| | Hypophosphatemia during nutritional rehabilitation in anorexia nervosa: implications for refeeding and monitoringAccepted 26 June 2002. Abstract PurposeTo determine the incidence of hypophosphatemia in adolescents with anorexia nervosa (AN) hospitalized for nutritional rehabilitation and to examine factors predisposing to its development. MethodsA retrospective chart review of 69 patients (66 female, 3 male) with AN consecutively admitted to an inpatient adolescent medical unit between July 1, 1998 and June 30, 2000. Mean age was 15.5 ± 2.4 (range 8 to 22) years and mean % ideal body weight (IBW) was 72.7 ± 7%. Serum phosphorus was measured daily for 1 week and then biweekly to weekly. Patients were started on 1200–1400 kcal/day and calories were increased by 200 kcal every 24–48 hours. ResultsFour (5.8%) patients developed moderate hypophosphatemia (<2.5 and ≥ 1.0 mg/dl) and 15 (21.7%) had mild hypophosphatemia (<3.0 and ≥ 2.5 mg/dl). Patients who developed moderate hypophosphatemia were significantly more malnourished than those who did not (p = 0.02). Phosphorus nadirs were directly proportional to % IBW (r = 0.3, p = 0.01). Over three-quarters of the patients (81%) reached their phosphorus nadir within the first week of hospitalization. The patient with the lowest phosphorus level experienced short runs of ventricular tachycardia. No other severe complications were seen. Overall, 19 (27.5%) patients required phosphorus supplementation. ConclusionsPhosphorus drops to its nadir during the first week of refeeding. We recommend daily monitoring of serum phosphorus with supplementation as needed during the first week of hospitalization, especially in those who are severely malnourished.
The refeeding syndrome is a well-known phenomenon seen in the course of nutritional rehabilitation in patients with AN. This syndrome is characterized by fluid and electrolyte abnormalities, most notably hypophosphatemia, in conjunction with a host of cardiac, neurologic, and hematologic complications 1, 2. A number of case reports on the refeeding syndrome in AN highlight the serious consequences of severe hypophosphatemia, including cardiac dysrhythmia, delirium, and even sudden death 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. The refeeding syndrome has been found in other populations of hospitalized patients undergoing nutritional rehabilitation (e.g., postoperative patients, chronic alcoholics, and patients with inflammatory bowel disease) 13, 14, 15, 16, 17, 18. The incidence of hypophosphatemia in these conditions appears to be related to the rate of refeeding and, in particular, to an increased intake of carbohydrate. The abrupt shift to glucose metabolism is accompanied by greater requirements for, and utilization of, phosphorus-containing intermediates, such as adenosine 5′ triphosphate (ATP) [2].
Caloric advancement and weight gain are essential in the management of AN. Many, although not all, of the medical complications of AN can be reversed with nutritional rehabilitation [19]. In this era of managed care, there is pressure to increase the rate of refeeding of malnourished patients in an effort to decrease the length of hospitalization [20]. At our institution, under earlier protocols that required a weight gain of 0.8 and then 1.2 pounds every 4 days, no evidence of the refeeding syndrome was noted, although phosphorus levels were not consistently monitored [21]. Over the last 7 years, patients have contracted to gain 1.6 pounds in 4 days. There appears to have been a greater incidence of the refeeding syndrome than in the past [10]. Our aim was to determine the incidence of hypophosphatemia in a sample of adolescents with AN hospitalized for nutritional rehabilitation, as well as to ascertain the factors predisposing to its development.
