NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

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ADVANCED LUNG DISEASE

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NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE The Pulmonary Cachexia Syndrome Michael Donahoe, MD

Patients with advanced lung disease (ALD) demonstrate changes in body composition characteristically manifested by a progressive loss of body weight. This "pulmonary cachexia" is associated with a decline in clinical status and predicts accelerated mortality.102 Careful assessment of body composition can demonstrate evidence of this wasting syndrome in obese as well as normal and undernourished patients. The relationship between ALD and cachexia has prompted enthusiasm for nutritional support as a major therapeutic initiative in both stable and unstable (intensive care unit) patients. A relationship, however, does not assure that treatment will alter the prognosis in a favorable manner. In most medical conditions, nutritional status is tightly linked to the underlying disease state and indices of nutritional state may serve simply as markers of disease severity. This review addresses current knowledge regarding the relationship between nutrition and ALD. The majority of investigative effort has been directed to the patient with chronic obstructive pulmonary disease (COPD) and that disorder therefore provides the focus of discussion. Treatment guidelines are outlined based upon our current understanding of the pulmonary cachexia syndrome.

MECHANISM OF PULMONARY CACHEXIA

Lean tissue mass in adult patients with ALD is influenced by a number of interacting variables, including aging, exercise, metabolism, inflammation, and drug (corticosteroid) use (Fig. 1). As such, a unifying mechanism to explain the progression of pulmonary cachexia in all patients is unlikely. The age-related reduction in lean tissue mass has been referred to as "sarcopenia."28 During adulthood, body composition undergoes a progressive loss of fat-free mass and an increase in fat mass. Nonmuscle lean tissue is preserved and the most significant reductions in fat-free mass occur in the muscle compartment.15The reduction in muscle mass is associated with a reduction in static and dynamic muscle strength and type I1 muscle fiber atrophy.57Changes in muscle mass have profound effects, reducing basal metabolic rate and limiting maximal exercise capacity. That "normal" process of aging is a factor in older ALD patients when considering issues of nutritional risk and therapy. The loss of muscle mass and strength may not be an inevitable part of the aging process. The changes may be primarily related to habitual activity patterns. Physically active

From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

CLINICS IN CHEST MEDICINE ~~~~~~~

VOLUME 18 * NUMBER 3 SEPTEMBER 1997

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Pulmonary Cachexia Syndrome

m

Systemic Inflammation

Therapy

Figure 1. The multiple factors which contribute to progressive weight loss in patients with advanced lung disease.

older subjects demonstrate a lesser decline in muscle mass and strength mass compared with inactive age-matched controls.52Investigations employing high-intensity training in older subjects have demonstrated improvements in muscle strength and size.lO,14,36, 64, 73 Physical activity therefore is a regulatory factor in muscle protein synthesis. The profound cardiopulmonary limitation to exercise, characteristic of ALD patients, likely contributes to muscle wasting. Metabolic changes also characterize the patient with ALD. In contrast to the normal agerelated reduction in metabolic rate, the basal metabolism in patients with COPD and interstitial lung disease does not correlate with reductions in lean tissue mass.32,8o Malnourished COPD patients may demonstrate an increase in resting metabolism normalized to predicted values compared with normally nourished COPD patients and controls. That state of hypermetabolism has been attributed to an increase in the oxygen cost of breathing.", 50 The contribution of energy imbalance to the cachexia syndrome is supported by evidence that positive energy balance in certain weight-losing COPD patients is associated with nitrogen retention and weight gain.40,75 These data provide strong evidence that, at a minimum, in select populations, weight loss in COPD patients is secondary to an energy deficit, reversed by calorie intake, with nitrogen retention and restoration of lean tissue mass. The pulmonary cachexia syndrome cannot be explained by hypermetabolism alone in all patients, however. Weight loss is not uniformily associated with hypermetabolism.16

In addition, total daily energy requirements are reported as comparable between underweight and normal-weight COPD patients when assessed in subjects living in a chamber, suggesting the increase in metabolic requirements of the respiratory muscles may be offset by restricted activity secondary to the severe lung disease.45 Could a tissue oxygen debt (dysoxia) explain the observed changes in body weight characteristic of ALD patients? Satisfactory tissue oxygenation requires the appropriate balance of tissue oxygen delivery (DO,) and tissue oxygen demand (VO,). Available evidence suggests both aspects of tissue oxygenation may be abnormal in the weight-losing COPD patient population. As mentioned previously, COPD patients have an elevated oxygen demand secondary to the work of breathingZ4,R4 The elevated energy demand of the respiratory muscles will be most obvious during times of ventilatory stress-i.e., exercise. DO, to meet the heightened demand is suboptimal in COPD patients, particularly patients with emphysema. Under normal conditions, DO, at rest exceeds Vo,. Albert et aI2 examined the DoJVo, relationship in 30 patients with COPD referred for right heart catheterization. Passive leg elevation was used to increase venous return, augment cardiac output, and therefore augment Do, without using vasodilators. At rest, the COPD patients demonstrated a significant relationship between Do, and Vo, (r = 0.5; P < 0.01). Following leg elevation, a further increase in VO, in relationship to the change in DO, was demonstrated ( r = 0.71; P < 0.001). No change in total oxygen consumption was seen

