Chăm Sóc Và Điều Trị Bỏng Toàn Diện (Total Burn Care – Tập 5)

25  •  Importance of Mineral and Bone Metabolism after Burn
270
parathyroid CaR by inflammatory cytokines followed by a
reduction in set point for Ca suppression of PTH production
remains the most attractive hypothesis.5,12
Studies of 24 children with massive burns demonstrated
a low serum concentration of 25-hydroxyvitamin D from
as early as 14 months after burn23 up to 7 years,24 correlat­
ing with low bone density Z-scores.24 Serum 1,25-
dihydroxyvitamin D concentrations were normal 2 years
after injury but were low at 7 years in 50% of patients.24
This suggests that these patients became progressively
vitamin D deficient.24
Possible explanations for postburn hypophosphatemia
include intracellular PO4 accumulation, inadequate intake,
excessive excretion (unlikely in view of documented hypo­
parathyroidism), or loss into the extravascular fluid. In a
review, Dolecek20 found increased urinary PO4 excretion
only during the third and fourth weeks after burn in adults,
but hypophosphatemia occurred earlier. Thus, increased
urinary PO4 excretion seen later may be more a function of
increased tissue breakdown and filtered load than of inap­
propriate or excessive urinary PO4 losses. There is little
documentation of inadequate PO4 intake after burns. We
administer a minimum of 1.6 g PO4 daily in enteral feed­
ings alone.17 What is clear is that the two major hormonal
facilitators of phosphate excretion, PTH12 and FGF23,25
are both suppressed in burns in children during the first
month postburn, suggesting a hormonal conservation of
phosphate.
The cause of sustained hypomagnesemia after burn is
unknown, although excessive urinary and fecal losses
occur in adults,20 and excessive losses occur in the burn
wound.26
Rationale for Therapy
Table 25.1 describes treatments for hypocalcemia and
hypophosphatemia. Hypocalcemia, especially during the
resuscitation effort, can potentiate hypokalemia-induced
abnormalities in cardiac muscle27 and block responsiveness
to fluid repletion in shock.27 Parenteral Ca during resuscita­
tion does not benefit patients without hypocalcemia28-30
unless they have hyperkalemia, hypomagnesemia, or Ca
channel blocker toxicity.31 Similarly, although caution
should be exercised during massive transfusion with citrate-
containing blood, Ca therapy may not be necessary in nor­
mocalcemic patients and if hepatic and renal functions are
minimally impaired. The liver will clear citrate, which may
transiently chelate Ca at a rate of 1 unit of blood transfused
every 5 minutes.32 Treatment should be initiated only when
clinical and electrocardiographic evidence suggests hypo­
calcemia. Ca infusions should be administered slowly
because rapid Ca replacement can produce cardiac
arrhythmias.27,32
Hypophosphatemia may cause tissue hypoxemia due to
increased hemoglobin affinity for oxygen and decreased
tissue ATP, metabolic encephalopathy, hemolysis, short­
ened platelet survival, myalgias, weakness, and possible
impairment of myocardial contractility.33 Hypomagnese­
mia, or Mg depletion with normal serum Mg, blunts the
effect of PTH secreted in response to hypocalcemia on target
organs and impairs secretion of PTH itself.1 Mg deficiency
Ca. In the later phase (weeks 1–8 postburn), they found
increases in Ca and ionized Ca; intact PTH, FGF-23, and
phosphate all decreased in this period.18
Hypocalcemia cannot be diagnosed from total serum Ca
concentration, owing to variability in serum albumin con­
centrations after burn. Blood ionized Ca concentration
yields a more accurate diagnosis. Several mechanisms may
underlie hypocalcemia. One is the extracellular–intracellular
shift of Ca, supported by Ca accumulation seen in the
erythrocytes of a burn patient.19 Another is increased
urinary Ca excretion, which occurs in burned children and
is consistent with documented secondary hypoparathyroid­
ism.12 Ca loss in tissue exudates could also contribute to
hypocalcemia. Although the amount of Ca in wound exu­
dates is likely insufficient to account for postburn hypocal­
cemia,20 few studies have measured Ca content in burn
wound exudates.
Although fecal Ca losses can be high in burn patients20
and burn-induced increases in endogenous corticosteroids
may impair intestinal Ca absorption,21 no evidence suggests
that hypocalcemia is caused by corticosteroid-induced
impairment of intestinal reabsorption of Ca secreted into
the intestinal lumen. Other proposed mechanisms include
reduced bone turnover.17,22 However, upregulation of
Parathyroid
Kidney
Skin
Burn
↓ Vitamin D
synthesis
Vitamin D
deficiency
Inflammatory
response
Stress
response
Decreased
bone mass
↑ IL-1β
IL-6
↑ Glucocortico-
steroids
catecholamines
• Decreased
bone
formation
• Increased
apoptosis of
osteoblasts
• Decreased
osteoblast
differentiation
↑ Ca-sensing receptor
↓ PTH secretion
↑ Urine Ca
Fig. 25.2  Mechanisms of bone loss after severe burn. IL, Interleukin;
PTH, parathyroid hormone

25  •  Importance of Mineral and Bone Metabolism after Burn
271
patient admissions, and those with creatinine clearance less
than 50 mL/min developing in the intensive care unit 48
hours after admission made up about 20% of admissions.
