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On heat, respiration, and calorimetry
Nutrition 26 (2010) 939–950
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Review
On heat, respiration, and calorimetry David C. Frankenfield M.S., R.D. * Department of Clinical Nutrition, Penn State Milton S. Hershey Medical Center, Hershey, PA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 September 2009 Accepted 7 January 2010
The technique of indirect calorimetry developed with the sciences of nutrition and physiology over the course of hundreds of years. It was in fact fundamental to the establishment of these disciplines. This review describes the development of the technology and the principles of body function it has revealed. Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Indirect calorimetry Energy metabolism
Debate over the clinical use of indirect calorimetry is common, centered on whether outcomes are improved by its use. In the midst of this debate it is easy to forget the importance of calorimetry in our understanding of physiology and nutrition. The development of the technique and the principles it has revealed is a history worth relating. Prelude (300 BC–1750 AD) From the earliest times, body heat and respiration were understood to be linked. The ancient Greeks believed that man received heat from the cosmos at birth and breathed to cool this innate heat and thus extend life [1–3]. Through the Middle Ages and beyond, this idea survived, with additional theorizing that some heat was produced by body motion or friction of the blood [3]. John Mayow (1643–1679), an English physician, was the first to advance significantly beyond the Greek model. Using pneumatic troughs to collect reaction gasses (Fig. 1) [4], Mayow discovered in 1674 that animals and combusting candles consume a component of air and die without it. This discovery implied that air was a mixture of gasses, which was provocative because air at the time was believed to be a single element [3]. Because combustion generated heat, Mayow conjectured that respiration played a role in the generation of body heat. Although Mayow’s respiration work was largely correct, it failed to change beliefs about the source of body heat [3]. There was even doubt about his demonstration that air was consumed during respiration. In fact, Mayow’s work was largely forgotten in the enthusiasm over a new theory of heat. This was the * Corresponding author. Tel.: 717-531-6042; fax: 717-531-7995. E-mail address: Dfrankenfi[email protected] (D. C. Frankenfield). 0899-9007/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2010.01.002
phlogiston theory, first promulgated by Jochaim Becher in 1680 and Ernst Stahl in 1728 [3,5,6] to explain combustion. The theory held that flammable materials were made so by the presence of phlogiston, an odorless and weightless substance. Combustion released phlogiston, generating heat in the process. Because animals were warm, phlogiston theory came to be applied to physiology. Body heat was the result of phlogiston release and respiration was the route of phlogiston disposal [3,5,6]. Physiological chemistry and the first calorimeter (1750–1800) In the latter half of the 18th century, landmark discoveries were made regarding the composition of atmospheric and respired air and the nature of heat that would open the way to an understanding of human metabolism in health and disease. Joseph Black (Scottish physician, 1728–1799) discovered carbon dioxide in 1754 [7–9]. This discovery initially was not thought of in metabolic terms but while Black was characterizing carbon dioxide he found that it was a component of exhaled breath and therefore produced by the body [3,7,9]. Black also made discoveries on the nature of heat and techniques to measure it that would be incorporated into the first direct calorimeters [3,7,10,11]. Specifically, Black placed an object of known mass and temperature into a chamber bored into a block of ice. As heat from the object radiated into the chamber, it melted some of the ice. The amount of water produced was proportional to the amount of heat released because the law of latent heat of transformation dictates that a substance such as ice undergoing a phase change will not change its temperature until the phase change is complete (were this not so, then the heat release would be a function of the volume of water and of its temperature rather than just its volume).
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Fig. 1. Indirect calorimeter prototype (Mayow, 1674) [4,11]. A bell jar was inverted over a water seal with a mouse placed on a stand inside the jar. Consumption of air by the mouse reduced pressure in the bell, allowing water to intrude, thus proving the consumption. That this experiment worked was purely serendipitous. Carbon dioxide produced by the mouse dissolved in the water and thus did not replace the volume of oxygen being consumed within the bell. Mayow was unaware that the mouse was producing any gas, but only that it was consuming some.
Joseph Priestley (1733–1804), an English theologian and selftaught chemist, isolated oxygen from air in 1774 [3,5,10,12–14]. Priestley was such a firm advocate of phlogiston theory that he believed his discovery of oxygen to be rather the isolation of pure, ‘‘dephlogisticated air.’’ Building on the work of Black, Priestley, and others, Antoine Lavoisier (1743–1794) discovered that exhaled air differed from atmospheric air not only because it contained carbon dioxide but also because it was depleted of oxygen [10]. By 1777 Lavoisier was enunciating a respiration theory in which oxygen inspired into the lungs reacted there with carbon from the blood to produce carbon dioxide, liberating heat directly from the oxygen [15], that respiration was in fact a slow carbon combustion having nothing to do with phlogiston [16]. Lavoisier considered heat to be a substance which he called caloric, from which he derived the term ‘‘calorimetre’’ in 1789 [17]. From February to May 1783, Lavoisier and physicist Simon Laplace conducted experiments to prove that respiration generated body heat [3,10,16]. They wished to determine whether the amount of heat liberated per unit of carbon dioxide production was the same for animal respiration and carbon combustion. To measure heat production, they invented
Fig. 2. The first animal calorimeters (Lavoisier, 1783) [10,16]. The triple chamber construction of the ice calorimeter is shown at left. At upper right is shown a closed-circuit indirect calorimeter (respiration chamber) consisting of a bell jar inverted over a mercury bath. Lavoisier converted this apparatus to an open-circuit device by placing tubes into the bell to pump fresh air in and draw off exhaled air into bottles of alkali to capture and weigh the carbon dioxide being produced. Reprinted with permission from the Academie des sciences - Institut de France.
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Fig. 3. Adair Crawford built the first respiration calorimeter chamber for simultaneous measurement of gas exchange and heat production (1788) [10,19]. Like Lavoisier, Crawford constructed a three-compartment chamber (A). Unlike Lavosier, he used water instead of ice to absorb heat, making conditions inside the calorimeter much less likely to affect metabolism. The series of jars and tubs (B, C, D) were sequentially drained and refilled with water using stopcocks T, U, and V, which moved the chamber air into jars IK and NO for analysis. The gas measurements in this device must not have been satisfactory because for his work on animal heat, Crawford actually used the respiration chamber labeled Figure 2 for the respiratory experiments and only used the Figure 1 device for the heat measurement [10].
a triple-chambered ice calorimeter (Fig. 2). Heat produced by a guinea pig or burning charcoal placed in the inner chamber of the calorimeter melted ice packed into the middle chamber. The middle chamber was insulated from ambient heat by another layer of ice in the outermost chamber (even so, these experiments could only be conducted in the winter to prevent penetration of heat from outside the calorimeter). Following the law
of latent heat of transformation, the amount of ice melted was equivalent to the amount of heat produced. A bellows attached to the top of the calorimeter allowed for cold fresh air to be occasionally blown into the inner chamber (the animal studies lasted 10 h). Next, carbon dioxide production was measured with pneumatic troughs consisting of a bell jar inverted over a mercury
Fig. 4. The first human indirect calorimetry experiment (1790) [10]. Details of the experiment are scant, and this figure is known to be inaccurate. Gas collection was made by means of a copper facemask sealed with pine pitch and turpentine. It is surmised that oxygen was breathed from a reservoir (i.e., closed circuit) and that the residual air was collected in a pneumatic trough [10]. (The original of this figure is held by the heirs of Mrs. Lavoisier and was published in Edouard Grimaux, Lavoisier 1743–1794 d’apre`s ses manuscrits, ses papiers de famille et d’autres documents ine´dits, Paris, Felix Alcan, 1896.)
