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Prognosis in 41 severely malnourished anorexia nervosa patients
Clinical Nutrition 31 (2012) 693e698
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Original article
Prognosis in 41 severely malnourished anorexia nervosa patients Daniel Rigaud*, Isabelle Tallonneau, Marie-Claude Brindisi, Bruno Vergès Service d’Endocrinologie-Nutrition, CHU Le Bocage: 2, Bd du Maréchal de Lattre de Tassigny, 21000 Dijon, France
a r t i c l e i n f o
s u m m a r y
Article history: Received 13 October 2011 Accepted 25 February 2012
Background & aims: To report the prognosis in 41 anorexia nervosa (AN) patients suffering from very severe malnutrition (mean BMI: 10.1 0.57 kg/m2). Patients and methods: Compared with 443 less malnourished AN patients, the 41 patients were older (27.8 5.4 vs 22.4 2.1 yrs), their AN was longer (9.6 3.4 vs 5.0 1.5 yrs) and more often of the restrictive subtype (P < 0.05). Results: In 27% of the patients, all nutritional marker levels were in normal range. All patients received a prudent tube-refeeding: energy was increased from 12 to 40 kcal/kg/day, protein from 1.0 to 1.5 g/kg/ day within 10 days. During stay, 1 patient died, 2 others suffered from myocardial infarction, 2 others from acute pancreatitis, and 5 from mental confusion. Compared with the other 443 AN patients, the 40 remaining patients had worse 6-yr prognosis: 2 died (7% vs 1.2%), 29% had severe outcome (vs 10%), and only 41% recovered (vs 62%). Conclusion: In AN patients with BMI < 11 kg/m2, a prudent tube-refeeding could avoid short-term mortality, but long-term prognosis was bad. Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Anorexia nervosa Tube feeding Refeeding syndrome Enteral nutrition Malnutrition
1. Introduction Anorexia nervosa (AN) is a chronic and severe eating disorder. In Burgundy (France), its frequency was estimated at 1.6% of the 25e45-yr old girls and young women.1 AN was defined as the follow: 1 e a refusal to gain or maintain body weight at or above a minimally normal weight for age and height, 2 e an intense fear of gaining weight or becoming fat, even though under weight, 3 e a disturbance in the way one’s body weight or shape are experienced, an undue influence of body weight or shape on self evaluation, or denial of the seriousness of the current low body weight, 4 e amenorrhoea (at least three consecutive cycles). Weight loss was, at the meaning of these patients, the only way for obtaining their self-esteem. The fear of becoming fat increased month after month, pushing the patient into more intensive restricting dieting. At least one third of the patients are unable to eat during meals any sugar and sweet, added fat and fatty food, meat and fish, cheese, starchy food and bread, milk and cheese. This very low calorie diet was responsible to a very low intake of a lot of macronutrients and micronutrients: total protein, essential amino acids, total fat, essential fatty acids, calcium, phosphorus, iron, zinc and vitamins.
In many cases, this diet is responsible for malnutrition. The frequency and the severity of this malnutrition could be increased by excessive physical exercise, which occurs in 40e60% of the AN patients,2 and by purging (i.e. self vomiting), which occurs in 30e40% of the patients (both during and beside binge eating). About 5e15% of the AN patients died after 10 years of the condition.3,4 This is mainly due to the malnutrition, in particular in the restricting type of the disease.3,4 AN is one of the most frequent causes of malnutrition in girls and young women. It is not unusual to find patients with a body mass index (BMI) lower than 13 kg/m2. It was suggested in the past that a BMI lower than 10e11 kg/m2 was the limit of life in adults.5 Furthermore, the refeeding syndrome could increase the risk of dead in the most severely malnourished patients.6e9 No studies have reported the short-term and longterm prognosis of these patients. So, we would like to report our experience in 41 very severely malnourished AN adult patients hospitalized for malnutrition in our Nutrition unit. All these patients had a BMI < 11 kg/m2 at admission and were followed-up more than 6 years. 2. Patients and methods 2.1. Patients
* Corresponding author. Tel.: þ33 3 80 29 52 72; fax: þ33 380 293519. E-mail addresses: [email protected] (D. Rigaud), isabelle.tallonneau@ chu-dijon.fr (I. Tallonneau), [email protected] (M.-C. Brindisi), [email protected] (B. Vergès).
The main characteristics of these 41 patients were compared with those of 443 less malnourished AN patients (Table 1) followed during the same period.10 The 41 very severely malnourished
0261-5614/$ e see front matter Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. doi:10.1016/j.clnu.2012.02.016
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D. Rigaud et al. / Clinical Nutrition 31 (2012) 693e698 Table 1 Comparison of baseline demographic and clinical characteristics of women with severe and less severe malnutrition hospitalized for treatment of anorexia nervosa.
Number Sex Height (cm) Weight (kg) BMI at admission (kg/m2) Age at admission (median, extremes) Age at the first symptoms (yrs) Duration of AN (yrs) Physical hyperactivity (recently) Restrictive form Vomiting without binge Binge-eating/purging form Severe anxiety (Hamilton score>40) Severe depression (Beck score>20) Personality disorders
BMI < 11 kg/m2
BMI 11 kg/m2
41 39 women (95%), 2 men 160 3a 25.9 1.4b 10.1 0.57 (8.8e10.9)b 28.9 5.4 yrs (25 yrs; 17e45)a 18.2 4.7 (19 yrs; 14e31) 9.6 3.4 (7 yrs; 1.4e25.0)a 35 (85%)c 35 (85%)c 5 (12%) 1 (5%) 9 (22%)c 4 (10%)c 1 (2%)
443 428 women (96%), 15 men 165 5 39.7 þ 5.7 14.6 2.2 (11.1e17.0) 24.3 6.1 yrs (22 yrs; 15e32) 17.5 2.3 (19 yrs; 15e28) 5.0 1.5 (4 yrs; 1.1e14.5) 332 (60%) 317 (57%) 77 (14%) 159 (36%) 202 (37%) 102 (23%) 23 (4%)
Mean SD (median; extremes). The Hamilton and Beck scores were two validated scores. Maximal Hamilton anxiety score is 56 and maximal depression Beck score is 36. Physical hyperactivity was defined using a 8-items questionnaire. Personality disorders: diagnosis by psychiatric interview. a P < 0.05 (Student t test). b P < 0.001 (Student t test). c Chi-2 (P < 0.05).
patients represented 8.5% of this cohort. They were older, had a longer duration of AN and were more likely to have the restricting form of the disease; they were also more likely to be overactive, and less likely to be very anxious or depressed than were the 443 others (Table 1; P < 0.05 for all).
vitamin B1: 100 mg) and fifty (50 mL) intravenous lipids (IntralipidÒ 20% or IvelipÒ 20%), the latter to correct essential-fatty acids insufficiency. Enteral mixture (SondalisÒ, NutrisonÒ or NormoréalÒ) was intragastrically infused at the mean rate of 25 kcal/kg/day (extr: 21e25 kcal/kg/day).
2.2. Methods
2.3.3. Days 4 and 5 Energy intake was increased to 35 kcal/kg/day (extr: 780e950 kcal/day), including 100 mL intravenous lipids (200 kcal). Micronutrients were intragastrically infused at the above dose and phosphorus increased (added, PhosphoneurosÒ: 20 drops 2/day intragastrically), according to phosphorus plasma level. No food was allowed.
