2538 PART 10 Disorders of the Gastrointestinal System

TABLE 334-2 Body Composition, Laboratories, and Other Studies

TEST NOTES

Body Composition Studies

Anthropometrics Skinfolds and circumferences require training for reliability. Typical coefficient of variation is ≥10%.

Bioelectrical impedance Based upon differential resistance of body tissues. Equipment easily portable. Good measure of body water. Requires

population-specific validation of regression equations.

Water displacement Impractical for most clinical settings. Weighed in water tank. Historic reference measure.

Whole-body counting and isotope

dilution techniques

Research methodologies. Naturally occurring 40K isotope to measure body cell mass by whole-body counting. Total-body

water measurement by dilution volume of tritium, deuterium, or 18O-labeled water.

Air plethysmography Subject sits inside moderately sized BodPod chamber. Validated against water displacement and impedance.

Dual energy x-ray absorptiometry

(DEXA)

Often used for bone density but can be used for soft tissue measurements with appropriate software. Can compare truncal

and appendicular components. Modest x-ray exposure.

Imaging with computed tomography

(CT) or magnetic resonance imaging

(MRI)

State of the art research methods for visualizing body tissue compartments. Can quantify visceral fat. Costly, and CT entails

x-ray exposure.

Laboratories and Other Studies

Albumin Lacks sensitivity and specificity for malnutrition. Potent risk indicator for morbidity and mortality. Proxy measure for underlying

injury, disease, or inflammation. Half-life is 14–20 days. Also consider liver disease, nephrotic syndrome, and protein-wasting

enteropathy.

Prealbumin Sensitive to short-term changes in inflammation and protein nutrition with half-life of 2–3 days. Otherwise suffers the same

limitations of albumin with limited sensitivity and specificity for malnutrition. Levels may be decreased in liver failure and

increased in renal failure.

Transferrin Acute-phase reactant also altered by perturbation in iron status. Half-life is 8–10 days. Lacks sensitivity and specificity for

malnutrition.

Retinol-binding protein Responds to very-short-term changes in nutritional status, but utility is also limited by response to stress and inflammation.

Half-life is 12 h. Also affected by vitamin A deficiency and renal disease.

C-reactive protein C-reactive protein is a positive acute-phase reactant. It is generally elevated if an active inflammatory process is manifest.

Cholesterol Low cholesterol (<160 mg/dL) is often observed in malnourished persons with serious underlying disease. It is unrelated to

dietary intake in many clinical settings. Increased complications and mortality are observed. It appears that low cholesterol is

again a nonspecific feature of poor health status that reflects cytokine-mediated inflammatory condition. Vegans and patients

with hyperthyroidism may also exhibit low cholesterol.

Carotene Nonspecific indicator of malabsorption and poor nutritional intake.

Cytokines Research is exploring prognostic use of cytokine measurements as indicators of inflammatory status.

Electrolytes, blood urea nitrogen

(BUN), creatinine, and glucose

Monitor for abnormalities consistent with under- or overhydration status and purging (contraction alkalosis). BUN may also be

low in the setting of markedly reduced body cell mass. BUN and creatinine are elevated in renal failure. Hyperglycemia may

be nonspecific indicator of inflammatory response.

Complete blood count with differential Screen for nutritional anemias (iron, B12, and folate), lymphopenia (malnutrition), and thrombocytopenia (vitamin C and folate).

Leukocytosis may be observed with inflammatory response.

Total lymphocyte count Relative lymphopenia (total lymphocyte count <1200/μL) is a nonspecific marker for malnutrition.

Helper/suppressor T-cell ratio Ratio may be reduced in severely undernourished patients. Not specific for nutritional status.

Nitrogen balance 24-h urine can be analyzed for urine urea nitrogen (UUN) to determine nitrogen balance and give indication of degree of

catabolism and adequacy of protein replacement. Requires accurate urine collection and normal renal function. Nitrogen

balance = (protein/6.25) − (UUN + 4). Generally negative in the setting of acute severe inflammatory response.

Urine 3-methylhistidine Indicator of muscle catabolism and protein sufficiency. Released upon breakdown of myofibrillar protein and excreted without

reutilization. Urine measurement requires a meat-free diet for 3 days prior to collection.

Creatinine height index (CHI) CHI = (24-h urinary creatinine excretion/ideal urinary creatinine for gender and height) × 100. Indicator of muscle depletion.

Requires accurate urine collection and normal renal function.

Prothrombin time/international

normalized ratio (INR)

Nonspecific indicator of vitamin K status. Prolonged in liver failure.

Specific micronutrients When suspected, a variety of specific micronutrient levels may be measured: thiamine, riboflavin, niacin, folate, pyridoxine,

vitamins A, C, D, E, B12, zinc, iron, selenium, carnitine, and homocysteine—indicator of B12, folate, and pyridoxine status.

Skin testing—recall antigens Delayed hypersensitivity testing. While malnourished patients are often anergic, this is not specific for nutritional status.

Electrocardiogram Severely malnourished patients with reduced body cell mass may exhibit low voltage and prolonged QT interval. These

findings are not specific for malnutrition.

Video fluoroscopy Helpful to evaluate suspected swallowing disorders.

Endoscopic and x-ray studies of

gastrointestinal tract

Useful to evaluate impaired function, motility, and obstruction.

Fat absorption 72-h fecal fat can be used to quantitate degree of malabsorption.

Schilling test Identify the cause for impaired vitamin B12 absorption.

Indirect calorimetry Metabolic cart can be used to determine resting energy expenditure (REE) for accurate estimation of energy needs.

Elevated REE is a sign of systemic inflammatory response.

Source: Reproduced with permission from GL Jensen: Nutritional Syndromes. In: D Korenstein (Ed). ACP Smart Medicine [publisher archive]. Philadelphia (PA): American

College of Physicians, 2013.

2539Enteral and Parenteral Nutrition CHAPTER 335

hypersensitivity testing may be measured to demonstrate improvements with nutritional repletion, though it must be appreciated that

these are multivariable outcomes for which improved nutritional status

is but one variable.

■ FURTHER READING

Cederholm T et al: ESPEN guidelines on definitions and terminology

of clinical nutrition. Clin Nutr 36:49, 2017.

Detsky AS et al: What is Subjective Global Assessment of nutritional

status? J Parenter Enteral Nutr 11:8, 1987.

Guerra RS et al: Usefulness of six diagnostic and screening measures

for undernutrition in predicting length of hospital stay: A comparative analysis. J Acad Nutr Diet 115:927, 2015.

Jensen GL: Inflammation as the key interface of the medical and nutrition universes: A provocative examination of the future of clinical

nutrition and medicine. J Parenter Enteral Nutr 30:453, 2006.

Jensen GL: Malnutrition and inflammation—“Burning down the

house”: Inflammation as an adaptive physiologic response versus

self-destruction? J Parenter Enteral Nutr 39:56, 2015.

Jensen GL et al: Adult starvation and disease-related malnutrition:

A proposal for etiology-based diagnosis in the clinical practice setting

from the International Consensus Guideline Committee. J Parenter

Enteral Nutr 34:156, 2010.

Jensen GL et al: Adult nutrition assessment tutorial. J Parenter Enteral

Nutr 36:267, 2012.

Jensen GL et al: GLIM Criteria for the diagnosis of malnutrition:

A consensus report from the global clinical nutrition community.

J Parenter Enteral Nutr 43:32, 2019.

Keller H et al: Global Leadership Initiative on Malnutrition (GLIM):

Guidance on validation of the operational criteria for the diagnosis

of protein-energy malnutrition in adults. J Parenter Enteral Nutr

44:992, 2020.

White JV et al: Consensus statement: Academy of Nutrition and

Dietetics and American Society for Parenteral and Enteral Nutrition.

Characteristics recommended for the identification and documentation of adult malnutrition (under-nutrition). J Parenter Enteral Nutr

36:275, 2012.