Of the four hypercalcemia cases described, three responded
to standard doses of bisphosphonates. The onset of hyper­
calcemia occurred from 6 weeks to 6 months after injury.
Much remains to be learned about this complication of
burn management.
Bone
Silent bone loss may occur for up to 1 year after burn.
Linear growth and bone remodeling are adversely affected
by burns. Linear growth at the epiphyses of the long bones
usually occurs through cartilage cell proliferation with pro­
duction of extracellular matrix; these chondrocytes and
matrix undergo a series of biochemical changes, leading to
the formation of ossification centers. As these centers
expand, cartilaginous tissue is replaced by bone and a vas­
cular system that allows the delivery of nutrients, hor­
mones, and growth factors. Growth velocity in children is
retarded for the first year after a 40% TBSA burn.39 The
underlying mechanism is unknown, but growth velocity
does return to normal39 even though long-term stunting
may result.
The stress and inflammatory response contribute to
bone turnover abnormalities that lead to bone loss. Urinary
deoxypyridinoline excretion increases the first week after
burn.40 Deoxypyridinoline is a marker of bone resorption or
one of the byproducts of bone collagen type I breakdown.
Its increase in urine during the first week is because of a
three- to eightfold increase in glucocorticoid production41
and a three- to 100-fold increase in proinflammatory cyto­
kines produced by the systemic inflammatory response.24
In studies of sheep after a 40% TBSA burn, bone harvested
5 days postburn demonstrated an eroded surface and
decreased Young’s modulus consistent with bone resorp­
tion.42 Both glucocorticoids and inflammatory cytokines
stimulate bone resorption by increasing osteocyte and
osteoblast RANKL production.43 Normally, bone resorption
is coupled to bone formation. In high-turnover situations
(i.e., both resorption and formation are increased), bone
loss occurs because after bone is laid down, it takes time
for it to mineralize properly. Bone will be resorbed more
quickly than it can allow the type I collagen to crystal­
lize into hydroxyapatite with proper binding sites for Ca
and PO4.
also causes generalized convulsions, muscle tremors, and
weakness.1
Treatments for Maintaining
Mineral Homeostasis
Acute symptomatic hypocalcemia should be treated with IV
Ca. Adults should receive 90–180 mg of elemental Ca over
5–10 minutes to reverse twitching. Infants and children
should receive 20 mg/kg Ca chloride or 200–500 mg/kg Ca
gluconate in four divided doses.34,35 Parenteral chloride
should be used carefully because it may cause phlebitis,
acidosis, or both. While hypocalcemia is asymptomatic and
patients can tolerate enteral feeding, milk or infant formula
can provide as much as 3 g/day of bioavailable Ca.17 Hypo­
calcemia can occur despite enteral provision of such large
Ca quantities, making intermittent parenteral administra­
tion of Ca salts sometimes necessary. The amounts given
must be determined individually and may vary significantly
from patient to patient. Dosing in six of our patients with
greater than 40% TBSA burns ranged between 0.9 and
15 g of 10% Ca gluconate/day over the first 5 weeks after
burn. Treatments were given, on average, twice daily for
75% of the days.
Rickets secondary to PO4 deficiency can be treated with
20–25 mg/kg elemental PO4 in four divided oral doses per
day.35 Infants and children with symptomatic hypophos­
phatemia should receive 5–10 mg/kg infused over 6 hours
and then 15–45 mg/kg infused over 24 hours or until
serum PO4 exceeds 2.0 mg/dL (0.6 mmol/L).36
Adult patients who tolerate enteral feeding and consume
an average of 1.6 g/day PO4 should have consumed enough
to treat asymptomatic hypophosphatemia.17 Prolonged
hypophosphatemia has not been reported in burn patients;
however, parenteral supplementation would be necessary
in such cases. Patients who have signs or symptoms of
Mg deficiency with serum Mg concentration less than
1.5 mEq/L (1.8 mg/dL or 0.8 mmol/L) usually require par­
enteral therapy.37
Hypercalcemia and Impaired
Renal Function After Burns
Hypercalcemia with acute renal failure was reported in the
May 2010 issue of Burns.38 Adult patients with serum
ionized Ca of 1.32 mmol or greater constituted 30% of
Table 25.1  Treatment Options
Disturbance
Decision Point
Recommended Treatment
Hypocalcemia
Symptomatic
Intravenous calcium:
Adults 90–180 mg of elemental calcium over 5–10 minutes
Infants or children: calcium chloride as 20 mg/kg dose or Ca gluconate in a 200–500 mg/kg/dose in
four divided doses
Asymptomatic
Oral calcium carbonate or intravenous calcium gluconate
Hypophosphatemia
Symptomatic
Infants or children: 5–10 mg/kg infused over 6 hours followed by 15–45 mg/kg given by infusion
over 24 hours
Asymptomatic
Oral administration of 20–25 mg/kg of elemental phosphorus in four divided doses each day.

