TX de Malnutrici (On Calorico Proteica en Enf Cronica No Maligna

Review Article
Treatment of protein-energy malnutrition in chronic nonmalignant disorders1,2

Gunnar Akner and Tommy Cederholm
ABSTRACT Protein-energy malnutrition (PEM) is common in connection with chronic disease and is associated with increased morbidity and mortality. Because the risk of PEM is related to the degree of illness, the causal connections between malnutrition and a poorer prognosis are complex. It cannot automatically be inferred that nutritional support will improve the clinical course of patients with wasting disorders. We reviewed studies of the treatment of PEM in cases of chronic obstructive pulmonary disease, chronic heart failure, stroke, dementia, rehabilitation after hip fracture, chronic renal failure, rheumatoid arthritis, and multiple disorders in the elderly. Several methodologic problems are associated with nutrition treatment studies in chronically ill patients. These problems include no generally accepted denition of PEM, uncertain patient compliance with supplementation, and a wide range of outcome variables. Available treatment studies indicate that dietary supplements, either alone or in combination with hormonal treatment, may have positive effects when given to patients with manifest PEM or to patients at risk of developing PEM. In chronic obstructive pulmonary disease, nutritional treatment may improve respiratory function. Nutritional therapy of elderly women after hip fractures may speed up the rehabilitation process. When administered to elderly patients with multiple disorders, diet therapy may improve functional capacity. The data regarding nutritional treatment of the conditions mentioned above is still inconclusive. There is still a great need for randomized controlled long-term studies of the effects of defined nutritional intervention programs in chronically ill and frail elderly with a focus on determining clinically relevant outcomes. Am J Clin Nutr 2001;74:624. KEY WORDS Protein-energy malnutrition, chronic obstructive pulmonary disease, chronic heart failure, stroke, dementia, hip fracture, chronic renal failure, rheumatoid arthritis, elderly, nutritional support mortality, and extended hospital stays (1, 2). The causality of these connections is not clear. In addition, reduced food intake and breakdown of body tissues are partly the result of biochemical mechanisms activated by the disease. Accordingly, it is not certain that nutritional supplements can correct disease-related malnutrition or improve a patients health or prognosis. The purpose of this review was to summarize studies that evaluated the effect of nutritional treatment in cases of PEM or risk of PEM in connection with certain chronic disorders: chronic obstructive pulmonary disease (COPD), chronic heart failure, poststroke conditions, dementia, rehabilitation after hip fracture, chronic renal failure, rheumatoid arthritis, and multiple disorders in the elderly. We also briefly discuss the prevalence of PEM, the pathogenesis of catabolism, and the consequences of malnutrition in each of the disorders.
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METHODOLOGIC ASPECTS Most patients with chronic catabolic disorders can eat and drink unaided and have a functioning gastrointestinal tract. In most of the treatment studies described here, the treatment consisted of food enrichment or of oral supplements in the form of liquid nutritional drinks. Some studies involved enteral nutrition via a nasogastric tube or percutaneous endoscopic gastrostomy (PEG). We also evaluated studies in which pharmacologic interventions were used, eg, growth hormone or anabolic steroids, either alone or in combination with nutritional supplementation. MEDLINE (National Library of Medicine, Bethesda, MD) was searched for original articles by using the OVID and PUBMED query programs. Through MEDLINE searches and with access to our own and others reference files, we found 90 treatment-oriented studies [50 randomized controlled trials (RCTs) and 40 less-well-controlled studies] relevant to the disorders we were studying (Figure 1). For a better overview, the treatment studies are presented in tabular form in chronologic order with RCTs followed by controlled, nonrandomized, and
1 From the Departments of Geriatric Medicine at Karolinska Hospital and Huddinge University Hospital, Stockholm. 2 Reprints not available. Address correspondence to T Cederholm, Department of Geriatric Medicine, B56, Huddinge University Hospital, 141 86 Stockholm, Sweden. E-mail: tommy.cederholm@ger.hs.sll.se. Received October 2, 2000. Accepted for publication January 29, 2001.
INTRODUCTION Most longstanding, chronic diseases of the organsparticularly of the lungs, heart, nervous system, skeleton, kidneys, and jointsare associated with both general and specific catabolic or hypermetabolic processes, including reduced nutrient intake, that may lead to protein-energy malnutrition (PEM) in some individuals. Extensive documentation exists of the strong relation between PEM in chronic disease and increased morbidity, 6
Am J Clin Nutr 2001;74:624. Printed in USA. 2001 American Society for Clinical Nutrition
TREATMENT OF PEM IN CHRONIC DISEASE
FIGURE 1. Number of summarized nutrition intervention trials [either randomized controlled trials (RCTs) or observational trials (OTs)] in patients with chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), poststroke conditions, dementia (Dem), rehabilitation after hip fracture (Hip), chronic renal failure (CRF), and rheumatoid arthritis (RA) and in frail elderly with multiple disorders (Elderly).
tion with nutritional supplements (5, 3638), positive effects were noted for anthropometric measures and in 2 studies (5, 38) for muscular function. In 2 RCTs (27, 34), patients with COPD but without PEM were treated with nutritional supplements; in one of the studies (27), a positive effect on pulmonary function was noted. In a recent meta-analysis that included 277 subjects from 9 RCTs, the authors concluded that energy supplementation for 2 wk has no effect on anthropometric measures, lung function, or functional exercise capacity in patients with stable COPD (40). In one study, COPD patients not responding to nutritional supplementation were characterized by increased age, anorexia, and an elevated inflammatory systemic response (41). In summary, nutritional treatment of PEM in connection with COPD may positively affect body composition as well as muscular strength and respiratory function.
uncontrolled trials, respectively. In each section, food supplementation studies and studies with other forms of intervention are presented separately.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE The prevalence of malnutrition is reported to vary between 20% and 70% for different patient groups with COPD and appears highest in combination with emphysema (36). Malnutrition in patients with COPD is associated with an imbalance between energy expenditure and dietary intake (712). A study with doubly labeled water showed that although the basal metabolic rate was not higher in COPD patients, their total energy metabolism was 20% higher than in matched control subjects (10). Inflammatory activity probably contributes to catabolic processes (1316). In a recent study of COPD patients in a stable phase, it was reported that the basal metabolic rate is related to plasma concentrations of tumor necrosis factor (TNF- ), but not to respiratory function (17). The nutritional deterioration is aggravated during exacerbations of the disease (8, 18). The loss of lean body mass leads to reduced diaphragm mass (19), poorer respiratory muscle function (20, 21), and reduced peripheral skeletal muscle function (22, 23). Low body weight is an independent predictor of mortality in COPD (24, 25). As early as 30 y ago it was reported that COPD patients with weight loss have a shorter 5-y survival rate (average survival time of 3 y) than do COPD patients with no weight loss (26). In Table 1 we summarize 14 studies (5, 2739), 12 of which were RCTs. All but one (38) included 933 patients each, with treatment periods of 252 wk. Nine of the studies (8 RCTs: 5, 29, 3134, 3638) reported positive effects of nutritional treatment on various anthropometric measures, particularly body weight. Eight studies (7 RCTs: 5, 2731, 33, 38) noted functional improvements in the skeletal musculature (respiratory or extremity musculature), pulmonary or immune function, or a sense of well-being. Five studies (4 RCTs: 5, 29, 31, 33, 38) found positive effects on both anthropometric and functional measures. Two studies (both RCTs: 35, 39) recorded no effect of nutritional treatment. None of the studies reported effects on mortality. In the 4 studies involving treatment of COPD patients with anabolic steroids or growth hormone, alone or in combina-
CHRONIC HEART FAILURE The prevalence of PEM in connection with chronic heart failure, ie, cardiac cachexia (4245), varies between 10% and 25%, depending on the type of heart-failure patients studied (4650). The effects of increased usage of angiotensin-converting enzyme inhibitors in reducing the risk of developing cardiac cachexia has not been studied. Examples of pathophysiologic mechanisms, traditionally viewed as leading to cardiac cachexia, are reduced appetite or feeling full sooner, secondary portal hypertension with venous stasis in the hepatic-splanchnic area with dyspepsia, malabsorption of lipids and protein loss in the gut, and abnormalities in catecholamine kinetics (45, 5155). Cytokine-triggered catabolism, in conjunction with neuroendocrine abnormalities (56, 57), contributes to cardiac cachexia (5861). Although patients with chronic heart failure have 1520% higher basal metabolic rates than do matched control subjects (54, 62), total daily energy expenditure as measured by the doubly labeled water technique is lower in these patients (63). PEM causes a hypotrophy of the cardiac muscle in proportion to the hypotrophy of the skeletal muscles (64). In healthy individuals, this can partially be an adaptive mechanism to reduced metabolic requirements (bradycardia, hypotension, and reduced blood volume), which seldom gives rise to clinical cardiac insufficiency (52). Nutritional therapy in malnourished individuals may provoke cardiac insufficiency, ie, a refeeding syndrome, particularly in connection with parenteral nutrition (45, 52). PEM in patients with chronic heart failure is associated with elevated mortality rates (6567). In Table 2 we report the results of 4 studies of oral supplementation in cardiac patients. In one RCT, performed in patients without PEM, 8 wk of liquid dietary supplementation increased subcutaneous fat (49). The other 3 studies comprised a small number of patients. Two of the studies (64, 69) noted some improvement of cardiac function after nutritional treatment. In the former study (64), 2 of 5 cachectic patients developed cardiac decompensation after 3 wk of hyperalimentation. Recently, growth hormone treatment was attempted in patients with various forms of cardiomyopathy. Six of these reports (7075) are summarized in Table 3. In one study (72), growth hormone treatment worsened the clinical course of 3 patients with severe chronic heart failure, but appeared to be beneficial in 7 patients with more moderate chronic heart failure. Nutritional status was not assessed in any of the reports. Initially promising
TABLE 1 Nutritional treatment studies of patients with chronic obstructive pulmonary disease1 Effect Patients n2 PEM Type g/d RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT Yes Yes Yes Testosterone 27 wk 3 wk 8 wk Yes Oral supplement 5001000 kcal/d4 8 wk 184 No Oral supplement 360540 kcal/d4 8 wk 21324 Yes Oral supplement 690 kcal/d4 3 mo 294 Yes Oral supplement 400 kcal/d4 13 wk 204 Yes Enteral feeding (NG) 1000 kcal/d4 0 6d Weight Yes Oral supplement 1080 kcal/d4 3 wk No effect 434 Yes Diet? 0.3 REE4 4 mo Weight Yes Diet Energy 12 mo No effect No Oral supplement 10 kcal/kg BW4 2 wk 104 Lung function No effect on function; well-being Protein Duration Anthropometric or biochemical index Function or mortality Nutritional treatment Energy3
Author, year, and reference
Study design
Saudny-Unterberger et al, 1997 (27) Ganzoni et al, 1994 (28)
Rogers et al, 1992 (29)
Fuenzalida et al, 1990 (30)
Muscle strength (respiratory, grip, walking) Immunity Respiratory muscle strength
Whittaker et al, 1990 (31)
Otte et al, 1989 (32)
Efthimiou et al, 1988 (33)
Knowles et al, 1988 (34)
Weight ; subcutaneous fat Anthropometry ; lean body mass Weight No effect Anthropometry Lean body mass
No effect on function Muscle strength (respiratory, grip, walking); well-being No effect on function No effect on function No effect on function No effect on function Respiratory muscle strength
Lewis et al, 1987 (35)
Ferreira et al, 1998 (36)
Burdet et al, 1997 (37)
AKNER AND CEDERHOLM
Schols et al, 1995 (38)
24 [33] 20 [30] 24 [27] 9 [9] 10 [10] 28 [28] 14 [14] 25 [25] 21 [21] 17 [23] 16 [16] 203 [217] Diet and growth 40 kcal/kg BW5 hormone Oral supplement with 420 kcal/d4 and without nandrolone
Sridhar et al, 1994 (39) Pape et al, 1991 (5)
UCT UCT
9 7
Yes Yes
1.5 g/kg BW5 1/kg BW5

