Managing infants on bubble continuous positive airway pressure (Bubble CPAP) is like learning how to

​In the past, infants with respiratory distress syndrome (RDS) were intubated, mechanically ventilated and administered surfactant via an endotracheal tube (ETT). However, clinicians are now practicing in the era of widespread use of non-invasive ventilation (NIV). While increased use of NIV avoids the negative physiologic effects of intubation and mechanical ventilation, it has left infants without the traditional means to obtain surfactant, a medication which has been proven to dramatically improve RDS. In an effort to still provide surfactant, “less-invasive” methods to deliver surfactant into the lungs have been developed. Among these methods are: INSURE (INtubation, SUrfactant administration, Rapid Extubation), MIST (Minimally Invasive Surfactant Therapy)/LISA (Less Invasive Surfactant Therapy), LMA (Laryngeal Mask Airway) and nebulization/aerosol administration. While the contemporary methods are certainly “less invasive” than the traditional method of intubation and mechanical ventilation, they still remain “invasive”. This review will examine the different methods and discuss considerations involved when determining which method is to be used.

Contemporary methods available for surfactant administration

INSURE

The INSURE technique was the earliest to be developed and is the most widely studied. First described in a pilot study by Victorin1 in 1990 and further by Verder2 in Denmark in 1999, the technique mimics the “traditional” method of intubation, with use of a laryngoscope to place an ETT , and administration of surfactant through the ETT. However, unlike the tradition method of maintaining or slowly weaning (hours to days) off mechanical ventilation, INSURE aims for immediate or rapid (within minutes or hours) extubation.

LISA

The next technique to be developed was LISA (also called the Cologne method). Introduced by Kribs3 and co-workers in Cologne, Germany in 2007, this technique involves use of a laryngoscope and Magill’s forcep to pass a thin (2.5- 5 French), flexible feeding tube through the vocal cords into the trachea for surfactant administration. Infants remain on non-invasive ventilation (NIV), surfactant is administered in small boluses over 1-3 minutes, and infants remain spontaneously breathing throughout the procedure. A video of this procedure can be found at Application of surfactant to a spontaneously breathing preterm infant.

MIST

The MIST technique (also called the Hobart method), was first described by Dargaville4 in Hobart, Australia in 2011. This technique is similar to LISA but a vascular catheter (rather than a feeding tube) is passed through the vocal cords into the trachea for surfactant administration. Because the vascular catheter is semi-rigid, a Magill’s forcep is not required. With this technique, infants remain on NIV, surfactant is administered in small boluses over 1-3 minutes, and infants remain spontaneously breathing throughout the procedure5. A video of this procedure can be found at Surfactant instillation via thin catheter – the Hobart method.

Because of the similarities between LISA and MIST, meta-analyses have grouped these techniques and refer to them as the “thin catheter administration (TCA)”. In this review, LISA and MIST will collectively be referred to as TCA.

In addition to feeding tubes and vascular catheters, new “purpose- built” catheters and special introducers are now available.

LMA

Use of an LMA for surfactant administration was first described in 2004 in a case report of 2 infants6 and in 2005 with a prospective study of 8 infants7. Placement of a LMA is achieved with the thumb and index finger and does not require use of a laryngoscope or other instrumentation. With this technique, infants remain on NIV through the LMA, pressure ventilation (PPV) is used to distribute the surfactant, and infants remain spontaneously breathing throughout the procedure. LMAs fall under the category of supraglottic airway devices (SADs). Several companies manufacture SADs, with the LMA brand being the oldest and most widely recognized. In this review, LMA will be used in a generic sense, referring to the category of SADs, rather than to a specific manufacturer. Surfactant Administration through an LMA.

Nebulization/ Aerosolization

Nebulization or delivery of surfactant by an aerosol device to human infants was first described by Jorch8 and coworkers in 1997. While this method holds great promise for being the “least- invasive” of all the techniques, clinical use has been limited by technical problems including attaining a particle size that is inhaled, but not exhaled, stability of the surfactant, delivery over a reasonable time-frame, and delivery of an appropriate dose to the lungs. However, this method continues to be an active area of research and initial results show promise that aerosolization may be effective in certain populations. Since this method is currently not clinically available, it will not be discussed in detail in this review.