25  •  Importance of Mineral and Bone Metabolism after Burn
272
tetracycline is administered to children and adults before
iliac crest bone biopsies, tetracycline uptake is markedly
reduced, suggesting a reduction in surface osteoblasts and
functioning of the surviving osteoblasts.47 Finally, fewer
markers of osteoblastic differentiation (a feature of gluco­
corticoid toxicity) are present in cultured marrow stromal
cells from iliac crest bone of burned children than in
cells from bone of age- and gender-matched control
participants.41
Although endogenous glucocorticoids resulting from the
stress response reduce osteoblast numbers and the differen­
tiation of marrow stromal cells into osteoblasts, high circu­
lating cytokine levels remain unabated. Therefore, cytokines
would be expected to continue pushing the differentiation
of marrow stem cells into osteoclasts. However, this does
not occur. In fact, levels of urinary deoxypyridinoline (a
bone resorption marker) remain quite low.22 Thus, both
bone formation and bone resorption fall dramatically in the
second week after burn, leading to a low-turnover bone
loss. This condition, known as adynamic bone, results from
a lack of osteoblasts to process bone resorption stimuli.
IL-1β14,15 and IL-616 stimulate upregulation of the para­
thyroid CaR in vitro. Moreover, both inflammation and
stress produce oxidative stress, leading to a reduction in
both osteoblastogenesis and osteoclastogenesis.48 Thus,
although the stress response explains the low-turnover
acute bone loss after burn injury, the systemic inflamma­
tory response explains upregulation of the parathyroid CaR
in both humans and sheep. Parathyroid CaR upregulation
provides continuous hypoparathyroidism after burn and
renders the wasted urinary Ca unproductive in repairing
demineralized bone.
In summary, 1 week after burn injury, the stress and
inflammatory responses promote bone loss by increasing
bone resorption and Ca wasting in the urine. By 2 weeks,
osteoblasts are lost, markedly reducing bone replacement.
This hypodynamic bone continues to thin, as resorption is
reduced22 and compensatory bone formation is all but
shut off.
The silent events triggered by burn injury reduce bone
density (Fig. 25.5) in the lumbar spine and appendicular
skeleton (see radiograph in Fig. 25.6). The distribution of
lumbar spine bone density Z-scores (standard deviation
score) is shifted to the negative in children with greater than
40% TBSA burns (see Fig. 25.5) but not in those with less
than 20% TBSA burns. Thus, more severe burns trigger the
bone loss mechanisms discussed earlier. Obesity, an epi­
demic affecting children in the developed world, may also
be implicated as a contributing factor because obese pediat­
ric burn patients (defined as being in greater than the 85th
percentile of body mass index [BMI]) had higher loss of
bone mineral density (BMD) compared with their normal
BMI counterparts.49 This may be related to increased inflam­
mation because these children also had higher C-reactive
protein (CRP) levels in the months after burn injury than
their normal BMI counterparts.49
Burn injury increases the annual extrapolated fracture
incidence in boys and girls by 100% and 50%, respectively.50
Thus, burn-induced bone loss increases the risk of fracture
later on. Whereas bone remodeling recovers 1 year after
burn,51 the Z-score for at least lumbar spine BMD does not
improve.50,51 Given that peak bone mass is reached at 18 to
Osteoblasts (bone-forming cells) and osteocytes (termi­
nally differentiated osteoblasts acting as mechanotransduc­
ers in the bone matrix) are key parts of normal coupling.
They produce RANKL in response to cytokines (especially
IL-1β and IL-6) and PTH. When stimulated by low serum
Ca and downregulation of the parathyroid CaR, PTH
increases bone resorption by binding to PTH receptors on
osteoblasts. PTH also increases the number of osteoblasts
on bone surfaces in humans44 and animals.45 However, by
the second week after burn, glucocorticoids cause apoptosis
of surface osteoblasts, and we even observe a loss of the
ability for stromal cells to show markers of osteoblast dif­
ferentiation.11,46 This disappearance is apparent in iliac
crest bone biopsies (compare normal bone in Fig. 25.3 with
bone at 2 weeks after burn in Fig. 25.4). Similarly, when
Fig. 25.3  Goldner trichrome stain of an iliac crest bone biopsy of a
healthy person. The blue-green area represents mineralized bone. The
red area represents unmineralized osteoid. Spindle-shaped cells from
the osteoid surface are osteoblasts.
