24
Nutrition and Wound Healing
Ryan Katz, MD; Adrian Barbul, MD, FACS
SPECIFIC THERAPY IN ITS CURRENT
STATE
Although the importance of adequate nutrition
for the healing wound has long been understood,
the science of wound healing is still in its infancy.
As such, our current nutritional therapies con-
sisting of enteral or parenteral nutritional sup-
plementation in surgical patients are often
imprecise. We now understand that optimizing
nutrition is more than just optimizing calories; it
is also meeting the specific and complex nutri-
tional requirements of the patient given the
pathology, with the unique proteins, lipids,
vitamins, and trace elements at our disposal.
SHORTCOMINGS
Unfortunately, given our limited understanding
of the wound healing process, a specific mechan-
ism and effect of each nutritional supplement are
often difficult to clarify. Thus, we are often
severely limited in our ability to precisely identify
and adequately correct complex nutritional
deficits to ensure adequate wound healing in
our surgical patients.
FUTURE PROMISES
With early and appropriate identification of
those patients at risk of wound healing problems,
specific diets tailor-made to promote, speed,
initiate, or resume the wound healing process
can be instituted preoperatively or postopera-
tively as needed.
330
It has been known since biblical times that
there is a close link between adequate nutrition
and wound healing. Since then, clinical experi-
ence and rigorous scientific studies have con-
firmed the importance of nutrition to the healing
wound.
The wound healing process is a complex
series of events that is initiated with organ or
tissue damage. Under ideal circumstances, this
process results in wound closure and allows for
continued organ function. The elusive goal has
been to more clearly define these circumstances.
It is well accepted that there are certain tenets to
optimize the wound healing process, including
careful approximation of wound edges, gentle
tissue handling, elimination of dead space,
keeping wounds clean and moist, and minimizing
bacterial load. Some of these time-honored
technical teachings are centuries old, and further
progress needs to be made if the incidence of
wound infection and failure is to be minimized.
The internal wound environment—specifically,
the availability of protein, nutrients, vitamins,
cofactors, and caloric energy necessary to
synthesize matrix and to build, break down,
and remodel healing wounds—has proven to be
just as essential for successful healing.
This chapter discusses the concept of nutri-
tional supplementation in the surgical patient
and reviews the importance of a baseline nutri-
tional assessment. A brief evaluation of enteral
and parenteral nutrition is followed by a review
of the literature evaluating the role of nutritional
supplementation in the wound healing process.
The chapter specifically focuses on nutritional

supplementation with protein and lipids, the
amino acids arginine and glutamine, vitamins C
and A, and the trace element zinc.
NUTRITION IN SURGICAL PATIENTS
Trauma, surgical or accidental, causes significant
metabolic perturbations characterized by mobi-
lization of amino acids from muscle and other
organs, gluconeogenesis, and hypermetabolic
responses. Many of these metabolic responses
are mediated by the wound itself via afferent
nerve fibers, which perceive pain, inflammation,
and changes in pH.1
For wounds to heal appropriately, the
requisite building blocks and energy stores must
be available. In addition, an adequate blood
supply is required to ensure the delivery of
nutrients and reparative cells to the wound bed.
Compared with other locations in the human
body, the blood supply to the head and neck is
often not in question. However, in patients who
have had previous surgery or in those with a
clinical history of diabetes, trauma, or radiation,
compromised macro- or microvascular circula-
tion may impair the wound healing process. For
these patients, optimization of nutritional status
is imperative and nutritional assessment and
planning should begin at the preoperative con-
sultation.
NUTRITIONAL ASSESSMENT
Prior to implementing nutritional therapy, the
physician must first determine if a patient
requires such intervention and, if so, to what
extent. Malnutrition is well recognized as a risk
factor for healing and needs to be determined
and possibly treated preoperatively. On the other
hand, most operations in well-nourished patients
are successful with uncomplicated healing
responses, even if nutritional intake is absent or
curtailed for 7 to 10 days. Evaluation of
preoperative nutritional status is an important
consideration because improper administration
or implementation of nutritional therapies can
Nutrition and Wound Healing 331
result in increased patient morbidity and unne-
cessary health care costs.
