Respiratory management of preterm infants: primary respiratory therapy with CPAP or intubation and surfactant

This guideline presents two alternative strategies for initial respiratory support of the preterm infant at risk of respiratory distress syndrome. 

1) Primary therapy with nasal CPAP with mechanical ventilation as a rescue strategy  

2) Initial ventilation & surfactant administration, with consideration of early extubation to CPAP.

The choice of strategy will depend on a number of factors including the size and gestation of the infant, exposure to antenatal steroids, condition at delivery, experience of the staff in the delivery unit, any requirement for transportation to another hospital postnatally etc.  All these factors will require consideration by the paediatric team at the time of delivery and an appropriate strategy chosen.  See later sections of the document for a review of the evidence for these strategies.

Types of CPAP Machine & Interfaces:

The preferred method of CPAP delivery is by short binasal prongs or nasal mask using an Infant flow driver interface with humidification of the inspired gases (devices using this interface include – Infant Flow Driver, Viasys SiPAP and the Inspiration Systems Fabian ventilators / CPAP). This method of CPAP delivery, utilising the fluidic flip model, is more physiological, reduces the work of breathing and has been shown to be more effective. Where a device utilising such an interface is not available e.g. in labour ward, or for transfer to the neonatal unit, CPAP may be given via a face mask for transfer.  The infant should be transferred to an appropriate CPAP device as soon as is practicable.

CPAP initiation and Maintenance:

• CPAP should be started at least 6-7 cm H₂O and may be increased in increments of 1-2 cm H₂O based on the clinical situation (increased work of breathing, increasing respiratory acidosis, increasing oxygen requirement and increasing apnoea). However if higher pressures are required this may indicate the need to consider intubation and surfactant
• Each increment should be reviewed by a senior, and if needed by Chest X-ray/ blood gas.
• An initial oxygen requirement may be present during lung recruitment and this may be tolerated as long as this is stable or reducing and no other criteria for intubation are present.
• Caffeine citrate therapy should be commenced as soon as possible for infants <32 weeks gestation.

Complications associated with CPAP:

1. Air leaks (pneumothorax, pneumo-pericardium and pneumo-peritoneum).
2. Nasal excoriation, nasal septal injury (pressure necrosis), bleeding and secondary infection.
3. Gastric distension and Feed intolerance. The former may be minimised by having an orogastric tube, on free drainage, to decompress the stomach.  However it should be noted that randomised controlled trials have not shown any effect of gastric distension on the time taken to reach full enteral feeds.
4. Delay in surfactant treatment may lessen the surfactant effect.

Predictors of CPAP Failure:

Current evidence suggests that more than 50% of preterm infants not manage on CPAP therapy alone.  These babies will require intubation and surfactant therapy.  Evidence from systematic review would suggest that the effects of surfactant are greater when given early in the disease process.  It is therefore essential to identify early those infants who are going to fail CPAP.   Such a decision is based on multiple factors and a thorough clinical assessment, which should take into account the size and maturity of the infant, whether they received antenatal steroids, and the stage of their respiratory illness
(NB - lower thresholds should apply for an infant in the first few hours after birth). 

The following factors should prompt a consideration of the need to ventilate the infant.

• Worsening Respiratory distress – As evidenced by increasing tachypnoea, recession, use of accessory muscles etc
• Poor respiratory drive – As evidenced by periods of hypoventilation despite caffeine therapy
• Recurrent apnoea - ≥6 apnoeas within last 6 hours requiring stimulation / increased oxygen or 1 episode requiring IPPV despite caffeine therapy
• Persistent Increase in Fio2 requirement - Any infant with an FiO2 >40% OR, in the first few hours, any persistent rise in FiO2 associated with an increased work of breathing   
• Worsening Respiratory acidosis - PCO2 8-8.5kPa with H+ >60 nmol/l.
• Worsening hemodynamic status - Hypotension + poor perfusion requiring multiple saline infusions or inotropic support for > 2h.

Intubation in the labour suite

Clinical assessment at the time of delivery should take into account the size and maturity of the infant, antenatal steroid therapy, and the condition immediately following delivery.  The clinician may choose to intubate electively, on the basis of this assessment, or if one of the following is true.

• Asystole or persistent bradycardia in spite of effective resuscitation
• The infant demonstrates an increased work of breathing and consistently requires high FiO2 on initial CPAP

Where intubation is required in the delivery suite this will normally be performed without sedation.  Clinicians should refer to the intubation guideline to choose an appropriately sized ETT and determine the insertion length.  A method of detecting exhaled CO2 should be used to ensure that the ETT is correctly placed.  The appropriate insertion length should be confirmed both by ensuring that the position at the lips matches the predetermined insertion depth and by confirmation of equal air entry by auscultation.