15
Oral supplement Diet and growth hormone
50%4 35 kcalkg BW 1 d
4 mo 3 wk
Weight (oral supplement fat , combination lean body mass ) No effect Weight , nitrogen balance
No effect on function Respiratory muscle strength
BW, body weight; NG, nasogastric tube; PEM, protein-energy malnutrition; RCT, randomized controlled trial; REE, resting energy expenditure; UCT, uncontrolled trial. Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Intended supplementation. 5 Estimated total intake.
TABLE 2 Nutritional treatment studies of patients with chronic heart failure1 Effect Patients n2 PEM Type g/d 19 [22] 8 5 9 Yes6 8 wk 1350 kcal/d4 484 Yes6 46 wk Enteral or parenteral nutrition Oral supplement 30004000 kcal/d5 751355 Yes Enteral feeding 35 kcal/kg BW5 2 wk 1/kg BW5 No Oral supplement 750 kcal/d4 8 wk 304 No effect on function Protein Duration Nutritional treatment Energy3 Anthropometric or biochemical index Function or mortality
Study design
Broqvist et al, 1994 (49)
RCT, placebo
Heymseld and Casper, 1989 (68) CT UCT UCT
No effect on function
Heymseld et al, 1978 (64)
Chhetri et al, 1982 (69)
Subcutaneous fat ; no effect on metabolic markers in muscle Weight ; lean body mass Weight ; left ventricular mass
Cardiac function ; 2 partially decompensated Pre-ejection period ; left ventricular ejection time
BW, body weight; CT, controlled trial; PEM, protein-energy malnutrition; RCT, randomized controlled trial; UCT, uncontrolled trial. Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Intended supplementation. 5 Estimated total intake. 6 The study subjects had no cardiac illness.
TABLE 3 Growth hormone (GH) and pentoxifylline (P) treatment studies of patients with dilated cardiomyopathy (DCM) or chronic heart failure (CHF)1 Patients Study design RCT, placebo RCT, placebo RCT, placebo CT CHF DCM P GH CHF GH DCM GH n2 Diagnosis Type Treatment Duration 12 wk 3 mo 6 mo 6 mo Effect
Osterziel et al, 1998 (70)
Isgaard et al, 1998 (71)
Sliwa et al, 1998 (76)
Serum IGF-I ; LVM ; no effect on NYHA functional class, EF, or walking ability Serum IGF-I ; no effect on cardiac or overall function EF ; NYHA functional class ; serum TNF
Spallarossa et al, 1999 (72)
50 [50] 20 [22] 24 [28] 15
Jos et al, 1999 (73) Genth-Zotz et al, 1999 (74)
UCT UCT
6 7
DCM CHF
GH GH
6 mo 3 mo
Fazio et al, 1996 (75)
UCT
DCM
GH
3 mo
Serum IGF-I ; exercise capacity and well-being ; worse clinical course in patients with severe CHF LVM ; NYHA functional class Serum IGF-I ; LVM ; cardiac output ; NYHA functional class ; effects reversed 3 mo after discontinuation of treatment Serum IGF-I ; LVM ; cardiac output ; exercise capacity and life quality ; effects partly reversed 3 mo after discontinuation of treatment
1 CT, controlled trial; EF, ejection fraction; IGF-I, insulin-like growth factor I; LVM, left ventricular mass; NYHA, New York Heart Association; RCT, randomized controlled trial; TNF, tumor necrosis factor; UCT, uncontrolled trial. 2 Number of patients analyzed per protocol; number of subjects randomly assigned in brackets.
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AKNER AND CEDERHOLM In a meta-analysis of interventions against dysphagia in connection with acute stroke, the Cochrane Library (95) concluded that too few studies have been performed. PEG may improve the outcome and nutritional status of stroke patients in comparison with a nasogastric nutrient supply, but more studies of nutritional treatment in patients after stroke are needed. In dysphagia that is considered permanent, PEG inserted 2 wk after the onset of a stroke is preferable to a nasogastric tube.
results on cardiac function and clinical status were not confirmed by 2 RCTs. One RCT evaluated the effect of the TNF-modulating drug pentoxifylline in patients with idiopathic dilated cardiomyopathy. Improved left ventricular systolic function and New York Heart Association functional class were reported (76). Nutritional support in patients with chronic heart failure is complicated because the patients fluid and salt intakes should not exceed 1.5 L and 2 g Na per 24 h, respectively. Therefore, patients with cardiac cachexia should preferably consume highenergy, limited-sodium diets (54, 77). As summarized here, the nutritional treatment of PEM associated with chronic heart failure has been insufficiently studied.
POSTSTROKE CONDITIONS Eight to sixteen percent of stroke patients show signs of PEM at the time of stroke (7880). The frequency of malnutrition increases during the hospital stay: in one study from 16% at hospitalization to 22% at discharge (78) and in another study from 16% to 26% after 1 wk (80). More than 80% of patients hospitalized for > 21 d because of stroke had difficulty eating (81). About one-half of patients referred to a stroke rehabilitation clinic were malnourished (82). The effect of a stroke on many aspects of function can contribute to a patients nutritional impairment. Dysphagia afflicts 3045% of stroke patients (8384). Within 2 wk most stroke patients (87%) regain the ability to swallow (83, 85). Waiting for spontaneous improvement in the ability to swallow, and the lack of guidelines based on the results of controlled studies, often delays stroke and dysphagia patients nutritional supply (86). Other contributing factors to the risk of malnutrition after stroke are paralysis of the dominant side of the body and communication and perception disorders such as aphasia and an altered sense of smell and taste. Davalos et al (80) speculated whether an acute catabolic phase, expressed as increased cortisol concentrations in the urine and plasma, contributes to a negative energy and nutritional balance that may cause a rapid deterioration in the nutritional status of many stroke patients. Malnutrition in stroke patients is associated with an increased rate of infection, bed sores, extended treatment periods, and increased mortality (80, 87). As with many other conditions, hypoalbuminemia is a strong predictor of an unfavorable progression after stroke (88). Listed in Table 4 are 7 studies (3 RCTs: 80, 8994) that represent different types of nutritional treatment, focusing on the prevention of nutritional deterioration after a stroke. In one RCT (89), an increased nutritional intake and less pronounced deterioration of nutritional status were noted as a result of peroral nutritional supplementation. In one uncontrolled short-term study (80), treatment was unable to prevent the deterioration of nutritional status despite a nasogastric nutrient supply. In one RCT (90), PEG was compared with nasogastric tube feeding (NG). Mortality was signicantly lower, the hospital-stay shorter, the number of complications (aspiration pneumonia) fewer, and the nutritional status better in the PEG group than in the NG group. A retrospective study of the long-term results of stroke patients who received PEG showed that 25 of 37 consecutive patients died within 3 mo (92). The extent to which these patients poor prognoses were due to insufcient nutritional intake before the gastrostomy was unclear. Two studies evaluated the effects of dietary guidance and swallowing exercises in dysphagic stroke patients (91, 94).
