Dr Naveen Parkash Gupta - Neocon2019 · Dr Naveen Parkash Gupta Areas of Interest - Ventilation, Hemodynamics, Care of ELBW baby MD Pediatrics, DNB Neonatology, Fellowship in Neonatology

Senior Consultant Neonatology, Rainbow Children Hospital, Delhi.

Dr Naveen Parkash

Gupta

Areas of Interest - Ventilation, Hemodynamics, Care of ELBW

baby

MD Pediatrics, DNB Neonatology, Fellowship in Neonatology (BC

Children Hospital, Vancouver)

Recent Concepts in

Management of RDSDr Naveen Gupta

MD Pediatrics, DNB Neonatology

Fellowship in Neonatology (BC Children Hospital, Vancouver)

Senior Consultant Neonatology

Rainbow Children Hospital, Delhi.

Survivals records over the years …

How common is RDS?

In 2017, VON analyzed data of 8156 babies from

across Europe:

≤ 24 weeks:90% risk of RDS

At 28 weeks:80% risk of RDS

Surfactant required for 55% of VLBW babies

27% in the DR & 29% beyond 2 hrs

of life

18% of VLBW – Bronchopulmonary Dysplasia

(BPD)

Kjell Helenius, MD. PEDIATRICS Volume 140, number 6, December 2017

Antenatal Delivery Room

NICU

Antenatal

steroids

FIO2Ventilation

Strategies

Non invasive

ventilationSurfactant

Oxygen

targets

Permissive

HypercapniaCaffiene

Ventilaton

devices

Cochrane systematic review

30 studies

7774 women and

8158 infants

Reduction in

• Perinatal death (RR) 0.72,

• Neonatal death (RR) 0.62

• RDS (RR) 0.66,

• Moderate/severe RDS (RR) 0.59

• Intraventricular haemorrhage (IVH) (RR) 0.55

• Necrotising enterocolitis (RR) 0.50

• Need for mechanical ventilation (RR) 0.68 and

• Systemic infections in the first 48 hours of life

(RR) 0.60

Cochrane Systematic Review - 21 March 2017

Antenatal Steroids: Evidence

Recommendations: European Society

2018

Clinicians should offer a single course of prenatal corticosteroids to all

women at risk of preterm delivery from when pregnancy is considered

potentially viable until 34 weeks’ gestation ideally at least 24 h before birth

(A1).

A single repeat course of steroids may be given in threatened preterm birth

before 32 weeks’ gestation if the first course was administered at least 1–2

weeks earlier (A2).

European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019

Update. Neonatology. 2019;115(4):432-450.

Delivery Room Intervention

CPAP vs intubation vs

Sustained Inflations

Which FIO2 to start in case baby

needs resucitation

T piece resuscitator vs Self

inflating Bag

Georg M Schmölzer et al. BMJ 2013;347:bmj.f5980

CPAP vs intubation in delivery room

4 RCTS, 2782 BABIES

CONCLUSION:

One additional infant could survive to 36 weeks without bronchopulmonary dysplasia for

every 25 babies treated with nasal CPAP in the delivery room rather than being intubated.

Study design and characteristics

23 weeks to 26+6 weeks

Were eligible if they require PPV because of inadequate respiratory effort or

HR < 100/min

Sample size – 600 babies

Trial stopped early after enrollment of 426 babies.

Primary Outcome – Death or BPD


Which FIO2 to start in case baby needs resucitation

Oei et al, Acta Paediatrica 2016

Summary of all metaanalysis

No difference found in

Mortality of

neurodevelopmental

outcomes or short term

morbidities

Problems – No study is

powered to see effect on

death or disability at 2 years.

Oei et al, Frontier in Pediatrics 2019

TO2RPEDO trial

292 babies (<32 wks) were recruited to either room air or

100% O2 which were adjusted to target pulse oximetry of

65 to 95% at 5 min and 85% to 95% until NICU admission

Trial stopped early

Babies < 28 weeks have higher mortality in room air

group (22% vs 6% RR 3.9 (95%CI 1.1-13.4)

It was not a prespecified outcome

Oei et al, Pediatrics 2017


T piece resuscitator vs Self inflating Bag

T piece vs Self inflating Bag

1027 babies ≥ 26 weeks gestational age – cluster randomized 2 period cross

over trial

Primary outcome – proportions of newborns with HR ≥ 100/min at 2 min after

birth

Results

Primary outcome same

Less intubations in T piece group as compared to self inflating group.

Szyld E, J Pediatr. 2014 Aug;165(2):234-239.e3.