A complete history and physical examina-
tion should be performed on each patient. This
alone has been found to be 80 to 90% accurate
in evaluating patient nutritional status; the
addition of multiple or complex biochemical,
immune, or anthropometric measurements
does not greatly increase the accuracy of nutri-
tional assessment.2 Malnutrition may be
expected if the history reveals unintentional
weight loss (20% weight loss is indicative of
severe malnutrition), if the patient appears
cachectic with obvious muscle wasting, or if
the patient has a history of or reason for
alimentary malabsorption. These factors, along
with any comorbidities, such as diabetes,
other endocrinopathies, or renal or liver failure,
must be noted because they will guide nutritional
management. Some biochemical markers that
have been used as aids in diagnosing malnutri-
tion include measurement of serum proteins
(albumin , 3.5 mg/dL, prealbumin , 15 mg/dL,
transferrin , 200 mg/dL), nitrogen balance, total
cholesterol, and creatinine. Baseline assessment
documenting the status of these markers should be
obtained prior to implementing any nutritional
therapy, and optimization of nutritional status
should be tailored to each patient’s unique
history, pathology, and expected therapy.
Malnutrition contributes to increased mor-
bidity and mortality in both the hospital and the
community. Specifically, malnutrition (which can
be as prevalent as 50% in hospitalized patients)
predisposes patients to increased septic compli-
cations, prolonged ventilator dependence, pneu-
monia, and impaired or failed wound healing.3–5
Determining who would truly benefit from
nutritional supplementation is still a matter of
some debate, but there is evidence that pre-
operative nutritional support reduces infectious
complications and anastomotic breakdown in
severely malnourished patients undergoing major
elective surgery.6 Postoperative nutritional sup-
port should be considered in patients expected to
be unable to eat for a period of at least 2 weeks,
332 ESSENTIAL TISSUE HEALING OF THE FACE AND NECK
although it may not be beneficial in patients who
are able to eat within 2 weeks after surgery.7
ENTERAL VERSUS PARENTERAL
NUTRITION
In malnourished preoperative patients or in
postoperative patients unable to tolerate a diet
(or unable to meet nutritional and caloric needs)
for a protracted period of time, enteral or
parenteral feeds should be started or resumed
as early as possible. There have been multiple
prospective studies to demonstrate that enteral
feeding is superior to parenteral feeding in
reducing morbidity from septic complications
(pneumonia, abdominal abscesses, line sepsis) in
those patients requiring nutritional supplementa-
tion.7–10 Further studies reveal that enteral
nutrition stimulates gut luminal brush border
hydrolase, increases microvillus height, and
decreases mucosal permeability.4,11 These find-
ings suggest that enteral feeding reduces septic
complications by preventing bacterial transloca-
tion across the gut mucosa.
Unfortunately, the enteral route is not always
available or well tolerated by patients. In these
circumstances, parenteral nutrition should be
used as a means of maximizing the intake of
proteins and calories necessary for satisfactory
wound healing. However, parenteral nutrition
does not afford the patient the apparent immu-
nologic benefits of enteral feeding and should
therefore be either replaced by enteral feeding
when possible or augmented with enteral feeding
as tolerated. Furthermore, it should be noted
that parenteral nutrition carries the potential for
intravenous line complications, including the
morbidity associated with line insertion and the
ever-present risk of line sepsis.
PROTEIN AND LIPID SUPPLEMENTATION
Both proteins and lipids are important sources of
calories, and having deficiencies in either could
result in significant morbidity and disturbances
in the wound healing process. However, isolated
protein deficiency is actually very rare.
Inadequate protein stores are instead most
commonly seen in the setting of chronic mal-
nutrition. Historically, evaluation of a patient’s
albumin level has served as a bellwether for
protein stores, nutritional status, and subsequent
healing ability. In early studies of patients and
animals with hypoalbuminemia, wound healing
was compromised by delayed fibroplasia,
decreased wound strength, and an increased
incidence of wound dehiscence.12,13 Interest-
ingly, this impaired wound healing response
may be more a result of global malnutrition than
actual deficiencies in protein stores.14 Today,
there is no doubt that adequate energy stores are
necessary for successful wound healing, and it
has been repeatedly demonstrated that, in mal-
nourished patients, the healing of wounds will be
slower and more prone to infectious complica-
tions and will overall be weaker than in those
patients with adequate energy stores.12–14
Although it may not play a direct role in
contributing to the ultimate wound strength or
collagen content, protein does provide both
energy and amino acids necessary for the proper
functioning of the wound healing process. Thus,
protein plays an important role in the overall diet
and must be supplemented to overcome daily
losses and meet each patient’s differing protein-
energy requirements. For example, most post-
operative patients have protein requirements in
the range of 1.2 to 2 g/kg/d, whereas patients with
extensive burns may require greater than 2 g/kg/
d. Furthermore, patients with renal failure and
those with gastrointestinal malabsorption (seen
in inflammatory bowel disease) or excessive
gastrointestinal losses (associated with diarrhea
or fistulae) will also have increased protein
requirements. When in doubt, a nitrogen balance
can be calculated to determine the patient’s
nitrogen status and hence protein requirements.