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Fig. 5. Respiration calorimeter chamber of Despretz (1824) [25]. The water-jacketed chamber (c) was similar to Crawford’s. Improvements included the addition of a paddle (a) to distribute body heat throughout the water and the routing of air exiting the chamber through the water bath so that body heat contained in the air was captured (coils visible under the chamber). Air was pushed through the system from right to left by pouring water into the meter at right (G’). Gas analysis was performed on the air in the tank at left (G). A manometer in the right tank allowed air pressure to be maintained for accurate gas measurements.
bath (an innovation of Priestley; carbon dioxide does not dissolve in mercury as it does in water). A guinea pig was placed inside the jar until it showed signs of distress. The animal was removed and alkali pipetted into the jar to absorb the carbon dioxide (that carbon dioxide is absorbed by alkali was first observed by Black). As the carbon dioxide was absorbed, mercury intruded into the jar in proportion to the absorbed carbon dioxide volume. The residual air was analyzed for oxygen so that oxygen consumption could be calculated. Because every breath taken by the animal removed oxygen and added carbon dioxide, these experiments could only be conducted for a short time before the air became toxic. Lavoisier needed long experiment times to ‘‘factor out’’ extraneous sources of error, so he constructed an open-circuit modification whereby two tubes were introduced into the jar to pump in fresh air and remove exhaled air. The exit tube was connected to bottles containing alkali to absorb the carbon dioxide. Weight gain of the bottles revealed the carbon dioxide production. While this innovation allowed for studies lasting for hours, Lavoisier lost the ability to measure oxygen consumption. This problem with open-circuit devices persisted for more than 100 y, so that closed-circuit devices dominated the field until the mid-20th century. The results of these experiments indicated that in producing 224 grains of carbon dioxide, the guinea pig melted 13.0 ounces of water and the charcoal melted 10.4 ounces [10,16]. Lavoisier accepted this as proof that respiration is a carbon combustion that occurs in the lungs and releases heat. There were several problems with this conclusion, the most obvious being that there was a 20% gap between the two values of heat generated per unit of carbon dioxide produced. One reason for the gap was that the temperature inside the ice calorimeter was low, which would raise the animal’s heat production but not the charcoal’s, whereas the respiration experiments were conducted at room temperature and thus would not cause a similar rise in the animal’s carbon dioxide production [10]. Understandably, Lavoisier’s respiration theory had critics. Some took the 20% gap in heat production to mean that there was an additional source of body heat [3]. Many, including
Priestley, were unmoved from the theory that the sole purpose of respiration was to rid the body of phlogiston [3,10,13]. Still others, chiefly Adair Crawford, blended phlogiston and oxidative theory into a hybrid explanation of body heat [3]. Crawford (1748–1795) was a Scots-Irish physician and chemist [3,6,18]. In response to Lavoisier’s work, Crawford designed a respiration calorimeter that used water instead of ice to absorb heat (Fig. 3) [19]. With this device Crawford achieved 90% agreement between heat production and oxygen consumption from combustion and respiration. Lavoisier felt that the link between gas exchange and heat was proved [10] and so proceeded with measurements of oxygen consumption in humans uncorroborated by heat measurements. Thus the first metabolic measurement in mankind was conducted with indirect rather than direct calorimetry (Fig. 4). Measurements were made under conditions close to rest in warm and cool environments, after eating, and during work [10]. Lavoisier reported his findings in a letter to Joseph Black in
Fig. 6. Early open-circuit chamber apparatus for measuring respiratory gas in man (1849) [26]. Room air flowed from left to right through chamber A by the siphoning action of a steady leak of water (h) from barrel C. Fresh air was scrubbed of carbon dioxide by passing through potassium hydroxide (d). To eliminate variability in water content of the expired air, the air exiting the chamber was dried by passing through sulfuric acid (e); carbon dioxide was measured gravimetrically by absorption over potassium hydroxide (f). The dry air will have picked up moisture from the potassium hydroxide solution and so must be dried again (g) to assure an accurate measure of carbon dioxide. The necessity of this drying and redrying of air would be apparent in devices into the 20th century.
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Fig. 7. Regnault’s closed-circuit respiration calorimeter (1849) [23]. In the center is a water-jacketed bell jar holding a dog. The water jacket has thermometers inserted into it to measure the temperature change in the water caused by the dog’s body heat (the sources reviewed for this paper contradict one another as to whether the water jacket was used to measure body heat or simply to control temperature conditions inside the bell). To the left, on the bench, is the oxygen supply. Oxygen was admitted in a quantity to maintain pressure in the system (a manometer is located to the immediate right of the chamber). Further to the right is a set of reciprocating burettes containing potassium hydroxide for carbon dioxide absorption and air recirculation. Reprinted with permission from Prentice-Hall.
November 1790 [6,7,10]. In modern volume units, he found that oxygen consumption at rest was 400 mL/min, rising to 450 mL/ min in cooler ambient temperature; digestion increased oxygen consumption to 635 mL/min, and work increased it further to 1085 mL/min [6].
used to study the effects of respiration on atmospheric air [21]. They were not oriented toward studying metabolic needs [21]. By 1824, improved respiration calorimeters (i.e., chambers
Calorimetry and the development of nutrition science (1800–1900) By the beginning of the 19th century, phlogiston theory had largely been replaced by Lavoisier’s oxidative theory of body heat. Still, knowledge of the process was incomplete. At best, 90% of animal heat could be ascribed to respiration, the remainder either measurement error or proof that another source of body heat existed (friction caused by blood flow was still considered a possibility). The site of heat production was still debated and the presumed chemistry was wrong [3,10]. For example, Crawford and Lavoisier believed that oxygen was directly converted to carbon dioxide (the carbon supplied by food), that this conversion occurred in the lungs, and that the heat came from the oxygen [3]. They held no role for an exchange of gasses with the blood. Attempts to determine whether a gas exchange occurred between the blood and the lungs proved futile until 1837, when Gustav Magnus in Germany proved that blood did contain oxygen and carbon dioxide and that there was an arteriovenous gradient for both [3,20]. These observations proved that oxygen was being consumed and carbon dioxide produced in the body rather than the lungs and changed the theorized sight of heat production to the capillaries (i.e., body tissues) [3]. Technologically, crude respiration devices capable of human measurement existed by the early 1800s [18,21–24]. These were
Fig. 8. Open-circuit respiration chamber of Voit (1862) [33]. Respiration chamber is at left with ventilation pipes visible. Room air is drawn into the chamber by the action of a steam-driven pump and then through the large gas meter (right) (the engine is in the next room with connecting belts and pulleys visible above the meter). Aliquots of the expired air, room air, and residual air in the chamber are drawn off, measured for volume in the small gas meters above the table at center, dried in sulfuric acid, passed through barium hydroxide for absorption and weighing of carbon dioxide, then redried with sulfuric acid (the absorption train is visible on the table at center). Experiments had to last for hours to collect enough carbon dioxide to be measurable [to measure a man required a large chamber and therefore large amounts of ventilated air (500,000 L/d) while the amount of carbon dioxide produce would be comparatively quite small (perhaps 500 L/d) and difficult to detect] (public domain).
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Fig. 9. Respiration apparatus by Smith (1859) [22]. The absorption train that would be the hallmark of respiration devices is clearly taking shape (spirometer (B), air drying with sulfuric acid and pumice stone (C), absorption of carbon dioxide in alkali (D), redrying of air with sulfuric acid (C’), scale for weighing the alkali and sulfuric acid containers to determine carbon dioxide production gravimetrically). Reprinted with permission from the Royal Society.
Fig. 10. Open-circuit respiration calorimeter of Max Rubner in which heat production and respiration were shown to be equivalent (1892) [23]. The triple-walled respiration chamber was insulated by an outer water jacket. Air in the middle chamber picked up body heat generated by the animal residing in the inner chamber. Expansion of the air volume caused by the addition of body heat was measured using spirometers visible on the back shelf. A carbon dioxide absorption train of the Voit type is visible in the left background for simultaneous carbon dioxide measurement. Reprinted with permission from Prentice-Hall.
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Fig. 11. Apparatus developed by Zuntz (1885) [23,24] for studies of resting metabolism. A mouth piece and valves (not shown) were attached at port (P). Inspired and expired air was directed by the valves into the wet gas meter (M). The valves operated automatically by changes in pressure during inhalation and exhalation. Aliquots of the expired and inspired air were directed into burettes (B) contained in a water bath where volumes were measured before and after absorption of carbon dioxide by KOH and oxygen by phosphorus [by passing the air through pipettes (P’)]. Reprinted with permission from the Carnegie Institute of Washington.
