Refeeding syndrome in small ruminants receiving parenteral nutrition

Abstract Background Small ruminants presented to tertiary care facilities commonly suffer from severe protein‐calorie malnutrition. Some of these patients require parenteral nutrition (PN; amino acids and dextrose with or without lipids) during hospitalization. Refeeding syndrome, a potentially fatal shift of electrolytes seen in malnourished patients during refeeding, may occur. Objective (a) To report the prevalence of refeeding syndrome in small ruminants receiving PN and (b) to determine risk factors for the development of refeeding syndrome. Animals Hospitalized small ruminants (n = 20) that received PN from 2010 to 2018 and that had serial (≥2) monitoring of serum electrolyte concentrations after initiation of PN. Methods Retrospective case series. Refeeding syndrome was defined as the presence of at least 2 of the following electrolyte abnormalities after initiation of PN: hypophosphatemia, hypokalemia, hypomagnesemia, or some combination of these. Data was analyzed using Fisher's exact test, followed by univariate logistic regression. Results Eleven of 20 (55%) animals met the definition of refeeding syndrome. Mean minimum serum phosphorus concentration in animals with refeeding syndrome was 1.96 ± 0.69 mg/dL (reference range, 4.2‐7.6 mg/dL). Eleven of 20 animals survived to discharge. Survival rate did not differ significantly between refeeding cases (4/11, 36.3%) and nonrefeeding cases (7/9, 77.8%; P = .09). Mean serum phosphorus concentration was significantly lower in nonsurvivors than in survivors (1.88 ± 0.10 mg/dL vs 4.32 ± 0.70 mg/dL, P = .006). Conclusions and Clinical Importance We report the prevalence of refeeding syndrome in small ruminants receiving PN. Clinicians should anticipate refeeding syndrome after initiation of PN and consider pre‐emptive supplementation with phosphorus, potassium, magnesium, or some combination of these.


| INTRODUCTION
Small ruminants presented to tertiary care facilities often suffer from severe protein-calorie malnutrition related to severe endoparasitism, catabolism associated with an underlying disease process, or poor animal husbandry. With the rising popularity of small ruminants as pets and as the focus of social media rescue groups, malnourished small ruminants are becoming more frequent patients seen in veterinary practice. Refeeding syndrome, a shift in electrolytes in malnourished patients being refed, is a possible complication of increased nutrition in these veterinary patients. 1 Refeeding syndrome was first described in prisoners of war after World War II. 2 The hallmark feature of refeeding syndrome is hypophosphatemia, although the syndrome involves changes in potassium, magnesium, sodium and fluid balance, thiamine deficiency, and changes in glucose, protein, and fat metabolism. 1 In humans, refeeding syndrome most commonly is seen after prolonged starvation, in anorexia nervosa patients, patients with chronic alcoholism, obese patients undergoing massive weight loss, oncology patients undergoing chemotherapy, or in the refeeding of malnourished elderly patients. 3,4 Complications of refeeding syndrome are numerous and include electrolyte derangements, cardiac complications, and neurologic conditions. 3,4 The incidence of refeeding syndrome is highly variable depending on the study population. In a study of human internal medicine patients, 8% of the study population developed refeeding syndrome, whereas 54% of the patients were deemed to be at risk of developing refeeding syndrome. 5 Little information is available in the literature regarding refeeding syndrome in veterinary species. Refeeding syndrome has been reported in case reports of cats. 6,7 In a study of dogs, researchers induced hypophosphatemia and neurologic abnormalities in starved dogs fed via intragastric catheter. 8 In large animal species, limited information is available regarding refeeding syndrome. A retrospective study evaluating parenteral nutrition (PN) in alpacas reported refeeding syndrome in 3 of 21 alpacas. 9 One study evaluating PN in neonatal foals reported complications including hypertriglyceridemia and catheter-related complications, but no changes in serum electrolyte concentrations consistent with refeeding syndrome, 10

| Statistical analysis
Statistical analysis was performed using standard statistical software (Stata 15.1MP, StataCorp, College Station, Texas; WinSAAM, University of Pennsylvania, Kennett Square, Pennsylvania). Data were assessed for normality using the Shapiro-Wilk test for normality. Categorical data were analyzed using Fisher's exact test to evaluate the association between survival and refeeding syndrome. For all independent variables, univariate logistic regression was performed to confirm the association with the outcomes of interest, survival and the occurrence of refeeding syndrome. All analyses were conducted using 2-sided tests of hypotheses and a P-value of <.05 was set as the criterion for statistical significance.
Parenteral nutrition was prepared using a standard formula of 5 g/kg/day dextrose, 2 g/kg/day amino acids, and 1 g/kg/day lipids (n = 17) or 10 g/kg/day dextrose, 2 g/kg/day amino acids, and 1 g/kg/ day lipids (n = 1), based on previously published formulas 12 and at the discretion of the attending clinician. In 18 animals, these formulations provided 34 or 51 kcal/kg/day, respectively, and therefore provided a mean of 1.08 ± 0.23 × RER (range, 0.72-1.5 × RER) based on the standard calculation of 70 × (body weight in kg) 0.75 . Two animals received PN consisting of dextrose and amino acids without lipids, formulated to provide 5 g/kg/day dextrose and 2 g/kg/day amino T A B L E 1 Mean ± standard deviation electrolyte concentrations prior to and minimum concentration after initiation of parenteral nutrition (PN) in 20 small ruminants Eleven of 20 (55%) animals survived to discharge. Survival rate was lower in refeeding syndrome cases (4/11, 36.3%) compared to nonfeeding syndrome cases (7/9, 77.8%), but the difference was not In both human and veterinary medicine, a single accepted definition of refeeding syndrome is lacking. In general, refeeding syndrome is defined as severe electrolyte shifts in malnourished patients undergoing enteral or parenteral refeeding. 4 In human medicine, the incidence of refeeding syndrome varies in different studies, partly because of the lack of a universally accepted definition. One study found that 34% of human intensive care patients experienced refeeding hypophosphatemia. 13 Another study evaluating all hospitalized human patients on artificial nutrition found an incidence of 1%. 14 In veterinary medicine, limited information is available regarding the occurrence of refeeding syndrome. A number of reports in horses have evaluated PN, with most studies reporting no or few electrolyte abnormalities consistent with refeeding syndrome, regardless of age. 10,11 In retrospective studies of PN in horses, the most common findings were hypertriglyceridemia and catheter-associated complications. 10,11,15 Studies evaluating PN in calves similarly do not report the occurrence of refeeding syndrome. 16 In a more recent study evaluating PN in nondomestic ruminants, 13 of 24 animals developed metabolic complications, including hypokalemia in 5 animals and hypophosphatemia in 3 animals. 17 In that study, all animals that developed hypophosphatemia or hypokalemia died or were euthanized.
Notably, the small ruminants included in our study differ substantially with regard to their gastrointestinal physiology and carbohydrate metabolism as compared to monogastric species such as horses and humans, which make up the majority of literature regarding refeeding In conclusion, refeeding syndrome occurs in approximately half of cachectic small ruminants receiving total or partial PN. Clinicians should anticipate refeeding syndrome after initiation of PN and consider pre-emptive supplementation with phosphorus, potassium, magnesium, or some combination of these electrolytes.

CONFLICT OF INTEREST DECLARATION
Authors declare no conflict of interest.

OFF-LABEL ANTIMICROBIAL DECLARATION
Authors declare no off-label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION
Authors declare no IACUC or other approval was needed.

HUMAN ETHICS APPROVAL DECLARATION
Authors declare human ethics approval was not needed for this study.