Following this assessment the clinician may choose to administer an initial dose of surfactant prior to transfer or they may elect to administer surfactant following a confirmatory CXR on arrival in NICU.  See below regarding surfactant administration.

Intubation in NICU

Initial intubation in NICU usually results from the infant having met the above criteria for CPAP failure detailed above, although it may be required for other reasons, such as the need to transport an infant to another centre for ongoing care.  A persistent and rising oxygen requirement in the first few hours after birth may be an indication for intubation even at relatively low levels of oxygen requirement, especially if associated with a an increased work of breathing.  Later in the infant’s course, a higher level of FiO2, up to around 0.40, may be tolerated if none of the other criteria are met
Unless the infant requires urgent intubation this should be performed with sedation and paralysis - clinicians should refer to the separate guideline for premedication and intubation.

Following intubation a CXR should be performed promptly to ensure appropriate positioning prior to surfactant administration (if required).

NB - If FiO2 is rising rapidly consider DOPE

D – Displacement of ETT or CPAP prongs

O – Obstruction of ETT or nasal airway. Consider suction of ETT or nose as appropriate

P – Pneumothorax listen to air entry bilaterally, consider cold light / CXR

E - Equipment failure

If these are excluded then this may represent worsening RDS and need an increase in respiratory support. Senior review is advised

Surfactant

Type - The surfactant currently used in all neonatal units in the West of Scotland is Poractant alpha (Curosurf).

Timing of administration – Early (<2h) surfactant therapy is more effective than delayed surfactant therapy.  An initial dose may be given at birth in infants at high risk of RDS who are intubated on labour ward, or after an early CXR if electively intubated on the neonatal unit.

Initial Dose – The licensed initial dose is 100-200 mg / kg with evidence that the higher dose is more effective and results in the need for fewer repeat doses.  Given the cost per vial, it is usual practice to give multiples of whole vials (120 / 240 mg vials available) to approximate this dose.  If administering surfactant on labour ward where the weight is unknown it is reasonable to administer a whole 120mg vial and to consider a supplementary aliquot on arrival in NICU once the weight is known.

Repeat doses - Additional doses of surfactant may not be required for infants with low respiratory support requirements after the initial dose.  Such infants may meet the criteria for early extubation – see below.  One or two further doses may be administered if the infant continues to require high FiO2 or Inspiratory pressures.  The licensed dose for such additional treatments is 100 mg/kg, again usually giving a multiple of whole vials to approximate this dose.

Technique – To ensure even distribution, ensure the correct length of ETT insertion as described above.  Administer via a fine bore catheter inserted down the ETT, ensuring that the catheter is slightly shorter than the length of the ETT.  Administer as a single aliquot over 5-10 seconds (more rapid administration may induce a cough reflex forcing expulsion of part of the dose).  Ensure there is no surfactant bubbling up into the ETT connector before reconnecting to a ventilator, as this may damage the sensitive flow monitor of the ventilator.  (This may require a few manual breaths via a NeoPuff or Ambubag until surfactant is no longer visible in the ETT).  For a few minutes only, keep the head upright and the ETT held above the baby to ensure the whole dose has been absorbed before returning the infant to a developmentally appropriate position for ongoing care.

Post surfactant management – Lung compliance may improve rapidly after surfactant administration.  This will require close attention to weaning the Inspiratory pressures, or the use of a volume targeted ventilation strategy.  (see below)  

Caffeine therapy
All infants <30 weeks gestation and any infant <32 weeks with poor respiratory drive should be commenced on caffeine therapy, even if there are no immediate plans to extubate.  This improves respiratory mechanics and is a prerequisite for the consideration of early extubation.

Ventilation strategies

Ventilation strategies should aim to minimize lung injury by avoiding overinflation. 

Volume targeted ventilation (Volume guarantee (VG) / Targeted Tidal Volume (TTV)) as an adjunct to a Patient triggered ventilator mode (Patient triggered ventilation (PTV) / Synchronised intermittent positive pressure ventilation (SIPPV) / Assist-Control (A/C)) has been shown to reduce lung injury and subsequent Chronic Lung Disease.  If such a mode is not used then close attention will be needed to ventilation to ensure that appropriate weaning occurs as compliance improves.

pCO2 levels

It is unnecessary, and potentially injurious, to target “normal” CO2 values.  CO2 values of up to 8-8.5 kPA may be tolerated, assuming the infant can maintain an acceptable H⁺ <60 – 65 nmol/l).

