Friday, 5 December 2014

ARDS-Net 1 : Low volume ventilation in acute respiratory distress syndrome (The ARMA trial)

Key Question

Does the use of a low-volume ventilation strategy (5-7ml/kg ideal body weight) improve hospital mortality compared with traditional tidal volumes 10-12ml/kg)?

At a glance

  • Randomised - Yes
  • Controlled - Yes
  • Placebo used - No
  • Blinded - Single.  Clinicians were aware of the allocation arm
  • Groups same at randomisation - Almost.  The baseline minute ventilation rate was higher in the intervention arm
  • Groups treated the same - Almost (some variation in PEEP used).  No other differences were reported
  • Intention to treat analysis - Yes
  • Follow-up - Complete to hospital discharge; followed to 180 days
  • Significant primary endpoint - Yes - 8.8% mortality reduction


The background
When this paper was released in 2000, there was increasing awareness that the way in which we ventilated patients with ARDS was potentially worsening their condition.  

Early protocols for mechanical ventilation were largely based on traditional anaesthesia practices, where higher than physiological tidal volumes (thought to be 7-8ml/kg at rest) were commonly employed to prevent lung collapse during anaesthesia.  Tidal volumes used were often in excess of 10ml/kg, and sometimes up to 15ml/kg.

However, work done in animal models, followed by some early clinical research, led to the conclusion that traditional ventilation strategies that used 10-15ml/kg tidal volumes were likely to be harmful.  This was thought due to increased alveolar stretch due to higher pressures, volumes or both.  This is particularly true in ARDS, where due to the pathology at play, large sections of the lung are not available to ventilation, resulting in excessive stretch of the aerated lung.

Worsening damage to the lung was also suspected of playing a role in extra-pulmonary complications due to the release of inflammatory mediators into the circulation.  Consequently, protective lung ventilation was put forwards as a potentially life-saving intervention.  

On the flips side however, the potential down-sides are hypoxia, hypercarbia and acidosis, which are abnormal states physiologically, but their impact on survival is unclear.  The overall balance of benefit and consequence of low tidal ventilation strategies were unknown.

A number of clinical trials conducted in the late 1990s produced equivocal or negative results, though study numbers were small.  

The Study
The ARDS-NET study of 861 patients in 10 US university hospitals sought to test whether or not the application of a limit on the tidal volumes and pressures applied to patients with severe ARDS (defined by traditional criteria with a P/F ratio <300) would improve their outcomes.  The control group was given between 12 ml per kg of ideal body weight, limiting the plateau pressures to <50cmH2O, something thought to reflect typical practice at the time.  The intervention group by contrast was limited to 6ml/kg, with plateau pressures kept less than 30cmH2O.  Importantly, average mean airway pressures in the groups were 33cmH2O in the control group, and 25cmH2O in the intervention group.

The trial was terminated early when interim review results demonstrated a statistically and clinically significant benefit in the intervention group.  The results were striking - the intervention group had an 8.8% hospital-mortality reduction, from 39.8% to 31.0% (p=0.007).  It also increased ventilator free days, and reduced the number of days patients' had organ failure.  Reinforcing the belief that lung damage may actually promote systemic pathology, the Interleukin-6 levels measured were significantly lower in the intervention group.  

Interestingly, when comparing outcomes across a wide variety of causes of ARDS, the results were consistent.

Minor criticisms have been aimed at the trial.  The trial was single blinded, as the clinicians caring for the patients were aware of the allocation arm, but this did not appear to significantly impact on the treatment provided, though higher average PEEP levels were used which may have improved outcomes in the intervention arm. Additionally, the use of a group-sequential clinical trial strategy has been questioned, which is thought to favour a positive result.

Others have noted that the control arm ventilation strategy is strikingly different to conventional practice, arguing that it might not be that the intervention arm helps, but that the control arm harms.  Critics argue that 12ml/kg used in the control arm was not the standard of care at the time. It must be noted that this figure was based on "predicted" body weight - if you recalculate the tidal volume administered to the control arm based on "actual body weight", patients in the control arm received about 10ml/kg, certainly an acceptable figure at the time (by the same token, this also reduces the volume administered to the intervention arm!)

In an evidence based sense, we know that the 6ml/kg group does better than the 12ml/kg group, but we don't know that its better than any other specific setting between the two.  This point is reinforced by the accompanying editorial to this paper, which pointed out that the control arms in a number of the negative trials that preceded ARMA had relatively low plateau pressures compared with that of the ARMA trial.

What does this all mean?
The impact of this trial should not be underestimated.  The 9% absolute risk reduction translates to a number-needed-to-treat of 11 patients for 1 life saved, a massively successful intervention in the context.  

The structure of the trial means its difficult to determine whether or not it is the volume limitation or the reduction in mean airway pressures that make the difference.  In practical terms though, perhaps this isn't important, as applying gentler ventilation settings seems to improve outcomes.

Other interesting features from this study were that the intervention group actually had worse mean PaO2s than the control group, requiring higher PEEP levels to maintain oxygenation, yet still had improved mortality!  This has reinforced the theory that patients with ARDS don't die from the inability to exchange gas (though a minority do), but rather they die of the extra pulmonary complications of ARDS as described previously.  For a more detailed discussion on this, see the page on ARDS pathophysiology.  

This finding also serves as a reminder to us all of the folly of relying on surrogate outcomes.  Prior to the trial, it would not have been unreasonable to expect that if this intervention was good for the lungs, then oxygenation would have improved.  Had "better oxygenation" been used as the endpoint of this trial, it would have rejected the intervention and wasted an important opportunity to impact on patient outcomes.

Few trials have had the impact on practice in intensive care medicine that this trial did.  The key tenets of the trial have been adopted almost universally and are part of internationally recognised guidelines such as the surviving sepsis campaign.  Additional trials have demonstrated similar effects in abdominal surgical patients without ARDS (but at risk), reinforcing the position of this trial in the field.

Additional Resources
  • David Tuxen reviews current ventilation strategies in ARDS
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