Studies on delirium and associated cognitive and functional decline in older surgical patients
Beishuizen, Sara
DOI:
10.33612/diss.135861414
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Beishuizen, S. (2020). Studies on delirium and associated cognitive and functional decline in older surgical patients: The time is now to improve perioperative care and outcomes. University of Groningen.
https://doi.org/10.33612/diss.135861414
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Chapter 9
The aim of this thesis was to learn more about perioperative delirium and its effect on functional and cognitive outcomes. In the first part of the thesis we investigated whether acute cerebral damage might occur during delirium and could explain the link that is observed between delirium and cognitive decline. We also addressed a highly relevant clinical dilemma concerning blood transfusion for surgery patients at risk for perioperative delirium. In the second part of this thesis we investigated long term consequences of delirium on cognitive and functional performance after acute or elective surgery. We found that timing of the order of events, measuring outcomes over a longer period of time and the changes in geriatric medicine in current times, are of great influence on delirium research and clinical care. In this chapter we will reflect on this theme of “time” in the light of our findings and that of others in the field, by addressing strengths and limitations of our work and its clinical implications. We conclude this chapter with recommendations for future research. Our main findings and recommendations are summarized in figure 1.
CGA = comprehensive geriatric assessment, SDM = shared decision making
Figure 1. Main findings and recommendations of this thesis, with respect to the timeline of delirium
and outcomes
Surgery Use CGA (cognitive & functional status, delirium
risk) for patient selection
Consider timing when studying S100B and delirium Blood transfusion as delirium prevention S100B limited value as biomarker of brain damage in delirium Need for well
designed pro-spective cohort
Consider in SDM
Delirium increases risk for functional
decline/† This knowledge can help
inform patients and plan post hospital care
Distinct cognitive trajectories are seen Use alternative methods
to measure change over time Timeline Findings thesis Recommendations
First year after surgery
DELIRIUM
CGA before surgery
Timing is key
In part one of this thesis, we studied acute events in relation to the development of delirium. We learned that in these types of studies, it is essential to always describe the order of events with respect to delirium onset clearly to ensure that the proper conclusions are drawn.
In Chapter 2 and 3, we studied the value of the biomarker S100B as a measure of brain damage in delirium, and hypothesized that S100B levels would be elevated in patients with delirium, as compared to patients without delirium. We found no relation between S100B level and the presence of delirium. In our study of CSF measurements (chapter 2) it appeared that S100B levels were higher during delirium than before delirium. In our study of repeated serum measurements (chapter 3) we found no difference in S100B levels measured before, during or after delirium as compared to levels of patients without delirium. Previous clinical studies on S100B in patients with delirium have shown conflicting results on this matter. Studies that used CSF for S100B measurement are limited and only performed in hip fracture patients. One study found that S100B was elevated during delirium1, and another study found that S100B was
elevated before delirium but not during, as compared to patients without delirium.2 Studies that
measured S100B in serum are more numerous, but also more difficult to interpret due to differences in populations (acute or elective surgery, intensive care unit, general medical ward), number of serum samples collected (one versus several) and differences in important patient characteristics like age and prior cognitive impairment. Studies that specifically mentioned timing of sample collection with respect to onset of delirium, found them to be highest during3-6
or after7 delirium, or not different between patients with and without delirium.2,8 These findings,
as well as our own, are summarized in table 1.
Unfortunately, many authors did not describe the timing of serum sample collection and delirium onset, although they reported elevated S100B levels in patients with delirium11-13 or no difference
between groups.14-16 Thus, the association between elevated S100B levels and delirium is not
firmly established, and studies that showed an association show conflicting findings when it comes to the time point that S100B levels are highest (before, during or after delirium).
