Abstract
OBJECTIVE:
Refeeding syndrome occurs in patients with severe malnutrition when refeeding begins after a long period of starvation. This syndrome increases the risk of clinical complications and mortality. Hypophosphatemia is considered the primary characteristic of the syndrome. The aim of our study was to investigate the presence of other electrolyte alterations in patients with cancer during the early stage of refeeding.
METHODS:
In this observational study, we enrolled 34 patients with cancer of the upper aerodigestive tract receiving upfront radiotherapy who were also enrolled in a nutrition program. A caloric intake assessment, anthropometric measurements and biochemical laboratory tests were performed.
RESULTS:
Significant weight loss (∼20%) was found in these patients. In the patients receiving artificial nutrition, we found lower levels of potassium and total protein compared with those who were fed orally (p = 0.03 for potassium and 0.02 for protein, respectively). Patients on enteral tube feeding had a higher caloric intake compared with those who were fed orally (25±5 kcal/kg/day vs. 10±2 kcal/kg/day).
CONCLUSION:
Hypokalemia, like hypophosphatemia, could be a complication associated with refeeding in patients with cancer. Hypokalemia was present in the early stages of high-calorie refeeding.
Hypokalemia; Nutrition; Cancer
INTRODUCTION
Refeeding syndrome (RS) is a common condition occurring in patients with severe malnutrition
(11. Hearing SD. Refeeding syndrome: is underdiagnosed and undertreated, but
treatable. BMJ. 2004;328(7445):908-909, http://dx.doi.org/10.1136/bmj.328.7445.908.
http://dx.doi.org/10.1136/bmj.328.7445.9...
,22. Mallet M. Refeeding syndrome. Age Ageing. 2002;31(1):65-6,
http://dx.doi.org/10.1093/ageing/31.1.65.
http://dx.doi.org/10.1093/ageing/31.1.65...
). RS is
associated with an increased risk of clinical complications and mortality (11. Hearing SD. Refeeding syndrome: is underdiagnosed and undertreated, but
treatable. BMJ. 2004;328(7445):908-909, http://dx.doi.org/10.1136/bmj.328.7445.908.
http://dx.doi.org/10.1136/bmj.328.7445.9...
,22. Mallet M. Refeeding syndrome. Age Ageing. 2002;31(1):65-6,
http://dx.doi.org/10.1093/ageing/31.1.65.
http://dx.doi.org/10.1093/ageing/31.1.65...
). The incidence of this condition
remains unknown, given the heterogeneity of the studies on this issue and the fact that RS is
frequently unrecognized. RS is characterized by electrolyte disorders, such as hypophosphatemia,
acute vitamin B1 deficiency, volume overload, cardiac insufficiency and hyperglycemia.
Furthermore, it has been suggested that potassium and magnesium may also be altered in RS (33. Love AH. Metabolic response to malnutrition: its relevance to enteral feeding.
Gut. 1986;27(1):9-13, http://dx.doi.org/10.1136/gut.27.Suppl_1.9.
http://dx.doi.org/10.1136/gut.27.Suppl_1...
,44. Powers DA, Brown RO, Cowan GS Jr, Luther RW, Sutherland DA, Drexler PG.
Nutritional support team vs nonteam management of enteral nutritional support in a Veterans
Administration Medical Center teaching hospital. J. Parenter Enteral Nutr. 1986;10(6):635-8,
http://dx.doi.org/10.1177/0148607186010006635.
http://dx.doi.org/10.1177/01486071860100...
). These electrolytes
become depleted during starvation. Successively, during refeeding, when these electrolytes enter
cells, their serum levels further decline (55. Silberman H, Eisenberg D. Parenteral nutrition: non nutritional effects and
metabolic complications. Parenteral and Enteral Nutrition for Hospitalised Patients. Norwalk:
Appleton-Century Crofts. 1982;198-203.,66. Vanlandingham S, Simpson S, Daniel P, Newmark SR. Metabolic abnormalities in
patients supported with enteral tube feeding. JPEN J Parenter Enteral Nutr.
1981;5(4):322-4, http://dx.doi.org/10.1177/0148607181005004322.
http://dx.doi.org/10.1177/01486071810050...
