Two recent trials in adult ICU patients ask very interesting questions, questions which are only linked by testing something clinically simple versus a more technologically demanding evaluation.

The first was comparing the use of serum lactate concentrations versus capillary filling time in adults with septic shock. (Hernandez G, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019;321(7):654-64). If capillary filling is a valid indicator of peripheral perfusion, then it should react more quickly to changes in perfusion than the lactate. For example, if an intervention improves perfusion, then capillary filling should improve immediately, but the improvement in metabolism leading to lactate clearance and then actual reductions in serum lactate will take much longer.

This might be most important in countries with limited access to laboratory results, but in all countries, if our clinical evaluation of perfusion is accurate and can be followed in almost real-time and responds more quickly to changes in actual perfusion, then it would be an advantage for all of us to include it in our protocols.

28 hospitals in 5 South American countries participated in a trial which enrolled 424 adults with septic shock. The protocols for following either serum lactate or capillary filling time were clearly documented, and mostly followed. Cap filling was performed in a highly standardized way with a glass slide used to compress a nail bed of hand until blanched for 10 seconds, then released and the return of colour was monitored with a stop-watch.

To spare you all the details of the protocols, they were very similar apart from the methods used to evaluate perfusion.

Mortality was 35% in the cap filling group and 43% in the lactate group. This was not “statistically significant” but it looks to me like a big deal! I guess I should say now that the study was underpowered but having read this really clear blog post about using that phrase (https://towardsdatascience.com/why-you-shouldnt-say-this-study-is-underpowered-627f002ddf35) I will say that the study was underpowered to detect really important differences in mortality, differences that that anyone who has septic shock might be interested in.

In fact the 95% confidence intervals for the hazard ratio only just include 1.0 (0.55 to 1.02) and the p-value was 0.06, which might not conventionally be “significant”, but is at least highly suggestive. The patients in the cap refill group received about 0.5 L less fluid during the resuscitation phase, and had less organ dysfunction. Again suggesting that maybe we often give too much fluid to patients with septic shock, leading to organ dysfunction and death.

The second trial was in adults with severe ARDS, and the choice of PEEP between a clinical approach, adjusting the PEEP according to the FiO2, and a more physiologic invasive approach requiring the estimation of pleural pressure by inserting an esophageal pressure catheter. (Beitler JR, 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. 2019). Of note, the PEEP could be increased to 24 (!) cm H2O if the adult was in 100% oxygen in the FiO2 directed group, and was as high as 36 (!!) cmH2O in the esophageal pressure group, and mortality was about 30% in each group.

There were no advantages shown to the more invasive strategy, so the simple clinically directed adjustment of PEEP was equally effective.

One reason for discussing this study is that they don’t analyze “BPD or chronic lung disease” as an outcome! The primary outcome and the method of analysis are fascinating :

The prespecified primary end point was a ranked composite score that incorporated death and days free from mechanical ventilation through day 28, calculated in such a manner that death constitutes a worse outcome than fewer days off the ventilator.  Time free from mechanical ventilation was calculated as the number of days between successful liberation from the ventilator and study day 28. Each patient was compared with every other patient in the study and assigned a score (tie: 0, win: +1, loss: −1) for each pairwise comparison based on whom fared better. If one patient survived and the other did not, scores of +1 and −1 were assigned, respectively, for that pairwise comparison. If both patients in the pairwise comparison survived, the assigned score depended on which patient had more days free from mechanical ventilation: the patient with more days off the ventilator received a score of +1, while the patient with fewer days received a score of −1. If both patients survived and had the same number of days off the ventilator, or if both patients died, they both were assigned a score of 0 for that pairwise comparison. For each patient, scores for all pairwise comparisons were summed, resulting in a cumulative score for each patient. These cumulative scores were ranked and compared between treatment groups via the Mann-Whitney technique.

I think there are some very important lessons to be learned here. You can incorporate potentially competing outcomes without giving them the same importance in the analysis. In this analysis death is clearly considered more important than getting extubated more quickly.

The next post will take this discussion further.