For adequate and timely wound healing, protein
supplementation should be such that the patient
has a net positive nitrogen balance and meets
daily protein-energy requirements. Protein sup-
plementation can be achieved enterally or par-
enterally; there are a number of protein-rich
‘‘shakes’’ and total parenteral nutrition formula-

tions to meet this end. The optimal form of
protein supplementation for wound repair has
yet to be elucidated but most likely involves a
combination of intact proteins and specific
amino acids (see below).
Lipids, the primary components of all cell
membranes, play an integral role in the wound
healing process. As a source of calories other than
glucose and protein, a diet replete in lipids may
theoretically limit protein catabolism in the
stressed or wounded state. In young rats, healing
of skin, the stability of sutures in gut anastomoses,
and reepithelialization of partial-thickness burns
have all been shown to be compromised in the
setting of essential fatty acid deficiency.15 Impaired
wound healing has also been documented in
humans with essential fatty acid deficiencies.16
Most often these deficiencies arise in the hospital
setting when a patient is placed on parenteral
nutrition. Thus, it is important in the postsurgical,
burn, trauma, or severely stressed patient to
supplement parenteral formulas with lipids. In
practice, it has become common, especially in a
critical care setting, to see parenteral formulas
containing up to 30 to 50% of nonprotein calories
in the form of lipid emulsions. In theory, this may
be of benefit to selected patient populations by
decreasing the respiratory quotient (amount of
Nutrition and Wound Healing 333
endogenous carbon dioxide produced relative to
oxygen consumed). Tailoring the amount of lipid
supplementation should be done carefully, taking
into consideration the potential risk of infectious
complications, hyperlipidemia, and a higher post-
operative mortality rate with increased fat admin-
istration.17
ARGININE
Endogenously, arginine is synthesized from
ornithine via a citrulline intermediate. Like
glutamine, arginine is a nonessential amino acid
that, in the setting of severe injury, major
surgery, or critical illness, becomes conditionally
essential.18,19 The physiologic role of this amino
acid is varied and includes nitrogen scaveng-
ing, protein metabolism, the creation of high-
energy creatine phosphate bonds, and polyamine
biosynthesis. In addition, as the only known
substrate for the enzyme nitric oxide synthase
(NOS), arginine appears to be indispensable
for formation of the biologic effector molecule
nitric oxide (NO) (Figure 1).19 NO released
through the activity of NOS regulates collagen
formation, cell proliferation, and wound con-
traction in distinct ways during the course of
wound healing.
Figure 1. Arginine is a substrate for
nitric oxide synthase (NOS) and con-
tributes to cell proliferation and col-
lagen synthesis. Adapted from Witte
MB and Barbul A.19
334 ESSENTIAL TISSUE HEALING OF THE FACE AND NECK
Early studies examining animals with argi-
nine-deficient diets clearly demonstrate the
importance of this amino acid to the healing
wound. In the 1970s, one such experiment
examined the morbidity and mortality of rats
fed an arginine-deficient diet and subjected to
dorsal incision and closure. When compared with
rats fed a normal diet, those with dietary arginine
restrictions were found to have decreased perio-
perative weight gain, increased perioperative
mortality, and overall weaker scars with less
collagen.19 Subsequent studies demonstrated that
injured rats whose diets were supplemented with
arginine developed scars with higher breaking
strengths and more collagen than the control rats
fed normal diets.20,21 These experiments, coupled
with the knowledge that local wound environ-
ments are marked by very low arginine levels,
suggest that arginine is being actively used during
the wound healing process and that its supple-
mentation may aid in developing stronger scars
with more collagen. Indeed, this concept has
been studied in human volunteers subjected to
wounding. When compared with placebo con-
trols, those individuals with arginine-supplemen-
ted diets demonstrated healing wounds with
significantly higher levels of hydroxyproline—
an indirect marker of collagen deposition.22,23
Although these results are noteworthy and
encouraging, dietary arginine supplementation
has not yet become a widely implemented
measure to augment the process of wound
healing. Perhaps this is because the exact role
played by arginine within the healing wound is
uncertain. It does seem apparent that arginine
supplementation boosts initial collagen produc-
tion and subsequent deposition. Yet even with-
out arginine supplementation, most wounds go
on to heal with functionally strong scars. Of
important exception are the fragile and often
chronic wounds of diabetics, in whom many of
the wound healing problems are attributed to
NO dysregulation and local deficiencies of
arginine.24,25 In wounds of diabetic rodents,
dietary arginine supplementation appears to
restore order to the dysregulated NO pathway
and increase wound breaking strength and
collagen content.24 In humans, topical adminis-
tration of arginine to chronic diabetic ulcers
appears to result in more rapid and complete
wound closure.26 Although arginine supplemen-
tation may not be recommended for all patients
with wounds, it should be considered for diabetic
patients with chronic wounds or a history of
complicated wound healing. Furthermore, argi-
nine supplementation should be recommended to
patients in whom malnutrition is suspected.
