
==== Front
Med Arch
Med Arch
Medical Archives
Medical Archives
0350-199X
1986-5961
Academy of Medical Sciences of Bosnia and Herzegovina

38566872
10.5455/medarh.2024.78.112-116
Original Paper
Less Invasive Surfactant Administration (LISA) Versus INSURE Method in Preterm Infants: a Retrospective Study
Dini Gianluca 1
Santini Maria Grazia 1
Celi Federica 1
1 Neonatal Intensive Care Unit, “Santa Maria” Hospital, Terni, Italy
Corresponding author: Gianluca Dini, Neonatal Intensive Care Unit, “Santa Maria” Hospital, Terni, Italy. Address: Viale della Vittoria, 01021, Acquapendente, Italy. Phone: +39 3337797213. gianlucadini90@gmail.com. ORCID ID: https://orcid.org/0000-0003-1572-221X.
2024
78 2 112116
16 1 2024
04 3 2024
© 2024 Gianluca Dini, Maria Grazia Santini, Federica Celi
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background:

Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in preterm infants. Early nasal CPAP and selective administration of surfactant via the endotracheal tube are widely used in the treatment of RDS in preterm infants.

Objective:

The aim of this study was to compare the need for intubation and mechanical ventilation after surfactant delivery between LISA-treated and INSURE-treated premature infants with respiratory distress syndrome (RDS).

Methods:

Retrospective registry-based cohort study enrolled 36 newborns admitted to the neonatal intensive care unit of the “Santa Maria” Hospital of Terni between 2016 and 2023. As a primary outcome, we followed the need for intubation and mechanical ventilation within 72 hours of life, while the secondary outcomes were major neonatal morbidities and death before discharge.

Results:

The LISA group and the INSURE group included 13 and 23 newborns respectively. Demographic features showed no significant differences between the two groups. The need for mechanical ventilation in the first 72 hours of life was similar in both groups (p >0.99). There were no significant differences in morbidities.

Conclusion:

LISA and INSURE are equally effective modalities for surfactant administration for the treatment of RDS in preterm infants.

INSURE
LISA
respiratory distress syndrome (RDS)
surfactant
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pmc1. BACKGROUND

Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in preterm infants (1). Early nasal CPAP and selective administration of surfactant via the endotracheal tube are widely used in the treatment of RDS in preterm infants (2). Although treating RDS with surfactant improves clinical outcomes, mechanical ventilation (MV) can cause lung injury in preterm infants with RDS and contribute to the development of bronchopulmonary dysplasia (BPD) (3, 4). The intubation-surfactant-extubation (INSURE) technique was introduced in 1992 by Verder et al. (5) to reduce the duration of MV. However, the INSURE method does not allow to completely avoid MV and poses a potential risk of iatrogenic laryngeal or tracheal damage. On the other hand, during the “less invasive surfactant administration” (LISA) technique, surfactant is instilled into the trachea of a spontaneously breathing neonate on nCPAP, via a thin catheter placed in the trachea.

The LISA method is becoming increasingly popular in neonatology departments. In a recent systematic review, Isayama et al. have described that LISA decreased the need for MV as well as reduced the incidence of intraventricular hemorrhage (IVH) and BPD (6).

2. OBJECTIVE

The present study was planned to evaluate the effect of administering surfactant by LISA method using an orogastric feeding tube over the traditional INSURE method on the duration of MV and other modalities of respiratory support.

3. MATERIALS AND METHODS

3.1. Study design

This retrospective cohort study was performed in the level III neonatal intensive care unit of “Santa Maria” Hospital (Terni, Italy). Medical records of preterm infants, who were born between 25 to 36 weeks of gestation from January 2016 to December 2023, were collected from the database of our hospital. We included infants who presented with features of RDS within six hours of life and required surfactant therapy on nCPAP (requiring FiO2>30%). Newborns with major congenital anomalies as well as infants who required intubation in the delivery room were excluded from the study. The study was conducted in accordance with the Declaration of Helsinki as revised in 2008. Data obtained were used only for the purposes of this research, and the data and identity of each participant remained anonymous. An informed consent was obtained from the parents of all patients included in the study, according to the local legislation.