335 Enteral and Parenteral

Nutrition

L. John Hoffer, Bruce R. Bistrian,

David F. Driscoll

There are three kinds of specialized nutritional support (SNS):

(1) optimized voluntary nutritional support, which is indicated when

a patient’s barriers to adequate nutrition can be overcome by special

attention to the details of how their food is constituted, prepared, and

served and its consumption monitored; (2) forced enteral nutrition

(EN), in which a liquid nutrient formula is delivered through a tube

placed in the stomach or small intestine; and (3) parenteral nutrition

(PN), in which a nutritionally complete mixture of crystalline amino

acids, glucose, lipid emulsions, minerals, electrolytes, and micronutrients is infused directly into the bloodstream.

When does a hospitalized patient need SNS? When SNS is indicated,

how should it be provided? This chapter summarizes the physiologic

principles that guide the correct use of SNS and offers practical information about the diagnosis and management of nutritional disorders

in adult hospitalized patients.

The management of in-hospital nutritional disorders follows three

steps: (1) screening and diagnosis; (2) determination of the severity and urgency of treating a diagnosed nutritional disorder in its

overall clinical context; and (3) selection of the modality of SNS, its

composition, and the details of providing it. To follow these steps

properly, physicians require a general understanding of nutritional

physiology, nutrient requirements, and the pathophysiology and diagnosis of the nutritional disorders, and familiarity with the indications,

advantages, risks, and administration of the different kinds of SNS.

Because most physicians are incompletely trained in clinical nutrition,

they must collaborate with clinical dietitians and specialized pharmacists in this process.

■ NUTRITIONAL PHYSIOLOGY

(See Chaps. 332-334)

Energy Total daily energy expenditure (TEE) of a healthy sedentary

adult is ~36 kcal/kg. Resting energy expenditure (REE), which accounts

for ~75% of TEE, may be measured by indirect calorimetry or estimated using a variety of predictive equations that input weight, height,

age, sex, and sometimes, disease-related factors. Fever and some forms

of critical illness increase REE, whereas prolonged semi-starvation

induces an adaptive reduction in REE and voluntary physical activity.

Patients’ TEE identifies the amount of dietary energy they must consume and metabolize to maintain their existing store of body fat (and

protein). The amount of energy a patient requires may be less than TEE

(in obesity therapy or, temporarily, during periods of energy intolerance) or greater than TEE (during recovery from starvation disease).

Protein and Amino Acids Dietary protein must be consumed

throughout life because endogenous protein turnover entails a minimum obligatory rate of amino acid catabolism. Amino acid catabolism

increases and decreases in response to changes in protein intake,

but it cannot fall below a certain minimum rate that determines an

individual’s minimum dietary protein requirement. The average daily

minimum protein requirement of a healthy adult is 0.65 g/kg; the “safe”

or “recommended” intake is 0.80 g/kg. The average protein consumption in wealthy societies is approximately twice the average minimum

requirement.

Many diseases (or their treatments) increase the protein requirement, by (1) increasing amino acid loss from the body (as in malabsorption and protein loss via wound exudates, fistulas, or inflammatory

diarrhea), removing amino acids from the circulation (renal replacement therapy), or (2) increasing muscle protein catabolism, as occurs

as a side effect of high-dose glucocorticoid therapy and especially

as part of the metabolic response to systemic inflammation. Highly

protein-catabolic patients may excrete 15 g N (nitrogen)/d or more in

their urine in the absence of dietary protein provision—this is more

than three times faster than during simple fasting. Since 1 g N lost

from the body reflects the loss of 6.25 g formed protein, 15 g N loss/d

indicates the loss of 15 × 6.25 = 94 g protein/d; since the body’s metabolically active tissue mass (its body cell mass, 80% of which is skeletal

muscle) is ~20% protein, 94 g protein loss/d indicates the loss from the

body of ~470 g (1 lb) of muscle mass per day! Sufficiently generous

protein provision can reduce this kind of muscle atrophy. The extent

to which protein-catabolic illness increases the protein requirement is

debated, but the most frequent current recommendation for critically

ill patients is 1.5 g protein/kg normal body weight per day—close to the

habitual protein intake of healthy people in wealthy societies.

Protein-Energy Interactions Energy deficiency and systemic

inflammation increase the dietary protein requirement. Systemic

inflammation reduces, but does not prevent, the beneficial effect of

increased protein provision during energy deficiency, so long as there

is a minimum supply of energy, such as 50% of TEE. Energy provision

>50–70% TEE has little further protein-sparing effect in systemic

inflammation, and the additional amounts of glucose and fluid volume

required to deliver it can have adverse effects.

Permissive Underfeeding and Hypocaloric Nutrition These

terms have different meanings, and they should not be conflated or

confused. Permissive underfeeding is the deliberate underprovision

of all nutrients, including protein, whereas hypocaloric nutrition is

energy provision deliberately set less than TEE with a compensatory

increase in protein provision.

2540 PART 10 Disorders of the Gastrointestinal System

Micronutrients Minimum amounts of the nine water-soluble

vitamins (the B vitamins and vitamin C), four fat-soluble vitamins

(A, D, E, and K), eight minerals (calcium, phosphorus, potassium,

sodium, chloride, magnesium, zinc, and iron), essential fatty acids,

and several essential trace elements are required to avoid deficiency

diseases. Overt deficiencies of potassium, sodium, magnesium, and

phosphorus occur so frequently in hospitalized patients that it is standard practice to monitor for and correct them. Certain drugs induce

renal potassium, magnesium, or zinc losses that necessitate appropriate

increases in their provision. Gastrointestinal losses from nasogastric

drainage tubes or intestinal losses from fistulas or diarrhea incur losses

of potassium, sodium, calcium, magnesium, and zinc that increase

their daily requirement.

Less studied, but common, are subclinical deficiencies of zinc, vitamin C, vitamin D, and possibly other micronutrients. Physicians often

assume that consumption of a regular hospital diet protects patients

from these deficiencies. This assumption is not warranted when the

patient’s nutritional status was deficient when they were admitted to

hospital and remains so during their hospital stay.

■ MACRONUTRIENT MALNUTRITION SYNDROMES

The decision to embark on SNS must be justified by a well-formulated

nutritional diagnosis and clearly defined therapeutic goals. This chapter focuses on the diagnosis, treatment, and prevention of in-hospital

starvation-related malnutrition (SRM) and two related conditions:

chronic disease–related malnutrition (CDM) and acute disease–related

(or injury-induced) malnutrition (ADM). As explained in Chap. 334,

SRM results solely from prolonged semi-starvation. CDM is usefully

understood as SRM (i.e., simple starvation) that is complicated by

moderately severe systemic inflammation. SRM and CDM are anatomically (phenotypically) similar but etiologically and metabolically distinct variations of starvation disease. ADM refers to an injury-induced

metabolic condition that creates a high risk of severe body protein deficiency, rather than to an already-existing anatomic starvation disease.

Starvation-Related Malnutrition The pathologic features that

define SRM—and distinguish it from the semi-starvation that precedes

it—emerge when the body cell mass has been depleted enough to

impair specific physiologic functions. Other terms for SRM are “starvation-induced protein-energy malnutrition,” “starvation disease,” and

“hunger disease.”

The body normally adapts to starvation by reducing REE and

net protein catabolism, partly by means of hormone- and nervous

system–regulated changes in cellular metabolism and partly by reducing its muscle mass. These adaptations allow prolonged survival, but

survival comes at a cost that includes muscle atrophy (including of the

cardiac and respiratory muscles), skin thinning, lethargy, a tendency

to hypothermia, and functional disability. The cardinal anatomic

diagnostic features of SRM—generalized muscle atrophy and subcutaneous adipose tissue depletion—are easily identified by simple physical

examination.