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NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

in normal subjects with the same maneuver. The elevation in tissue Vo, at rest following a rise in Do, suggests a resting tissue oxygen debt in these patients. Corriveau et all8 have supported that hypothesis by demonstrating that augmentation of Vo, in response to oxygen supplementation predicts patients who will demonstrate an improved exercise tolerance with oxygen therapy. Openbrier and colleagues69associated malnutrition in COPD patients with the “pink puffer” features of emphysema and, specifically, a reduction in the diffusing capacity for carbon monoxide. Fillery et a131 examined, in detail, the components of tissue oxygen delivery in such patients. Patients were separated into ”pink puffer” (PP) and ”blue bloater” (BB) categories based upon clinical criteria. Examination of cardiac function revealed a lower cardiac index in the PP than in the BB population. To meet tissue energy demand, oxygen extraction by the tissues, as reflected by the arterio-venous (a-v) oxygen difference, was increased in PP patients compared with the BB patient population. During exercise, the PP group demonstrated a reduced ability to augment cardiac output. Despite better preservation of arterial oxygen saturation in the PP category, actual Do, was therefore impaired. Review of both cardiac and ventilatory variables confirmed that cardiac variables, rather than ventilatory variables, best separated the two patient categories. The investigators hypothesized that low cardiac output in PP patients allowed for a prolonged pulmonary transit time and permitted patients to avoid hypoxemia. In addition, impaired tissue oxygenation was associated with the clinical characteristics of emphysema patients. In support of a tissue oxygen debt in COPD patients, Gertz et aP9 demonstrated that peripheral and respiratory muscles in hypoxemic COPD patients are deficient in creatine phosphate and adenosine triphosphate (ATP). Those changes are reversed with oxygen supplementation. This limitation in energy supply at the tissue level would alter metabolism, potentially resulting in loss of tissue mass. Stable COPD patients demonstrate an abnormal rise in the ratio of intracellular forearm muscle organic phosphate and an abnormal drop in pH with increasing levels of work.88 Kutsuzawa and colleagues54explored this relationship in COPD patients versus normal controls. The investigators used 31Pnuclear magnetic resonance spectroscopy to investi-

gate the metabolic changes associated with repetitive loaded handgrip exercise. Changes in intracellular pH and relative concentrations of ATP, phosphocreatine (PCr), and inorganic phosphate (Pi) provide a measure of local energy metabolism. The investigators found that the ratio of PCr/(PCr Pi) was significantly reduced during exercise in COPD patients compared with normal controls, suggesting altered oxidative metabolism and earlier onset of anaerobic metabolism. The findings in malnourished COPD patients did not differ from normally nourished COPD patients. The data were presented after correction for forearm cross-sectional area, however, which might mask the differences between underweight and normal-weight patients. In summary, energy metabolism in patients with ALD may be altered by the proportionally higher energy output required by the ventilatory muscles. Under conditions of ventilatory stress (i.e., exercise), both nonrespiratory and respiratory muscle energy requirements increase. To meet that demand, Do, must increase through an augmentation of cardiac output. The ability of ALD patients to meet the increased demand may be compromised by an associated impairment in cardiac function. The body is faced with rationing Do, to crucial sites such as the respiratory muscles and viscera, producing a functional oxygen and nutrient debt in the peripheral tissues. The observations of Filley et a1,3 that the impairment in Do, is greater in weightlosing (emphysema) than weight-stable (chronic bronchitic) patients, support the contribution of tissue oxygen debt (dysoxia) to the weight-losing process. This debt would be associated with impaired generation of tissue energy stores (ATP) and nutrient metabolism. A greater understanding of peripheral skeletal muscle metabolism in ALD patients is needed to understand that relationship. A systemic inflammatory response, such as an infectious exacerbation, might also contribute to the weight-losing process. Significant interest has developed in the potential role of inflammatory cytokines and, specifically, tumor necrosis factor (TNF) in the wasting process that is characteristic of hypercatabolic patients. Two reports have suggested that production of TNF-a is increased in weightlosing COPD patients.33,38 Although it is appealing to conclude that TNF-a production explains the pulmonary cachexia syndrome,

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Body Weight (kg) Figure 2. Relationship between body weight (kg) and quadriceps force (kg) in patients with obstructive airways disease. The open circles represent patients taking a mean of 4 mg average daily dose of methylprednisolone over the previous 6 months. The solid circles represent patients taking less than 4 mg average daily dose. (From Decrarner M, Lacquet L, Fagard R, et al: Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 15O:ll-16, 1994; with permission.)

