Download STRATEGIES FOR ATTENUATING PROTEIN

Annu. Rev. Med.
1994.
45:459–80
ZIEGLER,
ATTENUATING
GATZEN
CATABOLISM
& WILMORE
Copyright © 1994 by Annual Reviews Inc. All rights reserved
STRATEGIES FOR ATTENUATING
PROTEIN-CATABOLIC RESPONSES
IN THE CRITICALLY ILL
Thomas R. Ziegler, M.D.
Department of Medicine, Brigham and Women’s Hospital and Joslin Diabetes Center,
Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215
Christopher Gatzen, FRCS
Department of Surgery, St. Mary’s Hospital, Praed Street, London W2 INY, England
Douglas W. Wilmore, M.D.
Department of Surgery and Laboratory for Surgical Metabolism and Nutrition, Brigham
and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115
KEY WORDS: nutrition, catabolic illness, growth factors, glutamine, muscle
ABSTRACT
Specialized enteral and parenteral nutrition are now a standard components of
care in critically ill patients. This adjunctive therapy corrects and prevents
nutrient deficiencies, attenuates the loss of body protein, and improves clinical
outcomes in malnourished patients. Several novel strategies designed to improve the metabolic and clinical effects of specialized nutrition are under
vigorous clinical investigation.
These new approaches include increased emphasis on enteral feeding to
maintain intestinal absorptive, immune, and barrier function; adminstration of
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conditionally essential amino acids (glutamine, arginine); use of specialized
lipid products and antioxidants; and administration of growth factors such as
human growth hormone. Randomized, controlled clinical trials will define the
clinical and metabolic efficacy and cost-effectiveness of these therapies in
specialized nutrition support.
INTRODUCTION
Loss of body protein occurs during catabolic states such as infection and
injury. Enhanced proteolysis may be due to increased rates of protein breakdown, reduced protein synthesis, or a combination of these two effects and is
generally directly related to the degree of catabolic stress and quantity of
nutrients in the diet. The mechanisms regulating erosion of body protein are
complex, but they undoubtedly involve counterregulatory hormones (e.g. cortisol and catecholamines) and proinflammatory cytokines (e.g. tumor necrosis
factor, or TNF, and interleukin-1). These signals interrelate with other mechanisms that favor net protein breakdown, including diminished nutrient intake,
acidosis, and inactivity.
Because body protein represents both structural and functional components
of the body, erosion of lean tissue is associated with diminished immune
function, increased infection rates, delayed tissue repair, decreased wound
healing, and diminished skeletal muscle function, which delays independence
and self care (1, 2). Malnutrition and net loss of body proteins therefore
contribute to increased morbidity and mortality, prolonged convalescence, and
higher hospital costs. Over the past several decades, specialized enteral and
parenteral nutrition have become routine in the clinical care of malnourished
and critically ill patients. Provision of adequate calories, protein, and other
essential nutrients (including vitamins and trace elements) is clearly beneficial
in many clinical situations when adequate food intake is precluded and/or
when nutrient losses are accelerated. Thus classical nutrient deficiencies in
intensive care unit (ICU) patients with current forms of specialized nutrition
are uncommon, and body protein loss is attenuated compared with responses
of comparable patients receiving limited or no dietary intake (3).
Recent information has highlighted the potential complications and clinical
limitations of adjunctive nutritional and metabolic support in attenuating body
protein loss and improving overall clinical outcomes (4–6). An increasing
number of therapeutic strategies are undergoing intensive clinical investigation
in an attempt to improve the efficacy of nutrient support in the ICU setting and
to enhance recovery and rehabilitation. This paper briefly reviews several of
these promising therapies, which include administration of somatic growth
factors, provision of tissue-specific or conditionally essential nutrients, use of
biologic response modifiers, and combinations of these approaches.
ATTENUATING CATABOLISM
461
CURRENT PRACTICES
Objectives and Efficacy of Specialized Nutrition
As outlined in recent guidelines published by the American Society for
Parenteral and Enteral Nutrition, the major objectives of nutritional and metabolic support in critical care are to (a) detect and correct preexisting malnutrition; (b) prevent progressive protein-calorie malnutrition; (c) optimize the
patient’s metabolic state (including fluid and electrolyte status); and (d) reduce
morbidity and time to convalescence (7). However, despite routine use in
critical care, the clinical efficacy of nutrition support has not been conclusively
demonstrated by appropriately designed, prospective randomized trials. Moreover, current forms of nutrition support are relatively inefficient in stimulating
protein synthesis or in reducing protein breakdown rates during critical illness
and are unable to induce net protein anabolism or positive nitrogen balance
(1–6). Losses of 4–8 g nitrogen/day (25–50 g protein/day) are not unusual in
severely catabolic hospitalized patients despite aggressive feeding (3). In addition, body composition studies have shown that much of the observed weight
gain associated with the provision of specialized nutrition represents a gain in
total body fat and extracellular fluid (3, 4).
The relative ineffectiveness of current therapy in preventing acute proteolysis in the setting of severe injury or critical illness is probably multifactorial,
i.e. related to a relative inability to effectively use exogenously supplied nutrients due to bed rest, organ dysfunction, the catabolic hormonal-cytokine environment and/or provision of imbalanced or deficient nutrient solutions (1, 3).
However, during the convalescence phase after severe illness or in patients
with mild catabolic stress, standard parenteral and enteral nutrition support
stimulates protein synthesis and promotes nitrogen equilibrium or slight positive balance, particularly in patients with preexisting protein-energy malnutrition who are avid for protein retention.
