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Abstract
Objectives Delirium, a neurocognitive disorder, typically occurs in older patients and those with advanced cancer. Although there have been numerous reports on delirium in patients with cancer in various conditions, there are no reports that specifically focus on patients with musculoskeletal tumours. This prospective study aimed to investigate the incidence, risk factors and prognostic implications of delirium in patients with musculoskeletal tumours.
Methods In this single institutional study, 148 patients with musculoskeletal oncology were enrolled. The estimated risk factors included age, sex, alcohol abuse, performance status (PS), dietary status, admission route, tumour malignancy, oncological stage and blood test results. The significance of delirium in survival was also examined.
Results Only 18 patients with malignant tumours had delirium (12.2%). Based on univariate analysis, older age, poor PS, dietary status, admission from another hospital, malignant tumour, carcinoma rather than sarcoma, anaemia and some laboratory abnormalities were found to be significant risk factors for delirium. Multivariate analysis showed that poor PS was significantly correlated with delirium. Additionally, delirium was significantly correlated with poor survival.
Conclusions The incidence of delirium among patients with musculoskeletal tumours was 12.2% and was observed only in patients with malignant tumours. PS is a significant risk factor for delirium. Delirium is correlated with poor prognosis.
- delirium
- sarcoma
- bone
- methodological research
- survivorship
- psychological care
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What is already known on this topic
Delirium is a frequently observed condition in patients with advanced cancer. Many reports have documented cases of delirium in patients with specific types of cancer, such as gastric and lung cancer. However, there have been noreports regarding delirium in patients with musculoskeletal tumours.
What this study adds
This study contributes the incidence, identifying risk factors associated with delirium, and impact on the survival in patients with musculoskeletal tumours.
How this study might impact research, practice, or policy
The findings from this study offer valuable insights into the occurrence and risk factors of delirium in patients with musculoskeletal tumors. This information can be used to anticipate and address the risk of delirium in this particular patients, which can inform future research, clinical practice, and healthcare policies.
Introduction
Delirium is a neurocognitive syndrome that commonly occurs in older populations and in people with cancer, particularly in those at advanced stage. This syndrome is often a severely distressing experience not only for the patients but also for their families and professional caregivers.1
There have been many reports of delirium in patients with various pathologies, and none for musculoskeletal tumours. There are many known risk factors for delirium, including older age, brain damage, dementia, alcohol abuse, history of delirium, at-risk medication and surgery under general anaesthesia.2 3 Furthermore, vitamin B1 (VB1) deficiency in patients with cancer, which is a risk factor for delirium caused by malnutrition and/or consumption caused by malignant tumour, is likely to be overlooked.4
Based on this background, we conducted a prospective study of delirium in patients with musculoskeletal tumours.
Materials and methods
Between June 2020 and September 2021, 148 patients were enrolled at our department with the authorisation and monitoring of the institutional review board. The study population consisted of 73 men and 75 women aged 20–93 years, with an average age of 58.5. Of the total patients enrolled, 51 had benign tumours and 97 had malignant tumours. Among the malignant tumour cases, 39 were diagnosed with carcinoma and 58 with sarcoma. Alcohol abuse was identified in 10 patients. As assessed by the performance status (PS),5 79 patients were classified as PS 0, 29 as PS 1, 9 as PS 2, 20 as PS 3 and 11 as PS 4. Oncological staging (UICC; Unio Internationalis Contra Cancrum, Sixth Edition) of 97 patients with malignant tumours revealed 5, 23, 19 and 50 cases in stages I, II, III and IV, respectively. Delirium was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.6 The duration of follow-up ranged from 0.1 to 19.2 months, with an average of 6.1 months.
Predicted risk factors such as sex, age, PS, nutrient status, alcohol abuse, admission route, tumour characteristics, oncological stage and laboratory testing of peripheral blood, including VB1, were analysed. In addition, the influence of delirium on overall survival was evaluated. Statistical analyses were performed using JMP Pro V.16.2 (SAS Institute, Cary, North Carolina). Factors with missing data were excluded from the multivariate analysis.
Results
Among the 148 patients included, 18 (12.2%) experienced delirium during their hospital stay. The age of these 18 patients ranged from 52 to 93 years (average 73.7). Notably, no delirium was observed in patients with benign tumours. VB1 deficiency was recognised in 33 patients, including 7 with delirium. Three cases showed hypercalcaemia. VB1 supplementation therapy was administered to VB1-deficient patients, which resulted in a marked improvement of delirium in 13 of 16 cases. Other necessary treatments for delirium were administered according to each patient’s condition.
Using univariate analysis, statistical significance was observed for age (p<0.0001), PS (p<0.0001), poor nutrient status (p<0.0001), admission from another hospital (p=0.0023), tumour malignancy (p=0.0004) and carcinoma rather than sarcoma (p=0.0021). Other factors such as sex (p=0.6220), alcohol abuse (p=0.3492) and oncological stage (p=0.0568) were not statistically significant.
Regarding laboratory parameters, haemoglobin (p=0.0085), haematocrit (p=0.0073), albumin (p<0.0001), lactate dehydrogenase (p=0.0444), sodium (p=0.0299), adjusted calcium (p=0.0445) and C reactive protein (p=0.0054) were significantly correlated with delirium. The VB1 (p=0.1257), vitamin B12 (VB12) (p=0.3065) and folic acid (p=0.2215) levels were not significantly correlated. However, these factors are not independent and presumably interact closely. In the multivariate analysis, only PS showed significant correlation with delirium (p<0.0001). The details of these analyses are presented in table 1.