). Electrolyte disorders develop during the early phase of
refeeding. These conditions could influence the clinical outcomes of patients because they increase
the risk of complications (77. Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. Relationship of
nutritional status to length of stay,hospital costs,and discharge status of patients hospitalized in
the medicine service. J Am Diet Assoc. 1997;97(9):975-8; quiz 979-80,
http://dx.doi.org/10.1016/S0002-8223(97)00235-6.
http://dx.doi.org/10.1016/S0002-8223(97)...
). The aim of this study was to
investigate the eventual presence of hypokalemia during the early phase of refeeding in patients
with cancer. In particular, we investigated a population of patients affected by tumors of the upper
aerodigestive tract (UADT), which are the most distressing cancers associated with a long survival
period (88. Gao J, Panizza B, Johnson NW, Coman S, Clough AR. Basic consideration of research
strategies for head and neck cancer. Front Med. 2012;6(4): 339-353,
http://dx.doi.org/10.1007/s11684-012-0213-7.
http://dx.doi.org/10.1007/s11684-012-021...
).
METHODS
Between 2009 and 2012, approximately 200 patients with different types of cancers underwent nutritional status examinations in the Clinical Nutrition Unit at the University Magna Grecia of Catanzaro. For this investigation, only patients having at least one UATD were enrolled. We included only subjects receiving upfront radiotherapy (RTx) and who had recently started a nutritional therapy (at least 1 week before enrollment) orally or as artificial nutrition. A total of 34 individuals were enrolled. The study protocol did not require institutional review board approval because the study was observational. The data were anonymous; all of the patients provided written consent to participate in the study, which was performed in accordance with the principles of the Declaration of Helsinki.
Nutritional intake and anthropometric measurements
All of the tests were performed after a 12-h overnight fast. The participants' caloric intake was evaluated with an interview performed by a dietician during the early days of refeeding (within 1 week) and was calculated using MetaDieta nutritional software, version 3.0.1 (Metedasrl, S. Benedetto del Tronto, Italy). Body weight was measured before breakfast with the subjects lightly dressed, subtracting the weight of their clothes. Body weight was measured with a calibrated scale, and height was measured with a wall-mounted stadiometer. BMI was calculated with the following equation: weight (kg)/height2 (m2).
Bioelectrical impedance analysis (BIA) (BIA-101; Akernsrl, Florence, Italy) was performed to estimate total body water (TBW), fat mass (FM) and total fat-free mass (FFM) (99. Talluri T, Lietdke RJ, Evangelisti A, Talluri J, Maggia G. Fat-free mass qualitative assessment with bioelectric impedance analysis (BIA). Ann N Y Acad Sci. 1999;873:94-8.).
Handgrip strength was measured using a hydraulic hand dynamometer (Hersteller/manufactures;
SAEHAN Corporation, Masan, Republic of Korea; Distributor Rehaforum Medical GmbH, Elmshorn, Germany)
with the subjects seated and their elbows flexed at 90°. The handgrip strength value was
considered to be the maximum amount of kilograms of force obtained during the test (1010. Montalcini T, Migliaccio V, Yvelise F, Rotundo S, Mazza E, Liberato A, et al.
Reference values for handgrip strength in young people of both sexes. Endocrine. 2013;43(2):342-5,
http://dx.doi.org/10.1007/s12020-012-9733-9.
http://dx.doi.org/10.1007/s12020-012-973...
).
Skin fold thickness was measured at the triceps with the GIMA Skinfold Caliper (Gessate, Milan,
Italy) (1111. Kwak L, Kremers SP, Candel MJ, Visscher TL, Brug J, van Baak MA. Changes in
skinfold thickness and waist circumference after 12 and 24 months resulting from the NHF-NRG In
Balance-project. Int J Behav Nutr Phys Act. 2010;7:26,
http://dx.doi.org/10.1186/1479-5868-7-26.
http://dx.doi.org/10.1186/1479-5868-7-26...
). The site was measured three times, and the mean
was calculated.