DEMENTIA Malnutrition occurs in 1250% of institutionalized patients with dementia disorders (9698). The frequency is reported to be higher in dementia of Alzheimer type (DAT) than in vascular dementia (99). Within 8 y of the onset of DAT, 50% of patients need help with feeding or require artificial nutrition (100). An annual weight loss of 4% was reported in institutionalized patients with DAT (101). Dementia leads to a reduced intake of energy, partly because of decreased appetite, hunger, and thirst; dyspraxia of eating function, such as chewing and swallowing; altered perception of smell and taste; refusal to eat; and forgetting to eat. Some DAT patients may have hyperactivity-related energy losses, but studies of energy metabolism in connection with dementia, performed with different techniques, produced conflicting results (102105). Weight loss was retrospectively observed to precede the onset of dementia (106). Inflammatory processes in the brain are suggested to be of etiologic importance in DAT, and patients with DAT show increased concentrations of TNF- and other proinflammatory cytokines in both plasma and cerebrospinal fluid (107109). We can speculate as to whether this may contribute to the weight loss. There is also evidence that patients with DAT have a general loss of homeostatic regulatory mechanisms, such as thermoregulation and cardiovascular reflexes, which can reduce the ability to conserve energy (101). A 6-y longitudinal study correlated weight loss with the degree and progress of DAT and with mortality, whereas weight gain was related to a reduced mortality risk (110). One RCT showed the results of diet therapy for dementia patients with PEM at a British psychiatric hospital (98). Of nearly 300 patients, 80 (27%) were underweight. Of these, 46 were included in a randomized treatment study using liquid dietary supplements of 600 kcal/d ( 2500 kJ/d) for 12 wk. The intervention group gained an average of 3.5 kg, whereas the control group maintained a stable weight. No evaluation of functional capacity or mortality was performed. The controversial use of tube feeding in cases of severe dementia was recently reviewed (111). A retrospective study of individuals with severe cognitive disorders in nursing homes found no survival advantages in those who were tube-fed compared with those who were not (112). In conclusion, the nutritional treatment of PEM associated with dementia has been insufficiently studied.
REHABILITATION AFTER HIP FRACTURE As many as one-half of all elderly patients who suffer hip fractures are malnourished (113116). Insufficient nutrient intake can contribute to osteoporosis, which is often an important cause of fractures in the elderly. PEM is also associated with muscular weakness and therefore an increased risk of falling (117) and reduced subcutaneous fat to cushion the fall (118). Prospective
TABLE 4 Nutritional treatment studies of stroke patients1 Effect n2 Type Oral supplementation 600 kcal/d
4
Author, year, and reference Duration 4 wk Function or mortality 40 [42] 30 [30] Yes Yes and no 2000 kcal/d5 (diet) or 30 kcalkg BW 1 d 1 (NG) 1 wk No effect, ie, percentage with low TSF, AMC, or serum albumin , from 17% to 32%, despite nutrition Yes 100 mL/h5 6 wk No
Study design
Patients Dysphagia Anthropometric or biochemical index
Nutritional treatment Energy3
Gariballa et al, 1998 (89)
RCT
Norton et al, 1996 (90)
RCT
Mortality ; hospital stay ; complications with PEG
DePippo et al, 1994 (91)
RCT
Serum albumin in control subjects; intake of energy (75%) and protein (50%) Weight and serum albumin with PEG; weight and serum albumin with NG
Davalos et al, 1996 (80)
UCT
114 [115] 91
Enteral feeding via PEG or NG (14 d after onset of stroke) Three levels of dysphagia training Diet or enteral feeding (NG) in case of dysphagia
Limited instructions as good as more intense
Wanklyn et al, 1995 (92) 52
UCT
37
Yes?
Nyswonger and Helmchen, 1992 (93) 38 Yes
UCT
25 of 37 patients died within 3 mo Hospital stay : 20 d with early NG or 29 d with late NG
Elmsthl et al, 1999 (94)
UCT
PEG 26 d (median) after onset of stroke Enteral feeding (NG) initiated before or after 72 h of stroke Training of oral muscles and swallowing technique
60% improved their swallowing and nutritional status
Protein-energy malnutrition was not used as a selection criterion in any of the studies. AMC, arm muscle circumference; BW, body weight; NG, nasogastric tube; PEG percutaneous endoscopic gastrostomy; RCT, randomized controlled trial; TSF, triceps skinfold thickness; UCT, uncontrolled trial. 2 Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Intended supplementation. 5 Estimated total intake.
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TABLE 5 Nutritional treatment studies in elderly patients during rehabilitation after hip fracture1 Effect Study design Type g/d No No 5 Enteral feeding Oral supplement Oral supplement Oral supplement 400 kcal/d4 3 wk 144 250 kcal/d4 32 d 204 204 38 d No No Yes 1500 kcal/d6 656 12 wk7 Enteral feeding 1400 mL/d4 15 d No effect Oral supplement 204 6 mo Bone density ; serum IGF-I Duration Function or mortality Patients n2 PEM Anthropometric or biochemical index Nutritional treatment Energy3 Protein
Schurch et al, 1998 (120) RCT RCT
RCT, placebo
Sullivan et al, 1998 (121)
Hartgrink et al, 1998 (122)
Hospital stay (in 1 y) : 33 compared with 54 d 6-mo mortality : 0% compared with 50% No effect on pressure sore risk
Tkatch et al, 1992 (123) RCT RCT? 38 [49] 122 [122] Yes Enteral feeding 1000 kcal/d4 4 wk 284
RCT, placebo
Hemoglobin ; serum albumin
Delmi et al, 1990 (124)
63 [82] 15 [18] 116 [129] 62 [68] 59
Williams et al, 1989 (125)
Complications ; hospital stay in 7 mo: 70 compared with 102 d Complications ; hospital stay : 24 compared with 40 d No effects on mobility or hand grip strength
Bastow et al, 1983 (126)
RCT
TSF and AMC unchanged in treatment group and in control subjects AMC
Sloan et al, 1992 (127)
RCT, placebo
29 [31]
No
Nandrolone, 2 mg/kg8 4 wk
No positive or negative effects
Faster rehabilitation: 10 compared with 12 d and 16 compared with 23 d in thin and very thin, respectively
AKNER AND CEDERHOLM
AMC, arm muscle circumference; IGF-I, insulin-like growth factor I; PEM, protein-energy malnutrition; RCT, randomized controlled trial; TSF, triceps skinfold thickness. Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Intended supplementation. 5 High-risk patients for pressure sore. 6 Estimated total intake. 7 High rate of tube intolerance. 8 Intramuscular dose.