T piece vs self inflating Bag: Indian

Data

90 babies ≥ 26 week gestation

Quasi randomized trial

Results

Duration of PPV significantly less in TPR group (30 vs 60 sec, p < 0.001)

Higher proportion of babies could be resuscitated with room air only (72.5% vs

38%)

Fewer neonates resuscitated with T piece required invasive ventilation

Thakur et al. Resuscitation. 2015 May;90:21-4.

Recommendations: Delivery Room

Stabilization

1. Gently support breathing using CPAP if possible, and if inflations are

needed avoid excessive tidal volumes.

2. Intubation at birth should be considered only for those not

responding to the above

3. Pulse oximetry can help guide heart rate response to stabilisation.

Start with 21–30% oxygen for 28–31 weeks’ GA and 30% oxygen for

<28 weeks’ GA and titrate up or down as needed according to

SpO2 targets Aim at SpO2 of 80% or more within 5 min.



NICU Care

Non invasive mode

Which one

If at all ventilate

then volume or pressure

Surfactant

Saturations and

PaCO2 targets

CaffienePost natal

steroids

Mechanism of Action

Physiologic Rationale

Challenges for Clinical

Research

Questio

n

Does it matter on type of

noninvasive support used in

given patient or NICU

HFNCNasal

IPPVSIPPV

Types of NIV

NIPPV vs Nasal CPAP – Primary mode

Primary Outcome No of Studies

(Participants)

Effect size Quality of

Evidence (GRADE)

Resp failure 9 (876) 0.62 (0.42 – 0.82) Moderate

Need for intubation 8(766) 0.79 (0.64-97) Moderate

Pneumothorax 9(876) 0.69 (0.35 – 1.34) low

Severe IVH 4 (430) 1.26 (0.53 -3.01) Very low

BPD 8 (727) 0.78 (0.58-1.06) Moderate

10 trials, 1061 infants

Lemyre et al, Cochrane 2017

With NIPPV less respiratory failure and less need of intubation but no reduction in

BPD

NIPPV vs Nasal CPAP – Post Extubation

Primary Outcome No of Studies

(Participants)

Effect size Quality of

Evidence (GRADE)

Resp failure 10 (1431) 0.7 (0.6 – 0.8) Moderate

Need for

reintubation

8(1301) 0.76 (0.65-0.88) Moderate

Pneumothorax 6(1229) 0.48 (0.28-0.82) Moderate

BPD 6 (1140) 0.94 (0.8-1.1) Moderate

10 trials, 1431 infants

Lemyre et al, Cochrane 2017

With NIPPV less respiratory failure and less need of reintubation but no reduction in

BPD

CPAP The Gold

Standard

HFNC The Contender

High Flow vs Nasal CPAP: HIPSTER Trial

Study Design

• Multicenter RCT

• 564 preterm ≥28 wks

• Non inferiority margin 10%

Primary Outcome

• Treatment failure in 72 hurs of randomization

• High flow group first went to CPAP before going to intubation

Results

• Treatment failure 25.5% of high flow as compared to 13.3% inCPAPgroups (p< 0.001)

N Engl J Med. 2016 Sep 22;375(12):1142-51.

High flow vs Nasal CPAP: Indian Study

272 babies with GA ≥ 28 weeks and Birth weight ≥ 1000 grams

Treatment failure significantly higher in HFNC group as compared to CPAP

(26.3% vs 7.9%, RD 18.4% (95% CI 9.7-27)

Murki et al, Neonatology. 2018;113(3):235-241

HFNC: Post Extubation CareStudy

Name

Type Device Subjects Primary

outcome

Results

Manley et

al, NEJM

2013

Multicent

er, RCT,

noninferi

ority

design

Device use

as per center

303 babies,

Born at GA

< 32 wks,

PMA < 36

wks at time

of

extubation

Treatment

failure with

in 7 day,

noninferiorit

y margin

20%

No

difference

(-1.9 –

18.7%)

Less nasal

trauma

Interested findings in this study

1.High flow not as good in babies < 26 weeks

2.50% of babies who fail on high flow avoided

reintubation if put on CPAP

CPAP Interface

Delivery system Advantages Disadvantages Evidence

Nasal prongs

(single/binasal)

• Simple device

• Lower resistance

• Mouth leak-Pop up valve

•Relatively

difficult to fix

• Risk of trauma

• Leak

Short binasal prongs are more

effective than nasopharyngeal

prongs

Nasopharyngeal

prongs

•Economical and easily

• Secure fixation

•Easily

blocked/kinked

Inferior to short binasal prongs

Nasal masks Minimal nasal trauma •Difficulty in

adequate seal

• nasal septum &

philtrum

Evidence is emerging

Use of Continuous Positive Airway Pressure in the Newborn, NNF Clinical Practice Guidelines

Devices and pressure sources for administration of nasal continuous positive

airway pressure (NCPAP) in preterm neonates (Review) De Paoli AG, Davis

PG, Faber B, Morley CJ

Review content assessed as up-to-date: 30 August 2007.

