Adjunct Therapy of Invasive

Mechanical Ventilation
Risma Kerina Kaban
Akhdan Aufa

Neonatology Division
Child and Health Department
Faculty of Medicine University of Indonesia
Cipto Mangunkusumo Hospital
Outline
• Surfactant Replacement Therapy During MV
• Nitrite Oxide Therapy During MV
• Antimicrobial Therapy During MV
• Methyl Xanthyne Therapy During MV
• Corticosteroid Therapy During MV
Surfactant Replacement Therapy During MV
• promote lung expansion during
↑ lung inspiration
compliance • prevent alveolar collapse at
end expiration
↓ surface tension at the
air-liquid interface in
the alveoli and distal • Facilitate clearing of lung fluid
↑ fluid
bronchioli clearance
as the surface tension draws
fluid across the alveolar wall

Functional residual capacity is maintained

Surfactant Gas exchange is enhanced
Work of breathing is substantially reduced
Surfactant Preparations and Recommended Doses

Generic Name Trade Name Source Producer Dose (Volume)

Ross Labs 100 mg/kg/dose
Beractant Survanta Bovine
(US) (4 mL/kg)

Lyomark 50 mg/kg/dose
Bovactant Alveofact Bovine
(Germany) (1,2 mL/Kg)

Chiesi Farmaceutici 100 – 200 mg/kg/dose

Poractan Alfa Curosurf Porcine
(Italy) (1.25 – 2.5 mL/Kg)

Bovine lipid extract BLES Biochemicals 135 mg/kg/dose

BLES Bovine
surfactant (Canada) (5 mL/Kg)

GlaxoSmithKline 64 mg/kg/dose
Colfosceril Palmitat Exosurf Synthetic
(US) (5 mL/kg)

ONY Inc. 105 mg/kg/dose

Calfactant Infasurf Bovine
(US) (3 mL/kg)
 Surfactant Indication
Born 10-30 minutes 2 hours 12 hours

Resusitation Stabilization of RDS Invasive or Non invasive ventilation in NICU for RDS

Prophylactic Early Rescue Surfactant Late Rescue Surfactant

Surfactant

High probability of RDS

Intubated babies
Established RDS
Europe : CPAP > 6cmH20; FiO2 > 30%  work of breathing, pCO2>60 mmHg, SpO2 <90%
IDAI : CPAP ≥ 8cmH20; FiO2 > 40%  work of breathing, pCO2>60 mmHg, SpO2 <90%

Engle WA. Pediatrics.2008;121:419-22

 Prophylactic VS Rescue Surfactant
• Prior to the routine application of CPAP demonstrated a ↓ in :
• Risk of air leak
• Neonatal mortality associated with prophylactic administration of surfactant
• However, the analyses of studies that allowed for routine stabilization on
CPAP demonstrated a ↓ in the risk of chronic lung disease or death in infants
stabilized on CPAP

When all studies were evaluated together,

the benefits of prophylactic surfactant could
no longer be demonstrated
Reyes R. Cochrane Databese Syst Rev. 2012, Issue 3. Art. No.: CD000510
 Early vs Delayed Surfactant

Author’s conclusion :
Early selective surfactant administration given to infants with RDS requiring
assisted ventilation leads to a decreased risk of acute pulmonary injury (↓ risk of
pneumothorax and pulmonary interstitial emphysema) and a decreased risk of
neonatal mortality and chronic lung disease compared to delaying treatment of
such infants until they develop worsening RDS

Early administration : Within 2 hours of Age Bahadue FL, Soll R. Cochrane 2012
Paediatrics & Child Health, 2021, 35–41
 Surfactant Administration
• Surfactant and stepwise weaning mechanical
ventilator
• INSUR-E (INtubate, - SURfactant – brief ventilation –
Invasive Extubate)
• INRECSURE (Intubate - RECruitment- SURfactant – brief
ventilation – Extubate)