Table 1. Studies on S100B levels measured at specific time point in patients with and without
delirium
Before delirium During delirium After delirium Elevated
S100B levels*
CSF Hov2 Hall1
Serum van Munster3, van
Munster4, Erikson5, van
den Boogaard6
van Munster7
No difference in S100B levels*
CSF Hall1, Beishuizen9 Hov2
Serum Grandi8, Beishuizen10 Hov2, Beishuizen10 Beishuizen10
*in comparison to patients without delirium CSF= cerebrospinal fluid
These results clearly point out a gap in our understanding of how S100B, when released by (damaged) astrocytes in the brain, is washed out in CSF and serum of patients with delirium. This temporal profile of S100B release has been studied in patients with traumatic brain injury, intracranial hemorrhage and subarachnoid hemorrhage.17 It was found that after such an event, a
rise in S100B level and washout after two to three days is measured in CSF. The subsequent change in serum levels differed among the underlying conditions, and overall showed a less clear pattern. For delirium, such a release and washout pattern of S100B is unknown. Given that the onset of delirium is not well demarcated and the underlying predisposing and precipitating factors can differ greatly between patients, this is likely to be a less homogeneous pattern than is observed in the populations mentioned above. Another important factor to consider is that serum levels of S100B are also influenced by concurrent release of S100B in extraneuronal tissue.18 In
patients with delirium contribution of these extraneuronal sources might be substantial. In the serum study (chapter 3) we were able to control for important confounders that related to extraneuronal sources of S100B release. Unfortunately, in our CSF study (chapter 2) the number of included patients was too small to control for confounders and draw firm conclusions. Taking all of this into consideration, currently S100B seems to be of limited value as a biomarker of brain damage in delirium, because studies show conflicting results with regard to the temporal profile of its release in CSF and serum during delirium (table 1). Given the
characteristics of both delirium and S100B, it seems less likely that a uniform release pattern of S100B during delirium exists, which makes further studying this biomarker to gain insight in delirium pathophysiology less relevant (figure 1).
The importance of timing was also reflected in our studies on blood transfusion and delirium (chapter 4 and 5). We were curious whether performing a blood transfusion would serve as a protective of precipitating factor for development of delirium in postoperative hip fracture patients with anemia that does not strictly needs to be treated according to current guidelines. Our literature review did not provide a solid answer. The most important draw back of the studies included in our review was that the timing of transfusion with respect to the onset of delirium was only accounted for in four of the included studies. For this reason, it was not clear whether delirium had developed before or after a blood transfusion was given. We therefore used data from a cohort of hip fracture patients and approached the issue of timing by including a subgroup of patients who assumably had developed delirium after blood transfusion was given. We found that transfusion resulted in decreased odds of developing delirium. Findings of our study, as well as from the four studies included in our review that properly addressed timing, are summarized in figure 2.
It might seem that our findings are in conflict with the study of Behrends. However, the type of blood transfusion given in the latter study was different (>1L during surgery) than in ours (usually two packed cells on the day of, or first day after surgery). This suggest that anemia was more severe in the study of Behrends and that some patients might have suffered from severe blood loss during surgery. As a result, our findings are not directly comparable. A limitation of our study is that it was not primarily designed to answer our research question, and the decision to administer a blood transfusion was not made at random. Also, we were not able to control for important confounders like amount of blood loss during surgery and a measure of general acute illness (for example APACHE score).
Figure 2. Findings of studies that addressed timing of transfusion with respect to delirium onset, on
blood transfusion as a risk factor for delirium
In all, studies that investigate a specific acute event (for example brain damage, or blood transfusion) that show a close temporal relation with the onset of delirium, should clearly describe the order in which these events take place. Otherwise no solid conclusions can be drawn from the results. Given that the exact onset of delirium within a 24 hour period is difficult to establish, we realize it is not possible to be completely sure on this point. But at least every effort should be made in order to improve the quality of our findings.
