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Untangling the triple low: causal inference in anesthesia research.

1 July 2014 I N 1965, Sir Austin Bradford Hill1 published a landmark article in which he considered under what circumstances could a clinician convert an observed association into a verdict of causation. In other words, if there is a link between a risk factor and an adverse outcome, does it hold true that removing or reducing this risk factor will reduce the risk of that adverse outcome occurring? He outlined nine criteria to support causal inference (table 1). Bradford Hill emphasized that clinicians should not solely rely upon these as hard and fast rules for evidence—he reminded readers that, “None of my nine viewpoints can bring indisputable evidence for or against a cause and effect hypothesis .... What they can do, with greater or less strength, is to help answer the fundamental question—is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?”1 He went on to remind readers that statistical tests of significance can not (and do not) answer this question. It is with this background that readers should consider the evidence addressing the “triple low” hypothesis first outlined by Sessler et al. in ANeStHeSIology in 2012.2 In brief, the triple low refers to an intraoperative state in which there is hypotension during the delivery of low alveolar concentration of volatile anesthesia, combined with a low bispectral index (BIS), a state presumed to reflect anesthetic hypersensitivity. Sessler et al.2 found that the triple low state was associated with a higher risk of 30-day mortality. This line of research first began with Monk et al.,3 who in 2005 reported an intriguing relation between cumulative deep hypnotic time as indicated by a low BIS and 1-yr mortality. Many other studies have since found similar associations.4 In this issue of ANeStHeSIology, Kertai et al.5 attempted to reproduce Sessler et al.’s original findings in an observational study of an electronic perioperative database that included 16,263 patients undergoing noncardiac surgery. They did identify an association between the cumulative duration of the triple low state and 30-day mortality, but this association disappeared after adjusting for specific patientand procedurerelated characteristics. In other words, the triple low state was not independently associated with 30-day mortality. There are several reasons why this study may have missed a true association—similar to many large-scale observational studies, the data were derived from an electronic perioperative medical record linked to administrative databases whose prime purposes are not research; the latter is more likely to have inaccurate and incomplete data and a greater risk of residual confounding compared with prospectively collected data in a clinical trial.6 on the contrary, such datasets are large and so provide statistical power, are readily available, and offer greater generalizability because they reflect routine practice. With multivariable testing, Kertai et al.5 found a possible relation between low blood pressure alone (P = 0.0197), and intriguingly, a low BIS seemed to be associated with a lower risk of mortality (but P = 0.0683). These findings could indicate true associations or they could be false because of residual confounding or collinearity.7,8 great caution is needed when interpreting multivariable Untangling the Triple Low