“…[is] delirium…simply a marker for other factors that may contribute to postoperative cognitive dysfunction risk…[or does] delirium itself actually contribute to longer-term postoperative cognitive dysfunction[?]”
Are postoperative delirium and postoperative cognitive dysfunction entirely separate disorders, or are they two manifestations of the same underlying spectrum of postoperative neurocognitive dysfunction? Evidence exists in support of both the “splitters” (those who view these as two completely different disorders) and the “lumpers” (those who view these disorders as two parts of the same spectrum of postoperative neurocognitive dysfunction; fig. 1). Indeed, this nosological debate is not unique to anesthesiology; nosological debates have been at the heart of classifying medical disorders and syndromes ever since Victor McKusick used and illustrated the terms “splitters” and “lumpers” in 1967.1 In this issue of Anesthesiology, Brown et al. provide further evidence in favor of the “lumpers” position, by demonstrating that delirium after cardiac surgery is associated with worse cognitive function at 1 month after surgery.2 Before further discussion of these findings, it is worth reviewing the evidence on each side of the “splitters” versus “lumpers” debate about postoperative delirium and postoperative cognitive dysfunction.
The splitters can point to at least four key differences between postoperative delirium and postoperative cognitive dysfunction. First, these syndromes are measured in different ways. Postoperative delirium is typically assessed by instruments that evaluate attention, level of consciousness, and disorganized thinking, such as the Confusion Assessment Method for the Intensive Care Unit or the 3-min Diagnostic Interview for Confusion Assessment Method-defined Delirium.3 In contrast, postoperative cognitive dysfunction is typically assessed by a drop in cognitive performance from before to after anesthesia and surgery on detailed neuropsychological testing.4 Second, these syndromes don’t necessarily include deficits in the same cognitive domains. All patients with delirium have attention deficits, while many patients with postoperative cognitive dysfunction show deficits in other cognitive domains (such as memory or executive function) and do not have attention deficits. Third, these syndromes occur at different times. Postoperative delirium is typically assessed within days after surgery and shows a peak incidence on postoperative days 1 to 3, but postoperative cognitive dysfunction is typically assessed at 1 to 3 months after surgery. Fourth, there are few if any human studies demonstrating that these disorders share the same pathophysiologic mechanisms.
On the other side of this debate, the “lumpers” can point to at least four key similarities between postoperative delirium and postoperative cognitive dysfunction. First, several risk factors are common to both postoperative delirium and postoperative cognitive dysfunction, such as lower preoperative education level, poor preoperative cognitive function, and depression.5 Second, postoperative delirium and postoperative cognitive dysfunction (occurring between 6 and 12 weeks after surgery) are both associated with worse cognitive decline in the 3 to 5 yr after anesthesia and surgery,4,6,7 decreased quality of life,8 and increased 1-yr postoperative mortality risk.9 Third, animal studies raise the possibility that common pathophysiologic processes such as neuroinflammation and Alzheimer disease pathology may play a role in both postoperative delirium and cognitive dysfunction.5 Fourth, many patients with delirium develop postoperative cognitive deficits, and conversely, many patients with postoperative cognitive dysfunction also had postoperative delirium earlier in their postoperative recovery period (reviewed in Berger et al.5 ).