SRM always manifests as weight loss, but weight loss alone may

not reveal its full severity. Semistarvation increases the extracellular

fluid (ECF) volume (and body weight), sometimes seriously enough to

cause edema (“starvation edema”). In adults with initially normal body

composition, starvation-induced weight loss tracks the loss of body

cell mass (since weight change due to reductions in adipose tissue and

increases in ECF volume tend to cancel one another out). A 25% reduction in body weight significantly compromises physiologic function; a

50% reduction places otherwise uncompromised young adults on the

cusp of thermodynamic survival; older patients with comorbidities are

at even greater risk. People with SRM feel unwell, lack strength, are

frail, and are at risk of hypothermia.

The main cause of SRM worldwide is involuntary food deprivation;

its causes in hospitalized patients are many. They include inadvertent

or physician-ordered food deprivation; psychologic depression or

distress; anorexia nervosa; poorly controlled pain or nausea; badly

presented unappealing food; communication barriers; physical or sensory disability; dysphagia and other mechanical difficulties ingesting

food; partial obstruction of the esophagus, stomach, or intestinal tract;

thrush; intestinal angina; and most commonly, combinations of these

causes.

Chronic Disease–Related Malnutrition and Cachexia These

terms refer to SRM complicated by chronic systemic inflammation.

CDM is prevalent among patients with chronic infection, inflammatory autoimmune disease, chronic severe hepatic, renal, cardiac, and

pulmonary disease, and neoplastic diseases that induce a systemic

inflammatory response or cause tissue injury. CDM causes and is

worsened by anorexia—a strong disinclination to eat even when there

is no physical barrier to it—and is characterized by an increased rate

of muscle protein catabolism, muscle atrophy, weakness, fatigue, and a

subverted adaption to starvation, all of which contribute to a vicious

cycle of worsening disease. Fortunately, the nutritional deficit on the

input side of this equation (anorexia-driven inadequate food consumption) is often a stronger driver of the patient’s CDM than increased

nutrient loss on the output side (increased amino acid catabolism and,

sometimes, increased energy expenditure). This makes CDM amenable

to a well-organized nutritional intervention while effective treatment

of the primary disease is implemented. The challenge becomes more

daunting when there is no effective therapy for the primary disease.

Cachexia is an older term that refers to a disease-induced metabolic

syndrome characterized by moderate systemic inflammation, unrelenting and severe generalized muscle atrophy, and the symptoms associated with them; it is, therefore, approximately synonymous with CDM.

Anyone with cachexia has CDM, but in the view of some clinicians,

CDM that is milder and less sustained does not qualify for the term.

Acute Disease–Related Malnutrition Other terms for ADM are

“injury-induced malnutrition” and “protein-catabolic critical illness.”

The metabolic-inflammatory response to severe tissue injury and sepsis mobilizes muscle amino acids and leads to rapid and severe generalized muscle atrophy and variable increases in REE under conditions in

which voluntary food intake is almost always impossible. SRM or CDM

may or may not be present at the onset of their critical illness, but muscle atrophy will rapidly develop or worsen unless the inciting medical

or surgical disease is rapidly and effectively treated and SNS provided.

The rate of loss of body cell mass in ADM can be three to five times

greater than in simple starvation. Death from simple starvation of nonobese adults occurs within ~8 weeks; death due to untreated starvation

of patients with sustained ADM will occur correspondingly sooner.

■ NUTRITIONAL DIAGNOSIS

The cardinal anatomic features of starvation disease (SRM or CDM)

are generalized muscle atrophy and diminished body fat. A routine

physical examination will reveal these features, but what should be an

easy diagnosis is often overlooked. This section explains the details and

pitfalls of diagnosing SRM and CDM.

Muscle Mass Generalized muscle atrophy is easy to identify, and its

severity is determinable almost at a glance. Serum creatinine adjusted

for renal function or urinary excretion, adjusted for height and sex,

may also confirm severe muscle atrophy. A problem with diagnosing

SRM and CDM is that muscle atrophy has many causes. They include

(1) old age–related muscle atrophy (sarcopenia); (2) disuse muscle

atrophy; (3) high-dose glucocorticoid therapy and certain endocrine

diseases (uncontrolled diabetes mellitus, adrenocortical insufficiency,

hyperthyroidism, androgen deficiency, hypopituitarism); and (4) primary muscle or neuromuscular diseases. The guiding clinical principle is that SRM and CDM are extremely common causes of and

contributors to muscle atrophy. Whenever generalized muscle atrophy

is observed, its potential causes should be evaluated and the treatable

ones addressed. Old age is irreversible, but adequate protein and energy

provision to starving patients, combined with physical rehabilitation

for immobile patients, can be lifesaving.

Generalized muscle atrophy of any cause is especially dangerous

in ADM, because patients suffering from ADM and muscle atrophy

are closer to the cliff edge of lethal depletion of their body cell mass.

In addition, a diminished muscle mass is less able to release adequate

2541Enteral and Parenteral Nutrition CHAPTER 335

amounts of amino acids into the circulation for protein synthesis at

sites of tissue injury and healing and to the central protein pool to

regulate the immunoinflammatory response.

Subcutaneous Adipose Tissue Severe adipose tissue depletion

indicates starvation disease, but it need not be present to make the

diagnosis. The current obesity epidemic has created a population of

obese patients with SRM or CDM in whom muscle atrophy has outpaced fat loss. A conscientious physical examination easily identifies

these patients’ atrophic muscles despite their residual subcutaneous fat.

ECF Volume The ECF volume normally represents ~20% of body

weight. SRM moderately increases ECF volume. Patients with CDM

have additional edema-promoting conditions, especially hypoalbuminemia. Unless the effect of ECF is accounted for, its increased volume may conceal the severity of muscle atrophy in patients with SRM

and CDM.

Body Mass Index Body mass index (BMI) is defined as body

weight (kg) divided by the square of height (m2

). BMI normally ranges

from 20 to 25 kg/m2

; values <19–20 usually indicate reduced muscle

and fat mass. BMI <15 indicates severe starvation disease; BMI <13

is usually thermodynamically incompatible with life, especially in

older patients with comorbidities. Some guidelines and clinical trial

enrollment criteria define “malnutrition”—in this context, a synonym

for starvation disease—as a BMI <16 or 17. Using these criteria alone

can lead to serious error. A BMI <17 certainly indicates starvation

disease—the body architecture associated with such a BMI can only be

created by jettisoning a large fraction of the body cell mass and adipose

tissue store. But a BMI >17 does not rule out starvation disease. Many

patients with starvation disease have a normal or above-normal BMI

despite their muscle atrophy because of residual obesity or an expanded

ECF volume.

Visual BMI After some practice and verification, clinicians can

accurately predict the BMI of nonobese, nonedematous patients by

attentively examining their muscle groups. Once acquired, this skill

enables them to interpolate the severity of starvation disease in obese

or edematous patients—in whom measured BMI is unreliable—by

evaluating their muscles while intuitively discounting their subcutaneous fat and edema. Visual BMI may also be used to estimate a patient’s

normalized dry body weight (i.e., weight adjusted for obesity, edema,

or ascites). For example, the normalized dry body weight of a 1.75-m

adult with a visual BMI of 17 is 1.752

 × 17 = 52 kg. Since protein and

energy targets are based on the patient’s body normalized weight, this

calculation is useful when body weight is unreliable or difficult to

measure.

Laboratory and Technical Assessment Clinical laboratory

measurements have three main purposes in the evaluation and management of starvation disease.

MUSCLE MASS Bedside ultrasound is a potentially valuable technique

for quantifying muscle mass at specific body sites, but it need not, nor

should it, replace the comprehensive evaluation provided by the eyes,

hands, and discerning mind of a bedside examiner.

SYSTEMIC INFLAMMATION The absence or presence of systemic

inflammation distinguishes SRM from CDM. The most useful laboratory indicators of systemic inflammation are a reduced serum albumin

concentration and increased serum C-reactive protein concentration.

Systemic inflammation increases the permeability of capillary walls to

large molecules; the resulting osmotic shift increases the ECF volume.

