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 Table of Contents  
Year : 2022  |  Volume : 11  |  Issue : 1  |  Page : 45-51

Minimally or less invasive surfactant replacement therapy in neonates: A narrative review

Consultant Neonatology, Medeor 24x7 Hospital, Dubai, UAE

Date of Submission02-Jan-2021
Date of Decision04-Oct-2021
Date of Acceptance07-Oct-2021
Date of Web Publication03-Jan-2022

Correspondence Address:
Gengaimuthu Karthikeyan
5th Floor, Montrell Apartments, Al Furjan West, Dubai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.jcn_2_21

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Surfactant replacement therapy is a major cornerstone in the successful management of neonates with respiratory distress syndrome. Until recently, the INtubate, SURfactant, Extubate protocol was the best a trade-off achieved to deliver the surfactant to the air exchanging respiratory epithelium against the barotrauma of prolonged intubation and ventilation. Minimal or Less Invasive Surfactant Therapy (MIST or LISA) was adapted in clinical practice as a gentler and a gentler way of delivering surfactant. LISA or MIST is associated with a significant reduction in the oxygen days and chronic lung disease, intraventricular hemorrhage of grade 2 or above, retinopathy of prematurity and other key neonatal outcomes. This translates into shortened neonatal intensive care unit stay and a significant reduction in the stress levels of neonatal nurses, parents, and caregivers. This procedure needs to be performed by skilled professionals with appropriate training to achieve the desired results.

Keywords: Bronchopulmonary dysplasia, minimally invasive surfactant therapy, neonate, prematurity, respiratory distress syndrome, surfactant replacement therapy

How to cite this article:
Karthikeyan G. Minimally or less invasive surfactant replacement therapy in neonates: A narrative review. J Clin Neonatol 2022;11:45-51

How to cite this URL:
Karthikeyan G. Minimally or less invasive surfactant replacement therapy in neonates: A narrative review. J Clin Neonatol [serial online] 2022 [cited 2022 Aug 8];11:45-51. Available from: https://www.jcnonweb.com/text.asp?2022/11/1/45/334733

  Introduction Top

Noninvasive respiratory support is the accepted strategy of neonatal care and maximizing the alveolar area available for gas exchange by minimizing atelectrauma is the basic philosophy of managing preterm neonates with surfactant deficient lung disease.[1],[2],[3] This is achieved by combining the early initiation of continuous positive airway pressure (CPAP) with appropriate and optimum use of surfactant to minimize the additional insults of barotrauma volutrauma and biotrauma as well.[4],[5],[6],[7] Given the global consensus on noninvasive respiratory support philosophy and the visible benefits that accrue from this standard of neonatal care, an advanced less invasive technique to replace the conventional intubation for surfactant administration INtubate, SURfactant, Extubate (INSURE) strategy became a valuable addition to this bundle of care.[7],[8],[9] The evolution of Minimally Invasive Surfactant Therapy (MIST) that has been widely assimilated in clinical practice by European neonatologists has to be taken in this context.[10],[11],[12],[13],[14],[15] This article attempts to unveil the mystique of MIST by a thoughtful review of the published articles and inferences derived therein and from our own experience.

  Invasive Surfactant Therapy versus Intubate, Surfactant, Extubate: Just an Upgrade or Much More Than That? Top

Invasive to quasi-invasive (INSURE) to Less or Minimally Invasive is how the surfactant replacement therapy (SRT) has evolved. Probably, an entirely noninvasive way of SRT may also evolve eventually. Simplistically speaking, if INSURE has proved better than the initial way of delivering surfactant then MIST will at least be an advantageous upgrade of INSURE. From a research and hypothetical point of view, this author frames two important issues for academic arguments on this subject that will facilitate a more lucid understanding of the pathobiological and the physiological principles underlying MIST.

The first one is the effectiveness and safety aspects of MIST that should at least be noninferior to INSURE. The second one is how factors other than the procedure per se, the so-called facilitation strategies employed for the procedures MIST and INSURE influence the outcomes.

  Comparison of Effectiveness and Safety Aspects of the Invasive Surfactant Therapy with Intubate, SURfactant, Extubate Top

The procedure of administration of surfactant by the MIST technique differs from the INSURE technique in that a smaller diameter tube in the airway is nonventilable and cannot support mechanical ventilation. The implication herein is that during surfactant administration by the MIST technique, it is the spontaneous breathing of the baby boosted by the noninvasive respiratory support that is maintaining the oxygenation.

