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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 4  |  Page : 157-161

Leptin as a predictor of delirium in geriatric inpatients: An observational study


1 Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
3 Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission14-Sep-2022
Date of Decision02-Oct-2022
Date of Acceptance17-Oct-2022
Date of Web Publication27-Dec-2022

Correspondence Address:
Dr. Avinash Chakrawarty
Department of Geriatric Medicine, Room No. 3095A, 3rd Floor, Academics Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiag.jiag_51_22

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  Abstract 


Background: Delirium is a complex, reversible neuropsychiatric disorder that frequently occurs in the geriatric age group in acute care settings with multifactorial etiology and numerous knowledge gaps in the pathogenesis. Objective: This study aimed to establish an association between leptin levels and delirium in patients aged 60 years and above admitted under the geriatric medicine department of a tertiary care hospital. Materials and Methods: A prospective observational study was conducted in consecutively admitted patients to the geriatric ward. Patients were assessed for delirium within 24 h of admission and daily thereafter until they were discharged from the hospital or died using the Confusion Assessment Method (CAM) or CAM-intensive care unit with subsequent division into delirium and nondelirium groups. Serum leptin levels were measured using enzyme-linked immunosorbent assay. Results: Two hundred patients were recruited in the study. The mean age of participants was found to be 73.1 ± 8.8 years. Prevalence rates of delirium at the time of admission and incidence rates during hospital stay were found to be 20% and 5%, respectively. The occurrence of delirium was also found to be significantly associated with mortality (32.5% vs. 8.7%, P = 0.001). Serum leptin levels were found to be significantly lower in patients with delirium (2.58 ± 1.01 ng/mL vs. 10.72 ± 1.46 ng/mL, P = 0.03). Multivariable regression analysis revealed delirium to significantly correlate positively with age (Odds Ratio [OR]: 1.63 (1.07–2.47), P = 0.021) and negatively with leptin levels (OR: 0.94 (0.90–0.99), P = 0.018). Conclusion: Delirium is a frequently occurring condition in hospitalized older adults with high mortality rates. Leptin might serve as a potential predictor of delirium owing to its probable role in the pathophysiological processes of delirium.

Keywords: Delirium, leptin, older adults


How to cite this article:
Ajmera Y, Chakrawarty A, Anwar M, Khan MA, Chatterjee P, Dey S. Leptin as a predictor of delirium in geriatric inpatients: An observational study. J Indian Acad Geriatr 2022;18:157-61

How to cite this URL:
Ajmera Y, Chakrawarty A, Anwar M, Khan MA, Chatterjee P, Dey S. Leptin as a predictor of delirium in geriatric inpatients: An observational study. J Indian Acad Geriatr [serial online] 2022 [cited 2023 Jan 29];18:157-61. Available from: http://www.jiag.com/text.asp?2022/18/4/157/365776




  Introduction Top


Delirium is a complex, reversible neuropsychiatric disorder characterized by an acute onset and fluctuating course with disturbance in attention and awareness and additional disturbances in cognitive domains.[1] It may result from a wide variety of both physiological and structural insults; however, the overall mechanism is still not fully understood.

In India, people aged 60 years and above are projected to rise from 8.6% in 2011 to 19% by the year 2050.[2] Hospitalized older adults constitute the most vulnerable group for delirium, with high morbidity, mortality, and health-care costs. However, it stays preventable in up to 40% of cases; therefore, it becomes of utmost importance to develop strategies and tools to identify those at maximum risk.[3],[4]

Leptin is a 16kD protein produced mainly by white adipose tissue and is the key regulator of body weight via its effects on the hypothalamic arcuate nucleus. It is considered to be a neuroprotective hormone with broad effects on immunomodulation and energy homeostasis. Low leptin levels have been found to increase levels of pro-inflammatory cytokines, leading to cognitive dysfunction and emotional disturbances. In recent studies, hypoleptinemia is also found to be associated with delirium in critically ill adult patients and surgical patients.[5],[6]

The paucity of evidence in the geriatric population, sparked off the need for this study which aims to establish an association between leptin levels and delirium in patients aged 60 years and above admitted under the geriatric medicine department of a tertiary care hospital.