Methods  Subjects All patients with an eating disorder consecutively admitted to the Schneider Children’s Hospital inpatient adolescent medical unit between July 1, 1998 and June 30, 2000 constituted the sample. Male and female patients, between 8 and 22 years of age, were included in the study if they met Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM-IV) criteria for AN, binge-purge or restrictive subtype [22]. Multiple admissions over the 2-year period were considered separately for individual patients. Patients were excluded if nutritional rehabilitation had begun or was continued at another institution or if they were admitted for any reason other than nutritional rehabilitation (e.g., correction of electrolyte disturbances). Some patients were treated prophylactically with phosphorus supplementation because of a dropping phosphorus level or clinical concern that they would develop the refeeding syndrome. This group was also excluded from analysis. Of the 125 charts reviewed retrospectively, 100 patients met DSM-IV criteria for AN. Reasons for subsequent exclusion from the study group were: admission for acute medical stabilization only (n = 2); transfer to another institution within 1 week of admission (n = 3); leaving against medical advice within 1 week of admission (n = 4); transfer from another institution after nutritional rehabilitation had already begun (n = 6); prophylactic treatment with phosphorus supplementation (n = 10); comorbid metabolic disorders (e.g., diabetes mellitus) (n = 1); and use of medications known to cause hypophosphatemia (e.g., chronic beta-agonists, bisphosphonates, diuretics, and glucocorticoids) (n = 5). The study group thus comprised 69 patients (66 female, 3 male) with a mean age of 15.5 ± 2.4 years. Protocol The following data were collected from the chart review: age, daily weight, % ideal body weight (IBW) on admission, body mass index (BMI) on admission, change in weight from day of admission to phosphorus nadir, caloric intake on day of phosphorus nadir, change in caloric intake from day of admission to phosphorus nadir, daily phosphorus levels, lowest serum phosphorus, day of hospitalization that nadir was reached, initiation of phosphorus supplementation, use of supplemental nasogastric (NG) tube feeds, length of hospitalization, weight on discharge, % IBW on discharge, and BMI on discharge. Ideal body weight was defined as the median weight for age, gender, and height using the National Center for Health Statistics percentiles 23, 24, 25. The study was approved by the North Shore-Long Island Jewish Health System Institutional Review Board. Standard of care on our unit Upon admission, blood was sent for serum chemistries, including phosphorus. This was repeated daily for 1 week and then biweekly to weekly. All patients received maintenance intravenous fluids containing 5% dextrose and one-third normal saline for the first 24 hours of admission. Caloric intake was initiated at 1200 to 1400 kcal/day and was gradually increased by 200 kcal every 24 to 48 hours. All patients received nutrition orally, some with supplemental NG tube feeding. Patients received phosphorus supplementation if the serum phosphorus fell below 3.0 mg/dl, as suggested by Clark et al. [26]. Additionally, the Harriet Lane Handbook has definitions for standard values of the lower limit of phosphorus for children aged 0 to 15 years (3.2 mg/dl) and for adults (2.7 mg/dl) [27]. The value of 3.0 mg/dl falls midway between the two, and is generally accepted as the definition of hypophosphatemia on our eating disorders unit. The initial dose prescribed was Neutraphos 250 mg orally, three times a day. All patients were placed on cardiac telemetry upon admission and monitoring continued until vital signs stability was evident. Statistical analysis The major outcome variable was serum phosphorus level. Subjects were divided into three groups: those with a phosphorus less than 2.5 mg/dl (moderate to severe hypophosphatemia); those with a phosphorus less than 3.0 mg/dl and greater than or equal to 2.5 mg/dl (mild hypophosphatemia); and those with a phosphorus greater than or equal to 3.0 mg/dl (normal). These previously described set points were chosen based on recommendations 26, 28. Age, absolute weight, % IBW, change in weight from admission to nadir in phosphorus, caloric intake, and change in caloric intake from admission to nadir in phosphorus were compared among groups using analysis of variance, with significance established at p < 0.05. Pearson correlation coefficient was used to analyze the relationship between serum phosphorus and % IBW. Results The admission and discharge characteristics of the 69 study patients are illustrated in Table 1. Of these 69 patients, 19 (27.5%) required treatment with phosphorus supplementation: four (5.8%) developed moderate hypophosphatemia and 15 (21.7%) had mild hypophosphatemia. None developed severe hypophosphatemia (serum phosphorus less than 1.0 mg/dl). Patients who developed moderate hypophosphatemia were significantly more malnourished than those who had mild hypophosphatemia or those whose levels were normal (p = 0.02). The relationship between the lowest serum phosphorus level and % IBW is demonstrated in Figure 1. The phosphorus nadirs were directly proportional to % IBW (r = 0.3, p = 0.01). Three of the four patients with moderate hypophosphatemia were less than 70% of their IBW. Age, absolute weight, change in weight, caloric intake, and change in caloric intake did not significantly affect the development of hypophosphatemia (Table 2). | | |  | Characteristic | Mean (SD) | |