GLUTAMINE
In a physiologic state, glutamine is the most
abundant amino acid in blood and tissue.27 This
is a testament to the multiple roles it plays in the
human body as an ammonia scavenger, nitrogen
donor during protein metabolism, and precursor
of nucleotides and nucleic acids.28 The cycliza-
tion of glutamate, the acid form of glutamine,
produces proline, which is necessary for collagen
formation and connective tissue stability. In
addition, glutamine appears to play an important
role in the growth of rapidly dividing cells such as
fibroblasts, enterocytes, and lymphocytes and
also has an immunologic function, enhancing or
enabling macrophage phagocytosis and cytotox-
ity.27,28
The pool of glutamine, an otherwise nones-
sential amino acid, becomes depleted and may
contribute to a relative immunosuppressive state
in the setting of trauma, sepsis, critical injury,
burns or severe wounds, bone marrow transplan-
tation, intense chemotherapy, or radiotherapy.29–
33
Given that the formation of a well-healed
wound requires a properly functioning immune
system, fibroblast division, and protein and
nucleic acid metabolism, it would be fair to ask
whether glutamine supplementation could
enhance the wound healing process. To date,
no convincing data have been obtained to
support a role for glutamine in wound healing.
There is, however, some evidence that enteral
glutamine supplementation in elective surgical
patients and burn victims may lead to decreased
hospital stay and infectious complications.34,35
Furthermore, in critically ill patients in whom

glutamine depletion is thought to contribute to
immunosuppression and increased hospital mor-
bidity, glutamine supplementation may be of
benefit.35
Before initiating glutamine supplementation,
it is important to assess the patient’s hepatic,
renal, and central nervous system (CNS) func-
tion, and the benefits of supplementation must be
weighed against the accumulation of ammonia (a
degradation product of glutamine) and the
potential deleterious effects on the CNS.
Similarly, since glutamine is a fuel of rapidly
dividing cells, some physicians would withhold
supplementation in patients with known tumors.
VITAMIN SUPPLEMENTATION
Specific vitamin deficiencies can greatly impair
the wound healing process and can often be
identified through careful assessment of the
patient’s diet, clinical history, and social history.
Although rarely seen in Western civilizations,
vitamin C deficiency must be considered in
severely malnourished patients, alcoholics,
patients with chronic illness, the elderly, and
patients on special restrictive diets. In that it is
essential for proline hydroxylation and, ulti-
mately, collagen cross-linking, vitamin C is of
utmost importance for ultimate wound healing
and strength. Initial manifestations of vitamin C
deficiency may not be recognized as they mainly
present as lethargy and weakness. However,
chronic vitamin C deficiency will ultimately
result in signs and symptoms consistent with
vascular fragility (petechia, easy bruising, pur-
pura, hemarthrosis) and tissue instability (bleed-
ing gums, impaired wound healing, the
breakdown of scars, and reopening of wounds).
Fortunately, such extremes are not common and
can be prevented and often reversed with the
proper and timely administration of enteral or
parenteral vitamin C.36 Of note, the recom-
mended daily allowance of vitamin C is 40 mg/
d for adults. For those patients with chronic
illness or those undergoing surgery, elevated
doses of 150 mg/d are recommended. In the
severely burned patient with massive tissue
Nutrition and Wound Healing 335
damage, levels as high as 500 mg/d to 2 g/d
should be administered while tissue turnover and
repair are ongoing. Because it is water soluble,
there is no known true vitamin C toxicity.27,37
However, excessive doses of vitamin C can lead
to renal stones or diarrhea.
