Chapter 5. Energy Needs: Assessment and Requirements in Humans

Resting Metabolic Rate

The resting metabolic rate (RMR) represents the largest portion of daily energy expenditure (60 to 75%) and is a measurement of the energy expended for

maintenance of normal body functions and homeostasis. These processes include resting cardiovascular and pulmonary functions, the energy consumed by the

central nervous system, cellular homeostasis, and other biochemical reactions involved in the maintenance of resting metabolism.

Another term to describe basal levels of energy expenditure is basal metabolic rate (BMR). While at the Mayo Clinic, Dr Boothby defined and popularized use of the

BMR for the diagnosis of thyroid disorders. He defined this function as the energy expended by an individual bodily and mentally at rest in a thermoneutral

environment 12 to 18 hours after a meal. Much to the inconvenience of the patient, measurements were done during the early morning hours when, in addition, the

circadian rhythm of oxygen consumption was known to be low. Because of the increase in metabolism caused by the muscular and mental unrest introduced by this

procedure, it is unlikely that the true basal metabolism was often measured. Therefore, for practical and conceptual reasons, the BMR is now rarely measured. In its

place, we now measure what is referred to as the resting metabolic rate (or resting energy expenditure), which may be (but is not always) higher than the BMR.

The RMR is primarily related to the fat-free mass of the body and is also influenced by age, gender, body composition, and genetic factors. For example, the RMR

decreases with advancing age (2 to 3%/decade), which is primarily attributed to the loss of fat-free mass. Males tend to have a higher RMR than females because of

their greater body size. The dependency of the RMR on body composition must be considered when individuals of different age, sex, and physical activity status are

compared. Other processes, such as sympathetic nervous system activity, thyroid hormone activity, and sodium-potassium pump activity, contribute to the variation in

the RMR among individuals. (See WHO equations for predicting basal metabolic rates from body weights and heights for different age groups and both sexes and

their derived data in Appendix Table III-10-b, Table III-10-c, Table III-10-d and Table III-10-e).

Thermic Effect of Feeding

The thermic effect of feeding (TEF) is the increase in energy expenditure associated with food ingestion. The TEF represents approximately 10% of the daily energy

expenditure and includes the energy costs of food absorption, metabolism, and storage. The magnitude of the TEF depends on several factors, including the caloric

content and composition of the meal as well as the antecedent diet of the individual. Following meal ingestion, energy expenditure increases for 4 to 8 hours, its

magnitude and duration depending on the quantity and type of macronutrient (i.e., protein, fat, or carbohydrate).

The TEF has been divided into subcomponents: obligatory and facultative thermogenesis. The obligatory component of the TEF is the energy cost associated with

absorption and transport of nutrients and the synthesis and storage of protein, fat, and carbohydrate. The “excess” energy expended above the obligatory

thermogenesis is the facultative thermogenesis and is thought to be partially mediated by sympathetic nervous system activity.

The TEF also decreases with advancing age and may be associated with development of insulin resistance ( 10). It is presently unclear how exercise training

influences the TEF, although there is clearly some interaction between physical exercise and TEF. There is presently no evidence that gender influences postprandial

thermogenesis.

Thermic Effect of Physical Activity

The most variable component of the daily energy expenditure is the thermic effect of physical activity ( 11). The component includes the energy expended above the

RMR and the TEF and includes the energy expended through voluntary exercise and the energy devoted to involuntary activity such as shivering, fidgeting, and

postural control. In sedentary individuals, the thermic effect of activity may be as low as 100 kcal7sol;day; in highly active individuals it may approach 3000 kcal/day

(see Chapter 47). Thus, physical activity represents a significant factor in the daily energy expenditure in humans because it is extremely variable and subject to

voluntary control. Physical activity tends to decrease with advancing age; this decrease in physical activity may be associated with a loss of fat-free mass and an

increase in adiposity. Males in general tend to have a greater caloric expenditure associated with physical activity than females, partially because of the greater

energy cost of moving a larger body mass. Average values of the energy cost of different grades of physical activity for men and women are given in Appendix Table

III-A-11-D and Table III-A-11-E.

The RMR, TEF, and physical activity often overlap during the course of a normal day. Although daily variations in energy balance put individuals in a slight energy

deficit or surplus, maintenance of a stable body weight depends on tight coupling of energy intake and energy expenditure over long periods of time. It is presently

unclear which psychologic and/or physiologic factors influence the coupling of energy intake with energy expenditure to maintain energy balance.



METHODS OF MEASUREMENT

Many methods of measuring energy expenditure have become available over the years, and they vary in complexity, cost, and accuracy ( 12). It is important to gain an

appreciation of the differences in the methods and of their applications in laboratory and other settings. The techniques used to measure total daily energy

expenditure and its components are briefly described below. A more detailed explanation of the laboratory methods of measuring energy expenditure has been

published (13).

The most widely used methods for measuring the energy expenditure involve indirect calorimetry. Direct calorimetry (measurement of heat loss from a subject) has

been used to measure energy expenditure, but the high cost and complicated engineering of this method have discouraged investigators from using this approach.

Indirect Calorimetry

The term indirect refers to the estimation of energy production by measuring O 2 consumption and CO2 production rather than by directly measuring heat transfer. This

method requires a steady state of CO 2 production and respiratory exchange and subjects with a normal acid-base balance. To determine the RMR, measurements are

usually taken with the subject in a supine or semireclined position after a 10- to 12-hour fast. Depending on the equipment, the subject typically breathes through a

mouthpiece, face mask, or ventilated hood or is placed in a room calorimeter in which expired gases are collected. Typical RMR values range from 0.7 to 1.6 kcal/min,

depending on the subject's body size, body composition, level of physical training, and gender. The room in which the measurements are made is usually darkened

and quiet, and the volunteer remains undisturbed during the measurement process. Measurement of RMR typically lasts 30 minutes to 1 hour, whereas postprandial

measurements frequently take 3 to 8 hours. These measurements are generally easily reproducible (with a coefficient of variation below 5%).