Although increased flow of amino acids from skeletal muscle in catabolic
stress may result in skeletal muscle weakness and diminished muscle function,
acute proteolysis provides amino acid fuel and substrates for wound healing,
visceral organ structural protein and acute-phase protein synthesis, gluconeogenesis, and immune cell support. Thus the proteolytic response represents an
important adaptation during critical illness.
Administration of Nutrition Support in Critical Illness
COMPLICATIONS OF THERAPY Provision of carbohydrate, protein, and fat in
excess of maintenence nutrient requirements (hyperalimentation) has been
associated with metabolic complications in the ICU setting, including hyperglycemia, electrolyte disturbances (e.g. hypophosphatemia, hypomagnesemia),
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fatty liver and liver function abnormalities, azotemia, and respiratory insufficiency due to excess CO2 production (3, 7). These complications were much
more common in the past when very large amounts of energy in the form of
carbohydrate and lipid (> 40 kcal/kg per day) and high-protein diets (> 2.5 g/kg
per day) were routinely prescribed.
An increased rate of infection is associated with parenteral feeding in
normally nourished individuals (8–9). Additionally, parenteral nutrition (PN)–
associated infections often involve sites distant from the intravenous catheter
such as the lung, urinary tract, and wounds (8). Available data suggest that
some component(s) of the nutrient solutions themselves, including potential
immunosuppressive effects of current soybean or safflower oil–based lipid
emulsions (9–10), the route of feeding (7), and/or provision of inadequate
amounts of immune-stimulating nutrients (4) in standard formulations, plays a
role in infection risk. Recent studies clearly show that enteral feeding with
standard, commercially available tube-feeding solutions is associated with a
much lower rate of infection in catabolic and surgical patients when compared
with PN (9, 11). This beneficial effect of enteral feeding on infection rates may
be due in part to (a) maintenence of intestinal morphologic barrier and immune function via stimulation of trophic intestinal hormones (e.g. gastrin,
cholecystokinin, enteroglucagon, and insulin-like growth factors) or via provision of diets that are more complete or balanced relative to intravenous formulas; (b) reduced total caloric intake, usually provided when the enteral route is
used exclusively; and (c) avoidance of intravenous hypertonic dextrose infusion and the associated infection risk with hyperglycemia or multiuse central
venous catheters (4, 7, 11). Because infection induces further proteolysis and
because malnutrition reduces immune defenses (thus creating a vicious cycle),
strategies to reduce infection rates should thereby diminish protein losses and
malnutrition.
The practice of
providing nutritional support to critically ill patients has evolved in recent years.
In general, the total doses of energy, protein, and fats commonly administered
are lower than the amounts used from the 1970s to the early 1980s, and
increasing emphasis is being placed on enteral feeding, provision of balanced
nutrient mixtures, and administration of larger amounts of specific nutrients (e.g.
glutamine, arginine, antioxidants, and specialized lipids, as outlined below). An
experienced nutrition support consultative service, including physicians, dietitians, pharmacists, and nurses, is crucial to ensure appropriate nutritional and
metabolic support in ICU patients (7). Numerous studies have demonstrated the
efficacy of the nutrition support team in preventing feeding-associated complications, diminishing over- or underuse of specialized nutrient solutions, and
reducing the cost of feeding (3, 7).
GENERAL ADMINISTRATION GUIDELINES IN ICU PATIENTS
ATTENUATING CATABOLISM
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Current recommendations advocate enteral feeding whenever possible,
even in small amounts. In contrast to the usual impressions at bedside, many
studies indicate that enteral tube feeding is well tolerated in critically ill
patients fed past the pylorus (7). If intravenous feeding is initiated, it should be
discontinued as soon as the gut becomes functional, as determined by frequent
assessment of gastric residual volumes, ileus, diarrhea, and other clinical parameters.
Normally, lactose-free, isotonic, nonelemental liquid diets should be administered in the ICU and supplemented by parenteral feeding until maintenence intake is achieved. Some patients may also tolerate oral food. The ICU
dietitian is an invaluable resource for the provision of appropriate diets with
supplements as needed. Numerous specialized, disease-specific liquid diet
formulas are commercially available; these contain varying amounts of energy
in the form of carbohydrate or lipid (including medium-chain triglycerides or
fish oil), modified amino acid composition, and other differences in macro- or
micronutrient content. In general, the clinical and metabolic efficacy of most
of these diets has not been directly compared in controlled, blinded trials in
similar groups of ICU patients; therefore, product choice is often based on cost
considerations and clinical judgement (see section on use of specific nutrients).
To avoid complications associated with overfeeding, the current approach
in most centers is to provide maintenance amounts of energy (∼ 25–40 kcal/kg
per day, as required) and protein at doses of ∼ 1.5–2.0 g/kg per day in catabolic
patients with normal renal function (3, 7). The protein dose should be lowered
or raised to the target range as a function of the level and rate of change of
azotemia and hyperbilirubinemia. This strategy takes into account the inability
of many patients to efficiently utilize exogenous nutrients during severe catabolic illness, as well as the fact that most protein and lean tissue repletion
occurs over a period of several weeks during convalescence, after the acute
phase of injury or illness (when large amounts of body protein are rapidly
lost). Branched-chain amino acid–enriched solutions have not been shown to
improve clinical outcomes in critically ill patients (7); therefore, standard
amino acid formulations should generally be used, pending the results of
ongoing research as outlined below.