In a baby who is receiving surfactant by Less Invasive Surfactant Therapy (LISA) or MIST whilst being on nasal CPAP the CPAP aimed to distend the alveoli has to maintain its effectiveness. The main argument that this is a difficulty is that there is an unavoidable and a variable leak up to 40%, when the mouth is opened for laryngoscopy when an appropriate interface is delivering nasal CPAP.[16] This is unavoidable because the baby's mouth has to be opened for laryngoscopy to perform the procedure of surfactant either by the INSURE technique or the MIST technique. Post INSURE technique at least 10% that can extend up to 30% of the babies remain ventilated, and hence, they are on the support of mechanical breathing. On the other hand, if MIST or LISA is performed at a FiO2 cutoff of between 30% and 40%, the need for mechanical ventilation that is intubation by an endotracheal tube and hooking on to ventilator is minimized.[17] Hence, the success rate of MIST is almost 100% in babies of gestational age 27 weeks and above in the centers performing MISA or LIST routinely.[18]

It was agreed in an earlier review that optimization of surfactant effectiveness is directly related to the achievement of homogenous distribution of exogenous surfactant in the alveolar sacs by a rapid administration of the drug and an appropriate alveolar recruitment technique.[19] Studies with the latest imaging technology like Electro Impedance Tomography have proven that spontaneous breathing achieves better surfactant diffusion across airways than mechanical breaths.[20],[21] This, when coupled with CPAP that has expanded the alveoli to the extent possible and preventing the collapse during the procedure, achieves a more physiological way of administering the surfactant. MIST or LISA procedure is better completed faster so that sedation and analgesia can be safely avoided. With adequate training, the procedure of LISA does not take more than 2 min once the glottis is visualized.

From an anatomical standpoint, an extreme preterm baby <28 weeks has a mean tracheal diameter of 2–3 mm. This equates to roughly 40%of the tracheal diameter of a term neonate and 12% of the tracheal diameter of an adult.[22] It is argued that the insertion of a nonventilable tube for MIST technique increases the resistance and the spontaneous breathing has to perforce happen through the space available surrounding the tube, the peri-tubal space. The airway resistance is inversely proportional to the fourth power of radius of the tube inserted with the laminar flow or the fifth power of the radius of the tube in case of nonlaminar flow. In a sedating modeling study, it was proven that CPAP transmission and spontaneous breathing during the LISA procedure is grossly reduced because of the increased airway resistance.[23] A standard 2.5 mm endotracheal tube has an effective ventilable area of 4.9 mm2 with a wall dead space of 8.3 mm2 as the outer diameter is 4 mm.[24] This author had published his experience with using the 2.0 mm endotracheal tube as the MIST conduit in Dubai that has an outer diameter of 2.7 mm, thus corresponding size-wise to an 8Fr feeding tube.[15] The smaller the tube, the better for the LISA procedure, and in a baby whose airway or tracheal diameter is 2 mm in diameter, it is prudent not to exceed 5Fr-6Fr size of catheters.[24] It is equally important that the person performing the procedure shall be of such a caliber that he achieves a success rate of more than 90% and completes that in the shortest possible time.

  The Influence of Surfactant Replacement Therapy Procedure Facilitation Steps or Strategies Top

INSURE, by definition, is a semi-elective procedure and in preparation for ventilation, these babies are often sedated and many times also administered analgesia, including narcotic drugs. Pain in neonates is real, and it is proven.[25] The mere process of visualization of the glottis by laryngoscopy is nociceptive and elicits a crying response in the babies. This happens as early as within 5 s of this procedure. The laryngoscopy procedure using the conventional laryngoscopy blades which are available is by itself painful, and the resultant pain leads to reflex bradycardia and hypoxia. Therefore, the procedural ease becomes the immediate determinant of the efficacy of MIST versus INSURE. It is known, and we understood by our own personal hands-on experience that MIST is easier to perform by experienced hands, and the procedure can be completed within 2 min.

