Published online: 2018-11-10 THIEME Original Article 943 Underdosing of Surfactant for Preterm Babies with Respiratory Distress Syndrome in Clinical Practice: A Retrospective Cohort Study Hector Boix, MD1 Segundo Rite, MD, PhD2 Luis Arruza, MD, PhD3 Cristina Fernandez, MD1 Itziar Serrano, MD2 Irene Baquedano, MD2 Ana Sanchez, MD4 Erika Ferreira, MD4 Patricia Fernandez, MD3 Rosa Gonzalez, MD3 M. Dolores Elorza, MD, PhD4 1 Department of Neonatology, Hospital Universitari Vall d’Hebron, Address for correspondence Hector Boix, MD, Department of Universitat Autònoma de Barcelona, Barcelona, Spain Neonatology, Hospital Universitari Vall d’Hebron, Passeig Vall 2 Division of Neonatology, Hospital Universitario Miguel Servet, d’Hebron 119-129, E-08035 Barcelona, Spain Zaragoza, Spain (e-mail: hboix@vhebron.net). 3 Department of Neonatology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain 4 Department of Neonatology, Hospital Universitario La Paz, Madrid, Spain Am J Perinatol 2019;36:943–948. Abstract Objective To evaluate the initial doses of surfactant administered to preterm infants with respiratory distress syndrome. Study Design This is a retrospective cohort study of 206 preterm infants admitted in four level III neonatal intensive care units of acute tertiary care hospitals in Spain between 2013 and 2015. Results The mean initial dose of surfactant was 173.9 (37.3) mg/kg, and 47.5% of infants received a dose of 200 mg/kg  10% (180–220 mg/kg), 47% less than 180 mg/ Keywords kg (–10%), and 5.4% more than 220 mg/kg (þ10%). Very preterm infants (<28 weeks) ► dosage received higher initial doses than more mature infants, but in all cases, the mean doses ► preterm babies were below the recommended 200 mg/kg (by 9.2% in gestational age 23–28 weeks, by ► respiratory distress 15.9% in 29–32 weeks, and by 24.3% in >32 weeks). syndrome Conclusion Administration of surfactant below the prescribed dose is a frequent error in ► surfactant clinical practice. Inadvertently rounding down doses seems a plausible explanation. Surfactant is the cornerstone of the treatment of respiratory Animal-derived surfactants differ in their concentration of distress syndrome (RDS) in preterm infants. Treatment with phospholipids and surfactant proteins, which may affect effi- surfactant has been shown to reduce the risk of pulmonary cacy. There is evidence of the superiority of porcine (poractant morbidity (pneumothorax and pulmonary interstitial emphy- alfa) versus bovine (beractant, bovactant) surfactants with sema) and neonatal mortality.1–3 Mechanical ventilation is respect to clinical outcomes, including mortality, the need for considered the single most important risk factor for the redosing, oxygen requirements, duration of oxygen treatment, development of bronchopulmonary dysplasia (BPD).4 The and duration of mechanical ventilation.6–10 A survival advan- clinical focus on avoiding mechanical ventilation and the tage for the high dose (200 mg/kg) of poractant alfa to treat care of infants of less than 26 weeks’ gestation has spurred RDS as compared with the low dose (100 mg/kg) and the new approaches of surfactant administration.5 100 mg/kg/dose of beractant and 50 mg/kg/dose of bovactant received DOI https://doi.org/ Copyright © 2019 by Thieme Medical May 4, 2018 10.1055/s-0038-1675645. Publishers, Inc., 333 Seventh Avenue, accepted after revision ISSN 0735-1631. New York, NY 10001, USA. September 25, 2018 Tel: +1(212) 584-4662. published online November 10, 2018 944 Underdosing of Surfactant in Clinical Practice Boix et al. has been reported.10 Also, the 100 mg/kg/dose has been shown surfactant administration required FiO2  0.3 to achieve O2 to be an independent predictor of surfactant redosing.11 In this saturation between 90 and 95%. Surfactant administration sense, the 2016 update of the European Consensus Guidelines methods included intubation–surfactant–extubation (INSURE), on the Management of RDS12 recommends the administration less invasive surfactant administration (LISA), and endotracheal of poractant alfa in an initial dose of 200 mg/kg. Early surfactant tube (ETT). administration reduces failure of