Minimally Invasive Surfactant Therapy (MIST) vs intubate-surfactant-extubate (InSurE) technique, in a Peruvian Neonatal Intensive Care Unit (NICU)

doi:10.21203/rs.3.rs-4289599/v1

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Minimally Invasive Surfactant Therapy (MIST) vs intubate-surfactant-extubate (InSurE) technique, in a Peruvian Neonatal Intensive Care Unit (NICU)

https://doi.org/10.21203/rs.3.rs-4289599/v1

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Objective

To compare the outcomes of premature infants with respiratory distress syndrome treated by minimally invasive surfactant therapy (MIST) vs intubate-surfactant-extubate (InSurE) in a Level-3 NICU in Peru. Study Design: We analyzed a historical cohort with InSurE technique vs a prospective cohort with MIST. Surfactant was administered through a feeding tube in MIST cohort.

Results

91 patients included, 48 treated by InSurE and 43 by MIST. Groups were similar in gestational age and birth weight, had poor prenatal care. There were no differences in demographic characteristics, nor in main outcomes: need for mechanical ventilation, bronchopulmonary dysplasia or mortality. The duration of mechanical ventilation, time of oxygen therapy and hospital stay were similar.

Conclusions

Our study shows that reduction of intubation for surfactant administration in preterm neonates with RDS can be achieved by MIST. No difference in outcomes between MIST and InSurE in preterm infants with RDS.

Health sciences/Diseases/Respiratory tract diseases

Health sciences/Health care/Paediatrics

Neonate

respiratory distress syndrome

surfactant

minimally invasive surfactant therapy

Respiratory distress syndrome is one of the most common neonatal diseases. It is an important cause of morbidity and mortality in preterm infants. Approximately 70% of preterm infants below 33 weeks of gestational age present with RDS (1). A significant proportion of these patients may require invasive mechanical ventilation, non-invasive mechanical ventilation, and surfactant replacement therapy.

Early use of continuous positive airway pressure (CPAP) after birth in preterm infants, provides adequate management for RDS, diminishing the need for invasive mechanical ventilation(2–4) The American Academy of Pediatrics and the European Society for Pediatric Research recommend noninvasive ventilation as the initial management of preterm infants. The use of surfactant and CPAP has shown to improve survival and decrease bronchopulmonary dysplasia (BPD) (5, 6).

In 1990s Verder et al proposed a technique of surfactant administration. Patient was intubated, surfactant administered and subsequently extubated (in less than 2 hours) (InSurE). The aim of the InSurE technique was to diminish the exposure of preterm infants to prolonged positive pressure ventilation (7). Although this method is less invasive to previous surfactant replacement techniques, this method requires intubation and exposes the infant to a short time of positive pressure ventilation (PPV). Studies in lambs have shown that even short periods of endotracheal PPV exposure might initiate lung injury which might increase the risk of BPD (8).

Recent studies have demonstrated that surfactant can be delivered intratracheally without the use of an endotracheal tube, using a fine catheter under direct laryngoscopy in spontaneously breathing preterm infants. This allows the vocal cords to adduct and the glottis to play an active role, which permits adequate distribution of surfactant during spontaneous breathing. This procedure is done keeping the infant on nasal CPAP (9). This method is called less invasive surfactant administration (LISA) or MIST.

In 2011, Dargaville et al., described a similar technique in which the trachea was catheterized using a semi-rigid instillation catheter. It was called the Hobart Method. The infant was kept on nasal CPAP to allow for spontaneous breathing throughout the procedure (10).

Various techniques have been used since 2007 for a less invasive instillation of surfactant. Kanmaz et al conducted a randomized controlled trial comparing early administration of surfactant via a thin catheter, without the use of McGill forceps, during spontaneous breathing (Take Care technique) vs InSurE (11).

Although there is still no compelling evidence demonstrating improved long-term outcomes using MIST or LISA, these methods look promising and further studies should be conducted (12–15).

The aim of our study was to compare the results of two cohorts of patients treated for RDS, one through a MIST technique utilizing a nasogastric feeding tube, maintaining the patient on nCPAP vs a historic cohort of patients who received surfactant replacement therapy through InSurE. Also, to assess the feasibility of introducing a modified MIST technique in a low or middle-income setting.

Our study was conducted in a neonatal intensive care unit (NICU) in Cayetano Heredia Hospital, in Lima, Peru, between January 2018 and October 2020. It is a level 3 NICU, with approximately 5000 deliveries and 500 admissions to the NICU per year. It is a referral center in a marginal urban area of Lima. The study was approved by the Institutional Review Board (IRB). The IRB waived the need for informed consent in both groups.