Intravascular albumin redistributes into this larger volume, decreasing

the serum albumin concentration (increased albumin catabolism also

contributes). Dietary protein deficiency and muscle atrophy combine

to perpetuate inflammation-induced hypoalbuminemia, because the

amino acids used for hepatic albumin synthesis are derived from the

diet and endogenous muscle protein.

Hypoalbuminemia and reduced serum prealbumin concentrations are often claimed to diagnose “malnutrition.” This is incorrect.

Serum albumin and prealbumin are negative acute-phase reactants

that indicate systemic inflammation. Systemic inflammation induces

anorexia and increases muscle catabolism, increasing the risk of

CDM, but the disease itself may or not exist at the time and may never

develop. The serum concentrations of acute-phase reactants will not

improve while systemic inflammation persists, even with prolonged

optimal nutritional therapy.

PROTEIN-CATABOLIC INTENSITY The defining feature of proteincatabolic disease (which occurs in a moderate form in CDM and

severely in ADM) is increased net muscle amino acid catabolism. Conditions that substantially increase body protein loss can be identified

by measuring body N loss. Most N leaves the body in the urine (almost

all of it in urea, ammonium, and creatinine). Total N is not usually

measured in hospital laboratories, but the analysis of urinary urea N

(which normally accounts for ~85% of urinary N) is routinely available. A recent, validated formula estimates daily total N loss as follows:

N loss (g) = g N in urinary urea/0.85 + 2.

Net muscle protein catabolism follows approximately first-order

kinetics, such that the rate of N loss from muscle is proportional to

the existing amount of N available to be lost. Muscle-atrophic, proteincatabolic patients lose less body N per day than equivalently catabolic

patients whose muscle mass is normal, but they are nevertheless at

greater risk of succumbing to their critical illness. The interpretation of

a patient’s rate of N loss should include an evaluation of their existing

muscle mass.

Instrumental Nutritional Assessment Many nutritional assessment instruments claim to identify “malnutrition” by enumerating and

summing a list of risk factors, laboratory results, and physical findings.

These tools are often hindered by ambiguity about the definition of

malnutrition and by failure to distinguish between screening and

diagnosis. Diagnosis is the process of identifying a known pathologic

entity—SRM or CDM, for example—by considering the patient’s

medical history, pertinent findings on physical examination, and laboratory or imaging reports. Diagnosis also involves an estimation of the

probability that the diagnosis is correct and a judgment of its severity.

By contrast, screening is the application of a simple test that identifies

people at sufficiently high risk of a certain disease to warrant definitive

procedures to establish the diagnosis or rule it out or that identifies

people at sufficiently high risk of developing the disease to warrant

specific preventive interventions. Screening tools and risk predictors

are useful, but it is a mistake to confuse them with clinical diagnosis.

■ SPECIALIZED NUTRITIONAL SUPPORT

Optimized Voluntary Nutritional Support When feasible, this

is the approach of choice because it engages and empowers the patient,

encourages mobilization and reconditioning, is consistent with the

objectives of patient-centered medicine, and is risk-free. Its disadvantage is that it is time-consuming and labor-intensive, and it demands

interest in and attention to the specific needs of individual patients.

Enteral Nutrition This is nutrition provided through a feeding

tube placed through the nose into the stomach or beyond it into the

duodenum, by insertion of a tube through the abdominal wall into the

stomach or beyond it into the jejunum, or by an open surgical approach

to access the stomach or small intestine. EN is the treatment of choice

when optimized voluntary nutritional support is impossible or has

failed. It is relatively simple, safe, and inexpensive and maintains the

digestive, absorptive, and immunologic barrier functions of the gastrointestinal tract. EN is appropriate when optimized voluntary nutrition

is not feasible or has failed and the patient’s gastrointestinal tract is

functioning and can be accessed.

EN Products The most common forms of EN used are commercially manufactured formulas with defined compositions.

STANDARD POLYMERIC FORMULAS These are the most widely used

sources of EN. They are available in a wide variety of formats that

generally meet the nutritional requirements of a normal, healthy person. Carbohydrates provide most of the energy. The proteins in them

(casein, whey, or soy) are intact and require normal pancreatic enzyme

2542 PART 10 Disorders of the Gastrointestinal System

function for digestion and absorption. They are isotonic or nearly so

and provide 1000–2000 kcal and 50–70 g protein/L.

POLYMERIC FORMULAS WITH FIBER The addition of dietary fiber to

formulas sometimes improves bowel function and feeding tolerance.

Fermentable (soluble) fibers such as pectin and guar are metabolized

by colonic bacteria, yielding short-chain fatty acids that fuel colonocytes. Nonfermentable (insoluble) fibers increase fecal bulk, improve

peristalsis, and may improve diarrhea.

ELEMENTAL AND SEMI-ELEMENTAL FORMULAS The macronutrients

in these formulas are partially or completely hydrolyzed. They are

primarily designed for patients with known maldigestion and malabsorption, but they are sometimes used empirically for patients who

have had prolonged bowel rest or are critically ill without strong evidence of their superiority, or when a patient is intolerant of a standard

polymeric formula.

IMMUNE-ENHANCING FORMULAS In addition to providing macronutrients and conventional amounts of micronutrients, these EN products

contain large amounts of certain nutrients designed to favorably modulate the immune response: arginine and n-3 fatty acids especially, but

also various combinations of glutamine, nucleotides, and antioxidants.

PROTEIN-ENRICHED FORMULAS Most EN formulas provide calories and protein in a ratio appropriate for a healthy person, whereas

protein-enriched formulas provide ~90 g protein and 1000 kcal/L.

Originally marketed to meet the increased protein requirement of

weight-reducing obese patients, these products are increasingly used

to provide protein-catabolic patients with a more generous amount

of protein without energy overfeeding. EN can be further protein-enriched by adding flushes of water-soluble powdered protein

supplements.

OTHER FORMULAS Various disease-specific EN products are available

for patients with diabetes and hepatic, renal, or pulmonary disease.

Their use can improve some metabolic endpoints, but there is no definitive evidence that they improve clinical outcomes.

Parenteral Nutrition PN delivers a complete nutritional regimen directly into the bloodstream in the form of crystalline amino

acids, glucose, triglyceride emulsions, minerals (calcium, phosphate,

magnesium, and zinc), electrolytes, and micronutrients. Because of

its high osmolarity (>1200 mOsm/L) and often large volume, PN is

infused into a central vein in adults. Ready-to-use PN admixtures

typically containing 4–7% hydrated amino acids and 20–25% glucose

(with or without electrolytes) are available in two-chamber (amino

acids and glucose) or three-chamber (amino acids, glucose, and lipid)

bags that are intermixed with vitamins, trace minerals, and additional

electrolytes then added just prior to infusion. Although convenient

and cost-effective, these products have fixed nutrient compositions

and are dosed according to the volume required to meet a patient’s

energy requirement but not necessarily their protein requirement. In

some situations—especially ADM—a more sophisticated approach is

justified that uses a computer-controlled sterile compounder to create

combinations of amino acids and glucose that meet the precise protein

and energy requirements of individual patients.

Amino Acids PN amino acid admixtures vary, but all of them provide appropriate amounts of the essential amino acids and nonessential

amino acid N. The hydrated state of the mixed free amino acids in PN

solutions reduces their energy density from 4.0 (in formed protein) to

3.3 kcal/g, and it reduces the amount of protein substrate they provide

by 17%. For example, 100 g of free mixed amino acids provides 83 g

protein substrate and 330 kcal.

