Table 5.

Characteristics of surfactant replacement RCTs in ARDS/ALI

Study	Design	Cohort	Number of patients	Surfactant type	Delivery mode and dose	Outcome	Comments
Spragg and colleagues [46]	Multicentre RCT, phase III	Direct lung injury with PaO2/FiO2 ≤170 mmHg (aspiration+ pneumonia)	843	rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs	Intratracheal, 1 ml/kg LBW for maximum of eight doses until 96 hours	1. No difference in 28-day mortality, oxygenation or ventilator-free days	1. Differ from other rSP-C studies by no improvement in oxygenation
						2. Similar adverse events	2. Shearing step used to improve dispersion may have altered the property
							3. Prematurely stopped due to futility
Kesecioglu and colleagues [42]	Multicentre RCT, phase III ALI/ARDS	ALI/ARDS	418	HL10 - freeze dried natural porcine surfactant (90-95% phospholipids and 1-2% of SP-B and SP-C)	Intratracheal, up to three doses - cumulative doses of 600 mg/kg at 0, 12, 36 hours	1. Increased trend towards mortality in surfactant group with no improvements in secondary outcomes such as oxygenation and SOFA scores	1. Prematurely terminated due to futility
						2. More adverse events in the surfactant group
Markart and colleagues [45]	Multicentre RCT, phase I/II	ARDS	31	rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs	Intratracheal, 1 ml/ kg LBW up to four doses in the first 24 hours	1. Improved gas exchange in surfactant group	1. Not designed to assess mortality
						2. Normalisation of surfactant PLs and proteins	2. Treatment period was 24 hours
Spragg and colleagues [44]	Multicentre RCT, phase III	ARDS	221 and 227	rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs	Intratracheal, 1 ml/kg LBW up to four doses at 4-hour intervals in the first 24 hours	1. No difference in survival or ventilator free days but improved oxygenation in the surfactant group	1. Post hoc analysis for intrinsic ARDS showed trend towards improved mortality.
						2. More adverse events in the surfactant group in the first 24 hours after treatment	2. Treatment period was 24 hours
Spragg and colleagues [43]	Multicentre RCT, phase I/II	ARDS	40	rSP-C based (synthetic), 1 ml = 1 mg rSP-C and 50 mg PLs	Intratracheal, two groups: group 1, 1 ml/kg LBW; group 2, 0.5 mg/kg LBW, up to four times in the first 24 hours	1. Safety was comparable with no differences in oxygenation and ventilator free days	1. Treatment period was 24 hours
						2. Decreased plasma IL-6 in group 1
Gregory and colleagues [41]	Multicentre RCT, phase II/III	ARDS	59	Natural bovine lung extract (Survanta; contains phospholipids, neutral lipids, fatty acids, and surfactant proteins with additional DPPC, palmitic acid and tripalmitin)	Intratracheal, three groups: group 1, 8×50 mg/ kg LBW; group 2, 4×100 mg/kg LBW; group 3, 8×100 mg/kg LBW	1. Oxygenation was better with surfactant group 2	1. Small number of patients in each group
						2. Trend towards improved mortality in groups 2 and 3
Anzueto and colleagues [40]	Multicentre RCT, phase III	Sepsis-induced ARDS	725	Exosurf (synthetic), 13.5 mg DPPC/ml	Aerosol, 112 mg DPPC/kg/day for 5 days	1. No difference in 30 day mortality, oxygenation or mean number of ventilation days	1. Only sepsis cohort was studied
							2. Aerosolised preparation with poor alveolar deposition
							3. No surfactant proteins in the preparation
Weg and colleagues [39]	Multicentre RCT, phase II	Sepsis-induced ARDS	51	Exosurf (synthetic), 13.5 mg DPPC/ml	Aerosol, two groups: group 1, 21.9 mg DPPC/ kg/day; group 2, 43.5 mg DPPC/kg/ day. Aerosolised for either 12 or 24 hours for 5 days	1. Safety was comparable between three groups	1. Aerosolised preparation with poor alveolar deposition
							2. No surfactant proteins in the preparation

ALI, acute lung injury; ARDS, acute respiratory distress syndrome; DPPC, dipalmitoyl phosphatidylcholine; IL, interleukin; LBW, lean body weight; PL, phospholipid; RCT, randomised controlled trial; rSP-C, recombinant surfactant protein C; SOFA, Sequential Organ Failure Assessment score.