What Do Cancer Surgery and orthopedic Surgery Elderly Patients Have in Common? A Long-term Postoperative Cognitive Dysfunction in Orthopedic and Cancer Patients Original Research

Abstract

Objectives-background:

Postoperative cognitive dysfunction (POCD) involves decline in several cognitive domains after surgery and is particularly common after cardiac surgery, while also common among other types of surgery. Given the potential effects of such cognitive dysfunction on the quality of life, it is important to study it in multiple populations in order to limit its occurrence.

Study design:

We present the long-term neuropsychological outcome of 200 patients, 100 of whom had orthopedic surgery and 100 oncological surgery.

Methods:

We administered a series of neuropsychological tests assessing attention, complex scanning, verbal working memory, executive functioning, short-term and long-term memory, and visuospatial perception before surgery, prior to discharge, at 3-month follow-up and 6 years after surgery. We compared the performance of these patients to normative datasets.

Results:

Despite equivalent levels of pre-surgery performance between patients, oncology patients exceeded their preoperative neurocognitive levels, suggesting less postoperative cognitive dysfunction in orthopedic patients overall, in all neuropsychological domains at a 6-year follow-up, except short-term retention. In contrast, orthopedic patients showed no improvement, and, instead, showed some cognitive decline, which remained consistent over time.

Conclusions:

Our findings highlight the critical role of the type of surgery utilized in the development of POCD and have implications for clinical management and patients’ quality of life in the very long term. Health policy professionals should be aware that patients’ low POCD may persist in the long term, and this is useful from a clinician’s point of view.

Keywords

Postoperative cognitive dysfunction neuropsychological tests orthopedic surgery cognitive domains quality of life

Postoperative Cognitive Dysfunction

Postoperative cognitive dysfunction (POCD) refers to impairment in one or more cognitive domains after surgery. This may include decrements in attention, orientation, memory, and learning and may improve to baseline levels by 3 months after surgery.¹ A potential, slight decline in cognition that may occur after a patient has recovered from the acute effects of surgery and hospitalization is known as postoperative cognitive dysfunction (POCD). Postoperative cognitive dysfunction is now classified as either “postoperative neurocognitive disorder” if it occurs within a year of surgery or “delayed neurocognitive recovery” if it occurs within 30 days of surgery.² There has been a significant difference between published studies as a result of the inconsistent POCD diagnosis and testing. There is some evidence that suggests modifying certain aspects of anesthesia may lower the risk of POCD.³

The severity of POCD covers a broad range, varying from mild cognitive decline to severe dementia and postoperative delirium.² Researchers suggest that approximately a quarter of elderly patients who undergo major surgery suffer from cognition dysfunction and 50% of these patients will experience a permanent dysfunction.³ While present after various types of surgery, it is most common after cardiac surgery employing cardiopulmonary bypass, orthopedics and vascular surgery.^4,5

The reason of cognitive decline after anesthesia and surgery remains unclear, but research indicates that this could be a result of anesthesia, surgery, the patient, or any combination of these.^2,3,6 The temporal relationship to anesthesia and surgery that was identified does not imply causation. Although poor cerebral oxygenation can lead to poor cerebral and cognitive outcomes, cognitive decline after surgery in the elderly can develop in the absence of cerebral hypoxemia.^6,7

Whereas the incidence of postoperative cognitive decline among cardiac surgery patients is far from trivial, orthopedic surgical procedures are correlated with a great amount of POCD.⁸ Specifically, studies have reported rates ranging from 11% to 80%, and it persists in as many as 42% of patients for a period of up to 3 to 5 years later, which is referred to as long-term POCD.^8,9 In contrast, the incidence of POCD after non-cardiac surgery appears to be much lower,⁴ showing substantial improvement over time; the prevalence rate 1 week after surgery is 25.8%, at 3 months it is 9.9 % and at 2 years it is 1%.¹⁰

Cancer survivors are exposed to several risk factors for cognitive dysfunction, such as general anesthesia and surgical trauma, among others. Sekiguchi et al twice examined patients with breast cancer who underwent surgery: 1 week after surgery and 6 months later. These patients showed attentional dysfunction and thalamic volume reduction immediately after surgery.^10,11 This is considered to happen due to changes in brain structure, particularly in the thalamus, which occur immediately after surgery. Patients who would develop clinical POCD are those with risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments.¹¹