Carbohydrate and Lipids The glucose in PN is dextrose monohydrate; its hydrated state reduces its energy density from 4.0 (in

formed carbohydrate) to 3.4 kcal/g. Lipid emulsions provide energy

(~10 kcal/g) and the essential n-6 and n-3 fatty acids. Traditional lipid

emulsions are based solely on soybean oil, but they are giving way to

mixed emulsions that include medium-chain triglycerides, n-9 monounsaturated fatty acids, and n-3 fatty acids. Emulsions of pure soybean

oil, a mixture of 80% olive oil and 20% soybean oil, and a mixture of

30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and

15% fish oil are available in the United States. (A 10% fish oil emulsion

is approved for intestinal failure–associated liver disease in neonates

and infants.) Fish oil (either as a component of a mixed emulsion or

administered separately) may reduce the risk of infections and length

of stay in critically ill patients. The complex lipid emulsions are more

highly enriched in n-3 fatty acids and/or contain fewer n-6 polyunsaturated fatty acids than soybean lipid, which is more prone to lipid

peroxidation and could promote the formation of the proinflammatory

n-6 derivatives. Standard lipid infusion rates should not exceed 8 g/h,

equivalent to 175 g (1925 kcal)/d in a 70-kg patient; pure fish oil emulsions must be infused at lower rates.

Minerals, Micronutrients, and Trace Elements The default

concentrations of electrolytes, minerals, and micronutrients in PN

solutions are designed to meet the requirements of a healthy adult.

These starting doses must be adjusted to meet the frequently abnormal

and often-changing requirements of individual patients. Being unstable, multivitamin mixtures are injected into PN bags just prior to their

delivery to the medical unit. Parenteral water-soluble vitamin requirements are greater than standard oral requirements, because hospitalized patients often have vitamin deficiencies or increased requirements

and because intravenous administration of vitamins increases their loss

in the urine. Ascorbic acid degrades spontaneously in PN solutions,

even when light-protected. The amount of vitamin D in currently

available intravenous vitamin products is inadequate.

APPROACH TO THE PATIENT

Indications, Selection, and Provision of

Specialized Nutritional Support

Most hospitalized patients do not require SNS because they can eat

and will improve with appropriate management of their primary

disease. Others have a terminal disease whose downward course

will not be slowed by SNS. Patients who cannot eat enough hospital food and who have or are at high risk for SRM or CDM are

candidates for optimized voluntary nutrition support. When this

most desirable approach is inappropriate or impractical or has been

properly tried and failed, invasive SNS must be considered. The

decision to provide or withhold EN or PN is based on a synthesis

of four factors: (1) the determination that nutrient ingestion will

likely continue to be inadequate for many days; (2) the patient has

important muscle atrophy (of any cause) or fat depletion; (3) the

patient’s nutrient requirements are increased (as from inflammatory

diarrhea, enterocutaneous fistulas or exudates, or a pronounced

inflammatory protein-catabolic state); and (4) the reasoned judgment that SNS has a reasonable prospect of improving the patient’s

clinical outcome or quality of life.

EN THERAPY

EN is indicated when the patient is unable to eat enough food

and is unlikely to do so for a long time, their gastrointestinal tract

is functional and accessible, and optimized voluntary nutrition

is impossible or cannot meet their nutritional requirements. EN is

commonly used for patients with impaired consciousness, severe

dysphagia, or severe upper gastrointestinal tract dysfunction or

obstruction or who need mechanical ventilation. Equally commonly, situations arise in which a patient’s voluntary food intake is

seriously curtailed by anorexia, unappealing food, nausea, vomiting, pain, distress, delirium, depression, chewing difficulties, mild

dysphagia, physical and sensory disability (including dysgeusia), or

undiagnosed thrush. In these complicated and difficult situations,

the clinical diagnosis of SRM or CDM should tip the decision from

optimized voluntary nutrition toward EN or PN.

EN is contraindicated in patients with intestinal ischemia,

mechanical obstruction, peritonitis, and gastrointestinal hemorrhage. High-dose pressor therapy is another relative contraindication,

2543Enteral and Parenteral Nutrition CHAPTER 335

due to the rare but lethal risk of intestinal ischemic injury. Severe

coagulopathy, esophageal varices, absent gag reflex, hypotension,

paralytic ileus, pancreatitis, diarrhea, and nausea and vomiting are

not absolute contraindications, but they increase the risk of complications and make it less likely that EN will succeed in achieving its

nutritional goal.

Initiation, Progression, and Monitoring Nasogastric tube feeding

may proceed when the patient’s gastrointestinal function is adequate with respect to gastric contractility (e.g., nasogastric tube

output <1200 mL/d), intestinal contractility (absence of a known

or suspected intraabdominal pathologic process and presence of

a nondistended abdomen with detectable bowel sounds, although

the absence of bowel sounds is not, in itself, a contraindication),

and adequate colonic function (passage of stools and flatus). After

consent has been obtained and the appropriate feeding tube (usually a nasogastric tube for short-term feeding) has been placed and

its position verified, the head of the patient’s bed is raised to at least

30° and kept raised to reduce the risk of regurgitation. Clinical

dietitians ordinarily order the formula and adjust its rate of provision. When a standard polymeric formula is infused, it normally

commences at 50 mL/h and is advanced by 25 mL/h every 4–8 h

until the goal rate is attained. Elemental formulas are commenced

at a slower rate and progress more slowly. Intragastric bolus feeding

is an option (200–400 mL feeding solution infused over 15–60 min

at regular intervals with verification of residual gastric contents

every 4 h).

Complications and Their Management The most common complications of EN are aspiration of regurgitated or vomited formula,

diarrhea, fluid volume and electrolyte derangements, hyperglycemia, nausea, abdominal pain, constipation, and failure to achieve

the nutritional goal.

Aspiration Patients with delayed gastric emptying, impaired

gag reflex, and ineffective cough are at high risk of aspiration

pneumonia. Ventilator-associated pneumonia is mostly caused by

aspiration of microbial pathogens in the mouth and throat past

the cuffs of endotracheal or tracheostomy tubes, but tracheal suctioning induces coughing and gastric regurgitation. Measures to

prevent ventilator-associated pneumonia include elevation of the

head of the bed, mouth hygiene and gastrointestinal decontamination, nurse-directed algorithms for formula advancement, and

sometimes, postpyloric feeding. EN does not have to be suspended

for gastric residual volumes <300–400 mL in the absence of other

signs of gastrointestinal intolerance (nausea, vomiting, severe

abdominal pain, abdominal distention). Continuous EN is often

tolerated better than bolus feeding, and it is the only option during

jejunal feeding.

Diarrhea Diarrhea commonly occurs when the patient’s

bowel function is compromised by disease or drugs (most often,

broad-spectrum antibiotics). Once infectious and inflammatory

causes have been ruled out, EN-associated diarrhea may be controlled by using a fiber-containing formula or adding an antidiarrheal agent to it. H2

 blockers or proton pump inhibitors may help

reduce the net volume of fluid presented to the colon. Since luminal

nutrients have trophic effects on the intestinal mucosa, it is often

appropriate to persist with tube feeding despite moderate, tolerable

diarrhea, even if it necessitates supplemental parenteral fluid support. Except for patients with markedly impaired small-intestinal

absorptive function, there are no well-established indications for

elemental formulas, but they may be used empirically when diarrhea persists despite the use of fiber-enriched formulas and antidiarrheal agents.

Gastrointestinal Intolerance Abnormally high gastric residual

volumes, abdominal distention, pain, and nausea are distressing

for patients, increase the nursing workload, and delay the progression of EN. These problems can be avoided or minimized by

ensuring normal fluid and electrolyte balance, by preventing severe

hyperglycemia, and, when a patient experiences nausea, vomiting,

or abdominal distention, by the judicious use of antiemetic and

prokinetic drugs (and sometimes proton pump inhibitors) on a

regular—rather than as-needed—basis. Patients with gastroparesis

require postpyloric feeding.

Fluid Volume, Electrolyte, and Blood Glucose Abnormalities

EN’s essential purpose is to provide macronutrients at an appropriate rate. EN also provides standard amounts of fluid, electrolytes, minerals, and micronutrients. They are not designed to

manage abnormal fluid volume, electrolyte, and mineral requirements, which vary considerably among different patients and can

change rapidly. Blood glucose concentrations should be monitored

regularly, and additional measures—including intravenous fluid,

electrolyte, and insulin therapy—should be taken to maintain

homeostasis.

