For critically ill, or patients with highly inflammatory conditions, the estimated basal metabolic rate

is adjusted upward. Not surprisingly, basal energy requirements increase significantly with an active

inflammatory response, but minimally after elective surgery. The largest increases in energy

expenditure are seen in patients with severe polytrauma or major burns.35

Other Parameters for Nutritional Assessment

In addition to the aforementioned methods of assessment of nutritional status, many more

anthropomorphic, clinical and laboratory parameters have been described. These include total

lymphocyte count (<2,000/mm3), CHI (<80%), ideal body weight (<90%), weight loss over time

(>10%/6 months), and skin antigen testing (<3/4 reactive sites over number placed). The numbers in

the parentheses are suggestive of malnutrition.

OVERFEEDING AND MALNUTRITION

Overfeeding

While adequate caloric intake is necessary to maintain weight and promote health, overprovision of

calories can lead to overfeeding and obesity. Excess calories, especially as carbohydrates, can lead to

increased carbon dioxide production (which may prolong ventilatory weaning), hyperglycemia (which

can contribute to immunosuppression and increase the risk for infectious complications), lipogenesis

(indicated by a respiratory quotient >1), and hepatic steatosis (which can interfere with normal liver

function). Additionally, excessive nutritional support, may lead to mineral or vitamin poisoning, and

severe electrolyte imbalances, with hypophosphatemia being the most common. To avoid overfeeding,

specifically in critically ill patients with numerous active medical conditions, indirect calorimetry may

be indicated to accurately estimate energy expenditure during the various stages of disease.

Malnutrition

Starvation

3 During short periods of fasting, insulin levels drop and glucagon levels rise in the plasma, while

glycogen is being broken down in the liver to release glucose. Liver glycogen stores are typically

depleted within 24 hours of fasting. After carbohydrate stores are used up, caloric needs are met by

protein and fat degradation. During starvation, down-regulated insulin results in net muscle wasting, as

protein is broken down to release amino acids. These amino acids – most commonly alanine and

glutamine – are used for gluconeogenesis in the liver. The resulting glucose is used primarily by the

central nervous system and the hemopoietic system that rely heavily on glucose metabolism for their

energy requirements. Hepatic gluconeogenesis itself also requires energy, which is typically supplied by

the free fatty acid oxidation. The drop in circulating insulin levels, along with the concomitant rise in

plasma glucagon, activates hormone-sensitive lipase in fatty tissue that hydrolyzes triglycerides to

release free fatty acids, which in turn help generate energy for the aforementioned gluconeogenesis.

Both gluconeogenesis and fatty acid oxidation require the permissive effect of cortisol and thyroxine.

During starvation, the human body attempts to recycle energy sources to the greatest extent possible.

Lactate produced by the white blood cells or the muscles during anaerobic metabolism is recycled back

to glucose in the liver, through the Cori cycle. BCAAs, unlike glutamine and alanine, which are taken up

by the liver, are secreted by the gland, in order to provide skeletal and cardiac muscles an energy

substrate. Once BCAAs are oxidized for energy, their residual amino groups are utilized to recycle

alanine and glutamine, which in turn return to the liver to allow further gluconeogenesis. However

efficient this conservation of energy and substrates may seem, gluconeogenesis from amino acids in the

liver results in a significant loss of lean body mass, which may reach fatal levels after approximately 4

weeks. The brain adapts to prolonged starvation after about 7 to 10 days (chronic starvation) to use

ketones derived from fat, as its primary energy source. At this stage, the basal metabolic rate decreases

by as much as 30%, and all functions requiring significant amounts of energy expenditure slow down,

including voluntary muscle activity and cardiac function.

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Starvation versus Inflammation as the Cause of Malnutrition

Both starvation and the systemic inflammatory response result in lean body mass loss, which should

indicate nutritional support.1–4 However, the two processes have key dissimilarities that differentiate

one from the other. On one hand, starvation leads to progressive loss of both lean mass and body fat,

preservation of serum protein levels, and reversal of the metabolic response with feeding. The most

common causes of starvation in the surgical patient are functional, and include nausea and emesis, ileus,

dysphagia, and malabsorption. On the other hand, during a significant inflammatory response, the basal

metabolic rate increases significantly (both anabolism and catabolism) and becomes relatively

insensitive to feeding, and levels of acute-phase proteins change. Inflammation may additionally worsen

malnutrition by interfering with caloric intake acutely (anorexia of acute illness) or in the chronic state

(cancer cachexia). The key differences between the metabolic response to simple starvation and injury

are summarized on Table 3-6.