All the 41 patients were hospitalized in emergency in a specialized Nutrition unit with a large experience in renutrition of such AN patients. Our unit is not an intensive care unit. Among these AN patients, only two needed to be admitted after one to two days in the intensive medical care unit for multiple organ failure (see below). In each patient, we measured body weight each day, resting energy expenditure, body composition and biological markers as seen below. 2.3. Nutritional rehabilitation Our schedule was codified and summarized in guidelines for medical staff from 1992. All values are given by reference of actual body weight. It was (and it is) the following. 2.3.1. Day 1 A catheter was inserted into a cubital vein (or, if needed, in a central vein). An intravenous infusion of glucose was prescribed, with 30e40 mL/kg body weight of water/day and no more than 3 g glucose/kg BW/day. Phosphorus (0.20 mmol/kg BW/24 h, phosphate di-potassique), KCl (0.1 g/kg/day), sodium (NaCl, max: 2 g/day, except in the case of vomiting and dehydration), vitamins, minerals (iron, selenium, zinc.) were added in the form of parenteral solution (CernévitÒ, NonanÒ or similar). 2.3.2. Day 2 A chariere-08 or 09 nasogastric tube was positioned in the distal part of the stomach and its position controlled (nasal mark: 70 cm; radiography for control). Except in the case of patent dehydration, sodium input did not exceeded 3 g/24 h. No food was allowed. Were intravenously infused water (max 40 ml/kg/24 h), sodium (<3 g/24 h), phosphorus (Phocytan: glucose: 1 g, phosphate 6.6 mmol, phosphorus: 200 g, Naþ: 0.8 g), calcium (500 mg), trace elements and vitamins (DecanÒ and CernevitÒ: one bottle plus
2.3.4. Days 6e10 Generally, intravenous infusion was stopped. Energy intake was maintained at 35e40 kcal/kg/day. Other intakes (minerals, trace elements, vitamins) were at this time infused via the nasogastric tube. Potassium was increased in cases of hypokaliemia. Sodium input was maintained at <3 g level per day, except in 6 patients: 3 for diarrhoea, 1 for vomiting, 1 for fever and 1 for tubular sodium loss. During this 10-day period, body weight should not increase by more than 100 g/day, since energy input was at the level of energy expenditure. 2.3.5. Days 11e21 Foods were introduced, in the form of small meals (around 300e400 kcal/day) having a low-sodium content (<4 g/day). Energy intake was calculated each day in order to give no more than 45 kcal/kg actual BW/day, including enteral feeding, until the 20th day. For example, for a body weight of 30 kg, the maximal energy need was calculated (1350 kcal/day): if energy intake by meals reached 850 kcal, tube feeding input was reduced to 500 kcal/day. The daily calcium and phosphorus doses were 500 and 300 mg, respectively (except in cases of deficiency). During these 3 weeks, no psychotropic drug was allowed. From the 4th week onwards, energy intake was determined as the energy needs þ700e1000 kcal/day, in order to obtain a BW gain from 0.7 to 1.0 kg/week. Daily energy need was calculated as resting energy expenditure (REE, measured) 1.5. The diet was a low-sodium diet with no more than 6 g NaCl/day, until a 15-kg/m2 BMI was obtained.11
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2.4. Biological measures During the first 10 days, were measured daily creatinin, Naþ, Kþ, Cl, CO 2 , phosphorus, Caþþ, creatinin, and urea. Electrocardiogram was performed each day. Thereafter, blood was drawn twice a week during 2 weeks, then once a week. Every 3 days, then once a week, we also measured ALAT and ASAT, red and white blood cells, platelets, albumin, transthyretin transferrin, haemoglobin, and iron. Every week, the 48 h-urinary output of Naþ, Kþ, creatinin, and urea were measured. Body weight was measured every 2 days in a hospital gown, after urine voiding, while the patient was fasting (Scale Seca 770 alpha Intellisense, UK). Height was measured by a stadiometer using a Seca scale (model 222, UK), as soon the patient was able to stay in upright position. Body composition was estimated each week using both a 2-frequency (5 kHz and 1 MHz) bioelectrical impedance analysis with a portable 2-subcutaneously electrode impedancemeter12 and skinfold thickness at 4 sites (Harpenden calliper, John Bull Inc., UK), as published by Pollock et al.13: it was measured at the 4 classical areas (triceps, biceps, subscapular, suprailiac). Then body FM and FFM were calculated as follow: body density ¼ 1.1599 (0.0717 (log S)), where S is the sum of the 4 skinfold. From bioelectrical impedance, we estimated fat-free mass (FFM) and fat mass (FM), as well as total, extracellular and intracellular body water, as published by Boulier et al.12 We measured REE by indirect calorimetryusing the Deltatrac II, Datex-Ohmeda, as previously published,14 in 33 patients. These patients, who were in a fasting state (tube feeding and oral feeding stopped at 22.00 h), were placed in a quiet room. After 20 min rest, REE was recorded for 20 min with the patients in a supine position. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured by open-circuit indirect calorimetry with a ventilated-hood system (mean flow rate 50 5 L/min). Oxygen concentration was assessed using a differential paramagnetic analyzer (Klogor, Lannion, France), and carbon dioxide concentration with an infrared analyzer (Hartmann and Braun Instruments, Frankfurt, FRG). Gas flow was measured with a linear mass flowmeter (Setaram, Lyon, France) and raw data were continuously recorded on line every 30 s. Gas exchanges were calculated as the product of gas flow and the differences in both oxygen and carbon dioxide concentrations
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in room air and expired gas, using continuous monitoring of gases at the inlet and the outlet of the ventilated hood. Corrections were made for the effects of the respiratory quotient (RQ) on gas flow measurements. Before each measurement, the system was calibrated with 21% oxygen and a mixture of 99% nitrogen and 1% carbon dioxide. The system was checked regularly by burning butane: the mean recovery of oxygen and carbon dioxide was 98 1% and 99 1%, respectively, and the RQ for butane was 0.614 0.003. The reproducibility was >96%. REE was calculated according to Ben Porat et al.15 This study reported data from a clinical survey, so the approval of an ethical committee was not required. 2.5. Statistical analyses In order to compare the two groups of AN patients, we used Student t test and chi-2 test. Statistical analyses were done with SPSSÒ. (Statistics Standard 12.0.1). The state of outcome formed the dependent variables. Its association with independent variables (prognosis factors) was explored by analysis of variance (ANOVA), then chi-2. 3. Results 3.1. At hospital admission 3.1.1. Clinical findings Some characteristics of the 41 patients are shown in Table 1. Malnutrition was clinically very severe at admission: major wasting of muscle masses, disappearance of any subcutaneous fat mass, emaciated face, alterations of skin, nails and hair were in all patients. Stomatitis and cheleitis were observed in 35 and 39 patients, respectively (85% and 95% of the patients), melanoderma in 32 (78%), severe hair loss in 13 (32%) and hemorrhagic gum in 10 patients (24%). 3.1.2. Biological findings Biological abnormalities were frequent but not constant. This contrasted with the normality of biological markers in most of the less malnourished AN patients (Table 2). Low serum or plasma level
Table 2 Comparison of baseline biological measures of women with severe and less severe malnutrition hospitalized for treatment of anorexia nervosa. Blood or serum
BMI < 11 n ¼ 41
% Abnormal findings
BMI 11 n ¼ 443
% Abnormal findings
Red blood cells (<3.3 M/mm3) Haemoglobin (<11 g%) White blood cells (<5.000/mm3) Lymphocytes (<1.500/mm3) Platelets (<100.000/mm3) Iron (<10 mmol/L) Ferritin (<20 ng/mL) Glucose (<0.60 g/L) Phosphorus (<0.60 g/L) Calcium (<2 mmol/L) ALAT (>30 UI/L) ASAT (>40 UI/L) Creatinin (>70 mmol/L) Sodium (<135 mmol/L) Potassium (<3.0 mmol/L) Albumin (<35 g/L) Transthyretin (<0.20 g/L) Transferrin (2.0 g/L) Haptoglobin (<0.70 g/L)
3.1 1.0b 9.9 2.4b 3700 1150a 1180 580b 188 126a 11 6 20 10b 0.58 0.12c 0.64 0.24b 2.06 0.23a 145 (28e1025)b 91 (22e943)b 85 15a 134 17c 4.5 0.2 31.2 0.37c 0.16 0.9b 1.75 0.63b 0.57 0.44c
26% 32% 22% 36% 10% 27% 41% 54% 35% 31% 70% 39% 48% 37% 4% 75% 69% 71% 78%
4.2 0.6 14.4 1.2 5970 1800 1890 720 246 108 19 7 39 13 0.87 0.15 0.87 0.15 2.31 0.18 25 (19e185) 26 (10e153) 70 11 140 12 3.7 0.4a 44.7 3.5 0.29 0.11 2.27 0.64 1.25 0.56
5% 7% 8% 9% 6% 11% 13% 16% 7% 5% 15% 11% 9% 6% 17% 6% 8% 8% 9%
Mean SD (median. extremes). a P < 0.05 (Student t test). b P < 0.01 (Student t test). c P < 0.001 (Student t test).