Sedation/Paralysis

Routine use of sedation or paralysis is discouraged as it is known to prolong the time on ventilation.  Infants should be regularly assessed for pain or discomfort and offered appropriate analgesia as indicated.

Consideration of early extubation
If an infant has a good response to Surfactant then consideration should be given to early extubation to non-invasive respiratory support.  As with intubation, a full clinical assessment is required but if early extubation is considered the infant should fulfil the following criteria

• Consistent, spontaneous breathing
• Minimal or no sedation.
• Paco2 <8 and Fio2 <30%.
• Mean airway pressure of 8-10.
• No hemodynamic compromise.

Extubation may be to CPAP, high flow or to air, dependent on the size and maturity of the infant and the presence or absence of residual respiratory symptoms.

Abbreviation: BPD: Broncho-Pulmonary dysplasia, CLD- Chronic Lung disease CPAP: Continuous Positive airway pressure, FRC: Functional Residual capacity; LISA: Less invasive surfactant administration, MIST: minimally invasive surfactant treatment, NDI: Neuro-Developmental Impairment; NLS: Neonatal life support; PIE: Pulmonary Interstitial emphysema; RCT: Randomized control trial, RDS: Respiratory distress syndrome.

Definitions:

• Primary CPAP: Initiation and maintenance of CPAP for those preterm infants who are at risk of RDS, after initial period of resuscitation, even before signs of RDS develops.
• Effective CPAP: consistent and effective CPAP is usually delivered by use of bi-Nasal prongs/Nasal mask with heated, humidified gas (CPAP/Flow driver).
• Prophylactic surfactant: Intubation and administration of surfactant to those infants who are at risk of RDS, after initial period of resuscitation, even before signs of RDS develops usually within 10-30mins of life.
• Surfactant treatment: administration of surfactant to those infants who have established RDS. Rescue: usually within12 hours when specific criteria for RDS severity was met. Early use of Surfactant: Usually within 2hrs, those who have signs of/Risk of RDS.

Research Questions & Search strategy: Research questions were developed to define the optimal respiratory management in the preterm population (24+0 weeks to <=32 weeks) to improve both short term and long-term outcomes. We used Systematic review method of literature search.

CPAP at Delivery

Earlier systematic review on prophylactic surfactant showed decreased risk of pneumothorax, a decreased risk of pulmonary interstitial emphysema and a decreased risk of mortality when compared to selective use of surfactant. But there was no routine use of CPAP in the control arm of the studies⁵.

Four recent major RCTs: SUPPORT (24 wks-27 6/7wks), COIN (25+0/7wks -28 6/7), VON (26-296/7wks), CURPAP (25+0/7wks -28 6/7), showed individually no difference in the primary outcome of death or BPD between the CPAP and intubation groups, but did show a positive short term respiratory outcomes including the need for intubation, days of mechanical ventilation, mechanical ventilation at 7days, and post natal steroids use for BPD in the CPAP group. The overall meta-analysis with 1296 infants in the CPAP group and 1486 in the intubation group showed a significant benefit for the combined outcome of death and/or BPD in the CPAP group (RR 0.91, 0.84 to 0.99, Number needed to treat 25)⁶. The SUPPORT trial also showed a significant decrease in mortality, [23.9% vs. 32.1%, RR=0.74, (0.57, 0.98), p=0.034] in the immature strata of 24 to 25 6/7 weeks gestation randomized to CPAP. Moreover in the latest Cochrane review it has been shown that prophylactic use of surfactant is associated with higher risk of death /BPD ((RR: 1.12; 95% CI: 1.02–1.24; P <. 05)⁷.

Limitations of these trails:

• All these trials are done in spontaneously breathing infants.
• Except for SUPPORT study all the trails have enrolled preterms with gestational age of 25 weeks and above. So data for 24 weeks is only from SUPPORT study.
• In all these trails, indications for intubation is different and there are differences in their methodology.
• Different types of CPAP devices were used in these trials.
• Each center has different levels of experience with usage of CPAP.
• 50-75% of infants in these trials got intubated at some point.

With the understanding of these limitations, it is evident from the studies that CPAP is at least as effective/better than intubation in preterm population for prevention BPD or BPD/death.

Rationale for CPAP: CPAP increases the trans-pulmonary pressure and increased thoracic gas volume, thereby maintaining functional residual capacity (FRC) and recruits the collapsed alveoli. This increases surface area for gas exchange, reduces the amount work done by the infant each time and reduces intra-pulmonary shunt. This also triggers the release of surfactant from the pool. In animal studies constant distending pressure was also associated with lung growth.