strength within 2 to 4 weeks, and recovery is these findings must be interpreted with caution. Fluctuations in energy intake could indelayed.98The effect of lesser doses (-20 mg/ day) on the respiratory muscles is more confluence the production of TNF-a by peripheral troversial. Some investigators have suggested blood mononuclear cells. Increased TNF-a no effect on respiratory muscle function in production by peripheral blood mononuclear normal humans.97In contrast, studies in pacells is seen in healthy subjects who undergo severe caloric deprivation (420 k J / d a ~ ) . ~ l tients with obstructive airways disease demonstrate reduced inspiratory and expiratory Weight-losing anorexic patients demonstrate muscle strength in relation to recent steroid a suppression of elevated TNF-a production usage (Fig. 2).19 during therapeutic refeedingg2 These latter investigations suggest the possibility that inIn conclusion, multiple variables can potencreased TNF-a levels result from, rather than tially regulate the size of the lean tissue mass in patients with ALD. Pulmonary cachexia in contribute to the process of muscle wasting. Medications may have an important role in such patients results from the interaction of the multiple variables. Similar cachexia synthe regulation of body composition in ALD patients. Corticosteroids, in particular, are dromes are seen in patients with end-stage cardiac and renal disease, in which the work recognized to inhibit protein synthesis and of breathing might be normal but inactivity, promote protein catabolism, leading to prohypoperfusion, inflammation, and drug therfound muscle wasting. Animal models suggest that corticosteroid use is associated with apy are present.65,96 type I1 fiber atrophy and a reduction in musThe potential interaction of those factors is best illustrated by a simple COPD exacerbacle 59 The effect of corticosteroid use in humans may be dose related. Hightion. COPD flares are often associated with dose corticosteroids (-60 mg/day) result in increased respiratory muscle metabolism, inreductions in maximal respiratory muscle activity, limited caloric intake, systemic in-

NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

flammation, and frequent steroid use. The progression of pulmonary cachexia would be expected in that setting. Identification of Patients at High Nutritional Risk

The primary goal of nutritional assessment in a patient with ALD is to identify those at high risk for an adverse outcome. Once identified, the nutritional parameters can be used to assess selected patients’ response to an intervention program. Effective screening tools must be safe, cost-effective, widely applicable, and yet accurate in predicting adverse sequelae. The majority of studies examining the value of nutritional assessment tools in patients with ALD have been conducted in patients with COPD. Two specific nutritional assessment tools, percent ideal body weight (PIBW) and the fat-free-mass index (FFMI) predict an adverse outcome in patients with COPD. Epidemiologic surveys of COPD patients during the 1960s first identified the nutritional parameter of body weight as an important predictor of disease mortal it^?^ Subsequently, Wilson et allo2 examined the Intermittent Positive Pressure Breathing trial population of 779 male participants. Subjects were grouped into categories based on severity of lung function and body weight on entry. Patients less than 90% IBW demonstrated a greater overall 5-year mortality, independent of lung function, compared with normal or overweight patients. Most significantly, the negative impact of low body weight was evident even in patients with the mildest airflow obstruction (forced expiratory volume in 1 second [FEV,] > 46% of predicted). This study served to identify a PIBW less than 90 as an important indicator of an adverse outcome. Maximal oxygen consumption during incremental cycle ergometry is also reduced in underweight (<90 PIBW) patients with COPD, whereas timed walking distance (6 78 Harris and or 12 minute walk) is extended those observations and demonstrated in a logistic regression model that thigh muscle mass, determined by CT scan measurements, is a predictor of maximal exercise capacity in COPD patients independent of FEVI, oxygen desaturation, or the deadspace-to-tidal volume ratio.

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A second nutritional assessment tool associated with an adverse outcome is the estimate of FFM using bioelectric impedance analysis (BIA). Total body weight can be divided into a fat and fat free (lean) mass in a two-compartment model. BIA measures the total body impedance to a nondetectable current, applied with electrodes placed at the unilateral hand and foot. The theoretical basis of BIA for determination of body composition lies in the assumption of the human body as a series of connected cylinders in which impedance is related to the length and area of the cylinders.82In humans, the current is conducted by body water and electrolytes. Because the body’s water and electrolytes are concentrated in the lean body mass (LBM), a mathematical relationship exists between the length (or height) of the person, resistance to current flow, and the size of the LBM. Bioelectric impedance is an appealing nutritional assessment tool for use in all malnourished populations because of its simplicity, safety, low cost, and repeatability. Schols and colleagues78described a FFMI in COPD patients as the FFM (determined by BIA) divided by the predicted PIBW. Examination of this parameter in 255 patients with COPD disease78showed that a FFM/PIBW less than 63% (female patients) or 67% (male patients) is associated with a reduction in submaximal exercise performance in both normal weight (90-110 PIBW) and underweight (<90 PIBW) patients. Those data are particularly important because they suggest that different patterns of body composition may be associated with specific physiologic outcomes. The patient with ALD with weight loss consisting of a prominent depletion in fat mass, for example, may note a benefit to exercise tolerance.86In contrast, the patient with depletion of lean tissue mass may suffer adversely. Additional detailed studies of body composition in relation to physiologic outcome variables are needed. Other methodologies for nutritional assessment offer safety, cost-effectiveness,and wide applicability, but have not been related to specific outcomes in ALD patients. Detailed anthropometric measurements assess the size of skinfolds, skeletal breadths, and circumferences at various body sites. As with body weight, individual measurements can be compared with a group norm using traditional measurement sites such as the triceps skinfold and mid-arm circumference.61

