susceptibility: interaction between genetic, Environmental and constitutional factors

Genetic predisposition to RDS : 

Genetic predisposition to RDS Very preterm infants Common alleles predict RDS: SP-A 6A2, SP-B 121Thr, SP-C 186Asn Rare alleles predict the risk of Bronchopulmonary dysplasia (BPD): SP-B i4del, ABCA3 rs13332514, TNF-a -238A Near term infants (> 32 w) Rare alleles increase the risk: SP-A 6A3, GPRA H4H5 Term infants Loss of function mutations of SP-B, SP-C, ABCA3 cause fatal respiratory failure initially mimicking RDS

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Genes preferentially expressed in the lung Association of Common Genotypes with RDS and Respiratory Diseases Risk genotype Protective genotype SP-A Very premature Multiple pregnancy Presenting twin RDS COPD Prolonged course Near Term

Lung in fatal mutations of SP-B, SP-C and ABCA3 genes, destroying T2-Cell function : 

Lung in fatal mutations of SP-B, SP-C and ABCA3 genes, destroying T2-Cell function SP-B ABCA3

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Transcellular interaction between placenta and fetal lung: Connection between preterm birth and fetal lung maturity Listeria, Viruses LPS IL-1 influences lung maturation . SP-B Bry et al JClin Invest 1997 Cytokines

Cytokines in chorioamnionitis and immature lung : 

Cytokines in chorioamnionitis and immature lung In chorioamnionitis, IL-1 increases the surfactant components and chemokine IL-8. As a result, surfactant synthesis and secretion is induced and granulocytes appear in the lung. Persistent lung inflammation allows lung growth, however. Immature airways and air spaces have very few macrophages that poorly respond to microbes. During fetal life interstitial macrophages increase. Alveolar macrophages are required on host defense and surfactant metabolism (GMCSF). Immature fetal lung does not respond to TNF-a, and have generally low expression levels of TNF-a, and anti-inflammatory cytokines (IL-10, IL-4) Shortly after very preterm birth alveolar macrophages increase in number and reactivity. While anti-inflammatory surfactant proteins and anti-inflammatory cytokines increase after the birth, some infants fail to develop the balance between pro- and anti-inflammatory factors and persistent respiratory failure – bronchopulmonary dysplasia, BPD - develops.

Cytokines and glucocorticoids (GC) influence differentiation & growth of fetal lung : 

Cytokines and glucocorticoids (GC) influence differentiation & growth of fetal lung In very immature lung IL-1 and GC additively enhance the differentiation of the surfactant In near term lung IL-1, TNF-a and LPS additively decrease the synthesis of surfactant proteins. GC has little effect alone, but it decreases dose-dependently the detrimental effects of cytokines. After birth, the LPS-responsiveness of alveolar macrophages increases. Some individuals fail to develop robust anti-inflammatory GC responses, increasing the susceptibility to BPD.

Pharmacologic effects of maternal glucocorticoids on the immature fetal lung : 

Pharmacologic effects of maternal glucocorticoids on the immature fetal lung Glucocorticoid given to mother Increases surfactant synthesis & secretion Induces epithelial Na+ pump and clearance of water from airways Decreases epithelial permeability Enlarges air spaces and decrease lung interstitium Macrophages: suppression of LPS response (1-4 days) followed by strong activation of LPS response (7 + days) Inhibition of the growth of the fetal lung Analogous effects on the other organs and the extra pulmonary immune system

Prevention of RDS : 

Prevention of RDS Prevention of spontaneous preterm births generally modest success Prevention of acute asphyxia Avoiding iatrogenic prematurity IVF – implantation of single embryo Restriction of elective low-risk preterm births Antenatal glucocorticoid

Single dosage of antenatal glucocorticoidMeta analysis of randomized trials : 

Single dosage of antenatal glucocorticoidMeta analysis of randomized trials * Only with betamethasone (BM) rather than with dexamethasone (DX) Crowley 2002 BPD Bronchopulmonary dysplasia; IVH Intraventricular hemorrhage NEC Necrotizing enterocolitis

Single dosage of antenatal glucocorticoid (GC) : 

Single dosage of antenatal glucocorticoid (GC) Trials mostly in presurfactant era Antenatal glucocorticoid effective in decreasing severe RDS and IVH when surfactant treatment available – additive effect (Kari et al 1994) Preterm birth within 24 h after GC does not prevent RDS but decreases IVH The protective effect of GC disappears if patients remain undelivered for >7 days GC has been repeated weekly, biweekly or in imminent preterm birth No randomized trials supported these practices

Randomized trials on the effects of repeating antenatal glucocorticoid (ANS) in threatened preterm birth : 

Randomized trials on the effects of repeating antenatal glucocorticoid (ANS) in threatened preterm birth *Severe RDS, BPD, severe IVH, PVL, NEC, proven sepsis or death. †Survival without RDS or IVH gr 3-4

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Primary clinical outcomes for liveborn infants, assessed before hospital discharge (Crowther et al. 2006) Data are number (%) unless otherwise indicated. Relative risk is treatment effect, or median (interquartile range). Analyses are adjusted for gestational age at entry, preterm labor rupture of the membranes, and antepartum haemorrhage necessitating admission to hospital.

