Trials and guidelines for respiratory medicine and mechanical ventilation

This compilation of papers is probably not as useful as other better resources which compile this information, such as Critical Care Reviews and The Bottom Line. However, it is probably at least harmless. Wherever possible, the original paper is linked from the name of the study, and the Bottom Line review is linked from the year of publication.

ARDS ventilation and adjunctive therapies

ARMA - 2000 - the original trial that gave us lung protective ventilation. 6ml/kg versis 12 ml/kg, n=861 (in the US). Lower mortality with low VT (31.0% vs. 39.8 %)

ALVEOLI - 2004 - what if moar PEEP (8 vs 13)? n=549 in the US. No difference in mortality (24.9% vs  27.5%).

ARDNET Fluids - 2006 - what if less fluids? n=1000 in the US. No difference in mortality (25.5% vs 28.4%) but more ventilator-free days (14.6 vs. 12.1).

LOVS - 2008 - again, what if moar PEEP (9.8 vs 14.6)? n= 983 in Canada, Australia, and Saudi Arabia. No difference in mortality (36.4% vs 40.4%) but reduced use of rescue therapies (5.1% vs 9.3%) and no extra risk of barotrauma.

EXPRESS - 2008 - seriously, open lung again. PEEP of 5-9 vs. PEEP titrated to achieve a Pplat of 28-30. n=767 in France. No difference in mortality (39.0% vs 35.4%) but more ventilator-free days (7 vs 3) and reduced use of rescue therapies (18.7% vs 34.6%).

ACURASYS - 2010 - early paralysis for 48 hours vs. light sedation in ARDS,  n=339 in France. Improved mortality with paralysis (31.6% vs. 40.7%), but not plausible, because seriously.

OSCAR - 2013 - HFOV vs conventional ventilation, n=795 (in the UK); no difference in mortality (41.7% vs  41.1%) 

OSCILLATE - 2013 - HFOV vs conventional ventilation; n=571, all over the world. Higher mortality with HFOV (47% vs 35%). Terminated early, because harm.

Kacmarec et al - 2016 - open lung ventilation with recruitment manoeuvre up to PEEP 30; n=200, mostly in Spain. No mortality difference (29% vs 33%) but various ventilator parameters and oxygenation did improve.

PROSEVA - 2013 - prone vs standard ventilation in severe ARDS (n=466 in France).  Lower mortality with prone (16.0% vs 32.8%), 16 hours seemed to be the "dose".

BILEVEL-APRV - 2017 - what if APRV instead of ARMA protocol? n=118, single centre in China. Significantly more ventilator-free days with ARPV (16 vs 2).

PreVENT - 2018 - what if lung-protective volumes, but not in ARDS? 6 vs 10ml/kg. n=961 (Netherlands). No difference in any of the outcomes, because minimal volume separation between groups from Day 1 onwards (7.4 vs 9.1 ml/kg from Day 2).

ART - 2017 - recruitment manouvres (PEEP=45 × 2 min). n=501, all over the world. Increased mortality with recruitment manoeuvres (55.3% vs 49.3%).

PHARLAP - 2019 - open-lung with recruitment maneuvers in severe ARDS, n=115 all around the world. No difference in ventilator-free days (16 vs 14.5); but stopped early when the ART trial caused a loss of equipoise.

ROSE - 2019 - paralysis vs. light sedation in ARDS,  n=1006 in the US. No mortality difference (42.5% vs 42.8%), nor in any other outcomes except for cardiovascular effects.

EPVent2 - 2019 - oesophageal manometry to guide PEEP; n=200 in US and Canada. No mortality difference (49.6% vs 50.4%) because no PEEP difference (17 vs 16).


CESAR - 2009 - early-ish ECMO (within 7 days); n=180, in the UK. No difference in mortality; 24% got randomised to ECMO but never received it.

EOLIA - 2018 - early ECMO for ARDS - n=249, mostly in France. Difference in mortality 35% (ECMO) vs 46% (control) but not statistically significant, plus 28% crossed over to ECMO. 

SUPERNOVA - 2019 - feasibility study of ECCO2R to keep the Pplat under 28 ; n=95 in Europe and Canada. Outcome: most (82%) had achieved a VT ~4ml/kg within 24hrs.