3.2. Methods

The diagnosis of RDS was based on clinical symptoms (tachypnea, grunting, subcostal and intercostal retractions, nasal flaring, and/or cyanosis) and a chest radiograph consistent with a reticulogranular appearance to the lung fields (7). Preterm infants with RDS were initially stabilized on non-invasive ventilation (NIV) in the form of nCPAP. The technique for surfactant administration was chosen at the physician’s discretion. Patients who received surfactant via the INSURE technique were first orally intubated with a single lumen appropriate sized endotracheal tube, and poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) at a dose of 200 mg/kg was instilled to the trachea in 30 seconds. Manual lung inflation by using T-piece device (Neopuff Infant Resuscitator; Fisher and Paykel, Auckland, New Zealand) at 20/5 cm H2O pressure was performed during the surfactant instillation, and then the patient was rapidly extubated. After extubation, nCPAP support was maintained.

The LISA method was performed as follows: a 5 Fr, flexible, sterile nasogastric tube was inserted through the vocal cords under direct vision using a laryngoscope, without the need for Magill forceps and any sedation. Porcine surfactant (Curosurf; Chiesi Farmaceutici, Parma, Italy) at a dose of 200 mg/kg, which was previously prepared by drawing up in a 5-mL syringe with an additional 1 mL of air for dead volume of the instillation catheter, was administered in bolus in 30 to 60 seconds. The catheter was immediately removed and non-invasive respiratory support was continued.

The primary outcome of the study was the need for MV in the first 72 hours of life. Secondary outcomes were the requirement of ≥2 doses of surfactant, rates of hemodynamically significant patent ductus arteriosus (hsPDA), pneumothorax (PNX), IVH (grade ≥2; Papile classification (8)), retinopathy of prematurity (ROP; stage >2 as defined in the international classification (9)), necrotizing enterocolitis (NEC; modified Bell’s stage ≥2 (10)), BPD (as defined by Jobe and Bancalari (11)), sepsis, duration of hospital stay, and mortality before discharge. PNX was diagnosed via a chest X-ray (12). When the clinical team suspected sepsis based on perinatal risk factors or clinical signs a sepsis screen was performed. Echocardiography was done for suspected patent ductus arteriosus and treated if hemodynamically significant.

3.3. Ethical considerations

Ethical committee approval was not requested because the General Authorization to Process Personal Data for Scientific Research Purposes (Authorization no. 9/2014) declares that ethical approval is not needed for retrospective archive studies that use ID codes, preventing the data from being traced back directly to the data subject). Written informed consent was obtained from the parents of all subjects included in the study. All methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards.

3.4. Statistical analysis

Qualitative data were presented as frequencies and percentages. Quantitative data were expressed as mean (standard deviation) or median (interquartile range). Pearson’s chi-square test or Fisher’s exact test was used to compare categorical variables. To compare numerical variables, independent samples t-test or Mann–Whitney U-test was used. p-value <0.05 was considered significant. Data analysis was performed using SPSS statistical software version 29.0 (IBM SPSS Statistics).

4. RESULTS

4.1. Clinical characteristics

A total of 36 infants, who were stabilized by nasal CPAP at birth and were administered surfactant via INSURE or LISA method were enrolled in the study. Of those, 23 infants received surfactant by INSURE and 13 infants by LISA method. Demographic and clinical characteristics of the infants in the LISA and INSURE groups were similar as summarized in Table 1.

Table 1. Baseline characteristics of infants enrolled in the study. INSURE, intubation-surfactant-extubation; LISA, less invasive surfactant administration; SGA, small for gestational age; IQR, interquartile range.. * Chi-squared test. ** Unpaired t-test. *** Fisher’s exact test. **** Mann-Whitney U-test

Baseline characteristics	INSURE (n = 23)	LISA (n = 13)	p-value	
Gender				
Male, n (%)	8 (34.7%)	5 (38.5%)	0.825*	
Female, n (%)	15 (65.2%)	8 (61.5%)		
Birth weight, g, mean (± SD)	1554 (±502)	1718 (±717)	0.428**	
Gestational age (weeks), mean (± SD)	30.78 (±2.50)	31.46 (±2.75)	0.456**	
SGA, n (%)	1 (4.3%)	2 (15.3%)	0.539***	
Delivery mode				
Vaginal, n (%)	1 (4.3%)	3 (23%)	0.124***	
C-section, n (%)	22 (95.6%)	10 (76.9%)		
Apgar score, median (IQR)				
1 min	7 (7-8)	7 (7-8)	0.488****	
5 min	9 (8-9)	9 (8-9)	0.582****	

A high proportion of babies (88%) were delivered by cesarean section. The mean birth weight (BW) of infants who received the surfactant by the INSURE method was 1554 g ± 502, with a minimum of 805 g and a maximum of 2805 g. In the LISA group, gestational age ranged from 25+5 to 35+0 weeks and the BW ranged from 760 to 3075 g.