• Catheter  feeding tube, umbilicat cath, etc

Minimally invasive • Small diameter tube (angiocath)
• Laryngeal mask

• Aerosol
Non Invasive
 INSURE VS Surfactan and Stepwise Weaning MV

• 6 randomized controlled clinical trials

• Intubation and early surfactant therapy followed by extubation to
nasal CPAP compared with later selective surfactant
administration and continued mechanical ventilation with
extubation from low ventilator support
 Decreased mechanical ventilation [typical RR 0.67, 95% CI
0.57 - 0.79]
 Decreased air leak syndromes [typical RR 0.52, 95% CI 0.28-
0.96]
 Decreased BPD [typical RR 0.51, 95% CI 0.26-0.99]
 Higher incidence of patent ductus arteriosus requiring treatment [typical RR
2.15, 95% CI 1.09, 4.13]
Syteven T.P. Cochrane Databese Syst Rev.2007;14.CD003063
 INSURE
• Reduced mortality  91.3%
survived
• Success rate was 74.6%
• Failure to extubate  sedative effect

Risk factor for INSURE failure are :

 GA < 28 weeks; BW< 1000
gram
 Hb < 14 g/dL
 Antenatal steroid used
 Apgar score < 7 at 5 minute
 Umbilical cord pH < 7,2
 Patent ductus arteriosus
 IVH
Naseh A. Turk J Pediatr.2014;56(3).232-7
Awayseh. Med Arch. 2019 AUG; 73(4): 240-243
Courtesy of dr. Lilly Rundjan and UKK Neonatologi IDAI
 INRECSURE
 Vento et al (RCT) to compare INSURE VS
INRECSURE  using HFOV

 The need for MV within the first 72 h of life

occurred 40% VS 60% :
RR 0.75, 95% CI 0.57–0.98; p=0.037 NNT
7,2

 No difference in all secondary outcome

Lung recruitment before surfactant

administration  improve gas exchanged,
lung function and better surfactant distribution
Lancet Respir Med.2020
1
Set mean airway pressure (MAP) at 6-8 cmH2O

2
and adjust FiO2 to give an SpO2 90-95% (A)

Increase MAP by 1-2 cmH2O every 2-3 min.

IN-REC-SUR-E
Reduce FiO2 stepwise by 0.05-0.10 to maintain
SpO2 90-95%
3
Stop increasing MAP when FiO2 is smaller than
Pre-surfactant opening continuous
0.3 or when FiO2 is not able to be decreased distending pressure (CDPO)
with an increase in MAP (B)
4
Decrease MAP by 1-2 cmH2O everey 2-3 min Pre-surfactant closing pressure (CDPC)
until SpO2 falls (C)
5
Recruit the lung again by returning to the known Pre-surfactant optimal pressure
CDP (step 3) for 2-3 min then decrease MAP to (CDPOPT)
2 cmH2O above the closing pressure (CDPC)
from step 4 (D&E)
Obtain chest X-ray & give surfactant
6

Extubate to nCPAP with acoordingly MAP

Jenny Pillow. HFOV Booklet.2016

 INSURE, Less Invasive Surfactant Administration
(LISA) and Minimal Invasive Surfactant Therapy
(MIST)

Different aspect INSURE MIST/LISA

Using laryngoscope Yes Yes
ETT Regular size Smaller diameter
Sedation Yes No/minimal
Vocal cord Can not be adducted Can be adducted
PPV Yes No
Surfactant delivery rate Bolus 5-10 S Bolus 30-60 S

Vento M.Neonatology.2019; 116(3):211-226

 1.An early rescue 1.Rescue surfactant should
surfactant should be be given early
1.Babies with RDS should be standard 2.suggested protocol  treat
given an animal-derived 2.but surfactant should be babies who are worsening
surfactant preparation (A1) given in the delivery suite if when FiO2 >0.30 on CPAP
intubation is needed for pressure of at least 6 cm
stabilisation H2O (B2)

1.A 2nd or 3rd dose of

1.LISA is the preferred mode surfactant should be given if
1.Poractant alfa initial dose of surfactant administration there is ongoing evidence
for spontaneously of RDS: persistent high
2. 200 mg/kg (A1) breathing babies on CPAP oxygen requirement and
(B2). other problems have been
excluded (A1).
Sweet et al. Neonatology 2019;115:432–450
Nitrite Oxide Therapy
1.Inhaled nitric oxide (iNO) therapy for the treatment of
newborns with hypoxemic respiratory failure and pulmonary
hypertension has dramatically changed management strategies
for this critically ill population

1.Multicenter randomized clinical studies have demonstrated

that iNO therapy reduces the need for extracorporeal
membrane oxygenation (ECMO) treatment in term neonates
with hypoxemic respiratory failure

Donn S.M (2017), Manual of Neonatal Respiratory Care.