Enteral or parenteral feeding should be initiated at a caloric dose that
provides ∼ 50% of energy requirements (determined by routine normograms
based on age, sex, body surface area, and severity of illness or measured by
indirect calorimetry). Energy intake may then be advanced slowly over several
days to provide maintenance energy intake (i.e. to meet estimated or measured
resting energy expenditure). Intravenous lipid emulsions are used only in
patients requiring PN to provide essential fatty acids (1.0–1.5 liters of a 20%
solution/week) and/or dietary calories at ∼ 20–30% of nonprotein energy
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intake, infused over a 24-h period. Dextrose should be administered at a dose
providing ∼ 70–80% of nonprotein energy, not to exceed 4–5 mg/kg per
minute. Larger doses of dextrose are not efficiently oxidized for energy, resulting in hyperglycemia and excessive carbon dioxide production (3). The dextrose load should be reduced, and/or insulin should be provided in parenteral
feeding (or as a separate insulin drip) to maintain blood glucose between 100
and 200 mg/dl.
Supplemental zinc (and possibly other trace elements such as selenium)
should be given to patients with burns, large wounds, and/or significant gastrointestinal (GI) fluid losses. For example, ∼ 12 mg of zinc are lost per liter of
small bowel fluid lost. Although blinded, controlled trials in ICU patients have
not been reported, many clinicians provide supplemental antioxidant nutrients
(e.g. vitamins C and E, beta-carotene, glutamine) via the enteral route during
severe catabolic stress. Plasma glucose, electrolytes (including magnesium),
and triglycerides, as well as renal, hepatic, and pulmonary function in response
to specialized feeding must be closely monitored and the nutrient mix adjusted
as needed to avoid metabolic complications that may be associated with feeding. If the patient is extremely unstable, it is often prudent to lower the amount
of parenteral and enteral diet or to simply administer intravenous dextrose with
vitamins and minerals for a few days until organ function stabilizes.
NEW STRATEGIES FOR ATTENUATING
PROTEIN-CATABOLIC RESPONSES
Administration of Growth Factors and Anabolic Hormones
Recombinant techniques have enabled large-scale production of peptide
growth factors for clinical investigation and patient care. The most clinical
information on adjunctive growth factor administration in ICU patients concerns the use of human growth hormone (GH) and insulin. Ongoing studies are
also evaluating effects of recombinant insulin-like growth factor-I (IGF-I)
administration. Additional studies have assessed protein-sparing effects of
anabolic steroid hormones in the ICU setting.
Pituitary GH administration in clinically stable non-GHdeficient patients has long been known to enhance retention of nitrogen, phosphorus, potas sium, sodi um, magnesium, and calci um (wit h a
nitrogen-to-mineral retention ratio similar to that of skeletal muscle). GH also
causes lipolysis, diminishes urea production, and increases plasma insulin levels
(owing to insulin resistance in glucose homeostasis) (12). In several early
studies, severely catabolic burn patients given adjunctive i.m. pituitary GH (5-10
mg/day s.c. or i.m.) consistantly exhibited improved nitrogen and mineral
GROWTH HORMONE
ATTENUATING CATABOLISM
465
retention, increased appetite, and an antecdotal improvement in wound healing
(13–15).
Recombinant GH as an adjunct to nutritional support has been extensively
studied in clinically stable patients during the postoperative period (16, 17)
and in malnourished patients with end-stage renal disease (18–19), chronic
obstructive lung disease (20), AIDS, (21) or GI diseases (e.g. inflammatory
bowel disease, intestinal fistulas, chronic pancreatitis, and short bowel syndrome) (22–23).
In general, these studies in noncritically ill patients revealed a marked
improvement in enteral and parenteral nutrient efficiency with recombinant
GH, even when hypocaloric diets were provided (24). Significantly increased
plasma insulin and IGF-I levels and corresponding positive nitrogen balance
have been observed with s.c., i.m., or intravenous GH doses ranging from
0.06–0.18 mg/kg per day, compared with responses in controls receiving identical isonitrogenous, isocaloric diets. GH improved whole-body protein synthesis rates, reduced muscle amino acid efflux and urea generation, and enhanced whole-body retention of nitrogen, potassium, phosphorus, magnesium,
and sodium in these individuals studied over a wide range of nutrient intakes
and clinical conditions (16–24). In addition to improved metabolic effects, a
recent large study in Spain of patients given GH after cholecystectomy or
choledochoduodenostomy showed improved indices of immune function, reduced postoperative infection rates, and shortened hospital length of stay in
GH-treated patients (17).
Limited data is available on direct improvements in skeletal muscle function with GH therapy in stable patients. In two studies, GH significantly
improved skeletal muscle strength, as shown by maintained hand grip strength
in the postoperative period (16), and respiratory muscle strength, as evidenced
by greater inspiratory capacity in patients with chronic obstructive pulmonary
disease (COPD) (20). In another study in stable patients with chronic lung
disease, GH therapy improved nitrogen balance, but this result was not associated with improved indices of respiratory muscle strength (25). However, in
GH-deficient adult patients treated with physiologic doses of GH or placebo
for several months, physiologic replacement doses of GH improved indices of
isometric exercise capacity (26).
Normal adult subjects subjected to skeletal muscle biopsy before and after a
6-h GH infusion (2 µg/kg per hour) demonstrated a 60% increase in postinfusion levels of myosin heavy-chain mRNA, indicating an improved capacity for
synthesis of key proteins involved in skeletal muscle structure and/or function
after acute GH administration (27). Other studies in normal adults demonstrated acute stimulation of protein synthesis in forearm muscle with shortterm GH infusion. These changes occurred without measurable changes in
muscle arterial or venous IGF-I concentrations, which suggests that GH may
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play a direct role in this response, although tissue IGF-I levels were not
measured (28). Furthermore, in a controlled study of stable postoperative
patients, GH therapy reduced 3-methylhistidine urinary excretion. This finding
implies that the rate of myofibrillar protein breakdown is diminished in this
setting (16).
