Diagnostic Challenges and the Potential of Clinical Decision Support Systems
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Background: Refeeding syndrome (RFS) can occur in malnourished patients when normal, enteral, or parenteral feeding is resumed. The syndrome often goes unrecognized and may, in the most severe cases, result in death. The diagnosis of RFS can be crucially facilitated by the use of clinical decision support systems (CDSS).
Methods: The literature in PubMed was searched for current treatment recommendations, randomized intervention studies, and publications on RFS and CDSS. We also took account of insights gained from the development and implementation of our own CDSS for the diagnosis of RFS.
Results: The identification of high-risk patients and the recognition of manifest RFS is clinically challenging due to the syndrome’s unspecific symptoms and physicians’ lack of awareness of the risk of this condition. The literature shows that compared to patients without RFS, malnourished patients with RFS have significantly greater 6-month mortality (odds ratio 1.54, 95% confidence interval: [1.04; 2.28]) and an elevated risk of admission to intensive care (odds ratio 2.71 [1.01; 7.27]). In a prospective testing program, use of our own CDSS led to correct diagnosis in two thirds of cases.
Conclusion: RFS is difficult to detect and represents a high risk to the patients affected. Appropriate CDSS can identify such patients and ensure proper professional care.
Malnourished patients in whom feeding is resumed following significantly reduced or no caloric intake lasting at least 5 days are at risk for refeeding syndrome (RFS). Any form of feeding can cause RFS: oral, enteral, parenteral as well as simple normal meals. Enteral feeding poses the highest risk for RFS (1).
The cardinal symptom is considered to be hypophosphatemia with onset within 2–5 days of resumed feeding, accompanied by hypokalemia and/or hypomagnesemia (2). This can be associated with severe fluid shifts and cause central and peripheral edema. In addition, neuromuscular, cardiac, and central nervous complications such as tachycardia and impaired cognition may develop.
RFS often goes unrecognized due to the fact that its symptoms are nonspecific (3). By way of example, a recent survey of 281 physicians clinically active in Germany and based on sample case vignettes of RFS found that only 14 % of physicians and nutritionist teams correctly diagnosed RFS (4). Moreover, half of the respondents in audits (New Zealand and the United Kingdom) of prescribing practices in parenteral nutrition (PN) were unable to identify patients at risk or name risk factors for RFS despite correct determination of serum electrolytes (5, 6).
The clinical relevance of RFS is high: If unrecognized and untreated, fatal treatment outcomes are possible (7, 8). Treatment includes replacement therapy of the affected electrolytes and other vitamins (in particular, vitamin B1), as well as the reintroduction of feeding in a calorie-reduced manner. Against the background of the diagnostic challenges posed by RFS, a clinical decision support system (CDSS) for the automated diagnosis of the syndrome was newly developed and tested at the University of Leipzig Medical Center, Germany.
A selective literature search on RFS was carried out in the PubMed database on the basis of current treatment recommendations, meta-analyses, systematic review articles, randomized controlled studies, cohort studies, and observational studies. Publications in English and German from between 1990 and 2022 were taken into consideration. Particular focus was placed on publications relating to RFS in conjunction with CDSS. The following search terms were used: “refeeding syndrome” [AND] “diagnosis,” “recognition,” “incidence,” “management,” “prospective” “clinical decision support system,” and “CDSS.” Practical experience with the use of our own CDSS for RFS diagnosis in inpatient care was additionally taken into consideration.
Definition and epidemiology
There is no standardized definition of RFS still today. In April 2020, the American Society for Parenteral and Enteral Nutrition (ASPEN) published consensus recommendations on RFS, thereby offering for the first time standardized diagnostic criteria for future studies. RFS is defined as falls in serum levels of phosphate, potassium, and/or magnesium by 10–20% (mild), 20–30% (moderate), or > 30% (severe), with or without organ damage, within 5 days of resumption of previously strongly decreased caloric intake (2). A significantly decreased caloric intake is defined as a reduced food intake over at least 5 days, meeting less than 50% of the individual patient’s calorie requirements. For the identification of risk patients, application of the British National Institute for Health and Care Excellence (NICE) criteria (9) has become established in clinical practice (Table 1).
