REVIEW

CURRENT
OPINION Less invasive surfactant administration: best
practices and unanswered questions
Egbert Herting, Christoph Härtel, and Wolfgang Göpel

Purpose of review
The purpose of this review is to describe current concepts in the field of Less Invasive Surfactant
Administration (LISA). The use of continuous positive airway pressure (CPAP) has become standard for the
treatment of premature infants with respiratory problems throughout the world. However, if CPAP fails,
technologies like LISA are needed that can combine surfactant delivery and spontaneous breathing with the
Downloaded from https://journals.lww.com/co-pediatrics by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GlzJh/RXoJ6HQaW7AJ3/SOK8I94f53j9BrRzgNLwDyk= on 07/31/2020

support of noninvasive modes of ventilation.

Recent findings
LISA with thin catheters has been in use in Germany for more than 15 years. In the last 5 years, there was
substantial interest in this method around the world. Randomized studies and recent metaanalyses indicate
that the LISA technique helps to avoid mechanical ventilation especially in emerging respiratory distress
syndrome (RDS). LISA is also associated with improved outcomes of preterm infants, specifically in the
prevention of bronchopulmonary dysplasia (BPD) and intracranial hemorrhage (ICH). By now, a variety of
different LISA catheters, devices and techniques have been described. However, most of the technologies
are still connected with the unpleasant experience of laryngoscopy for the affected infants, so that the
search for even less invasive techniques, for example, surfactant application by nebulization, goes on.
Summary
Maintenance of spontaneous breathing with support by the LISA technique holds big promise in the care of
preterm infants. Patient comfort and lower complication rates are strong arguments to further investigate and
promote the LISA approach. Open questions include exact indications for different patient groups, the usefulness
of devices/catheters that have recently been built for the LISA technique and – perhaps most urgently – the issue
of analgesia/sedation during the procedure. Studies on long-term outcome after LISA are under way.
Keywords
continuous positive airway pressure, less invasive surfactant administration, noninvasive ventilation

INTRODUCTION intubation with a standard large diameter endotra-

Modified natural surfactants have been in clinical use cheal tube are performed accompanied by analgesia
for the treatment of respiratory distress syndrome and sedation. Following surfactant bolus administra-
(RDS) for about 30 years [1,2]. Replacement therapy tion, the infants are either ventilated with bag valve
with exogenous surfactant preparations derived from masks and/or connected to a mechanical ventilator
animal sources dramatically reduced RDS-related delivering gas volumes with the help of positive
morbidity and mortality and became the most effec-
tive evidence-based therapy for RDS. In the first Department of Pediatrics, University Hospital of Schleswig-Holstein,
decade of replacement therapy, surfactant bolus Campus L€
ubeck, L€
ubeck, Germany
administration during mechanical ventilation was Correspondence to Egbert Herting, MD, PhD, Professor and Head of
the method of choice. In the 1990s, continuous Department of Pediatrics, University Hospital of Schleswig-Holstein,
positive airway pressure (CPAP) became increasingly Campus L€ ubeck, Ratzeburger Allee 160, D - 23538 L€
ubeck, Germany.
Tel: +49 451 500 42800; fax: +49 451 500 42804;
popular especially in Scandinavia. In 1992, a ‘small
e-mail: [email protected]
catheter surfactant delivery method’ was described
Curr Opin Pediatr 2020, 32:228–234
for the first time [3]. However, it was believed that at
DOI:10.1097/MOP.0000000000000878
least a short interval of positive pressure ventilation
was needed to move surfactant from the central air- This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
ways to the lung periphery, so that the INSURE (CCBY-NC-ND), where it is permissible to download and share the work
(Intubate SURfactant Extubate) method was devel- provided it is properly cited. The work cannot be changed in any way or
oped [4]. However, with INSURE laryngoscopy, and used commercially without permission from the journal.

www.co-pediatrics.com Volume 32  Number 2  April 2020

 Less invasive surfactant administration Herting et al.