Several short-term studies evaluating short-term (three days to six weeks)
adjunctive recombinant GH treatment in critically ill patients have been reported (29–37). In general, these studies document markedly improved net
protein anabolism; enhanced nitrogen, potassium, and phosphorus retention;
reduced urea generation; and/or stimulated wound healing with GH therapy at
doses of 0.1–0.2 mg/kg per day (29–35). However, minimal protein-anabolic
effects were seen in two studies using lower GH doses for short periods
following sepsis or burn injury (36–37).
The metabolic and clinical effects of up to six weeks of recombinant
GH therapy were studied in severely catabolic adult patients receiving
conventional enteral and parenteral nutrition support following severe burn
injury (∼ 60% body surface area) or vehicular trauma (29). Daily s.c. recombinant GH (10 mg/day; dose range 0.096–0.172 mg/kg per day) was administered after an initial control week. In all patients, body protein, potassium, and
phosphorus losses decreased markedly and rapidly with GH treatment (Figure
1). Marked protein-anabolic effects persisted throughout GH therapy, and
nitrogen excretion and urea generation decreased by ∼ 30% within the first few
days of GH. Serum IGF-I levels rose approximately fivefold with GH, serum
magnesium and alanine aminotransferase fell significantly, and serum calcium
and triglycerides rose slightly but significantly with GH over time. Potassium,
sodium, and phosphorus levels as well as other blood chemistries remained
stable, despite mineral retention, suggesting mineral incorporation into cells
with protein anabolism (29).
Additional studies in other groups of critically ill and septic patients have
documented increased whole-body and limb protein synthetic rates, improved
nitrogen balance, and increased fat oxidation rates with short-term GH administration compared with findings for clinically similar patients receiving placebo injections and comparable diets (30–35). The improvement of nitrogen
balance with GH in these studies has ranged from ∼ 2–5 g/day in comparison
to nitrogen balance with comparable feeding without GH. This change represents a relative improvement in protein-rich tissue of 0.4–0.9 kg/week with
GH therapy (22–24).
In a blinded, controlled trial in adult burn patients, two weeks of GH
therapy (10 mg/day) attenuated expansion of the extracellular water (ECW)
compartment and minimized loss of intracellular water (ICW). These effects
were contrary to those observed in control patients, who experienced the
expansion of ECW and contraction of ICW common in the critically ill (35).
ATTENUATING CATABOLISM
Total nitrogen
Urea N
Potassium
Phosphorus
125
25
grams/24 hrs
*
**
**
15
75
50
10
*
mmols/24 hr
100
20
25
5
0
467
Con GH
Con GH
Con GH
Con GH
0
* P < 0.05; ** P < 0.01 growth hormone vs control; mean ± SE
Figure 1 Nutrient excretion rate with recombinant GH in severely injured adult burn and trauma
patients studied during a control week and a week of GH therapy (10 mg/day s.c.). Patients received
maintenance calorie intake (35 kcal/kg per day) and protein intake (1.5g/kg per day). Nitrogen and
urea excretion were markedly reduced within a few days of GH therapy, indicating reduced urea
generation and diminished whole-body net proteolysis. Patients also experienced significant retention of potassium and phosphorus, with no significant alteration in plasma levels.
Such observations suggest a possible effect of GH on cell membrane stability
or permeabilty and are of particular importance given that the state of cellular
hydration is a key independent variable controlling cellular protein turnover
(38). Because ICW contraction appears to stimulate catabolic responses by
reducing protein synthesis and increasing protein degradation rates in skeletal
muscle (38), these effects may be minimized during GH treatment by inhibiting ICW loss (35). Further studies on this possible mechanism for GH anabolic effects are necessary.
Although many authors report antectodal improvements in respiratory muscle strength, time to wean from the ventilator, and other indices of physical
rehabilitation during GH therapy in critical illness, such endpoints have not
been well characterized in the small patient groups reported on to date. Thus,
whether GH improves skeletal muscle function in ICU patients is unclear at
present. Several studies are currently underway to directly examine this critical
issue.
Improved wound healing of skin graft donor sites with GH administration
in burn patients was confirmed in two blinded, randomized trials (31–32). In
one study of adults requiring skin grafting, a significant reduction in healing
time of 2–4 days was noted with GH (10 mg/day) vs healing responses in
matched patients receiving placebo injections (31). In the most dramatic study
documenting improved clinical outcome with GH in ICU patients to date,
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ZIEGLER, GATZEN & WILMORE
Herndon et al gave a s.c. GH dose of 0.1–0.2 mg/kg per day to severely burned
children in a randomized, double blind trial (32). GH at the higher dose was
associated with improved wound healing rates in all degrees of burn injury; at
this GH dose, length of hospitalization was markedly decreased compared
with that of matched placebo-treated control patients (32). Intermediate effects
on wound healing and length-of-stay were observed in the low-dose group.
Several patients receiving GH required insulin to control mild to moderate
hyperglycemia (32).
