DISPLASIA BRONCOPULMONAR

TERAPIAS ATUAIS E NOVAS ABORDAGENS

BRONCOPULMONARY DYSPLASIA

CURRENT THERAPIES AND NEW APPROACHES

Gustavo Rocha

Serviço Neonatologia, Centro Hospitalar Universitário São João, Porto

Bronchopulmonary Dysplasia

• Chronic lung disease associated with

preterm / undeveloped lungs

• Rates in ELBW ± 30% (11% to 50%) (O2 at 36 wks PMA)

• Rates as high as 68% at 28 days

• Chronic lung disease to adulthood

• New group of chronic obstructive pulmonary disease in adulthood

• Potentially shorten life expectancy

• Public health problem

Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78. doi: 10.1038/s41572-019-0127-7

RISK FACTORS

• Prematurity

• fetal growth restriction (IUGR)

• white race

• male sex

• chorioamnionitis

• smoking

• tracheal colonization with Ureaplasma

• RDS

• excessive early IV fluid administration

• symptomatic PDA

• sepsis

• vitamin A deficiency

• oligoamnios

• family history of atopic disease

• preeclampsia

• genetic factors

CONTRIBUTING FACTORS

InflammationMechanical ventilation

(volutrauma/barotrauma)Oxygen exposure (oxidative stress)Poor protein and caloric intake

Thébaud B et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78. doi: 10.1038/s41572-019-0127-7

1st definition of the NIH

2016 NICH - Suggested refinements to the definition of BPD. Bronchopulmonary Dysplasia: Executive Summary of a Workshop-J Pediatr. 2018 Jun; 197: 300–308. Higgins R, Jobe A et al

A preterm (<32 wks’ GA) with BPD has persistent parenchymal lung disease + radiographic confirmation, and at 36 weeks PMA requires 1 of the following FiO2 ranges/oxygen levels/O2 concentrations for ≥3 consecutive days to maintain arterial oxygen saturation in the 90%–95% range.

*Excluding infants ventilated for primary airway disease or central respiratory control conditions. Values are percents.CPAP, continuous positive airway pressure; IPPV, intermittent positive pressure ventilation; N-CPAP, nasal continuous positive airway pressure; NIPPV, noninvasive positive pressure ventilation.

Grades Invasive IPPV*

N-CPAP, NIPPV, or nasal cannula

≥ 3 L/min

Nasal cannula flow of 1–<3

L/min Hood O2

Nasal cannula flow of <1 L/min

I — 21 22–29 22–29 22–70

II 21 22–29 ≥30 ≥30 >70

III >21 ≥30

III(A) Early death (between 14 days and 36 weeks) owing to persistent parenchymal lung disease and respiratory failure that cannot be attributable to other neonatal morbidities (eg, NEC, IVH, redirection of care, sepsis, etc).

Prevention of BPDAvoid extreme preterm birth; antenatal corticosteroids; tocolytics; MgSO4; ATB; level III center delivery

Prevention of fetal growth restriction; smoking cessation; drugs

Delayed cord clamping /cord milking; delivery room protocols for ressuscitation;

Good temperature control/ polyethylene bag

PEEP in the delivery room and early NCPAP

Less invasive surfactant administration (LISA/MIST)

RDS guidelines

Suitable energy and protein intake

Early full parenteral nutrition /avoid excessive fluids

Control of sepsis (reduces invasive ventilation)

Skin care

Stress reduction

Vitamin A

Caffeine

Volume targeted ventilation + permissive hypercapnia

Avoid hyperoxia (SpO2: 90-94%; alarms: 89-95%)

Hs-PDA treatment

Postnatal corticosteroids

Fortified maternal/ human milk

Management of established BPD

• Multidisciplinary team (neonatologist, cardiologist, pneumologist, otolaringologist, gastro, nutrition,…)

• Screaning of pulmonary hypertension

• Adequate ventilation strategy and oxygen – SpO2 90-95%; if PHT > 95%

• Higher calories (130-150 Kcal/kg/day) , fluid limitation (120 ml/kg/day)

• Corticosteroids (for extubation)

• Diuretics

• Bronchodilators - β2 agonist – salbutamol, …

• If PH: nitric oxide; sildenafil; bosentan; treprostinil

• Immunizations, Palivizumab

Early systemic dexamethasone• Widely used in the 90´s and 2000´s led to an increase in cerebral palsy

• Doyle LW et al. Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology. 2010;98(3):217-24. doi: 10.1159/000286210.