[8] and NINSAPP [9] trials. An observational study

KEY POINTS using a matched pairs design in more than 1000
 LISA allows combining surfactant delivery with infants demonstrated that this effect is robust in
spontaneous breathing. clinical practice also outside the specific setting of
trials [10]. The effectiveness of LISA in preventing
 LISA allows maintained laryngeal function. mechanical ventilation in the first 72 h strongly
 LISA has the potential to improve patient comfort by depends on gestational age [10]. Some of the most
avoiding mechanical ventilation. immature infants need intubation after the first days
of life, mainly because of apnoea and/or muscular
 LISA improves outcomes when compared with
fatigue. However, the low intracranial hemorrhage
mechanical ventilation, other modes of noninvasive
ventilation or short-time intubation and surfactant (ICH) rate, for example, in the LISA group of the
instillation (INSURE). NINSAPP trial points [9] into the direction that
postnatal circulatory adaptation under spontaneous
 LISA is recommended in recent surfactant guidelines on breathing is of potential advantage also for the
the basis of individual studies and metaanalyses.
tiniest infants.
 LISA needs further research in order to optimize Metaanalyses [19–21] point out that LISA is
patient comfort. superior to CPAP alone or the INSURE technique
both in terms of avoidance of bronchopulmonary
dysplasia (BPD) and ICH [19]. However, the quality
pressure at least for a short interval. In that way, of some of the studies included in these metaanal-
INSURE is different and more invasive than LISA. yses was questionable, so that further confirmative
When CPAP became more popular even for randomized controlled studies (RCT) are still
premature infants, it became evident that CPAP needed.
failure because of RDS, that is, surfactant deficiency,
is common especially in the most immature infants
HOW TO PRACTICE LESS INVASIVE
[5]. This prompted the search for the LISA technique
SURFACTANT ADMINISTRATION
with the aim to effectively provide an adequate dose
of surfactant while the infant is breathing sponta- Prenatal lung maturation with corticosteroids and
neously with the support of CPAP [6,7 ].
&
good obstetrical care are very important factors for
The ‘small diameter tube method’ (synonym for spontaneous breathing directly after birth, which is
LISA) was rediscovered, about 10 years after its initial a prerequisite to make LISA work. Infants who are
description [3] by Kribs et al. [6] in Cologne and from not crying/breathing are stabilized with a mask and
2003 onwards, LISA was also used in Lu € beck. The distending pressure after delivery. Most centers use
German Neonatal Network (GNN) facilitated the CPAP at 6–9 cmH2O after birth with a variety of
initial randomized trials (AMV and NINSAPP trials) different devices, whereas sustained inflations are
[8,9] and additional observational studies on LISA not current practice. The use of high-flow nasal
&
[10 ] that underlined that LISA was also ready for cannula (HFNC) is increasing in popularity, but in
routine use in neonatal ICUs (NICUs). The cohort of Germany, still uncommon in the delivery suite as
LISA-treated infants documented in the GNN has CPAP seems to allow higher distending pressures.
increased to more than 5000 patients by now [7 ].
&
Giving regard to the low physiological saturation
More than 50% of all surfactant treatments are per- limits, adaptation to postnatal life is allowed with as
&
formed by LISA in Germany [7 ] and the international little intervention as possible. Gentle stimulation,
interest in this technique has steeply increased with late cord clamping, caring for patency of the airways
studies reporting LISA results from, for example, (often a lateral position is more adequate than keep-
Austria, Australia, Turkey, Spain, Iran and China ing the baby in a strictly supine position), avoiding
[11–16]. Both the national German [17] and the unnecessary suctioning, maintenance of body tem-
recent European guidelines [18] for surfactant perature and avoiding stress as much as possible are
replacement therapy mention LISA as the method of utmost importance to establish effective sponta-
of choice for surfactant delivery in infants with RDS. neous breathing. By now, the majority of infants
below 1000 g in Germany receive caffeine for stim-
ulation of breathing/apnoea prevention already in
the delivery suite, although there is no clear evi-
EFFECTS OF LESS INVASIVE dence from RCTs supporting this approach. In this
SURFACTANT ADMINISTRATION way, LISA is not simply a single technical procedure
LISA has been shown to reduce the need for mechan- but rather a component of a complex care bundle
ical ventilation in the randomized controlled AMV supporting the individual capacity of a premature