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Regression equations employing assorted measurement sites are available to predict body density, which can be used to estimate total body fat.26, y5 Using a two-compartment model, FFM is determined as the difference between anthropometric fat mass and total body weight. Data from COPD patients suggest that anthropometric measurements tend to overestimate FFM compared with bioelectric impedance analysis in the same pat i e n t ~ .81~ ~ , Anthropometric measurements are limited by the assumption of a uniform distribution of total body fat. That assumption may be incorrect, particularly for the elderly, who may centralize and internalize adipose tissue in the trunk.9 Anthropometric measurements remain useful, however, because they identify an adverse nutritional effect in ALD patients that is not evident with the monitoring of body weight alone. Weight gain in the ALD patient may be interpreted as favorable; however, weight gain of primarily fat mass is unlikely to be beneficial. That type of detailed anthropometric assessment can provide valuable insight into the patient’s progress during a rehabilitation program if measured and interpreted correctly. Hepatic secretory proteins such as albumin, pre-albumin, transferrin, and retinol-binding protein are often included in a comprehensive nutritional assessment program as an indication of visceral protein stores. Malnourished ALD patients generally do not present with decrements in those parameters and routine serum measurements are probably not indicated.27,53, 58, 70 Body weight, anthropometrics, bioelectric impedance, and visceral proteins assess primarily the size of a body compartment (fat mass, lean tissue, or visceral protein stores). An alternative approach to nutritional assessment involves a more ”functional” assessment. Significant interest in the relationship between nutritional status and respiratory muscle function has prompted a broad range of animal and clinical investigations. Animal models of unstressed protein-calorie malnutrition (PCM) have shown that progressive weight loss is associated with a loss of isometric muscle force at high stimulation frequencies. Malnourished subjects with anorexia nervosa demonstrate reductions in respiratory muscle strength and maximum voluntary ventilation that respond to restoration of caloric intake.66The effects of PCM on critical

parameters of muscle function, including shortening properties and susceptibility to fatigue, are poorly defined. The underlying mechanism of force loss with PCM is also unclear. Loss of muscle power could result from changes in muscle fiber size or biochemical parameters. Skeletal muscle, characterized by a process of ongoing protein synthesis and degradation, should demonstrate net catabolism in the setting of PCM. The net muscle catabolism would explain the diaphragm changes seen in animal models of PCM, in which diaphragm fiber frequency is maintained but type I1 fiber atrophy is present and maximal strength is reduced. Conflicting data raise questions regarding whether the changes in muscle function can be attributed to fiber atrophy alone. Physiologic evaluation in certain animal models suggests that muscle tension per unit of muscle cross-sectional area or per unit weight of the animal is not affected by malnutrition, suggesting that strength loss in PCM is secondary to type I1 fiber atrophy.51,6o Alternatively, animal models, using very short-term (4 days) protein calorie deprivation have demonstrated reductions in diaphragm maximal muscle strength, raising the question as to whether such functional changes can be entirely attributed to changes in muscle bulk over such a short time Respiratory muscle function in the setting of PCM could also be adversely affected by depletion of intracellular electrolytes, including calcium, magnesium, and phosphate.6,7, 21 Regardless of the mechanism, the characteristic loss of muscle power in undernourished states can be employed as a nutritional assessment tool. Clinical investigations of undernutrition have focused primarily on the adductor pollicis muscle because of the ulnar nerve’s ready accessibility for neural stimulati0n.4~ At low stimulation frequencies, the adductor pollicis responds with a single twitch that generates a small percentage of the maximum muscle force. Above 20 Hz, the muscle is tetanized and, above 50 Hz, the force is maximal. Malnutrition is associated with an increase in the ratio of the force produced at 10 Hz relative to 50 Hz because of a loss of force at the higher stimulation frequencies. Additional changes associated with malnutrition include slowing of the relaxation rate following supramaximal stimulation and a reduction in muscle endurance.

NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

The respiratory muscles (i.e., diaphragm and sternocleidomastoid)demonstrate similar neurophysiologic properties to peripheral muscles during electrical stimulation. The changes in the adductor pollicis characteristic of malnutrition have been demonstrated in the sternocleidomastoid in malnourished COPD patients by Efthimiou et alZ7and in the diaphragm by F r a ~ e r Efthimiou .~~ demonstrated a higher 10:50 ratio, a slower maximal relaxation rate, and a shorter time to fatigue of the sternocleidomastoid muscle in malnourished COPD patients compared with normally nourished controls. Importantly, those changes were shown to reverse with 3 months of nutritional therapy, supporting the belief that respiratory muscles are equally susceptible to the effects of malnutrition as nonrespiratory muscles. Availability of equipment and technical expertise limit the widespread use of neuromuscular stimulation in nutritional assessment. A simpler, although less precise alternative to neurophysiologic testing is the use of voluntary tests of maximal muscle strength, such as handgrip dynamometry or respiratory muscle pressures. Handgrip strength has been used in surgical populations to predict outcome more precisely than possible through other nutritional parameters, such as triceps skin fold or albumin.46This measure provides an inexpensive and simple method of assessing muscle function and is easily obtained in the outpatient setting. Handgrip strength can be incorporated into an initial assessment with little difficulty and can be used serially to confirm strength changes stimulated by nutrition and exercise. Clinical studies attempting to correlate nutritional status with measurements of respiratory muscle strength in patients with severe pulmonary disease have led to conflicting reports. For patients with cystic fibrosis and COPD a variable relationship between body weight and respiratory muscle strength has been noted.3,13, s5, 72, 74, 87 Those conflicting findings may relate to inherent difficulties with the measurement variables. First, muscle mass is a difficult parameter to assess in ALD patients. A standard indice is the 24-hour collection of urinary creatinine. That measurement requires a controlled diet and meticulous collection of the urine sample, making it impractical in the outpatient setting. When more practical indices of muscle mass, such as body weight or arm muscle

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circumference, are compared with the urinary indice, the correlations are Studies that compare body weight to respiratory muscle strength therefore may be limited by poor estimation of true muscle mass. Detailed assessment of lean tissue mass, using dual photon absorptiometry, and respiratory muscle strength have suggested a strong correlati~n.~~ Second, the inspiratory muscles in patients with airflow obstruction are ”disadvantaged” by the change in length-tension characteristics of hyperinflation. This makes direct comparisons between nutritional state and inspiratory muscle function difficult in underweight, hyperinflated patients. The expiratory muscles are not “disadvantaged” by hyperinflation and a reduction in expiratory muscle strength may provide the best index of a myopathic Studies that compare body weight to inspiratory muscle strength often fail to account for the impact of hyperinflation on measured inspiratory muscle strength. Despite those limitations, several investigators report improvement in respiratory pressures with weight gain in the same pop~ l a t i o n . 75, ~Q Serial measurement of inspiratory and expiratory pressures can be employed as a ”functional” nutritional a s sessment tool in a pulmonary rehabilitatior program. A second ”functional” assessment tool is measurement of immune function. The ad. verse effects of protein calorie malnutritior on the immune system occur particularly ir the cell-mediated component. Markers o such abnormal cell-mediated immune func tion include lack of delayed cutaneous hyper sensitivity to common antigens, reduced tota lymphocyte counts, and abnormal lympho cyte stimulation assays. Undernourished pa tients with COPD demonstrate abnormalitiei in those markers that appear to improve fol lowing the institution of nutritional ~ u p p o r t . ~ The primary limitation of functional nutri tional assessment tools such as musclc strength or tests of immune function is thi multifactorial nature of the measured deficii Altered T-cell function is associated wit1 aging, corticosteroid use, chronic infection and malnutrition, all of which are typical17 present in the patient with ALD. That limit the ability of the functional assessment tool to identify patients at nutritional risk, a1 though the tools are still valuable for as loor

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sessing the response to a nutritional intervention program. Based upon the available studies, primarily in COPD patients, nutritional assessment of patients with ALD should include regular screening of body weight. Patients with a history of progressive weight loss or a PIBW less than 90 are at increased mortality risk based upon epidemiologic studies. Furthermore, reduced body weight is associated with impaired maximal exercise capacity. The use of electrical impedance or similar techniques to estimate lean tissue mass may be of value to detect individuals with specific depletion of LBM even when total body weight has been preserved. Bioelectric impedance or anthropometric indices can then be combined with functional assessment of muscle strength or immune function to assess the response to rehabilitation or other treatment programs. The summary of all physiologic and historic findings are used to identify the specific nutritional problems of the individual patient and to develop a comprehensive care plan. Interventions appropriate and beneficial to each patient can be implemented and evaluated to assess patient outcome and the success of the rehabilitation program (Table 1). OUTCOME OF NUTRITIONAL INTERVENTION IN PATIENTS WITH ADVANCED LUNG DISEASE Clinical Trials Clinical trials have been conducted in weight-losing COPD patients to examine the Table 1. SUMMARY OF NUTRITIONAL ASSESSMENT TOOLS FOR EVALUATING PATIENTS WITH ADVANCED LUNG DISEASE I. Measurements of body size A. Body weight (“A ideal body weight) B. Measurements of body compartments 1. Bioelectric impedance analysis (fat-free mass index) 2. Anthropometrics 3. Hepatic secretory proteins II. Functional analysis A. lmmunocompetence 1. T-cell counts 2. Delayed cutaneous hypersensitivity B. Muscle physiology 1. Neurophysiologic studies a. Adductor pollicis b. Sternocleidomastoid 2. Clinical assessment a. Handgrip dynamometry b. Respiratory muscle pressures

