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You are watching: What condition brings about positive nitrogen balance

Institute of Medicine (US) Committee on Military Nutrition Research. The Role of Protein and Amino Acids in Sustaining and Enhancing Performance. Washington (DC): National Academies Press (US); 1999.


Douglas W. Wilmore1

Injury and infection elicit a fairly stereotypic metabolic response identified by hypermetabolism, increased gluconeogenesis, boosted fat oxidation, and also negative nitrogen balance (Wileven more, 1997). These responses are especially apparent in young, formerly healthy and balanced, well-nourimelted people, such as members of the military, who have a well-occurred lean body mass and also no connected conditions or dyspractical organs. Since body protein represents an indispensable structural and sensible element of the body, the mechanisms that regulate the sped up proteolysis in the time of these catabolic claims have got a lot attention. This is because considerable erosion of lean body mass results in immunosuppression, bad wound healing, reduced stamina and also task, and expanded convalescence. Methods of attenuating the catabolic response or enhancing protein anabolism are now being evaluated in patients in an initiative to shorten convalescent recovery and also decrease the length of hospital continue to be (Wilmore, 1991).

This chapter outlines some of the alters that happen in whole body protein metabolism following infection and also injury. Evidence will be presented that these catabolic states bring about marked translocation of protein from the carcass to visceral tconcerns, resulting in a net loss of skeletal muscle mass. Such loss outcomes in lessened stamina and activity.

Background and also General Response Characteristics

Over 200 years back, John Hunter, the British surgeon and also biologist, known that accidental injury initiated a collection of responses in the hold that presumably aided tworry repair and general recoincredibly (Hunter, 1794). In the late 1800s, the principle of nitrogen balance was establiburned by Voit and also his German colleagues functioning in this location of physiological biochemisattempt (Munro, 1964). They provided that nitrogen balance might be regarded the body"s protein economy and was affected positively by the enhanced ingestion of both energy and also protein and affected negatively by sepsis-induced fever before. These concepts were confirmed and also extended in the beforehand 1900s, as soon as Coleguy and also DuBels (1915) stupassed away both energy and protein balance in a team of patients through typhoid fever. Using both straight calorimetric approaches and totality body balance methodology, they stupassed away patients throughout the acute and convalescent phases of their condition. The investigators described the increased net loss of nitrogen that was linked through the febrile episodes of typhoid fever; the negative nitrogen balance could not be counter by the ingestion of huge amounts of energy at the moderate level of protein intake that was utilized.

In 1932, Cuthbertson (1932) defined a group of patients that had either undertaken orthopedic surgical measures on their reduced extremities or that had actually sustained lengthy bone fractures. He provided that these injuries to the long bone were connected with an amplified loss of nitrogen from the body. This negative nitrogen balance was maximal during the first week postinjury and persisted for as much as I month. Cuthbertkid separated the metabolic response to injury into two phases: a very early, acute "ebb" or shock phase and also a latter "flow" or hyperdynamic phase. Throughout the ebb phase, tbelow was lessened metabolic task, which was complied with within 12 to 48 hours by the flow phase, a hypermetabolic state in which metabolic price, temperature, and urinary nitrogen excretion all enhanced. Others have actually because added to the area of postinjury metabolism, through classical contributions being made by John Howard, Oliver Cope, Francis Moore, John Kinney, and many others (Wilmore, 1997).

Throughout the at an early stage 1900s, researchers realized that infection was related to increased loss of protein from the body, however it was not till the 1960s that the organized examine of the metabolic response to infection was undertaken and also publimelted. William Beisel and colleagues (1967), functioning via the Army to understand the influence of infectious illness on the host, stupassed away normal people that were infected under speculative conditions with tularemia, sand also fly fever, or Q fever before. The individuals received a resolved diet of well-known complace, and after metabolic baseline was establimelted, the contagious agent was administered. A well-characterized sequence of occasions occurred over time: phagocyte attribute increased; serum amino acids, zinc, and also iron concentrations fell; glucocorticoids and growth hormone concentrations enhanced in the blood stream, and acute-phase protein levels were additionally changed. The patients subsequently came to be febrile, kept salt and water, yet excreted even more nitrogen in the form of urea. The negative nitrogen balance was regarded the decreased dietary intake of energy and also protein and also to the fever-connected increases in metabolism. In a sepaprice experiment, exogenous glucocorticoids were administered to noninfected controls. Although this mimicked in part the adrenal cortical response to infection, this perturbation did not simulate the negative nitrogen and mineral balance observed in the febrile volunteers. Likewise, when noninfected normals consumed a caloric and also protein intake equivalent to that ingested by the topics who had actually speculative tularemia, the negative nitrogen balance was slight (18 g cumulative), demonstrating just around one-3rd of the losses observed in the infected patients (52 g cumulative). Due to the fact that of the degree of the protein loss, it frequently took weeks for the infected individuals to replete their lean body mass.

