. 2023 May 24;12(6):1149. doi: 10.3390/antiox12061149

Table 1.

Randomized controlled trials comparing LISA with the continuation of CPAP or S-ETT.

Reference	Study Design	Intervention	Comparator	Main Results
LISA vs. continuation of CPAP
Gopel et al., 2011 (AMV trial) [34]	12 centers 26–28 weeks GA Various types of surfactant (poractant alfa, beractant, bovactant) Surfactant dose: 100 mg/kg Analgosedation: per physician decision	FiO₂ > 0.3, CPAP ≥ 4 cmH₂O Cologne method 4 Fr NGT LISA was allowed to be repeated if FiO₂ > 0.4 Rescue intubation according to the judgment of physician (unclear tresholds)	Rescue intubation and surfactant according to the judgement of the attending physician (unclear tresholds) Extubation was recommended *	n = 220, LISA group n = 108 (65 LISA, 15 S-ETT per physician decision, 28 never received surfactant), comparator group n = 112 (72 S-ETT, 1 LISA per physician decision, 39 never received surfactant) ↓ need for MV on day 2 or 3 (28% vs. 46%, p = 0.008) ↓ need for MV during hospital stay (33% vs. 73%, p < 0.0001) ↓ median days on MV (0 vs. 2 days, p < 0.0001) ↓ need for O₂ at 28 days (30% vs. 45%, p = 0.032)
Dargaville et al., 2021 (OPTIMIST-A trial) [37]	33 centers 25–28 weeks GA Double-blinded Surfactant criteria: FiO₂ > 0.3, CPAP 5–8 cmH₂O Surfactant: poractant alfa Surfactant dose: 200 mg/kg Premedication: atropin and sucrose per physician decision	Hobart method 16G vascular catheter or LISAcath LISA was not allowed to be repeated Rescue intubation if FiO₂ ≥ 0.45 (or 0.4 per physician decision) or recurrent apnea or persistent respiratory acidosis	Sham treatment (only transient repositioning) Rescue intubation if FiO₂ ≥ 0.45 (or 0.4 per physician decision) or recurrent apnea or persistent respiratory acidosis After intubation, surfactant could be administered according to clinical judgement.	n = 485 ↔ death or BPD (43.6% vs. 49.6% p = 0.1) ↓ death (10% vs. 7.8%, p = 0.51) ↓ BPD in survivors (37.3% vs. 45.3%, p = 0.03) ↓ PTX (4.6% vs. 10.2%, p = 0.005) ↓ CPAP failure (36.5% vs. 72.1%, p < 0.001)
LISA vs. surfactant administration via ETT with extubation
Kribs et al., 2015 (NINSAPP trial) [35]	13 centers 23–26 weeks GA Surfactant criteria: FiO₂ > 0.3, CPAP cmH₂O or Silverman score ≥ 5 Surfactant type: poractant alfa Surfactant dose: 100 mg/kg No premedication	Cologne method 4 Fr NGT	S-ETT then MV as per local standards Extubation criteria: FiO₂ > 0.3 and MAP < 10 cmH₂O	n = 211 ↔ survival without BPD (67.3% vs. 58.7%, p = 0.2) ↓ need for MV (74.8% vs. 99% ^∆, p = 0.04) ↓ median duration of MV (5 days vs. 7 days, p = 0.031) ↓ PTX (4.8% vs. 12.6%, p = 0.04) ↓ IVH (10.3% vs. 22.1%, p = 0.02) ↑ survival without major complications (50.5% vs. 35.6%, p = 0.02).