Failure to Reach the Nutritional Goal EN is frequently

delayed or interrupted by diagnostic tests and procedures (including dialysis), physical or occupational therapy, a clogged or pulled

out tube, and intolerance to EN. The result can be a long delay in

the progression of EN and ultimate failure to meet the patient’s

nutrient requirements.

EN in the Intensive Care Unit Most critically ill patients cannot

eat anything—they depend entirely on SNS. EN serves two purposes in this setting. The first is to meet the patient’s macronutrient

requirements, especially their often dramatically increased protein

requirement. The second purpose is to infuse nutrients into the

intestines at a rate that sustains normal intestinal barrier and immunologic functions in the face of a systemic inflammatory response

that threatens intestinal integrity and immune function. Current

guidelines recommend starting EN soon after a critically ill patient

has been fluid resuscitated and stabilized. Once EN is underway,

the rate of delivery is increased as tolerated until the patient’s nutritional goal is achieved. EN often falls far short of the protein provision target, even after a week or longer in the intensive care unit.

Newer, high-protein EN products and the addition of powdered

protein supplements can correct this protein shortfall.

PN THERAPY

PN is more resource-intensive, is potentially riskier, and requires

more expertise than EN. It is used when invasive SNS is indicated

and EN is impossible, inappropriate, or insufficient to meet the

patient’s nutritional needs. The risks of PN are those of inserting

and maintaining a central venous catheter (traumatic injury from

the insertion, serious infection, and venous thrombosis); allergy

to some of its components; glucose, electrolyte, magnesium, phosphate, and acid-base balance abnormalities; and the adverse effects

of the large intravenous fluid volumes. PN that is prolonged for

many weeks—especially when it delivers excess energy—may cause

or contribute to hepatic dysfunction.

Initiation, Progression, Monitoring, and Discontinuation When

indicated, PN should begin as soon as possible after the patient

has been hemodynamically resuscitated, glucose, electrolyte, and

acid-base homeostasis has been established, and they can tolerate

the fluid volume required to deliver it. The high osmolarity of adult

PN solutions and need for strict sterility require their infusion

through a dedicated port in a central venous catheter. Jugular or

femoral vein catheters should not be used because of the difficulty

maintaining a dry, sterile dressing over the insertion site. The initial

dose of glucose should not exceed 200 g/d to avoid hyperglycemia

(and—in susceptible patients with adapted SRM—the refeeding

syndrome). The full dose of amino acids can be administered from

the very first day—an option that is, unfortunately, unavailable

when premixed PN solutions are used.

Most non–critically ill patients (e.g., dry body weight 70 kg) do

not require >500 g glucose (1700 kcal)/d, and many, if not most,

patients with ADM do not require >350 g (1200 kcal)/d during the

intense phase of their disease. A glucose infusion rate of ~200 g/d

2544 PART 10 Disorders of the Gastrointestinal System

is physiologic and commonly does not have to be exceeded. When

it eventually becomes appropriate to set the energy goal equal to

TEE, it may be achieved by infusing a lipid emulsion. Even lower

glucose infusion rates (e.g., 100–200 g/d) are safe during deliberate

hypocaloric nutrition and may prevent or minimize hyperglycemia

in insulin-resistant patients.

We recommend hypocaloric nutrition (high in protein but limited in glucose, lipid, and fluid volume) for the first 2 weeks of SNS

in fat-sufficient or obese patients with ADM. Energy provision can

increase, if indicated, after the catabolic storm abates. Lipids are

commonly introduced after the first week of PN and can be used

to make up energy shortfalls. Serum triglyceride concentrations are

measured before commencing lipid infusions to detect preexisting

hypertriglyceridemia (>400 mg/dL)—a relative contraindication.

Lipids may be infused daily or two to three times weekly. Lipid

infusions are not necessary to prevent essential fatty acid deficiency

during hypocaloric nutrition of obese patients, because the mobilization of body fat during energy deficiency provides the body with

endogenous essential fatty acids.

Capillary blood glucose concentrations are monitored several

times daily, and subcutaneous regular insulin is added to the PN

admixture as required to maintain average serum glucose concentrations <140 mg/dL and >80 mg/dL. (Upper and lower limits of

180 and 100 mg/dL appear to be appropriate for critically ill patients

with diabetes mellitus.) The dose of regular insulin required on

a given day can be added to the following day’s PN solution. The

insulin dose increases roughly proportionately to the glucose dose.

Certain benchmarks are useful. Basal endogenous insulin secretion is ~30 units/d in normal people. When insulin is required

for nondiabetic, noncatabolic patients, 10 units of regular insulin

roughly cover 100 g infused glucose. Patients with non-insulindependent diabetes require ~20 units/100 g glucose. Noncatabolic

patients with insulin-dependent diabetes usually require approximately twice the at-home insulin dose, because parenteral glucose

stimulates insulin release more potently than oral carbohydrate and

because some insulin adheres to the infusion bag.

Biochemical Monitoring Serum urea, creatinine, electrolytes,

glucose, magnesium, phosphate, calcium, and albumin concentrations are measured prior to starting PN and followed daily for the

first few days, then twice weekly or as required. Serum triglycerides

and liver function tests (and often ferritin) are measured at baseline and after PN is underway to confirm that the lipid infusions

are well tolerated. N balance, calculated from 24-h urinary urea N

excretion, is useful at the outset for evaluating the severity of protein catabolism in patients with CDM or ADM, to identify patients

who require more generous amino acid provision, and during PN

to determine whether the patient’s N balance is improving with

therapy.

Discontinuation PN is tapered and discontinued when the

patient can be adequately nourished by the enteral route. The dose

of PN is gradually reduced as food intake increases. Once a patient

is tolerating one-half to two-thirds of their food requirement by the

enteral route and there is no mechanical or other barrier to further

increases in intake, PN should be terminated. The transition to

oral nutrition can be slow for patients with CDM. In this situation,

optimized voluntary nutrition, although labor-intensive, is much

preferred to replacing PN with invasive EN because it is safe, effective, fosters well-being, and prepares patients for discharge home.

The temptation to discontinue PN to stimulate a patient to eat more

food should, in general, be resisted. PN does not create anorexia,

nor does discontinuing it stimulate appetite. Too-early discontinuation of PN may delay a patient’s progression to full voluntary food

consumption by inducing anxiety and recreating starvation conditions. A patient is most successfully weaned from PN by optimizing

their voluntary nutrition (including food from home), providing

emotional support, encouraging physical activity, and being patient.

Some patients, stuck on the cusp of adequate oral nutrition, will

benefit from discharge to the security and pleasure of home life and

homemade food; these patients are identified by observing, asking,

and listening.

Drawbacks, Side Effects, and Complications Patients receiving

PN are at greater risk of bloodstream infections than other patients

with central venous catheters. Rigorously aseptic insertion technique, meticulous dressing care, one port dedicated solely to PN,

and careful glycemic control reduce this risk.

Hyperglycemia The most frequent metabolic complication

of PN is hyperglycemia in patients with insulin resistance due to

non-insulin-dependent diabetes mellitus, high-dose glucocorticoid therapy, or severe systemic inflammation; the problem is

exacerbated by excessively high rates of glucose provision. Glucose

concentrations are most easily kept at <140 mg/dL with the least

risk of hypoglycemia by infusing hypocaloric amounts of glucose

and, when necessary, meeting the patient’s energy requirement

with intravenous lipid. In ADM, the benefits of using the lowest

possible insulin dose—minimal hyperinsulinemia and a reduced

risk of hypoglycemia—almost always outweigh the doubtful goal of

rapidly matching energy provision to the energy expenditure rate of

patients whose existing fat store is normal.

Hypoglycemia Reactive hypoglycemia is uncommon but may

occur when high-glucose, non-insulin-containing PN is abruptly

discontinued. It is prevented by slowing the PN infusion rate to

50 mL/h for 1 or 2 h prior to discontinuing it (or replacing it with

10% glucose) or, when the oral route is available, providing a snack.