4.2. Outcomes

MV was required in 39.1% (9/23) of infants in the INSURE group and 38.4% (5/13) in the LISA group. Among the secondary outcomes, the incidence of BPD was higher in the INSURE group. However, this difference was not statistically significant (p = 0.288). No differences were observed between the two groups for IVH, NEC Bell’s stage II or more, hsPDA, ROP requiring treatment, sepsis, and mortality before hospital discharge (Table 2). There was no statistically significant difference in the total duration of respiratory support in both groups.

The median (IQR) duration of MV was similar in both groups. The median (IQR) duration of hospital stay was 38 (24-49) days in the INSURE group and 27 (15-46) days in the LISA group with a p-value of 0.328. LISA reduced the median duration of hospital stay although the result was not statistically significant.

5. DISCUSSION

Management of RDS aims to provide interventions to maximize survival whilst minimizing potential adverse effects including BPD. For a long time, the standard approach to treating RDS involved surfactant therapy administered during intermittent positive pressure ventilation (IPPV). However, since MV has been identified as a risk factor for BPD due to potential airway and lung injuries (barotrauma/volutrauma), different strategies have been developed over time to address this issue (13, 14). Although the INSURE procedure has been standard since the 1990s, it involves short-term endotracheal intubation followed by a brief period of MV. To avoid the negative effects of intubation and MV, less invasive procedures of surfactant replacement with thin catheters have emerged. The LISA method delivers the surfactant via a thin catheter while the infant is spontaneously breathing directly into the proximal airway (15). Multiple randomized, controlled trials suggest that, compared to more invasive methods like INSURE, LISA reduces the need for MV at 72 hours of life, and may potentially reduce the risk of BPD and mortality (16, 17). LISA was also associated with reduced duration of hospital stay, reduced duration of oxygen supplementation, lower rates of other common neonatal morbidities, such as IVH, and lower rate of interventions for ROP (18). Despite these findings supporting the feasibility and safety of LISA, some relevant adverse events of LISA have been reported, including tracheal surfactant reflux, bradycardia, hypoxia, need for intubation, unilateral deposition of the surfactant, and mucosal bleeding (19).

Table 2. Outcome parameters of infants with RDS after surfactant administration. INSURE, intubation-surfactant-extubation; LISA, less invasive surfactant administration; MV, Mechanical Ventilation; NIV, non-invasive ventilation; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; hsPDA, hemodynamically significant patent ductus arteriosus; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; IQR, interquartile range. * Fisher’s exact test ** Mann-Whitney U-test

Outcome	INSURE
(n = 23)	LISA
(n = 13)	p-value	Relative risk (95% CI)	
Need for MV in the first 72 h, n (%)	9 (39.1%)	5 (38.4%)	>0.99*	1.017 (0.432-2.394)	
Median (IQR) duration of MV (days)	3 (2-6)	3 (2-10.5)	0.898**		
Median (IQR) duration of NIV (days)	7 (4-23)	7 (4-30.5)	0.770**		
Total duration of respiratory support (days), median (IQR)	7 (4-26)	9 (5.5-30.5)	0.454**		
Median (IQR) length of hospital stay (days)	38 (24-49)	27 (15-46)	0.328**		
Repeat dose of surfactant, n (%)	1 (4.3%)	1 (7.6%)	>0.99*	0.565 (0.038-8.302)	
Pneumothorax, n (%)	2 (8.6%)	3 (23%)	0.328*	0.377 (0.072-1.972)	
Moderate-severe BPD, n (%)	3 (13%)	0 (0%)	0.288*		
Any sepsis, n (%)	5 (21.7%)	2 (15.3%)	>0.99*	1.413 (0.318-6.283)	
ROP, n (%)	0 (0%)	0 (0%)	NA		
hsPDA, n (%)	4 (17.3%)	0 (0%)	0.274*		
IVH > grade II, n (%)	0 (0%)	0 (0%)	NA		
NEC ≥ stage II, n (%)	0 (0%)	0 (0%)	NA		
Death, n (%)	1 (4.3%)	1 (7.6%)	>0.99*	0.565 (0.038-8.302)	