20 trials enrolling a total of 2,860 participants

earlier extubation and decreased risks of BPD or death (at both 28 days' and 36 weeks’)

BUT increased rates of gastrointestinal bleeding, intestinal perforation, hyperglycaemia and hypertension

cerebral palsy and the combined outcome death or cerebral palsy were significantly more common in survivors

CONCLUSION: early DEXA (≤7 days) to prevent BPD do not outweigh risks, and it cannot be recommended for routine clinical practice.

Late systemic dexamethasone

• Doyle LW et al. Dexamethasone treatment after the first week of life for bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology.2010;98(4):289-96. doi: 10.1159/000286212.

19 RCTs enrolling 1,345 participants

reductions in failure to extubate, BPD and the combined outcome of death or BPD

no increase intestinal perforation or cerebral palsy

• CONCLUSIONS: It appears prudent to reserve the use of late DEXA to infants who cannot be weaned from mechanical ventilation, and to minimise the dose and duration of any course of treatment.

DART for extubation• Doyle LW et al. Low-dose dexamethasone facilitates extubation among chronically ventilator-

dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics 2006 Jan;117(1):75-83.

70 PT infants <28 wks or <1000 g ventilator dependent after the first wk of life

DEXA (0.89 mg/kg over 10 days)

DEXA group (35 patients) control group (34 patients)

successful extubation in DEXA group: 60% vs 12% (OR: 11.2; 95% CI: 3.2-39.0)

reduced BPD: 85% vs 91%; (OR: 0.58; 95% CI: 0.13-2.66) although not statistically significant.

CONCLUSIONS: Low-dose DEXA after the 1st week of life clearly facilitates extubation without any obvious short-term complications.

DART for extubation

• Doyle LW et al. Outcome at 2 years of age of infants from the DART study: a multicenter, international, randomized, controlled trial of low-dose dexamethasone. Pediatrics. 2007 Apr;119(4):716-21.

59 survived to 2 years of age, and 58 (98%) were assessed at follow-up, but data for cerebral palsy were available for only 56 survivors

no significant difference in cerebral palsy

CONCLUSIONS: data indicate no significant association with long-term morbidity.

“early” low dose HYDROCORTISONE

Low cortisol levels during 1st wk of life associated to BPD (Watterberg KL, 1995)

A pilot study with HYDRO showed improved survival without BPD (Watterberg KL, 1999)

A larger RC trial was stoped because of an increased risk of gastrointestinal perforation (Watterberg KL, 2004)

Cochrane Syst Rev 2010, 2012, 2014

HYDRO reduced the combined outcome of mortality or BPD, without causing any obvious long-term harm. However, gastrointestinal perforation was more frequent in the HYDRO group.

“early” low dose HYDROCORTISONE

2016 – Results of the PREMILOC studyBaud O et al; PREMILOC trial study group. Lancet 2016 Apr 30;387(10030):1827-36.

• Double-blind, placebo controlled, RCT, 21 french level III NICU´s, 2008-2014

• inborn preterms 24+0 to 27+6 Wks

• Excluded: major malformations or chromosomal anomalies; severe asphyxia; BW<

3rd centile; rupture membranes < 22 Wks gestation

• IV hydrocortisone hemisuccinate started D1: 1 mg/kg/day divided 2id for 7 d, followed by0.5 mg/kg/day 1id for 3 days (the lowest dose ever)

• Primary outcome: survival without BPD at 36 Wks PMA

• Secondary outcomes (several) and adverse events related to HYDRO

“early” low dose HYDROCORTISONE

2016 – Results of the PREMILOC study

1072 neonates- 123 excluded- 426 not consented – 521 randomly assigned

255 – Hydro vs 266- placebo

Baseline characteristics of mothers and infants well balanced between groups

Primary outcome survival without BPD: Hydro 153 (60%) vs placebo 136 (51%);

ORad=1.48, 95%CI 1.02-2.16, p=0.04. NNT = 12

“early” low dose HYDROCORTISONE2016 – Results of the PREMILOC study

• Significant secondary outcomes:

HYDRO PLACEBO

Extubation at D10 152 (60%) 116 (44%) p= 0.0002

Without O2 at 36 Wks PMA 139 (55%) 119 (45%) p=0.04

PDA ligation 37 (15%) 55 (21%) p=0.03

Better results for HYDRO in females (NNT = 7) p=0.006 and chorioamnionitis p= 0.04

Higher rate of LO sepsis in the subgroup 24-25 Wks GA treated with HYDRO, p=0.02

No differences → in gastrointestinal perforation, p=0.56

→ on z-scores of weight and head circumference at 36 Wks PMA

→ in MRI findings at term equivalent age performed in 85% of the survivors

“early” low dose HYDROCORTISONE

• 2016 – Results of the PREMILOC study

INTERPRETATION:

Survival without BPD at 36 wks of PMA age was significantly increased by prophylactic low-dose HYDRO;

this strategy could lead to substantial improvements in the management of the most premature neonates.