From these and connected researches, some general conclusions have the right to be made concerning the entirety body protein catabolic response complying with injury or infection:

The raised nitrogen loss occurs through the urine. Urea represents the major component of the nitrogen shed and also contributes 85 to 90 percent to the negative nitrogen balance.
More nitrogen is lost from a well-nouriburned individual than from a depleted patient complying with a similar catabolic insult. Thus, a connection exists in between the dimension of the lean body mass and also the extent of protein catabolism, and also this may account for variation in nitrogen balance that occurs with age and also gender. Both older individuals and also womales are thneed to excrete less nitrogen following a conventional stimulus than carry out their appropriate controls.


Figure 8-1

Hypermetabolism and nitrogen excretion are closely related, present a dose-response partnership, and also deal with through time. Patients obtained 12 g of dietary nitrogen per day. Source: Adapted from Kinney, 1966.

Negative nitrogen balance represents the net loss of nitrogen from the body. The nitrogen lost mirrors a balance between protein synthesis and protein breakdown, which are simultaneously emerging in all tissues of the body. A variety of secure isotopic research studies have attempted to measure these absolute prices. A summary of these research studies is displayed in Table 8-2. Injury and infection bring about the boosted entirety body flux of amino acids throughout the body. Catabolic prices outstrip rates of protein synthesis in the partly fed state; feeding improves protein synthesis and attenuates the negative nitrogen balance that occurs. Despite feeding, protein flux rates remajor high in these catabolic says, and also these rates carry out not return to normal until the inflammation is readdressed.



Alterations in Rates of Protein Synthesis and Catabolism That May Affect Hospitalized Patients.

The Transarea of Nitrogen from Carcass to Viscera

Although the protein-catabolic response may appear to be a generalised effect of net protein breakdown throughout the body, this is not the case. Skeletal muscle is known to come to be catabolic; arterial-venous dimensions of amino acid concentration across noninjured extremities of injured patients have recorded the increased release of nitrogen that occurs from skeletal muscle during the circulation phase (Aulick and also Wileven more, 1979). However before, catheterization of vessels giving and draining visceral organs in equivalent patients has actually demonstrated enhanced uptake of amino acids (Wilmore et al., 1980), and these rates of uptake mainly complement the rates of peripheral amino acid release. That transarea of nitrogen occurs from the carcass to visceral organs is additionally sustained by the adhering to phenomena:

In addition to the nitrogen lost in the urine, tright here is raised excretion of potassium and phosphorous. All of these elements are lost in proportion to their concentrations discovered in skeletal muscle.
Following a catabolic occasion, creatinuria occurs. In enhancement, tbelow is boosted excretion of 3-methyl histidine. Both of these substances are found mainly in skeletal muscle.
A prevalent, clinical observation is that wasting of skeletal muscle occurs throughout catabolic says, and this is accompanied by muscle weakness.

A characteristic pattern of amine acids released from catabolic muscle has actually been described: alanine and glutamine constitute 50 to 70 percent of the amine acid nitrogen released (Muhlbacher et al., 1984). This represents sped up de nero synthesis of these amine acids; hydrolysis and analysis of skeletal muscle protein reveals that both alanine and glutamine add less than 10 percent to the all at once amine acid residues. Transarea of these amine acids to visceral tissues presumably occurs for a purpose; both amine acids serve as vital glucose precursors and assistance the intensified price of gluconeogenesis. In the liver, nitrogen residue from this reactivity is converted to other nonessential nitrogen compounds or converted to urea and excreted in the urine. Glutamine is likewise extracted by the kidneys, wbelow it contributes ammonia to incorporate via hydrogen ions to form ammonium (NH4+), which is excreted in the urine. This is a vital component of acid-base homeostasis, for the loss of every H+ in the urine is accompanied by the secretion of a bicarbonate ion right into the bloodstream. Glutamine is likewise taken up by enterocytes, lymphocytes, and macrophperiods, where it serves as a major fuel source for these tproblems, sustaining proliferation and also signaling or sustaining various other crucial responses.