continuous positive airway pressure (CPAP).4 In a population-based study, failure of CPAP Statistical Analysis for initial respiratory management in preterm infants occurred According to the primary objective of the study and con- in 43% of those at <29 weeks’ gestation and was associated with sidering a theoretical standard deviation (SD) of 52.75 in the adverse outcomes including death and other major morbid- study population, a sample size of 167 infants was required ities.13 Moreover, CPAP failure usually occurs because of unre- to estimate, with a confidence interval (CI) of 95%, the mean mitting RDS and is predicted by the need of a FiO2  0.3 in the dose of surfactant with a level of precision of 8 mg/kg. The first hours of life.14 required sample size of 167 was increased to 196, assuming a Despite clinical and pharmacokinetic data supporting the percentage of 15% loss due to lack of minimal data required. dose of poractant alfa of 200 mg/kg,11,12,15 real-world stu- Data extracted from patients’ records were entered into dies have brought attention to the fact that the correct dose is an electronic database for analysis. All data were anon- not often given as clinicians may be tempted to administrate ymized. Categorical variables are expressed as frequencies a rounded dose to the vial content.16–18 To further explore and percentages, and quantitative variables as mean and 95% everyday clinical practices in neonatal intensive care units CI, mean and SD, or median and interquartile range (IQR) (NICUs) regarding the optimal dosing of surfactant, in an (25th–75th percentile) as appropriate. Continuous data were effort to ensure high standards of newborn care, a retro- compared using Student’s t-test and the analysis of variance spective cohort study was designed. The objective of the or the Mann–Whitney U test and the Kruskal–Wallis test, and study was to evaluate the initial dose of surfactant used in categorical data with the chi-square (χ2) test or Fisher’s exact preterm infants with RDS. test according to the distribution and size of the variables. Analyses were performed for the overall study population and for the groups categorized by gestational age between 23 Materials and Methods and 28 weeks, between 29 and 32 weeks, and >32 weeks. All Study Design and Participants tests of significance were two-sided and set at p < 0.05. The A multicenter, retrospective cohort study was performed in Statistical Analysis Systems software version 9.4 (SAS Insti- four level III NICUs in Spain. The primary objective of the tute, Cary, NC) was used for statistical analysis. study was to evaluate the mean initial dose of surfactant administered to preterm infants diagnosed with RDS. Sec- Results ondary objectives were (1) to assess the total number of doses of surfactant, (2) to determine the percentage of A total of 219 infants was eligible during the study period, but patients treated with the initial dose of poractant alfa of 13 (5.9%) were excluded because inclusion criteria were not 200 mg/kg  10%, and (3) to describe adverse events and met (n ¼ 5) or because of lack of minimal data required short-term respiratory outcomes. (n ¼ 8). Therefore, the study population included 206 infants, Between January 1, 2013, and December 31, 2015, all 116 males and 90 females, with a mean (SD) gestational age of preterm babies (gestational age < 37 weeks) with clinical 28.8 (3.1) weeks, mean birth weight of 1,227.3 (582.6) g, and symptoms of RDS receiving surfactant were eligible for the median Apgar scores at 1 minute and 5 minutes of 6 (IQR 4–7) study. By protocol, in all four participating hospitals, the and 8 (IQR 7–9), respectively. According to gestational age, initial surfactant dose prescribed was 200 mg/kg in accor- there were 120 infants in the 23- to 28- week group, 56 in the dance with the recommendations of the 2013 European 29- to 32-week group, and 30 in the >32-week group. Clinical Consensus Guidelines on the Management of RDS.19 The findings before the administration of surfactant are shown availability of a minimal dataset in clinical records, including in ►Table 1. Antenatal corticosteroid treatment