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was observed for phosphorus in 17% of the patients, for sodium in 20%, for chloride in 27%, and for potassium in 4%. In three patients, renal functional insufficiency was noted (serum creatinin >250 mmol/L), which disappeared with refeeding. The mean low serum albumin and transthyretin levels contrasted with the normal levels observed in the less malnourished patients. But only 4 patients had albumin level lower than 25 g/L (10% of the patients). 3.1.3. Complications during stay Leg oedema was observed in 14 patients (34%). Only 4 patients, all having a low albumin level (<30 g/L), had very large oedema. Clinical ascites was showed in two cases and pleural oedema in one case. In 8 patients (19%), hepatomegaly of soft-consistence edge was observed. Seven patients (17%) were unable to stand up out of their bed. In five other patients, mental confusion was noted during the first week, partly explained by a GayeteWernicke syndrome (mental confusion, ataxic gait and ophthalmoplegia, with low thiamine serum level in 3 patients). In 3 patients who were unable to walk, peripheral motor-sensitive neuropathy was observed, which was corrected by renutrition and vitamins B infusion. Two patients were transferred to intensive care unit within 48-h, because of clinical and ECG signs of myocardial infarction. No vital complication occurred. Ischaemia resumed in few days. Except Q wave, electrical signs disappeared in 10 days. In 3 other patients, acute abdominal pain and increased amylase and lipase levels (>5 N) led to a diagnosis of acute pancreatitis. In 4 patients (including one with pancreatitis), acute liver cell damage was observed: prothrombin index <50%, increase in serum alanine aminotransferase (>10 times normal; mean: 848 IU/L) and the absence of significant hepatocyte necrosis on histology. None of these patients suffered from severe complication during the prudent renutrition. In this series of 41 very severely malnourished AN patients, one patient died within 24 h of admission. One patient developed severe bradycardia (less than 10 bpm) on day three: she was transferred to the intensive care unit after resuscitation, and had no more complications. She was able to leave hospital after 6 months (her BW increased from 30.5 kg for 1.70 m to 53 kg). All of the six patients with neuropathy at admission were able to walk normally within 3 weeks. In nine patients, leg oedema appeared during refeeding, and AldactoneÒ was prescribed (1 cp 3 times a week). In four patients with a normal serum phosphorus level at admission, a low phosphorus level occurred during the first 7 days (<20 mmol/L), despite phosphorus supplements (see methods section). Phosphorus intake was therefore increased for 4e8 days (PhocytanÒ: 2 units). None of these patients developed severe ECG abnormalities. Two patients presented very low calcium levels (<1.6 mmol/L), and i.v. calcium was prescribed. In three cases, a low sodium level (<125 mmol/L) associated with a high total protein level (>80 g/L) led to rehydration with sodium solute.
Table 4 shows the prescribed energy intake in the 41 AN patients. Energy intake, expressed as kcal/kg BW/day, increased from 12 to 40 kcal/kg BW/day and proteins from 1.0 to 1.5 g/kg BW/day during the first ten days. 3.1.4. Biological findings Out of the 41 patients, eight had haptoglobin level lower than 0.10 g/L (N > 0.80 g/L), two of whom had documented haemolytic anaemia (Hb < 9 g%). In these two patients, haemoglobin level progressively increased from 7.3 and 6.8 g% to 10.5 and 10.9 g% in one month without other treatment than refeeding. In 27% of the cases, all of the 20 biological markers above were in the normal range. Five patients (23e34-yr old women) had severe anaemia and low leukocyte and platelet counts (Hb < 7 g%, leukocytes < 2000, lymphocytes < 500 and platelets < 120,000/mm3). In all cases, bone marrow biopsy showed gelatinous bone marrow transformation with hypocellularity. 3.1.5. Body composition and energy expenditure Triceps skinfold thickness was lower than 10 mm in all patients (minimal value in woman: 17 mm; personal data). Arm muscle circumference was lower than 14 cm in all patients (minimal value in woman: 23 mm; personal data). The mean fat mass was lower than 2 kg (Table 3) using skinfold thickness. Using BIA, the mean fat mass value was estimated as negative, while total body water was 75.3% of body weight and the extra/intracellular water ratio at 1.15 (normal value: 0.75e0.85). 3.1.5.1. Energy expenditure. The resting energy expenditure (REE) was 790 112 kcal/day (n ¼ 33). The patients having the lowest BMI (<10 kg/m2) had also the higher REE (913 93 vs 720 46 kcal/day). As shown in Fig. 1, BMI value lower than 10.0 kg/m2 was associated with elevated REE/FFM. The REE/FFM in all of the patients with a fat mass >2 kg (skinfold thickness) was below 29 1.20 kcal/kgFFM/day, vs. 40.8 4.5 kcal/kgFFM/day in the patients with almost no fat mass (P < 0.01). The RQ was 0.79 0.03 (extr: 0.77e0.82) in the 12 patients having the lowest BMI (<10.3 kg/m2), and 0.72 0.04 (extr: 0.67e0.76) in the 20 others (P < 0.05). 3.1.6. After discharge Two patients died from malnutrition within three years (they refused to return to hospital). With a mean follow-up of 6 years (extr: 3e18 yrs), 15 out of the 41 patients (36%) recovered (normal BMI, no restrictive diet, no binge), and 11 (27%) had a relatively good prognosis: BMI 16.6 1.4 kg/m2, remaining on restrictive diet (no added fat at all), with no alimentary pleasure. The condition of other six patients (14.6%) deteriorated after discharge: their BMI was, as a mean, at 14.2 1.3 kg/m2, they had a very restrictive diet and should be hospitalized again more than four times. In the last 6
Table 3 Changes in body composition in 41 severely malnourished AN patients.
Body weight (kg) BMI (kg/m2) Fat-free mass (SFT, kg) Fat-free mass (BIA, kg) Fat mass (SFT, kg) Fat mass (BIA, kg) Total body water (kg) Intracell water (kg) Extracell water (kg) Extra/intra ratio
Day 1e2
Day 6e8
Day 13e15
Day 20e22
Day 28e32
25.9 1.4 10.1 0.28 24.1 1.1 26.3 1.4 1.6 0.9 0.62 1.1 19.5 1.6 9.1 0.8 10.4 1.3 1.15 0.32
27.1 1.1 10.7 0.2 25.3 0.9 27.3 1.0 1.8 0.7 0.12 0.7 20.4 1.3 8.9 1.0 11.5 1.1 1.29 0.28
28.7 1.0 11.3 0.3 26.5 1.0 28.4 1.1 2.2 0.8 þ0.28 0.9 20.7 1.3 8.8 1.1 11.9 1.0 1.35 0.26
30.1 1.3 11.9 0.2 27.6 0.8 29.1 0.8 2.6 0.9 þ1.01 1.1 20.2 1.4 9.3 0.9 11.0 1.3 1.18 0.24
30.5 1.2 12.1 0.2 27.4 1.0 29.1 0.9 3.1 0.9 þ1.42 0.8 20.0 1.1 8.9 1.3 11.1 1.2 1.24 0.22
Mean SD. SFT: skinfold thickness; BIA: bioelectrical impedance analysis (two-frequency). Water estimated only by BIA.
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Table 4 Input during the first ten days in the 41 severely malnourished AN patients (BMI < 11 kg/m2). Prescribed
Day 1
Day 2
Body weight (kg) Water (mL/day) Water (mL/kg/day) Energy (kcal/day)a Energy (kcal/kg/day) Proteins (g/day) Proteins (g/kg/day)
25.9 1.4 998 140 38.5 2.6 309 18b 11.9 0.6 0 0
25.9 692 25.7 689 26.6 25.9 1.0
Day 3 1.2 240 1.4 58 1.1 2.4 0.09
26.3 744 27.1 754 28.7 28.3 1.08
Day 4e5 1.1 220 1.1 62 1.9 2.1 0.10
26.5 692 28.7 923 34.8 34.6 1.29
0.9 240 1.0 84 1.8 2.7 0.15
Day 6e7 27.1 820 30.1 1039 38.4 39.0 1.44
1.0 280 1.3 102 2.2 2.8 0.15
Day 8e10 27.4 920 30.5 1105 40.3 41.4 1.51
1.3 270 1.2 118 2.6 3.6 0.20
Enteral mixtures were isoenergetic and isonitrogen. Meals reintroduced generally at the 10th e 12th days. a All included (i.v. þ enteral). b i.v. serum glucose and 50 mL IvelipÒ.
patients, the course was very severe: BMI 13.4 1.7 kg/m2, more than four hospitalizations (5, 7, 9, and 13 times), relapsing soon after each hospital discharge and a very high level of excessive exercising. This prognosis could be compared to that of our other 443 less malnourished AN patients (BMI 11 kg/m2), as defined above and according to a previous publication10: after the same follow-up, 66% had recovered (vs. 36%), 28% had a relatively good prognosis (vs. 27%), 7% (vs. 15%) a poor and 7% a very poor (vs. 15%) prognosis (chi-2, P < 0.05). Among the 41 severe AN patients, none had a binge-eating/purging form of AN and none changed from the restrictive to the binge-eating/purging form thereafter, which was significantly lower than the 38% observed in the 443 other AN patients (chi-2, P < 0.01). 4. Discussion The present study reported the follow-up of 41 AN patients having a BMI lower than 11 kg/m2. These patients had more often a restrictive form of AN, a concomitant physical hyperactivity, and were less likely to be very anxious and very depressive than were the AN patients with higher BMI. In these severely malnourished AN patients, biological abnormalities were frequent, but curiously not constant, while a normal biological status was generally observed in less malnourished AN patients. Like others, we observed several medical complications in our severely malnourished patients: acute pancreatitis in three patients,16,17 acute liver cell damage in four patients,18e20 peripheral
Fig. 1. Resting energy expenditure in 33 of our 41 severely malnourished AN patients. REE was expressed as a function of fat-free mass (REE/FMM) in order to compare REE at constant FFM (and thus at different BMI). In the figure, the patients were classified in the order of increasing REE/FFM. The patient n 23 had had an acute pancreatitis, the patients n 28 and 32 an acute hepatitis and the patients n 31 and 33 had had a myocardial ischaemia one week before.