Several methods have been used to measure O2 consumption and CO2 production at rest. Generally, an “open circuit” method is used in which both ends of the

system are open to atmospheric pressure and the subject's inspired and expired air are kept separate by means of a three-way respiratory valve or nonrebreathing

mask. The expired gases are usually collected in a Douglas bag or Tissot respirometer for measurement of O 2 and CO 2 content. Hyperventilation may occur in

subjects who are not well adapted to a mouthpiece and may result in inappropriately high levels of O 2 consumption and CO2 production. When a mask is used, it is

frequently difficult to obtain an airtight seal around the subject's nose and mouth.

To circumvent some of these problems, ventilated hoods have been developed in which the subject is fitted with a transparent hood equipped with a snugly fitting

collar. Fresh air is drawn into the hood via an intake port, and expired air is drawn out of the hood by a motorized fan. The flow rate is measured by a

pneumotachograph, and aliquots of the outflowing air are analyzed for O 2 consumption and CO2 production after temperature and water vapor content have been

adjusted. O2 consumption and CO2 production are calculated from the differences in their concentrations in the inflowing and outflowing air and the flow rate.

Ventilated hoods are excellent for both short- and long-term measurements but are less useful in measuring the energy expenditure of physical activity; in the latter

case the subject may find the hood uncomfortable, and there is a problem with dissipation of perspiration and water vapor.

Measurement of the energy expenditure of physical activity has traditionally presented several methodological challenges. Indirect calorimetry using a mouthpiece or

face mask has been used to assess O 2 consumption and CO2 production. This method generally yields reliable and accurate measurements of the energy cost of

physical activity in a laboratory setting but provides no information about the energy cost of physical activity under free-living conditions because of the stationary

nature of the equipment. Portable respirometers use a face mask with valves that direct expired air through collection tubes to a respirometer carried on the subject's

back. The respirometer contains a flowmeter and a sampling device that collects an aliquot of expired gases for analysis at a later time. There are drawbacks to this



method: first, there is an inherent delay in obtaining results, and second, the rate of energy expended during work performance is integrated over the entire period of

gas collection.

In an attempt to avoid some of the problems associated with measurement of free-living physical activity, several less complicated (and less accurate) methods have

been devised. These methods use physiologic measurements, observation, and records of physical activity, as well as activity diaries or recall. Heart-rate recording,

used to measure energy expenditure, is based on the correlation between heart rate and oxygen consumption during moderate to heavy exercise ( 13, 14). The

correlation, however, is much poorer at lower levels of physical activity, and a subject's heart rate may be altered by such events as anxiety or change in posture

without significant changes in oxygen consumption.

It is possible to estimate energy expenditure over relatively long periods of time by measuring energy intake and changes in body composition. However, there are

errors inherent in attempting an accurate determination of energy intake over several days, weeks, or months, as well as in the methods available for determination of

body composition.

Time-motion studies have also been used to estimate the energy expenditure of physical activity in real-life situations. In time-motion studies, detailed records of

physical activity are kept by an observer, and energy expenditure is estimated from the duration and intensity of the work performed. The major problem with this

method is the marked individual variations in the energy costs of doing a particular task.

Physical activity diaries and physical activity recall instruments have been used to quantify the energy costs of different activities over a representative period of time.

Record keeping is often inaccurate and may interfere with the subject's normal activities. Furthermore, the subject's recall of physical activity depends on his or her

memory, which may not always be reliable. Measuring motion by devices such as a pedometer or an accelerometer may provide an index of physical activity (i.e.,

counts) but does not quantitate energy expenditure. In summary, measurement of free-living physical activity continues to be the most significant challenge in the field

of energy metabolism.

In recent years, large respiration chambers have been built in laboratories. Such a chamber operates on the same principle as the ventilated hood system: it is

essentially a large, airtight room in which temperature and humidity are controlled. Fresh air is drawn into the chamber and allowed to mix. Simultaneously, air is

drawn from the chamber, and the flow rate is measured and analyzed continuously for O 2 and CO 2 content. The size of the room affords the subject sufficient mobility

to sleep, eat, exercise, and perform normal daily routines, making detailed measurements of energy expenditure possible over a period of several hours or days.

Room calorimeters are probably the best method currently available for conducting short-term studies (several days) of energy expenditure in humans when the object

is to measure RMR, TEF, and the energy expenditure of physical activity. Physical activity level is quantified by a radar system that is activated by the subject's

movement within the chamber. As with other movement devices, the radar system does not quantitate the intensity of activity. It is also likely, however, that free-living

physical activity is blunted in the room calorimeter because of its confining nature. Thus room calorimeters do not offer the best model for examining adaptations in

free-living physical activity. Although room calorimeters are moderately expensive to construct, they provide reliable information on daily energy expenditure and

substrate oxidation.

Substrate Oxidation

The assessment of nutrient use is frequently used in combination with the assessment of energy expenditure. This area has been previously reviewed ( 14) and is

briefly summarized in this chapter. When the measurement of O2 is available (in liters of O 2 STPD [standard temperature (0°C), pressure (760 mm Hg), and dry] per

minute), metabolic rate (



), which corresponds to energy expenditure, can be calculated (in kJ/min) as follows:



where 20.3 is the mean value (in kJ/L) of the energy equivalent for the consumption of 1 L (STPD) of O 2. To take into account the heat generated by the oxidation of

the three macronutrients (carbohydrates, fats, and proteins), three measurements must be performed: oxygen consumption ( O2), carbon dioxide production (

VCO2), and urinary excretion (N). Simple equations for computing metabolic rate (or energy expenditure) from these three determinations are written in the following

form:



The factors a, b, and c depend on the respective constants for the amount of O 2 used and the amount of CO2 produced during oxidation of the three classes of

nutrients (Table 5.1). An example of such a formula is given below:



Table 5.1 Energy Equivalent from Oxidation of Substrates



where M is in kilojoules per unit of time, VO2 and VCO2 are in liters STPD per unit of time and N is in grams per unit of time. For example, if O2 = 600 L/day,

= 500 L/day (respiratory quotient, or RQ = 0.83) and N = 25 g/day, then M = 12,068 kJ/day. The simpler equation (5.1) gives a value of 12,180 kJ per day.



