Delirium, an acute state of confusion, often affects older adults following surgery or serious illness. So says an article published in Journals of Gerontology, Series A: Biological Sciences and Medical Sciences. Data from SAGES—the Successful Aging after Elective Surgery Study—a study of 566 noncardiac surgical patients, showed elevated interleukin levels in those who developed delirium. The Pain Reporter contacted lead researchers and coauthors Sarinnapha Vasunilashorn, PhD, and Long Ngo, PhD, at Harvard Medical School and Beth Israel Deaconess Medical Center, to answer a few questions.
Q. When you were testing older patients with delirium, did you already suspect interleukin was the culprit? Did you do a host of tests to determine what the problem might be?
A. Our study was a nonhypothesis driven approach, so we began the analysis from a discovery approach point-of-view. There have been several potential biological mechanisms of delirium that have been previously proposed, one of which is a neuroinflammatory model. Based on our finding of a link between interleukin (IL)-6 and delirium, we suggest that this provides some evidence for an inflammatory response associated with delirium.
Q. Is the delirium postsurgery usually short-term? How and when does it become long-term, and is that when you classify it as dementia?
A. To put it simply: Delirium is defined as an acute change in cognition that can appear abruptly (over days and weeks) and fluctuate over time, and typically resolves over time. Dementia on the other hand is typically a slow (over months and years), progressive degenerative disease that does not resolve with time. [For a summary of this from the Alzheimer's Association, click here.]
We know there is a link between the delirium and dementia:
One general question is: What is driving this link between delirium and dementia? Since dementia has been previously associated with inflammation, one of the potential conclusions from our study is that inflammation may be one shared pathway that links delirium and dementia.
Q. How did you determine delirium? Are delirium and dementia very closely related? Might one be mistaken for the other?
A. For our study, we used the Confusion Assessment Method (CAM) diagnostic algorithm to assess the presence of delirium. Based on the CAM, patients were considered to be delirious if they had the following 3 symptoms: 1) an acute change in mental status or fluctuating course, 2) presence of inattention, 3) altered level of consciousness; and if they also had disorganized thinking. Given the overlap between symptoms associated with delirium and dementia individually, it is quite possible that delirium may be mistaken for dementia (or vice versa). It can also be a challenge to assess the onset of one condition when the other is already present. Because of this, understanding similarities and differences between delirium and dementia remains an important scientific goal.
Q. Do these particular patients already have elevated interleukin levels and/or do the interleukin levels rise during and/or after surgery?
A. Our analysis compared differences between patients with and without delirium who were matched based on 6 variables likely to be important in the relationship between inflammation and delirium. These variables included: age, baseline cognition, sex, surgery type, presence of vascular comorbidity, and apolipoprotein E (ApoE) genotype (ApoE is a gene for which being an ε4 carrier has been associated with an increased risk of Alzheimer’s disease). We did not consider the role of baseline levels of interleukins (or other inflammatory markers) given our initial matching procedure and statistical approach. We did, however, conduct additional sensitivity analyses to consider whether 4 additional factors (including preoperative connective tissue disease, anesthesia route, postoperative infectious complications, and major complications) altered our initial findings. From these sensitivity analyses, we found that our main findings remained consistent, suggesting that after considering these 4 factors our IL-6 finding remained.
Q. Is the rise in interleukin levels caused by anesthesia?
A. As mentioned above, we considered this possibility in our sensitivity analyses where we excluded delirium case / no delirium control matched pairs who received anesthesia via different routes (general or spinal anesthesia). When we re-ran our analysis using this set of participants who were concordant with respect to anesthesia route, we found that our main findings remained: IL-6 remained elevated among patients who developed postoperative delirium relative to patients who did not develop delirium.
Q. Does the type of surgery affect interleukin levels?
A. We also considered the possibility that type of surgery (orthopedic, vascular, or gastrointestinal) may play a role in the relationship between inflammation and delirium by including the type of surgery as 1 of the 6 variables used to match delirium cases with no delirium controls (see above for a list of the other 5 matching variables). These 6 matching variables were selected since they were thought to influence the relationship between inflammation and delirium. Matching on these variables allowed us to in essence ‘control’ for these factors in our analysis.
Q. Do you foresee a time when interleukin levels will be routinely checked in patients presurgery?
A. This may well be a possibility, but future work is required to validate our study in other patient populations before consideration of interleukin levels are incorporated into routine presurgical procedures.
Q. What is the next step in this study?
A. There are several potential next projects that stem from this study. We are currently looking at the role of inflammation on additional outcomes beyond presence of delirium, including delirium severity, duration, and cognition 1 month following surgery. It will be particularly interesting to see if the relationship between inflammation and delirium revealed a dose-response relationship with the severity of delirium and whether inflammation is associated with more downstream effects like changes in cognitive function 1 month postsurgery. We are also very interested in considering the joint effects of multiple inflammatory markers on delirium incidence and intend to pursue this work in future analyses.
Q. If someone currently has dementia, can their decline be slowed by controlling inflammation? Or is it too late?
A. These are excellent questions, and they represent an active area of study among experts in dementia research. We have no definitive answer to these questions, but hopefully they will be answered in the near future.