potential role of nutritional rehabilitation therapy. The investigations also ”test” the hypothesis that adverse nutritional status contributes to a decline in function in patients with advanced COPD. Clinical trials have been conducted with a variety of study designs, making comparison difficult, but a few general conclusions from the published results are appropriate. Clinical studies conducted predominantly in the inpatient setting (Table 2) have typically been of small sample size (6-12 patients), often not randomized, and of short duration (1-3 weeks). They have most frequently suggested that oral nutrient supplementation is associated with an increase in body weight and some measurable improvement in musde strength, most often respiratory muscle strength. None of these investigations has reported improvements in quality-of-life measures or dyspnea indices. The short duration of the investigations and the modest weight gain reported suggest that a significant increase in the lean tissue compartment is an unlikely explanation for the improvements in muscle strength that have been noted. Clinical investigations conducted solely in the outpatient environment have produced slightly different observations (see Table 2). Those investigations are characterized by slightly larger patient sample sizes (12-15 patients), usually of a randomized study design, and of longer duration (typically approximately 3 months). Weight gain in those studies, despite the longer duration, has generally been modest (<5 kg). Improvements in muscle strength, walking distance, quality-of-life measures, or dyspnea indices have been inconsistent. Based upon the small weight gain noted in the studies, oral nutrition intervention programs must be viewed as limited in effectiveness, making a complete assessment of their therapeutic potential difficult. Presumably, feeding via an enteral feeding tube or percutaneous endoscopic gastrostomy would provide for a controlled level of caloric intake, potentially allowing evaluation of the effect of nutrition on outcome. Two investigations have been reported using that feeding methodology. Whittaker et allooreported a placebo-controlled, randomized study of enteral feeding in malnourished inpatients with COPD over a 16-day period. The refed patients demonstrated significantly more weight gain and significant increases in maximal expiratory pressure and mean sustained inspiratory pressure.

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Table 2. SUMMARY OF INVESTIGATIONS OF NUTRITIONAL SUPPORT IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE Weight Change

Subjects Study

(4

Design

Duration

Outcome

(kg)

Inpatient Investigations Wilson et allo1 NR/NC Goldstein et a140 NWNC EnteraVParenteral Rogers et R/C (Inpatient and Outpatient)

6 10

3 Weeks 2 Weeks

3.1 2.0

27

3 Months

2.1

Increase in respiratory muscle strength Increase in respiratory muscle and peripheral muscle strength Increase in respiratory muscle and handgrip strength

Outpatient Investigations ~~~~

~

No change No change Increase in respiration and handgrip strength Increase in 6-minute walk No change Increase in respiratory muscle and handgrip strength and walking distance

Lewis et also Knowles et aIs3 Efthimiou et aF7

R/C R/C/CR R/C

21 25 14

8 Weeks 8 Weeks 3 Months

1.1 1.1 4.2

Otte et aI7O Rogers et

R/C/P R/C (Inpatient and Outpatient) R/C Enteral versus Oral Feeding NR/NC

28 27

13 Weeks 3 Months

1.5 2.1

12

4 Months

3.3

No effect

12

4 Months

0.3

No effect

Donahoe et aI2* Sridhar et aIo5 R

=

randomized, C

=

controlled, P

=

placebo, N = non.

We extended this technique to the outpatient setting in a randomized study of nocturnal enteral nocturnal supplementation (ENS) in COPD patients with a severe reduction in body weight (-35% predicted IBW). The feeding regimen was designed to assure adequate caloric intake over a prolonged time interval (4 months).22The intervention population had nightly enteral feedings adjusted to maintain a total daily caloric intake greater than two times measured resting energy expenditure for sustained weight gain. Despite the magnitude of the intervention, a mean weight gain of only 3.3 kg (6% of body weight at baseline) was seen in the study population. Weight gain was limited by the magnitude of the required calorie intake and by significant shifting of caloric intake in the ENS population between oral and enteral intake. The majority of increase in body weight occurred in the body fat compartment. No significant advantage in physiologic function was noted in the intervention population compared with a control group receiving an oral dietary supplement. How do we interpret these conflicting clinical data? The investigations of nutrition support in patients with ALD address specifically

the role of protein-calorie supplementation alone in the pulmonary cachexia syndrome. Those studies suggest a certain level of protein/energy supplementation in patients with ALD and weight loss may be beneficial. A small increase or stabilization of body weight appears to achieve the expected improvements in muscle strength, although the benefits are inconsistent. Calorie-protein supplementation would be expected to address the mechanism of hypermetabolism as a cause of progressive cachexia. As previously mentioned, however, the cachexia syndrome in those patients is likely multifactorial. A comprehensive strategy is necessary to address the impact of cachexia in all patients. Aggressive nutritional support programs in the absence of a comprehensive rehabilitative strategy, particularly if associated with an increased risk profile (i.e., parenteral feeding), cannot be justified. The therapeutic impact of isolated nutritional support in patients with ALD is limited. Limitations of Nutritional Support in Advanced Lung Disease

A number of factors appear to limit the effectiveness of nutritional support programs