1040-8703 Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-pediatrics.com 229
Neonatology and perinatology

baby to adapt to extrauterine life (so called: minimal In Germany, mainly thin (3.5–5.0 French) and
handling approach or ‘soft landing’). soft catheters (e.g. gastric tubes, suction catheters,
If respiratory distress becomes evident shortly umbilical arterial or bladder catheters) are used for
after birth, as indicated by increasing oxygen demand LISA and are mostly introduced into the larynx with
and/or tachypnoea, grunting and/or retractions, sur- the help of a laryngoscope and a Magill forceps (see
factant deficiency is likely and surfactant may be also Fig. 1). Video laryngoscopy [22] holds some
delivered by LISA already in the delivery room. The promise for well tolerated placement of the cathe-
more stable, often also more mature, infants are ters in the trachea and also for teaching (see also
transferred to the NICU under CPAP therapy and Fig. 2). However, most neonatologists will tend to
often receive surfactant only when certain thresholds remove the laryngoscope for comfort reasons as
in oxygen demand are reached (often a fraction of soon as possible securing the adequate catheter
inspiratory oxygen (FiO2) greater than 0.30 or greater position with the fingers on the lips/the nose of
than 0.40 is used as indication limit, also considering the babies. In the tiniest infants, the catheter is
the gestational age (see e.g. [18]). introduced only 1–2 cm beyond the vocal cords.
For the most immature infants (e.g. <25 weeks Some gastric catheters have the disadvantage of side
of gestational age) some centers follow a (quasi-) holes that are rather distant from the tip. Side holes/
prophylactic LISA approach and use LISA as early as not inserting the catheter deep enough carries the
at 20 min of life with the argument that in these risk of increased surfactant reflux, whereas too deep
infants with very delicate lung structures, surfactant insertion of the catheter may result in unilateral
treatment should be given as early as possible and surfactant deposition. The surfactant instillation is
most infants in this age group would receive surfac- done in small boluses and only slowed down when
tant anyhow in the hours to come. Clearly, RCTs are bradycardia, apnoea or increased surfactant reflux is
needed addressing the question of the superiority observed. Some air is often placed in the syringe
of such a ‘prophylactic’ approach compared with ‘behind/on top of the surfactant’ to allow removal of
waitful watching and ‘rescue’ LISA treatment, the surfactant from the dead space in the syringe
if indicated. and the catheter. As silicone oil may bind to the

FIGURE 1. Devices for surfactant instillation by the standard and the less invasive surfactant administration method. From left
to right: endotracheal tube size 2.5 (outer diameter 4.1 mm, see also Fig. 2a), soft suction catheter 5 French (outer diameter:
1.7 mm see also Fig. 2b), stiffer straight catheter (Lisacath) (outer diameter 1.7 mm) and special device (Neofact) with 3.5
French (outer diameter: 1.2 mm) catheter that is sliding out from the tip. Lisacath and Neofact have special ‘softer’ tips to
avoid injury.

230 www.co-pediatrics.com Volume 32  Number 2  April 2020

 Less invasive surfactant administration Herting et al.

