key: cord-0013102-i7fza8m2 authors: Germain, Alexandra; Nouraeyan, Nina; Claveau, Martine; Leone, Marisa; Sant’Anna, Guilherme title: “Optimal surfactant delivery protocol using the bovine lipid extract surfactant: a quality improvement study” date: 2020-10-03 journal: J Perinatol DOI: 10.1038/s41372-020-00846-1 sha: 5930feaa6858454f8b54d7dc20c695d47c919455 doc_id: 13102 cord_uid: i7fza8m2 IMPORTANCE: Episodes of severe airway obstruction (SAO) are reported during surfactant administration. OBJECTIVE: To evaluate adherence to and impact of a surfactant protocol on adverse events. METHODS: An evidence-based protocol for surfactant administration was developed (2011), implemented (2012) and re-implemented (2014), including three major steps: lung recruitment, manual bagging, and bolus instillation. Three epochs were evaluated: E(0) (2010), E(1) (2015) and E(2) (2018). Adherence was defined as compliance with all steps. Adverse events such as hypoxia (<80%) and severe airway obstruction (SAO) were investigated. RESULTS: 197 infants (246 administrations) were included: E(0) 81 (110), E(1) 52 (63), and E(2) 64 (73). Adherence improved from 49% (E(1)) to 67% (E(2)). Full adherence to protocol significantly decreased SAO from 26% to 1.25% (E(2); p < 0.005) and hypoxia/bradycardia events (5 to 0% E(2); p < 0.005), without any side effects. CONCLUSIONS: Adherence to a surfactant administration protocol improved over time and significantly decreased important adverse events. Even though surfactant has been effectively used in neonates for several decades [1] [2] [3] [4] , the best instillation technique for optimal delivery into the pulmonary airways is still unclear. This is quite noteworthy since administration technique, to assure homogenous distribution, is recognized as a major component of therapy efficacy [5] [6] [7] [8] . In addition, it is unknown if the technique should change based on the population being treated and drug composition and/or volume; and how this can affect distribution. The Bovine Lipid Extract Surfactant (BLES® Biochemicals Inc., London, Canada) has 27 mg of phospholipid/mL and should be administered at a dose of 5 mL/kg (135 mg of phospholipid) [9] . This low cost surfactant has been used since 1983 but some adverse events were reported during instillation in infants with birth weight <1000 g [10] . The most stark was the occurrence of severe airway obstruction (SAO) during or immediately after delivery, which lead to significant hypoxia, hemodynamic changes, and ultimately the need of endotracheal tube (ETT) removal and reintubation. Indeed, a number of these events were observed in our unit during the administration of bovine lipid extract surfactant. The clear reason why these events occurred is unknown but in extremely preterm infants, delivery of surfactant without disconnection from the ventilator was associated with a high incidence of airway obstruction [11] . Therefore, adverse events during surfactant delivery might be related to the technique, and type of surfactant and/or targeted population. With the increased and effective use of non-invasive respiratory support at birth, surfactant administration is now mostly used in smaller and more immature preterm infants, a population under higher risks of complication. Therefore, a few years ago we performed a review of the literature and identified three important aspects for optimal surfactant delivery into the pulmonary airways: use of large volumes by bolus administration, manual bagging, and recruitment of the lungs prior to instillation [12] . This led to the implementation of a bovine lipid extract surfactant administration protocol in our unit with the aim to streamline administration techniques and decrease rates of adverse events, notably SAOs. Thus, the primary objective of the quality improvement (QI) study is to evaluate the occurrence of severe airway obstruction events. The administration of the bovine lipid extract surfactant in extremely preterm infants has been reported as associated with adverse events such as SAOs. In 2010, we observed a rate of 26% of SAO in infants with birth weight (BW) < 1250 g that received surfactant. This finding combined with inconsistent surfactant administration techniques prompted the development of an evidence-based protocol for surfactant administration in our unit. The aim was to decrease SAO events from 26 to 2% over a 2-years period following protocol implementation. In this QI study we assessed all steps involved during the overall period of 8 years (2011-2019). Infants <32 weeks of gestational age (GA) treated with surfactant therapy at the Royal Victoria Hospital or Montreal Children's Hospital during the study periods, were analyzed. Patients were identified using the local Canadian Neonatal Network databases. Infants with a genetic surfactant deficiency syndrome, complex genetic syndromes, or infants where surfactant was given at referring