INSURE way of surfactant delivery as described and performed needs preparation, sedation, analgesia, intubation with a standard endotracheal tube, ventilation by bag and mask to stabilize the baby, and confirmation of the position of the endotracheal tube. A feeding tube is threaded down the endotracheal tube to administer the surfactant and a variable period of ventilator dependency and mechanical ventilation follows the procedure. The duration of the intubation that combines both the procedure and the mechanically assisted breathing following the procedure and the resultant volutrauma and barotrauma predispose to bronchopulmonary dysplasia (BPD). The risk of infection as revealed by the neutrophil counts of the broncho-alveolar lavage increases manifold in intubated neonates commensurating with the duration of intubation and dependency on ventilator. It has been conclusively proven that a biofilm that serves as a nidus of bacterial and pathogenic organisms described in relation to percutaneously inserted long lines also does happen in an intubated neonate who is dependent on his endotracheal tube. This serves as a reservoir of pathogenic organisms predisposing to overt and covert infections of the lung parenchyma that are additional causative factors for oxygen dependency and subsequent chronic lung disease.[26]

It is reasonably clear from these arguments and averments that on both the issues framed, MIST (LISA) outscores INSURE and has to be the preferred and the beneficial way of administering SRT in preterm neonates.

  The Proof of Pudding is in Eating: The Experience Gained Henceforth Worldwide Top

The German Neonatal Network cohort on less invasive surfactant therapy or minimally invasive surfactant therapy

LISA has been an inherent part of the noninvasive schema of newborn respiratory support in German Neonatal units for more than a decade.[27] In the large German Neonatal Network cohort of 7533 preterm neonates with gestation ranging from 22 to 28 weeks LISA procedure as the way of delivering surfactant has steadily increased from 28.7% in 2009 to 50.1% in 2016.[28] Of the entire cohort of 7533 GNN neonates of 22–28 weeks gestation, 6319 (83.9%) received surfactant, 41.5% (2624 of 6319) by LISA, and 58.5% (3695 of 6319) by ETT. LISA brings about a significant reduction in mortality and the serious preterm specific morbidities intraventricular hemorrhage (IVH), bronchopulmonary dysplasia BPD, sepsis, and retinopathy of prematurity (ROP). The Number Needed to Treat (NNT) to prevent one instance each of the preterm morbidity or mortality is tabulated below. The most favorable beneficial effects are towards prevention of BPD or death the NNT being only 5. The NNT to prevent one case of BPD is 6 and to prevent one death is 27. The Number Needed to Harm for Focal Intestinal Perforation needing surgery the only attributable harm is also displayed in the last row of this [Table 1]. But even this is neutralized when analyzed in combination with the beneficial NNT to prevent one case of necrotizing enterocolitis requiring surgery.
Table 1: Minimal or less invasive surfactant therapy versus INtubate, SURfactant, Extubate: The German Neonatal Network data*

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Experience from other European countries

In the Netherlands, 185 spontaneously breathing neonates with gestational age 24–31 weeks received surfactant by Minimally MIST using umbilical catheter 4–5 Fr over the period of June 2014 to October 2016 in 2 tertiary neonatal centers.[21] Noninvasive ventilation success rate of 50% or more is achieved with nasal CPAP alone in 29 weeks and above. With the addition of MIST, the gestational age of 50% or more success of NIV improves to include 25 weeks to 28 weeks as well. This study also documents that MIST reduces the incidence of IVH as MIST procedural failure requiring intubation and surfactant administration bears a significant association with severe grades of IVH.

A recent article from Poland presented the analysis of 500 LISA procedures performed in 31 tertiary neonatal centers over 1 year from February 2018 to February 2019 as a post-analysis of the drive to implement LISA procedure for surfactant administration in neonates.[29] 77% of them were <32 weeks gestational age, and the median age of surfactant administration was 2.1 h (0.8–6.7). 22.8% (114 of 500) needed intubation and ventilation within 72 h of the procedure (failure) the chances of failure ranging from a maximum of 69% at 24 weeks to 4% at 34 weeks. No significant differences in outcomes were observed with the modality of noninvasive respiratory support (Nasal CPAP, BiPAP or Nasal Intermittent Positive Pressure Ventilation [NIPPV]) in these babies receiving surfactant by LISA procedure. LISA catheter was used for the procedure in 430 babies (86%). 98% of babies received poractant alpha, and the remaining 2% beractant. The median duration of surfactant instillation was 1.5 min (1–2 min). Only 24% of the babies who received surfactant therapy during the study period had been treated by LISA procedure (76% were still intubated for surfactant in the conventional manner).