“early” low dose HYDROCORTISONE

PREMILOC-Neurodevelopmental outcomes at 2 years of age

• 379 patients were evaluated (HYDRO=194 ; placebo=185) at a median corrected age of 22 months (IQ:21-23):

without neurodevelopmental impairment (73% hydro vs 70% placebo)

mild neurodevelopmental impairment (20% hydro vs 18% placebo)

moderate to severe neurodevelopmental impairment (7% hydro vs 11% placebo)

• NOT statistically significantly different between groups (P = .33).

• The mean global developmental quotient score was not significantly different between groups (91.7 HYDRO vs 91.4 placebo; 0.3 [95% CI, -2.7 to 3.4]; P = .83).

• The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups.

CONCLUSIONS AND RELEVANCE:

Early low-dose HYDRO was not associated with a significant difference in neurodevelopment at 2 years of age. Further randomized studies are needed to provide definitive safety .

HYDROCORTISONE initiated 7-14 days after birth in ventilated infants

• Stop-BPD Study Group- JAMA 2019 (Wes Onland, Anton H van Kaam, et al)

• Double-blind, placebo, controlled randomized trial

• 19 level III NICU´s Netherlands and Belgium, 2011-2016

• PT infants < 30 Wks GA and/or BW < 1250g

• All ventilator dependent at 7-14 days of life

• Randomly assigned to receive IV HYDRO or placebo

• Primary outcome: death or BPD assessed at 36 wks PMA

• 29 secondary outcomes

HYDROCORTISONE initiated 7-14 days after birth in ventilated infants

• Hydrocortisone sodium succinate – 22 d , cumulative dose 72.5 mg/kg

1.25 mg/kg - 4 doses – 7 days

1.25 mg/Kg - 3 doses – 5 days

1.25 mg/Kg - 2 doses – 5 days

1.25 mg/Kg-1 dose – 5 days

• Hydro = 181 / Placebo = 190

• Death or BPD: Hydro = 70.7% vs placebo = 73.7%

• Adjusted OR= 0.87 [95%CI: 0.54-1.38, p=0.54]

HYDROCORTISONE initiated 7-14 days after birth in ventilated infants

• Significant secondary outcomes:

• more successful extubation with HYDRO on D 3,7,14: p:0.01

• lower rate of pneumonia (p=0.048) with HYDRO

• greater weight at 36 wks (p= 0.03) with HYDRO

• hyperglicemia/Insulin HYDRO= 18.2% vs placebo= 7.9%, p=0.004

• No serious drug reactions

HYDROCORTISONE initiated 7-14 days after birth in ventilated infants

• CONCLUSIONS AND RELEVANCE OF BPD-STOP TRIAL:

Among ventilated PT infants, HYDRO between 7 and 14 days after birth did not improve the composite outcome of death or BPD. These findings do not support the use of hydrocortisone for this indication.

The neuromotor evaluation at 22-24 m has not yet been published.

• A similar study is going on- the NICHD TRIAL OF HYDROCORTISONE

INHALED STEROIDS- early inhaled budesonide

• Neurosis trial- Bassler D, et all- N Engl J Med 2015

PT < 28 Wks GA

Early Inhaled Budesonide (< 24h of life) vs placebo

until no oxygen and pressure support or 32 Wks

856 infants: 437 -Budesonide vs 419 – placebo

BPD- 27.8% in budesonide group and 38% in placebo (RR= 0.74; 95%CI: 0.60-0.91; p=0.004)

Death or BPD stratified by GA: 0.86; 95%CI: 0.75-1; p=0.05

Death – 16.9% in budesonide group and 13.6% in placebo (RR= 1.22; 95%CI: 0.91-1.69; p=0.17)

Conclusion: The incidence of BPD was lower in Budesonide group BUT the advantage may have been gained at the expense of increased mortality

INHALED STEROIDS- early inhaled budesonide

• Long-Term Effects of Inhaled Budesonide- Bassler D, N Engl J Med. 2018

Outcomes at 18-22m: cerebral palsy, cognitive delay (MDI score of <85 on Bayley scales, deafness, or blindness

no significant difference in any of the individual components of the prespecified outcome

more deaths in the budesonide group vs placebo (19.9% vs 14.5%)