Considerations

While all contemporary methods deliver surfactant to the lungs, several aspects of the procedures vary and deserve further consideration. These aspects include:

• Physiologic effect on the infant


• Use of premedication


• Selection of patient population


• Effect on functional residual capacity (FRC)


• Need for positive pressure ventilation (PPV)


• Potential adverse effects


• Provider skill and familiarity


• Efficacy of treating RDS

Physiologic effect on the infant

A driving focus behind the development of contemporary methods to administer surfactant is to gain the benefits of surfactant while avoiding the negative physiologic effects of intubation and mechanical ventilation. One of the major differences between methods is whether direct visualization of the vocal cords, and therefore use of a laryngoscope, is needed for placement of the device: with INSURE and TCA requiring, and LMA not requiring, direct visualization. This is an important difference when considering the physiologic effect of the procedure on the infant.

Direct comparison of the physiologic effect during placement of an ETT or thin catheter is difficult given the wide variation in whether premedication is used, and if so, what agents. However, since these devices all require use of a laryngoscope and advancement of a device through the vocal cords, adverse physiologic effects can be generalized as being similar to traditional intubation and to each other. Studies investigating intubation without premedication have shown adverse physiologic effects such as bradycardia9-10, hemodynamic instability including hypo- and hypertension9-15, hypoxia9,10,14,16-18 and increased intracranial pressure10,11,13,15,19,20. Premedication has been shown to mitigate the adverse effects of intubation; with atropine mitigating bradycardia10,13-15, an analgesic mitigating hemodynamic instability18 and a muscle relaxant mitigating the increase in intracranial pressure10,11,13,15,19. However, use of premedication may lead to difficulty with rapid extubation with the INSURE technique or failure to remain spontaneous breathing with TCA.

Studies comparing INSURE and TCA have shown higher rates of adverse physiologic effects with TCA, including higher rates of transient hypoxia and bradycardia4,21-23 and decreased cerebral regional oxygenation (as measured by near-infrared spectroscopy (NIRS))24.

A study of surfactant via an LMA25 showed the procedure had minimal adverse physiologic effects on the infants, with heart rate and oxygen saturation (SpO2) maintained close to baseline (+1 bpm and -6% respectively)26.

Premedication

The American Academy of Pediatrics27 and Canadian Society28 both state that premedication with an anti-cholinergic, analgesic and muscle relaxant should be used for all non- emergent intubations. Despite these statements, there is a great deal of variation amongst clinicians on whether premedication is given for intubation and, if so, what medications are used29. For traditional intubation, premedication with the recommended triple combination is possible. However, if using the INSURE technique, a muscle relaxant needs to be avoided or rapid extubation must be delayed until the muscle relaxant wears off. With TCA, the infant must remain spontaneously breathing so a muscle relaxant cannot be used. This may prolong the procedure as muscle relaxants have been shown to decrease the time and number of attempts required to successfully place the device30.

Placement of an LMA into the posterior pharynx does not require direct visualization of the vocal cords or use of a laryngoscope. In the Pinheiro trial31, INSURE (premedication of atropine and morphine) was compared LMA (premedication of atropine) and found an increased incidence of early failure (defined as within 1 hour of surfactant therapy; 67% vs 3%, p<0.001). The authors concluded that premedication with morphine likely contributed to early post-surfactant failures in the INSURE group. In other RCTs investigating LMAs, two32,33 did not use premedication, one34 used lidocaine gel on the mask and one25 used atropine and 24% sucrose solution. Bubble CPAP Setup

Patient population

Gestational age and weight are important aspects of the various techniques. INSURE and TCA are similar to the traditional method of endotracheal intubation and have been investigated in infants down to 23 weeks gestation3,23,35. For the extremely preterm infant, a birth weight <750 grams is a risk factor for failure of the INSURE method. In contrast, TCA appears to be well tolerated in extremely preterm infants but is not well tolerated in the older infants36, likely secondary to lack of premedication for the procedure. LMAs have traditionally not fit well in infants < 28 weeks and <1.2 kg. However, an LMA designed to fit infants as small as 500 grams is currently in clinical trial. This is encouraging as the < 28 weeks gestation population represents about one-third of the infants with RDS37.