TREATMENT OF PEM IN CHRONIC DISEASE epidemiologic studies showed that maintained weight after menopause is a significant factor in preventing fractures (119). A study evaluating the prognostic importance of PEM in patients with hip fractures noted that the risk of PEM was associated with longer hospitalization and a lower degree of rehabilitation (114). Eight studies of postoperative nutritional treatment of hipfracture patients are summarized in Table 5 (120127). All studies were controlled and randomized, but the randomization procedure was not always clearly described. Two studies described the treatment of established PEM in hip-fracture patients (125, 126), whereas the other studies did not use PEM as an inclusion criterion. Four dietary supplement studies reported a shorter hospitalization period for those who received supplements (120, 123, 124, 126). Two studies from the same researchers showed fewer postoperative complications, such as infections (123, 124). One study indicated beneficial effects on mortality (121). However, the number of deaths was small. In one of the studies, researchers noted that a 4-wk treatment with anabolic steroids (nandrolone) had no effect (127). A meta-analysis of 943 patients aged > 65 y performed by the Cochrane Library (128) concluded that there was evidence of positive effects of oral protein and energy supplements. In general, however, the quality of the studies was assessed as low and further studies were requested. In conclusion, oral or enteral postoperative treatment with balanced or protein-rich nutritional supplements (protein supplement of 20 g/d) for 34 wk may shorten hospitalization periods in hip-fracture patients.
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a positive effect of nutritional treatment on anthropometric or biochemical measures. Five studies (3 RCTs) found positive functional effects of nutritional therapy (149, 150, 153, 163, 164), 2 studies (1 RCT) found no functional effect (152, 161), and the other 16 studies (including all oral supplementary studies) did not investigate functional measures. For patients who do not tolerate oral or enteral nutrition, IDPN [ie, intravenous supplementation of glucose, amino acids, or lipids during the hemodialysis sessions (170)] can provide a high protein-to-energy quotient to compensate for a poor protein intake. Existing studies, including an RCT (153), show small positive effects on weight (153, 161, 162) and biochemical nutritional markers (168), improved immune function (163), and possibly improved survival rates (155, 156, 164). The use of IDPN was recently reviewed (171), and an evidence-based evaluation concluded that the data supporting the use of IDPN are weak and that no clear recommendation can be made (172). In conclusion, the available nutritional treatment studies of PEM associated with renal failure indicate positive effects on anthropometric and biochemical variables. However, only a few studies, and no oral supplementary study, reported clinical outcome data.
CHRONIC RENAL FAILURE The prevalence of PEM in patients with chronic renal failure is reported to vary between 30% and 76% (129132); PEM is particularly common in elderly patients, especially those with chronic renal failure secondary to diabetes mellitus (133). PEM in connection with chronic renal failure is multifactorial and depends on nutritional, metabolic, hormonal, and inflammatory factors (134135). The prescription of protein-restricted diets to persons with chronic renal failure may contribute to the risk of PEM (136). Metabolic acidosis can contribute to muscular proteolysis (134) and reduced albumin synthesis (137). However, it is unclear whether the development of PEM can be inhibited by treating the metabolic acidosis (138). Other factors that contribute to PEM in patients with chronic renal failure are insulin resistance, increased glucagon concentrations, secondary hyperparathyroidism, and reduced thyroid hormone concentrations. In addition, comorbidity factors also occur, such as diabetes mellitus, depression, drug-induced side effects, and physical inactivity. It is unclear whether patients with chronic renal failure have an elevated energy metabolism (133, 139141). The activity of proinflammatory cytokines with anorexic and muscular catabolic effects is elevated in cases of renal failure and is associated with the development of PEM (142). PEM is a strong risk factor for both morbidity and mortality in connection with chronic dialysis (143145). Data also exist that implicate PEM per se as having a negative effect on renal function (146). Summarized in Table 6 are 23 studies (7 RCTs: 147169) reporting the effects of various forms of nutritional treatment: oral supplementation (7 studies), hormonal therapy (9 studies), and intradialytic parenteral nutrition (IDPN; 7 studies). The studies comprised 750 patients each and the treatment periods ranged from 7 d to 12 mo. Twenty-one studies (7 RCTs) reported
RHEUMATOID ARTHRITIS The prevalence of malnutrition in cases of rheumatoid arthritis varies between 26% and 71% (173, 174). Rheumatoid arthritis patients seldom have reduced appetites and can suffer from pronounced malnutrition that goes undetected at clinical examination (175). However, young persons with rheumatoid arthritis are rarely malnourished (176). Rheumatoid arthritis implies a risk of PEM for several reasons. Patients with rheumatoid arthritis lose muscle mass even if they have high protein intakes (177), which is consistent with the catabolism linked to the chronic inflammatory process. This in turn is consistent with findings of increased systemic TNF- activity being related to the development of PEM in rheumatoid arthritis (175, 177). The activity of the disorder (ie, pronounced radiological changes, extraarticular manifestations, and low functional class) is a strong indicator of risk of PEM (173, 178). Often the patient loses weight during flareups (179). New treatment strategies, focused specifically on TNF activity, are being introduced for rheumatoid arthritis (180, 181). The effects that these strategies have on the general disorder-related catabolism are as yet unknown. Other contributing factors to PEM in rheumatoid arthritis can be adaptation to low physical activity, treatment with systemic glucocorticoids (182), and sicca in associated Sjgren syndrome. In addition, repeated periods of fasting or elimination diets to reduce the activity of the rheumatoid arthritis may contribute to the risk of PEM in rheumatoid arthritis patients. No studies have been published on the effect of nutritional treatment of PEM associated with rheumatoid arthritis.
MULTIPLE DISORDERS IN THE ELDERLY The combination of advanced age, multiple chronic disorders, and polypharmacy leads to an increased risk of PEM. In one study of internal medicine patients (49), the prevalence of malnutrition was twice as high among patients aged > 74 y (27%) than among those aged 6574 y (13%). PEM occurs in 2050%
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TABLE 6 Nutritional treatment studies of patients with chronic renal failure1 Effect Patients n2 Dialysis PEM Yes 32 kcal/kg BW
4
Author, year, and reference Type 8 g/d