(RR 1.37; 95% CI, 1.01 to 1.86; P=0.04)

EARLY INHALED STEROIDS

• Cochrane Database Syst Rev. 2017 - Early administration of inhaled corticosteroids for preventing chronic lung disease in very low birth weight preterm neonates. Shah VS, et al

Ccs initiated within the first two wks of life (budesonide, beclomethasone, fluticasone, flunisolide)-10 trials that enrolled 1644 neonates

Combined outcome death or BPD: RR=0.86 ; 95%CI 0.75-0.99 (p=0.04) NNT=17(CI-9 to infinit)

Reduced extubation failure: RR=0.58, 95%CI 0.35-0.96; NNT=25

Conclusions: there is some evidence that early inhaled ccs reduces death or BPD, but the effect may not be of clinical relevance; they cannot be recommended

LATE INHALED STEROIDS• Cochrane Database Syst Rev. 2017 Late (≥ 7 days) inhalation corticosteroids to reduce

bronchopulmonary dysplasia in preterm infants. Onland W, Offringa M, van Kaam A.

8 trials randomising 232 preterm infants (small number)

did not reduce the separate or combined outcomes of death or BPD

reduced risk in favour regarding failure to extubate

both analyses showed increased statistical heterogeneity (I2 statistic 73% and 86%, respectively)

• AUTHORS' CONCLUSIONS: inhalation ccs initiated at ≥ 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety.

INTRATRACHEAL CORTICOSTEROIDS

• Curr Med Sci. 2019 Early Intratracheal Administration of Corticosteroid and Pulmonary Surfactant for Preventing Bronchopulmonary Dysplasia in Preterm Infants with Neonatal Respiratory Distress Syndrome: A Meta-analysis. Zhong YY, et all

8 RCT- 838 patients (inhalations or instillation)

reduced BPD: RR= 0.56 (95%CI:0.42-0.76) (p=0.001)

reduced need for 2nd dose of surfactant: RR =0.551 (95%CI:0.45-0.67) p=0.0001)

reduced mortality: RR= 0.67 (95%CI:0.45-0.99) (p=0.04)

• Conclusion: …early administration of CCS + PS is an effective and safe option for preterm infants with RDS in preventing BPD and reducing mortality…

INHALED VS SYSTEMIC CORTICOSTEROIDS

• Cochrane Database Syst Rev. 2017 Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates. Shah SS et all.

2 trials with 294 infants

death or BPD at 36 weeks' was not significantly different (RR 1.09, 95% CI 0.88 - 1.35)

duration of mechanical ventilation was significantly longer in the inhaled steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%)

as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).

• CONCLUSIONS: no evidence that early inhaled steroids confer advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids

Diuretics for BPD - furosemide• Improve pulmonary edema

• Allow restriction of volume (120-130 ml/kg/day) maintaining calories

LOOP diuretics- potente diuretics – furosemideRisks: electrolyte imbalance; ototoxicity; nephrocalcinose; osteopenia; metabolic alkalosis;hyperuricemia

No data to support its routine use (1 systematic review and 1 meta-analysis for enteral and 1 for aerosolized)

Reserved for chronically ventilated with moderate/severe impaired lung function after fluid restriction

A trial of enteral furosemide 2 mg/kg/day, for 3-5 days. If improvement keep fusosemide or change to thiazide

Greenberg RG et al Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee. J Pediatr. 2019 May;208:134-140

retrospective cohort study; 37 693 infants; 23-29 wkers; 19 235 (51%) exposed to furosemide day 7 and 36 weeks

CONCLUSIONS: More days of furosemide exposure between postnatal day 7 and 36 weeks was associated with decreased risk of BPD and a combined outcome of BPD or death.

A trial with furosemide for BPD is ongoing: https://ClinicalTrials.gov/show/NCT02527798

Diuretics for BPD - thiazides• Work on distal convoluted tubules

• Less potent than loop diuretics

• Preferred for chronic use – decreased risk for electrolyte imbalance

• NOT recommended for routine use

• Reserved for moderate/severe cases: edema, ventilated, high FiO2

Johnson AK et al,Adv Neonat Care 2017

• Hydrochlorotiazide – risk of hypoKalemia

• Used or NOT in association with a K+ sparing diuretic (Spironolactone)

• 1 single study associated Spironolactone to hypercalciuria and risk of nephrocalcinose –Hoffman DJ et al:J Perinatol. 2000 Jan-Feb;20(1):41-5. Many centres now use Hidrochlorotiazide alone

Bronchodilators for BPD• Bronchodilators for the prevention and treatment of chronic lung disease in preterm infants.