centers or during transport, were excluded. The surfactant administration protocol was developed during the year of 2011 by a multidisciplinary committee based on the best-quality evidence available. (Fig. 1 ) Details of the protocol have been published [12] and are publicly available (https://www.cjrt.ca/wp-content/uploads/surfactant-a dministration-in-neonates-a-review-of-delivery-methods. pdf). Briefly, it includes surfactant administration criteria and guidance for all phases of drug delivery (before, during and after administration). Of note, a pre-recruitment maneuver using a positive end expiratory pressure of 8 cm H 2 O for a minimum of 30 s should be performed without changing the tidal volume of 4-5 mL/kg used during the assisted control volume guaranteed mode of ventilation. Furthermore, surfactant is then given as bolus, divided into two equal aliquots, and while providing manual ventilation with the flow-inflating bag or a T-piece during drug instillation. Vital signs are recorded carefully by both the bedside nurse and the respiratory therapist and no suctioning of the endotracheal tube was to occur until 2 h post administration. In this QI study, in order to evaluate the impact of the surfactant administration protocol three epochs (E) were established: E 0 = before surfactant protocol (January-December 2010); E 1 = after protocol development, implementation, and re-implementation (January-December 2015) and E 2 = 3-4 years after protocol re-implementation (January-December 2018). The outcome measure of the study was the number of SAO events. Process measure was adherence to the protocol and balancing measures were the occurrence of adverse events associated with surfactant administration such as pneumothorax, pulmonary hypertension, and episodes of bradycardia and desaturations. All information was extracted from medical records but for E 1 and E 2 data was also obtained from a specially designed form filled by respiratory therapy during drug administration. The following variables were also extracted: GA, BW, gender, singleton status, antenatal steroid therapy (complete or incomplete), mode of delivery, maternal use of antibiotics, Apgar scores at 1 and 5 min, positive pressure ventilation requirements and need for intubation at delivery. The lack of compliance to any of the three steps established in the protocol was defined as non-adherence and unknown adherence was defined as absence to fully fill the form. Minor events were defined as hypoxia (oxygen saturation <80%) and/or bradycardia (<100 bpm) and major events as pulmonary hypertension (pre/post SpO 2 difference greater than 5-10% checked in the surfactant form by the respiratory therapist or diagnosed by the medical team within 48 h after procedure), pulmonary hemorrhage, pneumothorax, and SAO. SAO was defined as an episode of hypoxia (<80% saturation)/bradycardia (<100 bpm) AND any of the following: (a) need to increase PIP, (b) need to suction the ETT, (c) lack of chest rise or (d) need for ETT exchange. Major complications were reported only if they occurred within a certain timeframe to ensure causality: (a) pulmonary hemorrhage and pulmonary hypertension within 48 h after the procedure; (b) pneumothorax within 24 h after the procedure and (c) SAOs during or immediately at the end of the procedure. Categorical variables are expressed as counts and percentages and continuous variables as mean ± standard deviation (SD). The Chi-square test and the Fischer exact test were used for categorical variables and the Student t test for continuous variables. All results were analyzed for infants that received surfactant with full protocol adherence during the study period and for the overall population. Statistical analysis was performed using the software SPSS (Statistical Package for the Social Sciences). A p value < 0.05 was considered as statistically significant. The protocol development and implementation followed all steps of the McGill University Health Center policies and was approved for implementation and use in 2012. The present study was approved by the research ethics board of the institution. A number of complications were reported by different neonatologist, respiratory therapists, and neonatal nurse practioners during the administration of the bovine lipid extract surfactant in the delivery room or the neonatal intensive care unit. Cases were discussed in morbidity rounds and given lack of consistence in administration techniques used and a previous study from Canada describing similar events [10] , general consensus was attained for the need to develop an evidence-based protocol for surfactant administration in our unit (Fig. 1 ). The protocol was developed in 2011 and implemented in 2012. In 2013, a random review for the 2012 year revealed very low adherence rates. Thus, during the year of 2014 a reimplementation process was undertaken using several steps: presentation of the