Frailty measures, inflammatory biomarkers and post-operative complications in older surgical patients

SIR—The syndrome of frailty is a state of increased vulnerability towards stressors in older individuals, leading to an heightened risk of experiencing adverse health outcomes [1]. An operational definition is the one-dimensional physical ‘frailty phenotype’, which includes the presence of at least three of the following five criteria: unintentional weight loss, exhaustion, muscle weakness, slow walking speed and reduced physical activity [2]. A different tool to detect vulnerability in older patients is the Comprehensive Geriatric Assessment (CGA)—a multidimensional evaluation of health status including comorbidity, polypharmacy, physical functioning, nutritional and cognitive status, depression and social support. Based on a CGA, patients may be categorized into groups of fit, intermediate or frail [3]. CGA may uncover potentially remediable medical problems with implications for treatment, prognosis and rehabilitation [4–6]. We have previously shown that a CGA-based frailty measure predicts postoperative complications in older patients undergoing surgery for colorectal cancer [7]. An important aspect of the pathophysiology of frailty seems to be dysregulation of inflammatory pathways and of the coagulation system [1]. Thus, measuring circulating biomarkers might contribute to the clinical diagnosis of frailty. Higher serum levels of the acute-phase protein C-reactive protein (CRP), as well as the inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), have been associated with reduced physical function and different frailty measures [8–13]. Increased levels of plasma D-dimer, a marker of ongoing coagulation and fibrinolysis, have also been linked to these outcomes [8, 11]. The purpose of this study was to compare levels of inflammatory biomarkers (CRP, IL-6, TNF-α), and D-dimer in elderly colorectal cancer patients classified according to a modified version of the physical frailty phenotype and according to a CGA. We further wanted to investigate the predictive value of the individual biomarkers for the development of post-operative complications [7]. This was a substudy of a prospective study designed to explore whether CGA frailty predicted post-operative complications in elderly patients with colorectal cancer [7]. The Regional Committee for Medical and Health Research Ethics in Eastern Norway approved the study. Patients provided a written informed consent. Eligible participants were inpatients from three public hospitals in Norway (Ullevål, Aker and Akershus University Hospitals), 70 years and older, undergoing elective resections of tumours in colon or rectum. A physician trained in geriatrics performed a pre-operative CGA, and blood samples were collected within 14 days before surgery. For details on assessment tools, frailty classifications and the analyses of blood samples, see Supplementary data available in Age and Ageing online. Information on post-operative complications was retrospectively collected from hospital records, along with information from staff, patients and caregivers. Complications were classified as minor (grade I), potentially life-threatening with (grade II) or without (grade III) sequelae or fatal (grade IV) based on the grading system developed by Clavien et al. [14]. Details on this are given in Supplementary data available in Age and Ageing online. The outcome variables were defined as ‘severe’ (≥grade II) versus ‘no/mild’ complications (≤grade I) and ‘any’ complication versus ‘no’ complications. Non-parametric statistics were applied due to skewed distribution of biomarkers. The D-dimer analyses had a lower detection level of 0.04 mg/l and measurements below threshold were given this value. To examine differences in the levels of the various biomarkers within each frailty measure, the Kruskal–Wallis test was used. When overall significant differences (P < 0.05) were found, we performed Mann–Whitney U tests between group pairs, adjusting the statistical level of significance to 2.5% using the Bonferroni correction. We grouped levels of individual biomarkers into quartiles or tertiles and examined their association with post-operative complications by chi-square tests. Trend analyses were performed to identify cut-off points. CRP-levels were dichotomized into values below the 25th percentile versus higher levels and IL-6 into values below the 66.66th percentile versus higher levels. The dichotomized variables were subsequently included in crude and adjusted logistic regression models to examine their relative predictive value for post-operative complications. All analyses were performed with SPSS 16.0 software (Chicago, IL, USA). A total of 187 patients were recruited, and blood was collected from 137. Median age was 80 years and 69% had colon cancer. Further patient characteristics are shown in Supplementary data available in Age and Ageing online. Levels of biomarkers by the physical frailty phenotype and CGA-category are shown in Table 1. Overall significant differences within the physical frailty phenotype were found for concentrations of CRP (P = 0.001), IL-6 (P < 0.001), TNF-α (P = 0.004) and D-dimer (P = 0.031). The frail group had significantly higher levels of CRP and IL-6 than the pre-frail group (P < 0.025). The same pattern was not found for TNF-α, where the pre-frail group demonstrated higher levels of this biomarker than the robust group (P < 0.025). Comparison of biomarkers by the physical frailty phenotype and CGA category IQR, interquartile range. aFor difference between groups, by the Kruskal–Wallis test. *Significantly different from fit/robust group, P < 0.025 by the Mann–Whitney test. **Significantly different from intermediate/pre-frail group, P < 0.025 by the Mann–Whitney test. Comparison of biomarkers by the physical frailty phenotype and CGA category IQR, interquartile range. aFor difference between groups, by the Kruskal–Wallis test. *Significantly different from fit/robust group, P < 0.025 by the Man