5
Study design Protein 3 mo Weight ; muscle mass ; AA prole Weight ; LBM ; fat mass LBM Duration 19 [22] HD HD HD HD Yes GH 6 mo No GH 6 mo 6 mo 400600 kcal/d5 6 mo HD
Nutritional treatment Energy3 Anthropometric or biochemical index Function or mortality
Tietze et al, 1991 (147)
RCT
Allman et al, 1990 (148)
RCT
Johansen et al, 1999 (149)
Oral supplement (sh proteins) No Glucose polymer Yes Nandrolone
Mobility ; feeling of fatigue Mobility ; hand grip strength
Johannsson et al, 1999 (150)
Jensen et al, 1999 (151)
RCT, placebo RCT, placebo RCT, placebo 17 [17] 26 18 7 HD HD Yes HD Yes 3 mo HD, PD Yes 48 wk
21 [32] 26 [29] 17 [20] 20 [31]
Iglesias et al, 1998 (152)
RCT
No effect on function
Cano et al, 1990 (153)
RCT
Diet and GH or diet alone IDPN
DCH
Kuhlmann et al, 1999 (154)
CT
AKNER AND CEDERHOLM
Chertow et al, 1994 (155)
CT
Oral supplement IDPN
45 and 35 kcal/ kg BW4,6
1.5 and 1.2 g/ 3 mo kg BW4,6 12 mo
Fat free mass ; serum IGF-I ; serum albumin LBM ; fat mass ; serum IGF-I ; serum IGFBP-1 ; serum IGFBP-3 Weight ; serum IGF-I ; serum transferin ; serum urea in the diet + GH group Weight ; AMC ; serum albumin Weight in high energy and protein intake group
Capelli et al, 1994 (156) 15 HD No EAA and energy EAA
CT
50
HD
Yes
IDPN
9 mo 14 d
Weight ; fat mass
Mortality if serum albumin 35 g/L or serum creatinine 8 mg/dL; mortality if serum albumin > 35 g/L; immunity Mortality
Acchiardo et al, 1982 (157)
CT
670725 kcal/ dialysis5 665 kcal/d5
75100 g/ dialysis5 6.6 (1 g/ kg BW)5
Hecking et al, 1978 (158) 22 8 7 16 HD HD Yes Yes PD ? HD Yes
CT
13
HD
Yes (?)
3 mo 6 mo 15 g/d5 4 mo
Serum protein ; serum albumin ; serum transferin ; TLC ; bone density No effect 16 (1 g/ kg BW)5 0 Anthropometry ; fat mass Nitrogen balance
Milano et al, 1998 (159)
UCT
35 kcal/ kg BW4 380 kcal/d5 85 kcal/d5 700 kcal/dialysis5
Elias et al, 1989 (160)
UCT
Berneis et al, 1999 (161) Mortelmans et al, 1999 (162)
UCT UCT
Oral supplement Oral supplement IDPN IDPN
3 mo 9 mo
No effect on quality of life
Smolle et al, 1995 (163)
UCT
16
HD
Yes
IDPN
16 wk
Weight ; fat mass ; LBM Weight ; fat mass ; serum prealbumin ; serum transferrin No effect on anthropometry; serum albumin ; serum prealbumin ; TLC
DCH
(Continued)
TABLE 6 (Continued) Effect Patients n2 Dialysis PEM Yes