CO2



Indirect calorimetry also allows computation of the nutrient oxidation rates in the whole body. An index of protein oxidation is obtained from the total amount of

nitrogen excreted in the urine during the test period. One approach to calculating the nutrient oxidation rate is based on the O 2 consumption and CO2 production due

to the oxidation rates of the three nutrients, carbohydrate, fat, and protein, respectively. In a subject oxidizing c g/min of carbohydrate (as glucose) and f g/min of fat,

and excreting n g/min of urinary nitrogen, the following equations, based on Table 5.1), can be used:



and



We can solve equation 5.4 and equation 5.5 for the unknown c and f this way:



Because 1 g of urinary nitrogen arises from approximately 6.25 g protein, the protein oxidation rate p (in g/min) is given by the equation



Thus, indirect calorimetry allows calculation of net rates of nutrient oxidation. It is important to appreciate that indirect calorimetry measures the net appearance by

oxidation of a substrate. Moreover, it is important to understand that there is a slight difference in the heat produced per liter of O 2 consumed when one compares

carbohydrate, lipid, and protein oxidation. An examination of substrate oxidation has broadened our knowledge of the effects of environment (i.e., diet, exercise),

disease, and nutrient requirements in humans.

Doubly Labeled Water

The doubly labeled water technique offers promise as a method of determining energy requirements in free-living populations and in subjects in whom traditional

measures of energy expenditure, using indirect calorimetry, have proven impractical and difficult (e.g., infants and critically ill patients). The basis of this technique is

that after a bolus dose of two stable isotopes of water ( 2H2O and H 218O), 2H 2O is lost from the body in water alone, whereas H 218O is lost not only in water but also as

C 18O2 via the carbonic anhydrase system (9). The difference in the two turnover rates is therefore related to the CO 2 production rate, and with a knowledge of the fuel

mixture oxidized (from the composition of the diet), energy expenditure can be calculated.

The main advantages of the doubly labeled water technique are (a) it measures total daily energy expenditure, which includes an integrated measure of RMR, TEF,

and the energy expenditure of physical activity; (b) it permits an unbiased measurement of free-living energy expenditure; and (c) measurements are conducted over

extended periods of time (1 to 3 weeks). Thus, energy values derived from the doubly labeled water method are representative of the typical daily energy expenditure

and therefore the daily energy needs of free-living adults. Furthermore, this technique provides an accurate estimate of free-living physical activity. Daily free-living

physical activity is calculated from the difference between the total daily energy expenditure and the combined energy expenditures of the RMR and TEF. Thus the

doubly labeled water technique provides the most realistic estimate in free-living subjects of the average daily energy expenditure associated with physical activity.

Disadvantages of the doubly labeled water method are its expense and limited availability ( Table 5.2). Consequently, the technique does not lend itself to

epidemiologic studies or studies of large groups of subjects. However, this technique is now being used to examine energy requirements of persons in a variety of

healthy and diseased states. With use of the doubly labeled water method, measurement of daily energy expenditure becomes a proxy measure of daily energy

requirements.



Table 5.2 Advantages and Disadvantages of the Doubly Labeled Water Technique



Labeled Bicarbonate

The labeled bicarbonate ( 13C or 14C) method has recently won favor as a technique for measuring energy expenditure over shorter periods of time (several days) than

those covered by the doubly labeled water method ( 15). When labeled bicarbonate is infused at a constant rate, it reaches a rapid equilibrium with the body's CO 2

pool. The extent of isotopic dilution depends on the rate of CO 2 production, provided there is not isotopic exchange or fixation. Thus variations in the dilution of

isotope reflect variations in CO 2 production and hence energy expenditure. Because the method assesses CO 2 production rather than O 2 consumption, it requires

assumptions about the respiratory quotient similar to those required by the doubly labeled water method.

In the final analysis, cost and the specific research questions generated should direct the selection of methods of measuring energy expenditure. Questions of

substrate oxidation and its impact on the regulation of energy balance, for example, are most applicable to the techniques of indirect calorimetry using room

calorimeters and ventilated hood systems. On the other hand, more reliable information on the adaptations of free-living subjects to environmental perturbations

(exercise, dietary interventions, etc.) over long periods of time is provided by the use of the doubly labeled water method combined with indirect calorimetry systems.



CAN ENERGY INTAKE BE ACCURATELY MEASURED IN HUMANS?

Self-recorded food intake has been the traditional method of estimating energy requirements. However, available methods for estimating food intake are fraught with

limitations and methodological problems. While there is a clear need to provide well-founded recommendations for dietary energy, there have been major technical,

physiologic and conceptual problems in doing so. The establishment of individual energy requirements has been problematic because of reliance on (a) measurement

of energy intake from self-recorded diaries and/or dietary interviews, (b) the use of a multiple of BMR (or RMR) to predict energy needs, and (c) the failure of current

recommended daily energy requirements to take into account the diversity of the population with respect to body composition and physical activity. The shortcomings

of each of these approaches are briefly discussed below.

Self-recording of energy intake depends on the cooperation of the volunteer, and the very act of recording energy intake may actually alter ingestive behavior, even in

compliant volunteers who wish to “please” the investigator. Thus, recording food intake becomes an unreliable tool on which to base guidelines for determining energy

needs. Several recent studies suggest consistent underreporting of actual energy intake when validated against measures of total daily energy expenditure from

doubly labeled water (16, 17 and 18). Data from our laboratory suggest a significant underreporting of energy intake by as much as 30% in older individuals,

compared with measurement of daily energy expenditure (16). Underreporting was more pronounced in women (30%) than in men (15%). Thus, it is apparent that

using measures of energy intake to estimate energy requirements lacks scientific credibility because of the uncertainty and unreliability of subject reporting.