There are differing definitions of RFS in the literature, and reliable findings on the incidence of RFS are lacking. This is highlighted by the results of a recent meta-analysis of 35 observational studies (10). Malnourished individuals are at risk of developing RFS. According to the 2019 Nutrition Report of the German Nutrition Society (Deutsche Gesellschaft für Ernährung, DGE), 35% of patients in German hospitals are affected by malnutrition (15% to a moderate and 20% to a severe extent) (11). In the acute medical inpatient setting, multicenter randomized studies show an RFS incidence of 8–14.6% in the feeding of malnourished patients (12, 13).
Diseases associated with malnutrition increase the risk for RFS. These include consumptive diseases (for example, cancer, tuberculosis, HIV), malabsorption and malassimilation syndromes (chronic inflammatory bowel diseases, radiation enteritis, etc.), and psychiatric disorders (alcohol addiction, anorexia nervosa, etc.). Decreased food intake over several days (for example, due to multiple surgical procedures, loss of appetite) or chronic nutrient deficiency following bariatric surgery can also lead to RFS (2, 14, 15). The risk profile of oncology patients for RFS is characterized by weight loss, loss of appetite, persistent inflammation, and multiple medical interventions and is thus particularly unfavorable (16). The fact that chemotherapy is included in the NICE criteria takes this risk profile into account (Table 1). According to current knowledge, the metabolic switch from catabolic to anabolic is relevant from a pathophysiological perspective (more on pathophysiology in Figure 1).
Evidence from randomized controlled studies
For over 50 years, case reports have been published describing the severe courses of RFS, such as cardiac arrhythmias, delirium, and death, in a number of different patient populations (17). A large proportion of scientific investigations into RFS are observational studies. Prospective randomized controlled studies on RFS and its treatment, especially in non-anorexic patients, are rare (14). In German-speaking countries, there is only one secondary analysis of a multicenter randomized controlled study investigating the effect on malnourished medical inpatients of individualized nutritional therapy compared to standard hospital food (18, 19). The secondary analysis of this study on RFS was a planned part of the study design, screened the largest sample to date for the occurrence of RFS (n = 967), and analyzed its clinical outcomes. The secondary analysis compares malnourished patients under individualized nutritional therapy that did not develop RFS (n = 826) with malnourished patients that did develop RFS (n = 141). Patients with RFS exhibited significantly higher 180-day mortality (42/141 [29.8%] versus 181/826 [21.9%], odds ratio [OR] 1.53; p < 0.05), an increased risk for admission to intensive care (6/141 [4.3%] versus 13/826 [1.6%], OR 2.71; p < 0.05), and longer hospital stay (10.5 ± 6.9 versus 9.0 ± 6.6 days; median additional days 1.57; p = 0.01) (12). In addition, a recent meta-analysis on mortality in RFS patients showed a significantly increased 6-month mortality rate (OR 1.54; 95% confidence interval: [1.04; 2.28]) (20).
The therapeutic effects of low-calorie to high-calorie nutritional protocols on RFS have been investigated in randomized controlled studies in intensive care patients, in the normal inpatient setting, in patients on geriatric units, as well as in patients receiving treatment for anorexia nervosa. These studies yielded partially conflicting results.