We included all preterm infants below 35 weeks of gestational age with RDS who were not intubated at birth, who required nasal CPAP and who required surfactant administration, defined by respiratory distress presentation with radiological findings compatible with RDS and the need of a mean airway pressure ≥ 8 cmH20 via CPAP or nasal intermittent positive pressure ventilation (NIPPV) and/or fraction of inspired oxygen (FiO₂) ≥ 0.30. We excluded infants who required initial endotracheal intubation prior to surfactant or at any time point, as the need for mechanical ventilation was a primary endpoint. We also excluded those who required aggressive resuscitation or were hemodynamically unstable and those who presented with major congenital anomalies.

We analyzed two groups of patients. A historic cohort of patients (12 months prior to implementation of MIST technique) who received surfactant therapy via InSurE (48 patients) and a prospective cohort of preterm infants who received surfactant replacement therapy (SRT) via MIST (43 patients). The historic cohort was chosen pairing patients to the ones in the MIST group, according to gestational age and birth weight, to have comparable groups.

A clinical practice guideline for MIST utilizing a nasogastric feeding tube was developed in our NICU. Neonatologists in our Unit were trained in the simulation laboratory at Universidad Peruana Cayetano Heredia from September to December 2019. After training was completed, the MIST technique was established as the preferred mode of surfactant administration for preterm infants with RDS.

MIST cohort

MIST technique was established through a clinical practice guideline in our NICU. The procedure was performed by neonatologists or neonatal fellows. A nasogastric feeding tube (6Fr) was used as the catheter to instill surfactant. The tube was marked with a sterile thread at the approximate length to lip. The estimated depth for endotracheal insertion was calculated adding 6cm to the birthweight in kg. The nasogastric tube was inserted under direct laryngoscopy without using Magill forceps. Once the nasogastric tube (NGT) was inserted, the laryngoscope was withdrawn, maintaining the NGT in position with the hand of the neonatologist holding the catheter to the patient´s palate. The person assisting the neonatologist instilled the surfactant in small bolus for 15–30 seconds (2–3 bolus) pausing between bolus for 15–30 seconds, according to patient´s tolerance. When instillation was complete, the NGT was withdrawn, and the mouth was kept closed. At all times, the patient was maintained on nasal CPAP. Surfactant used was Poractant (Curosurf®, Chiesi Farmaceutici SpA, Parma, Italy) at a dose of 200 mg/kg. Sucrose (20% concentration) was administered prior to the procedure and swaddling of the infant was done as non-pharmacologic pain management. During the procedure FiO₂ was increased by 0.10. Vital signs were monitored throughout the procedure by a NICU nurse. If baby presented with desaturation, bradycardia or apnea, positive pressure ventilation was administered.

InSurE Cohort

Patients who received surfactant replacement therapy through the InSurE technique were intubated with an endotracheal tube according to patient´s weight. Poractant was administered at a dose of 200mg/kg or Beractant (Survanta®, Abbot Laboratories Inc., Columbus, OH, USA) at a dose of 100mg/kg. During surfactant administration, one of the physicians in the team administered positive pressure ventilation through a T-piece resuscitator (Neopuff® Infant Resuscitator, Fisher & Paykel, Auckland, New Zealand) at a pressure of 20 cmH₂O. After finishing the administration of surfactant, patient was extubated and placed on nasal CPAP.

Criteria for surfactant replacement therapy and intubation in our NICU remained the same during both cohorts. Criteria for invasive mechanical ventilation was failure to non-invasive ventilation, which was determined as requirement of positive end expiratory pressure (PEEP) of more than 7 cmH₂O or FiO₂ of more than 0.40, respiratory acidosis (pH < 7.20 and/or PCO₂ > 60mmHg) or recurrent apneas. (6)

We gathered the following demographic data: gestational age, birth weight, sex, Apgar score, mode of delivery, maternal medical history, such as pregnancy induced hypertension, diabetes, prenatal care, antenatal steroids administration, time interval from birth to surfactant administration. Our primary outcomes were need for mechanical ventilation, bronchopulmonary dysplasia, and all-cause mortality. We defined BPD as the use of oxygen at 36 weeks of corrected gestational age for those alive. Our secondary outcomes were respiratory outcomes such as need for repeated surfactant, length of invasive mechanical ventilation and other types of ventilation, hospital stay. Analysis was done using Excel and STATA® v. 16.0. Qualitative variables were described in absolute and relative frequency and quantitative variables were described using median and standard deviation (SD). Relative risk with confidence interval of 95% were calculated for primary results for statistical significance of p < 0.05. Analysis was stratified in two groups according to birth weight. Stratification was done by weight rather than gestational age given poor antenatal care and inaccurate gestational age estimation.