Time will tell
In chapter 3 and in the second part of this thesis we evaluated cognitive and functional status in the first year after surgery in older patients. We found that in both acute and elective populations, a substantial number of patients had negative outcomes on cognitive or functional status six to twelve months after surgery, and that delirium was an important factor associated with these negative outcomes. This is in contrast with the transient and reversible character that is often
Preoperative delirium assessment Postoperative delirium assessment Surgery Kawaguchi 2006:
Delirium excluded intraoperative transfusion OR delirium 1.41, CI 0.41-4.68 Behrends 2013:
Delirium excluded intraoperative transfusion>1L OR delirium 3.68, CI 1.32-10.94
Lee 2010:
Delirium excluded intraoperative transfusion OR delirium 0.36, CI 0.10-1.34 Sasajima 2000:
Delirium excluded intraoperative transfusion OR delirium 2.27, CI 0.98-5.24 Van der Zanden 2016:
Delirium before transfusion excluded transfusion OR delirium 0.26, CI 0.10-0.70 Time
attributed to delirium. Our studies therefore underline that delirium is not only an acute condition, but also effects daily functioning of older patients after a substantial period of time. In the hip fracture surgery population, cognitive outcome has been studied often. Several prospective cohort studies have found an increased incidence of dementia in patients who suffered from perioperative delirium and were free of dementia prior to surgery.19-21 In hip
fracture patients with premorbid cognitive impairment, delirium can further accelerate cognitive decline.22 Previous studies often restricted their analysis to predefined subgroups (with or
without delirium or cognitive impairment). Our results from both chapter 3 and 6 show that in an unselected population of hip fracture patients with a variety of levels of premorbid cognitive functioning, a substantial proportion of patients has a poor cognitive outcome in the first year after surgery. In chapter 6 we used the method of Group Based Trajectory Modeling (GBTM) to investigate cognitive trajectories in the first year after hip fracture surgery, and found that three different groups with a distinct trajectory could be identified: improving, stable and declining cognitive performance. With this approach, groups are formed based on similarity in the outcome measure (in this case MMSE score), instead of baseline characteristics that are assumed to be related to a good or poor outcome. By doing so, this method can be used to generate new hypothesis. For example, in our study we found that even in the group of patients with the most favorable cognitive trajectory after hip fracture, some (10.3%) had experienced perioperative delirium. By contrast, in the group of patients with the worst cognitive outcome, 66.6% had experienced delirium. This shows that not all patients with delirium have the same cognitive outcome, and this raises questions on what other factors are of influence on cognitive recovery, or further decline in these different groups. These might be factors that are currently less often studied, like cognitive reserve, social circumstances or (other) specific measures of resilience. By incorporating such measurements in future study designs, new and potential modifiable predictors of cognitive outcome can be identified. We therefore advocate to approach outcome data of hip fracture patients with an open mind so that we can continue to learn more about the reasons why older patients experience poor outcomes after this event.
functional outcome.23 Only two studies specifically assessed ADL and iADL limitations after
TAVI in relation to postoperative delirium, of which one found an association between delirium and poor ADL and iADL recovery or death after six and twelve months24 and the other reported
that delirium predicted more limitations in ADL at one month but not six months after TAVI.25
Our study is therefore a contribution to the limited evidence that suggests that delirium is an important predictor of poor outcome in the TAVI population. A limitation of our study was that functional status was only measured once, which prevented us to learn more about the possible fluctuations in functional status in the first year after TAVI. Since there are several treatment options for aortic stenosis (sAVR, TAVI or medical treatment), it is especially important to investigate long term outcomes of each treatment, so that a well informed decision can be made. In this, not only survival should be evaluated, but also outcomes like functional recovery and quality of life, as these were found to be important treatment goals for patients with severe aortic stenosis.26
Thus, when reflecting on our experiences with studying long term cognitive and functional outcome after surgery in older patients, we found it useful to adopt an alternative approach when a lot of research has already been done on a topic (as in the hip fracture population), or to study patient-centered outcomes like functional outcome and quality of life, when limited evidence is available (as in the TAVI population). Our results emphasis that delirium has serious long term effects on cognitive and functional performance in a large proportion of older surgery patients (figure 1).
Clinical implications in current times
Times are changing and as mentioned in chapter 1, currently the number of older patients that are considered suitable for surgery is growing due to the aging population and advances in diagnostic and therapeutic procedures.27 As we have shown in this thesis, not all patients benefit
from surgical procedures on important patient-centered outcomes. This leads to the question whether patient selection could be optimized to improve these outcomes. As also described in chapter 1, shared decision making (SDM) is advocated as a measure to improve this process.28 In
SDM, the benefits and risks of a procedure are weighted and incorporated with the patients values and treatment goals.29 Geriatricians are often involved in this process by performing a
preoperative Comprehensive Geriatric Assessment (CGA) to identify geriatric problems and vulnerabilities that might be of influence on surgery outcome. This results in a better
understanding of the benefits an risk tailored to a patients specific medical and psychosocial situation, which is an important part of SDM. Several findings from this thesis can help to improve this process (figure 1). In our study of hip fracture patients we have shown that the most likely postoperative trajectory of cognitive functioning can be estimated based on age, and prior cognitive and functional status, which are all routinely evaluated during a CGA. Although shared decision making is often not elaborately performed in case of an acute event like hip fracture, it could also be advocated in this setting as some patient might decide against surgery when they are better informed on their risks and possible outcomes.30 Our findings in the TAVI population
suggest that delirium risk should be an important factor to consider and inform patients about, as is appears to be related to poor outcomes. These suggestions can be applied to a wider range of older surgery patients and are not limited to the populations of hip fracture and TAVI patients.