The mechanisms of GH anabolic effects are undoubtedly multifactorial
when combined with nutritional support. For example, consistent and marked
elevations in circulating IGF-I occur with GH in these clinical settings and
clearly play a role in tissue anabolic responses to GH. Interestingly, this IGF-I
response is attenuated as injury severity increases in ICU patients (33). The
IGF-I response is also directly related to nutritional status (39). Thus certain
severely ill patients, e.g. those receiving low caloric or protein intakes, or
patients with hepatic failure or multiple organ failure may not generate adequate IGF-I responses to induce significant anabolic effects. The stimulation
of insulin release, production of endogenous fuel as free fatty acids (FFAs) via
enhanced lipolysis, and regulation of circulating or tissue IGF–binding proteins (IGFBP) with GH treatment represent additional mechanisms of GH
action that may influence protein-anabolic response during severe illness.
Although GH treatment has been well tolerated in the studies published to
date in catabolic patients, these studies have generally not included patients
with diabetes mellitus, severe fluid retention (e.g. congestive heart failure), or
malignancies. GH causes hyperglycemia and insulin resistance, which may
become severe in unselected patients with diabetes mellitus or underlying
glucose intolerance. In addition, we have observed several cases of unexplained hypercalcemia in complicated, immobilized, critically ill patients with
renal and other organ dysfunction temporally associated with GH therapy (29).
GH may cause mild fluid and sodium retention and arthralgias or carpel tunnel
syndrome in some individuals (22–24) and, as a growth factor, may theoretically stimulate neoplastic growth. Finally, several cases of benign intracranial
hypertension (pseudotumor cerebri) were reported in patients receiving GH (or
IGF-I) to enhance somatic growth (40). These and other unknown potential
problems with even short-term use of GH in pharmacologic doses make it
necessary to closely monitor and select all patients receiving this potent anabolic agent. Major metabolic and clinical effects of recombinant GH observed
in malnourished and catabolic patients are summarized in Table 1.
A number of studies have evaluated
the protein-anabolic effects of IGF-I (or somatomedin C) in humans without GH
deficiency (41–45). IGF-I may be synthesized in most organs of the body, but
INSULIN-LIKE GROWTH FACTOR-I (IGF-I)
ATTENUATING CATABOLISM
469
the liver is the primary site of production. GH is the primary regulator of IGF-I
synthesis and release, although IGF-I production is also markedly influenced by
nutritional status (39). IGF-I circulates in plasma largely bound to one of several
IGFBPs, which are also synthesized in multiple tissues throughout the body.
The six IGFBPs that have been characterized appear to variously potentiate or
inhibit IGF-I action and may influence plasma and tissue IGF-I half-life and/or
tissue distribution; however, the biological actions of the IGFBPs in catabolic
patients and their regulation by GH, IGF-I, or nutrients in these states have not
been widely studied.
When administered intravenously, IGF-I in healthy humans acutely lowered blood glucose by increasing peripheral glucose disposal and, to a lesser
degree, by suppressing hepatic glucose production (41). FFA levels fell significantly with IGF-I infusion, indicating reduced lipolysis, while total branchedchain amino acid levels fell by ∼ 50%, suggesting a possible protein-anabolic
effect (41).
Clemmons et al documented that parenteral IGF-I could reverse the protein
catabolic effects of hypocaloric oral diets, which provided 20 kcal/kg ideal
body weight/day with adequate protein in healthy adults (42). Subjects were
fed the hypocaloric diets for eight days prior to a six-day infusion of either
recombinant IGF-I (12 µg/kg per hour over 16 h/day) or GH (0.05 mg/kg per
day s.c.). IGF-I significantly attenuated nitrogen losses, a result similar to the
protein-anabolic effect observed with GH. Several episodes of symptomatic
hypoglycemia occurred with IGF-I infusion. In a subsequent study, these
authors compared the protein-anabolic effects of combined six-day GH plus
Table 1 Metabolic and clinical effects of growth hormone administration observed
in patients receiving specialized nutrition
Metabolic effects
Improved nitrogen retention, reduced urea generation
Stimulated protein synthesis, increased protein breakdown and turnover
Reduced amino acid efflux from muscle, maintained skeletal muscle
intracellular glutamine levels
Enhanced lipolysis
Increased metabolic rate (15–25%)
Enhanced retention of potassium, phosphorus, magnesium, and sodium
Insulin resistance, increased plasma glucose, free fatty acids, calcium, and IGF-I
Maintained extracellular and intracellular water compartments (in ICU patients)
Clinical/functional effects
Improved wound healing
Decreased infection rate, improved immune function
Increased postoperative grip strength
Variably increased respiratory muscle function in chronic obstructive lung
disease
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IGF-I infusion vs IGF-I infusion alone (43). Combined GH plus IGF-I therapy
resulted in a markedly improved nitrogen balance over the baseline diet period
compared with results with IGF-I alone. With IGF-I treatment, nitrogen balance improved from −139 ± 48 to −31 ± 29 mmol/day; however, with combined GH/IGF-I infusion, the subjects reverted to positive nitrogen balance
from a pretreatment mean of −140 ± 50 mmol/day to +122 ± 43 mmol/day.
Both therapies significantly reduced urea appearance, although combination
therapy with GH plus IGF-I therapy was more potent in lowering blood urea
nitrogen and in reducing urea and potassium excretion than IGF-I treatment
alone. The GH/IGF-I treatment protocol also considerably reduced hypoglycemic episodes (43). In another study, normal volunteers were fed hypocaloric,
adequate protein intravenous nutrition for 10 days prior to a 6-day infusion of
saline or IGF-I at a dose of 25 µg/kg per hour (44). Subjects receiving IGF-I
showed improved nitrogen balance and reduced amino acid efflux from skeletal muscle, without changes in fat oxidation (44).