REST - 2021 - ECCO2R to keep the tidal volumes 3ml/kg; n=412 in the UK. No difference in mortality (41.5% vs 39.5%) but higher rates of adverse events (52% vs 23%)

High flow nasal prongs

FLORALI - 2015 - HFNP vs NIV vs standard O2 (mostly in pneumonia); n=310, mainly in France. Much lower intubation rate in HFNP (38%), vs NIV (50%) or wall O2 (47%).

RECOVERY-RS - 2021 - CPAP vs HFNP vs normal O2 in COVID. n=1277, in the UK. Combined death/intubation endpoint significantly reduced in CPAP (36.3%) vs normal O2 (44.4%) but not in HFNP (44.4%); mainly because of reduced need for intubation.

Oxygenation targets

CLOSE - 2016 - sats 88-92 versus >96%; n=103 in Australia. Feasibility only, demonstrating that it is safe to achieve this sort of separation for 7 days. 

OXYGEN-ICU - 2016 - sats 94-98% vs 97%, n=434, single centre in Italy. Mortality significantly lower in the low sats group (11.6% vs 20.2%). 

ICU-ROX - 2019 - SaO2 91-96%, vs normal targets, in ventilated patients.   n=965 in Australia and NZ. No difference in ventilator free days (21.3 vs 22.1).

LOCO2 - 2020 - PaO2 55-70 vs 70-105 in ARDS. n=201, in France. No significant difference at 28 days, but enough of a difference (34.3% conservative vs. 26.5% liberal) to stop the trial early. Increased signal for risk of mesenteric ischaemia. 

HOT-ICU - 2021 - PaO2 60 vs 90 in acute hypoxic respiratory failure (mostly pneumonia, 57%). n=2888 in Europe. No mortality difference (42.9% vs 42.4%)

PILOT - 2022 - sats 88-92 vs 92-96 vs 96-100. n=2541 in Nashville. No difference in mortality (34.8% vs 34% vs 33.2%)  or ventilator-free days (20, 21 and 21).


ABC - 2008 - SBT and stop the sedation? Revolutionary. n=338, in the US. Markedly expedited weaning from ventilation (ventilator-free days = 14.7 vs 11.6)

BREATHE - 2018 - after a failed SBT, do you extubate on to NIV, or wait on PSV? n=364 in the UK. Median time to being off all ventilation was no different (4.3 vs 4.5 days) but the NIV group mostly stayed extubated, so that's a win.

Subira et al - 2019 - 30 minutes of PSV (PEEP 0, PS 8) vs 2 hrs of T-piece. n=1153 in Spain. Successful extubation more likely with PSV (82.3% vs 74%).

Thile et al - 2022 - T-piece vs PSV (PEEP 0, PS 8),  n=969 in France (only patients at high risk of extubation failure). No difference in ventilator free days (27 vs 27)

Steroids in respiratory disease

Blum et al - 2015 - 50mg prednisone for 7 days in non-ICU-level community-acquired pneumonia;  n=785 in Switzerland. Median time to clinical stability was shorter in the prednisone grou (3.0 vs 4.4 days)

Torres et al - 2015 - steroids (0.5mg/kg methylpred for 5 days) in severe community-acquired pneumonia with CRP > 150; n=120, in Spain. Less late treatment failure with steroids (composite of death, shock, hypoxia, intubation, and worsening CXR changes)

RECOVERY - 2020 - dexamethasone 6mg for 10 days, in COVID. n=6425, in the UK. Significantly improved mortality (21.6% vs 24.6%), mostly in the ventilated patients (29% vs 40.7%) 

DEXA-ARDS - 2020 - dexamethasone 20mg for 5 days, then 10mg for another 5 days,  in early non-COVID ARDS. n=277 in Spain. Markedly improved ventilator-free days (12.3 vs 7.5) and mortality (21% vs 36%)

CAPE COD - 2023 - steroids for severe community-acquired pneumonia without shock? n=800 in France. Improved mortality (6.2% vs 11.9%) especially if CRP was elevated to over 150.

Pulmonary embolism

Massive PE

Jerjes-Sanchez et al - 1995 - thrombolysis for haemodynamically unstable PE, n=8. All those randomised to receive thrombolysis survived; all of the others died. 