In a prospective single-center cohort study from Spain, neonates receiving beractant 100 mg/kg by INSURE technique from January 2012 to December 2013 were compared with neonates receiving beractant 100 mg/kg by LISA technique using a 5F multi-access catheter (KimVent Trachcare Technology, UK) during the subsequent 24 months from January 2014 to December 2016.[30] The need for invasive mechanical ventilation within the first 72 h of life was significantly reduced in the LISA cohort, and this was directly correlated to the higher free BPD survival rates in this group that was statistically significant in the 26–28 + 6 weeks' gestation subgroup. More neonates needed 2nd dose of surfactant in the LISA cohort than in the INSURE cohort (56.4% vs. 38.7%, P = 0.016). The use of Synchronized NIPPV during hospitalization (5.2% vs. 26.4%, P ≤ 0.001) and HFOV on the 3rd day 13.4% versus 24.6%, P = 0.002) were significantly higher in the LISA cohort period a reflection of updating of protocols of neonatal care with time.

LIST from other than European countries

This author introduced Minimally MIST in Dubai neonatal units in 2018 and published his initial experience with 3 neonates in 2018 all these were by infant feeding tube as the MIST conduit.[14] This was followed by a report on an innovative way of doing MIST using the smallest diameter endotracheal tube 2.0 mm, in 2019 and again in 2020 an analytical repertoire on the 15 MIST procedures performed on 13 preterm neonates constituting the Dubai cohort.[15],[31] Catheterization techniques were by infant feeding tube 10 times, LISA catheter once and the innovative 2.0 mm endotracheal tube way 4 times. Curosurf at 200 mg/kg was used on 9 occasions and survanta at 4 ml/kg on 6 occasions. The median age of administration of the first dose of surfactant by MIST was 12.5 h in this cohort which is in contradistinction to all the other studies reported herein. Logically this means that these were babies who were worsening despite being on noninvasive ventilation for more than 6 h and hence might be a true representation of surfactant deficient state. Surfactant reflux during MIST had been of major concern.[32],[33] This was effectively nullified in our MIST cohort by use of air boluses delivered through the MIST conduit after the instillation of surfactant.[34] All in our cohort have survived without a severe morbidity on follow-up ranging from 6 to 24 months. MIST failure rate was 7.7% (1 of 13) in this cohort, and this baby had grade 3 ROP, which was treated successfully.

From India, the (SURfactant without Endotracheal [SURE] tube intubation) group has published their first randomized controlled trial comparing the morbidity and mortality outcome until 36 weeks corrected gestational age in preterm babies of 29–33 weeks gestational maturity with Respiratory distress syndrome receiving surfactant Neosurf (bovine lipid extract surfactant, Cipla Pharmaceuticals Ltd.) at 5 ml/kg by SURE technique (n = 175) against those receiving by INSURE technique (n = 175).[35] 16G angiocath (Desielt, Vygon) and 5Fr infant feeding tube were the conduits used for SURE and median time of administration of surfactant was 1 h (0.5–3 h). The duration of mechanical ventilation, hospital stay, oxygen days, and incidence of BPD was significantly lower in the SURE group. 3% of SURE group had ≥ grade 2 IVH versus 2% in the INSURE group. What was more certain (SURE) in ensuring better outcome technique-wise is not reported in this article, the angiocath way or the infant feeding tube way of SURE.

In a report of a randomized controlled trial from Kolkata, India, 58 preterm babies (mean gestation 30 weeks and mean birth weight 1223 g) who were on NIPPV as the primary means of noninvasive support, MIST (Curosurf 200 mg/kg) by infant feeding tube Magil's aided procedure was compared with the unit standard INSURE for SRT. This study reports that MIST was not found to be of any significant benefit in this cohort[36] This is probably due to wrong sample size calculations as the presumed effect was a reduction in the need for Invasive Mechanical Ventilation from 55% in INSURE group to 20% with MIST whereas in the actual data reported, even in the INSURE the babies <28 weeks group only 20.69% (6 of 29) needed intermittent mandatory ventilation (IMV) within 72 h and hence the 10.3% (3 of 29) reduction of IMV incidence in the MIST group fails to achieve significance.