This last point is further strengthened by the findings of Brown et al. in this issue of Anesthesiology.2 They show that in a cohort of 142 cardiac surgery patients, patients with postoperative delirium had significantly worse cognitive function at 1 month after surgery. It is unclear how much of this cognitive decline was really associated with delirium versus lower baseline cognitive function, since the results were not adjusted for baseline cognition. This is a key issue, since it raises the question of whether delirium is simply a marker for other factors that may contribute to postoperative cognitive dysfunction risk, such as lower preoperative cognitive status, versus whether delirium itself actually contributes to longer-term postoperative cognitive dysfunction. Nonetheless, the Brown et al. study2 corroborates previous work by Saczynski et al.7 and Inouye et al.,6 both of whose studies did adjust for baseline cognitive status and demonstrated that patients with postoperative delirium had worse postoperative cognitive trajectories than patients who didn’t develop postoperative delirium. Interestingly, Brown et al. found no difference in 1-year postoperative cognitive function when comparing patients who did (vs. those who did not) develop postoperative delirium, while other studies have found that patients with postoperative delirium do have worse 1-yr postoperative cognitive function than patients who did not develop postoperative delirium.6,7 The discrepancy between these findings may reflect the use of different cognitive assessment tools, differing characteristics among these different study cohorts, or simply insufficient power in the Brown et al. study (a type II statistical error). This last point is a reasonable concern, as the studies that have shown 1-yr postoperative cognitive differences between patients with versus those without delirium had approximately 2- to 4-fold larger cohort sizes than the Brown et al. study.6,7 Despite these limitations, the Brown et al. study demonstrates that patients with postoperative delirium have worsened cognitive function at 1 month after surgery.2 Considering that we have recently argued that postoperative cognitive dysfunction should be conceptualized as a syndrome with a continuous severity distribution,5 these data suggest a link between delirium and increased postoperative cognitive dysfunction severity.
So where do we go from here? The debate about the relationship between postoperative delirium and postoperative cognitive dysfunction persists partly because we have an extremely limited pathophysiologic understanding of either disorder. In order to understand the extent of similarity between these disorders and why each is associated with long-term cognitive decline, we need to understand at least three things. First, we need a full understanding of what delirium and postoperative cognitive dysfunction are at a biologic level, ranging from the levels of molecules, to cells, to brain circuits and activity patterns, and ultimately to the dysfunctional neurocognitive processes of each disorder. Second, we need to understand the perioperative factors that contribute to alterations at each of these levels. Third, we need to understand the longer-term trajectory and implications of such pathophysiologic alterations.
Elucidating these pathophysiologic mechanisms of postoperative delirium and cognitive dysfunction is a nontrivial research endeavor that will likely occupy investigators for decades. Yet, there are relatively simple places to start. One potential opportunity is to take a closer look at medical disorders such as obstructive sleep apnea that predispose patients to postoperative delirium and cognitive decline and study what specifically predisposes these patients to these disorders. For example, patients with obstructive sleep apnea have increased levels of systemic inflammatory cytokines, morphologic brain changes, and higher rates of long-term cognitive decline compared to patients without obstructive sleep apnea.10 Studying specific neuroinflammatory processes in obstructive sleep apnea patients (vs. patients without obstructive sleep apnea) before and after surgery and assessing these patients for delirium and postoperative cognitive dysfunction provides an opportunity to investigate pathophysiologic processes that may play an etiologic role in these disorders. Further, such studies could help lead to future treatments for delirium, postoperative cognitive dysfunction, and even comorbid disorders such as obstructive sleep apnea. And, since anesthesiologists are both airway experts and perioperative physicians, who else is better positioned to understand the links between a disorder that involves the airway (obstructive sleep apnea) and common perioperative complications such as delirium and postoperative cognitive dysfunction?
Regardless of whether obstructive sleep apnea or any other specific comorbid illness contributes to postoperative delirium and cognitive dysfunction risk, the findings of Brown et al. and other studies indicate that postoperative delirium is associated with longer-term postoperative cognitive dysfunction. The key questions for the field now are to understand the mechanism(s) of this association and to clarify the extent to which preventing postoperative delirium also reduces longer-term postoperative cognitive dysfunction.
The authors acknowledge John Hopkins University Press (Baltimore, Maryland) for permission to reprint the cartoon in figure 1.
Dr. Berger acknowledges funding support from National Institutes of Health (NIH; Bethesda, Maryland) grant No. R03 AG50918, NIH grant No. K76 AG057022, a Jahnigen Scholars award, and additional support from NIH grant No. P30AG028716.
The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.