neuropathy in seven patients,21 GayeteWernicke’s encephalopathy in five patients22,23 and myocardial infarction in two patients.24 Two patients suffered from haemolytic anaemia,25 and five patients from pancytopenia with gelatinous bone marrow transformation and hypocellularity.26,27 A greater proportion of these 41 severely malnourished patients had the restrictive form of AN, compared with other AN patients (85% vs. 57%, P < 0.05). This could be related to the fact that bingeeating/purging episodes progressively induce an increase in BMI, because vomiting becomes less efficient with time (a larger part of the energy-rich foods ingested during the binges could be absorbed through the intestinal mucosa). A very interesting point is the higher than expected resting energy expenditure (REE) that we observed, when the BMI decreased to below 10.5-kg/m2. This is not usual, since in AN patients, REE was generally 5e8% lower than expected.28,29 In the present study, REE seems to be markedly increased, as expressed as a REE/FFM ratio, when the BMI dropped below 10.5 kg/m2 and the fat mass below 2 kg. There are several hypotheses to explain this phenomenon: first, one could hypothesize that, energy was extracted mainly from muscle, and no more from fat mass, which in turns increases the cost of energy extraction. It must be noticed that, below this value, BIA gave negative values, suggesting that it overestimated fat-free mass and total body water for extremely low values of fat mass. One can postulate that, in human, fat mass was not at disposable for energy expenditure under a 2-kg fat mass store, leading to exclusive protein oxidation from muscles. An argument for this hypothesis was the respiratory quotient (RQ), which was nearer to that of protein oxidation (0.78e0.82) than that of fat oxidation (0.68e0.72) in these patients. Moreover, the mean RQ was 0.79 in the 12 AN patients having the lowest BMI (<10.3 kg/ m2), and lower (0.72) in the 20 less severe AN patients. Another explanation is that five out of the 12 patients with the highest REE/ FFM had suffered from hepatitis, pancreatitis or myocardial ischaemia the week before the measurement of REE. It must be also stated that the present series includes five patients previously described.14 Ketosis can contribute to the RQ; unfortunately, it was not measured in our patients. The present renutrition program seems safe, since we have to deplore only one death in this series (2.5% of the patients). In comparison, in 2010, Vignaud et al.30 reported mortality of 10% in 68 AN patients with a mean BMI of 12 3 kg/m2 (mean age: 31 12 yrs) hospitalized in an intensive care unit. Other authors also published a more severe outcome.31,32 It could be interesting to note that we systematically use intravenous lipids (100e200 mL/day of IntralipideÒ, MedialipideÒ or IvelipÒ 20%) and phosphorus during the first 4e5 days in these very severe form of AN. Indeed, the energy content of i.v. lipids was included in the total energy input. We suggest that i.v. infusion of lipids may be needed, because of the severe deficiency in fatty acids. The effectiveness of this strategy must be demonstrated in a prospective study. Unfortunately, we did
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not measure plasma fatty acids in our patients. Another question is what level of energy intake is mandatory in these AN patients with a very severe form of malnutrition?29e32 With our protocol, including low-sodium diet, only one death and no other severe complications, such as refeeding syndrome, occurred. Another question is why the patients with the lowest BMI had the poorest long-term prognosis, compared with less malnourished patients?33 We suggest two explanations: 1 e the more severe the AN initially, the lower the BMI as the consequence (i.e. a very severe form of behavioural dysfunction explained); 2 e severe irreversible psycho-neuro-behavioural alterations were the consequence of deeply and chronically altered cerebral functions during the period of severe malnutrition. In this hypothesis, the irreversible cerebral lesions were the consequence of the severe malnutrition status. It would be interesting to explore this hypothesis by performing NMR or PET-scan imaging in severe forms of AN. Conflict of interest None declared. Acknowledgements All the present authors agree to the present version of this manuscript. Pr Rigaud has contributed to the conception of this study, the analysis of the data and the writing of the manuscript. Mme Tallonneau performed dietician inquiry and helped the patient to increase her energy intake. Mme Dr Brindisi performed statistical analyses and Pr Vergès helped to write the manuscript. References 1. Rigaud D, Pennacchio H, Van den Berg O, Lalanne-Mistrih ML, Huet JM, Fischler C, et al. Pensées et ressentis face à l’alimentation. Enquête auprès de 3732 personnes de la population du grand Dijon. Cahiers Nutr DiétFr 2006;46:353e63. 2. Dalle Grave R, Calugi S, Marchesini G. Compulsive exercise to control shape or weight in eating disorders: prevalence, associated features, and outcome. Compr Psychiatry 2008;49:346e52. 3. Lowe B, Zipfel S, Buchholz C, Dupont Y, Reas DL, Herzog W. Long-term outcome of anorexia nervosa in a prospective 21-year follow-up study. Psychol Med 2001;31:881e90. 4. Deter HC, Schellberg D, Kopp W, Friederich HC, Herzog W. Predictability of a favorable outcome in anorexia nervosa. Eur Psychiatry 2005;20:165e72. 5. Collins. The limit of human adaptation to starvation. Nat Med 1995;1:810e4. 6. Kohn MR, Golden NH, Shenker IR. Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. J Adolesc Health 1998;22:239e43. 7. Huang YL, Fang CT, Tseng MC, Lee YJ, Lee MB. Life-threatening refeeding syndrome in a severely malnourished anorexia nervosa patient. J Formos Med Assoc 2001;100:343e6. 8. Fisher M, Simpser E, Schneider M. Hypophosphatemia secondary to oral refeeding in anorexia nervosa. Int J Eat Disord 2000;28:181e7.
9. Georges B, Thissen JP, Lambert M. Severe hypophosphatemia in a patient with anorexia nervosa during enteral refeeding. Acta Clin Belg 2004;59:361e4. 10. Rigaud D, Pennachio H, Bizeul Ch, Réveillard V, Vergès B. Outcome in AN adult patients: a 13-year follow up in 484 patients. Diabetes Metab 2011;37:305e11. 11. Rigaud D, Boulier A, Tallonneau I, Brindisi MC, Rozen R. Body fluid retention and body weight change in anorexia nervosa patients during refeeding. Clin Nutr 2010;29:749e55. 12. Boulier A, Fricker J, Thomasst AL, Apfelbaum M. Fat-free mass estimation by the two-electrode impedance method. Am J Clin Nutr 1990;52:581e5. 13. Pollock M, Laughridge EE, Coleman B, Linnerud AC, Jackson A. Prediction of body density in young and middle-aged women. J Appl Physiol 1975;38:745e9. 14. Rigaud D, Hassid J, Meulemans A, Poupard AT, Boulier B. A paradoxical increase in resting energy expenditure in malnourished patients near death: the king penguin syndrome. Am J Clin Nutr 2000;72:355e62. 15. Ben Porat M, Sideman S, Bursztein S. Energy metabolism rate equation for fasting and postabsorptive subjects. Am J Physiol 1983;13:R764e9. 16. Park JH, Lee TH, Cheon SL, Sun JH, Choi IK, Kim YS, et al. Severe acute liver and pancreas damage in anorexia nervosa. Korean J Gastroenterol 2009;54:257e60. 17. Morris LG, Stephenson KE, Herring S, Marti JL. Recurrent acute pancreatitis in anorexia and bulimia. JOP 2004;5:231e4. 18. Rautou PE, Cazals-Hatem D, Moreau R, Francoz C, Feldmann G, Lebrec D, et al. Acute liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy. Gastroenterology 2008;135:840e8. 19. Furuta S, Ozawa Y, Maejima K, Tashiro H, Kitahora T, Hasegawa K, et al. Anorexia nervosa with severe liver dysfunction and subsequent critical complications. Intern Med 1999;38:575e9. 20. Di Pascoli L, Lion A, Milazzo D, Caregaro L. Acute liver damage in anorexia nervosa. Int J Eat Disord 2004;36:114e7. 21. Woodruff PW, Morton J, Russell GF, Woodruff PW, Morton J, Russell GF. Int J Eat Disord 1994;16:205e9. 22. Parkin AJ, Dunn JC, Lee C, O’Hara PF, Nussbaum L. Neuropsychological sequelae of Wernicke’s encephalopathy in a 20-year-old woman: selective impairment of a frontal memory system. Brain Cogn 1993;21:1e19. 23. Saad L, Silva LF, Banzato CE, Dantas CR, Garcia Jr C. Anorexia nervosa and Wernicke-Korsakoff syndrome: a case report. J Med Case Rep 2010;4:217e8. 24. Ono T, Kasaoka S, Fujita M, Yamashita S, Kumagai K, Kaneda K, et al. Complete recovery from severe myocardial dysfunction in a patient with anorexia nervosa. J Cardiol 2009;54:480e4. 25. Hütter G, Ganepola S, Hofmann WK. The hematology of anorexia nervosa. Int J Eat Disord 2009;42:293e300. 26. Thiel A, Heits F, Amthor M. Severe leukopenia and bone marrow hypoplasia with gelatinous transformation in anorexia nervosa. Dtsch Med Wochenschr 2007;132:2256e8. 27. Nonaka D, Tanaka M, Takaki K, Umeno M, Okamura T, Taketa H. Gelatinous bone marrow transformation complicated by self-induced malnutrition. Acta Haematol 1998;100:88e90. 28. Van Wymelbeke V, Brondel L, Brun JM, Rigaud D. Factors linked to the increase in resting energy expenditure during refeeding in malnourished anorexia nervosa patients. Am J Clin Nutr 2004;80:1469e77. 29. Gentile MG, Pastorelli P, Ciceri R, Manna GM, Collimedaglia S. Specialized refeeding treatment for anorexia nervosa patients suffering from extreme undernutrition. Clin Nutr 2010;29:627e32. 30. Vignaud M, Constantin JM, Ruivard M, Villemeyre-Plane M, Futier E, Azurea group. Refeeding syndrome influences outcome of anorexia nervosa patients in intensive care unit: an observational study. Crit Care 2010;14:R172e6. 31. Whitelaw M, Gilbertson H, Lam PY, Sawyer SM. Does aggressive refeeding in hospitalized adolescents with anorexia nervosa result in increased hypophosphatemia? J Adolesc Health 2010;46:577e82. 32. Cros G, Sznajder M, Meuric S, Mignot C, Chevallier B, Stheneur C. Rapid malnutrition in patient with anorexia nervosa: experience of a general pediatric department. Arch Pediatr 2010;17:112e7. 33. Rigaud D, Pennachio H, Bizeul Ch, Réveillard V, Vergès B. Outcome in AN adult patients: a 13-year follow up in 484 patients. Diabetes Metab 2011;37. ii (web site: 2010.12).
