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

AN is reported by 1-4% of women and 0.3 – 0.7% of men in Europe. 2-3% of women have subthreshold eating disorders¹. AN is a serious illness leading to substantial morbidity and mortality. The standard mortality ratios for patients with AN and a psychiatric comorbidity are 5.4 (95% confidence interval ^{CI 95%}: 4.6-6.4) and 18.1 (CI 95%: 15.2-21.3) for natural and unnatural causes of death, respectively².

The treatment of AN is often protracted with repeated hospitalizations. Nutritional refeeding is the first therapeutic step to recovery. In case and cohort studies different low and high-calorie diet protocols exist^{3, 4}. There are well known major complications during weight-restauration - called refeeding syndrome: a shift of electrolytes and fluid can occur in malnourished patients leading to (potentially fatal) cardiovascular, respiratory and neurological symptoms. However, prospective and retrospective studies showed that higher calorie diets instituted at admission predicted faster weight gain and less hospitalization in patients with AN^{5, 6, 7, 8, 9}. Such a rapid refeeding protocol was well tolerated with no indicators of refeeding syndrome. 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 offspring¹⁵. In 2007 Rigaud et al proved an above average increase in the thermic effect of food (TEF), ACTH, cortisol, norepinephrine and dopamine levels in AN patients after an injected gastric load¹⁶. However, none of the explanatory models of the pathophysiology has resulted in a concrete treatment plan for AN.

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 expenditure¹⁷.

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}.

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 significance threshold accounted for p=0.05. All statistical analyses were performed using SPSS 23 for Windows.

Due to different courses of disease, the length of admission of our patients varied. The in-patient care time averaged out to 30 days (as seen in Table 1). As for the major component of our statistical analysis, weight gain, we decided to make a cut after 25 days. Choosing a later moment would have shrunk the number of patients for statistical analysis, whereas an earlier moment might not have shown different impacts of our treatment regimens.

During in-patient care neither refeeding syndrome nor other severe complications such as hypophosphatemia or hypokalemia were observed in any patient.

All ratio variables shown in table 1 except ‘length of stay’ ‘RMSSD’ and ‘disease length’ were normally distributed. When we compared vegetarians versus carnivores all major baseline variables were normally distributed.

At the end of our chosen monitoring time frame of 25 days, weight gain was 121.4% higher in the highly standardized refeeding group than in the historical control group (66.5 ±52.4 vs 147.3 ±55.7g/day; t-Test p=0.004; CI95%: 29.3-132.2)(Table 2)

In order to visualize and make our study groups more comparable in spite of different baseline values, we studied weight during different days in relation to weight at admission (as seen in Table 3). On day 12 we observed a significant difference between the historical control and the highly standardized refeeding group using unpaired student t-test (p=0.04 CI95%: 0.2-4.9). Over the course of time the p-value decreased.

Based on anamnesis the weight before disease could be determined for 21 out of the 27 AN patients. At discharge, group 2 patients had reached 84.1% (SD: ±4.4) of their original weight compared to 82.3% (SD±10.0) by group 1 patients despite group 2 patients having a lower baseline value (74.4% ±6.3 vs 78.1% ±10.0). Nevertheless, only a single Phase 2 reached a BMI at discharge higher than 18.5 kg/m².

In accordance with Bardone-Cone et al we observed a high rate of AN patients were vegetarian. About 45% of our patients stated eating some form of vegetarian diet. One patient out of the 27 patients ate meat products irregularly and two AN patients were pesco-vegetarian. During refeeding at our hospital unit there was no attempt to convince patients of a meat diet.

With the Kolmogorov-Smirnov-Test we showed that all variables except ‘length of stay’, ‘RMSSD’ and ‘length of disease’ were normally distributed. Using student t-test we found a significant difference in the length of disease between vegetarians and carnivores (14.63 ±9.81 versus 7.70 ±3.37 months). Although we could only detect small differences in mean calorie intake/kg/day and mean calories/day, we found that vegetarians gained less weight on average than carnivores (1.35 ±2.37 versus 1.81 ±1.42 kg). However, this incongruence was not statistically significant (unpaired student t-test).

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).

Figure 2.Necessary caloric intake for weight gain rises during refeeding. Dashed line depicts caloric intake in kcal/kg/day while solid line shows weight gain per day in % of bodyweight

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, at a time when high energy liquid nutrition was replaced by a diet according the patient’s wishes.

Figure 3.A carbohydrate rich diet improves weight gain Weight gain in 21 patients with a carbohydrate rich diet > 50% and in 16 patients with < 50% carbohydrates according the patient’s own wishes. Daily caloric intake is comparable (9 931 ±251 versus 9 416±247 kJ / 2 372 ± 60 versus 2 249 ± 59 kcal). Unpaired student t-test:p=0.03 for day 20 and p=0.01 for day 25) Carbohydrate rich diet: 14.93% (±2.83) protein, 24.13% (±8.32) fat, 58.38% (±6.85) carbohydrates Carbohydrate poor diet: 14.97% (±3.89) protein, 34.02% (±11.94) fat, 41. 19% (±3.35) carbohydrates

This retrospective analysis is result of an internal quality management process of in hospital weight restitution in adolescents suffering from AN. As we were dissatisfied with the weight gain of our patients using a standard refeeding protocol we decided to introduce additional nutritional interventions beginning in January 2013. Our first analysis in 2015 showed a clear trend of improved weight gain but the therapy was still heterogeneous since the entire team did not stick to the changes of the new treatment plan. As a consequence, we implemented supervision by an experienced psychologist in which all professional groups participated. Our team now agreed on a standardization of the treatment protocol and a re-examination of the therapeutic results after one year.

Indeed, we were then able to show a significantly improved weight gain in 11 consecutive patients with AN who were treated with our new refeeding protocol. We did not need a nasogastric tube or anxiolytic medications in ten of the eleven patients. Together with the liberalization of our surveillance routines our refeeding protocol is extremely comfortable for the patients. For methodological reasons it must be stressed that in the past six years there have been no relevant personnel changes in the team.

In summary, we recommend introducing high energy liquid nutrition with a sufficient share of carbohydrates and nutritional supplements including omega-3 fatty acids for an improved weight gain during refeeding. Because of an increasing energy turnover during refeeding, caloric intake should be adjusted. In terms of a rapid weight gain nasogastric tube refeeding remains the benchmark. Nevertheless, regarding the disagreeableness accompanied by tube refeeding, the pros and cons should always be studied for each patient before inserting a nasogastric tube.

For a better understanding of the AN pathophysiology we are now analyzing the 24-hour ECGs.

We would like to thank Kate Keller, student of University of Oregon, USA, for editorial support.

Affiliations

Christoph Baumann: University of Wuerzburg, Medical Faculty, Josef-Schneider-Straße 2, Würzburg, Germany

Christian Willaschek, Tuende Kertess-Szlaninka, Lang Johanna, Reiner Buchhorn: Caritas-Krankenhaus Bad Mergentheim, Department of Pediatrics, Uhlandstraße 7, Bad Mergentheim, Germany

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