Recommendations for future research
As mentioned above, studies that use a biomarker to study the hypothesis of brain damage in the pathophysiology of delirium, should first establish if there is a uniform temporal release profile of this biomarker with respect to delirium onset. Only if this is found to be the case, this biomarker can be of value for hypothesis testing. For S100B, doing this in a population of hip fracture surgery patients receiving spinal anaesthesia would be a practical approach, as this provides the opportunity to acquire both at least one CSF sample before surgery and several serum samples in the perioperative period, although there are a number of confounding factors to consider, as outlined above.
In chapter 4 we described a study design to better capture the relation between blood transfusion and delirium incidence. A randomized trial would be ideal, although this might be difficult to conduct as the decision to perform a blood transfusion depends on many variables and physicians and patients might be reluctant to participate in a trial were this decision is left up to a randomization procedure. A prospective cohort with adequate information on possible confounders and timing of intervention and outcome could be second best.
surgery could provide additional insight in the characteristics of patients prone to functional decline, which could in turn improve patient selection. Another interesting study concerning shared decision making in this population, would be to assess patients goals for TAVI treatment, and whether or not these are reached, in relation to functional outcome.
More generally speaking, this thesis shows that data from observational cohorts of older patients can provide valuable information to improve the care for this group. We therefore encourage other researchers in this field to make use of the available observational data to answer research questions concerning the outcomes of older surgical patients or clinical dilemma’s (figure 1). We should also continue and expand our efforts to prospectively collect data of the patients that we see for a preoperative CGA, consult during their hospitalization for surgery and also often follow up afterwards. This type of data is relatively easy and less expensive to obtain (instead of performing a controlled trial for example). The Dutch Hip Fracture Audit, which aims to improve quality of care for hip fracture patients, is an example of such an effort.31 If researchers
would collaborate internationally, use the same set of measurements in their CGA and facilitate data exchange, we could create sufficiently large cohorts to address important research questions and thus further improve our knowledge of, and care for this growing population at risk of poor outcomes.
REFERENCES
1. Hall RJ, Ferguson KJ, Andrews M, et al. Delirium and cerebrospinal fluid S100B in hip fracture patients: a preliminary study. The American journal of geriatric psychiatry. 2013;21(12):1239-1243. 2. Hov KR, Bolstad N, Idland A-V, et al. Cerebrospinal Fluid S100B and Alzheimer's Disease Biomarkers in Hip Fracture Patients with Delirium. Dement Geriatr Cogn Dis Extra. 2017;7(3):374-385. 3. van Munster BC, Korse CM, de Rooij SE, Bonfrer JM, Zwinderman AH, Korevaar JC. Markers of cerebral damage during delirium in elderly patients with hip fracture. BMC neurology. 2009;9:21. 4. van Munster BC, Bisschop PH, Zwinderman AH, et al. Cortisol, interleukins and S100B in delirium in the elderly. Brain and cognition. 2010;74(1):18-23.
5. Erikson K, Ala-Kokko TI, Koskenkari J, et al. Elevated serum S-100β in patients with septic shock is associated with delirium. Acta anaesthesiologica Scandinavica. 2019;63(1):69-73.
6. van den Boogaard M, Kox M, Quinn KL, et al. Biomarkers associated with delirium in critically ill patients and their relation with long-term subjective cognitive dysfunction; indications for different pathways governing delirium in inflamed and noninflamed patients. Critical care. 2011;15(6):R297. 7. van Munster BC, Korevaar JC, Korse CM, Bonfrer JM, Zwinderman AH, de Rooij SE. Serum S100B in elderly patients with and without delirium. International journal of geriatric psychiatry. 2010;25(3):234-239.
8. Grandi C, Tomasi CD, Fernandes K, et al. Brain-derived neurotrophic factor and neuron-specific enolase, but not S100beta, levels are associated to the occurrence of delirium in intensive care unit patients. Journal of critical care. 2011;26(2):133-137.
9. Beishuizen SJ, Scholtens RM, Vellekoop AE, et al. Timing Is Critical in Determining the Association Between Delirium and S100 Calcium-Binding Protein B. Journal of the American Geriatrics Society. 2015;63(10):2212-2214.