It has to be noted that whereas the European units are the leaders in the implementation of this minimally or less invasive way of surfactant administration, acceptance and adaption of this technology is lower in other countries such as Japan, the USA, and the United Kingdom.[31] In a 2019 Web-based survey of 150 neonatal units in England, it was reported that only 11% are using LISA for surfactant therapy.[37]

The pro-INtubate, SURfactant, Extubate group contra views to Less Invasive Surfactant Therapy or Invasive Surfactant Therapy

Researchers who are not convinced that MIST is superior to INSURE have maintained that[38],[39] INSURE if performed with proper analgesia and/or sedation (promptly reversible short-acting) and or

  1. Delivering controlled Low peak pressure ventilation post surfactant administration by INSURE should be at least non inferior to MIST as skills of INSURE are more easily transferable
  2. An RCT in progress in 13 tertiary neonatal centers in China that is exploring the hypothesis that Low Positive Pressure Ventilation following conventional surfactant administration (LPPSA) is non inferior to LISA in preterm neonates of gestational age ranging from 25 weeks to 31 + 6 days.[40]

The strongest counter to these arguments is that the smallest endotracheal tube that is available for neonatal use is 2.0 mm inner diameter that has an outer diameter of 2.7 mm, and this logically cannot be the ideal way of delivering surfactant to extremely immature babies who are on noninvasive respiratory support.

Breathe easy my baby: Giving surfactant by invasive surfactant therapy

The following facts can be safely inferred from the published studies on MIST:

  1. Invasive mechanical ventilation within 72 h even for a shorter period (this bears a direct correlation to the gestational age) is dangerous, and this is a definite risk factor for BPD or chronic lung disease. MIST achieves a reduction in IMV by intubation, and this effect is consistent in all these studies
  2. Hospitalization, neonatal intensive care unit stay, and oxygen days are definitely reduced with MIST, this effect is also consistent across the studies, and this achieves significant cost savings and reduced stress for the parents, family, caregivers, and nurses
  3. The significant morbidities that will have a direct effect on the long-term outcome, major as well as minor such as IVH, sepsis, and ROP are reduced, and this effect is also consistent across studies provided the conforming factors in the sample size factors are normalized or equalized
  4. The pathobiology and pathophysiology of the success of MIST depends on delivering surfactant through a nonventilable tube if it maintains the spontaneous breathing and the effect of CPAP during the procedure. Surfactant Instillation time of 2 min or less coupled with techniques like syringe air flushes to prevent surfactant reflex. Throughout the procedure, effect of noninvasive support of the spontaneous breathing efforts of the babies is maintained by ensuring a sufficient airflow passage around the conduit, the peri-catheter space
  5. The overwhelming evidence derived from the review of published reports worldwide that we have presented concisely in this article is that MIST or LISA shall be the default way of administering surfactant to preterm babies. Nevertheless, failure of MIST necessitating emergency intubation without elective preparation is dangerous, and so the neonatal practitioners who are performing MIST or LISA have to undergo supervised training to acquire the requisite technical skills and comprehension of the procedure.

  Conclusions Top

LISA or MIST coupled with noninvasive support is the most beneficial way of managing preterm neonates with respiratory distress and shall be the preferred and default way of administration of surfactant in units with personnel experienced in this procedure.

The surfactant usage described as in these MIST studies have been more than 30%, increasing to 50% or more in extremely immature neonates <28 weeks gestational age. Hence surfactant is an essential part of less invasive or noninvasive scheme of managing newborns with respiratory distress, and noninvasive respiratory modalities such as nasal CPAP or NIPPV cannot be a substitute to surfactant therapy.

Results from further randomized trials that are evaluating whether INSURE performed with the addition of analgesia or INSURE by a different technique alone or coupled with faster extubation will equalize MIST are awaited. Studies are also underway to evaluate the need if any of sedation/analgesia during MIST procedure and if yes what agents have to be preferred and at what dosage, and in what sequence and or combination.[41]

While this all can be happening, it is imperative that teaching sessions of this technique of MIST is incorporated in the neonatologists' curriculum of training.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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