Short binasal prongs are more effective at preventing

re-intubation than single nasal or nasopharyngeal

prongs

RR 0.59 (CI: 0.41, 0.85)

Short Bi-nasal Prongs are more effective

CPAP Interface

Nasal Prongs vs Nasal Mask

Study (Year) Population Outcome Results

Yong et al, RCT

(ADC, 2005)

VLBW

(n=89)

Nasal trauma No significant difference

Primary site of trauma

Mask gp- Junction between nasal septum and

philtrum

Prong gp - Walls of nasal septum

Kieran et al, RCT

(Pediatrics, 2012)

<31 wk

(n=120)

Intubation within

72 hours of

starting CPAP

Less reintubation in prong vs mask gp

(28% vs 52%, p=0.007)

Goel et al, RCT

(Indian Pediatrics,

2015)

27-34 wk

(n=118)

Need for

ventilation

within 72 h of

initiating CPAP

Mask vs Prong

CPAP failure: 13% vs 25%; P= 0.15

PIE: 4.9% vs. 17.5%; P = 0.03

Nasal trauma: 36% vs 58%; P=0.02

Say et al, RCT

(Neonatology,

2016)

26-32 wk

(n=149)

Moderate/

severe BPD

Mask vs Prong

CPAP failure within 24 h of life: 0 vs 8%; p = 0.09

Median duration of CPAP: 2(1–3) vs 4(1–5) h, p <

0.01

Moderate & severe BPD: 2.7% vs 14.6%; p < 0.01

BPD/death: No diff

NIV: Recommendations

CPAP is modality of choice in preterm babies < 30 weeks at risk of RDS

Data is supportive for NIPPV to be used both as primary mode and in post

extubation phase

Starting CPAP can be 6 to 9 cm H2O

Delivery systems doesnot matter – Bubble CPAP being low cost device can

be preferred system.

During weaning HFNC can be used as an alternative to nasal CPAP for

some babies with advantage of less nasal trauma



NICU Care: Surfactant

Best mode of administration

Nebulized Surfactant

Surfactant + Budesonide

Aldana-Aguirre JC, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F17–F23

Less Invasive Surfactant Administration

Less Invasive Surfactant Administration

6 Trials, 895 babies

Reduction in composite outcome of death or BPD, BPD among survivors

Reduction in need for mechanical ventilatin within 72 hours of birth

Need for mechanical ventilation anytime during NICU stay

No differences in death or other morbidities

Aldana-Aguirre JC, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:F17–F23

Sur E or In Sur E

4 centers

Preterm babies < 34 weeks with RDS requiring CPAP were

either given surfactant by SurE (without intubation) or In

Sur E (with intubation)

175 babies in each group.

Need for MV in first 72 hours significantly low in Sur E

group (19% vs 40%, p < .01)

BPD was also significantly less

Jeena,et al. Pediatr Pulmonol. 2019 Nov;54(11):1747-1752.

Unanswered Questions with LISA

Need for sedation/analgesia

Fear of regurgitation of surfactant

Different studies have used different catheters (no comaprision yet)

Can we be more non invasive (Nebulized Surfactant)



Study design

•RCT single centerin Australia

•Preterm 29 to 33 weeks < 4 hrs requiring 22 – 30% O2

Intervention

•Randomized to Bubble CPAP or Bubble CPAP with nebulized poractant (200 mg/kg) using a customised vibrating membrane nebuliser (eFlowneonatal)

Results

•64 babies

•Reduced need of intubation with in 72 hours

•Conclusion

•Nebulized surfactant reduces need of intubation in 72 hrs in babies with mild RDS

Minocchieri S, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F7.

Surfactant: Recommendations

Animal derived surfactant

When – FIO2 needs > 30% on nasal CPAP

How – LISA

Which one – Poractant alpha in dose of 200 mg/kg is superior than

Poractant alpha 100 mg/kg or Beractant 100 mg/kg

Early rescue

If baby needs intubation in delivery room, give it as early as possible.



What happens when our earnest efforts

go in vain and baby is intubated?

Can we still improve outcomes?

