Chapter06

Contemporary Methods for Surfactant Administration in Neonates

Kari Roberts, M.D.

Introduction

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.

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.

Efficacy of treating RDS

Does surfactant enter the lungs?

INSURE and TCA provide direct instillation of surfactant into the lungs. With the TCA method, surfactant is administered in repeated small boluses with the rate of administration slowed if reflux is seen. Objective means to quantify the amount is not feasible given the surfactant is likely swallowed, aspirated back into the lung or spit up by the infant. In one TCA trial, reflux was noted in 30% of patients5. In contrast to direct tracheal instillation, LMAs rest in the posterior pharynx and have potential for leakage around the cuff. In one LMA trial25, leakage was quantified by aspirating gastric contents prior to and after surfactant administration. Over 50% of the infants had gastric aspirates that were <10% of the administered dose. Gastric aspirate is an imprecise indicator however, as all of the surfactant may not have been aspirated and/or the gastric aspirate may represent gastric secretions or other medications in addition to surfactant.

Clinical Response

Clinical response is currently the best indicator of whether surfactant reached the lungs. All methods have shown clinical improvement after surfactant administration and reduced need for mechanical ventilation.

RCTs comparing TCA vs INSURE are listed in Table 1. Individual trials found either no difference or TCA to be superior for the primary outcomes. Meta-analysis47 showed TCA to be superior for the effect on need for mechanical ventilation in the first 72 hours, incidence of pneumothorax and the combined outcome of bronchopulmonary dysplasia (BPD) and death. There was no effect on the non-combined outcomes of BPD or death.

RCTs comparing LMA vs INSURE or CPAP alone are listed in Table 2. Individual trials found either no difference or LMA to be superior for the primary outcomes. Meta-analysis48 showed LMA to be superior for the effect on need for mechanical ventilation in the first 72 hours. There was no effect on BPD or death. There are currently no studies comparing LMA to TCA.

As mentioned previously, the use of aerosolized or nebulized surfactant has been hindered by technical issues. The few studies that have investigated this method in humans are summarized in Table 3.

Conclusion

In conclusion, in the era of increased NIV, contemporary methods are available to provide the benefits of early surfactant without resorting to conventional means of intubation and mechanical ventilation. While the contemporary methods are effective, they do vary. In this authors’ opinion, the ease, short duration, physiologic stability and ability to maintain FRC during the procedure make the LMA the best way to administer surfactant for infants > 1200g. However, until LMAs are clinically available and shown to be effective in infants < 1200 grams, familiarity with TCA seems prudent. The literature is clear that traditional intubation and INSURE are inferior to contemporary methods and need to be phased out of clinical practice. Great strides have been made to improve care and outcomes for infants with RDS, but much work remains to be done to increase familiarity and use of “less invasive” methods and to develop an effective, truly “non-invasive” method for surfactant administration.

Table 1: Clinical studies of surfactant administration via thin catheter

Trial Intervention vs. control Gestation range Entry criteria Primary outcomes Findings
Procedure Trials
Dargaville5 2013 Hobart (n=61) vs historical controls (n=97) 25–32 wks Age < 24 hrs FiO2>30% (25- 28 wks), FiO2 > 35% (29-32 wks) Intubation < 72 hrs MV within 72 hrs: 25-28 wks 32%
vs 68% (p=.0011); 29-32 wks 22% vs 45% (p=.057). No
difference in duration of ventilation or BPD. Short duration of oxygen in the Hobart method group
Kribs3
2007		 Kribs (n=29) vs historical controls (n=34) 23-27 wks FiO2 > 40% Intubation < 72 hrs MV within 72 hrs: 34% vs 77%; decreased mortality, severe IVH and pulmonary interstitial emphysema
Klebermass-Schrehof35
2013		 Kribs (n=224) vs historical controls (n=182) 23-27 wks FiO2 > 30% Intubation < 72 hrs MV within 72 hrs 32%; MV within 7 days 25%; MV during hospital stay 59%; higher survival rates 76% vs 64% ; less IVH 28% vs 46%; less severe IVH 13% vs 24%, less cystic periventricular leukomalacia 1% vs 6%; more PDA 75% vs. 53%, more ROP 41% vs 21%
Aguar49 2014

SONSURE (Sonda Nasogastica Surfactante Extubacion, Spanish)

