RFS has grown to a research hotspot of multiple subjects in view of its prevalence and close relationship with disease outcomes. However, incidence and risk factors of RFS in AIS patients remains unclear and the its influence on stroke outcomes were rarely reported. Here in this study, we take the lead to specially focus on RFS in AIS population and found that there were 14.8% of AIS patients developing RFS. High NRS 2002 and NIHSS score, as well as albumin < 30 g/L and BMI < 18.5 kg/m2 were risk factors for RFS in AIS patients. Also, results showed that o RFS increased risk of poorer stroke outcomes with higher proportion of 3-month mRS of >2 and 6-month mortality.
The incidence of RFS in AIS patients in this current study was lower than other population in previous studies. By using the same definition of RFS, the incidence of RFS ranges from 34–45% in ICU patients as described by Olthof et al. and Hoffmann et al [7, 13]. However, with different definition, Flesher et al. found an even higher incidence of 80% in critically ill patients. Thus, different definition and population may induce adverse occurrence rate of RFS. Our study included AIS patients, partly of which were mild stroke with better conditions of nutrition. Moreover, since 2019 when ESPEN guidelines for RFS prevention and treatment were public , our stroke unit performed a calorie restriction combined with supplies of Centrum multi element during the first three days to prevent electrolyte disturbance for patients with high risk of malnutrition, which may decrease development of RFS and thus explain why we have lower incidence of RFS in AIS patients. Further studies with multi-subgroup analysis based on stroke severity and stroke subtypes are required to clarify the incidence of RFS in AIS patients.
Many screening tools reflecting disease severity and nutrition status were found to be associated with development of RFS in critically ill patients, including SOFA, Acute Physiology and Chronic Health Evaluation II (APACHE II) and MUST . In our study, we included multiple scoring systems and found that high NIHSS and NRS 2002 increased risk of RFS in AIS patients. NIHSS score is a universally accepted standardization to evaluate severity of acute ischemic stroke and higher NIHSS score indicates more extensive neurologic deficits, especially impairment of cognitive, consciousness and swallowing, and thus lead to metabolic disturbance . In addition, NRS 2002 was suspected to be collinearity with MUST in previous study, which is further demonstrated in our study due to its comparative predictive value of RFS . In terms of bio-metabolic markers, we identified albumin < 30g/L and BMI < 18.5 kg/m2 as risk factors for RFS in AIS patients. Hypoalbuminemia is also reported to be relative to RFS in ICU patients because of its reflection of systemic nutritional condition and immune to variety of diseases . Besides, low magnesium and low insulin-like growth factor-1 (ILGF-1) were considered as risk factors for RFS in ICU patients [17, 18], which was not investigated in our study. We did not find a significant relationship of CRP with RFS. We assumed that high level of CRP was attached to RFS because the higher CRP manifests systemic inflammatory status, which may induce increased nutritional requirement and lead to malnutrition . On this context, nutritional support, especially enteral support, may potentially cause acquired hypophosphatemia. Nevertheless, results in our study were in contrary to the hypothesis and the poor accuracy of CRP to recognize systemic inflammation may contributed to this result . It is worthy to further assess whether other AIS-associated inflammatory factors or combination of CRP with other biomarkers is more sensitive to predict RFS in AIS.
The sensitivity and accuracy of National Institute for Health and Care Excellence (NICE) criteria to predict RFS were only 78% and 38% respectively as reported in a previous study . A modified NICE criteria described by Friedli, which includes multiple demonstrated risk factors, such as BMI, large loss of weight, drug use of acid-inhibitor and so on, was also reported to have low sensitivity of RFS prediction . Hence, it is urgent to recognize relative risk factors for RFS and establish a comprehensive screening system reflecting both disease severity and nutritional status to facilitate RFS prediction.
With regard to outcomes of RFS on AIS patients, RFS was detected to be an independent risk factor for 6-month mortality, which was concordant with a recent study focusing on NCU patients . Also, results showed that RFS was significantly associated with a 3-month mRS of > 2. Poorer stroke outcomes may be attributed to hypophosphatemia that may directly induce secondary neuromuscular injury or aggravating neurologic ischemia through decreasing oxygen delivery of red blood cell [22–24]. Moreover, hypophosphatemia would lead to respiratory muscle dysfunction and potentially result to respiratory failure [25, 26]. All these pathologic changes ultimately lead to continuous neurologic disability and higher risk of death.
The major strength of this study is that it is the first investigation to focus on RFS in AIS population and included multiple biochemical indicators and scoring systems to evaluate risk factors and outcomes of RFS. Our results may provide reliable reference for nutritional management. There are also limitations. First, it is a retrospective, single-center study and excluded those lost to follow-up or without serum phosphate at 72 hours. We could not deny the selection bias and residual confounding. However, our prospective collected database may partly compensate for the retrospective nature. Second, part of patients may develop RFS beyond 72 hours and were divided into the non-RFS group, which may underestimate the incidence of RFS. Third, due to the small number of RFS patients, multi-subgroup analysis on diverse stroke severity and stroke subtypes were not conducted to further clarify the prevalence and risk factors of RFS in AIS patients. A prospective, randomized cohort study was required to further verify results in this current study.