Volume ventilation vs Pressure ventilation

Primary

Outcome

No of Studies

(Participants)

Effect size NNT Quality of

Evidence

(GRADE)

Death or BPD 8 (584) 0.73 (0.59 –

0.89)

8 Moderate

Pneumothorax 13 (825) 0.52 (0.31 -

0.87)

20 Moderate

IVH Grade 3 or

4

10 (712) 0.53 (0.33 –

0.77)

11 Moderate

Severe IVH or

PVL

6 (441) 0.47 (0.27 –

0.80)

11 Moderate

BPD 9 (620) 0.68 (0.53-0.87) 9 Moderate

20 trials, 1065 babies

Klingenberg C, Cochrane 2017

HFOV vs Conventional as primary

mode of RDS

19 studies, 4096 infants

No difference found in important outcomes.

At present consensus is put baby on conventional

mode first

Use HFOV as rescue therapy.

Cools F, Cochrane 2015

NICU Care

Non invasive mode Which

one

If at all ventilate


SurfactantSaturations and PaCO2

targetsCaffiene

Saturation targets: low(85-89%)vs High

(91 – 95%)

Outcome Effect size RR (95% CI) P value

Primary outcome (Death

or disability at 24 months)

1.04 (0.98 to 1.09) 0.21

Death 1.17 (1.04 to 1.31) 0.01

NEC 1.33 [1.10 to 1.61] .003

ROP 0.74 [0.63 to 0.86] < .001

5 trials, 4965 babies, median GA 26 weeks

Askie et al, Neoprom Metaanalysis, JAMA 2018

Conclusion

Although primary outcome was same in both groups.

Death and Severe NEC more in low saturation group

ROP was less in low saturation group

Recommendations

Target Saturations in NICU – 90-94%

Alarm limits 89% and 95%



Permissive hypercapnia: PHELBI Trial

16 centers in Germany

Birth weight 400 to 1000 grams, GA = 23 – 28 weeks

Babies who were intubated and ventilated with in first 24 hours of birth

Primary Outcome – Death or mod to severe BPD

Sample size – 1534 babies, trial stopped after 359 babies

Day of life High Target Group Control Group

D1 – D3 55 -65 mm Hg 40 – 50 mm Hg

D4 – D6 60-70 mm Hg 45 – 55 mm Hg

D7-D14 65-75 mm Hg 50-60 mm Hg

Thome et al, Lancet July 2015

PHELBI trial: Results

Primary outcome – same

Mortality (14% vs 11%, p= 0.32) and Grade 3 or 4 IVH

(15%vs 12%, p= 0.3) were higher in high target group

though not statistically significant

Follow up data at 2 years – No difference in

neurodevelopmental outcome.

Thome UH et al, Lancet July 2015

Thome UH et al, ADC Fetal and Neonatal edition 2017

NICU Care

Non invasive mode Which

one

If at all ventilate


SurfactantSaturations and PaCO2

targetsCaffiene

CAP trials till date

2006 babies between 500 grams to 1250 grams randomly assigned to

receive either Caffiene or placebo

Short term Results (36 weeks PMA)

Decrease Bronchopulmonary Dysplasia (36 vs 47%, OR 0.63 (95 CI 0.52-0.76,

p<0.001)

18-21 months data

Improves Rate of Survival without neurodevelopmental Disability at 18 to 21

months of age (40.2% vs 46.2%), OR 0.77 (95% CI 0.64-0.93), P=0.008

N Engl J Med. 2006 May 18;354(20):2112-21

N Engl J Med. 2007 Nov 8;357(19):1893-902.

CAP trials till date

5 years follow up data (1640 babies)

Neonatal caffeine therapy was no longer associated with a significantly

improved rate of survival without disability in children with very low birth weights

who were assessed at 5 years.

11 years follow up data

Reduced risk of motor impairment in 11-year-old children with very low birth

weight. No significant effect on combined motor, academic and behaviour

impairments.

JAMA. 2012 Jan 18;307(3):275-82.

JAMA Pediatr. 2017 Jun 1;171(6):564-572.

Review the timing trials

Problems with exisiting data on early vs

late caffiene

Only retrospective trials

High risk of bias and changes in practice despite adjusting for confounders

Difficult to do prospective trials

Providers unlikely to withhold caffeine for 3 days

Majority of US units are using caffeine between 2 to 12 hours (VON Data)

Increasing non invasive ventilation encourages earlier use of caffiene

High vs low dose

High (40 mg/kg loading followed by 20 mg/kg maintainence) vs Low (20 mg/kg loading followed by 10 mg/kg maintainence)

A total of 120 neonates (60 in each group) were enrolled.