Table 3-6 Metabolic Differences Between the Response to Simple Starvation and

Stress

METABOLIC RESPONSE TO STRESS

Neuroendocrine and Cytokine-Mediated Response to Stress

4 After injury, two distinct phases of a neurohumoral response that affect metabolism can be identified.

A shorter, early “ebb” or shock phase, which typically lasts 12 to 24 hours, occurs immediately

following injury. During this early phase, cardiac output, body temperature, oxygen consumption, and

therefore overall metabolism are reduced. These events are often associated with blood loss and

commonly lead to anaerobic metabolism and lactic acid synthesis. With restoration of the blood volume,

metabolism accelerates, and is associated with increased cardiac output, altered glucose metabolism,

faster tissue catabolism, and greater urinary nitrogen losses. During the “flow” phase, the basal

metabolism increases to greater rates than what would be predicted on the basis of age, gender, and

body size in a healthy individual. The degree of hypermetabolism is generally related to the severity of

the original insult, and hence the intensity of the inflammatory response. This delayed “flow” phase

response to injury is not dissimilar to what occurs following elective surgery. The response to injury,

however, is usually much more intense and extends over longer periods of time.

The response to accidental injury or elective surgery, with both its phases, comprises two

components: a neuroendocrine response and an inflammatory response. Catecholamines, corticosteroids,

and glucagon play a principal role in the neuroendocrine response. Cytokines, complement, eicosanoids,

and platelet-activating factor are key mediators of the inflammatory response. During elective surgery,

the inflammatory response is typically local and confined to the surgical wound. Following a major

accidental injury, extensive uncontrolled tissue damage triggers an inflammatory response and release

of mediators that commonly spills over into the systemic circulation.

The hormonal response to stress appears to be the result of extensive neuroendocrine stimulation.

Glucagon along with insulin resistance has potent glycogenolytic and gluconeogenic effects on the liver,

which signal the hepatocytes to produce glucose from hepatic glycogen stores and gluconeogenic

precursors. These gluconeogenic precursors are typically amino acids (alanine and glutamine) released

from muscle. This action is facilitated by thyroid hormone. Catecholamines also stimulate hepatic

glycolysis and gluconeogenesis and increase lactate production from peripheral tissues (skeletal muscle).

Catecholamines additionally increase metabolic rate and stimulate lipolysis (Fig. 3-4).

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The inflammatory portion of the response is arbitrated by a host of mediators, including cyto- and

chemokines, complement, and eicosanoids. The initial trigger stimulates local mast cells to release

numerous mediators, with pro- or anti-inflammatory properties.36 The intermediaries that promote

inflammation usually predominate early (tumor necrosis factor [TNF], interleukin [IL]-1, IL-6,

prostaglandin-E2 [PGE2], leukotriene-4 [LT4]), whereas anti-inflammatory effectors are released later,

as the body is trying to control the inflammatory response. The TNF and IL-1 stimulate IL-6 release. One

of the effects of IL-6 is to reduce the level of insulin-like growth factor 1 (IGF-1), which promotes

proteolysis and amino acid release from muscle. Cytokines act in concert with catecholamines, cortisol,

and thyroid hormone to mobilize amino acids from skeletal muscle. As the inflammatory stimulus is

controlled and eliminated, the anti-inflammatory cytokines (IL-4, IL-10, and IL-13) and eicosanoids

(PGE3 and LT5) begin to predominate, and bring the inflammatory response to a conclusion. This is not

to say that only pro- or anti-inflammatory mediators are being expressed, a balance between the two

sets of factors favors a pro- or anti-inflammatory state at any given time, depending on the presence of

ongoing stimulation.

This combined neuroendocrine- and cytokine-based response provides key nutrients to support

cellular metabolism at a time when enteral nutrition typically cannot be acquired. The primary

metabolic component of the acute-phase response affected by IL-6 is a qualitative alteration in hepatic

protein synthesis with a resulting alteration in plasma protein composition. Characteristically, proteins

acting as serum transport and binding molecules (albumin and transferrin) are reduced, and acute-phase

proteins (fibrinogen and C-reactive protein) are increased. While the role of many acute-phase proteins

remains unclear, many act as opsonins, antiproteases, or coagulation and wound-healing factors, with

the greater aim to minimize tissue destruction associated with inflammation. For example, fibrinogen

promotes thrombus formation to control bleeding, while antiproteases lessen tissue damage caused by

proteases released by dying cells. C-reactive protein has scavenger function and its serum levels have

been identified to be a measure of the inflammatory response.