An alternative method of estimating energy needs uses multiples of RMR ( 19). In this approach, estimates of daily energy expenditure are not derived directly but by a

factorial approach in which RMR and the estimated energy expenditure from various physical activities are summed ( 20). This method suffers from a number of

methodological problems. First, it does not consider the components of daily energy expenditure that contribute to individual variation in daily energy expenditure.

These “neglected” components include (a) the TEF, which contributes approximately 10 to 15% of daily energy expenditure ( 21), and (b) the thermic effect of physical

activity. Data from our laboratory showed that under free-living conditions, physical activity is highly variable in normal persons and can range from as low as 187

kcal/day to 1235 kcal/day (11, 16). Furthermore, knowledge of RMR alone provides insufficient information for explaining variation in daily energy expenditure, as



variation in RMR explains less than half of individual variation in daily energy expenditure ( 16).

Another “general method” of assessing energy needs is based on recommended daily allowances ( 22) (see Appendix Table II-A-2-a-1). The current RDAs divide the

adult population into two age groups those who are 19 to 50 years old and those 51 years old and older. The frequent use of the category of “51 and older” is

recognized as inappropriate, because normal and diseased aging produces increased heterogeneity in almost all physiologic measurements. The physiologic status

and energy requirements of individuals who are 50 to 60 years old are very different from those of persons who are 80 to 90 years old. Furthermore, the RDAs do not

take into account energy recommendations for individuals who vary in physical activity or disease state. It is evident, however, that the use of a single energy value is

far too crude an approach and should be abandoned for medical, nutritional, and planning purposes. These methods were necessitated, until recently, by the lack of a

direct method to measure daily energy expenditure under free-living conditions.

The World Health Organization Consultative Panel has stated that future guidelines should be based on measurements of energy expenditure “if and when these

became available” (19). As noted above, the doubly labeled water technique ( 2H 218O) provides a measure of free-living energy expenditure. In the adult individual,

daily energy expenditure defines the level of energy intake to maintain energy balance ( 23). Measurement of total daily energy expenditure with the doubly labeled

water technique therefore acts as a proxy indicator of the amount of energy intake that is required to maintain energy balance and body energy stores.



ENERGY NEEDS OF SPECIFIC POPULATIONS

Below, we examine recent applications of doubly labeled water methodology in healthy and diseased older individuals to understand better daily energy requirements

and the regulation of energy balance. We consider several diseases that are associated with negative energy balance and generalized wasting.

Heart Failure

Heart failure is an increasing important and frequent clinical problem, with the highest prevalence observed in the elderly ( 24). The incidence of heart failure

increases 50-fold between the ages of 40 and 60 years. The unexplained loss of body weight and muscle mass are hallmark clinical features of end-stage congestive

heart failure ( 25). It is unclear whether reduction in caloric intake or elevated caloric expenditure accounts for the negative energy balance and subsequent weight

loss in advanced heart failure. Furthermore, daily energy requirements in heart failure are unknown.

Several studies have examined energy expenditure in heart failure. RMR, body composition, and dietary intake were examined in 20 heart failure patients with

documented systolic dysfunction and compared with an age-matched cohort of 40 healthy elderly volunteers ( 26). RMR was measured by indirect calorimetric

techniques and fat mass and fat-free mass were measured by dual-energy x-ray absorptiometry. Fat-free mass (lean body mass minus skeleton) was approximately 4

kg lower in heart failure patients, despite similar amounts of fat mass. Although lower fat-free mass was noted, the RMR was 18% higher in heart failure patients than

in healthy controls (Fig. 5.2). These results suggest that heart failure patients have a higher RMR (for their metabolic size), which may contribute to their propensity

for unexplained weight loss and musculoskeletal wasting.



Figure 5.2. The relationship between resting metabolic rate and fat-free mass in healthy individuals and patients with heart failure. This figure shows that resting

metabolic rate (per kg of fat-free mass) is higher in heart failure patients. (Adapted from Poehlman ET, Scheffers J, Gottlieb SS, et al. Ann Intern Med

1994;121:860–2).



Measurement of the RMR, however, only provides partial information on whether energy needs are indeed higher in congestive heart failure patients. Ultimately, the

balance between daily energy expenditure and food intake regulates body composition in humans. Although recent work ( 26, 27 and 28) provided evidence that

resting energy requirements are higher in heart failure and that the magnitude of the increase in resting energy needs increases with symptom severity ( 27), it was

unclear whether daily energy needs are higher in heart failure patients in their free-living environment. Accordingly, daily energy expenditure and physical activity

were measured in free-living cachectic ( 12) and noncachectic (13) patients with heart failure and 50 healthy control volunteers, by doubly labeled water and indirect

calorimetry methodology (29) (Table 5.3). As expected, fat mass and fat-free mass were lower in cachectic patients than in noncachectic patients and controls. Daily

energy expenditure was lower (P < .05) in cachectic patients (1870 ± 347 kcal/day) than in noncachectic patients (2349 ± 545 kcal/day) and healthy controls (2543 ±

449 kcal/day) (Table 5.3). Differences in daily energy expenditure were due to lower ( P < .05) free-living physical activity energy expenditure in cachectic (269 ± 307

kcal/day) and noncachectic patients (416 ± 361 kcal/day) compared with healthy controls (728 ± 374 kcal/day). Thus, the hypothesis that daily energy requirements

are higher in heart failure patients is not supported by these initial studies using doubly labeled water methodology. Moreover, these findings underscore the need to

measure daily energy expenditure in free-living patients accurately before drawing conclusions about the presence or absence of elevated daily energy expenditure

and its relationship to weight loss. Because no evidence for an elevated daily energy expenditure in cachectic heart failure patients was found, the suggestion is that

inadequate energy intake is a likely determinant of weight loss. Several factors including abdominal pain and distention, gastrointestinal hypomotility, and delayed

gastric emptying have been suggested to contribute to anorexia in heart failure patients ( 25). The fact that daily energy expenditure was not elevated in noncachectic

patients, however, argues against an elevated daily energy expenditure preceding weight loss.