Post chemotherapy cognitive impairment (PCCI) caused by chemotherapeutic drugs that are cytotoxic affecting both normal and cancer cells contribute to cognitive impairment following chemotherapy treatment. Cognitive dysfunction is common following other anticancer treatments such as radiation therapy, hormonal therapy, surgery, or in patients with noncentral nervous system cancer, and has important effects on brain functioning. In addition, several studies suggest that clinical manifestations of cognitive dysfunction may occur in cancer patients prior to chemotherapy or in patients who are not treated with cancer therapies. Because of the above, some researchers suggest that it should be more correct if we use the term cancer-related cognitive dysfunction.¹² In addition, author (2020a) has found that breast cancer patients who received chemotherapy performed worse in cognitive tasks including attention, memory, executive functions and language¹³ compared to patients with prostate, colorectal or thyroid cancer. Moreover, breast cancer patients had significantly greater difficulty in performing IADL compared to patients with other types of cancer.¹⁴

Several investigators have speculated regarding the possible mechanisms of POCD, suggesting intraoperative cerebral ischemia and cerebral oxygen desaturation caused by hypoperfusion, arrhythmias, rapid rewarming and inflammation, either local or global, as potential risk factors.^15,16 As regards the etiologic role of cardiopulmonary bypass and anesthesia in the development of POCD, the main fact is that it remains quite controversial.² Among potential contributing factors that have not been well established is the subtle blood pressure change during coronary artery bypass surgery that can cause watershed strokes,¹⁷ as well as the drugs associated with anesthesia.¹⁸ In addition, it has been hypothesized that nonspecific effects of surgery, such as postoperative pain, medications, and sleep disturbance, may also be contributing factors for POCD.¹⁹ Demographic and clinical factors that are correlated with POCD include the patient’s age, their educational level, their preoperative cognitive performance and comorbidity²⁰. Older patients with limited education and comorbid cerebrovascular disease are the most likely to show POCD.^2,21 Thus, the pathogenesis of postoperative cognitive decline remains unclear as it seems to be a multifactorial phenomenon.

Moreover, POCD may have additional sequelae. It has been found to be associated with increased morbidity and mortality, prolonged hospitalization, and increased health care costs, and may have an adverse impact on social functioning and health-related quality of life.²² Most critically, it has important social implications for patients as well as their caregivers, as it can limit the patients’ social functioning, their independent living and autonomy.² Therefore, it would be important to assess all patients post-surgically for this condition. Perhaps due to the multifactorial nature of the pathogenesis of POCD, there does not appear to be a single intervention that might provide adequate protection to the brain during surgery.¹⁵

Prevention is the best treatment for many diseases and in the case of POCD, early detection and management of potential perioperative risk factors can lead to an optimal outcome for patients who undergo surgical procedures. Long-term follow-up of POCD is essential in understanding the factors related to its development and treatment. Most long-term follow-up assessments have been conducted as early as 1 month and as late as 5 years post-surgery.²² In the present study, we investigated 2 groups of patients at 4 time points: at baseline (pre-surgery), before discharge (7-10 days post-surgery), 3 months post-surgery and 6 years post-surgery.

We explored the critical role of the type of surgery utilized in the development of POCD long-term neuropsychological outcome of 200 patients, 100 of whom had orthopedic surgery and 100 oncological surgery. Our aim was to compare the performance of these patients to normative datasets to see which group of patients (orthopedic vs oncological surgery) has POCD to a great extent compared to others.

Method

Participants

The sample was recruited from 2 departments of AHEPA University Hospital of Thessaloniki, Aristotle University of Thessaloniki, from December 2022-May 2023. The study was part of a research study, and it was examined and approved by The Bioethics and Ethics Committee of AHEPA University Hospital, Medical School of Aristotle University of Thessaloniki, Greece under the number 34191. Written informed consent was obtained from all patients who agreed to enter the study. Participants in this study were 2 groups of patients. One group underwent joint replacement surgery and the other group with breast cancer were scheduled for mastectomy. The type of anesthesia that was performed was intravenous (IV) anesthesia with propofol and regional anesthesia (RA). The 2 study groups of patients were matched regarding their demographic and clinical characteristics, as seen in Table 1.

Table 1.

Patients’ demographic and clinical characteristics.