Details of clinical factors in the delirium and no delirium groups
Oncological outcomes were assessed in all patients, and 70 showed continuous disease-free survival, 9 showed no evidence of disease, 59 were living with the disease and 10 died due to the disease. The overall survival rates of these patients were analysed and a significant difference between those with (74.6%) and those without delirium (88.4%) (p=0.0018, log-rank test) was observed. Among the 97 patients with malignant tumours, those with delirium had poorer survival (74.6%) than those without delirium (86.7%) (p=0.0146, log-rank test).
Discussion
Up to 40% of patients will experience delirium when hospitalised or develop delirium during admission. Common risk factors for delirium include pre-existing cognitive impairment, multiple comorbid conditions such as depression, polypharmacy, impaired sensation, impaired functional ability, history of alcohol misuse and/or malnutrition, anaemia, severe illness, surgery/anaesthesia, new psychoactive medication, pain, environmental change, dehydration and/or electrolyte disturbances, and urine retention/faecal impaction.2 Because cancer is a severe illness, delirium occurs more commonly in older patients with advanced cancer. According to the European Society for Medical Oncology (ESMO) clinical practice guidelines, an incidence of delirium of up to 80% is expected.1 Many epidemiological studies have targeted specific patients within a certain unit or postoperative status. In general medicine or oncology wards, the prevalence rate ranges from 18% to 33%, with 42%–58% in acute palliative care units, and for older patients with cancer the range is between 22% and 57%.3 A study identified postoperative delirium (PD) in 44 (3.3%) of 1351 patients who underwent anatomical lung resection for lung cancer.7 In another report, PD during gastric cancer surgery was observed in 47 of the 1037 patients (4.5%).8 We believe that studies concerning groups of specific features are important for the early detection and treatment of delirium. Our study focused on patients in the orthopaedic oncology ward, which included those with cancer bone metastasis or tumours of musculoskeletal origin. To our knowledge, this is the first prospective study of delirium in patients with musculoskeletal tumours. Because this cohort has the common feature of motor impairment, the rate of delirium is expected to be higher than that in other cohorts. However, the rate of delirium of patients with musculoskeletal tumours in our study was close to 11%–42%, which was previously reported for patients in a common hospital.9 This probably implies that motor impairment is not always a significant cause of delirium.
The risk factors for delirium in patients with advanced cancer have also been discussed in many studies. According to the ESMO clinical practice guidelines, risk factors are classified into two major types: direct and indirect. The former is further divided into two subcategories—cancer-related factors and toxicities from anticancer treatments—while the latter has three subcategories: physical complications in patients with cancer, medication, and other status or predisposing comorbidity.1 In our study, we chose factors that can be acquired on patients’ admission. As expected, in the univariate analysis, many factors had a significant impact on delirium prevalence. However, in the multivariate analysis, PS was the only significant risk factor. This is presumably because the severity of musculoskeletal tumours on admission directly reflects patient mobility.
The ESMO guidelines include VB1 deficiency as a physical complication of indirect risk factors. Certain rapidly growing cancers increase thiamine consumption and cause rapid depletion of thiamine stores in the body.10 We included the VB1 levels of the patients in this study because VB1 deficiency may cause Wernicke’s encephalopathy and can cause irreversible damage to the brain. Onishi et al 4 demonstrated the importance of early detection of Wernicke’s encephalopathy and concluded that immediate proper treatment would yield successful outcomes. Although VB1 deficiency was not statistically significant, vitamin supplementation resulted in significant improvement in 13 of 16 cases (81%, p=0.001).
Regarding the prognostic impact of delirium, Hindiskere et al 11 reported that of the 276 patients who underwent surgery for bone metastasis, 84% with PD died, whereas 68% without PD died (p=0.012). This is commonly recognised in other situations, such as palliative care settings and intensive care units.12 13 The increased mortality in patients who develop PD is probably secondary to many underlying conditions that lead to the development of delirium.
The limitations of this study are as follows: the patients included had heterogeneous pathologies, which may have influenced the analysis of risk factors for delirium. As we administered vitamin supplementation to patients with VB1, VB12 and folic acid deficiency, this intervention presumably affected the prevalence of delirium. We did not take into account other factors such as surgery and medication history. Additionally, the follow-up period was short.
Conclusion
A total of 148 patients with musculoskeletal tumours were observed prospectively for the prevalence of delirium. Delirium occurred in 18 patients (12.2%) and all these had malignant tumours. PS was significantly correlated with delirium in the multivariate analysis. Vitamin supplementation improves delirium in patients. Delirium adversely affects the survival of patients.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Institutional Review Board of Saitama Medical University International Medical Center (19-258). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors thank Kaneda T, Otani T and Niijima H for data collection and data entry.
Footnotes
X @KeroyamaDaddy
Contributors HO and JI conceived, planned and supervised the study. YY and TT carried out the application of IRB, made actual test order for patients and acquired informed consents from the patients and/or their guardians. NM reviewed the patients’ charts and analysed the data. HO contributed to the interpretation of the results. NM and YY wrote the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.