Fig. 25.4  Goldner trichrome stain of an iliac crest bone biopsy of a
burned patient. The blue-green area represents mineralized bone. Com­
pared with Fig. 25.3, note that osteoblasts are absent from the osteoid
surface.

25  •  Importance of Mineral and Bone Metabolism after Burn
273
than 1 year after injury.23 Moreover, 7-dehydrocholesterol
levels were significantly lower in burn scar and adjacent
normal-appearing skin than normal control skin,23 point­
ing to ongoing problems in cholesterol biosynthesis. In the
previously discussed study of men after burn injury, they
found a negative correlation between the modified Vancou­
ver Scar Scale Score and serum vitamin D levels, suggesting
that more clinically significant scars are also scars that
affect vitamin D production.52 In general, they found that
burned patients had lower serum 25-OH vitamin D levels.
The role of vitamin D deficiency in failed restoration of bone
density is unknown. We found that 6 months after children
were discharged on a vitamin D2 (400 IU)-containing mul­
tivitamin, all but one of eight patients had vitamin D insuf­
ficiency.53 In another study, children after burns were
randomized to placebo, vitamin D2, or vitamin D3 supple­
mentation and monitored for fracture; fewer fractures were
observed in the vitamin D3 group, suggesting that vitamin
D3 supplementation may decrease postburn fracture risk.54
Thus, the vitamin D requirement for children during and
after burn injury remains unknown.53 A randomized con­
trolled trial (RCT) of adults with severe thermal burns found
that two-thirds of the patients (who were 2–5 years post­
burn) had vitamin D deficiencies and that more than half
were osteopenic. Supplementing cholecalciferol and
calcium orally improved serum vitamin D levels and quad­
riceps muscle strength but not BMD.55 Thus, it remains
unclear in adults as well what the optimal vitamin D supple­
mentation regimen would be to prevent postburn bone loss.
Treatment of Bone Catabolism
After Severe Burn
Several approaches have been studied to prevent, mitigate,
or reverse burn-induced bone loss. Daily subcutaneous
injection of 0.2 mg/kg of recombinant human growth
hormone (rhGH) from admission throughout hospitaliza­
tion immediately improves circulating insulin-like growth
factor-1 (IGF-1) levels but does not raise serum osteocalcin
levels to normal,56 suggesting that rhGH fails to increase
bone formation acutely. However, daily subcutaneous injec­
tion of 0.05 mg/kg rhGH for 1 year increases lean body
mass (LBM) by 9 months after burn and increases lumbar
spine bone mineral content (BMC), but not BMD, by 1
year.57 This increased lumbar spine BMC but not bone
density is notable for three reasons. First, the persistence of
high glucocorticoid levels during the first year may block
early efficacy of rhGH, a glucocorticoid antagonist. Next,
this finding raises the question as to whether the absence of
an increase in lumbar spine bone density reflects a failure
of rhGH activity. Given that BMD is the quotient of BMC and
bone area, an increase in BMC with no change in BMD
would imply a proportional increase in bone area. Thus, a
1-year treatment with rhGH increases LBM; increases skel­
etal loading; and creates bigger, more biomechanically
stable bone. Finally, one might ask whether the effects of
rhGH on bone are only secondary, resulting from an increase
in skeletal loading. This question cannot be directly
answered based on available data. However, Branski et al.58
recently showed that a 1-year treatment with 0.2 mg/kg/
day rhGH (subcutaneous injection) reduces lumbar spine
30 years, failure of bone density to catch up to one’s peers
places burn victims at risk of entering adulthood with less
than peak bone mass and may increase the risk of early-
onset osteoporosis. In adults as well, we see markers of
decreased BMD after prolonged follow-up. One study found
that men with 30% TBSA burns, when tested at least 1 year
postburn, had decreased femoral neck Z-score and femoral
neck BMD, as well as bone-specific ALP, relative to non­
burned control participants.52
Another obstacle to bone recovery is progressive vitamin
D deficiency, which affects burn patients who are not dis­
charged with vitamin D supplementation and related to a
failure in skin production of vitamin D.11 Sunlight exposure
becomes limited because of heat intolerance due to sweat
gland destruction, and the burn scar could become hyper­
pigmented. At 14 months postburn, biopsies have demon­
strated that ultraviolet light converts only 25% of the
normal quantity of 7-dehydrocholesterol into previtamin
D3, suggesting that skin is biochemically abnormal more
Patients (n)
2
4
6
8
10
12
14
16
18
20
22
24
26
0
BMD Z-score
–5
–4
–3
–2
–1
1
2
3
4
5
0
Fig. 25.5  Distribution of lumbar spine bone mineral density (BMD)
Z-scores of severely burned children compared with a standard distri­
bution curve. Note that the distribution after burn is shifted to the
negative side.