protocol at Neonatal Grand Rounds, teaching of the details and reasons for the three main steps to all respiratory therapists and neonatologists, improvement in protocol access at bedside and development of a surfactant administration form (bilingual) to be used during each administration. (Appendix 1) This form included a stepwise checklist to be filled by the respiratory therapists and a comprehensive description of the protocol on its back side. The form remained at bedside for 24 h after each surfactant administration event to ensure that information of any adverse complication was properly recorded. A carbon copy of the form was collected afterwards and kept with the respiratory therapy manager (ML); the original was left in the medical record. In addition, an internal survey with our respiratory therapy group was done to assure their knowledge on the protocol, specifically the three main steps. In 2016, a second audit on the use of our surfactant administration protocol was done for the year of 2015. Adherence rates and conclusions were then presented along with results of the internal survey done in 2014 to highlight the areas that could be improved. No other implementation process took place after this point. Finally, in 2019 this QI study was designed to evaluate adherence to the protocol and rates of adverse events (Fig. 1) . The initial steps of the intervention and their evolution over time are included in Fig. 1 . During the three epochs selected a total 197 infants received 246 surfactant administration events (Fig. 2) : E 0 = 81 infants (110 events), E 1 = 52 infants (63 events), and E 2 = 64 patients (73 events). In both E 1 and E 2 , infants were of significantly lower GA and BW, had lower Apgar scores at 1 and 5 min, and required more positive pressure ventilation despite improved usage of antenatal steroid therapy when compared to E 0 (Table 1) . Process measure-adherence to the protocol Protocol adherence increased over time, from 49% (E 1 ) to 67% (E 2 ) (Appendix 2). The reasons for lack of adherence were: E 1 = 14 events did not follow the protocol and 18 unknown adherence and E 2 = 13 events did not follow protocol and 11 unknown adherences (Table 2) . Full adherence to the protocol. There was a significant decrease in SAO events in infants that received surfactant in full adherence with the protocol ( Table 2 and Fig. 3) . Indeed, during E 1 and E 2 a total of 80 administrations followed the protocol with only one SAO event (1.25%). Also, no episodes of hypoxia/bradycardia and pulmonary hypertension, and no additional side effects were detected. No case of pneumothorax occurred during E 0 and only two cases (2.5%) were noted during E 1 and E 2 . Overall population. Following protocol implementation fewer (but not significant) minor events were observed during E 1 and E 2 . Importantly, a significant reduction in SAOs was noted: E 0 = 29 vs E 1 = 2 (p < 0.005) and E 0 = 29 vs E 2 = 2 (p < 0.005). Both SAO events in E 1 and one event during E 2 occurred in infants with unknown protocol adherence. In fact, the incidence of SAOs with unknown full adherence was 14% (E 1 ) and 8% (E 2 ). Two cases of pneumothorax were noted during E 1 and E 2 when the protocol was not followed. The details of all adverse events for the overall population are described in Appendix 3. In this study, adherence to a standardized surfactant administration protocol increased over time and was associated with a significant decrease on the number of SAO and hypoxia/bradycardia events, when using the bovine lipid extract surfactant for treatment of respiratory distress syndrome. Importantly, this improvement was sustained over time and occurred in a population of lower GA and BW. Clinical protocols are important pathways used to implement evidence-based therapies and reduce unnecessary variations in practice [13, 14] . Indeed, protocols for respiratory care have been increasingly used by Canadian NICUs [15, 16] . However, compliance rates are generally reported as low (25-50%) which can be improved by using of a multidisciplinary approach as done in our center [14] . Unfortunately, our study lacks precision on protocol adherence calculation since incomplete forms were classified as unknown. Thus, adherence rates could have been higher than the 67% reported on E 2 . Nevertheless, it is important to highlight that higher adherence rates (>90%) are possible but require a massive effort by institutions in their initial phases of implementation [17] . Despite the bovine lipid extract surfactant being a lowcost preparation used for several years, only six clinical studies were performed: four randomized controlled trials (RCT) [9, [18] [19] [20] , one prospective observational study [10] and one retrospective single center analysis [21] . Unfortunately, except for one study [10] , details on the surfactant Table 2 Adherence to the protocol and adverse events with full