  Materials and Methods Top


A prospective observational study was conducted between July 2019 and October 2019 after obtaining ethical clearance from Institute Ethics Committee (Reference no: IECPG-34/23.01.2019). Study participants aged 60 years and above, consecutively admitted to the geriatric medicine ward, were included in the study after seeking written informed consent from the patient or immediate attendant of the patient. Patients who withdrew consent, had a history of psychotic illness, were admitted due to alcohol withdrawal delirium, or died within 24 h of admission were excluded from the study. Based on the literature review, assuming delirium prevalence of 42% in elderly patients in medical wards with a 7% margin of error, the sample size was computed to be 200 for the conduct of the study.[7]

Patients were assessed for delirium within 24 h of admission and daily thereafter till the time they were discharged from the hospital or died using the Confusion Assessment Method (CAM) or CAM- intensive care unit (ICU) (for patients admitted in ICU/High Dependency Unit (HDU)) with subsequent division into delirium and Nondelirium group. Patients diagnosed with delirium at or within 24 h of admission were denoted as “Old Case” and those diagnosed after 24 h of admission were denoted as “New Case” (Incident case), and incidence and prevalence rates were calculated accordingly.

At baseline, the participant or immediate attendant of the patient was asked for sociodemographic data (including age, sex, state, education, and religion) and immediate diagnostic indication at the time of admission (admission diagnosis) by the treating geriatrician was noted. For analysis of leptin, a total of 4 ml of nonfasting venous blood was collected from each patient under aseptic conditions in a red top BD vacutainer (with no additives) and allowed to clot in a vertical position for 2 h at room temperature. The supernatant was subsequently centrifuged at 3000 rpm for 15 min at 4°C, and separated serum samples were stored at − 80°C in multiple small aliquots until analyzed to avoid unnecessary freeze-thaw cycle. The quantitative measurement of leptin in serum was performed using Enzyme-Linked Immunosorbent Assay (ELISA) kit (EIA-2395, DRG® Leptin (Sandwich) ELISA, Marburg, Germany), in accordance with the manufacturer's instructions. The person carrying out the assays was completely blinded to the clinical information.

Briefly, 100 μl of diluted leptin conjugate were dispensed into each well of the microtiter plate and incubated at room temperature for 1 h. The contents of the wells were discarded, and the wells were rinsed three times with diluted wash solution. 50 μl of samples were dispensed into each well and the standards at the specified concentrations in ng/ml. 50 μl of leptin antibody were then dispensed into the center of each well to achieve complete mixing, and the plate was incubated overnight at 4°C in a humidified chamber. The contents of the wells were discarded, the wells were rinsed thrice, and residual droplets were removed. 100 μl of diluted second antibody was dispensed into each well and incubated at room temperature for 2 h. The contents of the wells were discarded, and the wells were washed thrice. 100 μl of horseradish peroxidase enzyme complex were dispensed into each well and incubated at room temperature for 45 min. Removal and washing of the wells were repeated before 100 μl of tetramethylbenzidine substrate solution and then incubated at room temperature for 15 min. The enzymatic reaction was terminated by adding 50 μl of sulfuric acid stop solution into the center of each well, and the absorbance was captured at 450 nm using an ELISA microtiter plate reader (BioTeck instruments, USA). A standard curve was constructed by plotting a graph of the absorbance of each reference standard against its corresponding concentration in ng/ml. The leptin concentration of each serum sample was determined by using the corresponding absorbance to extrapolate the value from the standard curve.

Statistical analysis

It was performed using STATA 16.0 (StataCorp, College Station, TX, USA) software. For descriptive statistics, absolute frequency distribution and related percentage distribution were reported for qualitative variables, and mean and standard deviation or standard error of the mean were reported for quantitative variables having normal or nonnormal distribution, respectively.

Initially, to establish an association for categorical variables, the Pearson Chi-square test/Fisher's exact test was applied for normal and nonnormal distribution, respectively, and for quantitative variables, independent t-test/Wilcoxon rank sum test (Mann–Whitney U-test) were applied for normal and nonnormal distribution, respectively.

Association between delirium and its risk factors were estimated by odds ratios (ORs) and their corresponding 95% confidence intervals using univariable and multivariable logistic regression analysis. A stepwise selection procedure using entry probability of 0.15 and exit probability of 0.05 was used to select the variables for the regression model. The variables entered for multivariable analysis include age, sex, and leptin. No adjustments were made for multiple comparisons. All P were two-tailed, and statistical significance was set at <0.05.


  Results Top


A total of 206 consecutively admitted patients during the study period were screened, of which six patients were excluded from the study (one patient refused consent, one patient was admitted with alcohol withdrawal delirium, two patients had history of psychotic illness and two patients died within 24 h of admission). A total of 200 patients were included in the final analysis. In the delirium group, out of 40 patients, 30 were diagnosed with delirium at or within 24 h of admission and 10 were diagnosed after 24 h of admission giving “Incidence” and “Prevalence” rates to be 5% and 20%, respectively. The clinical characteristics of the study participants are given in [Table 1].
Table 1: Clinical characteristics of the study participants