combining indirect and direct calorimetry) were developed for small animals in unsuccessful attempts to eliminate Lavoisier’s 20% heat gap (Fig. 5) [18,25,26]. At this time, heat production was quantified as ‘‘heat-producing units,’’ which seem to be equivalent to g-calories (adopted from physics) [26]. Closed-circuit respiration chambers for the study of human gas exchange first appeared in 1843 (Fig. 6) [18,26,27] and by 1849 rudimentary calorimeter chambers for heat measurements in humans were being constructed [18]. (Only rudimentary descriptions of this device exist. It was constructed by EA Scharling of Sweden and is described as a chamber enclosed in a room. Inside resided a man. Heat production was measured simply by temperature change of the air in the chamber [28].) Also in 1849, Henri Regnault (1810– 1878) described a closed-circuit respiration apparatus for small animals (Fig. 7) [23,26,29,30] that is significant because all of the major respiration calorimeters into the 1920s and beyond reference it [18,25,27,28,30,31]. Regnault added to our knowledge of nutrition and metabolism by describing the respiratory quotient as a function of feeding (it had heretofore been thought to vary by species). Carl von Voit (1831–1908), starting in 1862 in Germany, made the first exploration of fuel utilization in man, making explicit the link between respiration and nutrition that Lavoisier’s work had implied. In fact, this work is considered by many to be the foundation for the study of human nutrition and dietetics [27,30]. Voit’s method was to trace the flow of nitrogen, carbon, and oxygen through the body. Nitrogen was tracked by measuring input from food and loss from feces and urine. Carbon flow was measured with an open-circuit respiration chamber (Fig. 8) [6,18,27,32–34]. It was not a calorimeter as it did not
measure heat production. It also did not measure oxygen consumption (a consequence of its open-circuit construction) but inferred it from material balances. Combining these balance studies with information gained from bomb calorimetry of foods, Voit determined the carbohydrate, protein, and fat utilization rates under various conditions of health and disease. Contemporary to the open-circuit chamber developed by Voit, respiration devices were beginning to take on the form that would still be recognizable in devices built 75 years later (Fig. 9) [22]. Tight-fitting face masks, spirometers for measurement of gas volume, and absorption trains to extract and weigh exhaled carbon dioxide were in use. The heyday of calorimetry (1890–1930) Max Rubner, a German physiologist who studied under Voit, finally brought the association of gas exchange and heat production to unity in 1892 (Fig. 10) [18,23,27,30]. He reported a 99.7% agreement between heat production measured directly and calculated from gas exchange in dogs [27,30]. After 110 years, Lavoisier’s 20% gap had finally been closed. Another notable German physiologist working in the 1890s was Nathan Zuntz (1847–1920). Eschewing large respiration chambers in favor of small, transportable, relatively easily maintained devices that collected respiration gasses via face masks and nose tubes over short time periods (Fig. 11) [18,23,24], Zuntz outlined the conditions defining the resting state, which became and remains today the standard state to compare metabolic rates in health and disease [27,30,35,36]. He also worked out the heat equivalents of oxygen and carbon dioxide
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Fig. 12. Respiration calorimetry reached a pinnacle with the construction of the Atwater Rosa respiration calorimeter (1892–1905) [28]. The apparatus was constructed on the model of the Regnault and Reiset device (closed-circuit measuring carbon dioxide and oxygen with recirculation of the air plus the measurement of body heat). At the top is a detail of the layout of the laboratory. The insulated respiration chamber had a cold water coil circulating through it (not visible) to absorb the body heat given off by the subject. The photograph shows the respiration train with the chamber in the background. The large canisters sitting on the shelf at either end are the drying vessels. The three vessels sitting on stilts are the carbon dioxide absorbers. Benedict commented that studies using this chamber could require 10 technicians and several days to complete. Reprinted with permission from the Carnegie Institute of Washington.
for every gradation of respiratory quotient between 0.7 and 1.0. Those heat equivalents remain with us today, incorporated into the Weir equation for metabolic rate [37]. One of Zuntz’s students, Adolf Magnus-Levy, made extensive studies of metabolism during disease, including heart failure, cancer, thyroid disease, myxedema, and fever due to infection [18,30,34,38]. In fact, using Zuntz’s apparatus, Magnus-Levy was the first to successfully apply indirect calorimetry to clinical medicine (1895) [18,27,34]. Wilbur Atwater, an American contemporary of Rubner and fellow student under Voit [14,27,30], built the Atwater Rosa respiration calorimeter starting in 1892 (Fig. 12) [28]. Edward Rosa, like Laplace who constructed the first calorimeter, was a physicist. This device was a highly sophisticated direct and indirect calorimeter large enough to study humans, and with it
Atwater repeated Rubner’s demonstration of the conservation of energy, but this time in man (99.4% agreement between direct measurement of heat production and calculation by gas analysis) [14,27,30]. Atwater advocated the kg-calorie as the preferred unit of heat in metabolism [39], and it is at this time that the terms indirect and direct calorimetry came into use, replacing the terms respiration apparatus and calorimeter. Atwater trained and employed Francis Benedict (1870–1957), who went on to head the Nutrition Laboratory of the Carnegie Institute [27]. This laboratory was dedicated to developing calorimetric techniques and to studying human metabolism, including in infants and children [35,40–44]. The influence of body size, age, and sex on metabolic rate was characterized and calculated into the biometric equation that bears Benedict’s name [35]. Racial differences were studied, as were the effects of
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Fig. 13. This device [40,47] was described by Benedict as a replacement for the complicated, time-consuming, and labor-intensive respiration calorimeter experiments that had heretofore been the gold standard of metabolic measurements (see Fig. 12) with mouthpieces or nose tubes replacing a chamber for gas collection. The device was portable (although Graham Lusk commented that whenever the apparatus was moved an air leak developed, which might explain the tools on the bottom shelf in the photograph) and could yield results in 20 minutes (image at left used with permission. Am J Physiol 1909;24:345–374). Gas handling is identical to that described in Figure 12 except on a smaller scale and with the addition of an air-moistener to return the dried air to a rebreathable condition. Images at right reprinted with permission from the Carnegie Institute of Washington.
starvation, disease, and muscle work. Benedict was an innovator of calorimeter design (Figs. 12 and 13) and was integral to the increasing emphasis of indirect over direct calorimetry and to the widespread application of indirect calorimetry to clinical medicine in the 1920s [38,41,45–48]. Into the 20th century, closed-circuit indirect calorimetry dominated over open-circuit because of the difficulty in measuring inspired gas volumes when the inspired air stream does not originate in the apparatus. Lavoisier struggled with this exact same problem in 1783. John Haldane (1860–1936), a Scottish physiologist, finally solved the problem in 1912 when he described an equation for calculating inspired gas volume from inspired and expired gas concentrations and expired gas volume (the Haldane transformation) [49]. Calculation of inspired gas volume was a critical step in the eventual triumph of opencircuit indirect calorimetry. The computation is based on the fact that inhaled and exhaled nitrogen volumes are equal because nitrogen is inert in gas exchange. Although this fact was observed by Lavoisier and by Zuntz, Haldane was the first to express it in a useful mathematical manner. Clinical calorimetry comes of age (1920s) In a symposium on clinical calorimetry published in the Journal of the American Medical Association in 1921 [50,51], several interesting statements were made, among them that the main role of calorimetry remained in the laboratory, that the use of calorimetry in the management of thyroid disease was useful, but not necessary, that inexperienced operators were using the devices and obtaining inaccurate results, and that some manufacturers were overly aggressive at marketing the devices, some of which had not been validated [50]. At least four commercial devices existed at the time (Fig. 14) [41,45]. All of these devices were of the closed-circuit type; none measured carbon dioxide,
but all used absorbers to keep the air circuit free of carbon dioxide. By not measuring carbon dioxide, the devices were simplified but a set respiratory quotient and therefore heat equivalent of oxygen had to be assumed to calculate metabolic rate. All the devices required temperature recordings so that the measured gas volumes could be adjusted in accordance with Boyle’s gas laws.
Doldrums (1930s–1960s) After being used to discover fundamental principles of respiration physiology and ushering in nutrition science, indirect calorimetry began to wane in the 1930s as other lines of nutrition investigation arose. The technique did not disappear, but its profile was much lower than it had been in the late 19th and early 20th century. However, two technological developments occurred during this time that would become important in a later resurgence of calorimetry. One was the simplification of the calculation of metabolic rate from gas exchange data [37]. Weir took the complicated method, with its partitioning of protein and non-protein respiratory quotient and assignment of a heat equivalent per liter of gas according to the respiratory quotient and devised a simple algebraic equation for calculating metabolic rate from total carbon dioxide production and oxygen consumption. An important improvement in technology was the development of gas analysis methods that did not depend on gravimetric measurements (e.g., paramagnetic oxygen analyzers and infrared carbon dioxide measurement [52,53]). These would become the backbone of the next generation of indirect calorimeters. On the clinical research front, Cuthbertson starting in the 1930s utilized Douglas bag indirect calorimetry to study metabolism after injury [54]. Kinney and coworkers developed a calorimetry system that could measure acutely ill patients using a ventilated canopy system (Fig. 15)
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Fig. 14. Clinical indirect calorimeters from the 1920s [41,45]. Clockwise from top left, the Benedict Roth spirometer (wet spirometer for measurement of oxygen consumption, carbon dioxide absorption system at the bottom of the stand to keep the air in the closed circuit respirable) (reprinted with the permission from the Carnegie Institute of Washington), the Jones Metabolimeter (oxygen tank from which gas disappearance was timed as a measure of consumption, carbon dioxide absorption canister on top for scrubbing the air of carbon dioxide, mouthpiece, and compliance device atop the canister), the Sanborn Handy calorimeter (carbon dioxide absorption via the bottom canister, oxygen contained in the wet spirometer at the top of the canister with measurement rod to measure the excursion of the spirometer bell at each breath. Breath volume (tidal volume) had to be stable from breath to breath for these types of devices to be accurate), and the McKesson Metabolor. This device uniquely had an air blower, was 17 inches high and weighed 40 pounds before the spirometer was filled with 12 liters of water. The absorber system is contained inside the air chamber.