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Original article
Prognosis in 41 severely malnourished anorexia nervosa patients Daniel Rigaud*, Isabelle Tallonneau, Marie-Claude Brindisi, Bruno Vergès Service d’Endocrinologie-Nutrition, CHU Le Bocage: 2, Bd du Maréchal de Lattre de Tassigny, 21000 Dijon, France
a r t i c l e i n f o
s u m m a r y
Article history: Received 13 October 2011 Accepted 25 February 2012
Background & aims: To report the prognosis in 41 anorexia nervosa (AN) patients suffering from very severe malnutrition (mean BMI: 10.1 0.57 kg/m2). Patients and methods: Compared with 443 less malnourished AN patients, the 41 patients were older (27.8 5.4 vs 22.4 2.1 yrs), their AN was longer (9.6 3.4 vs 5.0 1.5 yrs) and more often of the restrictive subtype (P < 0.05). Results: In 27% of the patients, all nutritional marker levels were in normal range. All patients received a prudent tube-refeeding: energy was increased from 12 to 40 kcal/kg/day, protein from 1.0 to 1.5 g/kg/ day within 10 days. During stay, 1 patient died, 2 others suffered from myocardial infarction, 2 others from acute pancreatitis, and 5 from mental confusion. Compared with the other 443 AN patients, the 40 remaining patients had worse 6-yr prognosis: 2 died (7% vs 1.2%), 29% had severe outcome (vs 10%), and only 41% recovered (vs 62%). Conclusion: In AN patients with BMI < 11 kg/m2, a prudent tube-refeeding could avoid short-term mortality, but long-term prognosis was bad. Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Anorexia nervosa Tube feeding Refeeding syndrome Enteral nutrition Malnutrition
1. Introduction Anorexia nervosa (AN) is a chronic and severe eating disorder. In Burgundy (France), its frequency was estimated at 1.6% of the 25e45-yr old girls and young women.1 AN was defined as the follow: 1 e a refusal to gain or maintain body weight at or above a minimally normal weight for age and height, 2 e an intense fear of gaining weight or becoming fat, even though under weight, 3 e a disturbance in the way one’s body weight or shape are experienced, an undue influence of body weight or shape on self evaluation, or denial of the seriousness of the current low body weight, 4 e amenorrhoea (at least three consecutive cycles). Weight loss was, at the meaning of these patients, the only way for obtaining their self-esteem. The fear of becoming fat increased month after month, pushing the patient into more intensive restricting dieting. At least one third of the patients are unable to eat during meals any sugar and sweet, added fat and fatty food, meat and fish, cheese, starchy food and bread, milk and cheese. This very low calorie diet was responsible to a very low intake of a lot of macronutrients and micronutrients: total protein, essential amino acids, total fat, essential fatty acids, calcium, phosphorus, iron, zinc and vitamins.
In many cases, this diet is responsible for malnutrition. The frequency and the severity of this malnutrition could be increased by excessive physical exercise, which occurs in 40e60% of the AN patients,2 and by purging (i.e. self vomiting), which occurs in 30e40% of the patients (both during and beside binge eating). About 5e15% of the AN patients died after 10 years of the condition.3,4 This is mainly due to the malnutrition, in particular in the restricting type of the disease.3,4 AN is one of the most frequent causes of malnutrition in girls and young women. It is not unusual to find patients with a body mass index (BMI) lower than 13 kg/m2. It was suggested in the past that a BMI lower than 10e11 kg/m2 was the limit of life in adults.5 Furthermore, the refeeding syndrome could increase the risk of dead in the most severely malnourished patients.6e9 No studies have reported the short-term and longterm prognosis of these patients. So, we would like to report our experience in 41 very severely malnourished AN adult patients hospitalized for malnutrition in our Nutrition unit. All these patients had a BMI < 11 kg/m2 at admission and were followed-up more than 6 years. 2. Patients and methods 2.1. Patients
* Corresponding author. Tel.: þ33 3 80 29 52 72; fax: þ33 380 293519. E-mail addresses: [email protected] (D. Rigaud), isabelle.tallonneau@ chu-dijon.fr (I. Tallonneau), [email protected] (M.-C. Brindisi), [email protected] (B. Vergès).
The main characteristics of these 41 patients were compared with those of 443 less malnourished AN patients (Table 1) followed during the same period.10 The 41 very severely malnourished
0261-5614/$ e see front matter Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. doi:10.1016/j.clnu.2012.02.016
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D. Rigaud et al. / Clinical Nutrition 31 (2012) 693e698 Table 1 Comparison of baseline demographic and clinical characteristics of women with severe and less severe malnutrition hospitalized for treatment of anorexia nervosa.
Number Sex Height (cm) Weight (kg) BMI at admission (kg/m2) Age at admission (median, extremes) Age at the first symptoms (yrs) Duration of AN (yrs) Physical hyperactivity (recently) Restrictive form Vomiting without binge Binge-eating/purging form Severe anxiety (Hamilton score>40) Severe depression (Beck score>20) Personality disorders
BMI < 11 kg/m2
BMI 11 kg/m2
41 39 women (95%), 2 men 160 3a 25.9 1.4b 10.1 0.57 (8.8e10.9)b 28.9 5.4 yrs (25 yrs; 17e45)a 18.2 4.7 (19 yrs; 14e31) 9.6 3.4 (7 yrs; 1.4e25.0)a 35 (85%)c 35 (85%)c 5 (12%) 1 (5%) 9 (22%)c 4 (10%)c 1 (2%)
443 428 women (96%), 15 men 165 5 39.7 þ 5.7 14.6 2.2 (11.1e17.0) 24.3 6.1 yrs (22 yrs; 15e32) 17.5 2.3 (19 yrs; 15e28) 5.0 1.5 (4 yrs; 1.1e14.5) 332 (60%) 317 (57%) 77 (14%) 159 (36%) 202 (37%) 102 (23%) 23 (4%)
Mean SD (median; extremes). The Hamilton and Beck scores were two validated scores. Maximal Hamilton anxiety score is 56 and maximal depression Beck score is 36. Physical hyperactivity was defined using a 8-items questionnaire. Personality disorders: diagnosis by psychiatric interview. a P < 0.05 (Student t test). b P < 0.001 (Student t test). c Chi-2 (P < 0.05).
patients represented 8.5% of this cohort. They were older, had a longer duration of AN and were more likely to have the restricting form of the disease; they were also more likely to be overactive, and less likely to be very anxious or depressed than were the 443 others (Table 1; P < 0.05 for all).
vitamin B1: 100 mg) and fifty (50 mL) intravenous lipids (IntralipidÒ 20% or IvelipÒ 20%), the latter to correct essential-fatty acids insufficiency. Enteral mixture (SondalisÒ, NutrisonÒ or NormoréalÒ) was intragastrically infused at the mean rate of 25 kcal/kg/day (extr: 21e25 kcal/kg/day).