10. Beishuizen SJ, Scholtens RM, van Munster BC, de Rooij SE. Unraveling the Relationship Between Delirium, Brain Damage, and Subsequent Cognitive Decline in a Cohort of Individuals Undergoing Surgery for Hip Fracture. Journal of the American Geriatrics Society. 2017;65(1):130-136. 11. Rasmussen LS, Christiansen M, Rasmussen H, Kristensen PA. Do blood concentrations of neurone specific enolase and S-1OOB protein reflect cognitive dysfunction after abdominal surgery? British Journal of Anaesthesiology. 2000;84(2):242-244.
12. Pfister D, Siegemund M, Dell-Kuster S, et al. Cerebral perfusion in sepsis-associated delirium. Critical care. 2008;12(3):R63.
13. Hughes CG, Pandharipande PP, Thompson JL, et al. Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients. Critical care medicine.
2016;44(9):e809-e817.
14. Aly WW, Abdul-Rahman SA, Said SMSE, Bastawy SA. S100B and delirium in the geriatric acute care setting. Advances in Aging Research. 2014;03(01):1-5.
15. Nguyen DN, Huyghens L, Zhang H, Schiettecatte J, Smitz J, Vincent JL. Cortisol is an
associated-risk factor of brain dysfunction in patients with severe sepsis and septic shock. BioMed research international. 2014;2014:712742.
16. Jorge-Ripper C, Alemán M-R, Ros R, et al. Prognostic value of acute delirium recovery in older adults. Geriatrics & gerontology international. 2017;17(8):1161-1167.
17. Petzold A, Keir G, Lim D, Smith M, Thompson EJ. Cerebrospinal fluid (CSF) and serum S100B: release and wash-out pattern. Brain Research Bulletin. 2003;61(3):281-285.
20. Bickel H, Gradinger R, Kochs E, Forstl H. High risk of cognitive and functional decline after postoperative delirium. A three-year prospective study. Dementia and geriatric cognitive disorders. 2008;26(1):26-31.
21. Krogseth M, Wyller TB, Engedal K, Juliebo V. Delirium is an important predictor of incident dementia among elderly hip fracture patients. Dementia and geriatric cognitive disorders. 2011;31(1):63-70. 22. Krogseth M, Watne LO, Juliebø V, et al. Delirium is a risk factor for further cognitive decline in cognitively impaired hip fracture patients. Archives of gerontology and geriatrics. 2016;64:38-44. 23. Kim CA, Rasania SP, Afilalo J, Popma JJ, Lipsitz LA, Kim DH. Functional status and quality of life after transcatheter aortic valve replacement: a systematic review. Annals of internal medicine. 2014;160(4):243-254.
24. Shi SM, Sung M, Afilalo J, et al. Delirium Incidence and Functional Outcomes After Transcatheter and Surgical Aortic Valve Replacement. Journal of the American Geriatrics Society. 2019;67(7):1393-1401.
25. Eide LSP, Ranhoff AH, Fridlund B, et al. Delirium as a Predictor of Physical and Cognitive Function in Individuals Aged 80 and Older After Transcatheter Aortic Valve Implantation or Surgical Aortic Valve Replacement. Journal of the American Geriatrics Society. 2016;64(6):1178-1186.
26. Coylewright M, Palmer R, O'Neill ES, Robb JF, Fried TR. Patient-defined goals for the treatment of severe aortic stenosis: a qualitative analysis. Health Expect. 2016;19(5):1036-1043.
27. Etzioni DA, Liu JH, Maggard MA, Ko CY. The aging population and its impact on the surgery workforce. Annals of surgery. 2003;238(2):170-177.
28. Richtlijn: Behandeling kwetsbare ouderen bij chirurgie. Nederlandse Vereniging voor Klinische Geriatrie. 2016.
29. Elwyn G, Cochran N, Pignone M. Shared Decision Making-The Importance of Diagnosing Preferences. JAMA internal medicine. 2017;177(9):1239-1240.
30. van der Zwaard BC, Stein CE, Bootsma JEM, van Geffen HJAA, Douw CM, Keijsers CJPW. Fewer patients undergo surgery when adding a comprehensive geriatric assessment in older patients with a hip fracture. Arch Orthop Trauma Surg. 2019:10.1007/s00402-00019-03294-00405.
31. Voeten SC, Arends AJ, Wouters M, et al. The Dutch Hip Fracture Audit: evaluation of the quality of multidisciplinary hip fracture care in the Netherlands. Arch Osteoporos. 2019;14(1):28.