was recorded gestational age, birth weight, FiO2 before surfactant admin- in 84% of infants. In relation to the use of ventilatory support istration, and total actual dose of surfactant received in mg immediately after birth in the delivery room, noninvasive or mL as the initial treatment, was required for inclusion in ventilation was used in 49% of neonates and invasive ventila- the study. The study protocol complied with all the relevant tion in 41.3%, and the remaining 9.7% did not require any type national regulations and institutional policies, adhered to of ventilatory support. All patients required some type of the tenets of the Declaration of Helsinki, and was approved ventilatory support during their stay in the NICU (invasive: by the Ethics Committee of Hospital Universitari Vall d’Heb- 51.9%; noninvasive: 48.1%). Ventilatory failure requiring an ron of Barcelona, Spain. increase in respiratory support was recorded in 42 (20.4%) infants, with mechanical ventilation used in 27 (64.3%) of Definition of Study Variables them, mostly in infants initially treated with CPAP. RDS was defined as clinical respiratory distress (tachypnea, The mean FiO2 value before the administration of surfac- nasal flaring, chest retractions, or grunting) that required tant was 0.47 (0.18). There were no significant differences in invasive or noninvasive ventilatory support. The need for FiO2 values according to gestational age, although higher American Journal of Perinatology Vol. 36 No. 9/2019 Underdosing of Surfactant in Clinical Practice Boix et al. 945 Table 1 Characteristics of the study population (n ¼ 206) values in infants in the >32-week group were found before the administration of surfactant (►Table 2). The median time between birth and the admin- istration of surfactant was 210 minutes (IQR: 60–497 min- Variables No. of patients (%) utes). The median time was significantly shorter for infants Gender in the 23 to 28 gestational weeks as compared with those in Male 116 (56.3) the 29 to 32 and > 32 weeks (p < 0.0001) (►Table 2). A total of 202 (98.1%) infants were treated with poractant Female 90 (43.7) alfa and the remaining 4 (1.9%) with beractant. Regarding the Antenatal corticosteroids 173 (84) administration methods, ETT was used in 94.7% of the Gestational age, mean (SD) 28.8 (3.1) patients and LISA in only 5.3%. In the ETT group, the INSURE 23–28 wk 120 (58.3) method (extubating in <1 hour) was used in 36.4% of babies and the remaining 63.6% were extubated for >1 hour after 29–32 wk 56 (27.2) surfactant administration. Extubation > 1 hour was signifi- >32 wk 30 (14.6) cantly more frequent in the 23- to 28-week group (74.8%) as Delivery-related data compared with the 29- to 32-week (47.1%) and >32-week Cesarean section 152 (73.8) groups (48.3%) (p ¼ 0.0005). In relation to the primary objective of the study, the mean Singleton 125 (60.7) initial dose of poractant alfa was 173.9 (37.3) mg/kg (median: Multiple (twins, triplets) 81 (39.3) 186.2; IQR: 149.1–200 mg/kg). As shown in ►Fig. 1, there were Premature rupture of membranes 54 (26.2) differences in the doses of surfactant according to gestational Chorioamnionitis 25 (12.1) age, with lower doses among infants in the >32-week group Cord prolapse 5 (2.4) (p < 0.001). A total of 47.5% of infants received an initial surfactant dose of 200 mg/kg  10% (180–220 mg/kg), 47% Fetal distress 27 (13.1) received doses < 180 mg/kg (–10%), and 5.4% received doses Presence of meconium 5 (2.4) > 220 mg/kg (þ 10%). Differences according to gestational age Preeclampsia 30 (14.6) were also observed, with a significantly higher percentage of Apgar score, mean (SD) infants in the >32-week group treated with <180 mg/kg as compared with the 29- to 32-week and 23- to 28-week groups 1 min 6 (2) (p ¼ 0.006) (►Table 3). Mean doses of surfactant administered 5 min 8 (2) according to birth weight are shown in ►Fig. 2. Birth weight, g, mean (SD) 1,227.3 (582.6) The need of increasing respiratory support after surfactant Length, cm, mean (SD) 37.3 (5.8) therapy occurred in 18.4% of patients, with mechanical venti- lation, intermittent positive pressure ventilation, and