[55] and conducted major work on injury metabolism in the 1960s [56]. A rebirth of sorts (1970s to today) With the advent of nutrition support, clinicians obtained the power to control more exactly the nutrient intake of patients. Having the ability to control intake stimulated a need to determine more exactly individual nutrient requirements. Therefore, starting in the 1970s and continuing today, a reemphasis on indirect calorimetry has occurred. The latest devices are generally open-circuit, computer-based, and portable. Expired gas volumes can be measured in a number of ways. One of the most common is the pneumotachometer, which converts the turbulent air flow of exhalation into laminar flow, measures the pressure exerted by this flow, and converts the pressure to a volume. Carbon dioxide is measured with non-dispersive
infrared absorptiometry (absorption of this light spectrum is proportional to the carbon dioxide concentration in the air being sampled). Oxygen can be measured in a number of ways, most of them some variation of an electrochemical cell in which the oxygen present in the airflow produces an electrical current that is proportional to the oxygen concentration. Paramagnetic methods are also used for oxygen sensing in which the magnetic properties of oxygen distort the rotation of a small glass vessel inside the sensor. The degree of distortion is proportional to the oxygen concentration in the air flow. The most recent technological advance is the handheld or hand-carried open-circuit indirect calorimeter for use in spontaneously breathing people. These devices are much less expensive and much more convenient than previous portable calorimeters. Part of the reduction in cost and device size was achieved by the sacrifice of a carbon dioxide sensor. Like the earliest forms of clinical calorimetry, these devices measure only oxygen consumption and compute
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References
Fig. 15. Open-circuit, indirect calorimeter developed in the 1960s by John M. Kinney [55]. The ventilated canopy took in air at a rate of 40 L/min, which the patient breathed from and exhaled into. The air stream was blown into the analysis equipment housed in a separate room. Air volume was measured continuously by a wet gas meter. Oxygen concentration was measured continuously with a paramagnetic sensor, while the carbon dioxide concentration was determined continuously with an infrared analyzer. In this system can be seen some of the components that would be incorporated into portable bedside calorimetry employed from the 1970s onward. Reprinted with permission.55
metabolic rate by assuming a respiratory quotient. Validation of these devices is ongoing. Direct calorimetry still exists as a research tool, especially for long-term studies and for partitioning the components of total metabolic rate. Some of the advances in nutrition science made with modern indirect calorimetry include the development of updated standard equations (e.g., Mifflin St. Jeor, which at least in the U.S. is beginning to supplant Harris Benedict as the standard calculated metabolic rate) [57,58], observation of a decrease in metabolic rate over the decades in critical care patients [59], probably reflecting improvements in the overall care of such patients, and the development of metabolic standards specific to critical care (supplanting the need for employing modified healthy equations in this role) [60,61]. Major questions still incompletely answered include whether clinical outcomes are improved by measurement of metabolic rate, comparative metabolic requirements among races, geographic locations, extremes of age and body composition, etc., and the development of calculation standards for sick people who do not require critical care. Thus indirect calorimetry, a technique that is now 227 y old, still has contributions to make to nutrition science, physiology, and clinical practice.
[1] Allbutt TC. The innate heat. In: Contributions to medical and biological research. Paul B. Hoeber: New York; 1919. Accessed from Google Books January 4, 2009. [2] Solmsen F. The vital heat, the inborn pneuma, and the aether. J Hellenistic Studies 1957;77:119–23. [3] Mendelsohn E. Heat and life, The development of the theory of animal heat. Harvard Cambridge, MA: University Press; 1964. [4] Mayow J. Medico-physical works. Being a translation of Tractatus Quinque Medico-Physici. Edinburgh: The Alembic Club, 1907 (original publication 1674). Accessed from Google Books March 9, 2009. [5] Ihde AJ. The development of modern chemistry. New York: Dover Publishers; 1984. [6] Lusk G. History of Metabolism. In: Barker LF, Hoskins RG, Mosenthal HO, editors. Endocrinology and metabolism. New York: D. Appleton & Co; 1922. Accessed from Microsoft Books, February 2009. [7] Ramsay W. The life and letters of Joseph Black. London: Constable and Company Ltd.; 1918 Accessed from www.archive.org, March 10, 2009. [8] Brown AC. On the acid humour arising from food and magnesia alba (translation). J Chem 1935;12:225–8, 268–73. [9] Fenby DV. Heat: its measurement from Galileo to Lavoisier. Pure Appl Chem 1987;59:91–100. [10] Holmes FL. Lavoisier and the chemistry of life. An exploration of scientific creativity. Madison, WI: University of Wisconsin Press; 1985. [11] Preston T, Cotter JR. The theory of heat. 2nd ed. New York: MacMillan & Co; 1904. p. 241. [12] Priestley J. Experiments and observations on different kinds of air. Vols. 1– 6. Johnson J, editor. St. Paul’s Church Yard, London, 1774–1777. Accessed from Google Books, March 10, 2009. [13] Leicester HM, Klickstein HS. A sourcebook in chemistry. London: Oxford University Press; 1952. Accessed from Google Books, March 9, 2009. [14] Nichols BL. Atwater and USDA nutrition research and service: a prologue of the past century. J Nutr 1994;124:1718S–27S. [15] Lavoisier AL. Experiences sur la respiration des animaux et sur les changements qui arrivent a l’air en passant par leur poulmon. Arch Acad Sci, read; 1777. published 1780. [16] Lavoisier AL, de Laplace PS. Memoir sur la chaleur. Memoirs Acad Sci 1780(1783). [17] Roberts L. A word and the world. The significance of naming the calorimeter. Isis 1991;82:198–222. [18] Carpenter TM. The historical development of metabolism studies. J Am Diet Assoc 1949;25:837–41. [19] Crawford A. Experiments and observations on animal heat and the inflammation of combustible bodies. Johnson J, editor. St. Paul’s Church Yard, London, 1788. Accessed from Google Books, March 19, 2009. [20] Rosenfeld L. Early studies on blood gasses, Four centuries of clinical chemistry. Amsterdam: Gordon and Breach Science Publishers; 1999. Accessed from Google Books, March 9, 2009. [21] Allen W, Pepys WH. On the changes produced in the experimental air and oxygen gas by respiration. Philos Trans 1808;2:249–81. [22] Smith E. Experimental inquiries into the chemical and other phenomena of respiration, and their modifications by various physical agencies. Philos Trans 1859;149:681–714. [23] Murlin JR. Normal processes of energy metabolism. In: Barker LF, Hoskins RG, Mosenthal HO, editors. Endocrinology and metabolism. New York: D Appleton & Co; 1922. [24] Carpenter TM. A comparison of methods for determining the respiratory exchange of man. Washington, DC: Carnegie Institute of Washington; Publication No. 216; 1915. [25] Matthews AP. Animal heat, Physiological chemistry. New York: William Wood & Co; 1915. Accessed from Google Books, January 5, 2009. [26] Landois L. Physiology of Respiration. Analysis of expired gasses. In A Textbook of Human Physiology including Histology and Microscopical Anatomy with Special Reference to the Requirements of Practical Medicine. 4th ed. Philadelphia, PA: P. Blakiston, Son & Co; 1892. Accessed from Google Books, January 5, 2009. [27] Lusk G. The elements of the science of nutrition. 3rd ed. Philadelphia, PA: WB Saunders Co; 1915. [28] Atwater WO, Benedict FG. A respiration calorimeter with appliances for the direct determination of oxygen. Washington, DC: Carnegie Institute of Washington. Pub 1905;42. [29] Regnault V, Reiset J. Recherches chimiques sur la respiration des animaux des diverses classes. Ann Chim Phys Paris 1849;26:299–519. [30] Wilder RM. Calorimetry. The basis for the science of nutrition. Arch Int Med 1959;103:146–54. [31] Douglas CG. The development of experimental methods for determining the energy expenditure in man. Proc Nutr Soc 1956;15:72–7. [32] Atwater WO. The potential energy of food. The chemistry and economy of food. Century 1887;34:397–405. [33] Atwater WO. Metabolism of energydIncome and outgo of body, Methods and results of investigations on the chemistry and economy of food. Bulletin No. 21. Washington, DC: Government Printing Office; 1895.