|---|
| Age (years) | 15.5 (2.4) | |
| Admission weight (kg) | 39.2 (7.0) | |
| Discharge weight (kg) | 44.1 (6.4) | |
| Admission % IBW | 72.7 (7.1) | |
| Discharge % IBW | 82.3 (6.0) | |
| Admission BMI (kg/m2) | 15.0 (1.5) | |
| Discharge BMI (kg/m2) | 16.9 (1.2) | |
| Admission phosphorus (mg/dl) | 3.6 (0.6) | |
| Length of hospitalization (days) | 25.6 (11.6) | | | | |
As shown in Figure 2, 32% of subjects had their nadir on the first hospital day, with 71% of patients having their nadir by day four and 81% during the first week of hospitalization. The phosphorus nadir occurred on average on hospital day four, but there was great variability, with some patients reaching their lowest levels on admission and others on days 20 and 24 (n = 2); the latter two patients were not hypophosphatemic, however. The lowest phosphorus level was 1.4 mg/dl in a patient who was admitted at 50% of her IBW; this occurred on day two of hospitalization. Only five patients received NG tube feeding during the study period, three of whom required treatment with phosphorus supplementation, one with a phosphorus level less than 2.5 mg/dl. The patient with the lowest phosphorus level experienced short runs of ventricular tachycardia on cardiac telemetry, without need for intervention; otherwise no patients manifested the extreme signs of the refeeding syndrome. Discussion The dangers of nutritional rehabilitation on malnourished individuals have been known since the 1940s. After World War II, serious complications secondary to refeeding were noted in Japanese prisoners of war [29] and in refugee camps in the Netherlands [13], as well as in the classic experiments of Keys et al. [30] on conscientious objector subjects who underwent 6 months of starvation, followed by nutritional recovery. In addition, it is known that individuals with kwashiorkor and other forms of protein-calorie malnutrition experience medical complications when refed [31]. The refeeding syndrome and its complications reemerged in the medical arena with the introduction of total parenteral nutrition (TPN) and its use in the nutritional rehabilitation of severely malnourished patients [18]. It can occur with oral, NG, and intravenous nutrition 3, 4, 6, 9, 10, 11, 12, 13, 14, 16. The refeeding syndrome involves a host of fluid and electrolyte derangements and leads to a constellation of cardiac, neurologic, and hematologic complications, including sudden, unexpected death, that occur in the weeks after the initiation of nutritional rehabilitation. One of the explanations for the group of findings, including sudden death, is the development of acute, severe hypophosphatemia after refeeding has begun 1, 2. In conditions of malnutrition, there is atrophy of cardiac muscle, as well as electrocardiographic abnormalities, most commonly sinus bradycardia, with prolongation of the corrected QT interval being perhaps the most ominous 8, 32, 33, 34. These findings may render the heart more vulnerable to the deleterious effects of phosphate depletion, thus leading to ventricular dysrhythmias and sudden death 3, 8, 18, 34. The identification of hypophosphatemia is therefore essential, as it is one of the earliest clinical indicators of the refeeding syndrome and is easily treatable. Our results show that 6% of a sample of adolescents with AN hospitalized for enteral nutritional rehabilitation experience moderate hypophosphatemia. Of note, these results parallel the incidence of symptomatic refeeding syndrome seen on the same medical unit 7 years earlier [10]. In contrast to that study, the biochemical abnormalities noted here were recognized and corrected early, with none of the subjects developing symptoms of the refeeding syndrome. Our findings also concur with those of Alvin et al. from France, who reported a 7% incidence of moderate to severe hypophosphatemia in 99 adolescents hospitalized for AN and bulimia nervosa (BN) [35]. We found that over one-quarter of our patients required phosphorus supplementation, as per our unit protocol. Patients most at risk for moderate hypophosphatemia were those who were extremely malnourished. The serum phosphorus drops to its nadir, on average, on hospital day four, with the majority of patients’ nadirs occurring during the first week, as noted by others 15, 36. We recommend checking daily levels of serum phosphorus during the first week of hospitalization, with oral supplementation of phosphate as needed. The use of cardiac telemetry during the first week allows even closer monitoring for the known cardiac arrhythmias seen during refeeding. Although not fully understood, many complications of the refeeding syndrome appear to be mediated by acute hypophosphatemia superimposed on chronic