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The mean age of the study participants was found to be 73.1 ± 8.8 years, with male patients (56%) outnumbering female patients (44%). In comparison to nondelirium group, participants in delirium group were found to be significantly older (P = 0.007), had significant difference in admission diagnosis (P = 0.009) with respiratory (32.5%), neurologic (30%), and urinary (17.5%) pathologies constituting the major reason for admission, had significantly lower levels of leptin (P = 0.03) [Figure 1] and significantly higher mortality rates (P = 0.001).
Figure 1: Comparison between serum leptin levels (ng/mL) in delirium versus nondelirium group (Significance P = 0.03)

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Univariable and multivariable logistic regression analysis revealed delirium to significantly correlate positively with age (OR: 1.63 [1.07–2.47], P = 0.021) and negatively with leptin levels (OR: 0.94 [0.90–0.99], P = 0.018) [Table 2].
Table 2: Factors associated with delirium in hospitalized older adults

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  Discussion Top


The main aim of this study was to determine the incidence and prevalence rates of delirium, its outcome in geriatric inpatients and its possible predictors to help clinicians identify those at maximum risk and develop their understanding to improve the treatment and prognosis.

The overall mean age of the study sample was 73.1 years, with male patients (56%) surpassing the female patients (44%). The prevalence rates of delirium at the time of admission and incidence rates during hospital stay were found to be 20% and 5%, respectively, in the study group, which are in line with previous studies which identified prevalence rates of 11%–42% and incidence rates of 6%–56% in older adults.[7],[8],[9],[10] However, the rates in the current study are lower than those obtained by studies conducted in old age medicine wards, which found prevalence and incidence rates to range from 25% to 57% and 20%–29%, respectively.[11],[12],[13] The possible explanation for low incidence rates in the current study could be the application of targeted multicomponent nonpharmacologic interventions in geriatric wards such as the provision of orientation clues, sensory rehabilitation, bed rails and rails in corridors and toilets, encourage regular visits from family and friends, promote early mobilization and regular ambulation, avoid physical restraints and medical/nursing procedures during sleep if possible and pain management.

Regression analysis revealed older age to be a significant predictor of delirium, which is in accordance with previous studies.[8],[14],[15],[16] Low serum leptin levels (2.58 ng/mL vs. 10.72 ng/mL) in the delirium group were also found to significantly predict delirium in the current study. These findings are in line with three recent publications in different study populations: Sánchez et al. performed a cross-sectional study in Colombia in acutely hospitalized patients aged 60 years and above and found leptin levels to be significantly lower in patients with delirium than those without delirium (2 vs. 8 ng/mL).[17] Li et al. performed a prospective cohort study in critically ill adult patients aged 18 years or more in Hunan Province, China and found that patients who developed delirium had significantly lower leptin levels at ICU entry than those who did not (6.1 vs. 9.2 ng/ml).[5] Chen et al. conducted a prospective study on patients aged 65 years and older after hip fracture surgery in Wenzhou, China. Results identified low plasma leptin levels as predictors of postoperative delirium independent of age in elderly hip fracture patients after surgery (4.6 ± 2.2 ng/ml vs. 7.5 ± 1.8 ng/ml, in those with delirium and without delirium, respectively).[6]

Leptin is a neural modulator, and the association found in this study is not surprising because low leptin levels have been associated with other neuropsychiatric disorders such as depression, Alzheimer's disease, and vascular dementia. The various pathophysiological processes by which low leptin may influence the occurrence of delirium can be modulation of protein synthesis in neurons and glial cells affecting neurogenesis, axon growth, synaptogenesis and dendritic morphology in hippocampal and cortical structures, immune modulation via increased levels of several cytokines and decrease in neuroprotective effect in dopaminergic cells. As aging has been associated with a decrease in the levels of leptin, and resistance to its actions, it might also explain the increased risk of development of delirium in this population.[5],[17]

Although these processes may shed some light on why delirium is more likely to occur when leptin levels are low, more work needs to be done to explicate the mechanisms by which leptin may intervene during the development of delirium.

Strengths and limitations

The study used a prospective design, and the presence of delirium was assessed daily until discharge or death by a geriatrician as principal investigator to avoid misdiagnosis or missed cases. A consecutive sampling technique was incorporated for the recruitment of patients to prevent selection bias. The person carrying out the laboratory assay of serum leptin was completely blinded to the clinical information throughout the study to prevent measurement bias. To the best of our knowledge, this is the pioneer study from the Indian subcontinent to evaluate serum leptin levels as a potential predictor of delirium. However, this study is limited by a relatively small sample size, majority of the patients in the study cohort belonging to one region of the country, rendering the sample as homogeneous and therefore limiting the generalizability of results to other settings due to diverse cultural and sociodemographic and clinical differences. As this is a hospital-based study, the results cannot be extrapolated to community settings.