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[34] Carpenter TM. The development of methods for determining basal metabolism in mankind. Ohio J Sci 1933;33:297–314. [35] Harris JA, Benedict FG. A biometric study of basal metabolism in man. Washington, DC: Carnegie Institution of Washington; Publication No. 279; 1919. [36] Compher C, Frankenfield DC, Keim N, Roth-Yousey L. Best practice methods to apply to measurement of resting metabolic rate in adults. A systemic review. J Am Diet Assoc 2006;106:881–903. [37] de V Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 1949;109:1–9. [38] DuBois Ef. A Brief history of the study of the respiratory metabolism, Basal Metabolism in Health and Disease. Phildelphia: Lea and Febiger; 1936. Accessed from Google Books, December 15, 2008. [39] Hargrove JL. History of the calorie in nutrition. J Nutr 2006;136:2957–61. [40] Benedict FG, Cathcart EP. Muscular work. A metabolic study with special reference to the efficiency of the human body as a machine. Carnegie Institute of Washington; Publication No. 187; 1913. Accessed from Google Books, July 15, 2009. [41] Benedict FG, Miles WR, Roth P, Smith HM. Human vitality and efficiency under prolonged restricted diet. Carnegie Institution of Washington; Publication No. 280; 1919. Accessed from Google Books, July 15, 2009. [42] Benedict FG, Joslin EP. Metabolism in diabetes mellitus. Washington, DC: Carnegie Institution of Washington; Publication No. 136; 1910. Accessed from Google Books, July 15, 2009. [43] Benedict FG. Old age and basal metabolism. N Engl J Med 1935;212:1111–22. [44] MacLeod G, Crofts EE, Benedict FG. The basal metabolism of some orientals. Am J Physiol 1925;73:449–62. [45] Sanborn F. Basal Metabolism. In: Sanborn F, editor. Its determination and application. Boston, MA: Sanborn Co. Publishers; 1922. Accessed from Google Books, November 17, 2009. [46] Webb P. The measurement of energy expenditure. J Nutr 1991;121:1897– 901.
[47] Benedict FG. An apparatus for studying the respiratory exchange. Am J Physiol 1909;24:345–74. [48] Lusk G. A respiration calorimeter for the study of disease. Arch Int Med 1915;15:1–12. [49] Haldane JS. Methods of air analysis. London: Charles Griffin; 1912. Accessed by Google Books July 20, 2009. [50] Means JH. Determination of the basal metabolism. J Am Med Assoc 1921;77:347–52. [51] DuBois EF. The basal metabolism of fever. J Am Med Assoc 1921;77:352–5. [52] Pauling L, Wood RE, Sturdivant JH. An instrument for determining the partial pressure of oxygen in a gas. Science 1946;103:338. [53] Fowler RC. A rapid infra-red gas analyzer. Rev Sci Instrum 1949;20:175–8. [54] Cuthbertson DP. Observations on the disturbance of metabolism produced by injury to the limbs. Quart J Med 1932;1:233–46. [55] Kinney JM, Morgan AP, Domingues FJ, Gildner KJ. A method for continuous measurement of gas exchange and expired radioactivity in acutely ill patients. Metabolism 1964;13:205–11. [56] Kinney JH, Roe CF. Caloric equivalent of fever. Ann Surg 1962;156:610–20. [57] Mifflin MD, St. Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO. A new predictive equation for resting energy expenditure in healthy individuals. Am J Clin Nutr 1990;51:241–7. [58] Frankenfield DC, Roth-Yousey L, Compher C. Comparison of predictive equations for resting metabolic rate in healthy non-obese and obese adults: a systematic review. J Am Diet Assoc 2005;105:775–89. [59] Wilmore DW. From Cuthbertson to fast-track surgery: 70 years of progress in reducing stress in surgical patients. Ann Surg 2002;236:643–8. [60] Frankenfield DC, Hise M, Malone A, Russell M, Gradwell E, Compher C. Prediction of resting metabolic rate in critically ill adult patients: results of a systematic review of the evidence. J Am Diet Assoc 2007;107:1552–61. [61] Frankenfield DC, Coleman A, Alam S, Cooney RN. Analysis of estimation methods for resting metabolic rate in critically ill patients. J Paren Ent Nutr 2009;33:27–36.
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Review
On heat, respiration, and calorimetry David C. Frankenfield M.S., R.D. * Department of Clinical Nutrition, Penn State Milton S. Hershey Medical Center, Hershey, PA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 September 2009 Accepted 7 January 2010
The technique of indirect calorimetry developed with the sciences of nutrition and physiology over the course of hundreds of years. It was in fact fundamental to the establishment of these disciplines. This review describes the development of the technology and the principles of body function it has revealed. Ó 2010 Elsevier Inc. All rights reserved.
Keywords: Indirect calorimetry Energy metabolism
Debate over the clinical use of indirect calorimetry is common, centered on whether outcomes are improved by its use. In the midst of this debate it is easy to forget the importance of calorimetry in our understanding of physiology and nutrition. The development of the technique and the principles it has revealed is a history worth relating. Prelude (300 BC–1750 AD) From the earliest times, body heat and respiration were understood to be linked. The ancient Greeks believed that man received heat from the cosmos at birth and breathed to cool this innate heat and thus extend life [1–3]. Through the Middle Ages and beyond, this idea survived, with additional theorizing that some heat was produced by body motion or friction of the blood [3]. John Mayow (1643–1679), an English physician, was the first to advance significantly beyond the Greek model. Using pneumatic troughs to collect reaction gasses (Fig. 1) [4], Mayow discovered in 1674 that animals and combusting candles consume a component of air and die without it. This discovery implied that air was a mixture of gasses, which was provocative because air at the time was believed to be a single element [3]. Because combustion generated heat, Mayow conjectured that respiration played a role in the generation of body heat. Although Mayow’s respiration work was largely correct, it failed to change beliefs about the source of body heat [3]. There was even doubt about his demonstration that air was consumed during respiration. In fact, Mayow’s work was largely forgotten in the enthusiasm over a new theory of heat. This was the * Corresponding author. Tel.: 717-531-6042; fax: 717-531-7995. E-mail address: Dfrankenfi[email protected] (D. C. Frankenfield). 0899-9007/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2010.01.002
phlogiston theory, first promulgated by Jochaim Becher in 1680 and Ernst Stahl in 1728 [3,5,6] to explain combustion. The theory held that flammable materials were made so by the presence of phlogiston, an odorless and weightless substance. Combustion released phlogiston, generating heat in the process. Because animals were warm, phlogiston theory came to be applied to physiology. Body heat was the result of phlogiston release and respiration was the route of phlogiston disposal [3,5,6]. Physiological chemistry and the first calorimeter (1750–1800) In the latter half of the 18th century, landmark discoveries were made regarding the composition of atmospheric and respired air and the nature of heat that would open the way to an understanding of human metabolism in health and disease. Joseph Black (Scottish physician, 1728–1799) discovered carbon dioxide in 1754 [7–9]. This discovery initially was not thought of in metabolic terms but while Black was characterizing carbon dioxide he found that it was a component of exhaled breath and therefore produced by the body [3,7,9]. Black also made discoveries on the nature of heat and techniques to measure it that would be incorporated into the first direct calorimeters [3,7,10,11]. Specifically, Black placed an object of known mass and temperature into a chamber bored into a block of ice. As heat from the object radiated into the chamber, it melted some of the ice. The amount of water produced was proportional to the amount of heat released because the law of latent heat of transformation dictates that a substance such as ice undergoing a phase change will not change its temperature until the phase change is complete (were this not so, then the heat release would be a function of the volume of water and of its temperature rather than just its volume).
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Fig. 1. Indirect calorimeter prototype (Mayow, 1674) [4,11]. A bell jar was inverted over a water seal with a mouse placed on a stand inside the jar. Consumption of air by the mouse reduced pressure in the bell, allowing water to intrude, thus proving the consumption. That this experiment worked was purely serendipitous. Carbon dioxide produced by the mouse dissolved in the water and thus did not replace the volume of oxygen being consumed within the bell. Mayow was unaware that the mouse was producing any gas, but only that it was consuming some.