More often, hypoglycemia occurs when the intensity of the patient’s

metabolic stress (or their glucocorticoid dose) decreases without

an appropriate downward adjustment of the insulin dose. This

problem is avoided by frequent capillary glucose determinations

and careful attention to medication doses and the patient’s general

condition.

Artefactual Hyperglycemia and Hyperkalemia Blood samples must be meticulously collected from a dual-port central venous

catheter. Intermixing of the sample with even a tiny volume of PN

solution will falsely indicate hyperglycemia and hyperkalemia and

may trigger a treatment error. The sampling error is identified when

the patient’s apparent serum glucose (and potassium) concentrations abruptly increase without reason and the apparently very high

glucose concentration is out of keeping with concurrent capillary

glucose readings.

Volume Overload Hypertonic intravenous glucose triggers a

more intense insulin response than oral glucose that can increase

urinary sodium and water retention. In this setting, net fluid retention is likely when total fluid provision exceeds 2 L/d in patients not

experiencing large gastrointestinal losses. The problem of volume

overload can be minimized by using a compounder to prepare PN

solutions, infusing glucose at a rate that minimizes the need for

exogenous insulin therapy, and avoiding energy overfeeding.

Hypertriglyceridemia This complication occurs when the rate

of lipid infusion exceeds plasma triglyceride clearance capacity.

Sepsis, renal failure, diabetes mellitus, high-dose glucocorticoid

therapy, and multiple-organ failure reduce triglyceride clearance.

An impaired immune response, increased risk of acute pancreatitis,

and altered pulmonary hemodynamics are potential, but not well

documented, complications of PN-induced severe hypertriglyceridemia. Lipid infusion rates should not usually exceed ~50 g

(500 kcal)/d in ADM.

Liver Disease Mild elevations of serum liver enzyme concentrations can occur within 2–4 weeks of initiating PN, but in most

cases, they return to normal even when PN is continued. Clinically

important hepatic dysfunction, although common in children, is

uncommon in adults when energy overfeeding and resultant fatty

liver are avoided. Intrahepatic cholestasis occasionally occurs after

many weeks of continuous PN and is most often multifactorial in

2545Enteral and Parenteral Nutrition CHAPTER 335

origin. Cyclic PN—in which PN is infused for only 12 h of the day—

may prevent or reduce the severity of this complication.

PN in the Intensive Care Unit Current guidelines recommend

starting EN soon after a critically ill patient has been resuscitated,

stabilized, and enteral access established to an adequately functioning gastrointestinal tract. EN is then advanced over the following

days. If the energy goal has not been achieved after 7–10 days, PN

is recommended, especially if the patient’s protein-catabolic state

has not yet abated. Soy-based lipid emulsions should be avoided

during the first week of PN during critical illness; alternative lipid

emulsions may prove to be safe and beneficial.

SPECIAL CLINICAL SITUATIONS

Critical Illness–Nutrition Paradox High-quality evidence now

confirms what has long been indicated by the biologic evidence,

physiologic reasoning, formal observational studies, and objective

clinical observation, namely, that personalized nutritional interventions improve the clinical outcomes of starving, non–critically

ill patients. The case for SNS would appear to be even stronger in

ADM—with its rapid, severe muscle atrophy and maintained or

increased energy expenditure under conditions in which patients

are almost always unable to eat voluntarily—but well-designed clinical trials of nutritional interventions in critical illness have repeatedly failed to demonstrate that currently prescribed SNS regimens

improve the clinical outcomes of critically ill patients. The evidence

does indicate that, unlike in noncritical illness, energy provision

that is set at or near the rate of energy expenditure in fat-sufficient,

insulin-resistant critically ill patients does not improve their clinical

outcomes and may be deleterious to some of these patients. The

inability of currently prescribed SNS to improve outcomes in critical illness has several possible explanations: (1) severe prolonged

starvation is so harmful to all people, whether critically ill or not,

that ethical considerations preclude using deliberate starvation as

a treatment arm in a clinical trial; (2) critical illness is enormously

heterogeneous, and not every critically ill patient is or remains

severely protein-catabolic for long; (3) owing to more generous

admission criteria and thanks to the high quality of modern intensive care, many patients admitted to intensive care units improve

and are discharged within a handful of days, whereas others are

so mortally ill that their clinical outcome is virtually predetermined, and proof-of-concept clinical trials that enroll and report

the outcomes of such patients could fail to demonstrate a benefit

from SNS; and (4) in current practice, the EN-based SNS regimens

that are prescribed for most critically ill patients commonly fail to

deliver more than one-half the currently recommended amount of

protein. The low protein-to-energy ratio of most standard EN and

PN products makes it difficult to provide critically ill patients with

a sufficiently generous amount of protein or amino acids while

avoiding energy overfeeding. (The problem can be exacerbated by

use of the sedative drug propofol, which is infused in a solution of

10% lipid that commonly delivers ~500 kcal/d.) For these reasons,

together with other experts, we continue to recommend EN and

PN for critically ill patients with ADM, with the additional advice

to avoid energy overfeeding during the initial weeks (or as long as

systemic inflammation remains severe) by deliberately erring on

the side of hypocaloric nutrition while simultaneously providing

suitably generous protein or amino acids, as guided by physiologic

reasoning and a personalized evaluation of the anatomic and etiologic-metabolic condition of each patient.

Iron and PN Iron deficiency is common in hospitalized patients;

its usual causes are preexisting deficiency, inadequate in-hospital

dietary provision, macro- or microscopic gastrointestinal blood

loss, and repeated blood sampling. The diagnosis is often missed

because the anemia of systemic inflammation is much more common, and it increases serum concentrations of ferritin, a positive

acute-phase reactant. Iron is not routinely added to PN mixtures.

Iron dextran is incompatible with lipid emulsions, and although

it appears to be chemically compatible with aqueous solutions of

amino acids and glucose, there is realistic concern that interactions

between iron molecules and certain vitamins and amino acids

in PN solutions could catalyze the formation of free radicals that

degrade vitamins and exert subtle adverse systemic effects. In principle, all micronutrient deficiency states, including iron deficiency,

should be prevented and corrected. In-hospital iron deficiency

causes and prevents recovery from anemia, and subclinical iron

deficiency could contribute to cognitive and immune dysfunction.

Serum ferritin concentrations should be determined when PN

commences and remeasured at approximately 8-week intervals.

Iron deficiency is strongly suggested by an intermediate serum

ferritin concentration in the setting of systemic inflammation and

by decreasing mean red cell volumes (even within the low-normal range). Intravenous iron should be administered according

to standard guidelines. A termination order should be written to

prevent inadvertent iron overdosing. Parenteral iron therapy should

be avoided in ADM because a substantial rise in the serum iron

concentration could release free iron and increase susceptibility to

gram-negative (and possibly other microbial) infections, as well as

catalyze the formation of free radicals that increase the intensity of

the catabolic response to major tissue injury.

Zinc One liter of secretory diarrhea contains ~12 mg of zinc.

Patients with intestinal fistulas or high-volume chronic diarrhea

require this amount of zinc in addition to their daily requirement of

15 mg to avoid zinc deficiency. Zinc may be provided parenterally

or enterally. Because of its low bioavailability, 12 mg of parenteral

zinc is equivalent to 30 mg of oral zinc.

Old Age In addition to their other frailties, elderly people commonly suffer from age-related muscle atrophy (sarcopenia) compounded by disuse muscle atrophy. These factors place them at

high risk of the consequences of starvation disease and make them

candidates for early SNS.

Inactivity Physical activity and adequate nutrition are closely

interdependent. Reduced physical activity reduces appetite, and

physical rehabilitation and its associated emotional benefits restore

optimism and appetite. Full nutrient provision will maintain or

normalize many physiologic functions in bedridden patients, but

they will not increase muscle mass.

Renal Failure Protein provision should not be reduced in patients

with renal failure unless renal replacement therapy is unavailable.