 OXYGENATION INDEX (OI)

Oxygenation Index (OI) = Mean airway pressure MAP × FiO2 × 100

paO2

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

 Candidates for iNO Therapy

1. Newborns with hypoxemic respiratory failure

2. MAS has complicated cardiopulmonary pathophysiology
3. Atelectasis and air space disease (pneumonia, pulmonary
edema)
4. Adjuvant treatment before and after ECMO therapy in
patients with sustained pulmonary hypertension
5. Mechanically ventilated term or near-term infants with HRF
with clinical or echocardiographic evidence of PPHN
Assisted Ventilation of the Neonate, 7th Edition, 2021
Donn S.M , Manual of Neonatal Respiratory Care, 2017
 Indications for use
Term and late-preterm infants Preterm infants
≥ 34 weeks gestation (<34 weeks gestation)

• Clinical amd/or echocardiographic • Echographic evidence of PPHN with

evidence of PPHN including: structurally normal heart, and
− Hypoxic respiratory failure [oxygenation
− Hypoxic respiratory failure (OI >15),
index (OI) >15,
and/or
− and/or pre & post-ductal SpO2 difference
− Pre & post-ductal SpO2 difference 10%, when receiving an FiO2 > 1.0
≥ 10%, receiving an FiO2 > 1.0 or − OI > 20 when receiving an FiO2 > 0.8.
− OI > 20 when receiving FiO2 > 0.8. • No severe intraventricular haemorrhage
on cranial ultrasound

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

With iNO and Without iNO

Assisted Ventilation of the Neonate, 7th Edition, 2021

 Nitride Oxide Treatment Strategies

•Recommended starting dose for iNO in the term newborn is 20

ppm, but the dose was increased to 80 ppm -> if PaO2 was less
than 20 torr
Dose •Although brief exposures to higher doses (40–80 ppm) appear to
be safe, sustained treatment with 80 ppm NO increases the risk of
methemoglobinemia.

•In multicenter, clinical trials, the typical duration of iNO

treatment has been <5 days
Duration of Treatment •If iNO is required for >5 days, investigations into other
causes of pulmonary hypertension

• iNO was reduced from 20 to 6 ppm after 4 h of treatment

Weaning without acute changes in oxygenation.

Assisted Ventilation of the Neonate, 7th Edition, 2021

Donn S.M , Manual of Neonatal Respiratory Care, 2017
 Before commencing INO
• Indications for commencing INO should be fulfilled, without any
contraindications present
• Optimise the medical management:
− Ventilation: HFOV or conventional ventilation
− Cardiac function: review if volume and/or inotrope required
− Adequate sedation, analgesia and muscle-relaxation.
• An echocardiogram should be performed, where possible (or at the earliest
opportunity after commencing INO to exclude structural heart disease.
• Arterial line: Ideally a pre-ductal arterial line is inserted for all patients treated
with INO. However, a UAC is acceptable.

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

 Trial of use INO
When an arterial line is present, use the following guideline for a trial of INO:
1. An arterial blood gas is taken and an OI is calculated prior to commencement
2. Pre and post – ductal SpO2 and FiO2 are documented
3. INO is commenced at 20ppm (10ppm in preterm) for 30-60 minutes
4. A second arterial blood gas is taken and OI calculated to assess response
5. Pre and post-ductal SpO2 and FiO2 are documented.

When an arterial line is not present, use the following guideline for a trial of INO:
1. Pre and post – ductal SpO2 and FiO2 are documented
2. INO is commenced at 20ppm (10ppm in preterm) for 30-60 minutes
3. Pre and post-ductal SpO2 and FiO2 are documented.

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

 Assessment of Response INO
No response
• No change in FiO2 after 30-60 minutes of INO
• No change in OI after 30-60 minutes of INO
• No change in pre and post-ductal difference after 30-60 minutes of INO (remains 8-10% difference).

Partial response
 10-18% reduction in FiO2 and/or
 10-18% reduction in OI
 Pre and post-ductal SpO2 difference reduced to 3-6%.

