VOLUMES

ARDSNet (2000)

Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome-

12mls/kg vs 6mls/kg

Pre study- Larger tidal volumes possibly cause greater detrimental effects such as disruption of pulmonary epithelium, lung inflammation, atelectasis, hypoxemia and the release of inflammatory mediators.

Concern that lower tidal volumes may cause respiratory acidosis and decrease arterial oxygenation.

• Trial stopped after 861 patients
• 31% vs 39.8% mortality
• More ventilator free days

LESS STRETCH BETTER OUTCOMES.

Low Tidal Volume versus Non–Volume-Limited Strategies for Patients with Acute Respiratory Distress Syndrome. A Systematic Review and Meta-Analysis (2017)

Evaluate the effect of LTV on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation

Seven randomized trials involving 1,481 patients met eligibility criteria for this review

The trend toward lower mortality with LTV ventilation in the primary analysis and the significant relationship between the degree of tidal volume reduction and the mortality effect together suggest, but do not prove, that LTV ventilation improves mortality among critically ill adults with ARDS.

Some association with LTV/High PEEP strategy

PEEP

ALVEOLI (2004)

We randomly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels.

These results suggest that in patients with acute lung injury and ARDS who receive:

• mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight
• and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes are similar whether lower or higher PEEP levels are used.

LOV Open Lung (2008)

983 patients

Open-lung approach combining:

• low tidal volume,
• lung recruitment maneuvers, and
• Higher plateau pressures (40)
• high positive-end–expiratory pressure. (similar ranges to above study)

No significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy.

EXPRESS (2008)

767 patients- French

Tidal volume was set at 6 mL/kg of predicted body weight in both strategies.

• Moderate PEEP strategy (5-9 cm H₂O)
• or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H₂O

A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality.

However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure.

ART (2017)

120 ICUs. 9 countries. 1010 patients.

• Lung recruitment (25, 35, 45 for 1 minute) and PEEP titration vs
• Low PEEP

In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality.

These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients.

PHARLAP (2018)

Combined open lung procedure (COLP)

Staircase recruitment maneuver (SRM)

PEEP increased to 20 cmH₂O.  Step-wise increases in PEEP every 2 minutes to 30 cmH₂O and then 40 cmH₂O

PEEP titration

Subsequent management

P_insp titrated to achieve P_plt 25 – 28 cmH₂O and a V_T 4 – 6 mL/Kg PBW

FiO₂ titrated to SpO₂ 90 – 95%

After 1 hr, a decrease in SpO₂ was considered a strong indication to repeat a BRM

In patients with moderate – severe ARDS, an open lung strategy that included maximal RMs and PEEP titration compared to conventional lung-protective ventilation did not improve VFDs or mortality.

STEROIDS - (quality of evidence poor)

LASARUS (2006)

180 patients with ARDS:

• 7 day methylpred
• Or placebo

Do not support the routine use of methylprednisolone for persistent ARDS.

The largest ARDS Network steroid study, LASARUS, changed its ventilation protocol during the study to reflect the results of the ARDS Network ARMA low tidal volume study

Use of corticosteroids in acute lung injury and acute respiratory distress syndrome (2009)

• 5 cohort studies
• Four RCTs

The use of low-dose corticosteroids was associated with improved mortality and morbidity outcomes without increased adverse reactions.

FICM/ICS point out elements of study design which create a serious risk of bias

FLUIDS

Comparison of two fluid-management strategies in acute lung injury. 2006

1000 patients

Conservative or liberal strategy

Among patients with ALI/ARDS, a conservative fluid management strategy targeting a CVP <4 mmHg improves lung function, decreases ventilator days, and reduces ICU days compared to a liberal strategy.

Fluid balance

Cumulative -136 vs. +6992 mL (P<0.001)

Day 1: +1187 vs. +2529 mL (P<0.001)

Day 2: -376 vs. +1643 mL (P<0.001)

Day 3: -408 vs. +936 mL (P<0.001)

Day 4: -165 vs. +564 mL (P<0.001)

Day 5: -226 vs. +483 mL (P<0.001)

Day 6: -145 vs. +508 mL (P<0.001)

Day 7: +130 v.s +459 mL (P=0.04)

Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. (2017)

49 studies- MA of 11 RCTs

No diff in mortality but improved VFD and decreased length of IC stay

OSCILLATION

Oscillate (2013)

39 ICUs, 5 countries

Moderate to severe ARDS

• HFOV
• LTV/High PEEP

Trial stopped after 548 pts of planned 1200

In hospital mortality 47% vs 35%

Higher doses of midazolam and more vasoactive drugs

OSCAR (2013)

27 ICUs UK, 795 patients

• HFOV
• Local practice

No benefit or harm was found from the use of HFOV in adult patients with ARDS. HFOV should not be used for routine care.