Therefore, skeletal muscle serves as a vital resource of substprice in the time of catabolic says to assistance vital framework and attributes of the visceral tissue necessary for hold survival. However, the enhanced loss of skeletal muscle protein occurs via a cost—the price passist is loss of muscle mass and the disturbance of normal muscle feature. These alterations in composition of organs in catabolic states have been oboffered in both pet models (Artuson, 1961) and also human patients following injury or infection (Bararc-Nieto et al., 1978) (Figure 8-2).


Figure 8-2

Body composition in patients via mild and major chronic infection. Keep in mind the loss of fat-complimentary tconcern and also muscle via serious infection, with maintenance of visceral tworries. *, P < 0.05. Source: Adapted from M. Bararc-Nieto et al., 1978.

Regulators of the Translocation of Protein

Various components have been linked via the enhanced skeletal muscle proteolysis and translocation of nitrogen from the carcass to visceral organs. Anorexia frequently accarriers infection, and the diminiburned food intake reasons hormonal changes, such as a autumn in insulin and also insulin-like expansion factor-1, which decrease skeletal muscle protein synthesis. Infection and injury are additionally connected with a selection of constitutional symptoms including pain, fever before, myalgia, headache, and fatigue. As task decreases, or bed remainder is applied, the dynamics of net skeletal muscle protein synthesis are altered, enhancing net skeletal muscle proteolysis.

Other components that regulate intermediate metabolism are known to be connected via the transformed protein metabolism that occurs in the time of injury and infection. A characteristic hormonal response pattern has been oboffered during catabolism. Early while course, insulin levels are low, after which the blood levels generally rise to normal or supranormal levels. However, the counterregulatory hormones glucagon, glucocorticoids, and catecholemines are all elevated, and they mostly remajor so throughout the duration of catabolism.

To evaluate the duty of this transformed hormonal atmosphere, Bessey and associates (1984) and also Watters and colleagues (1986) infsupplied these catabolic hormones right into normal volunteers with or without the addition of a pyrogen. Hormonal infusion resulted in many, but not all, of the responses observed adhering to infection and injury. Specifically, as soon as glucagon, glucocorticoids, and also catecholemines were infoffered to attain blood levels equivalent to those that occur in catabolic claims, negative nitrogen balance, hypermetabolism, and increased gluconeogenesis were oboffered (Bessey et al., 1984). The administration of a pyrogen added fever before and also activation of many type of components of acute-phase response to this straightforward complicated (Watters et al., 1986).

In succeeding researches, Bessey and Lowe (1993) provided somatostatin to block insulin elaboration, as occurs during the beforehand phases of injury or infection. Under these conditions, the triple hormone infusion caused a lot higher nitrogen losses, reminiscent of excretion prices observed in bum or seriously injured patients. Thus, the hormonal setting plays a significant duty in determining body protein balance. Hormonal transforms during critical condition may define much of the negative nitrogen balance observed, especially if food intake is offered by enteral or parenteral support

Alterations in the hormonal setting are triggered by yet another set of signals, those of the cytokines and other pro-inflammatory mediators. Cytokines are glycoproteins synthesized by inflammatory cells and also in other places in the body in response to inflammation and also various other noxious stimuli. Although these mediators mainly signal various other cells in the regional environment, they might be developed in abundance and also have the right to, on occasion, be detected in the blood stream (Cannon et al., 1990). Those cytokines central to the pro-inflammatory response are interleukin (IL-1), tumor necrosis variable (TNF), and also IL-8 (a potent chemo-attractant). These and other pro-inflammatory mediators (e.g., match, fatty acid metabolites, vascular endothelial factors) initiate both cellular (Hill et al., 1996) and also hormonal changes (Hill et al., 1996; Michie et al., 1988) that induce skeletal muscle proteolysis (Mitch and Goldberg, 1996), change carbohydprice metabolism, and also stimulate hypermetabolism, every one of which are components of the metabolic responses observed adhering to injury and infection (Ling et al., 1997).