 Kribs (n=44) vs historical controls with INSURE (n=31) 24-35 wks FiO2 > 21% Intubation < 72 hrs MV within 72 hrs 34% vs 26%, p=.44; trend toward reduction in NEC 0% vs 9%, p=.067, more need for second surfactant dose 35% vs 6%, p<.0001; no difference in duration of MV or CPAP
Teig50 2015 Kribs (n=53) vs historical controls (n=44) 23-28 wks FiO2 30-50% Intubation < 72 hrs MV within 72 hrs 42% vs 77%, p<0.0005; MV during hospital stay 55 % vs 77%, p=0.02; duration of MV 2 vs 3 days, p=0.056; No difference in survival without BPD. Improved Mental Developmental Index (89 vs. 98, p=0.16) and Physical Developmental Index (83 vs. 91, p=0.03) at 3 years
Gopel51 2015 Kribs (n=1103) vs historical controls (n=1103) < 32 wks (22-32 wks) Matched controls, FiO2 not specified Need for MV MV during hospitalization 41% vs 62%, p<.001; postnatal dexamethasone use 3% vs 7%, p < 0.001; BPD 12% vs 18%,
p = 0.001; BPD or death 14% vs 21%, p < 0.001
Krajewski52
2015		 MIST (n=26) vs historical controls with INSURE MV 19% vs 65%; duration of MV 5 d vs 3.5 d, duration of CPAP 5.5 d vs 4 d; higher IVH≥ 2 50% vs 30%, less NEC 12% vs 23%, increased PDA 54% vs 45%, less BPD 15% vs 40%, less ROP 4% vs 12%
Templin53 2017 MIST (n=52) vs historical controls (n=40) 24-27 wk Intubation in the delivery room Intubation in the delivery room 31% vs 90%, p=.001; MV at 72 hrs 28% vs 62%, p=.002); MV during hospitalization 75% vs 93%, p<.05)
Randomized Controlled Trials
Göpel21 2011
Avoidance of Mechanical Ventilation (AMV) Trial		 MIST (n=108) vs. CPAP followed by ET instillation (n=112) 26–28 wk Age <12 hr FiO2> 30% Intubation days 2–3 MV days 2–3 28% vs 46% (NNT: 6, 95% CI: 3–20, P=0.008); intubation at any time: 33% vs 73% (P<0.001); median days on MV: 0 vs 2; Oxygen at 28 days: 30% vs 45% (P=0.032)
Kanmaz22 2013
Take Care Trial		 MIST (n=100) vs. INSURE (n=100) <32 wk Age<72 hr FiO2>40% Intubation <72 hr MV within 72 hr: 30% vs. 45% (P=0.02); MV at any time: 40% vs. 49% (P=0.08); BPD: 10% vs. 20% (P=0.009)
Mirnia54
2013		 LISA (n=66) vs INSURE (n=70) 27-32 wk FiO2≥ 30% MV requirement in first 72 hrs No difference on need for MV within first 72 hrs (20% vs 23%) or duration of MV (25 vs 13 hrs)
Kribs23
2015NINSAPP Trial (Non-intubated Surfactant Application)		 MIST (n=107) vs. CPAP, ET instillation (n=104) 23–26 wk Age<2 hr
FiO2≥ 30% or Silverman score ≥5		 Survival without BPD at 36-wk GA Survival without BPD 67.3% vs. 58.7% (P=0.20); intubation: 74.8% vs. 99.0% (P=0.04); pneumothorax: 4.8% vs. 12.6% (P=0.02); Severe IVH: 10.3% vs. 22.1% (P=0.02); survival without major complications: 50.5% vs. 35.6% (P= 0.02).
Mohammadizadeh55 2015 MIST (n=19) vs. INSURE (n=19) ≤34 wk Age<1 hr
FiO2≥ 30% or Silverman score ≥5		 Need for MV and duration of oxygen therapy No difference in need for MV, but duration of surfactant therapy significantly shorter in intervention group (243 vs 476 hrs, p=0.018)
Bao56 2015 MIST (n=47) vs. INSURE (n=43) 28–32 wk Age<2 hr
FiO2≥ 30% (28+0–29+6 wk) or FiO2≥ 35% (30+0–32+6 wk)		 Feasibility, rate of MV in the first 72 hr, duration of MV, CPAP, and oxygen requirement, neonatal morbidities No differences in rate of MV in the first 72 hr, duration of oxygen and neonatal morbidities, duration of MV and CPAP significantly less in the intervention group
Oliver57
2017		 MIST (n=24) vs INSURE (n=21) 32-36 wk Age < 24 hr
FiO2≥ 35%		 Need for MV or development of a pneumothorax requiring a chest tube Primary outcome criteria favored intervention group (33% vs 90%, (ARR 0.57, 95% CI 0.54 to 0.60). One patient in each group reached the primary outcome because of pneumothorax occurrence.