15
Author, year, and reference Type IDPN IGF-1 GH Protein Duration Function or mortality 72 6 30 10 7
15
Study design HD CAPD HD PD HD HD Yes No Yes Yes Yes
Nutritional treatment Energy3 Anthropometric or biochemical index
Foulks, 1994 (164)
UCT
Foque et al, 2000 (165)
UCT
17 kcalkg BW 1 dialysis
Shinobe et al, 1997 (166)
UCT
Ikizler et al, 1994 (167) Schulman et al, 1993 (168) 16
UCT UCT
Ziegler et al, 1991 (169)
UCT
GH IDPN and GH GH
18 kcalkg BW 1 dialysis
159321 d Weight and serum albumin Hospitalizations and in responders (74%) mortality in responders 20 d Nitrogen balance ; no effect on weight 2 wk Anthropometry ; serum IGF-I ; serum albumin Stable 7d Serum IGF ; serum albumin 0.7 gkg 6 wk Nitrogen balance ; serum BW 1 dialysis 1 5 albumin; serum transferin 2 wk Serum IGF-I; protein catabolism
1 AA, amino acid; AMC, arm muscle circumference; BW, body weight; CAPD, continuous ambulatory peritoneal dialysis; CT, controlled trial; DCH, delayed cutaneous hypersensitivity; EAA, essential amino acids; GH, growth hormone; HD, hemodialysis; IDPN, intradialytic parenteral nutrition; IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth factor binding protein-3; LBM, lean body mass; PEM, protein-energy malnutrition; PD, peritoneal dialysis; RCT, randomized controlled trial; TLC, total lymphocyte count; UCT, uncontrolled trial. 2 Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Estimated total intake. 5 Intended supplementation. 6 Compared with spontaneous intake. 7 Multicenter national database study including 1679 HD patients receiving IDPN and 22 517 HD control subjects.
TABLE 7 Nutritional treatment studies in frail elderly and elderly with multiple chronic disorders.1 Effect Study design Type kcal/d RCT, placebo RCT Oral supplement Oral supplement Oral supplement 4005 4005 590,5 6405 2505 Oral supplement Glucose and vitamins6 5405 Y/N Y/N Y/N Yes RCT RCT RCT Y/N4 3605 g/d 205 22,5 245 155 10 wk 60 d 15 d 17 wk 10 d, 12 d 6 mo 30 d Weight ; fat mass ; LBM Weight in PEM patients No effect on physical activity, cognition, or mood MNA score in PEM ; no effect on grip strength Risk for pressure ulcer Patients n2 PEM Nutritional treatment Energy3 Protein Duration Anthropometric or biochemical index Function or mortality
Fiatarone Singh et al, 2000 (202) Laque et al, 2000 (203)
Bourdel-Marchasson et al, 2000 (204) de Jong et al, 1999 (205) Enriched food and exercise Oral supplement, enteral feeding
McWhirter and Pennington, 1996 (206) RCT RCT, placebo No Yes
50 [50] 78 [88] 672 [672] 145 [145] 86 [98]
Volkert et al, 1996 (207)
Vitamins ; no effect on weight or serum proteins Weight after both oral supplement and enteral feeding No effect on weight No effect
ADL ; independence No effect on cognition, ADL, or hospital stay
Hogart et al, 1996 (208)
46 [72] 87 [106]
15
(Continued)
16
TABLE 7 (continued) Effect Patients n2 PEM No 12 wk 3 mo 10 wk 8 wk 26 wk No effect Weight Weight ; AMC ; body fat ADL in controls Yes7 Oral supplement 3605 7005 4005 165 245 155 No No Y/N Oral supplement 500 (1 mo)5 Oral supplement kcal/d 1505 Weight Fall accidents g/d 55 Type Protein Duration Function or mortality Energy3 Anthropometric or biochemical index Study design RCT RCT RCT RCT RCT Nutritional treatment
Gray-Donald et al, 1995 (209) Woo et al, 1994 (210)
Fiatarone et al, 1994 (211)
Hankey et al, 1993 (212)
Oral supplement and exercise Oral supplement
No effect on physical function with oral supplement only Activity in WN after 8 wk
Unosson et al, 1992 (213)
46 [50] 81 [81] 94 [100] 14 [20] 430 [501] Y/N 26 wk 4 wk 14 wk 25 wk 10 d 6 wk 12 wk Weight Yes No Yes Yes Y/N Yes Y/N Y/N Yes No No Yes No Yes Oral supplement 8155 Oral supplement Oral supplement 3905 2404105 Enteral feeding 13005 685 4105 305 95 Oral supplement Oral supplement Energy-enriched diet Oral supplement 4505 4005 175 405 Oral supplement 4005 305 Megestrol acetate Oral supplement Oral supplement 6445 2655 365 185 Oral supplement 4005 165
Larsson et al, 1990 (214) RCT RCT
RCT
McEvoy and James, 1982 (215) Banerjee et al, 1978 (216)
Weight index and AMC in WN; serum prealbumin Weight ; TSF Skinfold thickness
DCH in both PEM and WN; mortality in WN Appetite ; well-being Physical activity Grip strength ; DCH Weak effect on DCH
Yeh et al, 2000 (217)
Bos et al, 2000 (218) CT CT CT CT UCT UCT UCT UCT UCT UCT 12 9 12 14 28 46 58 109 36 23
AKNER AND CEDERHOLM
RCT, placebo CT
435 [501] 51 50 [63] 51 [69] 23
Olin et al, 1996 (219) Cederholm and Hellstrm, 1995 (220) Bunker et al, 1994 (221) Johnson et al, 1993 (222) 26 wk 12 wk 8 wk 16 wk 12 wk 21 d
Protein accretion ; fat-free mass Weight Weight ; AMC ; TSF
12 wk Retrospective Weight
Hbuterne et al, 1995 (223)
Grip strength ; well-being Grip strength Mobility
Gray-Donald et al, 1994 (224) Elmsthl and Steen, 1987 (225) Lipschitz et al, 1985 (226) Oral supplement 2045 Oral supplement 180025008 or enteral feeding
Weight ; TSF ; AMC ; serum prealbumin Weight Weight
Katakity et al, 1983 (227) Lipschitz and Mitchell, 1982 (228)
Weight ; serum albumin ; serum TIBC Weight ; serum albumin ; serum TIBC
1 ADL, activity of daily living; AMC, arm muscle circumference; CT, controlled trial; DCH, delayed cutaneous hypersensitivity; LBM, lean body mass; MNA, Mini Nutritional Assessment; PEM, proteinenergy malnutrition; RCT, randomized controlled trial; TIBC, total iron binding capacity; TSF, triceps skinfold thickness; UCT, uncontrolled trial; WN, well nourished. 2 Number of patients analyzed per protocol; number of subjects randomly assigned in brackets. 3 To convert kcal to kJ, multiply by 4.184. 4 Denotes that patients were not selected according to nutritional status. 5 Intended supplementation. 6 Poor compliance with supplementation. 7 Mainly lung patients discharged after chest infections. 8 Estimated total intake.
TREATMENT OF PEM IN CHRONIC DISEASE of hospitalized patients with multiple disorders (47, 49, 183185). Similarly, PEM is found in a large percentage of the elderly cared for in nursing homes (186189). In elderly patients, it is often difficult to link malnutrition to the course of a specific disorder. The degenerative changes of aging lead to a decreased reserve capacity in many organs. Elderly patients often have concurrent disorders in several organ systems, meaning that different disorder-specific pathophysiologic mechanisms can be combined. PEM is a strong risk factor for increased mortality in the elderly and chronically ill (66, 190200). A retrospective study of malnourished elderly nursing home patients showed that patients who increased their body weight by > 5% over an average followup period of 1011 mo had significantly lower mortality than did malnourished patients whose weights remained stable or decreased (201). In Table 7 we summarize the results of 26 nutritional treatment studies (202228; 15 RCTs) of elderly, multiple-disorder patients with and without concurrent PEM. In nearly all of these studies, liquid, oral nutritional supplements were used. The duration of the studies was from 2 wk up to 6 mo, encompassing 12435 patients. Twenty of the studies (11 RCTs) noted an improvement in anthropometric or biochemical measures in the intervention groups. Ten of the studies (6 RCTs) found an improvement both in anthropometric or biochemical measures and in function. One RCT described how the nutritional supplement reduced the number of fall-related traumas (209). In one study (213, 214), diet therapy given to nonmalnourished patients was associated with both reduced mortality and increased function in general. One recent study (217) showed promising results when it tested the effect of megestrol acetate, which is often used in patients with HIV (229) or cancer-related wasting (230). Little evidence supports the often-used routine of providing poor-eating elderly with complementary parenteral nutrition during hospital stays. One randomized study evaluated the effect of total parenteral nutrition in 16 malnourished elderly patients. The results of this study showed that the energy from carbohydrates and fats had to total 200% of the basal metabolic rate to stimulate protein synthesis (231). In conclusion, many studies have shown that nutritional treatment of PEM associated with multiple disorders in the elderly can yield positive effects on body composition, and in some cases on muscular strength, wellbeing, and immune function.
17
