A comparison of LISA versus InSurE: A single center experience

1 Introduction

Surfactant replacement therapy (SRT) for respiratory distress syndrome (RDS) has been a mainstay therapy across neonatal intensive care units (NICU) since the early 1990s [1]. SRT in preterm and term infants with RDS has resulted in decreased mortality, and lower incidence and severity of RDS, pulmonary air-leak syndrome, and other risk factors associated with the development of bronchopulmonary dysplasia (BPD) [2, 3]. Still, BPD incidence has remained relatively unchanged in recent years regardless of SRT use, likely due to the increase in survival of more immature infants and changes in the pathogenesis and presentation of BPD [4].

BPD is the most common neonatal morbidity am-ong very low birth-weight (VLBW) infants, affecting an estimated 22–45% of these infants in the United States [5–7]. BPD also has significant financial imp-act, and recent research has demonstrated a median hospitalization cost in the first year of $377,871 per infant with BPD, as compared with $175,836 per infant without BPD [8]. Moreover, despite being studied extensively, progress in the reduction of BPD has proven elusive [9]. For this paper, BPD will be defined as the need for supplemental oxygen at 36 weeks corrected gestation.

Traditionally, SRT has required endotracheal in-tubation, including the Intubation Surfactant Extubation (InSurE) method [10]. The InSurE method reduces mechanical ventilation exposure, but still requires placement of an endotracheal tube and positive pressure breaths for surfactant delivery. There is concern even brief exposure to artificial ventilation can trigger an inflammatory cascade, increasing the risk of BPD. In animal studies, brief periods of positive pressure ventilation have deleterious effects on lung function [11, 12].

Less invasive methods of SRT delivery, specifically, the Less Invasive Surfactant Administration (LISA) method has been successfully implemented and evaluated across Europe [13, 14]. The LISA method avoids the need for intubation and positive pressure ventilation (PPV). LISA method delivers the surfactant instillation via thin catheter while the infant is spontaneously breathing directly into the proximal airway [15]. LISA has been clinically implemented in Germany for over 15 years and appears to be pre-ferred by most neonatologists throughout Europe [16]. While American neonatologists are aware of the efficacy of LISA and its popularity in foreign healthcare facilities, LISA remains underused and understudied in the United States (US) [17].

Multiple randomized, controlled trials and retrospective SRT studies suggest that, compared to more invasive SRT methods like InSurE, LISA reduces the need for mechanical ventilation (MV) at 72 hours of life, and may potentially reduce the risk of BPD and mortality [18, 19]. More recent research has shown that InSurE, as compared to LISA, results in a higher need for MV, increased need for oxygen, and associated with higher rates of BPD [20, 21].

Several meta-analyses have corroborated these findings. Specifically, the use of LISA has been linked to increased survival of preterm infants, decreased risk of BPD, and a lower rate of CPAP failure, defined as the need for mechanical ventilation within 72 hours of life [22–25].

While the literature indicates LISA is more efficacious than InSurE in terms of neonatal respiratory outcomes, there is a lack of US-based clinical trials and retrospective studies of LISA [17]. This study aimed to address this research gap and demonstrate the potential for LISA as a safe and potentially advantageous alternative to InSurE. We hypothesized infants that received SRT via LISA would have a lower incidence of BPD and require less mechanical ventilation when compared to infants that received SRT via InSurE.

2 Methods

This was a retrospective chart review conducted at Orlando Health Winnie Palmer Hospital for Women and Babies in Orlando, Florida. Institutional Review Board approval was obtained prior to beginning the study. Charts were reviewed for infants born at our facility that received SRT. Infants were included if they were born between 25 through 32 weeks gestation and received SRT via InSurE only (Group 1) or via LISA only (Group 2). Infants were excluded if they received multiple doses of surfactant with different methods, e.g., one via LISA and one via InSurE. Data collection period was from September 3, 2017 through April 15, 2019, centered around a LISA quality improvement and training project conducted in our hospital unit (see Fig. 1).

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Fig. 1

Chart review process. All charts reviewed between September 3, 2017 through April 15, 2019 for infants that received surfactant replacement therapy (SRT). Infants excluded if they were > 32 weeks gestational age (GA) or < 25 weeks GA. Patients excluded if they were transferred or expired before reaching 36 weeks GA, due to inability to make a full determination of bronchopulmonary dysplasia.