adherence. administration technique is not provided and reports on major adverse effects were quite variable. The only large multicenter trial (unpublished) compared the BLES® with colfosceril palmitate (Exosurf® Neonatal; Glaxo Wellcome). A total of 568 infants of significant higher GA and BW received BLES® and a 6% incidence of any type of ETT obstruction (not defined) was reported [9] . In 2005, Lam et al. compared BLES® with a bovine lung extract (Berac-tant®, Ross Laboratories, Columbus, OH) and no adverse events were described with both preparations [18] . A recent small multicenter Canadian RCT compared BLES® with an extract of natural porcine lung surfactant (Curosurf®, Chiesi Pharmaceuticals, Parma, Italy) [19] . Surfactant was administered by using one or two aliquots instilled as bolus and five episodes (11%) of SAO occurred only in infants who received BLES®. Unfortunately, details on the administration technique/protocol were not described [19] . In 2018, another RCT included 100 infants (median of 30 weeks of GA) and compared BLES® with a bovine lung extract (Beractant®). Again, no significant difference on complications was observed between the groups and no case of SAO was stated [20] . Altogether, these trials enrolled 692 infants and some type of ETT obstruction was reported in between 6 and 11% of infants treated with BLES® [19] . A retrospective single center study done in Canada investigated the time to reach room air following BLES® administration in infants <37 weeks and no side effects were identified [21] . In the only prospective study, we described an incidence of 15% of SAO, mostly in extremely low birthweight infants (83%), an incidence similar to the Canadian RCT [19] . In that study a non-evidence based surfactant administration protocol that included multiple aliquots, no disconnection from the ventilator, and no lung recruitment prior to instillation was used [10] . Thus, our administration protocol was modified to promote better lung distribution without adverse events while using the same surfactant preparation [12] . Surfactant was given after a quick lung recruitment maneuver (30 s) and by bolus into two aliquots, and manual bagging was done after instillation of each aliquot (Appendix 1). It is important to note that in the present study, the lung recruitment strategy prior to the first dose was not tested independent of the other interventions and the use of positive pressure prior to surfactant administration may be harm in infants who have not been exposed to antenatal steroids as previously demonstrated in animal studies. Interestingly, with this modified technique the number of SAO events significantly decreased on epochs E 1 and E 2 combined (p < 0.005). Indeed, only one SAO occurred in the 80 administrations performed in full adherence with the protocol. These rates of SAO are significantly lower than previously reported [10, 19] , and demonstrate the critical role of surfactant delivery technique to these immature infants when using a preparation that requires high instillation volumes [9] . Indeed, during the years of 2015 and 2018, a SAO rate of 14% (E 1 ) and 8% (E 2 ) was observed when adherence to the protocol was unknown; within the range reported by the literature. Full adherence to the protocol was also associated with a significant decrease in hypoxia/bradycardia events and no cases of pulmonary hypertension. Furthermore, when the protocol was fully followed only two cases of pneumothorax were detected (2.5%), a rate lower than that observed in large RCTs where surfactant was only administered to immature infants that failed an initial conservative approach of non-invasive support from birth [1] [2] [3] , as the case for E 1 and E 2 . The results of our study demonstrate that surfactant administration technique should consider the type of surfactant used and target population, as preparations using much lower administration volumes (2.5 mL/kg) are effective and do not report such adverse events without using all the steps outlined here [1] . This is probably due to the favorable tridimensional anatomy of the preterm lungs for adequate drug distribution even at lower instillation volumes [22] . Therefore, neonatal units should implement local evidencebased protocols for surfactant administration including costs analyzes while ensuring optimal care. In our case, the cost of the bovine lipid extract surfactant is estimated between two to four times less expensive (per patient/kg) than the other two available preparations in Canada (data from 2019 obtained from IQVIA Solutions Canada Inc. and our Pharmacy Department). The study reviewed a single center experience making difficult to ascertain generalizability of the work. Some other limitations were the inability to assure correct fulfilling of the surfactant form and missing data due to its retrospective nature. Thus, we analyzed outcomes with full protocol adherence and for