A multicenter randomized study conducted by Doig et al. investigated 60-day survival in intensive care patients that developed RFS 72 h following commencement of nutritional support and received either caloric restriction (n = 163) or standard nutritional support (n = 164). The group receiving caloric restriction had significantly better 60-day survival (standard nutritional support: 128/164 [78%] versus caloric restriction 149/163 [91%]; p = 0.002) (21). In 2021, Olsen et al. investigated the effect of an intensive nutritional protocol of 20 kcal/kg/day, whereby energy intake was increased to reach the targeted caloric intake within 3 days, compared to a reduced-calorie protocol of 10 kcal/kg/day, whereby energy intake was increased to reach targeted caloric intake within 7 days. The 85 geriatric patients were investigated for hand grip strength, 3-month mortality, and the development of RFS. All patients could be classified as high-risk patients for RFS according to NICE criteria. Nutrition was administered enterally via nasogastric tube feeding. Patients receiving intensive nutrition were more likely to develop RFS (group receiving 20 kcal/kg/day 17.1% versus group receiving 10 kcal/kg/day 9.3%; p = 0.29). The occurrence of RFS was not statistically significant, but patients were significantly more likely to experience respiratory distress (group receiving 20 kcal/kg/day 53.6% versus group receiving 10 kcal/kg/day 30.2%, p = 0.029). There were no differences in hand grip strength or mortality (22). Lower-calorie refeeding had a favorable effect on morbidity and mortality in the investigations carried out by Doig et al. and Olsen et al. (21, 23).
A UK interventional study conducted at two centers investigated the effect of different refeeding rates with a newly prescribed PN on the occurrence of electrolyte disturbances, ECG changes, infections, and hospital stay in patients at risk for RFS. Within the first 48 h, patients at risk for RFS received low-calorie (15 kcal/kg/day) or high-calorie (30 kcal/kg/day) PN, followed by a standard PN regimen of 30 kcal/kg/day in line with standard practice for the two centers. The different refeeding rates had no effect on the endpoints (24). However, the study protocol was significantly hampered by problems during the inclusion of patients. Instead of the planned 225 patients, ultimately only 48 were included in the final data analysis (24). This resulted in small samples in the study arms (for example, moderate RFS risk and high-calorie feeding with 30 kcal/kg/day = 10). It was unlikely that an effect would be demonstrated with this reduced sample size.
Investigations conducted in the US on patients with anorexia nervosa show contrasting results for caloric restriction as a therapeutic intervention in RFS. A multicenter study investigated the effect of oral refeeding on the medical stability of hospitalized patients receiving high-calorie (n = 60, starting at 2000 kcal/day, increasing daily by 200 kcal) compared to low-calorie refeeding (n = 51, starting at 1400 kcal/day, increasing daily by 200 kcal). High-calorie refeeding resulted in faster medical stability during hospitalization (hazard ratio 1.67 [1.10; 2.53]; p = 0.01) (25). Medical stability was determined by heart rate (HR) > 45/min, systolic RR > 90 mmHg, body temperature > 35.6° C, an intact orthostatic response (maximum increase in HR ≤ 35 and maximum decrease in systolic RR 20 mmHg), as well as reaching at least 75% of an age- and sex-adjusted median BMI. RFS did not develop more frequently in the high-calorie group than it did in the low-calorie group (four versus three individuals) (25). The stable long-term study effects that were published in 2022 confirm the robustness of these results (26).
Despite the conflicting results from interventional studies, caloric restriction is the therapeutic feeding intervention recommended in RFS. The reliability of the UK interventional study is reduced by its diminished sample size. It is unclear whether the results from anorexia nervosa patients can be extrapolated to other patients. The mean age of the 111 individuals included in the abovementioned study was 16.4 ± 2.5 years (mean ± standard deviation [SD]) (25). One can assume that the organism of a 16-year-old patient can better tolerate faster refeeding than can a multimorbid patient of more advanced age.