Effect on functional residual capacity

Because INSURE and TCA require use of a laryngoscope during placement of the device, the inability to maintain distending pressure may result in loss of FRC. Jourdian38 found that during TCA, placement of the catheter into the trachea resulted in a 99% loss of distending pressure during mouth opening and closing in both an in vitro airway-lung model and in 19 neonates under the same conditions. In contrast, an adapter can be placed on the distal end of an LMA allowing for distending pressure (or PEEP, positive end expiratory pressure) and therefore FRC, to be maintained throughout placement and surfactant administration.

Positive pressure ventilation

Another major difference between the methods is use of PPV; TCA does not use PPV while INSURE and LMA methods use PPV. Studies have shown even a short duration of PPV can be associated with barotrauma, volutrauma and excitation of the inflammatory cascade39. However, PPV has also been shown to be beneficial in the recruitment of alveoli and result in an increase in FRC40.

Whether PPV or spontaneously breathing results in better surfactant distribution is an area of debate. Animal studies have resulted in conflicting results with one study showing spontaneous breathing to be superior41 while another found that surfactant deposition was significantly lower in preterm lambs who were spontaneously breathing42. Clinical trials in humans comparing TCA (which does not use PPV) to INSURE (which does use PPV) found TCA to be superior. However, it is worth noting that infants receiving surfactant via TCA may require PPV due to hypoxia or bradycardia, with 44% of infants in the Dargaville trial requiring PPV5 and 56% in the Kribs trial experienced hypoxia that resolved with PPV23. In addition, because of the ability to maintain PEEP through an LMA, surfactant may be able to be administered without PPV and should be an area for further investigation.

Potential adverse effects

In addition to the adverse physiologic effects already discussed, INSURE and TCA have the potential for right mainstem placement with resulting unilateral administration of surfactant, mouth/pharyngeal trauma or bleeding, and vocal cord or subglottic injury. The LMA method does not require use of a laryngoscope or passage of a device through the vocal cords, therefore, these potential adverse effects are negated. However, with the LMA, surfactant is administered above the vocal cords, which does raise the possibility of laryngospasm. While a theoretic risk, laryngospasm has not been reported in an animal study43, human case reports6,7, or randomized, controlled trials6,7,25,31-34,44. Malposition of the device into the esophagus is possible with all methods.

Provider skill and familiarity

Given the need for use of a laryngoscope and direct visualization of the vocal cords, INSURE and TCA have similar skill requirements to traditional intubation. While intubation was a frequently performed procedure in the past, increased use of NIV and the Neonatal Resuscitation Program42 (NRP) guideline changes in 2006 which discourage routine suctioning of meconium for vigorous infants have led to a significant decrease in the number of intubations available for providers to obtain or maintain this skill. For those comfortable with intubation, use of a Magill’s forcep to aid in the placement of a device may be a foreign concept, potentially making the LISA technique less attractive to those providers.

While becoming more common, many neonatologists and neonatal nurse practitioners have had little or no experience placing an LMA. In the past, NRP guidelines mentioned the LMA as an alternative device to establish an advanced airway in the event that intubation was not successful or feasible45. However, the 7th edition of the guidelines46 (2016) now recommend and incorporate training on placement of an LMA. This recommendation will result in increased exposure and familiarity with the device, as most neonatal clinicians are NRP certified.

In the Roberts25 study, successful placement of the LMA was achieved in the majority of infants in a single attempt and completed within 35 seconds26. Providers involved in the study stated they felt comfortable with the technique after their second experience. While there is a learning curve, it may be much less steep than for the techniques that require direct visualization and insertion through the vocal cords.