synchro- Immediate ventilatory support (delivery room) nized nasal intermittent positive pressure ventilation being the most commonly used rescue ventilation modes. Invasive 85 (41.3) Redosing was needed in 57 patients (59 redosings) due to Mechanical ventilation 85 (41.3) persistent high oxygen requirements in 86.2% of the cases. The Noninvasive median time between the initial dose and the first redosing IPPV prongs/nasal mask 58 (28.1) was 16.3 hours (IQR: 10.5–27), and the total mean dose of surfactant retreatment was 121.2 (36.9) mg/kg. Need for SNIPPV 2 (1) intubation within the first 72 hours after surfactant adminis- CPAP 40 (19.4) tration was recorded in 27 (13.1%) patients. Other 1 (0.5) A total of 168 (81.6%) patients were treated with caffeine None 20 (9.7) citrate, 134 (79.8%) of them for the prophylaxis of apnea and Ventilatory support in the NICU 206 (100) 33 (19.6%) for the treatment of apnea. Among all patients treated with at least one dose of Invasive 107 (51.9) surfactant, only one case of transient bradycardia (93 beats/ Mechanical ventilation 107 (51.9) minute) and oxygen desaturation (82%) possibly related to Noninvasive 99 (48.1) treatment was recorded. IPPV 16 (7.8) CPAP 78 (37.9) Discussion BIPAP 5 (2.4) This study performed in routine daily practice provides evi- O2 saturation, %, mean (SD) 89.7 (5.7) dence of administration of surfactant doses below the recom- mendations for treating babies with RDS. The mean first dose of Abbreviations: BIPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; IPPV, intermittent positive pressure ventila- poractant alfa was 173.9 (37.3) mg/kg, which is 13.5% lower tion; NICU, neonatal intensive care unit; SD, standard deviation; SNIPPV, than the theoretically prescribed and recommended dose of synchronized nasal intermittent positive pressure ventilation. 200 mg/kg. Interestingly, we found statistically significant American Journal of Perinatology Vol. 36 No. 9/2019 946 Underdosing of Surfactant in Clinical Practice Boix et al. Table 2 FiO2 values and time from birth until the administration of surfactant in the overall study population and according to gestational age All patients Gestational age p-Value (n ¼ 206) 23–28 wk (n ¼ 120) 29–32 wk (n ¼ 56) > 32 wk (n ¼ 30) FiO2, % Mean (SD) 0.47 (0.18) 0.47 (0.18) 0.44 (0.18) 0.52 (0.21) 0.137 Median (IQR) 0.40 (0.34–0.50) 0.40 (0.35–0.50) 0.40 (0.31–0.50) 0.47 (0.39–0.60) Time from birth to use of surfactant, minutes Mean (SD) 416.1 (566.6) 219.1 (322.9) 566.1 (594.4) 924.3 (873.1) <0.001 Median (IQR) 210 (60–497) 100 (30–272) 301.5 (196–837) 669 (285–144) Abbreviations: IQR, interquartile range; SD, standard deviation. Fig. 1 Initial doses of surfactant (mg/kg) according to the gestational Fig. 2 Initial doses of surfactant (mg/kg) according to birth weight. age. Table 3 Initial doses of surfactant in the overall study population and according to gestational age Surfactant doses All patients Gestational age p-Value (n ¼ 202) 23–28 wk (n ¼ 118) 29–32 wk (n ¼ 56) >32 wk (n ¼ 28) Median dose, mg/kg 186.2 190.1 171.1 166.4 Target 200  10%, mg/kg 0.026 >220 11 (5.4) 9 (7.6) 2 (3.6) 0 0.271 180–220 96 (47.5) 64 (54.2) 23 (41.1) 9 (32.1) 0.057 <180 95 (47) 45 (38.1) 31 (55.4) 19 (67.9 0.006 Mean (SD) dose, mg/kg >220 239 (22.9) <0.001 180–220 197.7 (8.1) <180 142.2 (27.5) Abbreviation: SD, standard deviation. differences in the doses of surfactant administered to patients preterm infants (< 28 weeks) received a mean dose of among the three gestational age groups. In this respect, infants 181.6 mg/kg, which was 9.2% below the recommended dose of lower gestational age at birth received higher initial doses of of 200 mg/kg. Infants of 29 to 32 weeks’ gestational age and surfactant than infants of a more advanced gestational age, but those >32 weeks’ gestational age were given mean doses of in all cases, doses were below those prescribed. Extremely 168.2 and 151.3 mg/kg, respectively, which were 15.9 and American Journal of Perinatology Vol. 36 No. 9/2019 Underdosing of Surfactant in Clinical Practice Boix et al. 947 24.3% inferior to the target dose. A further analysis according to mg/kg.6 Other outcomes