Treatment and monitoring
A number of different recommendations for the prevention and treatment of RFS have been published in Europe and the US (9, 27, 28). The most recent treatment recommendations on refeeding in patients at risk for RFS are the consensus recommendations of the American Society for Parenteral and Enteral Nutrition (ASPEN) published in 2020 (2). These recommend extensive replacement of the required electrolytes and vitamins (in particular vitamin B1) and a stepwise approach to refeeding with a reduced caloric intake (Figure 2) (2, 9, 27, 28, 29). The primary goal of a stepwise reintroduction of nutrition is to prevent RFS, much like prophylaxis. If manifest RFS develops, the further nutrition and replacement therapy follows the recommendations on the refeeding of high-risk patients (Figure 2). Due to the above-mentioned conflicting results from interventional studies, the level of evidence for the recommendations on caloric restriction is based on expert consensus. The increase in caloric intake is determined by the risk for RFS, the patient’s clinical status during refeeding, and the intensity of occurring electrolyte disorders, in particular phosphate. The severity of electrolyte disturbances determines the frequency of electrolyte monitoring and simultaneously serves as a decision-making criterion for increases in caloric intake. In the intensive care setting, monitoring should be adapted to the individual needs of the patient. The initial caloric amount per kilogram body weight is 5–20 kcal/kg/day, depending on the specialist society, whereby the following applies: the higher the risk of RFS, the lower the initial caloric amount per kilogram bodyweight (2, 9, 27). The ASPEN recommends an initial caloric intake of 10–20 kcal/kg/day. There is no recommendation for a restriction of salt, fluid, or protein intake. Usually, the targeted caloric intake can be reached within 7 days.
Diagnostic challenges and the potential offered by clinical decision support systems
As a result of the nonspecific symptoms of RFS, physicians often fail to recognize this clinical picture. If the risk for the development or manifestation of RFS goes unrecognized, it is not possible to initiate clinical steps. This results in vulnerable patients being put at risk (8, 30). Due to its characteristic electrolyte disturbances, RFS lends itself to the development of an automated diagnostic algorithm with a notification system. Automated diagnostic suggestions, complemented by treatment recommendations, can be represented in a CDSS. To date, CDSS are poorly established in clinical nutritional medicine. However, they have already been able to achieve improved compliance with protein and calorie targets (31) and improved glycemic control in clinical nutritional medicine (32, 33, 34). As part of the AMPEL research project (35) (analysis and notification system to improve patient safety through real-time integration of laboratory findings, www.ampel.care), a CDSS of this kind has been newly developed for RFS at the University Medical Center Leipzig (UMCL). It was prospectively tested over a 6-month period (for inclusion and exclusion criteria as well as CDSS development, see the eMethods Section). The CDSS checks adult patients with hypophosphatemia (< 0.84 mmol/L) as to whether other states of electrolyte deficiency in relation to potassium and magnesium have been present in the preceding 5 days. In the case of electrolyte imbalances suspicious for RFS, the CDSS then checks exclusion criteria using laboratory values and coding data pointing to the presence of procedures and comorbidities (for example, terminal kidney failure with dialysis) that cause hypophosphatemia of other etiology (36, 37, 38). In the 6-month exploratory prospective test phase, the CDSS was able to identify 21 individuals with suspected RFS (patient characteristics, Table 2). Their diagnoses were confirmed in subsequent bedside visits. RFS severity was determined on the basis of the ASPEN diagnostic criteria. The distribution of principal diagnoses shows that RFS patients encounter physicians in all specialties (Table 2). According to a telephone survey of the treating physicians, 13 (62%) cases would not have been recognized without a CDSS notification (Table 2, patients above the cut-off line). Determination of the necessary serum electrolytes alone failed to establish the diagnosis in a relevant proportion of patients. Thus, an additional assessment by a CDSS can improve diagnosis, enabling affected individuals to receive nutritional medical support. Due to the low case numbers in the retrospective development phase (100 patients in 30 months, eFigure), neither randomization nor comparison to a control group could be performed in the prospective testing (6 months).
The greatest limitation of the CDSS is the detection of hypophosphatemia as the initiator of the subsequent automated electrolyte analysis. Phosphate determinations are not routine in clinical practice: Only 18% of investigated individuals (n = 13,325, eFigure) had this checked in the retrospective CDSS development phase. Hypophosphatemia was found in approximately a third of these (n = 4186, eFigure). The CDSS is unable to identify patients with RFS without phosphate determination. Thus, it is not possible to determine the proportion of patients recognized as false-negative by the CDSS. The electrolyte disturbances in RFS show a frequency peak 72 h after nutrition therapy (12, 39). The use of the RFS-CDSS in combination with a standardized determination of serum phosphate 72 h following the initiation of feeding, at least in malnourished patients, would be a cost-effective approach to screening (laboratory costs according to the German Uniform Evaluation Standard [einheitlicher Bewertungsmaßstab, EBM] 32 086: 0.40 Euros) to improve the effectiveness of the CDSS. It is also necessary that physicians caring for people at increased risk for the development of RFS educate themselves about this clinical picture. This would enable at-risk patients to be promptly identified and correspondingly treated prior to the initiation of refeeding. Only then is it possible to prevent a hazardous drop in serum electrolyte levels and the development of RFS.