Preliminary results of one study of IGF-I use in catabolic patients have been
reported (45). Recombinant IGF-I (10 µg/kg per hour) or saline was infused
for 14 days following severe head trauma in 24 adult patients. In saline-treated
controls, daily nitrogen balance was negative (−2.9 g/day), falling to −5.0
g/day during the second week after injury. Nitrogen was significantly conserved during the first week postinjury in the IGF-I treated group (+ 1.3 g/day)
as IGF-I levels rose considerably from 178 to 466 ng/ml. However, IGF-I
levels fell to 220 ng/ml by day 14, despite continued IGF-I infusion, and the
nitrogen-retaining effect of IGF-I was lost (45). Therefore, IGF-I therapy may
be less efficacious than GH in promoting the sustained protein-anabolic response observed over several weeks in other groups of ICU patients (29, 35)
IGF-I may induce hypoglycemia, which is probably the major potential
complication of this growth factor for patients requiring specialized enteral or
parenteral nutrition. However, low-dose therapy, use in combination with
dextrose-containing nutrient solutions, or use in combination with GH may
minimize this risk. The safety and potential metabolic and clinical utility of
this growth factor in humans requiring specialized feeding need to be further
defined.
Insulin is the major endogenous anabolic hormone in the body.
Several studies have demonstrated reduced nitrogen loss with insulin administration in nondiabetic injured patients (46–49). Hinton et al (46) and Woolfson
et al (47) documented marked reductions in protein breakdown rates and urea
generation with administration of high doses of regular insulin at doses of
200–600 units/day or 2–20 units/h in the respective studies with hypertonic
dextrose in burn and trauma patients (46–47). Reduced amino acid efflux from
skeletal muscle was observed with insulin treatment in postoperative patients
INSULIN
ATTENUATING CATABOLISM
471
(48). Addition of insulin at a dose of 25 units/liter to PN in stable malnourished
patients significantly improved lean body mass compared with PN alone, as
determined by body composition analysis (49).
A number of studies suggest that insulin may reduce protein loss in some
groups of catabolic patients. The limitations of this approach primarily relate
to the risk of hypoglycemia; electrolyte imbalance as a result of shunting of
potassium, phosphorus, and magnesium into cells; and fluid retention due to
the sodium-retaining effect of this hormone.
Several investigators have reported on the use of
anabolic steroid hormones (testosterone, testosterone derivatives) in surgical
and other catabolic patients (50–52). These agents have consistently led to
improved nitrogen balance, although the magnitude of this effect is minor.
However, complications such as sodium and water retention, edema, lipid
abnormalities, and unwanted virilizing effects may be observed with anabolic
steroid administration (intravenous or oral), and cholestatic hepatitis may occur
with oral administration; therefore, these hormones have not been routinely
prescribed. Many malnourished, elderly men admitted to the hospital exhibit
low circulating levels of testosterone. Further investigation of the short-term
metabolic and clinical efficacy of parenteral testosterone administration in this
patient group would be of interest.
ANABOLIC STEROIDS
USE OF SPECIFIC NUTRIENTS
Glutamine
Glutamine (GLN) is the most abundant free amino acid in the body (3). GLN
is the major compound that facilitates interorgan transport of nitrogen in
humans, particularly between skeletal muscle (the major site of GLN synthesis) and the splanchnic bed and kidney (the major sites of GLN uptake). GLN
is physiologically important in several key metabolic processes, including
nucleotide biosynthesis, skeletal muscle protein synthesis and breakdown,
renal ammoniagenesis, and gluconeogenesis. GLN also serves as a major
metabolic fuel in rapidly replicating cells such as the enterocyte (53).
Available data from both human and animal studies strongly support the
concept that GLN may become conditionally essential in catabolic states. GLN
requirements increase markedly during stress, as GLN-utilizing tissues and
cells (e.g. intestinal mucosa, stimulated immune cells, wounds) consume increased amounts of this amino acid as GLN use exceeds endogenous GLN
production from skeletal muscle. Thus a GLN-deficiency state may develop
with the fall of GLN concentrations in intracellular muscle and plasma pools,
as obligatory requirements are not satisfied by adequate provision of dietary
472
ZIEGLER, GATZEN & WILMORE
GLN. This conditional deficiency may manifest itself as altered structure and
function of GLN-utilizing tissues and cells. Net catabolism of skeletal muscle
(the major source of endogenous GLN) increases initially to provide greater
quantities of GLN for the body. Considerable experimental and clinical evidence suggests that dietary supplementation of GLN during catabolic states
may attenuate or reverse these sequelae (reviewed in Ref. 53).
L-glutamine is not present in most standard parenteral nutrient solutions
because of its poor solubility and its tendency to degrade to ammonia and
pyroglutamic acid with heat sterilization. However, these potential problems
are obviated by use of cold sterilization methods and proper storage techniques
(54). Glutamine dipeptides have recently been developed for parenteral use
that also obviate these problems (53).