including mortality up to 36 weeks in the distribution of initial surfactant doses by percentiles was neonates born at 32 weeks were also significantly lower in consistent with these findings. the 200 mg/kg group as compared with 100 mg/kg of poractant Globally, 47.5% of infants received doses of surfactant alfa or 100 mg/kg of beractant.6 Moreover, in a systematic < 180 mg/kg (below the  10%) and were considered to be review and meta-analysis of five randomized controlled trials undertreated. Considering a median dose of 186.2 mg/kg, involving 529 infants in which poractant alfa versus beractant 38.1% of extremely preterm babies were undertreated (<180 for rescue treatment was compared, infants treated with mg/kg) as compared with 67.9% of moderate-late preterm poractant alfa at 100 mg/kg (low dose) or 200 mg/kg (high babies. Also, overtreatment (>220 mg/kg) was more frequent dose) exhibited statistically significant reductions in deaths, in extremely preterm than in late preterm infants (37.6% the need for redosing, oxygen requirements, duration of versus 0%). Therefore, surfactant doses above or below the oxygen treatment, and duration of mechanical ventilation.21 recommendations showed a clear relationship with gesta- Further studies are needed to determine if treatment with tional age. surfactant doses below the recommendations, as seen in our The problem of inappropriateness of surfactant dosing for study, is associated with worse respiratory outcomes. preterm neonates with RDS has been addressed in two pre- A relevant finding of this study was an actual FiO2 mean vious studies only, both of which have drawn attention to the value of 0.47 before surfactant therapy, surprisingly higher urgent need of making clinicians aware of errors in surfactant than the recommended FiO2 threshold level of 0.30 to 0.40 administration.16,17 In a retrospective population-based depending on gestational age.12 Differences in FiO2 values cohort study of 455 infants, 25.4% were undertreated and according to gestational age were observed, with higher levels 24.8% overtreated, with a tendency to overtreat extremely in the >32-week group, although differences were not statis- preterm and extremely low birth weight neonates and a trend tically significant. Also, CPAP was the most frequent noninva- to undertreat neonates > 28 weeks’ gestation, which, in turn, sive ventilation method (78.8%). However, noninvasive were more often subjected to surfactant redosing.16 In a ventilation was associated with a higher percentage of venti- retrospective study of 119 infants with a median gestational latory failure. In these cases, mechanical ventilation was the age of 30 weeks and birth weight of 1,300 g, 51.2% received a rescue ventilatory support most frequently used when CPAP dose lower than 150 mg/kg (mean dose 145.8 mg/kg), with failed and intubation within 72 hours of birth was required. In rounding down as the most plausible explanation.17 Also, in a a study of CPAP failure in Australian and New Zealand Neonatal retrospective analysis of 987 infants with a median gestational Network data from 2007 to 2013 in a cohort of 11,684 babies age of 29 weeks and birth weight of 1,190 g, the median first initially managed on CPAP only, failure was recorded in 43% of dose was 170 mg/kg, with 79.8%, 19.1, and 1.1% requiring one, infants commencing on CPAP at 25 to 28 weeks’ gestation and two, and three doses, respectively.18 In this study, 47.5% of in 21% at 29 to 32 weeks.13 CPAP failure was associated with a infants received a dose of 200 mg/kg  10%, and the dose was substantially higher rate of pneumothorax, and a heightened lower than 180 mg/kg in 47% of patients. Dose rounding due to risk of death, BPD, and other morbidities compared with those vial optimization to minimize costs has been suggested as a managed successfully on CPAP.13 possible reason for inappropriate surfactant dosing.16,17 In a Results of this study should be interpreted taking into European survey of surfactant replacement therapy in 338 account some limitations, including variability of clinical preterm infants with a median gestational age of 27 weeks and