Some years ago I remember speaking to a rather well known intensivist who was advocating for the extracorporeal removal of CO2 in ICU patients. His logic was that in patients with hypoxic lung failure we know that low tidal volumes as part of a lung protective strategy are a good thing, but that it is not uncommon for this approach to be compromised by the need to maintain ventilation to control CO2 levels. It therefore follows that if we were able to remove CO2 by some other means, then it would be possible to protect the lungs more during the duration of the patients illness. This all seemed to make pathophysiological sense, but as we know, in medicine we need more than common sense and so it is great to see an RCT published on exactly this topic.
The abstract is below, but as always we strongly recommend you read the full paper yourself and also read other blogs/listen to podcasts on this important trial.
What type of paper is this?
It’s a randomised controlled trial which is an appropriate design for the topic. Patients were randomised by telephone and computer generated sequence in a 1:1 ratio. Block randomisation was used and stratified according to site.
Tell me about the patients.
Adult patients were recruited from 51 centres with a diagnosis of acute hypoxic respiratory failure. Patients were pretty sick. All were on mechanical ventilation with at least 5 cm H2O of positive end-expiratory pressure (PEEP); and were within 48 hours of onset of hypoxemia, defined as a ratio of the partial pressure of oxygen in arterial blood to the fractional inspired concentration of oxygen (Pao2/Fio2) of less than 150 mm Hg.
What was the intervention?
Patients were randomised to either a low volume strategy together with ECCO2R (extra-corporeal CO2 removal), or to the standard of care strategy based on a 6ml/Kg tidal volume and ARDS net protective lung strategies.
What about the outcomes?
The principle outcome for patients was mortality at 90 days, which is certainly patient focused. However, it may still be quite early to determine outcomes and I note that the authors are planning longer term follow up to be published later. I can’t see any outcomes regarding lung function in the future though.
What did they find?
The headline outcome is that there was no significant (clinical or statistical) difference in the outcome for patients at 90 days. The absolute difference in mortality rates was 2% (39.5% vs. 41.5% [95% CI, −7.6% to 11.5%]). These are quite wide confidence intervals.
Interestingly the trial was stopped early. An initial power calculation had suggested that over 1100 patients would be required to demonstrate a 9% difference in mortality (which in itself is quite ambitious). An interim analysis that was precipitated by a serious adverse event in the ETCO2R removal group indicated that it was extremely unlikely that further recruitment would result in a positive result and so the trial was stopped after the recruitment of 412 patients. However, it is worth noting that the confidence intervals for the main outcome are still quite wide and they do incorporate the possibility of significant harm or benefit.
In the secondary outcomes then those in the intervention (ETCO2R) group had lower ventilatory requirements in terms of pressure, volumes etc and fewer days of ventilation suggesting that the strategy of ETCO2R partly achieved its physiological aim, but these effects did not translate into a mortality benefit. Adverse events including one serious adverse event and were more common in the ETCO2R group.
So should we use ETCO2R?
Not as a main stream therapy on the basis of this trial. There is a very good review of the paper from our intensivist colleagues over at The Bottom Line discussing this in some detail. There are limitations in this study as there is with all studies, the early stopping of the trial means that is underpowered to detect a clinically important difference. There are some concerns that the practice described in the trial was not reflective of current UK practice in terms of proning rates and the low volumes intended to be achieved in the ETCO2 rates were arguably not achieved.
The authors have done a good job in looking at some of these concerns and also performing a number of sensitivity analyses to look for bias, but these did not reveal any additional influence on the results.
The bottom line.
In this trial a low volume ETCO2R strategy did not result in improved mortality at 90 days.
References and further reading
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. https://jamanetwork.com/journals/jama/article-abstract/2783809
The REST Trial ULTRA-LOW TIDAL VOLUME VENTILATION & EXTRACORPOREAL CO2 REMOVAL https://criticalcarereviews.com/blog/current