Response
 ≥ 20 % reduction in FiO2 and/or
 ≥ 20 % reduction in OI
 ≥ pre and post-ductal SpO2 difference reduced to ≤ 2%.

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

 Weaning FiO2 until down to 0.6

Wean INO from 20 to 15 ppm

Weaning Wait 1 hour, if no deterioration, wean to 10 ppm

Full response INO for
the term Infant
When down to an acceptable MAP and FiO2
< 0.6, commence weaning INO from 10ppm

Wean INO by 2ppm hourly until down to 4ppm

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014 Wean INO by 1ppm every 2 hours until ceased
 Weaning FiO2 until down to 0.6

Wean INO from 10 to 5 ppm

Weaning Wean MAP as determined by the pathophysiology

of the lung and/or clinical condition
Full response INO
for the Preterm Infant
When down to an acceptable MAP and FiO2
< 0.6, commence weaning INO from 5ppm

Wean INO by 1ppm 1-2hourly until ceased

Nitric Oxide - Use in NISC, Royal Women Hospital, 2014

 Respiratory disorders were the
commonest indication of MV in
NICU mostly RDS.

Othman, A.A., et al, Open Journal of Pediatrics, 2020

 Adjunctive Treatments Antibiotic

• No consensus guidelines for specific

antibiotics  empiric broad spectrum
antibiotic as first line
• The second line based on the result of
culture and sensitivity testing
• The third choice is for the MRSA
(Stapphylococcus aureus) 
Vancomycin

Goerens A et al, Front. Pediatr, 2018

 Adjunctive Therapy Methylxanthine
Mechanisms of action
a.Increase diaphragmatic contractility
Indication and decrease fatigability
b. Direct stimulant of respiratory
- Ventilatory support
center
- Peri-extubation support c. Reset CO2 responsiveness
- Apnea or periodic d. Diuretic effect
breathing
Complications
a. Gastric irritation and vomiting
b. Tachycardia
c. CNS irritation and seizures

Donn S.M , Manual of Neonatal Respiratory Care, 2017

 Benefits Caffein
• Faster weaning
• Reduced MV duration
• Decreased BPD
• Improved neurodevelopmental outcomes at 18 to 22 months of
age

Dose Caffein Citrate Periextubation

Loading dose 20 mg/kg and maintenance dose10/kg/day

Assisted Ventilation of the Neonate, 7th Edition, 2021

Moschino L, et al. ERJ Open Res 2020
 Theophylline
Contraindications and
Cautions
Dose Blood level monitoring indicated
PO, IV: (therapeutic range: apnea, 7–12
loading dose 5–6 mg/kg; mcg/mL; bronchospasm,
maintenance dose 1–2.5 mg/kg/dose 10–20 mcg/mL)
q6–12h;
Tachycardia (therapeutic range
Aminophylline (IV) dose = 15–20 mcg/mL)
Theophylline (IV) dose x 1.25
Seizures (therapeutic 40 g/mL
avoid rectal)

Assisted Ventilation of the Neonate, 7th Edition, 2021

 CAFFEINE VS THEOPHYLINE

Caffeine is the preferred first-line of treatment of AOP as it has a

wider therapeutic range and is associated with less adverse events
compared to theophylline

Abdel-Hady H et al. World J Clin Pediatr 2015

 Neonates treated by caffeine were at a higher risk of extubation failure (1.09 times) adjusted with
birth weight (31.5% versus 21.4%; RR=1.09) which was not statistically significant

Shivakumar M, et al Iranian Journal of Neonatology. 2017

 Adjunct therapy Corticosteroid

Prolonged exposure to invasive proportion of BPD increased from 15 days of

mechanical ventilation using an mechanical ventilation and became the
endotracheal tube is generally associated leading cause after 3 months of cumulative
with multiple poor outcomes mechanical ventilation

Choi, Y.-B., (2018). The Journal of Pediatrics

Postnatal corticosteroids have been used to prevent and treat

bronchopulmonary dysplasia (BPD), a significant cause of morbidity
and mortality in preterm infants

Paediatrics & Child Health, 2020

 ADVERSE EVENTS POTENTIALLY RELATED
TO SYSTEMIC CORTICOSTEROID TREATMENT
Steroids usage for treatment of BPD also has been shown to have adverse outcome