Fig. 25.6  Radiograph as an example of burn-induced osteoporosis 1
year after trauma.

25  •  Importance of Mineral and Bone Metabolism after Burn
274
communication, possibly a paracrine effect or effect in the
microenvironment, between bone and muscle.46
Two other promising drugs bear mention. The first is
recombinant human PTH (rhPTH). Daily subcutaneous
injection of rhPTH for 1 year adds new bone in women
with postmenopausal osteoporosis.63 However, because rat
studies have demonstrated an increase in osteogenic
sarcoma,64 the U.S. Food and Drug Administration does not
allow its use in children. If this changes, rhPTH would be a
potentially effective drug for adding bone mass in burned
children.
Beyond pharmaceutical therapies, recent research also
points to the possibility of exercise and other mechanical
types of therapy playing a role in the management of post­
burn bone loss. One study found that exercise, in combina­
tion with whole-body vibration therapy, helped maintain
truncal BMC in children after burn injury relative to exer­
cise alone.65
Heterotopic Ossification After
Burn Injury
Another abnormality of bone and mineral metabolism
observed after burn injury is the formation of heterotopic
ossification (HO). HO is lamellar bone that forms ectopically
via endochondral ossification. It is frequently seen after
trauma and burns, as well as after spinal cord or traumatic
brain injury and after orthopedic surgery. HO after burn
injury can develop quite quickly even in the initial hospi­
talization. In a study of the Burn Model System National
database, they found that the mean age of patients with
HO by the time of discharge was 42.6, the mean TBSA
was 18.5%, and the population was almost 75% male.66
The same study found that TBSA and the need for grafting
of the arm, head, neck, or trunk were risk factors for the
development of HO.66 In another study of patients from
high-volume burn centers, they found that 3.5% of burn
patients developed HO, almost all of whom had burns to the
arms and skin grafting to the arms, with the latter translat­
ing to a 96.4 times higher odds of developing HO.67 Patients
with greater than 30% TBSA had 11.5 times higher odds
of developing HO. More trips to the operating room and
more days on the ventilator were also risk factors for HO
development.67 Interestingly, the prevalence of HO is low
among elderly individuals. A recent website was developed
to allow for further optimization of HO risk assessment
()
Mouse studies suggest that the mesenchymal stem cells
of younger individuals have more bone formation capacity
than those of older invidiauls.68 Additionally, younger
patients are known to mount a more robust inflammatory
response.
The early detection of HO is essential to its management
with regards to how to manage occupational therapy. Addi­
tionally, an early diagnostic modality would allow for better
directed treatment. Numerous studies have been performed
to elucidate the optimal imaging modality to detect HO.
Although plain radiographs and computed tomography
(CT) are the mainstays of clinical HO diagnosis, mouse
studies suggest that whereas near infrared imaging can
detect HO as early as 5 days after burn injury, CT could
BMC, increases LBM, and dramatically decreases circulat­
ing PTH. These findings suggest that high-dose rhGH
directly stimulates bone resorption, with secondary sup­
pression of serum PTH levels. Little evidence supports a
direct effect at moderate rhGH doses.
The disadvantages of daily rhGH administration for at
least 1 year include the high cost and the need for subcuta­
neous injections, which may reduce compliance. Another
option is long-term use of the anabolic steroid oxandrolone.
Similar to rhGH, a 0.1-mg/kg dose given orally twice daily
for 1 year produced a rise in LBM succeeded by an increase
in lumbar spine BMC by 3–6 months, increasing skeletal
loading and bone size.59 It is believed to work via IGF stimu­
lation.11 A more recent study has suggested that even longer-
term treatment with oxandrolone may be even more
beneficial.60 An RCT of children with greater than 30%
TBSA burns randomized participants to placebo or 24
months of oxandrolone and found that the treatment group
saw increases in whole-body and spine BMC as well as
lumbar spine BMD along with a greater height velocity.
These improvements in bone mineralization were greater
than previous studies of 1 year of oxandrolone therapy.60
Oxandrolone is not costly and does not require subcutane­
ous injections, but it may produce clitoral hypertrophy.
However, no premature growth plate fusion has been dis­
covered on radiographs, and this clitoromegaly resolves
when the drug is discontinued.
Another drug that has been studied is the bisphospho­
nate pamidronate. The current generation of nitrogen-
containing bisphosphonates acts by adhering to the bone
matrix, where they are taken up by osteoclasts and interfere
with the cholesterol biosynthesis pathway, ultimately alter­
ing protein binding to the osteoclastic membrane and
inducing apoptosis.61 Bisphosphonates remain in bone for
a prolonged period, raising concerns that they may inter­
fere with growth or bone quality.61 However, most bone
resorption is thought to occur during the first week or two
after burns, when inflammatory cytokines cause significant
resorption of bone before osteoblast apoptosis. Thus, early
use of bisphosphonates may prevent acute bone loss.