Intermediate risk PE ("submassive")

MAPPETT3 - 2002 - what if full dose thrombolysis for submassive PE? n=256 in Germany; composite outcome (death and circulatory badness) much better with thrombolysis (11% vs. 24.6%)

MOPETT - 2013 - what if thrombolysis, but low dose? 10+40 mg tPA. n= 121, single centre in the US. Less pulmonary hypertension at 28 months (16% vs 57%).

TOPCOAT - 2014 - what if full dose thrombolysis? n=83 in the US. Better (15% vs. 37%) in terms of a confusing composite outcome measure, including too many variables.

PEITHO - 2014 - what if full dose thrombolysis, but moar data? n=1005 all over the world. Composite outcome of death of haemdiynamic decompensation mich better in the thrombolysis group (2.6% vs 5.6%)

Endovascular clot retrieval for PE

EXPRESS - 2019 - catheter-directed thrombolysis for submassive PE; n= 339 in the US. Improved mortality (3% vs 10%).


ARDS guidelines

COPD and asthma


Pulmonary embolism

Extubation guidelines

Oxygen therapy and HFNP


ECMO guidelines


Acute Respiratory Distress Syndrome Network. "Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome." New England Journal of Medicine 342.18 (2000): 1301-1308.

National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. "Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome." New England Journal of Medicine 351.4 (2004): 327-336.

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. "Comparison of two fluid-management strategies in acute lung injury." New England Journal of Medicine 354.24 (2006): 2564-2575.

Meade, Maureen O., et al. "Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial." Jama 299.6 (2008): 637-645.

Mercat, Alain, et al. "Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial." Jama 299.6 (2008): 646-655.

Ferguson, Niall D., et al. "High-frequency oscillation in early acute respiratory distress syndrome." New England Journal of Medicine 368.9 (2013): 795-805.

Papazian, Laurent, et al. "Neuromuscular blockers in early acute respiratory distress syndrome." New England Journal of Medicine 363.12 (2010): 1107-1116.

Young, Duncan, et al. "High-frequency oscillation for acute respiratory distress syndrome." New England Journal of Medicine 368.9 (2013): 806-813.

Simonis, Fabienne D., et al. "Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: a randomized clinical trial." Jama 320.18 (2018): 1872-1880.

Kacmarek, Robert M., et al. "Open lung approach for the acute respiratory distress syndrome: a pilot, randomized controlled trial." Critical care medicine 44.1 (2016): 32-42.

Guérin, Claude, et al. "Prone positioning in severe acute respiratory distress syndrome." New England Journal of Medicine 368.23 (2013): 2159-2168.

Cavalcanti, Alexandre Biasi, et al. "Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial." Jama 318.14 (2017): 1335-1345.

Zhou, Yongfang, et al. "Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome." Intensive care medicine 43 (2017): 1648-1659.

Hodgson, Carol L., et al. "Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A phase II, multicenter randomized controlled clinical trial." American journal of respiratory and critical care medicine 200.11 (2019): 1363-1372.

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. "Early neuromuscular blockade in the acute respiratory distress syndrome." New England Journal of Medicine 380.21 (2019): 1997-2008.

Beitler, Jeremy R., et al. "Effect of titrating positive end-expiratory pressure (PEEP) with an esophageal pressure–guided strategy vs an empirical high PEEP-Fio2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a randomized clinical trial." Jama 321.9 (2019): 846-857.


Peek, Giles J., et al. "Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial." The Lancet 374.9698 (2009): 1351-1363.

Combes, Alain, et al. "Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome." New England Journal of Medicine 378.21 (2018): 1965-1975.

McNamee, James J., et al. "Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs standard care ventilation on 90-day mortality in patients with acute hypoxemic respiratory failure: the REST randomized clinical trial." Jama 326.11 (2021): 1013-1023.

Combes, Alain, et al. "Feasibility and safety of extracorporeal CO 2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study." Intensive Care Medicine 45 (2019): 592-600.

High Flow Nasal Oxygen

Frat, Jean-Pierre, et al. "High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure." New England Journal of Medicine 372.23 (2015): 2185-2196.

Perkins, Gavin D., et al. "An adaptive randomized controlled trial of non-invasive respiratory strategies in acute respiratory failure patients with COVID-19." MedRxiv (2021): 2021-08.