surfactant instillation with LISA can usually be com-

pleted in less than 60 s. Rarely, 2 min or more are
needed, when intermittent bradycardia/apnoea
occurs and the injection has to be slowed down.
There are no data comparing different speeds of
surfactant delivery with LISA.
Mainly animal-derived modified natural surfac-
tants have been studied for LISA. The AMV study [8]
compared three different types of surfactant but was
underpowered for valid comparisons in terms of
LISA effectiveness between different surfactants.
The AMV-trial [8] used a phospholipid dose of
100 mg/kg, the NINSAPP trial [9] a whole vial of
120 mg porcine surfactant per infant and a retro-
spective study a dose of 200 mg/kg [11]. In daily
practice, often whole vials of surfactant are used,
especially when treatment is done in the delivery
room and an exact weight is not available. The
pragmatic way to use a whole vial of, for example,
120 mg surfactant in a baby with an estimated
weight of 800 g will result in a phospholipid dose
of at least 150 mg/kg. There is hope that such a dose
results in higher surfactant pool size than the
100 mg/kg used, for example, in the AMV study,
where the rest of the vial content was discarded.
Most studies report the need for retreatment in 20–
30% of LISA-treated infants. Theoretically, a higher
initial surfactant dose should supply a higher sur-
factant pool and hopefully thereby reduce the need
for (stressful) retreatment. Again, clearly RCTs are
needed here as well, before definitive dose recom-
mendations can be made.
Given special experience, LISA can be success-
FIGURE 2. (a) 2.5 Portex endotracheal tube inserted into to fully applied in infants as immature as 22 weeks [25].
the larynx. (b) 5 French Vygon suction catheter inserted into Personally, we do not favour the use of LISA in
the larynx. Note that the endotracheal tube virtually occludes infants above 32 weeks. There is no evidence for a
the laryngeal entrance (a), whereas the vocal cords and benefit of LISA in this group so far and the risk for
even a lumen can be seen above the small diameter suction BPD is low in this group [13]. More mature infants
tube (b) that is used for the LISA procedure. The pictures often struggle, and therefore, need sedation/analge-
were taken with a video larnygoscope (C-MAC, Karl Storz, sia to tolerate the procedure. On the other hand,
Tuttlingen, Germany) in a mannequin (PAUL, Sim medication interferes with the spontaneous breath-
Characters, Vienna, Austria) that simulates the conditions in ing that is crucial to make LISA work.
a 1000 g, 27 þ3 weeks premature baby with a body length
of 35 cm. The larynx in the model goes back to an
CATHETER TYPES
anatomically correct 3D printed larynx based on real-life
MRI of a preterm baby with a corresponding gestational A variety of catheter types and instruments are used
age. LISA, less invasive surfactant administration. for the LISA procedure (see Table 1 and Fig. 1). The
placement of a soft catheter with the help of the
Magill forceps is the method that most centers in
surfactant lipids, it is preferable to use syringes that Germany use. The catheter is often introduced via
contain no lubricated rubber parts [23]. the mouth and has already been mounted into the
Surfactant has unique spreading properties once forceps before the start of the procedure. Alterna-
it is instilled in the large airways. From animal tively, the soft flexible catheter is introduced via the
experiments, it is known that infusing surfactant nose (while a mononasal CPAP is in place in the
at too slow rates results in less even distribution other nostril) and then taken up with the forceps
compared with the bolus approach [24]. The similar to the technique of nasal intubation. Soft

1040-8703 Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-pediatrics.com 231
Neonatology and perinatology

Table 1. Published methods to combine continuous positive airway pressure, spontaneous breathing and surfactant
administration
Name Device type Procedure/instruments Reference

Cologne method Flexible suction catheter Laryngoscope þ Magill forceps Kribs et al. [6]
SONSURE Flexible nasogastric tube Laryngoscope þ Magill forceps Aguar et al. [26]
Take Care method Flexible nasogastric tube Laryngoscope, no forceps Kanmaz et al. [15]
Hobart method Semi-rigid vascular catheter Laryngoscope, no forceps Dargaville et al. [27]
Device name: for example, Lisacath
QuickSF Soft catheter Laryngoscope þ intrapharyngeal Maiwald et al. [28]
Device name: Neofact guidance device
INSURE Endotracheal tube Laryngoscope Verder et al. [3]
Laryngeal Mask method Special device placed in hypopharynx No Laryngoscope, no forceps Roberts et al. [29 ]
&

Aerosol method No catheter No Laryngoscope, no forceps Pillow et al. [30]