This inflammatory response occurs at various levels. Small-scale localized inflammatory changes can

be identified frequently in minor illness with no major systemic consequences, and the neuroendocrine

component is only minimally, if at all, activated. In fact, these responses may be an important

mechanism through which the body allows controlled exposure of the immune system to antigen.

Moderate inflammation is still localized, but its effects are more obvious. Severe accidental injury or

major surgery triggers a hyperactive inflammatory reaction, along with the full neuroendocrine

response, the systemic effects of which are more readily identifiable (hypermetabolism, body protein

catabolism, insulin resistance, fever, and acute-phase protein response). Occasionally, such an exuberant

response leads to multiorgan failure, in which widespread endothelial damage, metabolic derangements,

immune function collapse, and, finally, end-organ dysfunction occur.37 This type of inflammation-driven

illness is a major cause of death in the intensive care unit (ICU). Significant lean body mass loss is seen

in survivors, however, when convalescence is under way, the inflammatory-driven metabolic changes

abate, and the body can be repleted with appropriate nutritional support and exercise.

Inflammation, for reasons not fully understood, can occasionally become a chronic condition in

survivors, in which impairments in metabolism typically seen in the acute phase endure, and cachexia

sets in.38,39 This form of chronic inflammation is maladaptive and a common feature in many chronic

disease states, inflammatory or not (renal, hepatic, or cardiac failure, many autoimmune diseases,

cancer), and is increasingly identified in ICU survivors after prolonged and complicated ICU stays.38,39

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Figure 3-4. The neuroendocrine response to stress stimulates proteolysis and lipolysis, promotes gluconeogenesis and leads to

glucose intolerance.

Substrate Metabolism Changes during Stress

5 During the neuroendocrine response to stress, metabolism of commonly used nutritional substrates

undergoes significant changes.

Altered Carbohydrate Metabolism

Hyperglycemia occurs commonly after injury, and its intensity generally reflects the severity of the

stressor. During the ebb phase, insulin levels are low and glucose production is only minimally elevated.

During the flow phase, hepatic gluconeogenesis occurs at a faster pace from peripheral tissue-released

precursors and hyperglycemia persists, while insulin levels are normal or elevated. This phenomenon

suggests relative insulin resistance.

Altered Protein Metabolism

After major injury, nitrogen losses increase. These correlate to the extent of trauma and the injury

victim’s pre-existing nutritional status. In patients not receiving nutrition, protein breakdown exceeds

synthesis, and negative balance results. Providing exogenous calories is important to maintain a neutral

nitrogen balance.23 Skeletal muscle is the chief source of the nitrogen lost in urine following extensive

injury and it appears that amino acid release from muscle is heavily skewed toward glucogenetic

precursors (alanine and glutamine), even though these comprise less than 5% of muscle total protein.

In addition to skeletal muscle, the kidneys and the gastrointestinal tract also release alanine, which

may be used for glucogenetic purposes, even though the majority enters metabolic pathways that favor

the production of urea and ammonia, to be excreted from the body.

Altered Lipid Metabolism

To support the increased metabolic rates after injury or elective surgery, triglycerides are released from

adipose tissue for energy production. Glucose administration minimally affects this lipolysis, which

appears to be a result of continuous neuroendocrine stimulation. Although mobilization and oxidation of

free fatty acids are accelerated in injured subjects, ketone synthesis is minimal and occurs independently

of protein catabolism. When severely injured patients remain unfed, their fat and protein stores become

depleted rapidly, and the resultant malnutrition increases their susceptibility to infectious complications,

multiple organ system failure, sepsis, and ultimately death.

Stressor-Dependent Adjustments to the Metabolic Response

Response to Elective Surgery and Accidental Injury

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One of the earliest consequences of major surgery is the rise in levels of circulating cortisol in response

to a sudden release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. This

cortisol remains elevated for 24 to 48 hours after operation. Cortisol has generalized effects on tissue

catabolism and mobilizes amino acids from skeletal muscle that provide substrates for wound healing

and serve as precursors for the hepatic synthesis of acute-phase proteins or new glucose, as delineated

earlier (Fig. 3-5). Associated with the activation of the adrenal cortex is stimulation of the adrenal

medulla through the sympathetic nervous system, with release of epinephrine and norepinephrine.