Table 5.3 Daily Energy Expenditure, a Its Components and Energy Intake in Cachectic and Noncachectic Heart Failure Patients and Healthy Controls



Alzheimer's Disease

Alzheimer-type dementia, a growing health problem, is one of the leading causes of death among elderly people ( 30). The overall estimate is that more than 10% of

persons over 65 suffer from senile dementia of the Alzheimer's type ( 31). Annual medical costs for Alzheimer's disease are estimated to be more than 40 billion



dollars (32).

Unexplained weight loss is a frequent clinical finding in patients with Alzheimer's disease. The National Institute of Neurological and Communicative Disorders and

Strokes Task Force on Alzheimer's Disease has included weight loss as a “clinical feature consistent with the diagnosis of Alzheimer's disease” ( 33). Moreover, it has

been postulated that Alzheimer's disease may be characterized by dysfunction in body weight regulation ( 34).

Weight loss is due to a mismatch of energy intake with energy expenditure, which leads to low body weight, atrophy of muscle mass, and accelerated loss of

functional independence in persons with Alzheimer's disease. Weight loss also increases the risks of decubitus ulcers, systemic infection, mortality, and greater

consumption of health care resources ( 35, 36). Although it may not yet be possible to prevent, treat, or permanently alter the course of the underlying disease,

identification and amelioration of nutritional problems may prove an ideal strategy for lessening the burden of the disease.

Is the energy imbalance associated with Alzheimer's disease caused by reduced energy intake, an elevated rate of energy expenditure, or a combination of both?

Studies examining the caloric adequacy of diets of Alzheimer's patients as a potential contributor to weight loss ( 37, 38 and 39) have yielded inconclusive results. This

is not surprising, since the recording of food intake is an unreliable method that provides little useful information on an individual's actual habitual energy intake.

Therefore, investigators have focused on the possibility that elevated energy expenditure contributes to unexplained weight loss in Alzheimer's patients. Several

investigators found an elevated RMR in Alzheimer's patients, which might itself result in weight loss, ( 40, 41 and 42), although these results remain controversial ( 43,

44, 45 and 46). A more important question, however, is whether free-living Alzheimer's patients have a higher daily energy expenditure than normal elderly persons.

Doubly labeled water methodology was used to examine the hypothesis that Alzheimer's patients are characterized by high levels of daily energy expenditure ( 47).

Thirty Alzheimer's patients (73 ± 8 years of age; Mini-Mental score: 16 ± 8) and 103 healthy elderly persons (69 ± 7 years of age) were studied. Daily energy

expenditure and its components (RMR and free-living physical activity) from doubly labeled water and indirect calorimetry were measured over a 10-day period.

Fat-free mass tended to be lower in Alzheimer's patients (45 ± 9 kg) than in the healthy controls (49 ± 10 kg; P = .07), whereas no differences were noted in fat mass

between groups. Daily energy expenditure was 14% lower in Alzheimer's patients (1901 ± 517 kcal/day) than in the controls (2213 ± 513 kcal/day; P £ .001) because

of a lower RMR (1287 ± 227 vs. 1418 ± 246 kcal/day; P < .01) and physical activity–related energy expenditure (425 ± 317 vs. 574 ± 342 kcal/day; P < .05) (Table

5.4). There were no differences between groups when energy expenditure was normalized for differences in fat-free mass. Thus, the lower energy expenditure in

Alzheimer's patients is primarily due to their lower fat-free mass.



Table 5.4 Daily Energy Expenditure a and Its Components in Alzheimer's Patients and Healthy Elderly Persons



Daily energy expenditure was also examined in a subgroup ( N = 11) of Alzheimer's patients who had lost significant body weight (5.6 ± 2.3 kg) within the previous

year. A lower daily energy expenditure was found in cachectic Alzheimer's patients (1799 ± 474 kcal/day) than in noncachectic Alzheimer's patients (1960 ± 544

kcal/day) and healthy elderly controls (2213 ± 513 kcal/day; P < .01). Thus, daily energy expenditure is not higher, but lower in Alzheimer's patients, because of lower

levels of resting and physical-activity–related energy expenditure and fat-free mass.

Collectively, the hypothesis that an increased daily energy expenditure contributes to weight loss in heart failure or Alzheimer's diseases is not supported by these

findings. These findings, again, underscore the importance of assessing daily energy expenditure in free-living individuals before drawing conclusions regarding the

presence or absence of a “hypermetabolic state.

Parkinson's Disease

Approximately 50% of patients afflicted with Parkinson's disease experience significant weight loss during the course of the disease. The suggestion has been made

that inappropriately high levels of energy expenditure contribute to their unexplained weight loss. Several studies have compared differences in RMR between

Parkinson's disease patients and an age-matched control population in an attempt to address this question. Several investigators ( 48, 49 and 50) found an elevated

RMR in Parkinson's disease patients, compared with healthy controls. The elevated RMR was at least partially attributed to tremor, rigidity, and a general dyskinesia

in these patients.