Repeating weekly antenatal glucocorticoid in threatened preterm birth: decrease in fetal growth : 

Repeating weekly antenatal glucocorticoid in threatened preterm birth: decrease in fetal growth Crowther et al Lancet 2006

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Intact survival* after a single booster of 12 mg BM, given at <34 weeks at least 7 days after the 1st BM dosage *Survival during the first hospitalization without respiratory distress syndrome or gradus 3-4 intraventricular hemorrhage Peltoniemi et al Pediatrics in press Decreased intact survival due to increase in the incidence of RDS when birth occurs shortly after the steroid booster !

Repeating antenatal steroid (ANS) if imminent very preterm birth >1 week after the first dosage ? : 

Repeating antenatal steroid (ANS) if imminent very preterm birth >1 week after the first dosage ? Results inconclusive Short BM – delivery interval may be associated with increase in RDS (neonatal inflammatory activation, suppression of endocrine response) Weekly repeated dosage may result in intrauterine growth retardation and modest decrease in RDS According to present results ANS not indicated More studies, including the follow-up is required

Disaturated phosphatidylcholine (DPC) in epithelial lining fluid in VLBW infants : 

Disaturated phosphatidylcholine (DPC) in epithelial lining fluid in VLBW infants Hallman et al Am Rev Resp Dis 1991 0 1 2 3 4 5 0 1 2 3 4 5 6 7 21- 28 RDS No RDS RDS+Surf Days after delivery DPC mM

RDS - factors influencing the risk and severity : 

RDS - factors influencing the risk and severity Surfactant deficiency Excess of lung liquid Abnormal lung perfusion Inflammatory activation Deficient Na+ transport Poor ventilation, low PEEP High permeability edema ? Gas exchange, surfactant response ? Persistence of fetal circulation ? intractable respiratory failure Cardiac decompensation, mostly associated with PDA ? lung edema Triggered by volutrauma, infections, hyperoxia Detrimental to surfactant, airways, lung interstitium, growth Augments lung injury, prolongs respiratory failure, predisposes to BPD Lack of differentiation Dilution (edema) Inhibition (plasma proteins) Inactivation (proteases) ? Atelectasis, lung injury ?

Management of RDS : 

Management of RDS Centralization of very high risk deliveries Resuscitation Cardiopulmonary stabilization Management of ventilation, non-invasive ventilation, treatment of apnea Ancillary treatments (fluid therapy, nutrition) Management of ductus arteriosus

Adjusted mortality of very preterm infants in Finnish Hospitals according to the average number of very preterm births during the study period of 2000-2004 : 

Adjusted mortality of very preterm infants in Finnish Hospitals according to the average number of very preterm births during the study period of 2000-2004 Adjusted for maternal age, smoking, hospitalisation for hypertension, primiparity, gender, birth weight for gestational age, and classified gestational age. Rautava et al Pediatrics 2006

Neonatal mortality and RDS mortality in Oulu University Central Hospital District 1970 - 2004 : 

Neonatal mortality and RDS mortality in Oulu University Central Hospital District 1970 - 2004 CPAP ? PEEP ? Routine ANS ? Surfactant? nCPAP NO trials HC trials Smart respirators

Influence of RDS on the risk recurrent wheezing in first two years of life : 

Influence of RDS on the risk recurrent wheezing in first two years of life _____________________________________________________________________ All infants Infants with BPD excluded Variables OR (95%CI) p value OR (95%CI) p value _____________________________________________________________________ Siblings at home 2.53 (1.58 - 4.35) <0.001 2.29 (1.37 to 34.89) <0.0051 Male sex 2.52 (1.54 - 4.33) 0.001 2.62 (1.53 to 4.43) 0.0012 RDS 1.87 (1.12 - 3.02) 0.023 1.84 (1.10 to 3.00) 0.032 BPD 6.07 (2.66 - 13.65) <0.001_____________________________ Other covariates included in the regression model: chorioamnionitis, fetal distress (yes/no), antenatal steroid caesarean vs. vaginal delivery, Apgar score <4 at 5 minutes vs. other, gestational age < 32 weeks vs. = 32 weeks, patent ductus arteriosus (yes/no) and pneumothorax (yes/no) Koivisto et al J Pediatr 2005 Paired comparison between 346 RDS cases and 346 gestation adjusted controls born in Oulu University hospital during 1990-1999

Landmark studies on surfactant therapy : 

Landmark studies on surfactant therapy

Surfactant therapy - outcomes : 

Surfactant therapy - outcomes

Surfactant preparations used clinically : 

Surfactant preparations used clinically DPPC: dipalmitoylphosphatidylcholine, POPG: palmitoyloleoylphosphatidylglycerol; PA: palmitic acid; rSP-C: recombinant human SP-C; PG: phosphtatidylglycerol