In a randomized, double-blind study, children with 40%
TBSA or greater burns received 1.5 mg/kg of pamidronate
intravenously (maximum dose, 90 mg) within 10 days of
the burn and 1 week later. Pamidronate prevented the
reduction in BMC in the lumbar spine and total body after
6 months of hospitalization.62 By 2 years, BMC in the
placebo group had caught up to that of the pamidronate
group for the total body but not the lumbar spine.51 This
suggests that pamidronate effectively preserves the axial
skeleton from bone loss and preserves the appendicular
skeleton until bone replacement would otherwise “catch
up.” Pamidronate has glucocorticoid antagonistic proper­
ties similar to those of rhGH; however, the effects of pami­
dronate on bone are immediate.
Pamidronate use is not associated with hypocalcemia,
growth delays, or changes in bone histomorphometry.51,62
The next step in evaluating this drug is to determine whether
the fracture rate in pamidronate-treated patients differs
from that in the placebo group and from age- and gender-
matched normal values.50 Furthermore, some evidence
suggests that bisphosphonates preserve muscle protein
after burn, raising the question if there is some sort of

25  •  Importance of Mineral and Bone Metabolism after Burn
275
hip arthroplasty.80 Prospective trials studying nonsteroidal
antiinflammatory drugs (NSAIDs) versus radiation in pre­
venting HO have had mixed results, with studies showing
similar efficacy or slightly more success with radiation than
with NSAIDs but also noting that radiation is much more
expensive and that NSAIDs have unwanted gastrointestinal
side effects.81,82
For burn patients, bisphosphonates have also been used
as early prophylaxis. However, no RCTs have been per­
formed, and results from noncontrolled studies have had
mixed results. Future treatments are currently under inves­
tigation including retinoic acid agonists, however, they
should be approached with caution given their negative
effect on wound healing. Additional drug development is
underway to target bone morphogenetic protein receptors
using kinase inhibitors because they have been shown to be
effective in several animal studies. Although promising,
kinase inhibitors also can have off-target effects that may
impair wound healing and cause further osteopenia.
Acknowledgement
BL Supported by funding from NIH/National Institute of
General Medical Sciences Grant K08GM109105-0, Plastic
Surgery Foundation, the Association for Academic Surgery
Roslyn Award, American Association for the Surgery of
Trauma Research & Education Foundation Scholarship,
American Association of Plastic Surgery Academic Schol­
arship, American College of Surgeons Clowes Award,
AAPS/PSF Pilot Award, International FOP Association.
BL collaborates on a project unrelated to this review with
Boehringer Ingelheim and has a Patent application on
Rapamycin for use in heterotopic ossification which has not
been licensed.
Complete references available online at

Further Reading
Klein GL, Bi LX, Sherrard DJ, et al. Evidence supporting a role of glucocor­
ticoids in short-term bone loss in burned children. Osteoporos Int.
2004;15:468-474.
Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after
burns. Lancet. 2004;363:291-292.
Klein GL, Herndon DN, Goodman WG, et al. Histomorphometric and bio­
chemical characterization of bone following acute severe burns in chil­
dren. Bone. 1995;17:455-460.
Klein GL, Herndon DN, Langman CB, et al. Long-term reduction in bone
mass following severe burn injury in children. J Pediatr. 1995;126:
252-256.
Klein GL, Nicolai M, Langman CB, et al. Dysregulation of calcium homeo­
stasis after severe burn injury in children: possible role of magnesium
depletion. J Pediatr. 1997;131:246-251.
Przkora R, Herndon DN, Sherrard DJ, et al. Pamidronate preserves bone
mass for at least 2 years following acute administration for pediatric
burn injury. Bone. 2007;41:297-302.
not detect it until 5 weeks after the burn.69 Transcutane­
ous Raman spectroscopy can also detect HO as early as 5
days postburn injury in a mouse model.70 Serum markers
are not a reliable screening method for HO because ele­
vated bone ALP is seen in fewer than half of patients with
known hip HO, and CRP is elevated in 77% of patients
with hip HO.71 Recent studies have started to investigate
the potential use of single-photon emission computed
tomography (SPECT) imaging, which can detect increased
pre-HO blood flow. Larger studies are needed to further
validate its use. Furthermore, with increasing efficacy of
high-frequency spectral ultrasound, this modality holds
promise given the widespread and point of care use of
ultrasonography.