pathophysiologic changes are adaptive and homeostatic. Nutritional therapy interacts with the metabolic processes specific to the disorder and under such conditions nutritional therapy must be viewed in a broader medical context. As this literature review shows, our current knowledge is insufcient to provide a rm scientic basis for recommendations on how nutritional treatment should be formulated in most of the reviewed disease groups. Although many studies were performed, the results were heterogeneous. The denition of PEM varied between studies, which is a logical effect of there being no generally accepted definition of the condition. Several studies were limited by insufcient and widely varying patient data, short treatment periods, and a lack of clinically relevant outcome variables. Moreover, the results are difficult to compare and interpret because of the various nutritional therapies used. There are serious methodologic problems in performing randomized controlled nutritional treatment studies. Examples include uncertain adherence to the treatment and the existence of several other concurrent, interacting treatments. In addition, the results are difcult to monitor because the natural course of the chronic disorder is often the cause of the malnutrition. Positive effects can be difcult to detect because of the complexities that exist in nutritional treatment. One potential weakness in most treatment studies is that the total energy intake can seldom be specified. Nutritional therapy often corresponds to an energy supplement of 200500 kcal/d ( 8402000 kJ/d), which does not automatically mean that total intake increases accordingly. Elderly patients ability to follow a prescribed nutritional intake varies widely (208, 212, 233). Treatment with nutritional supplements can reduce habitual intake as a result of effects on the appetite or abdominal side effects (24, 35, 202, 211, 225). In contrast, several studies showed that supplementation or enrichment of the diet does improve nutrient intake (89, 203, 206, 207, 210, 219, 234236). In a retrospective study, the use of supplements in nursing homes was described as a nonspecific intervention for weight loss with no regard to diagnoses and management of underlying problems, amount of supplement consumed, and outcome (237). Also unclear is the degree to which the quality of the supplemented fat affects health other than being a high energy source. Today, meals are usually energy enriched by adding dairy products, ie, saturated fatty acids. Further evaluation is needed to determine whether this is associated with negative effects, such as increased thrombogenic activity. Effects on anthropometric and biochemical measures compared with function and mortality An important consideration is the relevance of treatmentinduced increases in anthropometric or biochemical variables. Weight loss and hypoalbuminemia are both strongly correlated with increased mortality in sick persons. However, the causality relations are often unclear, ie, does the patient die from or with reduced weight or low serum albumin? It is not certain that a nutrition-induced increase in anthropometric and biochemical variables improves the patients prognosis, or that functional capacity or life quality is amended. A balanced nutritional treatment affects the body composition in a specic time sequence. First, the total body uid volume rises, then the fat, and nally the lean body mass, ie, muscle and protein mass (238, 239). An important aim of nutritional treatment is to restore the lean body mass. In many of the reviewed studies, however, the nutrition treatment led primarily to increased fat storage. On the other hand, an improvement in
DISCUSSION Basal compared with medical nutrition Although treatment recommendations should be based on the results of RCTs, in some aspects, nutritional treatment is an exception to this scientific truism. We do not need randomized studies to validate the life-sustaining value of a nutrient supply in both healthy and sick individuals. However, how nutritional treatment should be pursued and evaluated in connection with imminent or manifest malnutrition associated with an existing disorder is not clear. Disease-associated malnutrition is caused in part by disease-activated biochemical and physiologic mechanisms, including a systemic inflammatory response and neurohormonal adaptations (232), that affect the individuals appetite, the bodys tissue composition, and the ability of the metabolic systems to metabolize energy and nutrients. In most cases these
18
AKNER AND CEDERHOLM anthropometric or biochemical indexes. One small study reported that growth hormone may be deleterious in severely ill heart failure patients (72). This is an important consideration in light of a recent report of increased mortality in critically ill patients treated with growth hormone (246). Otherwise, none of the studies we summarized showed any serious side effects. Even though many factors in the interpretation of the reviewed studies are uncertain, the available treatment data indicate that nutritional supplements, either alone as balanced or protein-rich liquid nutrient drinks or in combination with hormonal administration, can have positive effects when given to chronically ill, nonmalignant patients with manifest PEM or at risk of PEM. In malnourished patients with chronic obstructive pulmonary disease, positive treatment results such as improved respiratory function are seen. However, these results are not homogeneous. In elderly women after hip fractures, liquid oral supplementation (particularly protein-rich formulas) promotes rapid rehabilitation. In elderly persons with multiple disorders, nutrition treatment results in increased functional capacity. The results of several trials including malnourished patients with chronic renal failure imply positive effects on anthropometric and biochemical measures (especially when hormonal treatment is given), whereas few clinical outcome data were provided. The effectiveness of PEM treatment in stroke, dementia, chronic heart failure, and rheumatoid arthritis cannot be measured because of a striking lack of published studies in these areas. Deductions similar to ours were drawn in a recently published meta-analysis of 32 studies of 2286 randomly assigned patients who received oral or enteral dietary supplements (247). In this meta-analysis, however, there were no indications that the treatment advantages were limited to specific disease categories. We conclude that there is a great need for randomized controlled (preferably placebo-controlled) long-term studies of the effects of defined nutritional intervention programs for certain PEM conditions associated with both specific and multiple disorders. Along with determining biochemical and anthropometric variables, these studies should focus on determining clinically relevant outcomes such as morbidity, functional capacity, healthrelated quality of life, hospitalization periods, and mortality. In addition, we require experimental and randomized treatment studies to develop and fine-tune pharmacologic methods to modulate systemic inflammatory responses and to stimulate anabolic processes and appetite. REFERENCES
1. Pennington CR. Disease-associated malnutrition in the year 2000. Postgrad Med J 1998;74:6571. 2. Sullivan DH. The role of nutrition in increased morbidity and mortality. Clin Geriatr Med 1995;11:66174. 3. Openbrier DR, Irwin MM, Rogers RM, et al. Nutritional status and lung function in patients with emphysema and chronic bronchitis. Chest 1983;83:1722. 4. Wilson DO, Rogers RM, Hoffman RM. Nutrition and chronic lung disease. Am Rev Respir Dis 1985;132:134765. 5. Pape GS, Friedman M, Underwood LE, Clemmons DR. The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest 1991;99: 1495500. 6. Schols AMWJ, Soeters PB, Dingemans AMC, et al. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993; 147:11516.
TABLE 8 Number of nutrition intervention trials with positive effects or no effect in patients with chronic obstructive pulmonary disease (COPD), with chronic heart failure, during rehabilitation after hip fracture, or with chronic renal failure, and in elderly patients with multiple disorders1 Positive effects RCT OT COPD Mortality Function or morbidity Anthropometric or biochemical index Chronic heart failure Mortality Function or morbidity Anthropometric or biochemical index Rehabilitation after hip fracture Mortality Function or morbidity Anthropometric or biochemical index Chronic renal failure Mortality Function or morbidity Anthropometric or biochemical index Multiple disorders in the elderly Mortality Function or morbidity Anthropometric or biochemical index 7 8 13 3 14 4 4 3 7 15 7 11 1 1 5 5 3 2 14 6 9 No effect RCT OT 5 3 3 2 2 1 3 3 1 1 2 1 1 1
1 OT, observational trial (controlled and uncontrolled studies); RCT, randomized controlled trial. 2 Growth hormone to patients with severe heart failure might be deleterious. 3 Patients treated with pentoxifylline. 4 Small study of 18 patients. 5 Reduced mortality in nonmalnourished subjects only.
clinical function does not have to be related to increased weight or size of body compartments because nutritional treatment can affect an organs function faster than its size and mass (240). Several lines of evidence indicate that systemic inammation is one delineator of nonresponse to nutrition treatment (41, 220, 241). We cannot ignore the possibility that even optimal oral, enteral, or parenteral nutrition may have only a limited potential to improve the health of malnourished chronically ill patients, particularly if the malnutrition is linked to inflammation. Pharmacologic modulation of the inammatory response, by use of substances such as megestrol acetate, thalidomide, pentoxifylline, and dronabinol, may develop as supplemental methods to promote anabolism and appetite and to achieve growth of lean body mass. Physical exercise (211, 242245) and anabolic or growth hormone therapy may prove to be further complementary treatments. Conclusion We reviewed 90 nutrition treatment studies, 50 of which were RCTs. In 59 studies (66%) oral or enteral nutritional supplements were used. Some of the overall effects are summarized in Table 8. Five studies (6%; 2 RCTs) noted improved mortality, 38 studies (42%; 22 RCTs) found improved functional capacity, and 64 studies (71%; 35 RCTs) reported anthropometric or biochemical improvement. Seventeen studies (19%; 14 RCTs) found no improvement in functional capacity. Some of these studies did not have enough power to answer the question they addressed. Eleven studies (10%; 8 RCTs) noted no effects on