Types Of CPAP Machine & Interfaces: Infant flow driver, which works on the fluid flip model, is more physiological and shown to reduce the work of breathing and shown to be effective. Use of either short Bi-nasal prongs or nasal mask is the current practice. Discussion about individual CPAP machines/interfaces is beyond the scope of this review.

CPAP initiation and Maintenance:

• CPAP should be started at least 6-7 cmH2O and may be increased by increments 0f 1-2 cm H₂O based on the clinical situation (increased WOB, increasing respiratory acidosis, increasing oxygen requirement and increasing apnea) up to the maximum pressure of 10 cmH₂
• Each increment should be reviewed by a senior, and if needed by C-X-ray/ blood gas.
• Consider BiPAP beyond CPAP pressure of 8 cmH₂
• If pressures > 8 cmH₂O are required consider whether intubation is required.

Complications Of CPAP:

• Air leaks (pneumothorax, pneumo-pericardium and pneumo-peritoneum). It is evident from COIN trail that higher CPAP pressures (range of 8-10) may be associated with increased chance of air leaks.
• Nasal excoriation, nasal septal injury (pressure necrosis), bleeding and secondary infection.
• Gastric distension and Feed intolerance, but in many of these RCT, the time to reach full feeds is not different between the groups.
• Whether delay in surfactant treatment may lessen the surfactant effect, is still debatable.

Indication for Intubation.

• Indications for intubation during resuscitation are pragmatic and not based on evidence.
• Cochrane meta-analysis of early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants showed that lower treatment threshold (FIO2<0.45) confers greater advantage in reducing the incidences of air-leak syndromes and BPD; moreover a higher treatment threshold (FIO2 at study > 0.45) was associated with increased risk of PDA⁸.
• Most of the studies (SUPPORT, VON DRM, CURPAP) in the recent systematic review, defined CPAP failure and considered intubation when Fio2 of 40-50%, Pco2 of 60-65mmHg /8-8.5kPa with pH <7.22 and recurrent/severe apneas.
• This suggests that having threshold of 40-50% to intubate is preferable to later selective surfactant treatment.
• Apart from the issue of oxygenation, worsening respiratory distress, poor respiratory drive and hemodynamic instability could either in combination or even individual factor may be an indication for intubation.
• Low threshold to intubate in preterms with no complete antenatal steroids, preterm infants with lower gestational age (≤26 weeks) and lower birth weight (<1Kg).
• Oxygenation: Persistent Fio2 requirement of >40% to maintain SpO2 in the target range (based on the unit policy) even with optimal CPAP/NIPPV support.
• Recurrent/Severe Apnea (adapted from major RCTs): ≥6 apneas within last 6 hours requiring stimulation/intervention or 1 episode requiring positive pressure ventilation, in spite of optimal CPAP/BiPAP support and optimal caffeine therapy.
• Respiratory Acidosis: see the section “Permissive Hypercapnia”.
• Many a times assessment of respiratory distress is subjective, but use of a standardized scoring system like Silverman-Anderson score (Appendix 1) may help us in uniform objective assessment of respiratory distress.

Permissive Hypercapnia⁹

• Theoretical benefits of permissive hypercapnia are improved oxygen delivery (Bohr effect), increasing respiratory drive and enhancing host defense.
• By having higher PCO2 targets, the mean airway pressure/PIP required will be less and thereby least of barotrauma.
• Retrospective studies in CDH infants have shown that permissive hypercapnia was associated with improved survival and decreased need for ECMO.
• There are 7 RCT analyzing the outcome of permissive hypercapnia.
• 3 of the RCT (2 of them terminated prematurely) primary research question were about permissive hypercapnia and they showed no difference in any outcome.
• Recent, larger RCTs (COIN, SUPPORT, VON, NeoCosur) the primary objective is to evaluate the outcome of intubation versus CPAP and one of the indications for intubation was Pco2 (8-8.5 kPa with H+ > 65 nmol/l).
• By showing no difference in the primary outcome (BPD/Death), it is clear that Pco2 in high range (8-8.5 kPa with H+ < 65 nmol/l) may be safe.