NITRIC

Annals of Intensive Care-

“Given a quite favourable benefit-risk ratio, the physiological effects of iNO on the reduction in the intrapulmonary shunt, and the improvement of gas exchange, right ventricular performance, and cardiac flow may justify its use in severe ARDS when PP and optimization of mechanical ventilation do not correct hypoxemia”

FICM/ICS

“The recommendation that iNO is not used for adult patients with ARDS is based on low quality but consistent evidence suggesting a lack of mortality benefit and an association with renal dysfunction.”

NMBs

Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials- (2013)

Three trials (431 patients; 20 centers; all from the same research group in France) met inclusion criteria for this review.

All trials assessed 48-hour infusions of cisatracurium besylate.

French studies

Cisatracurium

MA showed sig mortality reductions

IMPORTANT CONCERNS OVER RISK OF BIAS IN ALL 3 STUDIES.- BLINDING

FICM/ICS

“All three studies, which were conducted by the same team of investigators in France, have been criticised for the lack of effective blinding of caregivers to study group allocation. In two of the studies, no attempt was made to blind caregivers while, in the third, it is questionable whether blinding was effective.”

ROSE- Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome- (2019)

1006 patient’s mod to severe ARDS

• 48 hr cisatracurium vs
• Routine care and lighter sedation levels

No sig diff 90 day mortality

PRONE

PROSEVA

Adult patients with severe ARDS who were intubated/ventilated for <36 hours at inclusion

• Supine position: Semi recumbent position with physiologic measurements every 6 hours
• Prone position: Turning to prone for ≥16h, repeated daily for ≥28 days; cessation of prone positioning

Primary outcome: all cause mortality at 28-days

16% in prone vs. 32.8% in supine (P<0.001)

Concerns with issues of:

• endotracheal tube displacement
• the incidence of pressure sores
• loss of venous access

2015 patients not screened for inclusion in trial. ?selection bias

• Differences in baseline characteristics. Comparing prone to supine group, at inclusion in the study:
• SOFA score 10.4 vs. 9.6
• Use of Vasopressors 83% vs. 72.6%
• Use of neuromuscular blockers 82.3% vs. 91%
• Centres all had >5 years with proning therefore results may not be generalisable to centres with limited experience

The efficacy and safety of prone positioning in adults patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials- (2015)

Eight trials.

1,099 and 1,042 patients were randomized to the prone and supine ventilation positions.

The mortality rates associated with the prone and supine positions were 41% and 47% but the heterogeneity was moderate.

In a subgroup analysis, the mortality rates for lung protective and duration of prone positioning >12 h were reduced in the prone position.

Prone positioning was not associated with an increased incidence of cardiac events or ventilator associated pneumonia

But it was associated with an increased incidence of pressure sores  and endotracheal dislocation.

“Prone positioning tends to reduce the mortality rates in ARDS patients, especially when used in conjunction with a lung protective strategy and longer prone position durations.”

ECMO

Extracorporeal Life Support for Acute Respiratory Failure. A Systematic Review and Meta analysis (2014)

ECLS was not associated with a mortality benefit in patients with acute respiratory failure. However, a significant mortality benefit was seen when restricted to higher-quality studies of venovenous ECLS

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (2018) EOLIA

ECMO for severe ARDS showed no significant benefit of mortality at day 60 as compared with a strategy of conventional mechanical ventilation, which included crossover to ECMO

However lots of flaws in the trial:

Underpowered to answer the trial question

Trial was stopped early at 249/331 (75% of recruitment) due to predefined futility rules (ie unlikely to get a definitive result), leading to a high risk the study was underpowered.

High cross over rate of controls

The 28% cross over rate resulted a reduction of separation between the two arms, and diluted the ECMO treatment effect. This potentially impacted the trial in the following ways:

The cross over complicates the interpretation of the two arms in an intention to treat analysis. It also introduces a potential bias against the ECMO group in the secondary risk of treatment failure analysis, as ECMO was initiated much later and in sicker patients than the rest of the controls

Lack of blinding of clinicians and patients/families (however difficult in such a trial)

Slow recruitment of 249 patients over 6 years, leading to potential trial fatigue and/or change of practice

Threats to external validity

Expertise of ECMO centers not clearly defined

Importance of VV ECMO configuration is uncertain (i.e. femoral-jugular versus femoral-femoral approach)

Majority of ARDS patients in this trial were male and had pneumonia and septic shock. Extrapolation to other ARDS patient groups is uncertain

The trial does not distinguish between the use of VV ECMO and VA ECMO. In particular, 7 cross over control patients underwent VA ECMO for cardiac arrest

Some inclusion criteria may have been too liberal (e.g. PaO2 <80mmHg for 6 hours), which may dilute the benefit of VV ECMO and expose patients who might otherwise have lived to the complications of ECMO

Time for Clinicians to Embrace Their Inner Bayesian? Reanalysis of Results of a Clinical Trial of Extracorporeal Membrane Oxygenation

In contrast, Goligher et al found it highly probable that ECMO lowers mortality, incorporating various assumptions, although it is unclear whether the benefit is as large as that assumed when the EOLIA trial was designed.