A total of 91 patients were included in our study. In the historic cohort, we included 48 infants treated via InSurE. In the prospective cohort, 43 infants received surfactant therapy via MIST.

MIST and InSurE groups were comparable in demographic characteristics, including gestational age, birth weight, sex, Apgar scores, rate of cesarean section, as shown in table 1. There was poor prenatal care, with most women having less than 4 antenatal check-ups. Less than half of VLBW infants’ mothers received complete antenatal steroids to enhance lung maturation.

VLBW infants received surfactant earlier (during first two hours of life) than those with birth weight above 1500g. This is to be expected given the nature of RDS and the association with gestational age. No differences were found when comparing the MIST to InSurE group.

Table 2 shows there were no significant statistical differences in our primary outcomes (need for invasive mechanical ventilation, bronchopulmonary dysplasia, and mortality) comparing MIST vs InSurE group in VLBW nor in those above 1500g.

Length of invasive mechanical ventilation, oxygen therapy and hospital stay were similar amongst between MIST and InSurE group, as shown in table 3.

Figure 1 shows the learning curve for the technique used for surfactant replacement therapy in our NICU. Throughout training, physicians used both techniques. Two months after completing training in our medical team, MIST technique was adopted by all our NICU physicians and fellows as the mode of surfactant administration for our preterm infants with RDS.

Over the last 20 years, MIST for preterm infants with RDS has emerged as a less invasive mode for SRT. Evidence supporting its use continues to be inconclusive regarding improved long-term outcomes, nonetheless, it seems to be a promising technique given it is less invasive. In our study, we used a modified MIST technique, utilizing a thin nasogastric tube during spontaneous breathing with nCPAP or NIPPV and demonstrated its feasibility.

In the last decade, several strategies for SRT have been proposed, with the purpose of minimizing intubation and delivering surfactant in a less invasive manner, while maintaining the patient on nCPAP. We decided to introduce modified MIST technique, similar to the study presented by Tomar et al in preterm infants between 24 weeks to 33 + 6 weeks of gestational age (16). There have been different specific catheters developed to administer surfactant such as LISAcath® (17) (Chiesi Farmaceutici SpA, Parma, Italy), Surfcath® (Vygon, Ecouen, France) or Neocath® (14).These catheters are not currently available or might not be affordable in low resource settings, like ours. Although the ideal type of catheter for this procedure is still controversial, our study demonstrated the feasibility of utilizing a thin NGT (4-6Fr) with adequate training.

Figure 1 shows the learning curve in the adoption of this new technique in our NICU. After adequate training for all medical personnel in our Unit, MIST was universally adopted as the preferred technique for SRT.

There have been several studies published that show the benefits of MIST. In the Avoid Mechanical Ventilation Trial, Gopel et al reported a shorter duration of mechanical ventilation in patients who received SRT via thin catheter vs standard group (which were intubated patients), although they did not find a difference between groups in rates of death or BPD (19). Kanmaz et al showed a successful reduction in BPD rates with the Take Care technique (10.3%) compared with the InSurE method (20.2%), lesser need for mechanical ventilation in the first 72 hours of life and lower duration of respiratory support (11). The meta-analysis by Rigo et al showed a decrease in invasive mechanical ventilation within 72 hours of birth, pneumothorax and CPAP failure, as well as a decrease in rates of BPD at 36 weeks or combined outcome of BPD and/or mortality (20). Also, the pneumothorax rate showed a trend towards reduction (RR = 0.61 [0.37–1.02]. Similar results were found by Aldana-Aguirre et al in their meta-analysis, as well as a decreased need for invasive mechanical ventilation anytime during the NICU stay (21). In the meta-analysis presented by Lau et al, MIST was associated with a decrease in the need for mechanical ventilation within 72 hours of birth, with a shorter duration of mechanical ventilation and days on oxygen therapy, as well as a decrease in BPD incidence rates (22).