Oxygenation targets

Girardis, Massimo, et al. "Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial." Jama 316.15 (2016): 1583-1589.

Barrot, Loic, et al. "Liberal or conservative oxygen therapy for acute respiratory distress syndrome." New England Journal of Medicine 382.11 (2020): 999-1008.

Nielsen, Frederik Mølgaard, et al. "Lower or higher oxygenation targets for acute Hypoxaemic respiratory failure: Protocol for an individual patient data meta‐analysis." Acta Anaesthesiologica Scandinavica (2023).

Mackle, Diane, et al. "Conservative oxygen therapy during mechanical ventilation in the ICU." The New England journal of medicine 382.11 (2019): 989-998.

Panwar, Rakshit, et al. "Conservative versus liberal oxygenation targets for mechanically ventilated patients. A pilot multicenter randomized controlled trial." American journal of respiratory and critical care medicine 193.1 (2016): 43-51.

Extubation assessment

Girard, Timothy D., et al. "Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial." The Lancet 371.9607 (2008): 126-134.

Perkins, Gavin D., et al. "Effect of protocolized weaning with early extubation to noninvasive ventilation vs invasive weaning on time to liberation from mechanical ventilation among patients with respiratory failure: the breathe randomized clinical trial." Jama 320.18 (2018): 1881-1888.

Subirà, Carles, et al. "Effect of pressure support vs T-piece ventilation strategies during spontaneous breathing trials on successful extubation among patients receiving mechanical ventilation: a randomized clinical trial." Jama 321.22 (2019): 2175-2182.

Thille, Arnaud W., et al. "Spontaneous-breathing trials with pressure-support ventilation or a T-piece." New England Journal of Medicine 387.20 (2022): 1843-1854.


Torres, Antoni, et al. "Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial." Jama 313.7 (2015): 677-686.

Horby, Peter, et al. "Effect of dexamethasone in hospitalized patients with COVID-19–preliminary report." MedRxiv (2020): 2020-06.

Dequin, Pierre-François, et al. "Hydrocortisone in severe community-acquired pneumonia." New England Journal of Medicine 388.21 (2023): 1931-1941.

Villar, Jesús, et al. "Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial." The Lancet Respiratory Medicine 8.3 (2020): 267-276.

Blum, Claudine Angela, et al. "Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial." The Lancet 385.9977 (2015): 1511-1518.


Konstantinides, Stavros, et al. "Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism.New England Journal of Medicine 347.15 (2002): 1143-1150.

Jerjes-Sanchez, Carlos, et al. "Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial." Journal of thrombosis and thrombolysis 2 (1995): 227-229.

Meyer, Guy, et al. "Fibrinolysis for patients with intermediate-risk pulmonary embolism." New England Journal of Medicine 370.15 (2014): 1402-1411.

Kline, J. A., et al. "Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double‐blind, placebo‐controlled randomized trial." Journal of Thrombosis and Haemostasis 12.4 (2014): 459-468.

Sharifi, Mohsen, et al. "Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial)." The American journal of cardiology 111.2 (2013): 273-277.D'Auria, Stephen, et al. "EXPRESS: Outcomes of Catheter-Directed Thrombolysis versus Standard Medical Therapy in a Retrospective Propensity Matched Cohort of Patients with Acute Submassive Pulmonary Embolism." Pulmonary Circulation (2019): 2045894019898368.


Matthay, Michael A., et al. "A New Global Definition of Acute Respiratory Distress Syndrome." American Journal of Respiratory and Critical Care Medicine ja (2023).

Matthay, Michael A., et al. "A New Global Definition of Acute Respiratory Distress Syndrome." American Journal of Respiratory and Critical Care Medicine ja (2023).

Tasaka, Sadatomo, et al. "ARDS clinical practice guideline 2021." Journal of intensive care 10.1 (2022): 1-52.

Griffiths, Mark JD, et al. "Guidelines on the management of acute respiratory distress syndrome." BMJ open respiratory research 6.1 (2019): e000420.

Membership of the Difficult Airway Society Extubation Guidelines Group: M. Popat (Chairman), et al. "Difficult Airway Society Guidelines for the management of tracheal extubation." Anaesthesia 67.3 (2012): 318-340.