An increasing number of clinical studies [in postoperative, septic, or traumatized patients and in patients receiving bone marrow transplantation
(BMT)] have demonstrated that GLN administration is safe and clinically
efficacious. Table 2 lists beneficial effects observed in trials comparing results
with specialized feedings enriched with L-GLN or GLN analogs [ornithine
α-ketoglutarate (OAK) and α-ketoglutarate (AKG)] vs GLN-free or low GLN
diets in nutrition support. In all clinical trials reported to date, GLN-enriched
feeding resulted in reduced net body protein breakdown, as evidenced by
improved nitrogen retention and enhanced protein synthesis compared with
results with isonitrogenous, isocaloric control diets (53–63). In a recent trial in
severely catabolic patients undergoing allogenic BMT, parenteral solutions
providing 0.57 g L-GLN/kg per day (∼ 40 g/day) markedly attenuated nitrogen
loss and 3-methylhistidine excretion during the acute post-BMT period compared with results from patients receiving standard, GLN-free PN (Figure 2)
(57). Significantly reduced microbial colonization rates and a lower incidence
of clinical infections were also observed during hospitalization with GLN
Table 2 Beneficial effects of nutrition supplemented with L-GLN, GLN dipeptides or GLN analogs in the clinical settinga
Maintained plasma and skeletal muscle intracellular GLN levels after operation or trauma
Improved nitrogen balance and attenuated 3-methylhistidine excretion during catabolic stress
Enhanced skeletal muscle protein synthetic rates
Attenuated extracellular fluid expansion after BMT
Enhanced wound healing following burns (enteral ornithine-alpha-ketoglutarate)
Improved intestinal nutrient absorption in severe short bowel syndrome (combined with GH
and fiber)
Reduced microbial colonization and clinical infection, and increased lymphocyte recovery after
BMT
Shortened hospital length of stay after allogeneic or autologous BMT
a
Adapted from Ref. 53; BMT = bone marrow transplantation
ATTENUATING CATABOLISM
473
supplementation. Furthermore, hospital stay was shortened by seven days,
with a considerable reduction in hospital costs.
Another recent study in a different patient population confirmed this
marked reduction in hospital stay with the use of specialized GLN-enriched
PN after allogeneic and autologous BMT (61). Although the mechanism(s)
resulting in improved clinical outcomes with GLN-supplemented nutrition is
as yet unclear, it may relate to multiple factors induced by GLN nutrition,
including reduced net proteolysis (53–57), maintenence of the gut mucosal
barrier function (58), protection of antioxidant capacity (GLN is a major
substrate for glutathione synthesis.) (59), normalization of body water compartments via attenuation of ECW expansion (60, 61), and/or enhanced lymphocyte recovery (63). Young and colleagues also demonstrated that intravenous GLN induces an improved state of well-being in catabolic patients, as
determined in a double blind trial of BMT patients that evaluated patient-ad-
Figure 2 Daily nitrogen balance in two groups of adult patients receiving isonitrogenous, isocaloric
PN between days 4 and 11 following allogeneic bone marrow transplantation. Nitrogen intake (mean
± SE) for the week is shown by the upper horizontal line, and nitrogen balance for each 24-h period
is indicated by the black (negative balance) or stippled (positive balance) areas. Patients receiving
standard feeding were given no glutamine, whereas the glutamine-supplemented group received
0.57 g glutamine/day. In the experimental diet, glutamine nitrogen replaced a proportion of nitrogen
provided as nonessential amino acids; this diet also contained ∼ 30% less total nitrogen in the form
of essential amino acids compared with the control diet. Glutamine supplementation significantly
attenuated nitrogen loss in these catabolic patients compared with those receiving standard nutritional support (P = 0.001 by ANOVA).
474
ZIEGLER, GATZEN & WILMORE
ministered mood-profiling instruments (62). These or other effects probably
interrelate to induce the beneficial effects of GLN nutrition observed in patient
subgroups to date. Additional studies evaluating the metabolic, molecular, and
clinical mechanisms of GLN action in catabolic states will further define the
potential benefit of this nutrient.
GLN administration has been well tolerated clinically, without appreciable
generation of endproducts such as ammonia, glutamate, or pyroglutamic acid
in plasma, despite the administration of relatively large amounts of GLN
(20–40 g/day, based on dose-response studies in animals and humans). However, patients with severe renal or hepatic failure or central nervous system
(CNS) dysfunction often do not efficiently metabolize or utilize large amino
acid loads. GLN supplementation may be contraindicated in such clinical
settings. Further study of the safety and clinical efficacy of this amino acid is
needed. Ongoing studies of enteral and parenteral GLN-enriched nutrition
provided as free L-GLN or GLN dipeptides or as OAK and AKG will further
define the clinical efficacy of this amino acid in nutrition support. Nevertheless, based on the available data, GLN should be considered a potentially
important dietary amino acid in a number of clinical settings (53).
Arginine
Several animal studies indicate that arginine has potent immunostimulatory
effects when provided in amounts greater than normally present in the diet.
Although data on the effects of arginine in humans are limited, a number of
studies suggest that it may improve immune functions, particularly when
provided with adequate nutritional support (64–65).
Barbul et al found that 30 g of arginine administered orally to normal
volunteers resulted in a significant increase in peripheral blood lymphocyte
blastogenic response to Con A and phytohemoagglutinen (PHA) (64). In the
first study of immune effects of supplemental arginine in injured humans, Daly
et al evaluated the immune and metabolic effects of L-arginine (25 g/day) or
isonitrogenous L-glycine added to enteral feeding solutions postoperatively in
30 patients with GI malignancies requiring operation (65). Immune parameters
were measured preoperatively and on days one, four, and seven postoperatively. The arginine-supplemented group exhibited increased plasma arginine
levels but only slightly improved nitrogen balance; however, this group
showed improved immune function by the end of the seven-day trial. Supplemental arginine significantly enhanced mean T-lymphocyte responses to mitogens PHA and Con-A vs controls on postoperative days four and seven.