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Review Article

Treatment of protein-energy malnutrition in chronic nonmalignant disorders1,2

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TREATMENT OF PEM IN CHRONIC DISEASE

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Author, year, and reference

Saudny-Unterberger et al, 1997 (27) Ganzoni et al, 1994 (28)

Rogers et al, 1992 (29)

Fuenzalida et al, 1990 (30)

Muscle strength (respiratory, grip, walking) Immunity Respiratory muscle strength

Whittaker et al, 1990 (31)

Otte et al, 1989 (32)

Efthimiou et al, 1988 (33)

Knowles et al, 1988 (34)

Lewis et al, 1987 (35)

Ferreira et al, 1998 (36)

Burdet et al, 1997 (37)

AKNER AND CEDERHOLM

Schols et al, 1995 (38)

Sridhar et al, 1994 (39) Pape et al, 1991 (5)

1.5 g/kg BW5 1/kg BW5

Oral supplement Diet and growth hormone

No effect on function Respiratory muscle strength

Downloaded from www.ajcn.org by on September 21, 2007

Author, year, and reference

Broqvist et al, 1994 (49)

Heymseld and Casper, 1989 (68) CT UCT UCT

Heymseld et al, 1978 (64)

Chhetri et al, 1982 (69)

Author, year, and reference

Osterziel et al, 1998 (70)

TREATMENT OF PEM IN CHRONIC DISEASE

Isgaard et al, 1998 (71)

Sliwa et al, 1998 (76)

Spallarossa et al, 1999 (72)

50 [50] 20 [22] 24 [28] 15

Jos et al, 1999 (73) Genth-Zotz et al, 1999 (74)

Fazio et al, 1996 (75)

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Patients Dysphagia Anthropometric or biochemical index

Nutritional treatment Energy3

Gariballa et al, 1998 (89)

Norton et al, 1996 (90)

Mortality ; hospital stay ; complications with PEG

DePippo et al, 1994 (91)

Davalos et al, 1996 (80)

Limited instructions as good as more intense

Wanklyn et al, 1995 (92) 52

Nyswonger and Helmchen, 1992 (93) 38 Yes

25 of 37 patients died within 3 mo Hospital stay : 20 d with early NG or 29 d with late NG

Elmsthl et al, 1999 (94)

60% improved their swallowing and nutritional status

TREATMENT OF PEM IN CHRONIC DISEASE

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Author, year, and reference

Schurch et al, 1998 (120) RCT RCT

Sullivan et al, 1998 (121)

Hartgrink et al, 1998 (122)

Hemoglobin ; serum albumin

Delmi et al, 1990 (124)

63 [82] 15 [18] 116 [129] 62 [68] 59