Characteristic	Group 1 (n = 100)	Group 2 (n = 100)
Type of surgery	Orthopedic	Oncology
Age (years)	75 (SD:5.80)	74 (SD:6.32)
Education (years)	12 (SD:6.72)	11 (SD:5.67)
Gender	Male (53)-Female (47)	Female
Surgery time (min)	90	93
Length of ICU stay (days)	2	1

Exclusion criteria for the original neuropsychological study were the following: a pre-existing psychiatric or neurological disorder; inability to cooperate with a neuropsychological assessment as judged by the researcher carotid artery stenosis greater than 60% as assessed with duplex ultrasonography; and, a history of substance and alcohol abuse. Cancer patients receiving chemotherapy or radiation therapy were also excluded.

Study Design

We administered a battery of neuropsychological tests and assessed all major cognitive domains in 200 patients; group A (n = 100) underwent joint replacement surgery and group B (n = 100) were patients with breast cancer scheduled for mastectomy.

A description of the 2 groups of patients follows:

Group 1: 100 patients with a mean age of 75 years (SD 5. 80) and mean education of 12 years (SD 6. 72). They underwent joint replacement surgery and received neuropsychological testing before surgery, prior to discharge (7-10 days after surgery), at three-months postoperatively, and 6 years after surgery.

Group 2: 100 patients with a mean age of 75 years (SD 6. 32) and mean education of 11 (SD 5.67). A neuropsychological assessment was conducted before surgery, prior to discharge (7-10 days after surgery), at three-month follow-up, as well as 6 years postoperatively. Flow chart can be seen in Figure 1.

Figure 1.

Flow chart.

Procedure

We administered a battery of neuropsychological tests and assessed all major cognitive domains (visual-spatial perception, executive functions, complex scanning and visual tracking, attention, verbal working memory, and short- and long-term memory). The battery included tests with multiple versions or tests that could be adapted to multiple administrations in order to avoid potential practice effects in follow-up testing. Also included were scales measuring anxiety, depression, and positive and negative mood as neuropsychological performance may be influenced by a patient’s mood state (Table 2). This assessment required approximately 60 minutes for each patient to complete and was blind to patient management.

Table 2.

Mean z-scores of neuropsychological declined performance of 2 groups at 4 time points.

Test	Time-point	Group 1	Group 2
Stroop Color-Word	T1	−0.70 (1.42)	0.70 (0)
	T2	−0.607^‡ (0.50)	0.607 (1)
	T3	−0.363^‡ (0.67)	0.363 (1.16)
	T4	−0.370^‡ (0.71)	0.370 (1.17)
Fuld Object Memory Test Storage	T1	−0,068(1,31)	0068 (0.554)
	T2	−0.876 (0.39)^‡	0.876 (0.54)
	T3	−0.889 (0.37)^‡	0.889 (0.52)
	T4	−0.886 (0.36)	0.886 (0.54)
Symbol Digit Modalities Test	T1	−0.142 (0.79)	0.142 (1.17)
	T2	−0.91 (0.34)	0.91 (0. 64)
	T3	−0.92 (0.35)	0.92 (0.43)
	T4	−0.92 (0.35)	0.92 (0.43)
Digit Span Backward	T1	−0.12 (0.73)	0.12 (1.20)
	T2	−0.77 (0.49)^‡	0.77 (0.74)
	T3	−0.70 (0.57)	0.70 (0.82)
	T4	−0.70 (0.57)	0.70 (0.82)

‡

This mark indicates cognitive decline relative to normative data and according to the 20% criterion.

We investigated cognitive changes prior to discharge, 3 months and 6 years after surgery in each patient by comparing their follow-up scores to pre-surgery baseline scores in each test as well as normative data.

Statistical analysis

The criterion of change that we chose to apply for was that of 20% decrease. We defined cognitive dysfunction as a postoperative 20% decrease, relative to pre-surgery performance, in one or more neuropsychological tests at each follow-up time point.⁷ Group analysis, which was performed using analysis of variance mixed design, with between-subjects factor (Group 1 vs Group 2) and within-subjects factor (preoperatively, at discharge, at 3-month follow-up and 6 years after surgery), with a P value of less than.05 was considered statistically significant. Post-hoc analysis by Bonferroni was used for multiple comparisons. Data were analyzed using the SPSS software package.