2.2. Methods
2.3.3. Days 4 and 5 Energy intake was increased to 35 kcal/kg/day (extr: 780e950 kcal/day), including 100 mL intravenous lipids (200 kcal). Micronutrients were intragastrically infused at the above dose and phosphorus increased (added, PhosphoneurosÒ: 20 drops 2/day intragastrically), according to phosphorus plasma level. No food was allowed.
All the 41 patients were hospitalized in emergency in a specialized Nutrition unit with a large experience in renutrition of such AN patients. Our unit is not an intensive care unit. Among these AN patients, only two needed to be admitted after one to two days in the intensive medical care unit for multiple organ failure (see below). In each patient, we measured body weight each day, resting energy expenditure, body composition and biological markers as seen below. 2.3. Nutritional rehabilitation Our schedule was codified and summarized in guidelines for medical staff from 1992. All values are given by reference of actual body weight. It was (and it is) the following. 2.3.1. Day 1 A catheter was inserted into a cubital vein (or, if needed, in a central vein). An intravenous infusion of glucose was prescribed, with 30e40 mL/kg body weight of water/day and no more than 3 g glucose/kg BW/day. Phosphorus (0.20 mmol/kg BW/24 h, phosphate di-potassique), KCl (0.1 g/kg/day), sodium (NaCl, max: 2 g/day, except in the case of vomiting and dehydration), vitamins, minerals (iron, selenium, zinc.) were added in the form of parenteral solution (CernévitÒ, NonanÒ or similar). 2.3.2. Day 2 A chariere-08 or 09 nasogastric tube was positioned in the distal part of the stomach and its position controlled (nasal mark: 70 cm; radiography for control). Except in the case of patent dehydration, sodium input did not exceeded 3 g/24 h. No food was allowed. Were intravenously infused water (max 40 ml/kg/24 h), sodium (<3 g/24 h), phosphorus (Phocytan: glucose: 1 g, phosphate 6.6 mmol, phosphorus: 200 g, Naþ: 0.8 g), calcium (500 mg), trace elements and vitamins (DecanÒ and CernevitÒ: one bottle plus
2.3.4. Days 6e10 Generally, intravenous infusion was stopped. Energy intake was maintained at 35e40 kcal/kg/day. Other intakes (minerals, trace elements, vitamins) were at this time infused via the nasogastric tube. Potassium was increased in cases of hypokaliemia. Sodium input was maintained at <3 g level per day, except in 6 patients: 3 for diarrhoea, 1 for vomiting, 1 for fever and 1 for tubular sodium loss. During this 10-day period, body weight should not increase by more than 100 g/day, since energy input was at the level of energy expenditure. 2.3.5. Days 11e21 Foods were introduced, in the form of small meals (around 300e400 kcal/day) having a low-sodium content (<4 g/day). Energy intake was calculated each day in order to give no more than 45 kcal/kg actual BW/day, including enteral feeding, until the 20th day. For example, for a body weight of 30 kg, the maximal energy need was calculated (1350 kcal/day): if energy intake by meals reached 850 kcal, tube feeding input was reduced to 500 kcal/day. The daily calcium and phosphorus doses were 500 and 300 mg, respectively (except in cases of deficiency). During these 3 weeks, no psychotropic drug was allowed. From the 4th week onwards, energy intake was determined as the energy needs þ700e1000 kcal/day, in order to obtain a BW gain from 0.7 to 1.0 kg/week. Daily energy need was calculated as resting energy expenditure (REE, measured) 1.5. The diet was a low-sodium diet with no more than 6 g NaCl/day, until a 15-kg/m2 BMI was obtained.11
D. Rigaud et al. / Clinical Nutrition 31 (2012) 693e698
2.4. Biological measures During the first 10 days, were measured daily creatinin, Naþ, Kþ, Cl, CO 2 , phosphorus, Caþþ, creatinin, and urea. Electrocardiogram was performed each day. Thereafter, blood was drawn twice a week during 2 weeks, then once a week. Every 3 days, then once a week, we also measured ALAT and ASAT, red and white blood cells, platelets, albumin, transthyretin transferrin, haemoglobin, and iron. Every week, the 48 h-urinary output of Naþ, Kþ, creatinin, and urea were measured. Body weight was measured every 2 days in a hospital gown, after urine voiding, while the patient was fasting (Scale Seca 770 alpha Intellisense, UK). Height was measured by a stadiometer using a Seca scale (model 222, UK), as soon the patient was able to stay in upright position. Body composition was estimated each week using both a 2-frequency (5 kHz and 1 MHz) bioelectrical impedance analysis with a portable 2-subcutaneously electrode impedancemeter12 and skinfold thickness at 4 sites (Harpenden calliper, John Bull Inc., UK), as published by Pollock et al.13: it was measured at the 4 classical areas (triceps, biceps, subscapular, suprailiac). Then body FM and FFM were calculated as follow: body density ¼ 1.1599 (0.0717 (log S)), where S is the sum of the 4 skinfold. From bioelectrical impedance, we estimated fat-free mass (FFM) and fat mass (FM), as well as total, extracellular and intracellular body water, as published by Boulier et al.12 We measured REE by indirect calorimetryusing the Deltatrac II, Datex-Ohmeda, as previously published,14 in 33 patients. These patients, who were in a fasting state (tube feeding and oral feeding stopped at 22.00 h), were placed in a quiet room. After 20 min rest, REE was recorded for 20 min with the patients in a supine position. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured by open-circuit indirect calorimetry with a ventilated-hood system (mean flow rate 50 5 L/min). Oxygen concentration was assessed using a differential paramagnetic analyzer (Klogor, Lannion, France), and carbon dioxide concentration with an infrared analyzer (Hartmann and Braun Instruments, Frankfurt, FRG). Gas flow was measured with a linear mass flowmeter (Setaram, Lyon, France) and raw data were continuously recorded on line every 30 s. Gas exchanges were calculated as the product of gas flow and the differences in both oxygen and carbon dioxide concentrations
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in room air and expired gas, using continuous monitoring of gases at the inlet and the outlet of the ventilated hood. Corrections were made for the effects of the respiratory quotient (RQ) on gas flow measurements. Before each measurement, the system was calibrated with 21% oxygen and a mixture of 99% nitrogen and 1% carbon dioxide. The system was checked regularly by burning butane: the mean recovery of oxygen and carbon dioxide was 98 1% and 99 1%, respectively, and the RQ for butane was 0.614 0.003. The reproducibility was >96%. REE was calculated according to Ben Porat et al.15 This study reported data from a clinical survey, so the approval of an ethical committee was not required. 2.5. Statistical analyses In order to compare the two groups of AN patients, we used Student t test and chi-2 test. Statistical analyses were done with SPSSÒ. (Statistics Standard 12.0.1). The state of outcome formed the dependent variables. Its association with independent variables (prognosis factors) was explored by analysis of variance (ANOVA), then chi-2. 3. Results 3.1. At hospital admission 3.1.1. Clinical findings Some characteristics of the 41 patients are shown in Table 1. Malnutrition was clinically very severe at admission: major wasting of muscle masses, disappearance of any subcutaneous fat mass, emaciated face, alterations of skin, nails and hair were in all patients. Stomatitis and cheleitis were observed in 35 and 39 patients, respectively (85% and 95% of the patients), melanoderma in 32 (78%), severe hair loss in 13 (32%) and hemorrhagic gum in 10 patients (24%). 3.1.2. Biological findings Biological abnormalities were frequent but not constant. This contrasted with the normality of biological markers in most of the less malnourished AN patients (Table 2). Low serum or plasma level
Table 2 Comparison of baseline biological measures of women with severe and less severe malnutrition hospitalized for treatment of anorexia nervosa. Blood or serum
BMI < 11 n ¼ 41
% Abnormal findings
BMI 11 n ¼ 443
% Abnormal findings
Red blood cells (<3.3 M/mm3) Haemoglobin (<11 g%) White blood cells (<5.000/mm3) Lymphocytes (<1.500/mm3) Platelets (<100.000/mm3) Iron (<10 mmol/L) Ferritin (<20 ng/mL) Glucose (<0.60 g/L) Phosphorus (<0.60 g/L) Calcium (<2 mmol/L) ALAT (>30 UI/L) ASAT (>40 UI/L) Creatinin (>70 mmol/L) Sodium (<135 mmol/L) Potassium (<3.0 mmol/L) Albumin (<35 g/L) Transthyretin (<0.20 g/L) Transferrin (2.0 g/L) Haptoglobin (<0.70 g/L)
3.1 1.0b 9.9 2.4b 3700 1150a 1180 580b 188 126a 11 6 20 10b 0.58 0.12c 0.64 0.24b 2.06 0.23a 145 (28e1025)b 91 (22e943)b 85 15a 134 17c 4.5 0.2 31.2 0.37c 0.16 0.9b 1.75 0.63b 0.57 0.44c
26% 32% 22% 36% 10% 27% 41% 54% 35% 31% 70% 39% 48% 37% 4% 75% 69% 71% 78%
4.2 0.6 14.4 1.2 5970 1800 1890 720 246 108 19 7 39 13 0.87 0.15 0.87 0.15 2.31 0.18 25 (19e185) 26 (10e153) 70 11 140 12 3.7 0.4a 44.7 3.5 0.29 0.11 2.27 0.64 1.25 0.56
5% 7% 8% 9% 6% 11% 13% 16% 7% 5% 15% 11% 9% 6% 17% 6% 8% 8% 9%
Mean SD (median. extremes). a P < 0.05 (Student t test). b P < 0.01 (Student t test). c P < 0.001 (Student t test).