More recently, total daily energy expenditure was assessed in Parkinson's patients to examine the hypothesis that free-living daily energy expenditure and its

components (RMR and physical activity energy expenditure) are elevated ( 51). In contrast to the proposed hypothesis, daily energy expenditure was 15% lower in

Parkinson's disease patients (2214 ± 460 kcal/day) than in healthy elderly controls (2590 ± 497 kcal/day). This was primarily due to lower physical activity energy

expenditure (339 ± 366) in Parkinson's disease patients compared with that of the controls (769 ± 412 kcal/day). Thus, although excessive muscular activity in the

form of rigidity and tremor may contribute to an elevated RMR ( 48, 49 and 50), the overall effect of Parkinson's disease is to lower daily energy expenditure by

reducing the energy expenditure associated with purposeful physical activity. Impairment of gain and movement associated with the signs and symptoms of

Parkinson's disease probably promotes a reduction in physical activity.

The absence of an elevated daily energy expenditure suggests that an abnormally elevated daily energy expenditure is not a likely predisposing factor to weight loss.

Thus, it is likely that a lower caloric intake is implicated in the weight loss of these patients. Swallowing disorders, impaired hand-to-mouth coordination, nausea,

excessive saliva production, and delayed gastric emptying time may contribute to reduced energy intake in Parkinson's disease patients ( 52).



ACKNOWLEDGMENTS

Supported in part by a grant from the National Institute of Aging to ETP (RO1AG-07857), a Research Career and Development Award from the National Institute of

Aging (KO4-AG00564) to ETP, Alzheimer's Association/Red Apple Companies Pilot Research Grants to ETP, GCRC RR-109 at the University of Vermont, and the

American Association of Retired Persons Andrus Foundation to ETP.

CHAPTER REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.



Holmes FL. Lavoisier and the chemistry of life. Madison: University of Wisconsin Press, 1985;3.

Voit E. Z Biol 1901;23:113–54.

Atwater W, Benedict F. 1905: Washington, DC: Carnegie Institute, publ no. 42, 1–193.

Benedict FG. Boston Med Surg J 1918;178:667–78.

Lusk G. The elements of the science of nutrition. 4th ed. Philadelphia: WB Saunders, 1928.

DuBois EF. Basal metabolism in health and disease. Philadelphia: Lea & Febiger, 1924.

Lifson N, Gordon GB, McClintock R. J Appl Physiol 1955;7:704–10.

Lifson N, Little WS, Levitt DG, Henderson RM. J Appl Physiol 1975;39:657–64.

Schoeller DA, Ravussin E, Schutz Y, et al. Am J Physiol 1986:250:R823–30.

Golay A, Schutz Y, Broquet C, et al. J Am Geriatr Soc 1983:31:144–48.

Dauncey MJ. Can J Physiol Pharmacol 1990;68:17–27.

Horton ES. Energy intake and activity. In: Pollitt E, Amante P, eds. Current topics in nutrition and disease. New York: Alan R Liss, 1984;115–29.

Murgatroyd PR, Shetty PS, Prentice AM. Int J Obesity 1993;17:549–68.



14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.



Schutz Y, Jequier E. Energy needs: assessment and requirements. In: Shils ME, ed. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Febiger, 1994;101–11.

Elia M, Fuller N, Murgatroyd P. Proc Nutr Soc 1988;47:247–58.

Goran MI, Poehlman ET. Metabolism 1992;41:744–53.

Mertz W, Tsui JC, Judd JT, et al. Am J Clin Nutr 1991;54:291–95.

Schoeller DA. Nutr Rev 1990;48:373–79.

World Health Organization, Food and Agriculture Organization, United Nations University. Energy and protein requirements. Geneva: World Health Organization, (Technical reports series,

724), 1985.

James WPT, Ferro-Luzzi A. Energy needs of the elderly: a new approach. In: Munro HN, Danford DE, eds. Human nutrition. A comprehensive treatise, vol 6: Nutrition, aging and the elderly.

New York: Plenum Press, 1989;129–51.

Poehlman ET, Melby CL, Badylak SF. J Gerontol 1991;46:B54–8.

National Research Council. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989.

Schoeller DA. J Nutr 1988;118:1278–89.

Minotti J, Masie B. Circulation 1992;85:2323–5.

Pittman JG, Cohen P. N Engl J Med 1964:271:403–9.

Poehlman ET, Scheffers J, Gottlieb SS, et al. Ann Intern Med 1994;121:860–2.

Obisesan TO, Toth MJ, Donaldson K, et al. Am J Cardiol 1996;77:1250–3.

Riley M, Elborn JS, McKane WR, et al. Clin Sci 1991;80:633–9.

Toth MJ, Gottlieb SS, Goran MI, et al. Am J Physiol 1997;272:E469–75.

Council on Scientific Affairs: Dementia. JAMA 1985;256:2234–8.

Evans DA, Funkenstein HH, Albert MS, et al. JAMA 1989;262:2251–6.

Butler R. Bull NY Acad Med 1982;58:362–71.

McKhann G, Drachman D, Folstein M, et al. Neurology 1984;34:939–43.

White H, Pieper C, Schmader K, et al. J Am Geriatr Soc 1996;44:265–72.

Sandman PO, Adolfsson R, Nygren C, et al. J Am Geriatr Soc 1987;35:31–8.

Pinchcofsy-Devin GD, Kaminski JR. J Am Geriatr Soc 1986;34:435–9.

Parvizi S, Nymon M. J Nutr Elderly 1982;2:15–9.

Bucht G, Sandman PO. Age Ageing 1990;19:S32–6.

Renvall MJ, Spindler AA, Ramsdell JW, et al. Am J Med Sci 1989;298:20–6.

Singh S, Mulley GP, Losowsky MS. Age Ageing 1988;17:21–8.

Adolfsson R, Bucht G, Lithner F, et al. Acta Med Scand 1989;208:387–8.

Wolf-Klein GP, Silverstone FA, Lansey SC, et al. Nutrition 1995;11:264–8.

Niskanen L, Piirainen M, Koljonen M. Age Ageing 1993;22:132–7.

Prentice AM, Leavesley K, Murgatroyd PR, et al. Age Ageing 1989;18:158–67.