The meta-analysis by Abdel-Latif et al reports a significant decrease in risk of BPD and death, a decrease in the need for intubation within 72 hours of birth and a decrease in the incidence of complications such as pneumothorax, intraventricular hemorrhage as well as a decrease in mortality, in the group who received SRT with a thin catheter vs administration through an endotracheal tube (14).

In our study, given the small number of patients we could not demonstrate an impact on the incidence of BPD, need for mechanical ventilation or mortality (Table 2). We did not find any differences in respiratory outcomes such as days of oxygen therapy, duration of invasive mechanical ventilation or length of hospital stay (Table 3). Our findings suggest that the modified MIST technique is not inferior to the usual InSurE technique. One of the strengths of our study is that we demonstrated the feasibility of the modified MIST technique for RDS treatment in a low-middle income setting.

Important negative factors in our population, are the limited use of antenatal steroids and poor prenatal care. More than half of our VLBW infants, in both the InSurE and the MIST group, did not receive or received an incomplete course of antenatal steroids.This could be a factor influencing the need for invasive mechanical ventilation (regardless of the mode of surfactant replacement therapy). According to Janssen et al, independently associated risk factors for MIST failure were extreme prematurity (GA less than 28 weeks), absence of antenatal corticosteroids, low surfactant dose and elevated C reactive protein levels (23).

It is well known that the absence of antenatal corticosteroids is strongly associated with RDS development and that the response to exogenous surfactant therapy is enhanced by antenatal steroid exposure (6) This probably explains the higher need for surfactant therapy compared to other published studies.

For the MIST procedure, we maintained our infants on spontaneous breathing with nCPAP at all times. We did not use premedication such as sedoanalgesia because of the risk of suppression of spontaneous breathing. We utilized 20% sucrose and swaddling as non-pharmacological measures to diminish pain and discomfort. According to a European survey, 52% of neonatologists do not use premedication when administering MIST or LISA (24). We consider spontaneous breathing as a very important factor for adequate surfactant distribution.

An important limitation of our study is that we are comparing a retrospective and prospective cohort (of InSurE technique and MIST technique respectively). Although the demographic characteristics are similar, and therefore the groups are comparable, there might be differences in management given the different time points, and possible changes in management in our NICU. Another limitation is the small number of patients included. Although there have been several published articles comparing MIST vs InSurE, we believe this is an important contribution, given that there is scarce data in Latin America. Another limitation is the limited generalizability of this study given the low use of antenatal steroids in both cohorts, although this might be the case in other low- or middle-income countries.

We conclude that bronchopulmonary dysplasia, mortality and need for mechanical ventilation were similar in both groups. A minimally invasive approach may result in an improvement in important neonatal morbidities such as BPD but our study did not find any differences. Further studies are needed to identify the most suitable technique for SRT for wider adoption.

The modified MIST technique used in our study is feasible as a mode for surfactant replacement therapy in newborns with RDS. We demonstrated that through adequate training, this technique might be safely introduced in a level 3 NICU in a low and middle income settings.

Statement of Ethics

This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was reviewed and approved by the Ethical Review Board at Universidad Peruana Cayetano Heredia, Comité Institucional de Ética e Investigación: approval number: 183-18-22. Written informed consent was not required. An exemption was granted by the IRB at Universidad Peruana Cayetano Heredia.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Author contributions

AM conceptualized and designed the study, designed the data collection instrument, collected data, carried out the analysis and reviewed and revised the manuscript. KZ collected data, carried out the analysis and reviewed and revised the manuscript. CH conceptualized and designed the study, designed the data collection instrument, collected data, drafted the initial manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgements

We would like to thank Roger Hernandez and Jaime Zegarra for their continued help and Alfonso Pantoja for his writing assistance.

Data availability statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Table 1 to 3 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

MISTTable1Demographiccharacteristics.docx
Table 1. Demographic characteristics
MISTTable2Primaryoutcomes.docx
Table 2. Primary outcomes
MISTTable3Respiratoryoutcomes.docx
Table 3. Respiratory outcomes

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Minimally Invasive Surfactant Therapy (MIST) vs intubate-surfactant-extubate (InSurE) technique, in a Peruvian Neonatal Intensive Care Unit (NICU)

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Abstract

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Introduction

Materials and Methods

MIST cohort

InSurE Cohort

Results

Discussion

Conclusion

Declarations

Statement of Ethics

Conflict of Interest Statement

Funding sources

Author contributions

Acknowledgements

Data availability statement

References

Tables

Additional Declarations

Supplementary Files

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