phosphorus depletion. Under conditions of starvation, such as AN, the body is in a state of catabolism. In such a state, energy is derived mainly from fat metabolism, which does not use phosphorus-containing intermediates such as ATP [2]. Despite total body depletion of phosphorus, there are no major untoward effects, because serum phosphorus levels are maintained by mobilization from bone and soft tissue [28]. During refeeding, the body enters into an anabolic state. Insulin release drives phosphorus intracellularly to produce phosphorylated compounds involved in glycolysis, such as ATP, 2,3-DPG, and G-3-PD [2]. In the face of total body depletion of phosphorus, accompanied by sudden increased requirements, serum phosphorus levels may drop during refeeding. Most of the serious consequences from refeeding are seen with severe hypophosphatemia (serum phosphorus less than 1.0 mg/dl) [28]. It has been postulated that a low serum phosphorus is directly cardiotoxic and can lead to myocardial ischemia 1, 18. In addition, the increased metabolic demands during refeeding, with subsequent ATP depletion, causes impaired cardiac output in a diminished left ventricle, leading to congestive heart failure 32, 33, 34. Hypophosphatemia can also cause respiratory failure secondary to decreased contractility of the diaphragm, as well as acute areflexic paralysis, paresthesias, cranial nerve palsies, delirium, and coma, all thought to be owing to tissue hypoxia [2]. Hematologic effects seen with hypophosphatemia include red blood cell, white blood cell, and platelet dysfunction. Hemolytic anemia is caused by a diminished production of 2,3-DPG and ATP. Although rare, there are possible leukocyte dysfunctions, related to chemotaxis, phagocytosis, and bactericidal activity; this could lead to increased risk of infection. Platelet dysfunction has not been reported in human subjects [1]. Some authors advocate supplementing phosphorus before and during refeeding 2, 4, 6, 11. However, by monitoring phosphorus and aggressively supplementing as needed, we were able to avert the clinical manifestations of the refeeding syndrome. Standard treatment regimens have not been established owing to limited data, as well as an inability to calculate the extent of intracellular phosphorus deficiency. However, there are several options for supplementation, depending on the clinical case. In general, a starting dose is chosen arbitrarily to correct the serum phosphorus level while simultaneously reducing side effects [37]. For moderate hypophosphatemia, oral supplementation with Neutra-phos (or other oral solutions) is usually sufficient, at a starting dose of about 30 to 60 mg/kg/day, divided three to four times per day [36]. In our patients, we have found 250 mg to 500 mg per dose to be sufficient, a range used by others as well 4, 7, 13, 36. However, with oral supplements, there is the potential for inconsistent gastrointestinal absorption and diarrhea. Therefore, for individuals with severe hypophosphatemia, it is recommended to use intravenous supplementation at a dose of 20 to 30 mg/kg/day, in divided doses, usually infused over 6 hours [27]. In our subjects, with supplementation, serum phosphorus tended to improve dramatically within 24 to 48 hours. The main limitations of this study were its retrospective nature and inability to document caloric intake in the days before admission. Many patients experienced their phosphorus nadir within 24 hours of admission. As described by Fisher et al. [6], some patients attempt to increase their weight by binging for a few days before appointments with their physician in an effort to avoid hospitalization. This may serve to explain some of the early phosphorus nadirs seen in our study. Based on our results, we cannot make recommendations for the rate of refeeding. However, many case reports describe morbidity, as well as mortality, with too vigorous initial refeeding 4, 6, 8, 9, 11, 14, 16, 18, 32, 36. Pertschuk et al. showed that the 11 patients with AN who received TPN gained weight at a faster rate than the 66 patients who received standard treatment. However, two of the 11 patients developed hypophosphatemia with neurological and respiratory symptoms, and one of these patients died [38]. Another limitation of this study was its relatively small sample size. In addition, our results may underestimate the incidence and seriousness of hypophosphatemia, because 10% of the patients with AN were treated prophylactically based on clinical grounds and were excluded from analysis. The findings of this retrospective study show that over one-quarter of adolescents with AN hospitalized for malnutrition experience mild to moderate hypophosphatemia. 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Biol Psychiatry. 1981;16:539–550. MEDLINE a Division of Adolescent Medicine, Department of Pediatrics, Schneider Children’s Hospital of the North Shore-Long Island Jewish Health System, New Hyde Park, New York, USA  Address correspondence to: Rollyn M. Ornstein, M.D., Division of Adolescent Medicine, 410 Lakeville Road, Suite 108, New Hyde Park, NY 11040, USA.
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