Donaldson KE, Carpenter WH, Toth MJ, et al. J Am Geriatr Soc 1996:44:1232–4.

Litchford MD, Wakefield LM. J Am Diet Assoc 1987;87:211–3.

Poehlman ET, Toth MJ, Goran MI, et al. Neurology 1997;48:997–1002.

Levi SL, Cox M, Lugon M, et al. Br Med J 1990;301:1256–7.

Brousselle E, Borson F, de Gonzalez JM, et al. Rev Neurol (Paris) 1991;147:46–51.

Markus H, Cox M, Tomkins A. Clin Sci 1992;83:199–204.

Toth MJ, Fishman PS, Poehlman ET. Neurology 1997;48:88–91.

Abbott RA, Cox M, Markus H, et al. Eur J Clin Nutr 1992;55:701–7.



SELECTED READINGS

Poehlman ET. Energy intake and energy expenditure in the elderly. Am J Hum Biol 1996;8:199–296.

Schwartz MW, Dallman MF, Woods SC. Hypothalamic response to starvation: implications for the study of wasting disorders. Am J Physiol 1995;269:R949–57.



Chapter 6. Electrolytes, Water, and Acid-Base Balance

Modern Nutrition in Health and Disease



Chapter 6. Electrolytes, Water, and Acid-Base Balance

MAN S. OH and JAIME URIBARRI

Regulation of Intra- and Extracellular Volume and Osmolality

Volumes of Body Fluid

Composition of Body Fluid

Osmolar Relations and Regulation

Routes of Fluid and Electrolyte Loss

Types of Dehydration

Principles of Fluid Therapy

Disorders of Potassium Metabolism

Potassium Flux and Excretion

Hypokalemia

Hyperkalemia

Pathophysiology of Water and Antidiuretic Hormone Metabolism

Regulation of Thirst and Antidiuretic Hormone Release

Hyponatremia

Hypernatremia

Acid-Base Disorders

Bicarbonate and CO Buffer System

2

Whole-Body Acid-Base Balance

Terminology

Metabolic Acidosis

Metabolic Alkalosis

Respiratory Alkalosis

Respiratory Acidosis

Mixed Acid-Base Disorders

Clinical Problems and Answers

Topical Reading Lists



REGULATION OF INTRA- AND EXTRACELLULAR VOLUME AND OSMOLALITY

The body fluid, an aqueous solution containing many electrolytes, consists of intracellular and extracellular compartments. The intracellular fluid is not a single large

compartment; each cell has its own separate environment, communicating with other cells only via interstitial fluid and plasma. Consequently, cells in various tissues

differ considerably in their solute content and concentrations.

Regardless of the nature of the solute and its electrical charge, however, osmotic equilibrium is maintained so that each particle of solute throughout the body is

surrounded by the same number of water molecules. Since cell membranes are very permeable to water, osmolality is the same throughout the body fluids. Operation

of normal metabolic functions of the body requires maintaining an optimal ionic strength in its environment, primarily the intracellular fluid, where most metabolic

activities occur. The homeostatic mechanisms of the body are therefore constantly at work to provide such an environment.

Because the extracellular fluid (ECF) is not the site of major metabolic activity, substantial alteration in its ionic strength may occur without adverse effects on the body

function. The main function of the ECF is to serve as a conduit between cells and between organs. The plasma is a route of rapid transit, and the interstitial fluid

serves as a slow supply zone, which by flowing around the cell permits the entire cell surface to be used as an area of exchange. The ability of the ECF to function

efficiently as a conduit requires maintenance of optimal extracellular volume, particularly of plasma volume, the vehicle of rapid transportation through the circulation.

An additional important function of the ECF is regulation of the intracellular volume and its ionic strength. Because of the requirement for osmotic equilibrium between

the cells and the ECF, any alteration in extracellular osmolality is followed by an identical change in intracellular osmolality, which is usually accompanied by a

reciprocal change in cell volume.

Although cells and organs can be supplied with substrate and relieved of metabolic products with a much slower circulation, normal circulation is required to supply

sufficient oxygen for the body's metabolic needs. Normal plasma volume is a prerequisite for maintenance of normal circulation. Because plasma is in equilibrium with

the interstitial fluid, the maintenance of normal plasma volume requires normal extracellular volume. A low extracellular volume can result in impaired organ perfusion,

and an excessive extracellular volume may lead to vascular congestion and pulmonary edema.

Volumes of Body Fluid

Total body water can be determined by dilution of various substances including deuterium, tritium, and antipyrine. Total body water measured with antipyrine in

hospitalized adults without fluid and electrolyte disorders is about 54% of the body weight. The fractional water content is higher in infants and children and decreases

progressively with aging. The water content also depends on the body content of fat; women and obese persons, because of their higher fat content, tend to have less

water for a given weight.

A useful short cut for calculation of total body water, using the fact that 54% of body weight in kg is body water, and 1 kg is 2.2 lb, is:

Total body water (L) = Body weight (lb)/4

For an obese subject, subtract 10% from the calculated body water, and for a lean person add 10%. For a very obese person, subtract 20%. Women have about 10%

less body water than men for the same body weight.

Extracellular volume is measured directly, and the intracellular volume is estimated as the difference between total body water and extracellular volume. Measurement

of total body water by dilution techniques is reproducible and reliable, but measurement of extracellular volume is not, because different markers have different

volumes of distribution. Markers such as sodium, chloride, and bromide penetrate the cells to some extent, whereas markers such as mannitol, inulin, and sucrose do

not penetrate certain parts of the ECF. Thus, depending on the type of marker used, ECF volume could vary from 27 to 53% of total body water ( Table 6.1).



Table 6.1 Volumes of Body Fluid Compartmentsa



Extracellular volume measured with chloride and expressed as percentage of total body water varies from 42 to 53%, greater in older subjects and women.