A fat-soluble vitamin, vitamin A is absorbed
with the other fat-soluble vitamins in the
terminal ileum. As such, vitamin A deficiency
should be considered in anyone who is malnour-
ished (impoverished, alcoholic, vegan, elderly, or
chronically ill patients) or has a history of
inflammatory bowel disease or previous bowel
surgery. Unlike the other fat-soluble vitamins,
vitamin A—specifically, its derivative, retinoic
acid—plays a direct and multifacted role in the
wound healing process.
Clinically, the manifestations of vitamin A
deficiency are myriad and include ophthalmolo-
gic symptoms (night blindness, scleral Bitot’s
spots, corneal dryness and ulceration, and, in
extreme cases, blindness), dermatologic symp-
toms (dry skin, dry or brittle hair and fingernails,
phrynoderma, excessive keratinization of epithe-
lial tissues), and hematologic symptoms (anemia,
leukopenia). Of these, all but excessive keratini-
zation can be reversed with appropriate supple-
mentation.36 In practice, doses of 25,000 to
30,000 IU/d are recommended for treatment of
mild clinical symptoms, with higher doses being
reserved for more severe clinical pathology.
Although vitamin A toxicity can occur with
chronic use and high doses, regimens as high as
100,000 IU/d have been used safely in cancer
patients.27 Clinical signs of toxicity include
arthralgias, nausea, vomiting, CNS changes,
and even elevated intracranial pressure.
From a wound healing perspective, retinoic
acid plays a role in promoting fibroblast pro-
liferation and cell differentiation. Retinoic acid
can restore wound tensile strength and collagen
content in diabetics, patients on chronic steroids,
and those with wounds in irradiated tissue
beds.27,38,39 Thus, in these patient populations,
vitamin A supplementation is likely to be
beneficial. However, controversy remains as to
whether retinoids can be of benefit to those
336 ESSENTIAL TISSUE HEALING OF THE FACE AND NECK
patients with unimpaired wound healing. One
trial designed to test the effect of oral vitamin A
supplementation on wound healing in rats with a
mild vitamin A deficiency demonstrated a
significant increase in wound tensile strength at
5 days but no significant increase when measured
at 2 weeks.40 A more recent study in mice
examining the use of a topical retinoid on
incisional wounds demonstrated a temporary
but significantly decreased initial wound break-
ing strength.41 Compared with controls, the
group treated with retinoic acid displayed a
prolonged inflammatory phase that seemed to
impair the early deposition of collagen; at 1
week, this resulted in markedly weaker scars.
However, this effect was transient, and wound
strength among treatment and control groups
equilibrated by 3 weeks. Another study examin-
ing pretreatment of full-thickness wounds in
photodamaged human skin with topical retinoic
acid demonstrated more rapid epithelialization in
the treatment group.42 Taken together, these
results are difficult to interpret and do not make
a strong case for either topical or enteral vitamin
A supplementation in patients without chronic
wounds or impaired wound healing.
TRACE ELEMENTS: ZINC
Trace elements should be considered mandatory
for adequate nutrition. These molecules act as
enzymatic cofactors and play a variety of roles in
regulating the body’s metabolic processes. Of the
seven known trace elements, zinc is perhaps the
most well known for its effects on the wound
healing process.
An essential element, zinc has long been
recognized to have a beneficial effect on wound
healing. It is mostly absorbed enterally through
the jejunum. Thus, impaired zinc absorption
should be considered in any patient with chronic
diarrhea, malabsorption, or a history of small
bowel resection. Given that it is a cofactor in
many enzymatic reactions, it is not surprising to
find that there are multiple manifestations of zinc
deficiency. Hallmarks of the deficient state include
dermatitis, alopecia, immunocompromise, growth
retardation, skin lesions, diarrhea, and impaired
wound healing.43,44 The exact mechanism by
which zinc deficiency impairs the wound healing
process is unknown but may be due to a delayed
inflammatory response.43,45 Deprived of sufficient
zinc, healing wounds have been shown to exhibit
an increased time to wound closure, delayed
fibroblast proliferation, decreased collagen
deposition, and decreased wound tensile strength.
Treatment of the zinc-deficient state can be
achieved by either parenteral (2 mg/d) or enteral
(15 mg/d) supplementation. Requirements may
be increased in patients with large wounds (as in
burns), impaired absorption, or pathologic
losses. For patients who are not zinc deficient,
however, there are no known benefits to zinc
supplementation.27
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