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in patients with pulmonary cachexia. A high frequency of gastrointestinal symptoms in patients with ALD limits caloric intake. Frequent patient complaints include bloating, early satiety, and postprandial dyspnea.12 Those symptoms are attributed to a number of factors, including peptic ulcer disease, effects of medication (i.e., theophylline compounds), or the abnormal position of the diaphragm relative to the stomach in association with lung hyperinflation. Therapeutic strategies to address the symptoms have been developed. The success of those interventions is highly dependent upon the motivation of the patient and counselor.23 Meal-related oxyhemoglobin desaturation may limit caloric intake and contribute to meal-related dyspnea in some patients.76Meal desaturation occurs primarily in patients with COPD who are hypoxemic at rest. Augmented caloric intake, even if achieved, does not assure restoration of lean tissue mass. As suggested, energy imbalance is only one factor that appears to contribute to the wasting of lean tissue mass in ALD patients. We examined the effect of refeeding on diaphragm structure in a rat model of refeeding following a 25% decrease in body weight. The animals demonstrated no significant improvement in diaphragm muscle atrophy with nutrient support Only with the addition of an anabolic agent, specifically growth hormone, were muscle dimensions restored to values comparable to control animals. Studies in elderly subjects without pulmonary disease have confirmed that exercise alone, or exercise with nutritional rehabilitation, is superior to nutritional rehabilitation alone in effecting an increase in lean tissue mass.3oSimilar concepts have been demonstrated in COPD subjects exposed to exercise training or androgen therapy with nutritional rehabilitati~n.~~ The use of growth hormone supplementation in a population of underweight COPD patients was effective in improving muscle strength in a nonrandomized in~estigation.~~ The potential advantage of anabolic agents is their ability to address multiple contributing factors to the pulmonary cachexia syndrome. At the current time, however, anabolic agents have not been shown to alter patient outcome. Given the potential risk of the compounds in patients with ALD, their use should be restricted to the research environment.

Nutritional Support and Metabolism

Nutrient administration is associated with an obligate increase in basal metabolism referred to as the thermogenic efecf of caloric intake. The basic stoichiometry of fuel oxidation and storage suggests the composition of the caloric intake can influence carbon dioxide production (Vco,) and, therefore, ventilatory demand. Investigators have hypothesized that the provision of more fat-based nonprotein calories to patients with underlying lung disease would lower Vco2 and ventilatory demand. This issue has been examined most closely in patients with respiratory failure on me8, 62, yo Comparison bechanical ~entilation.~, tween isocaloric pure carbohydrate formulas and formulas with mixed carbohydrate:fat ratios confirms that mixed formulas generally result in lower VCO~.Excessive V C O ~is well documented when carbohydrate caloric intake is significantly in excess of energy demand (21.5 times resting energy expenditure; 1.5 X REE). Talpers et a1,9O in a population of patients with respiratory failure, suggested that Vcoz increased a mean of 15% above the fasting level in subjects fed a caloric intake at 1 X REE, representing the thermogenic effect of caloric intake. As total caloric intake was increased to 1.5X and 2 X measured REE, it resulted in a further increase in Vco2 of 33%, then 54%, respectively (Fig. 3). Comparison of isocaloric formulas adjusted to caloric requirements (1.3 x REE) with variable carbohydrate:fat ratios had minimal effect on VCO~.~O For the majority of the reported investigations, the changes in Vcoz associated with administration of isocaloric formulas with variable fat:carbohydrate ratios are often less than metabolic changes associated with daily intensive care unit a c t i v i t i e ~ . ~ ~ Goldstein et a14"compared an isocaloric high-carbohydrate formula (53% of total calories) to a high-fat formula (55% of total calories) during enteral or parenteral nutrition in COPD patients. Caloric intake was provided at a value of 1.7 X REE measured during an infusion of 5% dextrose in water (D5W).REE increased significantly on both diets compared with the period on the D,W infusion in the COPD patient population, although the increase was less for the fat than the carbohydrate-based diet (14% versus 20% increase). That compared with a 9% and 8% increase for the fat- and carbohydrate-based diets, respectively, in the control population. The clin-

NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

400 350 300 -250 .>" .

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Figure 3. Comparison of carbon dioxide production (Vco,) in mechanically ventilated patients receiving variable dietary intake. Group A received energy intake at 1.3 x resting energy expenditure with three variable fat:carbohydrate ratios. Note that no significant change in Co, production was noted. Group B received increasing total calories with a constant ratio of carbohydrate to fat calories (60:20). Note the statistically significant increase in Vco2 with increasing total caloric intake. (From Talpers S, Romberger D, Bunce S, et al: Nutritionally associated increased carbon dioxide production. Chest 102:551-555,1992;with permission.)