Venous blood was collected into vacutainer tubes (Becton * Dickinson) and was centrifuged
within 4 h. For our purposes, only abnormalities in serum albumin, total protein, potassium and
sodium were investigated, all of which were assessed by standard laboratory techniques (with protein
electrophoresis and emission flame photometry for electrolytes) (1212. Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic review
of cases. Nutr Clin Pract. 2012;27(1):34-40,
http://dx.doi.org/10.1177/0884533611427916.
http://dx.doi.org/10.1177/08845336114279...
).
Statistical analysis
Data are reported as the mean ± S.D. We classified the population into three groups according to the route of nutrient intake/administration, i.e., oral nutrition (PO), enteral tube feeding (ETF) or total parenteral nutrition (TPN). Furthermore, we categorized the participants according to cancer type. The t-test and ANOVA were used to compare the means between groups. Significant differences were assumed to be present at p<0.05. All of the comparisons were performed using SPSS software, version 20.0, for Windows (Chicago, IL, USA).
RESULTS
The mean age of the population was 65±12years. A total of 82% of the population was male (n = 28). As expected, there were significant differences between genders with respect to handgrip strength (higher in men) and the number of examinations performed (higher in women) (p<0.001 and p = 0.038, respectively). Patients on PO had a mean caloric intake of 10±2 kcal/kg/day, while patients on ETF or TPN had a mean caloric intake of 25±5 kcal/kg/day.
The patient characteristics are shown in Table 1. In these patients, weight loss relative to the preceding 3-6 months was significant (19±10%).
Figure 1 depicts the types and prevalence of UADT in the patient population. The figure shows greater weight loss in patients with pharyngeal and esophageal tumors compared with the weight loss in patients with other cancer types.
Table 2 shows the significant differences in serum potassium and total protein levels between patients receiving different routes of nutrient administration, with the lowest values found in ETF patients.
DISCUSSION
In this study, we found lower potassium and total protein levels during the early phase of refeeding with artificial nutrition in patients with UADT compared with subjects who were fed orally (Table 3). In this population, we also found significant and worrisome weight loss (∼20%).
The relationship between cancer and malnutrition is well established. The percentage of patients
with malnutrition is particularly high for gastrointestinal and head and neck cancers (1313. Righini CA, Timi N, Junet P, Bertolo A, Reyt E, Atallah I. Assessment of
nutritional status at the time of diagnosis in patients treated for head and neck cancer. Eur Ann
Otorhinolaryngol Head Neck Dis. 2013;130(1):8-14,
http://dx.doi.org/10.1016/j.anorl.2012.10.001.
http://dx.doi.org/10.1016/j.anorl.2012.1...
), as confirmed by our study. It is well accepted that enteral
nutrition represents the most favorable nutritional approach because it can reduce hospital stays
and medical complications (1414. Lochs H, Pichard C, Allison SP. Evidence supports nutritional support. Clin
Nutr. 2006;25(2):177-9, http://dx.doi.org/10.1016/j.clnu.2006.02.002.
http://dx.doi.org/10.1016/j.clnu.2006.02...
). However, RS can occur as a
result of the reintroduction of nutrients in patients with severe malnutrition or in starved
patients on either ETF or TPN. Consequently, our study could play an important role in the
recognition, education and prevention of RS. In fact, it is well known that glucose levels decline
with starvation or under conditions of carbohydrate restriction (1515. Allison SP. Effect of insulin on metabolic response to injury. J. Parenter.
Enteral Nutr. 1980;4(2):175-9, http://dx.doi.org/10.1177/014860718000400221.
http://dx.doi.org/10.1177/01486071800040...
). Consequently, non-carbohydrate sources (muscle proteins) are metabolized into glucose.
In addition, in the hepatocytes, fatty acid oxidation can generate ketone bodies via the Krebs
cycle. Under this condition, there is significant depletion of potassium, phosphate and magnesium,
as well as losses of body fat and protein mass. However, a series of homeostatic mechanisms can
maintain the concentrations of these ions at normal levels (1616. Hill GL, Bradley JA, Smith RC, McCarthy ID, Oxby CB, Burkinshaw L, et al.
Changes in body weight and body protein with intravenous nutrition. J. Parenter. Enteral Nutr.