Renal replacement therapy removes large amounts of amino acids,

vitamins, and trace elements from the circulation, so protein and

micronutrient provision should be increased to compensate for

these losses.

Liver Failure Patients with severe hepatic disease are relatively

intolerant to starvation and commonly have CDM when admitted

to hospital, so they are prime candidates for SNS. Their SNS should

be generous both in energy and protein, despite an increased risk of

hepatic encephalopathy. The risk of encephalopathy can be reduced

by meticulous attention to fluid balance, acid-base balance, and

electrolyte status and by spreading protein provision over the day

to accommodate the liver’s reduced capacity to clear amino acid–

derived ammonia.

Perioperative SNS Patients with SRM or CDM awaiting elective

major surgery benefit from 7–10 days of preoperative SNS. When

feasible and properly implemented, optimized voluntary nutrition

is greatly to be preferred, but when a patient has been admitted

to hospital in a semi-urgent condition, EN or PN will meet the

patient’s nutritional goal more quickly. Preoperative SNS improves

immunity and reduces postoperative complications, but it will not

increase serum albumin concentrations, and it should not be provided for >7–10 days with that goal in mind. More prolonged preoperative EN or PN may confer slight additional nutritional benefits,

but they are counterbalanced by their risks and the consequences

2546 PART 10 Disorders of the Gastrointestinal System

of prolonged hospitalization and delayed surgery. Surgery should

not be delayed for starving patients whose muscle mass is normal

or only mildly depleted and who are not experiencing systemic

inflammation since they tolerate even major uncomplicated surgery well. The urgency of surgery often precludes otherwise indicated preoperative SNS. Early postoperative PN is usually indicated

for these patients, for they are at increased risk of postoperative

complications and are unlikely to consume an adequate amount of

food voluntarily over the next many days. Patients with only mild

muscle atrophy, no systemic inflammation, and no postoperative

complications do not require postoperative PN unless (1) adequate

feeding by mouth has not been achieved by day 5–7 after surgery

or (2) there are indications that voluntary feeding will be further

delayed. Perioperative immune-enhancing EN reduces morbidity in

patients undergoing major elective gastrointestinal surgery.

Cancer SNS plays a crucial role in cancer therapy. Many malignant neoplasms (especially those that involve the gastrointestinal

tract or induce systemic inflammation) and their cytotoxic therapies create the conditions for starvation and commonly lead to SRM

or CDM. The prevention or treatment of these starvation diseases

will improve patients’ quality of life and their tolerance to anticancer therapy. EN and PN are generally not prescribed to patients with

advanced cancer for which there is no effective anticancer therapy

because the side effects and complications of invasive SNS are not

counterbalanced by an improved disease trajectory. In some cases,

the disease may be progressing but so slowly that the patient will die

of the complications of starvation disease long before they would

from the cancer. EN or PN is appropriate for these patients.

Advanced Dementia Optimized voluntary nutrition is the key

approach in this situation, and it can be used to deal with problems

such as disability and dysphagia in patients who get pleasure from

eating. There is no evidence that EN or PN improves quality or

length of life in patients who have advanced dementia and show

little or no interest in food, and the side effects and complications

of EN and PN are unpleasant and sometimes dangerous.

REFEEDING SYNDROME

The refeeding syndrome can occur in patients with adapted SRM

during the first week of nutritional repletion if carbohydrate and

sodium are introduced too rapidly. Carbohydrate provision stimulates insulin secretion, which, owing to its antinatriuretic effect,

expands the ECF volume, especially when excessive sodium is

provided. Refeeding edema can be minimized by severely limiting

sodium provision and increasing carbohydrate provision slowly.

Carbohydrate refeeding may stimulate enough intracellular glucose-6-phosphate and glycogen synthesis to seriously lower serum

phosphate concentrations. It also increases the downregulated metabolic rate of patients with adapted SRM and stimulates N retention, new cell synthesis, and cellular rehydration. Phosphorus,

potassium, and magnesium deficiencies occur and are dangerous

during refeeding; their serum concentrations should be measured

frequently, and appropriate supplements provided. Left heart failure

may occur in predisposed patients; it has three causes: (1) an abrupt

increase of intravascular volume due to the administration of fluids

and of glucose, which stimulates insulin-mediated renal sodium

retention; (2) increased cardiac demand on an atrophic left ventricle

created by an insulin-mediated increase of resting energy expenditure; and (3) myocardial deficiencies of potassium, phosphorus, or

magnesium. Cardiac arrhythmias may occur. Acute thiamine deficiency encephalopathy is a devastating preventable complication of

refeeding, even with simple glucose infusions.

■ FURTHER READING

Gomes F et al: ESPEN guidelines on nutritional support for polymorbid internal medicine patients. Clin Nutr 37:336, 2018.

Kondrup J: Nutrition risk screening in the ICU. Curr Opin Clin Nutr

Metab Care 22:159, 2019.

Lambell KJ et al: Nutrition therapy in critical illness: A review of the

literature for clinicians. Crit Care 24:35, 2020.

Schuetz P et al: Economic evaluation of individualized nutritional

support in medical inpatients: Secondary analysis of the EFFORT

trial. Clin Nutr 25:25, 2020.

Sharma K et al: Pathophysiology of critical illness and role of nutrition. Nutr Clin Pract 34:12, 2019.

Van Zanten ARH et al: Nutrition therapy and critical illness: Practical

guidance for the ICU, post-ICU, and long-term convalescence phases.

Crit Care 23:368, 2019.

Yeh DD et al: Advances in nutrition for the surgical patient. Curr Probl

Surg 56:343, 2019.

Section 3 Liver and Biliary Tract Disease

336

A diagnosis of liver disease usually can be made accurately by careful

elicitation of the patient’s history, physical examination, and application of a few laboratory tests. In some circumstances, radiologic examinations are helpful or, indeed, diagnostic. Liver biopsy is considered

the criterion standard in evaluation of liver disease but is now needed

less for diagnosis than for grading (activity) and staging (fibrosis) of

disease. Noninvasive means of assessing fibrosis stage have become

increasingly helpful and may allow for avoidance of biopsy in a proportion of patients. This chapter provides an introduction to diagnosis

and management of liver disease, briefly reviewing the structure and

function of the liver; the major clinical manifestations of liver disease;

and the use of clinical history, physical examination, laboratory tests,

imaging studies, and liver biopsy.

LIVER STRUCTURE AND FUNCTION

The liver is the largest organ of the body, weighing 1–1.5 kg and representing 1.5–2.5% of the lean body mass. The size and shape of the

liver vary and generally match the general body shape—long and lean

or squat and square. This organ is located in the right upper quadrant

of the abdomen under the right lower rib cage against the diaphragm

and projects for a variable extent into the left upper quadrant. It is held

in place by ligamentous attachments to the diaphragm, peritoneum,

great vessels, and upper gastrointestinal organs. The liver receives a

dual blood supply; ~20% of the blood flow is oxygen-rich blood from

the hepatic artery, and 80% is nutrient-rich blood from the portal vein

arising from the stomach, intestines, pancreas, and spleen.

The majority of cells in the liver are hepatocytes, which constitute

two-thirds of the organ’s mass. The remaining cell types are Kupffer

cells (members of the reticuloendothelial system), stellate (Ito or

fat-storing) cells, endothelial and blood vessel cells, bile ductular cells,

and cells of supporting structures. Viewed by light microscopy, the liver

appears to be organized in lobules, with portal areas at the periphery

and central veins in the center of each lobule. However, from a functional point of view, the liver is organized into acini, with both hepatic

arterial and portal venous blood entering the acinus from the portal

areas (zone 1) and then flowing through the sinusoids to the terminal

hepatic veins (zone 3); the intervening hepatocytes constitute zone 2.

The advantage of viewing the acinus as the physiologic unit of the liver

is that this perspective helps to explain the morphologic patterns and

zonality of many vascular and biliary diseases not explained by the

lobular arrangement.

Approach to the Patient

with Liver Disease

Marc G. Ghany, Jay H. Hoofnagle