MIST, minimally invasive surfactant therapy (Hobart or Kribs method); CPAP, continuous positive airway pressure; ET, endotracheal; FiO2, fraction of inspired oxygen; MV, mechanical ventilation; NNT, number need to treat; CI, confidence interval; INSURE, intubation, surfactant and extubation; BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; GA, gestational age; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; ARR, absolute risk reduction

Table 2: Clinical studies of surfactant administration via an LMA

Intervention vs. control Gestation range Entry criteria Premedication Findings
Case Reports
Brimacombe6 2004 n=2 30 wk
37 wks		 FiO2 50%
FiO2 80%		 None
Midazolam		 Improvement in respiratory function
Trevisanuto7 2005 n=8 28-35 wks Age < 72 hrs
a/A PO2 <.2		 None a/A PO2 at 3 hrs after surfactant increased 0.13 to 0.34, p< .01
Vannozzi 44 2017

CALMEST (Catheter and laryngeal mask endotracheal surfactant therapy)

 n=4 BW >1.5 kg FiO2 ≥ 35% None Improvement on FiO2 requirement, respiratory rate and Silverman score at 3 hrs after surfactant
Randomized Controlled Trials
Attridge32 2013 LMA (n=13) vs CPAP alone (n=13) BW ≥1.2 kg Age <72 hr
FiO2 30-60%		 None FiO2 at 1 hr 25% vs 37%, p=.002; FiO2 at 12 hrs 27% vs 40%, p=.04; Required MV 8% vs 23%, p=.59
Sadeghnia33 2014 LMA (n=35) vs INSURE (n=35) BW ≥2 kg Age < 48 hrs FiO2 ≥ 30% None a/A PO2 after surfactant dose 0.48 vs 0.43, p=.014
Pinheiro31 2016 LMA (n=30) vs INSURE (n=31) 29-36 wks Age < 48 hrs
FiO2 30-60%		 LMA: Atropine
INSURE: Atropine and Morphine		 Failure requiring MV 30% vs 77%, p<.001; Early failure 3% vs 67%, p<.001; Late failure 10% vs 27%, p=.181; FiO2 decrease and adverse events similar between groups
Krajewski52
2015		 LMA (n=26) vs INSURE (n=22) 28-35 wks
BW > 1 kg		 FiO2 ≥40% LMA: Lidocaine gel on mask
INSURE: Remifentanil and Midazolam		 FiO2 ≤30% at 3 hrs post surfactant 77% vs 77%, p.977; 54% of LMA group did not require MV; lower Silverman- Anderson score at 3 and 6 hrs after surfactant 2 vs 0, p=.0001 and 0.5 vs 0, p=.017; similar second dose of surfactant 23% vs 18%,p=.735
Roberts25 2017 LMA (n=50 ) vs CPAP alone (n=53) 28-35 wks
BW ≥1250g		 Age ≤ 36 hrs
FiO2 30-40%		 LMA: Atropine and 24% sucrose solution MV in first 7 days 38% vs 64%, p=.006; Duration of MV, CPAP and supplemental oxygen at 7 days of age similar between groups

LMA, laryngeal mask airway; CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; MV, mechanical ventilation; a/A PaO2, arterial/alveolar ratio; BW, birth weight; INSURE, intubation, surfactant and extubation

Table 3: Clinical studies of surfactant administration via aerosolization/ nebulizer

Trial Intervention vs. control Gestation range Entry criteria Primary outcomes Findings
Procedure Trials
Berggren58
2000		 Jet nebulizer (n=16) vs CPAP alone (n=16) Age < 36 hrs FiO2>40% Intubation MV 31% vs 38%
Minocchieri59
2013		 Vibrating membrane nebulizer (n=64) vs CPAP alone 29-33 wks Age < 6 hrs
FiO2 22-30%		 Intubation < 72 hrs MV within 72 hrs: RR 0.56 (95th CI .34,.93);
No difference in BPD
Windtree Therapeutics60
2017		 Heated capillary nebulizer (n=143) vs CPAP alone FiO2>30% “Aerosurf nebulizer did not meet the desired end-point of a reduction in CPAP failure”

CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; MV, mechanical ventilation; BPD, bronchopulmonary dysplasia

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03. Bedside Management Strategies for infants on bubble CPAP 07. Laryngeal mask airway for surfactant administration in neonates: a practical guide