Ng G et al, Cochrane Database Syst Rev. 2016

1 study (173 patients) showed no significant benefit of salbutamol in preventing BPD (RR 1.08, 95%CI 0.50-2.31)

Conclusion: data are insufficient for reliable assessment of the use of salbutamol for prevention of CLD

• The impact of inhaled bronchodilators on bronchopulmonary dysplasia: a nonrandomized comparison from the NEuroSIS trial.Koch AJ et AL, J Matern Fetal Neonatal Med. 2019

Conclusion: Early inhaled bronchodilators did not reduce the risk of BPD and death in extreme preterms

Recommendation: Can be used in moderate/ severe BPD with acute episodes of bronchospasm

Caffeine for BPD prevention

• Schmidt B et al; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006

Caffeine therapy reduced BPD: ORad= 0.63; 95%CI: 0.52 - 0.76 (P<0.001).

• Schmidt B et al; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007

Caffeine improves the rate of survival without neurodevelopmental disability at 18 to 21 months in VLBW infants

There is an ongoing trial of caffeine administered < 2H of life vs > 12h

https://clinicalTrials.gov/show/NCT03086473

Vitamin A for BPD prevention

• Araki S et al. PLoS One. 2018 Nov Vitamin A to prevent bronchopulmonary dysplasia in extremely low birth weight infants: a systematic review and meta-analysis.

4 studies (IM = 3 oral = 1 study, total 0 1,011 infants)

Reduced BPD - R : 0.88; (95% CI, 0.77-0.99)

IM injections are painfull and may increase the risk of sepsis

Some centers : 5000 UI, IM; 3x Wk in ventilated patients, starting in the first week of life during 4 weeks

1 trial with enteral vitamin A is ongoing - vitamin A (5000 IU once a day) or placebo

• TRIAL REGISTRATION: ANZCTR; ACTRN12616000408482

Rakshasbhuvankar A, et al. BMC Pediatr. 2017 Dec 16;17(1):204.

Mesenchymal stem cells for BPD preventionMultipotent cells that can be isolated from the bone marrow, adipose tissue, Wharton’s jelly of the umbilical cord and

placenta. Ability to be induced into adipogenic, osteogenic, and chondrogenic lineages

• Augustine S et al. Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies. Stem Cells Transl Med. 2017

25 studies- animal model

In rodents, MSCs significantly improved alveolarization (Standardized mean difference of -1.330, 95%CI -1.724, -0.94, I2

69, ameliorated pulmonary hypertension, lung inflammation, fibrosis, angiogenesis, and apoptosis.

• Chang et al, MST for BPD: phase I dose-escalation clinical trial. J Pediatr 2014

Human model- 9 PT 25.3 ± 0.9 wks BW 790 ± 127g- ventilated for severe RDS vs 18 controls → reduction in moderate/severe BPD from 72% to 33%

• Ongoing clinical trials for MSC in BPD

1 – Korea – Phase II – 70 patients – 23-29 wks

2 – USA – Phase I/II – 12 patients – 23-28 wks

3- Spain – Phase I – 10 patients - < 28 wks

4 - China – Phase I – 100 patients – 1-3 months age with BPD

Therapies with no documented benefit

• Macrolide antibiotics• r-Human Clara Cells• Monteleukast leukotriene inhibitor• Inositol• Some antioxidants (CuZnSOD, A-acetyl-cysteine, vitamins E and C, lutein, zeaxanthins,…)• Omega-3 LCPUFA• Citruline• Nitric oxide• Estradiol and progesterone• Erythropoietin

Potential novel therapies

• Growth factors therapies (Insulin-like GF, proangiogenic factors)

• Anti-inflammatory and selective anti-cytokines therapies

• Cell-based therapiescord blood-derived mononuclear cells,

endothelial progenitor cells

amniotic epithelial cells

Conclusion• BPD is a multifactorial disease

• Caffeine, vitamin A, volume targeted ventilaton, non-invasive ventilation, permissive hypercapniareduce BPD

• The optimal role of corticoid therapy is as yet undefined. Studies have shown both, benefits and risks. DEXA can be used for extubation > 1st week of life. Early low dose HYDRO needs validation.

• Most of the used pharmacologic agents DO NOT have a solid base of evidence

• Diuretics, agonistsβ2 used in sellected cases only

• Clinical trials evaluating pharmacologic agentes to treat BPD or its complications must examine long-termas well as short term outcomes

• Novel therapies as surfactant+budesonide and mesenchymal stem cells seem promising

Thanks for your attention