  Conclusion Top


The study shows delirium to be a frequently occurring condition in hospitalized older adults with high mortality rates and therefore necessitates early identification and treatment. The targeted multicomponent nonpharmacologic interventions in the geriatric ward may help prevent the incidence of cases of delirium in geriatric inpatients. Leptin might serve as a potential predictor of delirium owing to its probable role in the pathophysiological processes of delirium. Nevertheless, acknowledging the study limitations of this study, further large multicenter prospective studies are needed to confirm our results.

Financial support and sponsorship

The funding for the study has been provided by the Department of Geriatric Medicine, AIIMS, New Delhi, India.

Conflicts of interest

The authors have no conflict of interest.



 
  References Top

1.
American Psychiatric Association, editors. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed. Washington, D.C: American Psychiatric Association; 2013.  Back to cited text no. 1
    
2.
Subaiya L, Bansod DW. Demographics of Population Ageing in India. In: Giridhar G, Sathyanarayana KM, Kumar S, James KS, Alam M, editors. Population Ageing in India. Cambridge: Cambridge University Press; 2014. p. 1-41. Available from: https://www.cambridge.org/core/product/identifier/CBO9781139683456A014/type/book_part. [Last accessed on 2020 Sep 22].  Back to cited text no. 2
    
3.
Rieck KM, Pagali S, Miller DM. Delirium in hospitalized older adults. Hosp Pract (1995) 2020;48:3-16.  Back to cited text no. 3
    
4.
Thom RP, Levy-Carrick NC, Bui M, Silbersweig D. Delirium. Am J Psychiatry 2019;176:785-93.  Back to cited text no. 4
    
5.
Li G, Lei X, Ai C, Li T, Chen Z. Low plasma leptin level at admission predicts delirium in critically ill patients: A prospective cohort study. Peptides 2017;93:27-32.  Back to cited text no. 5
    
6.
Chen XW, Shi JW, Yang PS, Wu ZQ. Preoperative plasma leptin levels predict delirium in elderly patients after hip fracture surgery. Peptides 2014;57:31-5.  Back to cited text no. 6
    
7.
Kukreja D, Günther U, Popp J. Delirium in the elderly: Current problems with increasing geriatric age. Indian J Med Res 2015;142:655-62.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Alamri SH, Ashanqity OA, Alshomrani AB, Elmasri AH, Saeed MB, Yahya SA, et al. Delirium and correlates of delirium among newly admitted elderly patients: A cross-sectional study in a Saudi general hospital. Ann Saudi Med 2018;38:15-21.  Back to cited text no. 8
    
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Garcez FB, Apolinario D, Campora F, Curiati JAE, Jacob-Filho W, Avelino-Silva TJ. Delirium and post-discharge dementia: Results from a cohort of older adults without baseline cognitive impairment. Age Ageing 2019;48:845-51.  Back to cited text no. 9
    
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Kim MS, Jun JY, Chun HJ, Kim YO. The Incidence and related risk factors of delirium in the older inpatients with neurological disorders in a tertiary hospital. Korean J Adult Nurs 2018;30:255.  Back to cited text no. 10
    
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Hshieh TT, Inouye SK, Oh ES. Delirium in the elderly. Clin Geriatr Med 2020;36:183-99.  Back to cited text no. 11
    
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Grover S, Kathiravan S, Dua D. Delirium research in India: A systematic review. J Neurosci Rural Pract 2021;12:236-66.  Back to cited text no. 12
    
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Weng CF, Lin KP, Lu FP, Chen JH, Wen CJ, Peng JH, et al. Effects of depression, dementia and delirium on activities of daily living in elderly patients after discharge. BMC Geriatr 2019;19:261.  Back to cited text no. 13
    
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Oldroyd C, Scholz AF, Hinchliffe RJ, McCarthy K, Hewitt J, Quinn TJ. A systematic review and meta-analysis of factors for delirium in vascular surgical patients. J Vasc Surg 2017;66:1269-79.e9.  Back to cited text no. 14
    
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Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in acute hospital medical units: A systematic review and meta-analysis. Age Ageing 2014;43:326-33.  Back to cited text no. 15
    
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Tosun Tasar P, Sahın S, Akcam NO, Dınckal C, Ulusoy MG, Sarıkaya OF, et al. Delirium is associated with increased mortality in the geriatric population. Int J Psychiatry Clin Pract 2018;22:200-5.  Back to cited text no. 16
    
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Sánchez JC, Ospina JP, González MI. Association between leptin and delirium in elderly inpatients. Neuropsychiatr Dis Treat 2013;9:659-66.  Back to cited text no. 17
    


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