Results

The 2 groups of patients did not differ from each other, nor from the normative datasets, in their neuropsychological performance preoperatively. Yet, the post-surgery patients’ cognitive performance of the 2 groups diverged (Table 2). Specifically, according to the 20% criterion, Group 1 had cognitive decline in attention (17 orthopedic patients vs 7 cancer patients, P < .001) at the 3-month follow-up time point, in executive functions (19 orthopedic patients vs 8 cancer patients, P < .001) immediately postoperatively, in short-term memory (20 orthopedic patients vs 10 cancer patients, P < .001), and in working memory (19 orthopedic patients vs 7 cancer patients, P < .001) at 3 follow-up time points. In contrast, Group 2 had no cognitive decline and showed increased performance at 3-month and at 6-year follow-up after surgery, compared to preoperative performance. Figure 2 shows the number of patients who showed POCD at 3 time points. The use of z-scores appears to be based on they within sample approach, given that in the tables when one group goes up the other group tends to go down. But this has a quite different interpretation than z-scores based on the normative correction, and both could provide useful, albeit quite different, inferences. The precise number of standard deviations that a data point is above or below the mean is measured by a z-score. As it allows us to compare 2 scores that come from different normal distributions, the standard score, also known as a z-score, is a very helpful calculation. To put it another way, the standard score achieves this by standardizing scores in a normal distribution by converting them to z-scores in a standard normal distribution.

Figure 2.

No. of patients with POCD on all 3 time points.

With respect to mood measures, no patient had elevated scores in depression, anxiety, or positive and negative mood scales, nor did they show any significant change over time.

Discussion

Our findings indicated different patterns of change postoperatively, despite equivalent levels of cognitive abilities preoperatively. The present study suggests long-term improvement of cancer patients and, on the contrary, failure to reach preoperative levels after orthopedic surgery. This improvement of cognitive functioning among cancer patients has implications for resuming social and occupational roles, as well as for the quality of life after surgery. In contrast, orthopedic operations are associated with an increased risk of cognitive decline 3 months after surgery, which appears not to improve over the course of a 6-year follow-up, with implications for reduced daily functioning.

Orthopedic surgery is strongly associated with POCD, which has memory impairment as its most common symptom, with patients showing impaired performance in cognitive tasks, too. POCD has been detected in 41.4% of elderly patients (aged ⩾ 60) who had undergone major surgery. Studies explored that at 3 months after surgery, POCD can still be present in 12.7% of elderly patients.²³ Specifically, cancer patients had no cognitive decline postoperatively, and, in fact, showed increased performance in attention, executive functioning, and short-term working memory, across the 4 time points. In contrast, orthopedic patients showed some cognitive decline, specifically in attention, executive functions, and short-term memory, which remained consistent over time, and never reached their pre-surgery baseline neurocognitive levels. In conclusion, both groups showed consistency at 6 years after surgery, relative to the 3-month follow-up, indicating that their cognitive status remained stable over time, and that any spontaneous recovery had ceased by 3 months postoperatively. On the contrary, the 2 study groups did not show any cognitive decline in long-term memory, visual–spatial perception, or verbal working memory.

Some limitations of the present study should be considered, with respect to the generalizability of our findings and sample size calculation was not performed. A long-term outcome was available for patients with cancer and non-cancer patients. Future investigations should include more comparison groups, or patients undergoing other major non-cardiac surgery with general anesthesia. These comparison groups could help to clarify the respective roles of surgical procedures in developing POCD. Glumac et al showed that preoperative administration of dexamethasone may attenuate inflammatory response induced by surgery, and thereby, decrease the incidence and severity of POCD.²⁴ These results implicate the importance of inflammatory response in the pathogenesis of POCD. Future research is necessary to study the role of variables such as age and degree of pre-existing cerebrovascular disease, peripheral vascular disease, or diabetes and personality factors.

Thus, the present findings suggest the influence of the type of surgery (orthopedic or oncology) on cognitive functioning. The clinical implications are substantial as POCD can have an adverse impact on the quality of life and social functioning.²⁵ In addition, it is a multifactorial problem that may have a serious social and economic impact on society. Any surgery-related technique or procedure with the potential of reducing POCD following surgery may be of great benefit to the patient and his/her family, health care professionals and community. Health policy designers and professionals should be aware that in some patients POCD may persist for 6 years following surgery, and this is useful from a clinician’s point of view.

Footnotes

Author Contributions

Conceptualization, KM; methodology, KM; software, ET. & GK; validation, KM and EK.; formal analysis, DK.; investigation, DP; resources, EA.; data curation, MT & MD.; writing—original draft preparation, KM.; writing—review and editing, KM, ET; visualization, KM; supervision, KM.; project administration, KM.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Statement Regarding Ethical Approval

N/A in my country.

Statement Regarding the Welfare of Animals

N/A

Informed Consent

All participants signed an informed consent.

ORCID iD

Kalliopi Megari

Data Availability Statement

Data are not available due to privacy.

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