The development of HO is a source of a significant
amount of investigation. In one mouse study, it was noted
that Adenosine Tri-Phosphate (ATP) hydrolysis as well as
inhibition of the SMAD pathway both decrease HO forma­
tion, suggesting that both of these pathways play a role in
the development of HO.72 Similarly, both trauma- and burn-
induced HO and genetic HO share a common pathway in
hypoxia-inducible factor 1 alpha (HIF1α), and inhibiting
this pathway can inhibit HO formation.73 The early hypoxic
wound is thought to stimulate HIF1α, which is a known
mediator of chondrogenic differentiation, allowing for
endochondral bone development. Inflammation has also
been implicated in activating progenitors and stimulating
osteogenic signals in the formation of HO.74 Mouse studies
also suggest that diabetic mice (i.e., leptin-deficient mice)
have decreased HO formation and more HO resorption; this
appears to be related to more osteoclasts noted on Tartrate-
resistant acid phosphatase (TRAP) staining.75
The prevention and treatment of patients with HO have
also been focuses of research. In patients who undergo
arthroscopic surgery for femoroacetabular impingement,
postoperative naproxen was exceedingly effective in pre­
venting HO formation (4% HO incidence in the naproxen
group vs 46% in the control group), so much so that they
had to stop the study.76 Another study of celecoxib found
that the medication was a protective factor against the
formation of HO and the development of limited Range
of Motion (ROM) at 3, 6, and 9 months postoperatively.77
Radiation is also efficacious in the prevention of HO in
high-risk patients. This was demonstrated in a 1986 study
of total hip arthroplasty patients.78 Two prospective ran­
domized trials have studied the optimal timing and dose of
radiation for the development of HO; generally, pre- and
postoperative radiation were both effective in preventing
HO after hip surgery or arthroplasty, with either low- or
medium-dose regimens that involved divided dosages of
radiation.79 Single-dose radiation therapy has also been
noted to be effective in preventing HO formation after total

275.e1
25  •  Importance of Mineral and Bone Metabolism after Burn
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28. Stueven H, Thompson BM, Aprahamian C, et al. Use of calcium in
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39. Rutan RL, Herndon DN. Growth delay in pediatric burn patients. Arch
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41. Klein GL, Bi LX, Sherrard DJ, et al. Evidence supporting a role of glu­
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42. Klein GL, Xie Y, Qin YX, et al. Preliminary evidence of early bone
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43. Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin
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44. Parisien M, Charhon SA, Arlot M, et al. Evidence for a toxic effect of
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45. Rodriguez M, Felsenfeld AJ, Llach F. Aluminum administration in the
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47. Parfitt AM, Drezner JK, Glorieux FH, et al. Bone histomorphometry:
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48. Klein GL. The effect of glucocorticoids on bone and muscle. Osteoporos
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and tumor necrosis factor-alpha on equine parathyroid cell function.
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18. Muschitz GK, et al. Early and sustained changes in bone metabolism after
severe burn injury. J Clin Endocrinol Metab. 2016;101(4):1506-1515.
19. Baar S. The effect of thermal injury on the loss of calcium from
calcium loaded cells: its relationship to red cell function and patient
survival. Clin Chim Acta. 1982;126:25-39.
20. Dolecek R. Calcium-active hormones and post-burn low-calcium syn­
drome. In: Dolecek R, Brizio-Moltens L, Moltens A, eds. Endocrinology
of Thermal Trauma: Pathophysiologic Mechanisms and Clinical Interpreta­
tion. Philadelphia: Lea and Febiger; 1990:216-237.
21. Hahn TJ, Halstead LR, Teitelbaum SI, et al. Altered mineral metabo­
lism in glucocorticoid-induced osteopenia: effect of 25-hydroxyvita­
min D administration. J Clin Invest. 1979;64:655-665.
22. Klein GL, Herndon DN, Goodman WG, et al. Histomorphometric and
biochemical characterization of bone following acute severe burns in
children. Bone. 1995;17:455-460.
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after burns. Lancet. 2004;363:291-292.

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67. Levi B, Jayakumar P, Giladi A, et al. Risk factors for the development
of heterotopic ossification in seriously burned adults: A National Insti­
tute on Disability, Independent Living and Rehabilitation Research
burn model system database analysis. J Trauma Acute Care Surg.
2015;79(5):870-876.
68. Peterson JR, Eboda ON, Brownley RC, et al. Effects of aging on osteo­
genic response and heterotopic ossification following burn injury in
mice. Stem Cells Dev. 2014;24(32):205-213.
69. Perosky JE, Peterson JR, Eboda ON, et al. Early detection of heterotopic
ossification using near-infrared optical imaging reveals dynamic turn­
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70. Peterson JR, Okagbare PI, De La Rosa S, et al. Early detection of burn
induced heterotopic ossification using transcutaneous Raman spec­
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71. Citak M, Grasmücke D, Suero EM, et al. The roles of serum alkaline
and bone alkaline phosphatase levels in predicting heterotopic ossifi­
cation following spinal cord injury. Spinal Cord. 2016;54(5):368-370.
72. Peterson JR, De La Rosa S, Eboda O, et al. Treatment of hetero­
topic ossification through remote ATP hydrolysis. Sci Transl Med.
2014;6(255):255ra132-255ra132.