High-dose caffeine

Significant reduction in extubation failure in mechanically ventilated preterm infants (p<0.05), the frequency of apnea (p<0.001), and days of documented apnea (p<0.001)

Need to be studied more.

Eur J Pediatr. 2015 Jul;174(7):949-56.

NICU Care

Non invasive mode

Which one

If at all ventilate


Surfactant

Saturations and

PaCO2 targets

CaffienePost natal

steroids

Early Hydrocortisone: Premiloc Study

21 French centers, Less than 28 weeks, 523 babies

Hydrocortisone in first 10 postnatal days (1mg/kg/d for first 7 days and 0.5

mg/kg/d for next 3 days)

Primary outcome – survival without BPD at 36 weeks

Results –

Survival without BPD (60% vs 51%, Adjusted OR 1·48, 95% CI 1·02-2·16, p=0·04)

2 years outcome –

No difference in neurologic impairment (mild, moderate, severe)

Premiloc study, Lancet. 2016 Apr 30;387(10030):1827-36.

Premiloc 2 years outcome, JAMA. 2017 Apr 4;317(13):1329-1337.

Hydrocortisone 7 to 14 days of life

Double Blind RCT in 19 NICUs in Netherland and Belgium,

< 30 weeks, Birth weight < 1250 grams

22 days course of hydrocortisone (cumulative dose 72.5 mg/kg)

Primary outcome – Death or BPD at 36 weeks

372 babies randomized

Results –

No difference in Death or BPD at 36 weeks

Hydrocortisone given between 7-14 days doesnot decrease Death or BPD at 36 weeks

Onland W, Stop BPD Study Group, JAMA. 2019 Jan 29;321(4):354-363..

Inhaled Budesonide

Metanalysis of 17 trials of inhaled budesonide

1807 babies

Significant Reduction in BPD (RR 0.79 (0.68-0.92)

Neurosis Trial

Same results but trend of increased mortality in inhaled budesonide group

was worrying.

Shah VS, Cochrane 2017

Bassler D, Neurosis trial. N Engl J Med. 2015 Oct 15;373(16):1497-506.

Surfactant with Budesonide –

Metaanalysis of 2 studies

381 babies from 2 studies

Surfactant + Budesonide was given every 8 hrly in intervention group vs

surfactant only every 8 hrly in control group

Results

Less BPD (RR 0.57 with 95% CI 0.43-0.76, NNT = 5)

Mortality same

40% reduction in composite outcome of death or BPD (RR 0.6 with 95% CI 0.49-

0.74, NNT = 3)

Large trials need to be done before reaching conclusions

Venkataraman R, Pediatr Pulmonol. 2017 Jul;52(7):968-975.

Summary of Recommendations:

Delivery Room

1. Gently support breathing using CPAP if possible, and if inflations are

needed avoid excessive tidal volumes.

2. Pulse oximetry can help guide heart rate response to stabilisation. Start with

21–30% oxygen for 28–31 weeks’ GA and 30% oxygen for <28 weeks’ GA

and titrate up or down as needed according to SpO2 targets.

3. Aim at SpO2 of 80% or more within 5 min.

4. Intubation at birth should be considered only for those not responding to

the above

Summary of Recommendations: NICU

1. An animal-derived surfactant should be used and given as early as possible

in the course of RDS.

2. Treatment threshold of FiO2 0.30 on CPAP pressure of 6 cm H2O seems

reasonable. Repeat doses of surfactant may be required if there is ongoing

evidence of RDS.

3. If possible, administer surfactant using the LISA method

4. If intubated, babies can often be extubated to CPAP, HFNC or NIPPV

immediately following surfactant, and judgement needs to be made if an

individual baby will tolerate this.

5. For those who require MV, use volume-targeted ventilation and saturation

alarm limits set at 89 and 95%.

Caffeine therapy should be used routinely to minimise need for ventilation.

Babies should be maintained on non-invasive respiratory support in

preference to MV if possible.

After 1–2 weeks, systemic steroids should be considered to facilitate

extubation if the baby remains ventilated.

In preterm babies receiving oxygen, the saturation target should be

between 90 and 94%. To achieve this, suggested alarm limits should be 89

and 95%.

Summary of Recommendations: NICU

Documents

Dr Naveen Parkash Gupta - Neocon2019 · Dr Naveen Parkash Gupta Areas of Interest - Ventilation, Hemodynamics, Care of ELBW baby MD Pediatrics, DNB Neonatology, Fellowship in Neonatology