Ventilation Strategies ¹⁰:

• Cochrane review with 12 RCT have shown that use of Volume targeted ventilation resulted in reduction of death or BPD (RR 0.73; 0.57-0.93), reduction in pneumothorax (RR 0.46; 0.25-0.84), days of ventilation (RR ;) and combined outcome of Intra ventricular hemorrhage/Peri-ventricular leukomalacia (RR 0.48 (95% CI 0.28 to 0.84) and helps in rapid weaning of ventilation (auto-weaning)¹¹.
• Assist control/ Patient triggered ventilation is more physiological, decrease the work of breathing by supporting every spontaneous breath (overcome the resistance of small endotracheal tube).
• Other ventilation strategies and High frequency ventilation are beyond the scope of this review.
• Regular use of sedation and muscle relaxants should be avoided.
• Every unit should have standard respiratory support weaning guidelines and extubation criteria.

Predictors of CPAP Failure:

• Based on the systematic review that early surfactant is beneficial and more than 50% of preterm infants fail CPAP, it is essential to identify early those infants who are going to fail CPAP.
• There are few retrospective studies available and all these studies were variable with results to predict CPAP failure^12-14.
• As we can expect the consistent factor for prediction of CPAP failure in all these studies were lower gestational age and lower birth weight.
• There is no clear evidence available with respect to Fio2 Requirements and other similar oxygenation criteria (like Pao2/Fio2, a-A Do2, product of CPAP pressure with Fio2) to predict CPAP failure.

Early Surfactant (<2hrs) Vs. Delayed surfactant:

• The meta-analyses with six RCT (4 used animal surfactant and 2 used synthetic surfactant) demonstrate significant reductions in the risk of neonatal mortality (RR 0.84; (0.74 to 0.95); chronic lung disease (RR 0.69; (0.55 to 0.86); and chronic lung disease or death at 36 weeks (RR 0.83; 0.75 to 0.91) associated with early treatment of intubated infants with RDS.
• Intubated infants randomized to early selective surfactant administration also demonstrated a decreased risk of acute lung injury including a decreased risk of pneumothorax (RR 0.69; 0.59 to 0.82;), pulmonary interstitial emphysema (RR 0.60; 0.41 to 0.89) and overall air leak syndromes (RR 0.61; 0.48 to 0.78)⁷.

Uses of surfactant:

• It is one of the well-studied drug therapies in neonatal medicine, which improved neonatal survival.
• Short term: improves Functional Residual capacity (FRC) and surface area for oxygenation and decreases the barotrauma.
• Systematic review on Surfactant use in established RDS have shown to reduce mortality, air leaks (pneumothorax, PIE), and BPD (at 28 days) /death ¹⁵. This surfactant therapy is more effective in preterms <30 wks. Birth wt. <1250g¹⁶.

Surfactant administration:

• To avoid uneven distribution of surfactant to one side of lung, consider confirmation of ETT position by chest X-ray, prior to surfactant administration.
• Large volumes, given as single bolus of surfactant will have better distribution than smaller dose/multiple aliquots distribution^17,18.
• There is limited data regarding benefits with maintenance of PEEP during surfactant administration (surfactant through side port adaptor).
• Until further optimum methods are described surfactant should be administrated as single bolus with largest dose possible and administered either through main port/side port as per the unit policy.

Post Surfactant Management:

• There is no clear evidence to answer whether mechanical ventilation or PPV with neopuff/ Flow inflating bag is better after the surfactant administration.
• Desaturation and bradycardia is a frequent event in all the clinical trails, post surfactant administration.
• If the desaturation/bradycardia is not improving consider increasing the PIP and/or Fio2.
• Once the surfactant is administered great care is needed to wean the ventilator settings as the compliance improves very rapidly.

Types of surfactant.

• With widespread use of curosurf in UK and proven clinical benefits (systematic review) of reduced mortality rates, reduced need for re-dosing and initial respiratory support¹⁹, it is recommended to use curosurf (at a dose of 200mg/kg).

Repeat Doses Of Surfactant.

• Single treatment dose of 100-200mg/kg surfactant is very large relative to the surfactant pool of preterm animal (>4mg/kg)²⁰.
• With long half life of surfactant of 12hrs, repeat dose of surfactant is unlikely to be needed, unless there is surfactant inactivation by blood /meconium.
• Many of the trials had scheduled doses of surfactant rather than based on clinical presentation like residual RDS. Those trials that used repeat doses of surfactant, many responded, few of them didn’t show any response probably due to underlying conditions like Pneumonia/pulmonary hypoplasia ^21,22.
• In the recent era of higher antenatal steroid coverage, primary CPAP there are no prospective clinical trials for repeat dose of surfactant.
• Repeat dose of surfactant should be individualized based on the residual lung disease which if not treated could lead to complications like prolonged ventilation/pneumothorax.