RFS receives insufficient clinical attention. It can occur in malnourished individuals across the entire spectrum of medicine and is characterized by nonspecific symptoms that hamper diagnosis. In severe cases, RFS can cause death. The ability to recognize this clinical picture and identify at-risk patients is relevant to all those treating malnourished patients. The use of CDSS can assist clinically active physicians in establishing its diagnosis. Evidence on the prevention and treatment of RFS is sparse. Current treatment recommendations based on expert consensus include replacement therapy of the necessary electrolytes and other vitamins (in particular, vitamin B1), as well as the reintroduction of feeding in an initially calorie-reduced form. Prospective randomized analyses are needed in the future in order to systematically improve RFS treatment guidelines while taking into account appropriate CDSS.
We would like to thank Kristin Gutsmuths, Carsten Güttich, and Anna-Sophie Junge for carrying out the study visits.
This initiative (eHealthSax guideline No.: 100331796) is co-financed by public funds based on the budget passed by members of the Saxon State Parliament.
Conflict of interest statement
Dr. Heuft, PD Dr. Kaiser, and Dr. Voigt were involved in the development of the CDSS, the clinical implementation of which is reported in this article.
Other research partners in this project publicly funded under the eHealthSax guideline No.: 100331796 include the Muldental Clinics in Grimma and Wurzen as well as Xantas AG. Upon completion of the project, the option exists to transform the CDSS into a product. All research partners have independent and autonomous access to the knowledge gained.
The remaining authors declare that no conflict of interest exists.
Manuscript received on 31 May 2022, revised version accepted on 15 November 2022.
Translated from the original German by Christine Rye.
Dr. med. Lara Heuft
Institut für Humangenetik
Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany
Cite this as
Heuft L, Voigt J, Selig L, Stumvoll M, Schlögl H, Kaiser T: Refeeding syndrome—diagnostic challenges and the potential of clinical decision support systems. Dtsch Arztebl Int 2023; 120: 107–14. DOI: 10.3238/arztebl.m2022.0381
** Joint last authors
Institut für Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig Medical Center, Leipzig, Germany: Dr. med. Lara Heuft, Dr. rer. nat. Jenny Voigt, Prof. Dr. med. MaHM Thorsten Kaiser
Institute for Human Genetics, University of Leipzig Medical Center, Leipzig, Germany: Dr. med. Lara Heuft
Department of Endocrinology, Nephrology, Rheumatology, Division of Endocrinology, University of Leipzig Medical Center, Leipzig, Germany: M. Ed. Lars Selig, Prof. Dr. med. Michael Stumvoll
Department of Endocrinology, Nephrology, Rheumatology, Special Division of Endocrinology, University of Leipzig Medical Center, Leipzig, Germany Klinik und Poliklinik für Endokrinologie, Nephrologie, Rheumatologie, Spezialbereich Ernährungsmedizin, Universitätsklinikum Leipzig: M. Ed. Lars Selig, Prof. Dr. med. Michael Stumvoll, Dr. med. Haiko Schlögl
Helmholtz Institute for Metabolic, Obesity, and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig, and the University Hospital Leipzig, Leipzig, Germany: Prof. Dr. med. Michael Stumvoll, Dr. med. Haiko Schlögl
Institute for Laboratory Medicine, Microbiology, Clinical Pathology, and Pathobiochemistry, University Hospital Lippe, Detmold, Germany: Prof. Dr. med. MaHM Thorsten Kaiser
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