1989;3(4):215-8.). During refeeding in great quantities, when a rapid increase in serum insulin occurs
(1515. Allison SP. Effect of insulin on metabolic response to injury. J. Parenter.
Enteral Nutr. 1980;4(2):175-9, http://dx.doi.org/10.1177/014860718000400221.
http://dx.doi.org/10.1177/01486071800040...
), the movement of extracellular potassium into the
intracellular compartment can result in a dangerous decrease in potassium levels (1515. Allison SP. Effect of insulin on metabolic response to injury. J. Parenter.
Enteral Nutr. 1980;4(2):175-9, http://dx.doi.org/10.1177/014860718000400221.
http://dx.doi.org/10.1177/01486071800040...
). Symptoms occur when the changes in serum electrolytes affect
the cell membrane potential. Hypokalemia could be considered an early sign of RS, and it must be
promptly corrected. To reduce the risk of developing RS, both enteral and parenteral feeding should
be started at a reduced calorie rate (1717. Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP, et al.
Nutrition in clinical practice—the refeeding syndrome: illustrative cases and guidelines for
prevention and treatment. Eur J. Clin Nutr. 2008;62(6):687-94,
http://dx.doi.org/10.1038/sj.ejcn.1602854.
http://dx.doi.org/10.1038/sj.ejcn.160285...
). In fact, in our
population, different amounts of caloric intake were found between the groups during the early phase
of refeeding (Table 2). This finding confirms the
effects of total energy administration on the development of hypokalemia and the risk of RS (1717. Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP, et al.
Nutrition in clinical practice—the refeeding syndrome: illustrative cases and guidelines for
prevention and treatment. Eur J. Clin Nutr. 2008;62(6):687-94,
http://dx.doi.org/10.1038/sj.ejcn.1602854.
http://dx.doi.org/10.1038/sj.ejcn.160285...
). It is likely that the higher caloric administration (mean
caloric intake of 25±5 kcal/kg/day) in the ETF and TPF groups, compared with the PO group, was
the cause of the lower levels of potassium.
The results of this study are important because RS is frequently unrecognized. Dietitians, nurses and physicians play important roles in reducing the risk of RS and improving the quality of life of these particular patients.
This study had some limitations that must be addressed. First, the results of this study should be interpreted with caution, as the study was not designed to assess the mechanisms of RS.
Furthermore, because of the serious clinical conditions of and limited collaboration obtained from these patients, we did not perform an accurate nutritional intake investigation to evaluate micronutrient intake. Finally, another limitation is the small sample size, although other studies on this topic used similar sample sizes [18,19].
However, this group of patients could be considered sufficiently homogeneous because all of the patients were affected by UADT and did not have significant clinical or biochemical differences (data not shown).
In conclusion, RS remains a current, unrecognized problem, and it includes electrolyte disorders, such as hypokalemia, during the early phase of refeeding. Because patients with UADT can have longer survival periods than other patients with cancer, dietitians, nurses and physicians could improve the quality of life of these particular patients by considering the complex biochemical manifestations of RS.
REFERENCES
-
1Hearing SD. Refeeding syndrome: is underdiagnosed and undertreated, but treatable. BMJ. 2004;328(7445):908-909, http://dx.doi.org/10.1136/bmj.328.7445.908.
» http://dx.doi.org/10.1136/bmj.328.7445.908 -
2Mallet M. Refeeding syndrome. Age Ageing. 2002;31(1):65-6, http://dx.doi.org/10.1093/ageing/31.1.65.
» http://dx.doi.org/10.1093/ageing/31.1.65 -
3Love AH. Metabolic response to malnutrition: its relevance to enteral feeding. Gut. 1986;27(1):9-13, http://dx.doi.org/10.1136/gut.27.Suppl_1.9.
» http://dx.doi.org/10.1136/gut.27.Suppl_1.9 -
4Powers DA, Brown RO, Cowan GS Jr, Luther RW, Sutherland DA, Drexler PG. Nutritional support team vs nonteam management of enteral nutritional support in a Veterans Administration Medical Center teaching hospital. J. Parenter Enteral Nutr. 1986;10(6):635-8, http://dx.doi.org/10.1177/0148607186010006635.
