Confounders versus Mediators: An Important Distinction.

To the Editor: With some degree of amazement, we read the article by Kashy et al.1 on the influence of 6% hydroxyethyl starch (HES) 670/0.75 (Hextend; Hospira Inc., USA) on perioperative acute kidney injury in patients undergoing noncardiac surgery. The data are derived from a database of more than 120,000 patients treated in Cleveland hospitals, in which 6% HES 670/0.75 was the most commonly used colloid between 2005 and 2012. After propensity-matched multivariable analysis, the authors found a higher risk of developing more severe acute kidney injury with the use of 6% HES 670/0.75 as compared with sole crystalloids. Notably, a higher rate of acute kidney injury had already been shown with the use of high-molecular HES (6% HES 200/0.62) in critically ill patients with sepsis as compared with gelatin in 2001.2 Moreover, direct comparison of lowmolecular (6% HES 130/0.4) versus high-molecular HES transfusion, and to AKI, that is, residual confounding is very likely. This is apparent in the sensitivity analysis (table 3),1 as the model with transfusion and vasopressor use as potential confounders showed no effect of HES on AKI (odds ratio, 1.10; 95% CI, 0.96 to 1.25; P = 0.12). The authors might also consider an instrumental variable approach (with calendar time as the instrument). The discontinuation of intraoperative HES use is essentially a “pseudorandom event” such that patients presenting for noncardiac surgery before the HES withdrawal date are probably very similar to patients presenting after this date (of course, all relevant baseline characteristics need to be tabulated to ensure that comparability exists, and where it does not, the parameter that is dissimilar between groups needs to be controlled for if it is a confounder). Such an observational study would emulate the “ideal” randomized controlled trial where essentially similar patients receive different interventions.