Arginine supplementation also increased the CD-4 phenotype on postoperative
days one and seven but had no effect on other phenotype subsets, including
total T cells, CD-8, and the CD-4 to CD-8 T-lymphocyte ratio. Arginine
ATTENUATING CATABOLISM
475
increased IGF-I levels, and it is possible that this hormone (or GH) may
mediate beneficial immune responses (17). No differences in infection rates
were noted in this short-term trial (65).
Combination Therapy of Growth Factors and Specific Nutrients
One strategy to enhance the efficacy of metabolic support is to combine
anabolic hormones with key nutrient substrates. We therefore studied the
combined effects of GLN (0.45 g/kg per day by the intravenous or enteral
route), parenteral GH (0.14 mg/kg per day), and a modified enteral diet in
adult patients with GI failure vs individuals who received standard nutritional
support (23).
After three weeks of therapy, the GH-GLN patients gained minimal body
fat but significantly more lean body mass (4.3 ± 0.6 kg vs 2.0 ± 0.2; P < 0.03)
and protein (1.4 ± 0.3 kg vs 0.9 ± 0.1; P < 0.03) than did individuals treated
with standard therapy. The increase in lean tissue was not associated with an
inappropriate expansion of extracellular water. In contrast, patients receiving
standard therapy deposited a greater proportion of body weight as extracellular
water and body fat (23).
In a subgroup of patients with short bowel syndrome, this combined therapy resulted in markedly improved intestinal absorption of nitrogen, calories,
sodium, and water (66), implying that this treatment enhances bowel function,
possibly through increased protein deposition. Further work is in progress to
determine the nature of this additive or synergistic effect of combined therapy
on nutrient absorption in patients with severe short bowel syndrome.
Several studies have demonstrated that GH attenuates or abolishes glutamine release from muscle and maintains free intracellular glutamine concentrations in skeletal muscle (16, 67). This finding is particularly important in
light of data documenting metabolic and clinical efficacy of glutamine-enriched nutrition in catabolic patients (53–63) and provides an additional rationale for combined glutamine plus GH therapy as a means of maintaining
intracellular glutamine concentrations in stressed patients. The effects of GH
on glutamine metabolism may be one mechanism by which GH improves
nitrogen balance and dietary protein use. Additional studies in rats show that
combined IGF-I and GLN-enriched nutrition therapy has additive effects on
intestinal protein content, plasma IGF-I levels, and plasma GLN levels after
partial small bowel resection. This finding implies an important interaction
between GLN and the GH–IGF-I action pathway (68).
Use of Specific Lipid Products and Antioxidants
Several new lipid products containing medium-chain triglycerides, fish oils,
and structured lipids are undergoing clinical tests. Although some evidence
suggests that these may have beneficial metabolic effects compared with com-
476
ZIEGLER, GATZEN & WILMORE
monly administered standard lipid products (9), only limited data on clinical
outcomes are available. In general, effects on protein metabolism have not
been impressive. Recent studies in postoperative patients have suggested that
arginine (12.5 g/liter) added to enteral diets containing nucleotides and fish oil
improves immune functions and possibly reduces infection rates compared
with standard enteral diets that contain low amounts of arginine (1.6 g/liter)
without RNA or fish oil (69–70). In one study, the arginine/RNA/fish oil–supplemented diet improved in vitro lymphocyte blastogenesis and appeared to
reduce wound complications and hospital length of stay (69).
As noted above, investigators are evaluating the possible beneficial effects
of antioxidant nutrients (e.g. vitamins C and E, beta-carotene, cysteine) in
nutritional and metabolic support. Although numerous studies are in progress,
no controlled clinical trial results demonstrating improved metabolic or clinical outcomes with use of antioxidant nutrients have yet been published.
Biologic Response Modifiers
Additional strategies to modify the biologic response to stress have been
evaluated in humans in an attempt to reduce proteolysis and/or to improve
clinical outcome. These include use of cyclooxygenase inhibitors such as
ibuprofen, which reduces protein breakdown and the hormonal-cytokine stress
response (71), as well as the administration of epidural anesthesia in critically
ill patients, which reduces protein breakdown rates (72, 73). Specific blocking
antibodies and other similar approaches designed to inhibit the effects of
endogenous endotoxin and cytokines are currently under clinical investigation,
but effects of these methods on protein metabolism in hospitalized patients
have not been reported.
SUMMARY
Current nutritional and metabolic support modalities are clearly less effective
in preventing body protein loss and improving clinical outcomes than previously believed. However, several promising new strategies are currently
under investigation in the clinical setting. These strategies may reduce the
Table 3 New strategies for nutritional/metabolic support in critical illness
Enteral feedings designed to maintain intestinal absorptive, immune, and barrier function
Administration of conditionally essential amino acids (e.g. glutamine, arginine)
Use of specialized lipid products (e.g. medium-chain tryglycerides, fish oil)
Provision of antioxidants (e.g. vitamin E, vitamin C, cysteine)
Administration of growth factors (e.g. GH, IGFI, EGF)
Combination approaches (e.g. GH + glutamine + dietary pectin)
ATTENUATING CATABOLISM
477
protein-catabolic response to illness and injury and improve other important
clinical outcomes (Table 3). In the future, increased amounts of certain nutrients (in particular glutamine, vitamins, and antioxidants) will likely be routinely administered in the care of patients with a variety of illnesses. In addition, use of peptide growth factors, modified lipids, and combinations of these
approaches will probably prove beneficial in a number of clinical settings.
Further clinical investigation will determine the safety, efficacy, and cost-effectiveness of these novel approaches.
Any Annual Review chapter, as well as any article cited in an Annual Review chapter,
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