» http://dx.doi.org/10.1177/0148607186010006635 -
5Silberman H, Eisenberg D. Parenteral nutrition: non nutritional effects and metabolic complications. Parenteral and Enteral Nutrition for Hospitalised Patients. Norwalk: Appleton-Century Crofts. 1982;198-203.
-
6Vanlandingham S, Simpson S, Daniel P, Newmark SR. Metabolic abnormalities in patients supported with enteral tube feeding. JPEN J Parenter Enteral Nutr. 1981;5(4):322-4, http://dx.doi.org/10.1177/0148607181005004322.
» http://dx.doi.org/10.1177/0148607181005004322 -
7Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. Relationship of nutritional status to length of stay,hospital costs,and discharge status of patients hospitalized in the medicine service. J Am Diet Assoc. 1997;97(9):975-8; quiz 979-80, http://dx.doi.org/10.1016/S0002-8223(97)00235-6.
» http://dx.doi.org/10.1016/S0002-8223(97)00235-6 -
8Gao J, Panizza B, Johnson NW, Coman S, Clough AR. Basic consideration of research strategies for head and neck cancer. Front Med. 2012;6(4): 339-353, http://dx.doi.org/10.1007/s11684-012-0213-7.
» http://dx.doi.org/10.1007/s11684-012-0213-7 -
9Talluri T, Lietdke RJ, Evangelisti A, Talluri J, Maggia G. Fat-free mass qualitative assessment with bioelectric impedance analysis (BIA). Ann N Y Acad Sci. 1999;873:94-8.
-
10Montalcini T, Migliaccio V, Yvelise F, Rotundo S, Mazza E, Liberato A, et al. Reference values for handgrip strength in young people of both sexes. Endocrine. 2013;43(2):342-5, http://dx.doi.org/10.1007/s12020-012-9733-9.
» http://dx.doi.org/10.1007/s12020-012-9733-9 -
11Kwak L, Kremers SP, Candel MJ, Visscher TL, Brug J, van Baak MA. Changes in skinfold thickness and waist circumference after 12 and 24 months resulting from the NHF-NRG In Balance-project. Int J Behav Nutr Phys Act. 2010;7:26, http://dx.doi.org/10.1186/1479-5868-7-26.
» http://dx.doi.org/10.1186/1479-5868-7-26 -
12Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic review of cases. Nutr Clin Pract. 2012;27(1):34-40, http://dx.doi.org/10.1177/0884533611427916.
» http://dx.doi.org/10.1177/0884533611427916 -
13Righini CA, Timi N, Junet P, Bertolo A, Reyt E, Atallah I. Assessment of nutritional status at the time of diagnosis in patients treated for head and neck cancer. Eur Ann Otorhinolaryngol Head Neck Dis. 2013;130(1):8-14, http://dx.doi.org/10.1016/j.anorl.2012.10.001.
» http://dx.doi.org/10.1016/j.anorl.2012.10.001 -
14Lochs H, Pichard C, Allison SP. Evidence supports nutritional support. Clin Nutr. 2006;25(2):177-9, http://dx.doi.org/10.1016/j.clnu.2006.02.002.
» http://dx.doi.org/10.1016/j.clnu.2006.02.002 -
15Allison SP. Effect of insulin on metabolic response to injury. J. Parenter. Enteral Nutr. 1980;4(2):175-9, http://dx.doi.org/10.1177/014860718000400221.
» http://dx.doi.org/10.1177/014860718000400221 -
16Hill GL, Bradley JA, Smith RC, McCarthy ID, Oxby CB, Burkinshaw L, et al. Changes in body weight and body protein with intravenous nutrition. J. Parenter. Enteral Nutr. 1989;3(4):215-8.
-
17Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP, et al. Nutrition in clinical practice—the refeeding syndrome: illustrative cases and guidelines for prevention and treatment. Eur J. Clin Nutr. 2008;62(6):687-94, http://dx.doi.org/10.1038/sj.ejcn.1602854.
» http://dx.doi.org/10.1038/sj.ejcn.1602854
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Nov 2013
History
-
Received
3 Apr 2013 -
Reviewed
14 May 2013 -
Accepted
28 May 2013