the overall population. The study reviewed more than 200 administration events in a high-risk preterm population receiving a type of commonly used surfactant. Moreover, we used a nationally wellorganized database to capture all infants who received surfactant. In addition, by using the specifically designed forms for each surfactant administration, data related to complications was prospectively collected for several years allowing a more reliable analysis of adherence rates and adverse events. Indeed, this is the first study specifically investigating the impact of a standardized surfactant administration protocol on rates of adverse events when using a specific low-cost and effective surfactant. Adherence to a bovine lipid extract surfactant evidencebased administration protocol improved over time and was associated with a significant decrease in the number of severe airway obstruction and hypoxia/bradycardia events. Importantly, this improvement was sustained over years while using a low-cost surfactant preparation despite treating a smaller and more immature population. Better adherence rates may further improve outcomes. Importantly, results of our study demonstrate that surfactant administration technique is an important variable related to adverse events and should be tailored to the type of surfactant and population treated. Future studies in this area should clearly define and report the technique used during surfactant administration. European consensus guidelines on the management of respiratory distress syndrome-2019 update Animal derived surfactant extract versus protein free synthetic surfactant for the prevention and treatment of respiratory distress syndrome Committee on Fetus and Newborn Surfactant replacement therapy for preterm and term neonates with respiratory distress Canadian Paediatric Society, Fetus and Newborn Committee. Recommendations for neonatal surfactant therapy Mechanisms to explain surfactant responses Comparison of rapid bolus instillation with simplified slow administration of surfactant in lung lavaged rats Pulmonary distribution and efficacy of exogenous surfactant in lung-lavaged rabbits are influenced by the instillation technique Distribution of surfactant and ventilation in surfactant-treated preterm lambs A randomized, controlled, double blinded multicenter trial to compare synthetic surfactant (Exosurf) with a bovine surfactant (Bovine Lipid Extract Surfactant) for the treatment of respiratory distress syndrome of the newborn Severe airway obstruction during surfactant administration using a standardized protocol: a prospective, observational study Assist control volume guarantee ventilation during surfactant administration Surfactant administration in neonates: a review of delivery methods Protocols to improve the care of critically ill pediatric and adult patients Developing a neonatal unit ventilation protocol for the preterm baby The use of mechanical ventilation protocols in Canadian neonatal intensive care units Implementation of a respiratory therapist-driven protocol for neonatal ventilation: impact on the premature population Large scale implementation of a respiratory therapist-driven protocol for ventilator weaning Randomized trial comparing two natural surfactants (Survanta vs. bLES) for treatment of neonatal respiratory distress syndrome Poractant alfa versus bovine lipid extract surfactant for infants 24 to 31 + 6 weeks gestational age: a randomized controlled trial Comparative evaluation of the effects of BLES and Survanta on treatment of respiratory distress syndrome in newborns Effects of bovine lipid extract surfactant administration in preterm infants treated for respiratory distress syndrome Surfactant delivery in rat lungs: comparing 3D geometrical simulation model with experimental instillation Acknowledgements The authors would like to acknowledge all health care workers of the units for their support to the protocol development and implementation, and data recordings. Author contributions AG-data acquisition, analysis, interpretation of data, drafting and revising of the manuscript, and final approval of the version to be published. NN-conception and design of the work; data acquisition, analysis and interpretation of data, drafting and revising of the manuscript, and final approval of the version to be published. ML-conception of the work; interpretation of data, drafting and revising of the, manuscript and final approval of the version to be published. MC-design of the work; data acquisition, interpretation of data, drafting and revising of the manuscript, and final approval of the version to be published. GS-conception and design of the work; data analysis and interpretation, drafting and revising of the manuscript, and final approval of the version to be published. Conflict of interest The authors declare that they have no conflict of interest.Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.