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D. Rigaud et al. / Clinical Nutrition 31 (2012) 693e698
was observed for phosphorus in 17% of the patients, for sodium in 20%, for chloride in 27%, and for potassium in 4%. In three patients, renal functional insufficiency was noted (serum creatinin >250 mmol/L), which disappeared with refeeding. The mean low serum albumin and transthyretin levels contrasted with the normal levels observed in the less malnourished patients. But only 4 patients had albumin level lower than 25 g/L (10% of the patients). 3.1.3. Complications during stay Leg oedema was observed in 14 patients (34%). Only 4 patients, all having a low albumin level (<30 g/L), had very large oedema. Clinical ascites was showed in two cases and pleural oedema in one case. In 8 patients (19%), hepatomegaly of soft-consistence edge was observed. Seven patients (17%) were unable to stand up out of their bed. In five other patients, mental confusion was noted during the first week, partly explained by a GayeteWernicke syndrome (mental confusion, ataxic gait and ophthalmoplegia, with low thiamine serum level in 3 patients). In 3 patients who were unable to walk, peripheral motor-sensitive neuropathy was observed, which was corrected by renutrition and vitamins B infusion. Two patients were transferred to intensive care unit within 48-h, because of clinical and ECG signs of myocardial infarction. No vital complication occurred. Ischaemia resumed in few days. Except Q wave, electrical signs disappeared in 10 days. In 3 other patients, acute abdominal pain and increased amylase and lipase levels (>5 N) led to a diagnosis of acute pancreatitis. In 4 patients (including one with pancreatitis), acute liver cell damage was observed: prothrombin index <50%, increase in serum alanine aminotransferase (>10 times normal; mean: 848 IU/L) and the absence of significant hepatocyte necrosis on histology. None of these patients suffered from severe complication during the prudent renutrition. In this series of 41 very severely malnourished AN patients, one patient died within 24 h of admission. One patient developed severe bradycardia (less than 10 bpm) on day three: she was transferred to the intensive care unit after resuscitation, and had no more complications. She was able to leave hospital after 6 months (her BW increased from 30.5 kg for 1.70 m to 53 kg). All of the six patients with neuropathy at admission were able to walk normally within 3 weeks. In nine patients, leg oedema appeared during refeeding, and AldactoneÒ was prescribed (1 cp 3 times a week). In four patients with a normal serum phosphorus level at admission, a low phosphorus level occurred during the first 7 days (<20 mmol/L), despite phosphorus supplements (see methods section). Phosphorus intake was therefore increased for 4e8 days (PhocytanÒ: 2 units). None of these patients developed severe ECG abnormalities. Two patients presented very low calcium levels (<1.6 mmol/L), and i.v. calcium was prescribed. In three cases, a low sodium level (<125 mmol/L) associated with a high total protein level (>80 g/L) led to rehydration with sodium solute.
Table 4 shows the prescribed energy intake in the 41 AN patients. Energy intake, expressed as kcal/kg BW/day, increased from 12 to 40 kcal/kg BW/day and proteins from 1.0 to 1.5 g/kg BW/day during the first ten days. 3.1.4. Biological findings Out of the 41 patients, eight had haptoglobin level lower than 0.10 g/L (N > 0.80 g/L), two of whom had documented haemolytic anaemia (Hb < 9 g%). In these two patients, haemoglobin level progressively increased from 7.3 and 6.8 g% to 10.5 and 10.9 g% in one month without other treatment than refeeding. In 27% of the cases, all of the 20 biological markers above were in the normal range. Five patients (23e34-yr old women) had severe anaemia and low leukocyte and platelet counts (Hb < 7 g%, leukocytes < 2000, lymphocytes < 500 and platelets < 120,000/mm3). In all cases, bone marrow biopsy showed gelatinous bone marrow transformation with hypocellularity. 3.1.5. Body composition and energy expenditure Triceps skinfold thickness was lower than 10 mm in all patients (minimal value in woman: 17 mm; personal data). Arm muscle circumference was lower than 14 cm in all patients (minimal value in woman: 23 mm; personal data). The mean fat mass was lower than 2 kg (Table 3) using skinfold thickness. Using BIA, the mean fat mass value was estimated as negative, while total body water was 75.3% of body weight and the extra/intracellular water ratio at 1.15 (normal value: 0.75e0.85). 3.1.5.1. Energy expenditure. The resting energy expenditure (REE) was 790 112 kcal/day (n ¼ 33). The patients having the lowest BMI (<10 kg/m2) had also the higher REE (913 93 vs 720 46 kcal/day). As shown in Fig. 1, BMI value lower than 10.0 kg/m2 was associated with elevated REE/FFM. The REE/FFM in all of the patients with a fat mass >2 kg (skinfold thickness) was below 29 1.20 kcal/kgFFM/day, vs. 40.8 4.5 kcal/kgFFM/day in the patients with almost no fat mass (P < 0.01). The RQ was 0.79 0.03 (extr: 0.77e0.82) in the 12 patients having the lowest BMI (<10.3 kg/m2), and 0.72 0.04 (extr: 0.67e0.76) in the 20 others (P < 0.05). 3.1.6. After discharge Two patients died from malnutrition within three years (they refused to return to hospital). With a mean follow-up of 6 years (extr: 3e18 yrs), 15 out of the 41 patients (36%) recovered (normal BMI, no restrictive diet, no binge), and 11 (27%) had a relatively good prognosis: BMI 16.6 1.4 kg/m2, remaining on restrictive diet (no added fat at all), with no alimentary pleasure. The condition of other six patients (14.6%) deteriorated after discharge: their BMI was, as a mean, at 14.2 1.3 kg/m2, they had a very restrictive diet and should be hospitalized again more than four times. In the last 6
Table 3 Changes in body composition in 41 severely malnourished AN patients.
Body weight (kg) BMI (kg/m2) Fat-free mass (SFT, kg) Fat-free mass (BIA, kg) Fat mass (SFT, kg) Fat mass (BIA, kg) Total body water (kg) Intracell water (kg) Extracell water (kg) Extra/intra ratio
Day 1e2
Day 6e8
Day 13e15
Day 20e22
Day 28e32
25.9 1.4 10.1 0.28 24.1 1.1 26.3 1.4 1.6 0.9 0.62 1.1 19.5 1.6 9.1 0.8 10.4 1.3 1.15 0.32
27.1 1.1 10.7 0.2 25.3 0.9 27.3 1.0 1.8 0.7 0.12 0.7 20.4 1.3 8.9 1.0 11.5 1.1 1.29 0.28
28.7 1.0 11.3 0.3 26.5 1.0 28.4 1.1 2.2 0.8 þ0.28 0.9 20.7 1.3 8.8 1.1 11.9 1.0 1.35 0.26
30.1 1.3 11.9 0.2 27.6 0.8 29.1 0.8 2.6 0.9 þ1.01 1.1 20.2 1.4 9.3 0.9 11.0 1.3 1.18 0.24
30.5 1.2 12.1 0.2 27.4 1.0 29.1 0.9 3.1 0.9 þ1.42 0.8 20.0 1.1 8.9 1.3 11.1 1.2 1.24 0.22
Mean SD. SFT: skinfold thickness; BIA: bioelectrical impedance analysis (two-frequency). Water estimated only by BIA.
