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Implementing High Energy Liquid Nutrition, Omega-3 fatty acids and Nutritional Supplements for the Treatment of Anorexia Nervosa

Objective: To assess the effect of different treatment approaches on the course of anorexia nervosa (AN) over time. Methods: The subjects were 27 hospitalized AN patients. In our retrospective analysis we compared weight gain in two groups. While one group was treated with a standard oral refeeding protocol (historical control) through January 2013 (N=16), the second group (highly standardized refeeding protocol) received a high energy liquid nutrition and nutritional supplements including omega-3 fatty acids (N=11). Results: On admission, the two groups were comparable in terms of height, weight, age and heart rate. At the end of our monitoring time frame of 25 days, weight gain was 121.4% higher in the highly standardized refeeding protocol group than in the historical control group (66.5 ±52.4 vs 147.3 ±55.7 grams/day; t-Test p=0.004; CI95%: 29.3-132.2). A carbohydrate rich diet clearly improved weight gain if high energy liquid nutrition was replaced by the diet according the patient’s own wishes. About 45% of our patients stated they were vegetarians at admission. However, we could not identify a vegetarian diet as a statistically significant negative prognostic factor for weight gain. Conclusion: The highly standardized refeeding protocol seems to be helpful in malnourished AN patients to improve weight gain without enhancing the risk of a refeeding syndrome. However, further studies with greater number of patients are needed to confirm the effectiveness of our standardized treatment protocol. Corresponding author: Christoph Baumann, Julius-Maximilians—Universität Würzburg, Gutenbergstraße 2, 97080 Würzburg, Germany, Tel: +491757019415, E-Mail: christoph.baumann1993@gmail.com

Particularly in prospective and randomized trails, tube refeeding proves to be the most effective method for gaining weight without major complications 10,11 .
Nevertheless, the underlying etiology and pathogenesis as well as the mechanism of weight restauration are still poorly understood.
Genetics and environmental factors appear to play an important role in the pathogenesis and etiology of AN. The HTR1B gene (5-hydroxytryptamine receptor 1B) possibly has an effect on the 'severity of anxiety in AN-spectrum patients' 12 . Additionally, recent prospective studies in humans show a link between maternal stress and the development of eating disorders 13,14 .
Emack and Mathews suggested in an animal study that 'acute phases of maternal stress in late pregnancy' had a significant impact on hypothalamus pituitary adrenal axis (HPA) function in adult offspring 15  In our own pathophysiological model we proceed on the assumption that AN patients suffer from an autonomic imbalance. We noticed that during refeeding almost all HRV-parameters changed. It seems that AN patients experience a shift from parasympathetic to sympathetic during refeeding which comes along with a higher resting energy expenditure 17 .
In this study, we examined the effects of two different treatment approaches over the course of AN.
We stepwise changed our treatment protocol by introducing high liquid energy nutrition, omega-3 fatty acids and nutritional supplements according to the NICE protocol. Until now no study has examined the effect of omega-3 fatty acids on the course of AN. Even so studies with heart disease and cancer patients have shown an improved weight gain or a decrease in weight loss under supplementation of omega-3 fatty acids [18][19][20] .

Methods and Patients:
We retrospectively analyzed the clinical charts of all consecutive patients admitted for hospital

Statistics
All patients who were admitted in our unit and agreed to the current protocol contributed data to our statistical analysis. Our primary end goal was weight gain. We also measured diet composition, energy intake, body composition and HRV-parameters. Due to staff shortage, the data for these secondary outcomes were partly fragmented. Moreover we could only capture the exact amount of calories eaten by AN patients who were in our hospital between June 2014 and January 2016 (N=22).
We checked the assumption of normality by using the Kolmogorov-Smirnov-Test and viewing boxplots and q-q diagrams. We compared our two groups using unpaired student t-test. The statistical  In contrast we found a strong correlation between daily mean calorie intake and weight gain until day 20 (Pearson r=0.44 p=0.04). As seen in figure 2 many patients initially lost weight. Over time our patients gained weight more rapidly. However, at some point most patients stopped gaining weight as rapidly.
This occurred especially from day 15-20 when we observed a very low rate of weight gain per kcal compared to day 5-10 (0.02 g/kcal vs 0.11 g/kcal; paired student t-test p=0.00).
Moreover, we observed a significant better weight gain in 21 patients who received a high-carbohydrate diet with more than 50% carbohydrates and concomitantly lower fat as shown in figure 3. The better weight gain starts after two weeks,    Compared to other refeeding protocols the study conducted by Rigaud et al showed the best weight gain by nasogastric tube feeding and seems to be the current "gold standard". We proved that oral high energy liquid nutrition can have a comparable benefit (Figure 1)  These beneficial effects of omega-3-fatty acids on heart rate variability occur in children as well 36 . We implemented omega-3 fatty acid supplementation in our refeeding protocol for all patients in group 2.
For a better understanding we routinely use Holter ECG monitoring to detect the switch of the autonomic nervous system from the so called 'hibernating circuit' with low heart rates and high HRV to the stress reaction with higher heart rates, low HRV and probably a higher resting energy expenditure after the first ten days of refeeding. Beneath the metabolic changes in our view the 'hibernating circuit' seems to delete the emotional memory of the patients, which is reawakened during nutritional rehabilitation 37  However, we were happy to deescalate our refeeding in patients with AN and improve weight gain with the current refeeding protocol.

Conclusions
In summary, we recommend introducing high energy liquid nutrition with a sufficient share of carbohydrates and nutritional supplements including