Olivier et al., 2017 [36]	3 centers 32–36 weeks GA Surfactant type: beractant Surfactant dose: 100 mg/kg Fentanyl 1 µg/kg + atropin 20 µg/kg	FiO₂ > 0.35, CPAP 6 cmH₂O Cologne method 5 Fr NGT	Rescue intubation and surfactant according to the judgment of the attending physician (unclear tresholds), Extubation criteria was not reported (extubation was not routinely performed)	n = 45 ↓ primary outcome (need for MV or respiratory failure criteria or PTX requiring chest drain) (33% vs. 90%, p ≤ 0.001)
LISA vs. INSURE
Kanmaz et al., 2012 (Take Care study) [38]	Single center <32 weeks GA Surrfactant criteria: FiO₂ ≥ 0.4, CPAP 5–7 cmH₂O Surfactant type: poractant alfa Surfactant dose: 100 mg/kg No premedication	Take Care method 5 Fr NGT (1 bolus in 30–60 s)	Double-lumen ETT During surfactant instillation (30 s), 20/5 cmH₂O pressure PPV was performed with a T-piece device, then extubation to CPAP	n = 200 ↓ CPAP failure (30% vs. 45%, p = 0.02) ↓ mean duration of CPAP (78 h vs. 116 h, p = 0.002) ↓ mean duration of MV (35.6 h vs. 64.1 h, p = 0.006) ↓ BPD (10.3% vs. 20.2%, p = 0.005)
Mirnia et al., 2013 [39]	3 centers 27–32 weeks GA Surfactant criteria: FiO₂ ≥ 0.3, CPAP 8–10 cmH₂O Surfactant type: poractant alfa Surfactant dose: 100 mg/kg Atropin 5 µg/kg	Take Care method 5 Fr NGT (1 bolus in 1–3 min)	No detail reported	n = 136 ↔ CPAP failure (19% vs. 22%, p = 0.6) ↓ mortality (3% vs. 15.7%, p = 0.01)
Mohammadizadeh et al., 2015 [40]	2 centers ≤34 weeks GA and and BW 1000–1800 g Surfactant criteria: FiO₂ > 0.3, CPAP 6 cmH₂O and/or Silverman score >4 Surfactant type: poractant alfa Surfactant dose: 200 mg/kg Atropin 25 µg/kg	Cologne method 4 Fr NGT	2.5–3.0 ETT Bolus injection then PPV with a T-piece device for at least 1 min or until SpO₂ ≥87%, then extubation to CPAP	n = 38 ↔ CPAP failure (15.8% vs. 10.5%, p = 0.99) ↓ duration of O₂ therapy (243.7 h vs. 476.8 h, p = 0.018) ↓ adverse events during surfactant administration (31.6% vs. 63.2%, p = 0.049)
Bao et al., 2015 [41]	Single center 28–32 weeks GA Surfactant criteria: FiO₂ > 0.3 for 28–29 weeks GA, FiO₂ > 0.35 for 30–32 weeks GA, CPAP 7–8 cmH₂O Surfactant type: poractant alfa Surfactant dose: 200 mg/kg No premedication	Hobart method 16G vascular catheter (5 boluses in 3–5 min)	Surfactant injection in 2–3 boluses in 3 min, brief MV (details not reported), then extubation to CPAP	n = 90 ↔ CPAP failure (17% vs. 23.3%, p = 0.44) ↓ duration of MV + CPAP (13.2 days vs. 15.9 days, p = 0.03)
Li et al., 2016 [42]	Single center 27–31 weeks GA Surfactant criteria: RDS grade I-II on CXR Surfactant type: poractant alfa Surfactant dose: various doses No premedication	Cologne method	No detail reported	n = 40 Both LISA and INSURE caused a transient impairment in cerebral autoregulation, the duration of this effect was shorter in the LISA group (<5 min vs. 5–10 min)
Mosayabi et al., 2017 [43]	Single center 28–34 weeks GA Surfactant criteria: FiO₂ > 0.4, CPAP 5–8 cmH₂O Surfactant type: poractant alfa Surfactant dose: 200 mg/kg No premedication	Take Care method 5 Fr NGT	Surfactant injection in 1–3 min, manual ventilation (bagging), then extubation to CPAP 3 min	n = 53 ↔ CPAP failure (38.3% vs. 36.8%, p = 0.827)
Choupani et al., 2018 [44]	Single center GA or BW criteria not reported Surfactant criteria: FiO₂ > 0.4, CPAP 6 cmH₂O Surfactant type: poractant alfa Surfactant dose: 200 mg/kg No premedication	Hobart method 16G vascular catheter (small aliquots in 2–4 min)	Bolus injection, then PPV with a T-piece device for at least 1 min or until SpO₂ ≥87%, then extubation to CPAP	n = 104 ↔ CPAP failure (15.4% vs. 25%, p = 0.222) ↓ incidence of hypoxia (SpO₂ < 80%) during surfactant administration (11.5% vs. 28.8%, p = 0.028)
Halim et al., 2019 [45]	Single center ≤34 weeks GA Surfactant criteria: FiO₂ > 0.4, CPAP 5–7 cmH₂O Surfactant type: beractant Surfactant dose: 100 mg/kg No premedication	Take Care method 6 Fr NGT	Bolus injection, then PPV with a T-piece device for 15–20 min, then extubation to CPAP	n = 100 ↓ need for MV at any time (30% vs. 60%, p = 0.003) ↓ median duration of MV (40 h vs. 71 h, p = 0.004)
Boskadabi et al., 2019 [46]	Single center <32 weeks GA and and BW <1500 g Surfactant criteria: FiO₂ > 0.4, CPAP 5–8 cmH₂O Surfactant type: poractant alfa Surfactant dose: 200 mg/kg No premedication	Take Care method 5 Fr NGT	Bolus injection, bagging for 30–60 s, then extubation to CPAP	n = 40 ↓ CPAP failure (0% vs. 30%, p = 0.002)