Extracellular volumes measured with inulin and sulfate are smaller, about 30 to 33% of total body water. For clinical application, a value of 40% of total body water will

be considered to represent extracellular volume. Extracellular volume is further divided into three fractions: interstitial volume (28% of total body water), plasma

volume (8%), and transcellular water volume (4%). Transcellular water includes luminal fluid of the gastrointestinal tract, the fluids of the central nervous system, fluid

in the eye as well as the lubricating fluids at serous surfaces ( Table 6.1).

Composition of Body Fluid

Extracellular Composition

The concentrations of electrolytes in plasma are easily measured and their values are well known. These concentrations increase by about 7% when expressed in

plasma water, because about 7% of plasma is solids. Thus, plasma sodium is 140 meq/L but the concentration in plasma water is 151 meq/L. The concentrations of

electrolytes in interstitial fluid differ from those in plasma because of differences in protein concentrations between plasma and interstitial fluid. The actual differences

in electrolyte concentrations can be predicted by the Donnan equilibrium. With normal plasma protein concentrations, the concentrations of diffusible cations are

higher in plasma water than in interstitial water by about 4%, while the concentrations of diffusible anions are lower in the plasma than in the interstitium by the same

percentage. The concentrations of calcium and magnesium in the interstitial fluid are lower than the values predicted by the Donnan equilibrium, because these ions

are substantially protein bound.

Interstitial fluid consists of two phases, the free phase and the gel phase. The latter is invested with a fibrous meshwork that is largely made up of collagen fibers that

hold the cells together. A ground substance consists of glycosaminoglycans, which also limit the mobility of water, holding some of the bound water in an icelike

lattice. That part of the interstitial fluid in the free form is what we usually regard as the free “interstitial fluid,” which is a route for water and solutes from capillaries to

lymphatics.

Intracellular Composition

While sodium, chloride, and bicarbonate are the main solutes in the ECF, potassium, magnesium, phosphate, and proteins are the dominant solutes in the cell. The

intracellular concentrations of sodium and chloride cannot be measured accurately because of technical difficulties and are estimated by subtracting the extracellular

amount from the total tissue value. Since concentrations of electrolytes in the ECF are high, a small error in extracellular water volume measurement causes a large

error in the measurement of intracellular concentration of these ions. The concentration of bicarbonate is calculated from cell pH, and the bicarbonate concentration

shown in Table 6.2 is based on the assumption that average cell pH is 7.0.



Table 6.2 Electrolyte Concentrations in Extracellular and Intracellular Fluids



The electrolyte composition of intracellular fluid is not identical throughout the tissues. For example, the concentration of chloride in muscle is very low, about 3

meq/L, but it is 75 to 80 meq/L in erythrocytes. The concentration of potassium in the muscle cell is about 140 meq/L, but in the platelets only about 118 meq/L. The

concentration of sodium in muscle and red blood cells is about 13 meq/L, but in leukocytes, about 34 meq/L. Because muscle represents the bulk of the body cell

mass, it is customary to use the electrolyte concentration of the muscle cells as representative of the intracellular electrolyte concentration.

Because a substantial part of the anions inside the cell consists of polyvalent ions such as phosphate and protein, a total ionic concentration in the cell in meq/L is

higher than that of the ECF, but osmolal concentrations of the extracellular and intracellular fluid are the same.

Osmolar Relations and Regulation

Measurement of Plasma Osmolality

The plasma osmolality can be measured with an osmometer or estimated as the sum of the concentration of all the solutes in the plasma. Because an osmometer

does not distinguish between effective osmols and ineffective osmols, effective osmolality can only be estimated. Urea is the only ineffective osmol that has

substantial concentration in the plasma. Still, its normal concentration is only 5 mosm/L. In the normal plasma, therefore, total osmolality is nearly equal to effective

osmolality. Plasma osmolality is estimated as follows:

Plasma osmolality = Plasma Na (meq/L) × 2 + glucose (mg/dL)/18 + urea (mg/dL)/2.8.

Many of the solutes that may accumulate abnormally in the body are anions of an acid (e.g., salicylate, glycolate, formate, lactate, b-hydroxybutyrate). These

substances should not be added in estimating plasma osmolality, since they are largely balanced by sodium and therefore already included in the value when plasma

sodium is multiplied by 2.

Nonelectrolyte solutes that accumulate abnormally in the serum, e.g., ethanol, isopropyl alcohol, ethylene glycol, methanol, and mannitol, will cause the measured

osmolality to exceed the calculated osmolality, producing an osmolal gap. This osmolal gap is frequently a useful clinical clue to the presence of the toxic substances

listed above. Accumulation of neutral and cationic amino acids can also cause a serum osmolal gap.

Control of Intracellular Volume: Concept of Effective Osmolality

When the osmolal concentration of the ECF increases by accumulation of solutes that are restricted to the ECF (e.g., glucose, mannitol, and sodium), osmotic

equilibrium is reestablished as water shifts from the cell to the ECF, increasing intracellular osmolality to the same level as the extracellular osmolality. When the

extracellular osmolality increases by accumulation of solutes that can enter the cell freely (e.g., urea and alcohol), the osmotic equilibrium is achieved by entry of

those solutes into the cell. Such solutes are ineffective osmols. Since most of the solutes normally present in the ECF are effective osmols, loss of extracellular water

will increase effective osmolality and hence cause water to shift from the cells. Reduction in extracellular osmolality either by loss of normal extracellular solutes or by

retention of water reduces effective osmolality for the same reasons and hence causes water to shift into the cells.

Effect of Hyperglycemia on Serum Sodium. The permeability of a membrane for a given solute varies with the cell type. For example, glucose does not accumulate

in the muscle. It does not enter the muscle cell freely, and when it enters the cell with the help of insulin, it is quickly metabolized. Thus, glucose is an effective osmol

for the muscle cell (i.e., hyperglycemia will cause water to shift from the muscle cell). On the other hand, glucose is an ineffective osmol for red blood cells and liver