These pro-inflammatory cytokines are well balanced by various other endogenous determinants. The elaboration of glucocorticoids is a result of cytokines signaling the central nervous system to initiate a pituitary-adrenal cortical response. Glucocorticoid elaboration is a critical mechanism that attenuates cytokine effects and also hence modulates catabolism (Santos et al., 1993). Other anti-inflammatory cytokines are elaborated (IL-4, IL-10, and IL-13), and these substances dampen or attenuate the inflammatory responses and also enhance tissue vicapability and/or promote repair. Nutritional aspects likewise serve as vital antioxidants to diminish the result of cost-free radicals, which are additionally created in the time of the inflammatory procedure. Of specific prestige in the time of bacterial infections are vitamins A, C, and E and also the minerals zinc and also selenium (Grimble, 1993). Glutathione is the the majority of important intracellular antioxidant, and also the provision of the amine acids cystine (as N-acetyl-cystine or methionine) and also glutamine is essential to assistance the recurring synthesis of this tripeptide. Other nutrients, such as omega-3 fatty acids and also arginine might also be valuable to amelioprice inflammation.


The mediators of the protein catabolic response are reduced food intake, reduced exercise, and a set of hormonal and also cytokine signals that favor protein breakdvery own. Only currently are researchers finding out how to modify some of these components in order to keep the helpful facets of the protein catabolic response while attenuating those elements that show up to be deleterious to the hold.

Colemale, W., and E.F. DuBels. 1915. Clinical calorimetry. VII calorimetric monitorings on the metabolism of typhoid patients with and also without food. Ann. Int. Med. 15:887-938.
Cuthbertkid, D.P.1932. Observations on disturbance of metabolism created by injury to the limbs. Quart. J. Med. 25:233-246.
Grimble, R.F.1993. The maintenance of antioxidant defenses in the time of inflammation. Pp. 347-366 in Metabolic Support of the Critically Ill Patient, D.W. Wilmore, editor; and Y.A. Carpentier, editor. , eds. New York: Springer-Verlag.
Kinney, J.M.1966. Energy deficits in acute illness and also injury. P. 174 in Proceedings of a Conference on Energy Metabolism and also Body Fuel Utilization. A.P. Mbody organ, editor. , ed. Cambridge: Harvard College Press.
Munro, H.N.1964. b. Historical introduction: The origin and expansion of our existing principle of protein metabolism. Pp. 1-29 in Mammalian Protein Metabolism, H.N. Munro, editor; and J.B. Allichild, editor. , ed. New York: Academic Press.
Wannamacher, R.W., Jr.1975. Protein metabolism (applied biochemistry). P. 133 in Total Parenteral Nutrition: Premises and also Promises, H. Ghadimi, editor. , ed. New York: John Wiley.
Wilmore, D.W.1997. b. Homeostasis: Bodily alters in trauma and also surgery. Pp. 55-67 in Textbook of Surgery, 15th ed., D.C. Sabiston, editor. , ed. Philadelphia: W.B. Saunders.


ROBERT NESHEIM: Thank you, Doug, for that exceptionally great and also amazing presentation. It is open up for questions.

JOHANNA DWYER: Just a quick question, Doug, on the dietary aspects. You discussed most antioxidants, some of which are nutrients. What around BHA and BHT? I remember that those are incredibly potent antioxidants.

DOUGLAS WILMORE: I think there are a whole variety of antioxidants that deserve to be made use of, Johanna. The reports on those are really a combined bag ssuggest because it is most likely going to be hard to check out results via single anti-oxidants. Tbelow is an extremely nice research, for example, of high-doses of vitamin C in long-distance runners who over-train, for instance. But it is rare to uncover reports of single nutrients alone working as antioxidants that have major types of effects.


WANDA CHENOWETH: You have actually talked around antioxidants. What about pro-oxidants for example?



DOUGLAS WILMORE: Iron? Well, it is an excellent suggest. Bill may have the ability to make some comments about this. The classical teaching is that iron is the single nutrient that have to not be administered throughout infection and injury. If it is addressed in food and also supplemented, in basic, in a very managed case, you would certainly take it out. You would not give it. This is sindicate because iron is redispersed after infection and also your iron level in your blood stream becomes very low bereason it really is an extremely important substance for bacteria and also some viroffers to usage for replication. So we would take it out or not provide it. This, again, gets ago to the problem of having actually addressed rations and also all of the components in a ration, and the assumption that a ration that is proper for well civilization is proper for sick civilization, which is a concept that I perform not take on.