Jena et al., 2019 [47]	3 centers ≤34 weeks GA Surfactant criteria: FiO₂ > 0.3, CPAP 6 cmH₂O Surfactant type: bovine lipid extract surfactant suspension Surfactant dose: 135 mg/kg No premedication	Hobart method 16G vascular catheter or Take Care method 6 Fr NGT based on individual preference	Bolus injection, then PPV with a T-piece device (no detail reported), then extubation to CPAP	n = 350 ↓ CPAP failure (19% vs. 40%, p < 0.01) ↓ duration of CPAP (4 days vs. 8 days, p < 0.01) ↓ duration of O₂ therapy (6 days vs. 12 days, p < 0.01) ↓ BPD (3% vs. 17%, p < 0.01)
Yang et al., 2020 [48]	Single center 32–36 weeks GA Surfactant criteria: FiO₂ > 0.4, CPAP 6 cmH₂O Surfactant type: poractant alfa Surfactant dose: 200 mg/kg No premedication	Cologne method 4 Fr NGT	Bolus injection then PPV (no detail reported), then extubation to CPAP	n = 97 ↔ need for MV (8.5% vs. 6%, p = 0.8) ↔ duration of MV (3.1 days vs. 3.3 days, p = 0.27)
Han et al., 2020 [49]	8 centers 25–31 weeks GA Surfactant criteria: FiO₂ > 0.4, CPAP 6–8 cmH₂O Surfactant type: calf pulmonary surfactant preparation Surfactant dose: 70–100 mg/kg No premedication	Modified Cologne method with 10 cm ophthalmic forceps 4 Fr NGT (in mini boluses over 1–5 min)	Bolus surfactant, MV as per local standards, then extubation if FiO₂ < 0.3 and MAP < 8 cmH₂O	n = 298 ↔ BPD (19.2% vs. 25.9%, p = 0.17) ↓ PDA (41.1% vs. 60.5%, p = 0.001) Subgroup analysis of <30 weeks GA (n = 51): ↓ BPD (29% vs. 70%, p = 0.004)
Gupta et al., 2020 [50]	Single center 28–34 weeks GA Surfactant criteria: FiO₂ > 0.3; NIPPV fr 40/min, PIP 12–15 cmH₂O, PEEP 5–6 cmH₂O Surfactant type: poractant alfa Surfactant doze: 200 mg/kg No premedication	Cologne method 5 Fr NGT (1 mL aliquots, each lasting for 10 s)	Bolus injection, bagging for 30–60 s, then extubation to NIPPV	n = 58 ↔ CPAP failure (10.34% vs. 20.69%, p = 0.47)
Pareek et al., 2021 [51]	Single center 28–36 weeks GA Surfactant criteria: NIPPV (unclear tresholds) at least 2 of the following criteria: Silverman score ≥ 4 or FiO₂ > 0.3 for <30 weeks GA and FiO₂ > 0.4 for ≥30 weeks GA or > stage II RDS on CXR Surfactant type: not reported Surfactant dose: 100 mg/kg No premedication	Cologne or Take Care method based on individual preference 5 Fr NGT	Bolus injection, then PPV with a T-piece device (no detail reported), then extubation to the NIPPV	n = 40 ↔ CPAP failure (30% vs. 30%, p = 0.99)
Anand et al., 2022 [52]	Single center 26–34 weeks GA Surfactant criteria: FiO₂ > 0.3 within 6 h of life Surfactant type: beractant Surfactant dose: 100 mg/kg No premedication	Take Care method 8 Fr NGT	Injection in four equal aliquots, bagging between aliquots, then extubation to CPAP	n = 150 ↔ duration of respiratory support (120 h vs. 120 h p = 0.618) ↓ need for MV (9.5% vs. 25%, p = 0.017) ↓CPAP failure (17.5% vs. 38.1%, p = 0.005)

Table notes: First % values refer to the LISA group and second values refer to the comparator group. ↑—significantly higher, ↓—siginificantly lower, ↔—not significantly different, * Despite the recommendation, of 81 infants who were intubated on the first day after birth, only 27 (33%) were extubated within the first 24 h, ^∆ One infant was not intubated since FiO₂ dropped below the treatment treshold immediatley after randomization Cologne method—insertion of a flexible catheter with Magill’s forceps, Take Care method—insertion of a flexible catheter without Magill’s forceps, Hobart method—insertion of a semi-rigid catheter. Surfactant administration via ETT with extubation in these trials, control infants remained intubated after surfactant delivery, with extubation after a period of mechanical ventilation. Abbreviations: LISA—less invasive surfactant administration, S-ETT—surfactant administration via endotracheal tube with (INSURE) or without extubation, GA—gestational age, NGT—nasogastric tube, FiO₂—fraction of inspired oxygen, MV—mechanical ventilation, INSURE—intubation–surfactant–extubation, BPD—bronchopulmonary dysplasia, IVH—intraventricular hemorrhage, CPAP—continuous positive airway pressure, CPAP failure—need for mechanical ventilation within 72 h of birth, RDS—respiratory distress syndrome, CXR—chest X-ray, ETT—endotracheal tube, PPV—positive pressure ventilation, PTX—pneumothorax, BW—birth weight, PDA—patent ductus arteriosus, NIPPV—non-invasive positive pressure ventilation.