D. Rigaud et al. / Clinical Nutrition 31 (2012) 693e698
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Table 4 Input during the first ten days in the 41 severely malnourished AN patients (BMI < 11 kg/m2). Prescribed
Day 1
Day 2
Body weight (kg) Water (mL/day) Water (mL/kg/day) Energy (kcal/day)a Energy (kcal/kg/day) Proteins (g/day) Proteins (g/kg/day)
25.9 1.4 998 140 38.5 2.6 309 18b 11.9 0.6 0 0
25.9 692 25.7 689 26.6 25.9 1.0
Day 3 1.2 240 1.4 58 1.1 2.4 0.09
26.3 744 27.1 754 28.7 28.3 1.08
Day 4e5 1.1 220 1.1 62 1.9 2.1 0.10
26.5 692 28.7 923 34.8 34.6 1.29
0.9 240 1.0 84 1.8 2.7 0.15
Day 6e7 27.1 820 30.1 1039 38.4 39.0 1.44
1.0 280 1.3 102 2.2 2.8 0.15
Day 8e10 27.4 920 30.5 1105 40.3 41.4 1.51
1.3 270 1.2 118 2.6 3.6 0.20
Enteral mixtures were isoenergetic and isonitrogen. Meals reintroduced generally at the 10th e 12th days. a All included (i.v. þ enteral). b i.v. serum glucose and 50 mL IvelipÒ.
patients, the course was very severe: BMI 13.4 1.7 kg/m2, more than four hospitalizations (5, 7, 9, and 13 times), relapsing soon after each hospital discharge and a very high level of excessive exercising. This prognosis could be compared to that of our other 443 less malnourished AN patients (BMI 11 kg/m2), as defined above and according to a previous publication10: after the same follow-up, 66% had recovered (vs. 36%), 28% had a relatively good prognosis (vs. 27%), 7% (vs. 15%) a poor and 7% a very poor (vs. 15%) prognosis (chi-2, P < 0.05). Among the 41 severe AN patients, none had a binge-eating/purging form of AN and none changed from the restrictive to the binge-eating/purging form thereafter, which was significantly lower than the 38% observed in the 443 other AN patients (chi-2, P < 0.01). 4. Discussion The present study reported the follow-up of 41 AN patients having a BMI lower than 11 kg/m2. These patients had more often a restrictive form of AN, a concomitant physical hyperactivity, and were less likely to be very anxious and very depressive than were the AN patients with higher BMI. In these severely malnourished AN patients, biological abnormalities were frequent, but curiously not constant, while a normal biological status was generally observed in less malnourished AN patients. Like others, we observed several medical complications in our severely malnourished patients: acute pancreatitis in three patients,16,17 acute liver cell damage in four patients,18e20 peripheral
Fig. 1. Resting energy expenditure in 33 of our 41 severely malnourished AN patients. REE was expressed as a function of fat-free mass (REE/FMM) in order to compare REE at constant FFM (and thus at different BMI). In the figure, the patients were classified in the order of increasing REE/FFM. The patient n 23 had had an acute pancreatitis, the patients n 28 and 32 an acute hepatitis and the patients n 31 and 33 had had a myocardial ischaemia one week before.
neuropathy in seven patients,21 GayeteWernicke’s encephalopathy in five patients22,23 and myocardial infarction in two patients.24 Two patients suffered from haemolytic anaemia,25 and five patients from pancytopenia with gelatinous bone marrow transformation and hypocellularity.26,27 A greater proportion of these 41 severely malnourished patients had the restrictive form of AN, compared with other AN patients (85% vs. 57%, P < 0.05). This could be related to the fact that bingeeating/purging episodes progressively induce an increase in BMI, because vomiting becomes less efficient with time (a larger part of the energy-rich foods ingested during the binges could be absorbed through the intestinal mucosa). A very interesting point is the higher than expected resting energy expenditure (REE) that we observed, when the BMI decreased to below 10.5-kg/m2. This is not usual, since in AN patients, REE was generally 5e8% lower than expected.28,29 In the present study, REE seems to be markedly increased, as expressed as a REE/FFM ratio, when the BMI dropped below 10.5 kg/m2 and the fat mass below 2 kg. There are several hypotheses to explain this phenomenon: first, one could hypothesize that, energy was extracted mainly from muscle, and no more from fat mass, which in turns increases the cost of energy extraction. It must be noticed that, below this value, BIA gave negative values, suggesting that it overestimated fat-free mass and total body water for extremely low values of fat mass. One can postulate that, in human, fat mass was not at disposable for energy expenditure under a 2-kg fat mass store, leading to exclusive protein oxidation from muscles. An argument for this hypothesis was the respiratory quotient (RQ), which was nearer to that of protein oxidation (0.78e0.82) than that of fat oxidation (0.68e0.72) in these patients. Moreover, the mean RQ was 0.79 in the 12 AN patients having the lowest BMI (<10.3 kg/ m2), and lower (0.72) in the 20 less severe AN patients. Another explanation is that five out of the 12 patients with the highest REE/ FFM had suffered from hepatitis, pancreatitis or myocardial ischaemia the week before the measurement of REE. It must be also stated that the present series includes five patients previously described.14 Ketosis can contribute to the RQ; unfortunately, it was not measured in our patients. The present renutrition program seems safe, since we have to deplore only one death in this series (2.5% of the patients). In comparison, in 2010, Vignaud et al.30 reported mortality of 10% in 68 AN patients with a mean BMI of 12 3 kg/m2 (mean age: 31 12 yrs) hospitalized in an intensive care unit. Other authors also published a more severe outcome.31,32 It could be interesting to note that we systematically use intravenous lipids (100e200 mL/day of IntralipideÒ, MedialipideÒ or IvelipÒ 20%) and phosphorus during the first 4e5 days in these very severe form of AN. Indeed, the energy content of i.v. lipids was included in the total energy input. We suggest that i.v. infusion of lipids may be needed, because of the severe deficiency in fatty acids. The effectiveness of this strategy must be demonstrated in a prospective study. Unfortunately, we did
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not measure plasma fatty acids in our patients. Another question is what level of energy intake is mandatory in these AN patients with a very severe form of malnutrition?29e32 With our protocol, including low-sodium diet, only one death and no other severe complications, such as refeeding syndrome, occurred. Another question is why the patients with the lowest BMI had the poorest long-term prognosis, compared with less malnourished patients?33 We suggest two explanations: 1 e the more severe the AN initially, the lower the BMI as the consequence (i.e. a very severe form of behavioural dysfunction explained); 2 e severe irreversible psycho-neuro-behavioural alterations were the consequence of deeply and chronically altered cerebral functions during the period of severe malnutrition. In this hypothesis, the irreversible cerebral lesions were the consequence of the severe malnutrition status. It would be interesting to explore this hypothesis by performing NMR or PET-scan imaging in severe forms of AN. Conflict of interest None declared. Acknowledgements All the present authors agree to the present version of this manuscript. Pr Rigaud has contributed to the conception of this study, the analysis of the data and the writing of the manuscript. Mme Tallonneau performed dietician inquiry and helped the patient to increase her energy intake. Mme Dr Brindisi performed statistical analyses and Pr Vergès helped to write the manuscript. References 1. Rigaud D, Pennacchio H, Van den Berg O, Lalanne-Mistrih ML, Huet JM, Fischler C, et al. Pensées et ressentis face à l’alimentation. Enquête auprès de 3732 personnes de la population du grand Dijon. Cahiers Nutr DiétFr 2006;46:353e63. 2. Dalle Grave R, Calugi S, Marchesini G. Compulsive exercise to control shape or weight in eating disorders: prevalence, associated features, and outcome. Compr Psychiatry 2008;49:346e52. 3. Lowe B, Zipfel S, Buchholz C, Dupont Y, Reas DL, Herzog W. Long-term outcome of anorexia nervosa in a prospective 21-year follow-up study. Psychol Med 2001;31:881e90. 4. Deter HC, Schellberg D, Kopp W, Friederich HC, Herzog W. Predictability of a favorable outcome in anorexia nervosa. Eur Psychiatry 2005;20:165e72. 5. Collins. The limit of human adaptation to starvation. Nat Med 1995;1:810e4. 6. Kohn MR, Golden NH, Shenker IR. Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. J Adolesc Health 1998;22:239e43. 7. Huang YL, Fang CT, Tseng MC, Lee YJ, Lee MB. Life-threatening refeeding syndrome in a severely malnourished anorexia nervosa patient. J Formos Med Assoc 2001;100:343e6. 8. Fisher M, Simpser E, Schneider M. Hypophosphatemia secondary to oral refeeding in anorexia nervosa. Int J Eat Disord 2000;28:181e7.
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