D. JOE MILLWARD: I was simply going to make the point in respect to BHT. I think that one of the interesting points about those sorts of antioxidants is that intakes of them are very high and also we generally ignore them as crucial components of our food because they are tbelow as additives. But, actually, we now take in huge amounts Of these compounds. It might well be that they are in truth a major component of our antioxidant defense mechanism. I think that we need to be thinking about them to a a lot higher extent than we perform.

ROBERT NESHEIM: John Vanderveen.

JOHN VANDERVEEN: Doug, the question is whether, on a long-term basis or a short-lived basis, we can build up body stores that are going to help us in the instance of an infection or injury event, or is it somepoint that is finest tackled in terms of a short preliminary type of preparative activity?

DOUGLAS WILMORE: That is a very strategic question from the standsuggest of preparing human being to go right into maneuvers or go to do a task. I guess that one means we could start thinking about it, and this might not be the just way to think about it, would certainly be to think in regards to water soluble and also fat soluble substances. Due to the fact that we can pretty well store many type of of the fat-soluble substances, yet we would probably need to administer many type of of the water-soluble substances. When we talk around genetic prejudice or phenoform altering, it may well be that omega-three fats might be fed over the duration of around three to four weeks, if you will, and also we can change responses in just that short a duration of time.

Vitamin E loading, in adequate doses, for example, takes around four weeks. And tright here are nice clinical information currently from heart biopsies of patients undergoing cardiac surgical treatment where various doses and time intervals have been offered for vitamin E loading as an antioxidant.

The University of Toronto team has reported that you require about four weeks before you deserve to obtain sufficient vitamin E loading in cardiac muscle. So that is one way to think about it.

Tright here is an additional method to think around it also and also that is—it is not all that negative for many of these people to have a surfeit of adipose tconcern which is their energy supply and also an enough skeletal muscle mass, bereason background has really told us that you have the right to attract on those stores and that will enhance your survival as long as you are within some kind of a functional zone. So there might be some techniques that we can think about that will have to carry out through loading or preparing people. Mackenzie Walser and also others may respeak to the interemainder civilization had actually through making use of odd-chain fats. Odd-chain fats would certainly then administer you through gluconeogenic precursors. If you were starving for a long period of time, these fats would certainly be drawn from your adipose tissue stores, yet if you were provided with gluconeogenic precursors and you would certainly not need to break down muscle as quick. So tbelow have actually been talks around that in the previous.


MACKENZIE WALSER: Is the mechanism of that known? Does it have actually etiological value?

DOUGLAS WILMORE: Presumably it is tbelow to protect circulating blood volume and also oxygen shipment capacity. The mechanisms are via most normal pathways that conserve salt and water.

ROBERT NESHEIM: Dr. Liehermale.

HARRIS LIEBERMAN: Doug, execute we know anything around fads of readjust in amine acids as a repercussion of either acute or chronic illness, especially those that are important to the brain, such as tryptophan or tyrosine?

DOUGLAS WILMORE: In basic, all of the indispensable amine acids are lowered, I suppose, as a type of a basic preeminence without discovering the specific pattern for studies. In basic, all crucial amine acids are low. The dispensable amine acids are mainly normal or slightly raised. Joe, are tbelow other thoughts? (No response.)

ROBERT NESHEIM: Steve Heymsfield, and then we will have to go on. We have actually a discussion period complying with the following presentation so we can cover many kind of of these points then. Steve.

STEVEN HEYMSFIELD: You discussed genes as being one element. Do sex or age influence the metabolic response to injury in any way?

DOUGLAS WILMORE: They need to, however the age problem is exceedingly difficult to examine bereason you present steady body organ dysfunction or change; you carry in various other disease procedures and also points like that.

But as soon as I remained in the Army Burn Unit in the 1970s, we were able to kind enduring from nonmaking it through patients by just their response to a cool environment. A cool setting, incidentally, was about this temperature (e.g. the temperature of an air conditioned room). It is just one of the worries of why hospitals have to not be cold. The older patients responded more promptly to cold exposure than the younger individuals.

MICHAEL RENNIE: Can I just say something around that metabolic response? We have actually simply done some studies on extremely young kids, neonates. In truth, as far as we can tell, they do not show a metabolic response to injury. So that shows up to be a developmentally-gained response.

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DOUGLAS WILMORE: And that is compatible with the fact that babies have the right to actually undergo complete hormonal blockade via heart surgical procedure and also actually do better in regards to their all at once response as soon as compared via non blockaded patients.