Joseph Priestley (1733–1804), an English theologian and selftaught chemist, isolated oxygen from air in 1774 [3,5,10,12–14]. Priestley was such a firm advocate of phlogiston theory that he believed his discovery of oxygen to be rather the isolation of pure, ‘‘dephlogisticated air.’’ Building on the work of Black, Priestley, and others, Antoine Lavoisier (1743–1794) discovered that exhaled air differed from atmospheric air not only because it contained carbon dioxide but also because it was depleted of oxygen [10]. By 1777 Lavoisier was enunciating a respiration theory in which oxygen inspired into the lungs reacted there with carbon from the blood to produce carbon dioxide, liberating heat directly from the oxygen [15], that respiration was in fact a slow carbon combustion having nothing to do with phlogiston [16]. Lavoisier considered heat to be a substance which he called caloric, from which he derived the term ‘‘calorimetre’’ in 1789 [17]. From February to May 1783, Lavoisier and physicist Simon Laplace conducted experiments to prove that respiration generated body heat [3,10,16]. They wished to determine whether the amount of heat liberated per unit of carbon dioxide production was the same for animal respiration and carbon combustion. To measure heat production, they invented
Fig. 2. The first animal calorimeters (Lavoisier, 1783) [10,16]. The triple chamber construction of the ice calorimeter is shown at left. At upper right is shown a closed-circuit indirect calorimeter (respiration chamber) consisting of a bell jar inverted over a mercury bath. Lavoisier converted this apparatus to an open-circuit device by placing tubes into the bell to pump fresh air in and draw off exhaled air into bottles of alkali to capture and weigh the carbon dioxide being produced. Reprinted with permission from the Academie des sciences - Institut de France.
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Fig. 3. Adair Crawford built the first respiration calorimeter chamber for simultaneous measurement of gas exchange and heat production (1788) [10,19]. Like Lavoisier, Crawford constructed a three-compartment chamber (A). Unlike Lavosier, he used water instead of ice to absorb heat, making conditions inside the calorimeter much less likely to affect metabolism. The series of jars and tubs (B, C, D) were sequentially drained and refilled with water using stopcocks T, U, and V, which moved the chamber air into jars IK and NO for analysis. The gas measurements in this device must not have been satisfactory because for his work on animal heat, Crawford actually used the respiration chamber labeled Figure 2 for the respiratory experiments and only used the Figure 1 device for the heat measurement [10].
a triple-chambered ice calorimeter (Fig. 2). Heat produced by a guinea pig or burning charcoal placed in the inner chamber of the calorimeter melted ice packed into the middle chamber. The middle chamber was insulated from ambient heat by another layer of ice in the outermost chamber (even so, these experiments could only be conducted in the winter to prevent penetration of heat from outside the calorimeter). Following the law
of latent heat of transformation, the amount of ice melted was equivalent to the amount of heat produced. A bellows attached to the top of the calorimeter allowed for cold fresh air to be occasionally blown into the inner chamber (the animal studies lasted 10 h). Next, carbon dioxide production was measured with pneumatic troughs consisting of a bell jar inverted over a mercury
Fig. 4. The first human indirect calorimetry experiment (1790) [10]. Details of the experiment are scant, and this figure is known to be inaccurate. Gas collection was made by means of a copper facemask sealed with pine pitch and turpentine. It is surmised that oxygen was breathed from a reservoir (i.e., closed circuit) and that the residual air was collected in a pneumatic trough [10]. (The original of this figure is held by the heirs of Mrs. Lavoisier and was published in Edouard Grimaux, Lavoisier 1743–1794 d’apre`s ses manuscrits, ses papiers de famille et d’autres documents ine´dits, Paris, Felix Alcan, 1896.)
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Fig. 5. Respiration calorimeter chamber of Despretz (1824) [25]. The water-jacketed chamber (c) was similar to Crawford’s. Improvements included the addition of a paddle (a) to distribute body heat throughout the water and the routing of air exiting the chamber through the water bath so that body heat contained in the air was captured (coils visible under the chamber). Air was pushed through the system from right to left by pouring water into the meter at right (G’). Gas analysis was performed on the air in the tank at left (G). A manometer in the right tank allowed air pressure to be maintained for accurate gas measurements.
bath (an innovation of Priestley; carbon dioxide does not dissolve in mercury as it does in water). A guinea pig was placed inside the jar until it showed signs of distress. The animal was removed and alkali pipetted into the jar to absorb the carbon dioxide (that carbon dioxide is absorbed by alkali was first observed by Black). As the carbon dioxide was absorbed, mercury intruded into the jar in proportion to the absorbed carbon dioxide volume. The residual air was analyzed for oxygen so that oxygen consumption could be calculated. Because every breath taken by the animal removed oxygen and added carbon dioxide, these experiments could only be conducted for a short time before the air became toxic. Lavoisier needed long experiment times to ‘‘factor out’’ extraneous sources of error, so he constructed an open-circuit modification whereby two tubes were introduced into the jar to pump in fresh air and remove exhaled air. The exit tube was connected to bottles containing alkali to absorb the carbon dioxide. Weight gain of the bottles revealed the carbon dioxide production. While this innovation allowed for studies lasting for hours, Lavoisier lost the ability to measure oxygen consumption. This problem with open-circuit devices persisted for more than 100 y, so that closed-circuit devices dominated the field until the mid-20th century. The results of these experiments indicated that in producing 224 grains of carbon dioxide, the guinea pig melted 13.0 ounces of water and the charcoal melted 10.4 ounces [10,16]. Lavoisier accepted this as proof that respiration is a carbon combustion that occurs in the lungs and releases heat. There were several problems with this conclusion, the most obvious being that there was a 20% gap between the two values of heat generated per unit of carbon dioxide produced. One reason for the gap was that the temperature inside the ice calorimeter was low, which would raise the animal’s heat production but not the charcoal’s, whereas the respiration experiments were conducted at room temperature and thus would not cause a similar rise in the animal’s carbon dioxide production [10]. Understandably, Lavoisier’s respiration theory had critics. Some took the 20% gap in heat production to mean that there was an additional source of body heat [3]. Many, including
Priestley, were unmoved from the theory that the sole purpose of respiration was to rid the body of phlogiston [3,10,13]. Still others, chiefly Adair Crawford, blended phlogiston and oxidative theory into a hybrid explanation of body heat [3]. Crawford (1748–1795) was a Scots-Irish physician and chemist [3,6,18]. In response to Lavoisier’s work, Crawford designed a respiration calorimeter that used water instead of ice to absorb heat (Fig. 3) [19]. With this device Crawford achieved 90% agreement between heat production and oxygen consumption from combustion and respiration. Lavoisier felt that the link between gas exchange and heat was proved [10] and so proceeded with measurements of oxygen consumption in humans uncorroborated by heat measurements. Thus the first metabolic measurement in mankind was conducted with indirect rather than direct calorimetry (Fig. 4). Measurements were made under conditions close to rest in warm and cool environments, after eating, and during work [10]. Lavoisier reported his findings in a letter to Joseph Black in
Fig. 6. Early open-circuit chamber apparatus for measuring respiratory gas in man (1849) [26]. Room air flowed from left to right through chamber A by the siphoning action of a steady leak of water (h) from barrel C. Fresh air was scrubbed of carbon dioxide by passing through potassium hydroxide (d). To eliminate variability in water content of the expired air, the air exiting the chamber was dried by passing through sulfuric acid (e); carbon dioxide was measured gravimetrically by absorption over potassium hydroxide (f). The dry air will have picked up moisture from the potassium hydroxide solution and so must be dried again (g) to assure an accurate measure of carbon dioxide. The necessity of this drying and redrying of air would be apparent in devices into the 20th century.
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Fig. 7. Regnault’s closed-circuit respiration calorimeter (1849) [23]. In the center is a water-jacketed bell jar holding a dog. The water jacket has thermometers inserted into it to measure the temperature change in the water caused by the dog’s body heat (the sources reviewed for this paper contradict one another as to whether the water jacket was used to measure body heat or simply to control temperature conditions inside the bell). To the left, on the bench, is the oxygen supply. Oxygen was admitted in a quantity to maintain pressure in the system (a manometer is located to the immediate right of the chamber). Further to the right is a set of reciprocating burettes containing potassium hydroxide for carbon dioxide absorption and air recirculation. Reprinted with permission from Prentice-Hall.