For this study, all infants receiving SRT were treated with Curosurf^® (poractant alfa) at a dose of 2.5 mL/kg (200 mg/kg) for the first dose and 1.25 ml/kg (100 mg/kg) for subsequent doses. The surfactant is drawn in a 3–5 mL syringe with an additional 0.5 mL of air. Surfactant doses were performed in 3–5 aliquots, pausing for 10–15 seconds in between aliquots to ensure infant tolerance. Surfactant was followed with 0.5 ml of air to clear the tubing of any remaining surfactant.

3 Results

SRT continues to be a mainstay therapy for RDS in premature infants, but overall BPD rates remains relatively unchanged or perhaps increasing [28]. The use of CPAP as a first line ventilation intervention has resulted in less ventilation associated trauma and lower rates of BPD. Due to these benefits, more infants are currently being treated with noninvasive ventilation methods since birth. The InSurE method was created to reduce the amount of time exposed to mechanical ventilation but it still requires PPV for surfactant administration. The LISA method avoids the need for intubation and PPV.

In our single center study, we wanted to evaluate whether LISA was feasible in infants 25–32 weeks GA and able to reduce the incidence of BPD. We were able to demonstrate the LISA method is feasible and safe option for SRT in these infants who are receiving CPAP. However, the clinical benefits of reducing BPD were insignificant regardless of surfactant method, InSurE or LISA. Notably, while there is not an official guideline for when to provide SRT at our site, both groups had virtually identical CPAP and FiO2 just prior to SRT.

We equally speculated that the days of mechanical ventilation would be decreased with the LISA procedure. We found ventilator outcomes were not significantly different between Groups. Our findings were consistent with the Aguar et al. study [29] but differed from the Dargaville et al. study [30] which demonstrated decreased need of mechanical ventilation. Krajewski et al. conducted a study involving 26 infants which reported significant reductions in mechanical ventilation and BPD rates, compared to historical results using InSurE technique [31]. We do not have a clear explanation for outcome differences between our study and Dargarville et al. [30] and Krajeski et al. [31].

Interestingly, in infants 25–27 weeks GA we did see a trend towards less BPD favoring the LISA group (53.8% vs 76.9%). These infants also weaned to unassisted room air earlier and had less oxygen needs at the time of discharge. We speculate there may be a benefit of LISA in the more premature infants whose lungs are more vulnerable to PPV utilized during the InSurE method, but more vigorous studies are warranted. Overall, the need for a second surfactant dose in both Group 1 and Group 2 were similar (12.5% vs 14.8%) which was unanticipated and potentially due to high CPAP utilization in the delivery room.

Our quality improvement initiative, i.e., the time period from which this study data was collected, showed there were no differences in the amount of complications between LISA and InSurE. Short term complications for LISA can include episodes of ap-nea, hypoxia, and bradycardia during surfactant instillation [15]. Also, esophageal intubation during LISA was a significant concern amongst staff, but this was not observed in this group of infants. We suspect aid of laryngoscope and two respiratory therapists during the LISA procedure provided a safeguard against these risks. Finally, focal intestinal perforation during LISA is a documented risk [32], but this did not occur at our site.

There are several strengths and limitations to our study. Because it is retrospective, several management factors may have influenced our study outcomes. Besides the adoption of LISA SRT, there were no other significant clinical practice changes recorded in the respiratory or nutritional management of infants within the study that may have impacted BPD rates. We primarily used the Neotech RAM Cannula^® (manufacturer location: Valencia, CA) interface to apply CPAP for both Group 1 and Group 2.

Moreover, the study was not a historical cohort comparison, but rather a comparison within overlapping periods of time. Our sample size may have been too small to detect a difference in BPD rates between Group 1 and Group 2 resulting in type II error. However, data from this study can be used to design larger, more robust randomized studies. It is also important to highlight that this study does suggest that LISA can be attempted in non-intubated infants born at 25–32 weeks gestation.

In conclusion, non-intubated preterm infants requiring surfactant therapy using the LISA method, as compared to the InSurE method did not result in decreased BPD rates, improved respiratory outcomes, or decreased length of stay. LISA shows promise as a safe and equally effective alternative to InSurE. Because LISA is less invasive and just as effective, LISA is now standard care at our site. However, further research is needed to establish best evidence-based surfactant replacement technique for non-intubated preterm infants.