These circulating neurotransmitters play an important role not only in increasing vascular tone, which

may be lessened from circulating cytokines, but also in promoting amino acid release from skeletal

muscle, lipolysis in adipose tissue, and gluconeogenesis in the liver.

The neuroendocrine response to surgical trauma can also modify the various mechanisms that

regulate salt and water excretion. Alterations in serum osmolarity and body fluid tonicity due to

anesthesia, operative stress, and fluid resuscitation, stimulate antidiuretic hormone (ADH) and

aldosterone secretion. ADH and aldosterone promote water and sodium reabsorption in the renal

tubules respectively. Thus weight gain from salt and water retention is not uncommon after major

surgery. Edema occurs to a varying extent in all surgical wounds secondary to local cytokine release

that increases vascular permeability, and this local water accumulation is proportional to tissue trauma.

This extravasated fluid eventually returns to the circulation as the postoperative inflammatory response

subsides and diuresis commences, typically 2 to 3 days after surgery.

Figure 3-5. During sepsis, metabolism shifts to greater glucose synthesis and utilization, likely mirroring the greater metabolic

needs of the pathogens and the mobilized host white blood cells.

Table 3-7 Differences Between Elective Surgery and Accidental Injury

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Glucagon from the endocrine pancreas is also released at greater rates postoperatively, while insulin

levels decrease. This response appears to be associated with the increased sympathetic activity that

typically follows surgical trauma. The rise in glucagon and the corresponding fall in insulin act as potent

signals accelerating hepatic glucose synthesis.

This postoperative catabolic period, which may be worsened by inadequate caloric intake, has been

termed the “adrenergic–corticoid phase,” which generally lasts 1 to 3 days and is followed by the

“adrenergic–corticoid withdrawal phase,” which may last an additional 1 to 3 days. An anabolic phase

ensues, which can occur at a variable time during a surgical patient’s convalescence. In general, in the

absence of significant postoperative complications, this stage starts 3 to 6 days after major abdominal

surgery, usually when the bowel function returns and an oral diet is initiated. This phase is

characterized by positive nitrogen balance and weight gain. Protein is synthesized at an increased rate,

and return of lean body mass and muscular strength ensues.

Whether the body is injured within the carefully monitored confines of the operating room or

accidentally, the response to tissue trauma is similar, although key differences exist. In accidental

injury, tissue damage is uncontrolled and happens in a contaminated environment. The associated

volume loss can be substantial and life-threatening. Pain and the sympathetic nervous system

overexcitation are heightened and uncontrolled. As a consequence, the magnitude of the physiologic

response to major accidental injury is considerable. In contrast, the elective tissue trauma inflicted

occurs in a planned and monitored setting, and the team caring after the surgical patient perioperatively

ensures appropriate resuscitation designed to attenuate such changes. Hydration during and after

surgery is common, and the latter typically happens in a clean field. At the same time, the

anesthesiologist provides medications to minimize anxiety and fear, to minimize the sympathetic

nervous system response. Appropriately selected pharmacologic agents are used to minimize undesirable

cardiovascular responses, and analgesic techniques are employed to minimize postoperative pain. As a

result, the physiologic responses to elective surgery are generally of lesser magnitude than those

following major accidental injury and are typically tolerated better (Table 3-7).

Metabolic Adaptations to Sepsis

The metabolic changes following invasive infection are not dissimilar to those seen after elective

surgery and accidental trauma, although they are typically less predictable. Severe infection is

characterized by fever, hypermetabolism, diminished protein economy, altered glucose dynamics, and

accelerated lipolysis, much like the injured patient. Anorexia that commonly follows systemic infection

is an added factor contributing to the loss of lean body mass.

Hypermetabolism and increased oxygen consumption are additional traits, with the latter reaching

peak levels that may be 50% to 60% higher compared to baseline in severe sepsis. A portion of this

metabolic acceleration can be attributed to the escalation in enzymatic reaction rates associated with

fever. It is estimated that the base metabolic rate rises by 10% to 13% for every 1°C rise in central

temperature. Glucose metabolism is increased to much greater levels in systemically infected subjects,

compared to trauma victims. As an example, burn patients synthesize glucose at a rate approximately

50% above normal. If superinfection ensues, hepatic glucose production doubles, and it appears that the

additional glucose requirements correlate with the bacterial burden and white blood cell activation (Fig.

3-5).

Increased proteolysis and nitrogen excretion leading to negative nitrogen balance typically occur

84