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Systematic Review Animal-derived vs. Non-peptide Synthetic Surfactants Outcome RR (95 % CI) NNT Prophylaxis (1 trial, total N= 846) Pneumothorax 0.62 (0.34-1.13) - Severe IVH 1.43 (0.95-2.15) - BPD 1.05 (0.76-1.46) - Mortality 0.88 (0.64-1.19) - BPD or Mortality 0.98 (0.91-1.06) - Treatment (8 trials, total N= 3704) Pneumothorax 0.63 (0.53-0.75) * 20 Severe IVH 1.02 (0.86-1.23) - BPD 1.01 (0.93-1.11) - Mortality 0.86 (0.75-0.99) * 37 BPD or Mortality 0.94 (0.88-1.01) - Soll RF and Blanco F. Cochrane Library 2004, Issue 2, updated Feb 2001 * P< 0.05

KL4 Surfactant, Lucinactant : 

KL4 Surfactant, Lucinactant Natural surfactant SP-B Air-Liquid interphase Surfaxin

Randomized Trials of Lucinactant Study Characteristics : 

Randomized Trials of Lucinactant Study Characteristics SELECT (N= 1294) Trial Design Superiority Inclusion Criteria GA 24–32 wks BW 600–1250 g Treatment Surfaxin 175 mg/kg (5.8 mL/kg) Exosurf 67.5 mg/kg (5.0 mL/kg) Survanta 100 mg/kg (4.0 mL/kg) Primary outcome Incidence of RDS at 24 hrs RDS-related deaths through 14d STAR (N= 252) Trial Design Non-inferiority Inclusion Criteria GA 24–29 wks BW 600–1250 g Treatment Surfaxin 175 mg/kg (5.8 mL/kg) Curosurf 175 mg/kg (2.2 mL/kg) Primary outcome Incidence of alive without BPD at 28d Moya F, et al. Pediatrics,2005;115:118-129 Sinha S, et al. Pediatrics, 2005;115:130-138

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SELECTPrimary Outcomes P = 0.005 P = 0.108 P-values adjusted by BW strata and center using logistic regression Surfaxin n=527 Exosurf n=509 Survanta n=258 47% 39% 33% P = 0.001 P = 0.001 4.7% 9.6% 10.5% Surfaxin n=527 Exosurf n=509 Survanta n=258 Moya F, et al. Pediatrics,2005;115:118-129 RDS deaths up to 14 days 0 5 10 15 20 % RDS at 24 hours 0 10 20 30 40 50 60 70 %

Surfaxin vs Exosurf Death and BPD : 

Surfaxin vs Exosurf Death and BPD FavorsSURFAXIN® FavorsExosurf® OR (95% CI) SURFAXIN®Rate (%) Exosurf® Rate (%) P Value 0.1 0.5 1 1.5 2 2.5 3 Moya F, et al. Pediatrics,2005;115:118-129

Surfaxin vs Survanta Death and BPD : 

Surfaxin vs Survanta Death and BPD SURFAXIN®Rate (%) Survanta® Rate (%) By day 28 By day 28 FavorsSURFAXIN® Favors Survanta® OR (95% CI) P Value Death or BPD By day 28 By 36 weeks PMA Death By 36 weeks PMA By 36 weeks PMA BPD 307 (58.3) 152 (58.9) .76 214 (40.6) 114 (44.2) .257 100 (19.0) 61 (23.6) .08 111 (21.1) 68 (26.4) .051 305 (57.9) 149 (57.8) .95 212 (40.2) 110 (42.6) .425 0.1 0.5 1 1.5 2 2.5 3 Moya F, et al. Pediatrics,2005;115:118-129

STAR TrialPrimary Outcome - Survival without BPD - Day 28 : 

STAR TrialPrimary Outcome - Survival without BPD - Day 28 % 37.8 33.1 0 10 20 30 40 50 60 70 P = NS Surfaxin vs. Curosurf Surfaxin n =119 Curosurf n = 124 Sinha S, et al. Pediatrics, 2005;115:130-138 Non-inferiority Test - Surfaxin vs. Curosurf

Examples of potential new therapies or untested managements practices of very preterm infants : 

Examples of potential new therapies or untested managements practices of very preterm infants Resuscitation practices Room air Oxygen saturation and tidal volume control from birth New modes of ventilation and monitoring Syncronized, volume-controlled ventilation, others Mechanical ventilation via nasal airway Nutrition, environment New micronutrients Blinded comparison of low vs high environmental oxygen Antiinflammatory drugs to focused infant population Nitric oxide inhalation Hydrocortisone supplementation Surfactant nebulization

Summary : 

Summary Breakthrough in management of RDS has virtually eliminated the mortality of this once uniformly lethal, common disease of the premature Chronic morbidity, including BPD has not been eliminated among the very preterm infants New promising treatments that may substantially reduce chronic morbidity, are underway. However, the cost of neonatal care may not decrease First the breakthroughs in understanding the mechanism of preterm birth and developing cost-effective and safe methods of prevention will substantially reduce the deaths and chronic morbidity at low cost