ical significance of the small differences in V c q remain to be determined. Brown et all1first noted that a carbohydrate load (920 kcal) during exercise was associated with a decrement in exercise performance in the immediate postprandial measurement period. Additional work has suggested that caloric intake (920 kcal) with a high 1ipid:carbohydrate ratio may cause less exercise impairment in the immediate postprandial period than a high-carbohydrate formula.34Such studies of postprandial exercise function are

often used to justify the need for a fat-based diet in patients with pulmonary disease. The focus of nutrient administration in patients with pulmonary disease should be directed to avoiding excessive nonproteincalorie administration rather than minor adjustments in the caloric composition. Estimation of the energy requirements of patients with respiratory disease can be difficult, however, and should be assessed directly by indirect calorimetry, particularly if complications are evident. In our experience, even patients

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with severe COPD experience little exacerbation of their underlying dyspnea during calorically adjusted meals. Protein administration has also been proposed to influence the ventilatory demand through alterations in ventilatory chemosensitivity (ventilatory drive). Zwillich et allu3 suggested protein administration, following a period of nutritional deprivation, is associated with increased ventilatory responses to hypoxia and hypercapnia. Askanazi et a15administered two levels of protein intake (12 g and 24 g of NJday) to six nutritionally depleted patients and suggested a greater effect on ventilatory response in the high-intake population. Additional work by those investigators has suggested that branched-chain amino acids may play an important role in mediating the effect of protein on respiratory drive.S3,84, Dietary intake of amino acids is postulated to influence central nervous system neurotransmitters through competitive transport of substrate at the blood-brain barrier.17 The magnitude of that effect and the potential role for manipulation of dietary protein intake as a therapeutic tool are not firmly established. Attempts to use branched-chain amino acids as a therapeutic tool to augment respiratory drive in postoperative patients have not had beneficial resu1ts.l. 2o At this point, it appears unlikely that protein intake plays a major role in regulating ventilatory drive. The intravenous administration of fat emulsions is commonly employed in nutritionally depleted patient populations to prevent essential fatty-acid deficiency and provide a source of calories. Such infusions can adversely affect pulmonary gas exchange under certain conditions. Intravenous lipid administration has been associated with transient decreases in pulmonary diffusion capacity at rest and with submaximal exercise in normal Additional studies in critically ill patients have produced conflicting results.47, 48, y4 The effect, if present, appears to be a reduction in oxygenation and may be related to the magnitude of the underlying lung disease and rate of lipid admini~tration.~~ The basic mechanism of worsening hypoxemia, although initially attributed to hypertriglyceridemia, may lie in modulation of prostaglandin levels within the lung in response to the lipid admini~tration.~~ The reported changes in gas exchange appear to be of little apparent clinical significance and can be eliminated with slower infusion rates (4-8 hours). No

significant changes in gas exchange parameters have been reported with oral or enteral administration of fat solutions. The potential beneficial effects of nutrient support must be weighed against the demand such support places on the ventilatory system. Although individual substrates have variable defined effects on metabolism and gas exchange, the primary focus must be directed to selection of caloric support that is adjusted appropriately to energy demands. TREATMENT RECOMMENDATIONS

The presence of ongoing weight loss in a patient with ALD is an important marker of disease progression. Because the mechanisms of cachexia in ALD patients are multiple, the treatment of the syndrome must be comprehensive in nature. The benefits of nutritional support are minimal in the absence of other therapies. Correction of hypoxemia, treatment of infectious exacerbations, limitation of corticosteroid use, and participation in an exercise program all serve to support lean tissue mass. The hypermetabolism in the patient population, however, often requires protein-calorie supplementation. The vast majority of patients with ALD have a functional gastrointestinal tract and the preferred method of nutrient support therefore is via the oral or enteral route. For many patients, the simple intervention of a dietitian trained in counseling patients with lung disease can provide adequate augmentation of caloric intake. Counseling to address the planning and preparation of a nutritionally adequate meal plan, adequacy of the food supply in the home, the use of nutritional supplements, and other details is essential to the success of any intervention program. That frequently involves inclusion of significant others or the development of social support systems, when patients lack familial support. Patients may suffer from limitation of activity, including ability to obtain and prepare meals. Convenience foods, social support, and meal providers are important considerations for such individuals. The aggressive use of supplements is to be avoided, if possible, because they most commonly result in calorie substitution: Supplement intake results in replacement of regular food intake, without augmentation of total caloric intake. For the majority of patients with ALD, caloric intake at approximately 1.3 X REE (measured

NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE

or estimated) meets ongoing energy requirements and limits further weight loss. Proteincalorie intake should be further adjusted, as needed, to prevent ongoing weight loss. Excess calorie administration (>1.7 X REE) is unlikely to be beneficial in ALD patients and carries the potential risk of loading the ventilatory apparatus. Under rare circumstances, more aggressive forms of nutrient delivery, such as enteral support, are necessary. Parenteral feeding, with its adverse risk profile, would be contraindicated in the absence of associated gastrointestinal dysfunction. Again, the more aggressive forms of nutrient support are unlikely to be beneficial in the absence of a program directed at general cardiopulmonary rehabilitation.

14.

15.

16. 17. 18.

19.

20.

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Address reprint requests to Michael Donahoe, MD Division of Pulmonary, Allergy, and Critical Care Medicine University of Pittsburgh School of Medicine 440 Scaife Hall Pittsburgh, PA 15261