Nebuliser with, for example, mask/prongues
Pharyngeal Surfactant Flexible short tube and syringe No Laryngoscope, no forceps Kattwinkel et al. [31]
Injection into the pharynx
&&
For review see [32 ].

catheter introduction without a forceps has been (Fig. 2b). A 5-French tube occludes a cross sectional
described as the so-called Take Care procedure [15]. area of approximately 1.8 mm2. A standard endotra-
Not all neonatologists are familiar with nasal intu- cheal size 2.5 tube has a total cross sectional area of
bation and the use of a Magill forceps. Oral intuba- 13.2 mm2. It must be emphasized that only 4.9 mm2
tion is much more common in other parts of the of this area is are available for respiration. The rest
world, so that direct laryngoscopy and the use of a (8.3 mm2) is occluded by the wall of the endotra-
stiff vascular catheter was described by Peter Darga- cheal tube [34].
ville as the so called Hobart method (MIST, minimal Videos demonstrate that such small catheters
invasive surfactant therapy) in 2011 [27]. allow movements of the vocal cords (e.g. Lancet TV:
&
By now, companies have developed straight [33 ] https://www.youtube.com/watch?-
(Lisacath) or catheters with an angulated tip (Surf- v=IYf92NN1kV0).
cath) that are easy to use via the oral route. These Recently, the use of a 2.0 endotracheal tube (the
catheters are relatively stiff, so that no extra devices smallest available size) has been described for LISA
are needed to introduce the tip through the vocal [35] but still this corresponds to an outer diameter of
cords. Special introducers [28] (Neocath) allowing to 8 French (2.7 mm).
slide out a soft thin catheter from the tip after the
device has been placed in front of the larynx and
devices to guide the catheter during video laryngos- UNANSWERED QUESTIONS
copy have recently reached the market. In addition to the technical issues, the dose question
and the matter of exact indications/treatment
thresholds for different groups of patients, there is
WHAT MAKES LESS INVASIVE an ongoing debate whether analgesia and sedation
SURFACTANT ADMINISTRATION during the LISA procedure is necessary, or may
DIFFERENT? actually endanger the success of the method.
LISA is different from other modes of surfactant
delivery as it allows the infant to keep on breathing
and to use the physiological function of the larynx Analgesia and sedation during the less
without (nearly complete) obstruction by a larger invasive surfactant administration procedure
diameter endotracheal tube. Figure 2a demonstrates It has to be stated clearly that the use of LISA does
how the glottis is nearly completely obstructed by a not exclude analgesia and/or sedation per se. Stress
size 2.5 endotracheal tube (inner diameter 2.5 mm, and pain in the neonatal period may have long-term
outer diameter 4.1 mm) in a mannequin airway negative effects and should be avoided whenever
simulating a 1000 g baby, whereas a small diameter possible. Currently, in Germany, in infants less than
catheter (e.g. 5 French, external diameter: 1.7 mm) 26 weeks, most centres will do the first LISA attempt
leaves most of the airway open allowing flow of gas without analgesia [25]. If the infant struggles, anal-
through the vocal cords with the catheter in place gesia and sedation is used for the second attempt.

232 www.co-pediatrics.com Volume 32  Number 2  April 2020

 Less invasive surfactant administration Herting et al.