Hydrocortisone Dexamethasone
- Air leaks - Hyperglycemia
- Pulmonary haemorrhage - Hypertension
- Insulin requirement - Hypertrophic cardiomyopathy
- Late-onset sepsis - Gastrointestinal bleeding, and perforation
- Necrotising enterocolitis (increases with concomitant indomethacin treatment)
- Gastrointestinal perforation - Chronic suppression of the hypothalamic-pituitary-
- Severe brain damage adrenal axis
- Death before discharge - Cerebral pasly
- Severe retinopathy of prematurity - Long-term neurodevelopmental delay

Gupta S, et al.. BMJ . 2012

Baud O, et al., randomised trial. The Lancet. 2016
Timing of postnatal corticosteroid

• Early (< 7 days)

• Moderately early (7-14 days)
• Late (> 3 weeks)
…..Timing of postnatal corticosteroid
• Optimal timing  should maximise pulmonary benefit without
increasing neurodevelopmental risk

Effect of delay administration :

Early exposure • Increase cumulative days of
mechanical ventilation
< 8 days – safety • Development of BPD
concern • Neurodevelopmental Impairment

O’Shea, et al. Pediatrics. 1999

Yeh TF, et al. Pediatrics. 1998
• HC 22 d (72 mg/kg) vs placebo
• N=372; GA=25.5; BW=750 g
• Primary outcome: death or BPD @ 36 wk

Among mechanically ventilated very preterm infants, compared to

placebo, administration of systemic Hydrocortisone did not improve
outcome (death or BPD at 36 weeks postmenstrual age)
Wes Onland, PhD, et al, JAMA 2019
 Comparison Lower versus higher cumulative dose dexamethasone regimen
Outcome 7 Days of mechanical ventilation

The duration of mechanical ventilation was significantly shorter in the high-dose

regimen compared to the moderate-dosage regimen

OnlandW, et al.. Cochrane Database of Systematic Reviews 2017

• 36 preterm infants
• Birth weight ≤ 1250 g, GA ≤ 30 weeks
• Oxygen and ventilator dependent at 2
weeks
• Received 42- day course of
dexamethasone VS 18-day course,
or placebo
• Starting dose of dexamethasone : 0.5
mg/kg/day
• No clinical complications of steroid
• Good neurodevelopmental outcome in
78% infants in 42-day group vs 22% in
18-day group

Cummings, et al. NEJM. 1989

 Cummings protocol

• Dexamethasone 42 days Dexamethasone 18 days

• 0.5 mg/kg/day, 3 days • 0.5 mg/kg/day, 3 days
• 0.3 mg/kg/day, 3 days • Reduce dose 50% every
3 days until dose 0.06 mg
• Decrease by 10% every per kg reached on day 10
3 days, until dose of 0.1 • 0.06 mg per kg at day 13
mg/kg/day on day 34 every second day until
• 0.1 mg/kg/day, every day 18
second day, until day 42
• Total dose 7.86 mg/kg Total dose 2.985 mg/kg
 Low Dose (DART) Regimen Dexamethasone
Consensus Australasian neonatal Medicines Formulary
(ANMF) 2021

ANMF Consensus Dexamethasone, 2021

 Moderate Dose Regimen Dexamethasone
Consensus Australasian neonatal Medicines
Formulary (ANMF) 2021

ANMF Consensus Dexamethasone, 2021

 High Dose Regimen Dexamethasone
Consensus Australasian neonatal Medicines
Formulary (ANMF) 2021

ANMF Consensus Dexamethasone, 2021

 Extubation Protocol Corticosteroid

• To Prevent Failure of ET Extubation and Post Extubation Stridor

• IV,Oral : 0,25 mg/kg/dose 8 hrly for 3 doses. Give Last Dose 1

hour prior to extubation

RWH Neonatal pharmacopoeia, 2005

Evaluation after use Corticosteroid
• Hypertension and Hyperglycaemia may occur
• Monitor BP and blood glucose
• Ensure all existing infections are treated before commencing
dexamethasone
• Oral antifungal medication (nystatin) to commence on day 1 of
treatment and continue for three days after dexamethasone has
ceased

RWH Neonatal pharmacopoeia, 2005

 Conclusion

Adjunctive therapies are interventions designed to help preterm

infants maintain adequate gas exchange and respiratory effort
during the weaning and postextubation periods
Thank You