November 1790 [6,7,10]. In modern volume units, he found that oxygen consumption at rest was 400 mL/min, rising to 450 mL/ min in cooler ambient temperature; digestion increased oxygen consumption to 635 mL/min, and work increased it further to 1085 mL/min [6].
used to study the effects of respiration on atmospheric air [21]. They were not oriented toward studying metabolic needs [21]. By 1824, improved respiration calorimeters (i.e., chambers
Calorimetry and the development of nutrition science (1800–1900) By the beginning of the 19th century, phlogiston theory had largely been replaced by Lavoisier’s oxidative theory of body heat. Still, knowledge of the process was incomplete. At best, 90% of animal heat could be ascribed to respiration, the remainder either measurement error or proof that another source of body heat existed (friction caused by blood flow was still considered a possibility). The site of heat production was still debated and the presumed chemistry was wrong [3,10]. For example, Crawford and Lavoisier believed that oxygen was directly converted to carbon dioxide (the carbon supplied by food), that this conversion occurred in the lungs, and that the heat came from the oxygen [3]. They held no role for an exchange of gasses with the blood. Attempts to determine whether a gas exchange occurred between the blood and the lungs proved futile until 1837, when Gustav Magnus in Germany proved that blood did contain oxygen and carbon dioxide and that there was an arteriovenous gradient for both [3,20]. These observations proved that oxygen was being consumed and carbon dioxide produced in the body rather than the lungs and changed the theorized sight of heat production to the capillaries (i.e., body tissues) [3]. Technologically, crude respiration devices capable of human measurement existed by the early 1800s [18,21–24]. These were
Fig. 8. Open-circuit respiration chamber of Voit (1862) [33]. Respiration chamber is at left with ventilation pipes visible. Room air is drawn into the chamber by the action of a steam-driven pump and then through the large gas meter (right) (the engine is in the next room with connecting belts and pulleys visible above the meter). Aliquots of the expired air, room air, and residual air in the chamber are drawn off, measured for volume in the small gas meters above the table at center, dried in sulfuric acid, passed through barium hydroxide for absorption and weighing of carbon dioxide, then redried with sulfuric acid (the absorption train is visible on the table at center). Experiments had to last for hours to collect enough carbon dioxide to be measurable [to measure a man required a large chamber and therefore large amounts of ventilated air (500,000 L/d) while the amount of carbon dioxide produce would be comparatively quite small (perhaps 500 L/d) and difficult to detect] (public domain).
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Fig. 9. Respiration apparatus by Smith (1859) [22]. The absorption train that would be the hallmark of respiration devices is clearly taking shape (spirometer (B), air drying with sulfuric acid and pumice stone (C), absorption of carbon dioxide in alkali (D), redrying of air with sulfuric acid (C’), scale for weighing the alkali and sulfuric acid containers to determine carbon dioxide production gravimetrically). Reprinted with permission from the Royal Society.
Fig. 10. Open-circuit respiration calorimeter of Max Rubner in which heat production and respiration were shown to be equivalent (1892) [23]. The triple-walled respiration chamber was insulated by an outer water jacket. Air in the middle chamber picked up body heat generated by the animal residing in the inner chamber. Expansion of the air volume caused by the addition of body heat was measured using spirometers visible on the back shelf. A carbon dioxide absorption train of the Voit type is visible in the left background for simultaneous carbon dioxide measurement. Reprinted with permission from Prentice-Hall.
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Fig. 11. Apparatus developed by Zuntz (1885) [23,24] for studies of resting metabolism. A mouth piece and valves (not shown) were attached at port (P). Inspired and expired air was directed by the valves into the wet gas meter (M). The valves operated automatically by changes in pressure during inhalation and exhalation. Aliquots of the expired and inspired air were directed into burettes (B) contained in a water bath where volumes were measured before and after absorption of carbon dioxide by KOH and oxygen by phosphorus [by passing the air through pipettes (P’)]. Reprinted with permission from the Carnegie Institute of Washington.
combining indirect and direct calorimetry) were developed for small animals in unsuccessful attempts to eliminate Lavoisier’s 20% heat gap (Fig. 5) [18,25,26]. At this time, heat production was quantified as ‘‘heat-producing units,’’ which seem to be equivalent to g-calories (adopted from physics) [26]. Closed-circuit respiration chambers for the study of human gas exchange first appeared in 1843 (Fig. 6) [18,26,27] and by 1849 rudimentary calorimeter chambers for heat measurements in humans were being constructed [18]. (Only rudimentary descriptions of this device exist. It was constructed by EA Scharling of Sweden and is described as a chamber enclosed in a room. Inside resided a man. Heat production was measured simply by temperature change of the air in the chamber [28].) Also in 1849, Henri Regnault (1810– 1878) described a closed-circuit respiration apparatus for small animals (Fig. 7) [23,26,29,30] that is significant because all of the major respiration calorimeters into the 1920s and beyond reference it [18,25,27,28,30,31]. Regnault added to our knowledge of nutrition and metabolism by describing the respiratory quotient as a function of feeding (it had heretofore been thought to vary by species). Carl von Voit (1831–1908), starting in 1862 in Germany, made the first exploration of fuel utilization in man, making explicit the link between respiration and nutrition that Lavoisier’s work had implied. In fact, this work is considered by many to be the foundation for the study of human nutrition and dietetics [27,30]. Voit’s method was to trace the flow of nitrogen, carbon, and oxygen through the body. Nitrogen was tracked by measuring input from food and loss from feces and urine. Carbon flow was measured with an open-circuit respiration chamber (Fig. 8) [6,18,27,32–34]. It was not a calorimeter as it did not
measure heat production. It also did not measure oxygen consumption (a consequence of its open-circuit construction) but inferred it from material balances. Combining these balance studies with information gained from bomb calorimetry of foods, Voit determined the carbohydrate, protein, and fat utilization rates under various conditions of health and disease. Contemporary to the open-circuit chamber developed by Voit, respiration devices were beginning to take on the form that would still be recognizable in devices built 75 years later (Fig. 9) [22]. Tight-fitting face masks, spirometers for measurement of gas volume, and absorption trains to extract and weigh exhaled carbon dioxide were in use. The heyday of calorimetry (1890–1930) Max Rubner, a German physiologist who studied under Voit, finally brought the association of gas exchange and heat production to unity in 1892 (Fig. 10) [18,23,27,30]. He reported a 99.7% agreement between heat production measured directly and calculated from gas exchange in dogs [27,30]. After 110 years, Lavoisier’s 20% gap had finally been closed. Another notable German physiologist working in the 1890s was Nathan Zuntz (1847–1920). Eschewing large respiration chambers in favor of small, transportable, relatively easily maintained devices that collected respiration gasses via face masks and nose tubes over short time periods (Fig. 11) [18,23,24], Zuntz outlined the conditions defining the resting state, which became and remains today the standard state to compare metabolic rates in health and disease [27,30,35,36]. He also worked out the heat equivalents of oxygen and carbon dioxide
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Fig. 12. Respiration calorimetry reached a pinnacle with the construction of the Atwater Rosa respiration calorimeter (1892–1905) [28]. The apparatus was constructed on the model of the Regnault and Reiset device (closed-circuit measuring carbon dioxide and oxygen with recirculation of the air plus the measurement of body heat). At the top is a detail of the layout of the laboratory. The insulated respiration chamber had a cold water coil circulating through it (not visible) to absorb the body heat given off by the subject. The photograph shows the respiration train with the chamber in the background. The large canisters sitting on the shelf at either end are the drying vessels. The three vessels sitting on stilts are the carbon dioxide absorbers. Benedict commented that studies using this chamber could require 10 technicians and several days to complete. Reprinted with permission from the Carnegie Institute of Washington.