Regarding the primary outcome of the present study, we found no significant difference in the need for MV within 72 hours of birth between the two groups. This is similar to findings from earlier studies. For example, a single-center randomized controlled trial in China among 90 spontaneously breathing preterm infants (from 28 to 32 weeks of gestational age) found no significant differences in the rate of MV in the first 72 hours of life (20). This aligns with the findings of a multicenter RCT from Iran involving 38 preterm infants (21). Another recent single-center RCT by Gupta et al., comparing INSURE and minimally invasive surfactant therapy (MIST), also did not find any difference in the need for MV in the first 72 hours (22).

MV has been associated with disruptions in the normal progression of alveolarization and pulmonary microvascular growth in preterm infants (23). Even brief periods of MV can activate complex inflammatory pathways and cause injury in preterm infants (24). Hence, minimizing the duration of MV is crucial to prevent damage and mitigate the risk of chronic lung disease. In this study, the incidence of BPD was lower in the LISA group, but the difference was not significant (p = 0.288). Similarly, a recent meta-analysis of three RCTs reported a lower risk of BPD (RR = 0.656 (0.375‐1.149)) with LISA compared to INSURE (25).

In the present study, the overall incidence of ROP was very low with no baby requiring laser therapy or surgery for retinopathy of prematurity. The incidence of PDA was similar in both study groups. A recent systematic review (26) reported a 35% incidence of PDA in the LISA group, with a comparable incidence in the INSURE group.

The length of hospital stay was similar in both the INSURE and LISA groups in our study, consistent with findings from a few other studies (27, 28). However, Jena et al. reported a shorter duration of hospital stay in the LISA group (p <0.01), possibly linked to the lower rate of BPD in their study (17). The early discharge is influenced by several factors which include complications occurring during NICU stay (sepsis, feeding problems), social factors (parental presence and involvement), and public health factors. Overall mortality rates were similar in both groups. This aligns with existing literature (16, 17, 25).

In our retrospective study, the INSURE group had a relatively higher number of infants compared to the LISA group. This discrepancy could be attributed, at least in part, to the influence of doctors' attitudes, as suggested by findings in previous surveys (29, 30).

One of the main limitations of the study was its retrospective design. In addition, the cohort was relatively small, and some patients were excluded due to inadequate data. Lastly, we only included patients who received poractant alfa. Therefore, the effects of other surfactant types were not analyzed.

As a result, we found that the LISA method is safe and effective as much as the INSURE method. Future randomized controlled trials are needed to investigate the effect of these two methods on morbidities, particularly BPD.

6. CONCLUSION

In this retrospective study, we did not find any difference in the need for MV during the first 72 hours of life, the requirement of more than one dose of surfactant, duration of ventilatory support, major complications, and mortality between the LISA and INSURE groups. The LISA procedure may be a good choice for spontaneously breathing infants with RDS. We believe that avoiding short-term intubation during surfactant administration could reduce the risk of BPD. The LISA method, involving surfactant instillation through a thin catheter, is seen as a promising technique for achieving these positive effects and is considered a viable option for daily clinical practice in many NICUs.

Abbreviations

BPD = bronchopulmonary dysplasia

BW = birth weight

nCPAP = nasal continuous positive airway pressure

hsPDA = hemodynamically significant patent ductus arteriosus

INSURE = intubation-surfactant-extubation

IVH = intraventricular hemorrhage

IPPV = intermittent positive pressure ventilation

LISA = less invasive surfactant administration

MIST = minimally invasive surfactant technique

NEC = necrotizing enterocolitis

NICU = neonatal intensive care unit

MV = mechanical ventilation

PNX = pneumothorax

RDS = respiratory distress syndrome

ROP = retinopathy of prematurity

Declaration of consent:

Written informed consent was obtained from the parents of enrolled children.

Author's Contribution:

GD, MGS, FC gave a substantial contribution to the conception and design of the work. GD, MGS gave a substantial contribution of data. GD gave a substantial contribution to the acquisition, analysis, or interpretation of data for the work. GD, MGS, FC had a part in article preparing for drafting or revising it critically for important intellectual content. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of interest:

There are no conflicts of interest.

Financial support and sponsorship:

This research received no external funding.
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