practice among the participating NICUs, the retrospective birth weight of 860 g, the median first dose of poractant alfa design of the study based on data collected from medical was 168 mg/kg.20 Moreover, in a Polish survey of 987 infants records, and results obtained for the use of poractant alfa. from 53 NICUs, the median first dose was 170 mg/kg,18 also Poractant alfa is the most common surfactant in Europe and lower than the recommended 200 mg/kg dose. was the main compound used and analyzed in this study. In our study, when total mean doses were compared in the In conclusion, underdosing of poractant alfa is an appar- different birth weight groups, greater decreases were observed ently inadvertent error in surfactant administration at the in the 1,251 to 1,500, 1,501 to 2,000, and >2,000 g groups for bedside. Preterm babies diagnosed with RDS requiring sur- which more than one vial content of poractant alfa (Curosurf) factant therapy may be at a risk of undertreatment. Specific should be used since the product is presented in 1.5- or 3-mL actions to avoid unintentional underdosage of surfactant are vials. However, the fact that 54.2% of neonates in the 23- to 28- urgently needed. week group received a dose of 200 mg/kg  10% as compared with 41.1% in the 29- to 32-week group and 32.1% in the >32- Authors’ Contributions week group may also reflect greater concern for the clinical The principal investigator H. B. had full access to the data care of very premature infants. On the other hand, the time in the study and takes responsibility for the integrity and elapsed from birth to the administration of surfactant was accuracy of the data analysis. H. B. was responsible for the significantly shorter in the 22- to 28-week group than in older original conception and design of the study and drafted infants. In a randomized, masked comparison trial of preterm the final version of the manuscript. Coauthors S. R., M. D. infants (n ¼ 293) with RDS treated with an initial dose of E., and L. A. assisted in the implementation of the project, either 100 (n ¼ 96) or 200 (n ¼ 99) mg/kg of poractant alfa or critical review of the manuscript at each step, and all data 100 (n ¼ 98) mg/kg of beractant, need of redosing was sig- analysis, and participated in the manuscript approval of nificantly lower in infants treated with an initial dose of 200 the final draft. American Journal of Perinatology Vol. 36 No. 9/2019 948 Underdosing of Surfactant in Clinical Practice Boix et al. Funding 8 Fujii AM, Patel SM, Allen R, Doros G, Guo CY, Testa S. Poractant alfa This study was supported by Chiesi España, S.A.U., Barce- and beractant treatment of very premature infants with respira- lona, Spain. Chiesi España, S.A.U. was not involved in the tory distress syndrome. J Perinatol 2010;30(10):665–670 9 Dizdar EA, Sari FN, Aydemir C, et al. A randomized, controlled trial collection and interpretation of data, as well as writing of of poractant alfa versus beractant in the treatment of preterm the manuscript. infants with respiratory distress syndrome. Am J Perinatol 2012; 29(02):95–100 Conflict of Interest 10 Singh N, Halliday HL, Stevens TP, Suresh G, Soll R, Rojas-Reyes MX. H.B. is a consultant of Chiesi España, S.A.U. L.A. has Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. participated as a speaker in clinical workshops sponsored Cochrane Database Syst Rev 2015;(12):CD010249 by Chiesi España, S.A.U. The remaining authors have no 11 Cogo PE, Facco M, Simonato M, et al. Pharmacokinetics and clinical conflicts of interest to be disclosed. predictors of surfactant redosing in respiratory distress syn- drome. Intensive Care Med 2011;37(03):510–517 Acknowledgment 12 Sweet DG, Carnielli V, Greisen G, et al. European Consensus The authors thank Marta Pulido, MD, PhD, for editing the Guidelines on the Management of Respiratory Distress Syndrome - 2016 Update. Neonatology 2017;111(02):107–125 manuscript and editorial assistance. 13 Dargaville PA, Gerber A, Johansson S, et al; Australian and New Zealand Neonatal Network. Incidence and outcome of CPAP fail- ure in preterm infants. 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