Nonpharmacological methods of analgesia like posi- on LISA infants suggested favourable neurocogni-
tioning, holding, (’facilitated tucking’) and/or tive outcome compared with historical controls
sucrose solutions are often used. In more mature [40–43]. Unpublished data from the 5-year follow-
and vigorous infants, it seems wise to use analgesia up of LISA infants in the GNN cohort suggest better
and sedation right away. So far, there is no ideal lung function (FEV1) and better neuro-outcome/
combination of drugs that would allow analgesia intellectual properties (WPPSI score) in infants
and sedation with a rapid onset, a short duration, no who received surfactant via LISA compared with
suppression of spontaneous breathing and a favour- infants who received surfactant via the standard
able overall short and long-term safety profile. This route. Follow-up results from the randomized stud-
is reflected by the fact that a variety of drugs have ies will soon become available.
been studied for the purpose of analgesia/sedation
during INSURE or LISA; fentanyl, ketamine and
propofol were the most frequently used medica- CONCLUSION
tions. First studies indicate that these drugs may LISA is part of the strategy of a minimal handling
help to reduce pain scores, but on the other hand, approach supporting the concept of spontaneous
interfere with spontaneous breathing and increase breathing. LISA reduces the need for mechanical
the number of infants that need respiratory support/ ventilation, and is therefore, in increasing use in
&&
mechanical ventilation during LISA [36 ]. Thus, &
NICUs around the world [44–50,51 ]. Short-term
practice patterns of using these drugs vary widely (ICH and BPD) and first long-term follow-up data
between countries and NICUs [37]. on neurocognitive and pulmonary function are
encouraging. The search for better strategies allow-
ing to deliver surfactant in an even gentler way goes
Short-term side effects
on. In this context, especially surfactant nebuliza-
Under the condition that LISA is performed by neo- tion may become one of the options on the horizon.
natologists experienced in airway management, there
are few acute side effects. Failure to insert the catheter
Acknowledgements
through the vocal cords at first attempt, significant
surfactant reflux, acute desaturations, bradycardia We are grateful to Philipp Jung, MD for help with the
and/or need for positive pressure ventilation during video laryngoscopy (Fig. 2).
LISA were observed in less than 10% [8] to more than
30% [13] of LISA/MIST manipulations. Short apnoea, Financial support and sponsorship
hypoxia and bradycardia can often be handled by Most of the clinical data on LISA in Germany were
slowing down the injection speed/interrupting the obtained with the help of the German Neonatal Network
surfactant administration or, if needed, by a couple of (GNN; www.vlbw.de) that is sponsored by the German
manual breaths via a CPAP device that in our experi- Ministry for Education and Research (BMBF-grant-No:
ence should stay in place during the LISA procedure. 01ER0805 and 01ER1501). This manuscript is in part
Studies with continuous monitoring of saturation based on the results of an international meeting on Less
and regional (e.g. also cerebral) saturation by near- Invasive Surfactant Application (LISA) that took part in
infrared spectroscopy (NIRS) seem to indicate that the Lu€beck, Germany, on 31 May 2018. This workshop was
laryngoscopy is more often the source of side effects sponsored by the German Research Foundation (DFG):
than the surfactant instillation itself [38]. The only Grant: DFG-He 2072-3.
potential adverse effect observed so far was a slight Patient consent/Ethics: Written consent from the
increase in the rate of focal intestinal perforation (FIP) parents for the participation in the German Neonatal
in a subset of infants born at 23 and 24 weeks of Network was obtained prior to enrollment. Approval by
gestation receiving LISA [39]. This finding may be the local institutional review board for research in human
related to the distension of the fragile intestinal wall subjects of the University of Lu€beck (file number 08-022)
in consequence the positive end-expiratory pressure and by the local ethic committees of all participating centres
applied during noninvasive ventilation, but clearly has been given. We are grateful for the support of the
this has to be followed in more detail. families and of the colleagues contributing to this network.

Conflicts of interest
Long-term outcome E.H., C.H. and W.G. have received study support, hono-
In individual studies [8,9] and metaanalyses [19,21] raria for presentations and travel support from Chiesi
LISA reduces the incidence of ICH and BPD, and Farmaceutici, a surfactant producer. E.H. and C.H.
thus, bears the potential to improve also the long- served as advisors for Draeger Medical, a company
term outcome. Small retrospective follow-up studies producing incubators, monitors and ventilators.

1040-8703 Copyright ß 2020 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-pediatrics.com 233
Neonatology and perinatology

25. Mehler K, Oberthuer A, Keller T, et al. Survival among infants born at 22 or 23

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234 www.co-pediatrics.com Volume 32  Number 2  April 2020