for every gradation of respiratory quotient between 0.7 and 1.0. Those heat equivalents remain with us today, incorporated into the Weir equation for metabolic rate [37]. One of Zuntz’s students, Adolf Magnus-Levy, made extensive studies of metabolism during disease, including heart failure, cancer, thyroid disease, myxedema, and fever due to infection [18,30,34,38]. In fact, using Zuntz’s apparatus, Magnus-Levy was the first to successfully apply indirect calorimetry to clinical medicine (1895) [18,27,34]. Wilbur Atwater, an American contemporary of Rubner and fellow student under Voit [14,27,30], built the Atwater Rosa respiration calorimeter starting in 1892 (Fig. 12) [28]. Edward Rosa, like Laplace who constructed the first calorimeter, was a physicist. This device was a highly sophisticated direct and indirect calorimeter large enough to study humans, and with it
Atwater repeated Rubner’s demonstration of the conservation of energy, but this time in man (99.4% agreement between direct measurement of heat production and calculation by gas analysis) [14,27,30]. Atwater advocated the kg-calorie as the preferred unit of heat in metabolism [39], and it is at this time that the terms indirect and direct calorimetry came into use, replacing the terms respiration apparatus and calorimeter. Atwater trained and employed Francis Benedict (1870–1957), who went on to head the Nutrition Laboratory of the Carnegie Institute [27]. This laboratory was dedicated to developing calorimetric techniques and to studying human metabolism, including in infants and children [35,40–44]. The influence of body size, age, and sex on metabolic rate was characterized and calculated into the biometric equation that bears Benedict’s name [35]. Racial differences were studied, as were the effects of
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Fig. 13. This device [40,47] was described by Benedict as a replacement for the complicated, time-consuming, and labor-intensive respiration calorimeter experiments that had heretofore been the gold standard of metabolic measurements (see Fig. 12) with mouthpieces or nose tubes replacing a chamber for gas collection. The device was portable (although Graham Lusk commented that whenever the apparatus was moved an air leak developed, which might explain the tools on the bottom shelf in the photograph) and could yield results in 20 minutes (image at left used with permission. Am J Physiol 1909;24:345–374). Gas handling is identical to that described in Figure 12 except on a smaller scale and with the addition of an air-moistener to return the dried air to a rebreathable condition. Images at right reprinted with permission from the Carnegie Institute of Washington.
starvation, disease, and muscle work. Benedict was an innovator of calorimeter design (Figs. 12 and 13) and was integral to the increasing emphasis of indirect over direct calorimetry and to the widespread application of indirect calorimetry to clinical medicine in the 1920s [38,41,45–48]. Into the 20th century, closed-circuit indirect calorimetry dominated over open-circuit because of the difficulty in measuring inspired gas volumes when the inspired air stream does not originate in the apparatus. Lavoisier struggled with this exact same problem in 1783. John Haldane (1860–1936), a Scottish physiologist, finally solved the problem in 1912 when he described an equation for calculating inspired gas volume from inspired and expired gas concentrations and expired gas volume (the Haldane transformation) [49]. Calculation of inspired gas volume was a critical step in the eventual triumph of opencircuit indirect calorimetry. The computation is based on the fact that inhaled and exhaled nitrogen volumes are equal because nitrogen is inert in gas exchange. Although this fact was observed by Lavoisier and by Zuntz, Haldane was the first to express it in a useful mathematical manner. Clinical calorimetry comes of age (1920s) In a symposium on clinical calorimetry published in the Journal of the American Medical Association in 1921 [50,51], several interesting statements were made, among them that the main role of calorimetry remained in the laboratory, that the use of calorimetry in the management of thyroid disease was useful, but not necessary, that inexperienced operators were using the devices and obtaining inaccurate results, and that some manufacturers were overly aggressive at marketing the devices, some of which had not been validated [50]. At least four commercial devices existed at the time (Fig. 14) [41,45]. All of these devices were of the closed-circuit type; none measured carbon dioxide,
but all used absorbers to keep the air circuit free of carbon dioxide. By not measuring carbon dioxide, the devices were simplified but a set respiratory quotient and therefore heat equivalent of oxygen had to be assumed to calculate metabolic rate. All the devices required temperature recordings so that the measured gas volumes could be adjusted in accordance with Boyle’s gas laws.
Doldrums (1930s–1960s) After being used to discover fundamental principles of respiration physiology and ushering in nutrition science, indirect calorimetry began to wane in the 1930s as other lines of nutrition investigation arose. The technique did not disappear, but its profile was much lower than it had been in the late 19th and early 20th century. However, two technological developments occurred during this time that would become important in a later resurgence of calorimetry. One was the simplification of the calculation of metabolic rate from gas exchange data [37]. Weir took the complicated method, with its partitioning of protein and non-protein respiratory quotient and assignment of a heat equivalent per liter of gas according to the respiratory quotient and devised a simple algebraic equation for calculating metabolic rate from total carbon dioxide production and oxygen consumption. An important improvement in technology was the development of gas analysis methods that did not depend on gravimetric measurements (e.g., paramagnetic oxygen analyzers and infrared carbon dioxide measurement [52,53]). These would become the backbone of the next generation of indirect calorimeters. On the clinical research front, Cuthbertson starting in the 1930s utilized Douglas bag indirect calorimetry to study metabolism after injury [54]. Kinney and coworkers developed a calorimetry system that could measure acutely ill patients using a ventilated canopy system (Fig. 15)
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Fig. 14. Clinical indirect calorimeters from the 1920s [41,45]. Clockwise from top left, the Benedict Roth spirometer (wet spirometer for measurement of oxygen consumption, carbon dioxide absorption system at the bottom of the stand to keep the air in the closed circuit respirable) (reprinted with the permission from the Carnegie Institute of Washington), the Jones Metabolimeter (oxygen tank from which gas disappearance was timed as a measure of consumption, carbon dioxide absorption canister on top for scrubbing the air of carbon dioxide, mouthpiece, and compliance device atop the canister), the Sanborn Handy calorimeter (carbon dioxide absorption via the bottom canister, oxygen contained in the wet spirometer at the top of the canister with measurement rod to measure the excursion of the spirometer bell at each breath. Breath volume (tidal volume) had to be stable from breath to breath for these types of devices to be accurate), and the McKesson Metabolor. This device uniquely had an air blower, was 17 inches high and weighed 40 pounds before the spirometer was filled with 12 liters of water. The absorber system is contained inside the air chamber.
[55] and conducted major work on injury metabolism in the 1960s [56]. A rebirth of sorts (1970s to today) With the advent of nutrition support, clinicians obtained the power to control more exactly the nutrient intake of patients. Having the ability to control intake stimulated a need to determine more exactly individual nutrient requirements. Therefore, starting in the 1970s and continuing today, a reemphasis on indirect calorimetry has occurred. The latest devices are generally open-circuit, computer-based, and portable. Expired gas volumes can be measured in a number of ways. One of the most common is the pneumotachometer, which converts the turbulent air flow of exhalation into laminar flow, measures the pressure exerted by this flow, and converts the pressure to a volume. Carbon dioxide is measured with non-dispersive
infrared absorptiometry (absorption of this light spectrum is proportional to the carbon dioxide concentration in the air being sampled). Oxygen can be measured in a number of ways, most of them some variation of an electrochemical cell in which the oxygen present in the airflow produces an electrical current that is proportional to the oxygen concentration. Paramagnetic methods are also used for oxygen sensing in which the magnetic properties of oxygen distort the rotation of a small glass vessel inside the sensor. The degree of distortion is proportional to the oxygen concentration in the air flow. The most recent technological advance is the handheld or hand-carried open-circuit indirect calorimeter for use in spontaneously breathing people. These devices are much less expensive and much more convenient than previous portable calorimeters. Part of the reduction in cost and device size was achieved by the sacrifice of a carbon dioxide sensor. Like the earliest forms of clinical calorimetry, these devices measure only oxygen consumption and compute
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References
Fig. 15. Open-circuit, indirect calorimeter developed in the 1960s by John M. Kinney [55]. The ventilated canopy took in air at a rate of 40 L/min, which the patient breathed from and exhaled into. The air stream was blown into the analysis equipment housed in a separate room. Air volume was measured continuously by a wet gas meter. Oxygen concentration was measured continuously with a paramagnetic sensor, while the carbon dioxide concentration was determined continuously with an infrared analyzer. In this system can be seen some of the components that would be incorporated into portable bedside calorimetry employed from the 1970s onward. Reprinted with permission.55
metabolic rate by assuming a respiratory quotient. Validation of these devices is ongoing. Direct calorimetry still exists as a research tool, especially for long-term studies and for partitioning the components of total metabolic rate. Some of the advances in nutrition science made with modern indirect calorimetry include the development of updated standard equations (e.g., Mifflin St. Jeor, which at least in the U.S. is beginning to supplant Harris Benedict as the standard calculated metabolic rate) [57,58], observation of a decrease in metabolic rate over the decades in critical care patients [59], probably reflecting improvements in the overall care of such patients, and the development of metabolic standards specific to critical care (supplanting the need for employing modified healthy equations in this role) [60,61]. Major questions still incompletely answered include whether clinical outcomes are improved by measurement of metabolic rate, comparative metabolic requirements among races, geographic locations, extremes of age and body composition, etc., and the development of calculation standards for sick people who do not require critical care. Thus indirect calorimetry, a technique that is now 227 y old, still has contributions to make to nutrition science, physiology, and clinical practice.
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