73. Agarwal S, Loder S, Brownley C, et al. Inhibition of Hif1α prevents
both trauma-induced and genetic heterotopic ossification. Proc Natl
Acad Sci U S A. 2016;113(3):E338-E347.
74. Kraft CT, Agarwal S, Ranganathan K, et al. Trauma-induced hetero­
topic bone formation and the role of the immune system: A review. J
Trauma Acute Care Surg. 2016;80(1):156-165.
75. Agarwal S, Loder S, Li J, et al. Diminished chondrogenesis and
enhanced osteoclastogenesis in leptin-deficient diabetic mice (ob/ob)
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Dev. 2015;24:2864-2872.
76. Beckmann JT, Wylie JD, Potter MQ, et al. Effect of naproxen prophy­
laxis on heterotopic ossification following hip arthroscopy. J Bone Joint
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77. Sun Y, Cai J, Li F, et al. The efficacy of celecoxib in preventing het­
erotopic recurrence after open arthrolysis for post-traumatic elbow
stiffness in adults. J Shoulder Elbow Surg. 2015;24(11):1735-1740.
78. Ayers DC, Evarts CM, Parkinson JR. The prevention of heterotopic
ossification in high-risk patients by low-dose radiation therapy after
total hip arthroplasty. J Bone Joint Surg Am. 1986;68(9):1423-1430.
79. Seegenschmiedt MH, Keilholz L, Martus P, et al. Prevention of hetero­
topic ossification about the hip: final results of two randomized trials
in 410 patients using either preoperative or postoperative radiation
therapy. Int J Radiat Oncol Biol Phys. 1997;39(1):161-171.
80. Pellegrini VD Jr, Konski AA, Gastel JA, et al. Prevention of heterotopic
ossification with irradiation after total hip arthroplasty. Radiation
therapy with a single dose of eight hundred centigray administered
to a limited field. J Bone Joint Surg Am. 1992;74(2):186-200.
81. Moore DK, Katy Goss K, Anglen JO. Indomethacin versus radiation
therapy for prophylaxis against heterotopic ossification in acetabular
fractures. Bone Joint J. 1998;80(2):259-263.
82. Sell S, Willms R, Jany R, et al. The suppression of heterotopic ossifica­
tions: radiation versus NSAID therapy—a prospective study. J Arthro­
plasty. 1998;3(8):854-859.
49. Kraft R, Herndon DN, Williams FN, et al. The effect of obesity on
adverse outcomes and metabolism in pediatric burn patients. Int J
Obes (Lond). 2012;36(4):485-490.
50. Klein GL, Herndon DN, Langman CB, et al. Long-term reduction
in bone mass following severe burn injury in children. J Pediatr.
1995;126:252-256.
51. Przkora R, Herndon DN, Sherrard DJ, et al. Pamidronate preserves
bone mass for at least 2 years following acute administration for pedi­
atric burn injury. Bone. 2007;41:297-302.
52. Terzi R, Güven M. Bone mineral density after burn injury and
its relation to the characteristics of scar tissue. J Burn Care Res.
2016;37(3):e263-e267.
53. Klein GL, Herndon DN, Chen TC, et al. Standard multivitamin supple­
mentation does not improve vitamin D insufficiency after burns. J
Bone Miner Metab. 2009;27:502-506.
54. Mayes T, Gottschlich MM, Khoury J, Kagan RJ. An investigation of
bone health subsequent to vitamin D supplementation in children
following burn injury. Nutr Clin Pract. 2015;30(6):830-837.
55. Rosseau AF, Foidart-Desalle M, Ledoux D, et al. Effects of cholecalciferol
supplementation and optimized calcium intakes on vitamin D status,
muscle strength and bone health: a one-year pilot randomized con­
trolled trial in adults with severe burns. Burns. 2015;41(2):317-325.
56. Klein GL, Wolf SE, Langman CB, et al. Effect of therapy with recom­
binant human growth hormone on insulin-like growth factor system
components and serum levels of biochemical markers of bone forma­
tion in children following severe burn injury. J Clin Endocrinol Metab.
1998;83:21-24.
57. Hart DW, Wolf SE, Klein G, et al. Attenuation of post-traumatic
muscle catabolism and osteopenia by long-term growth hormone
therapy. Ann Surg. 2001;233:827-834.
58. Branski LK, Herndon DN, Barrow RE, et al. Randomized controlled
trial to determine the efficacy of long-term growth hormone treat­
ment in severely burned children. Ann Surg. 2009;250(4):514-523.
59. Murphy KD, Thomas S, Mlcak RP, et al. Effects of long-term oxandro­
lone administration in severely burned children. Surgery. 2004;136:
219-224.
60. Reeves PT, Herndon DN, Tanksley JD, et al. Five-year outcomes after
long-term oxandrolone administration in severely burned children: a
randomized clinical trial. Shock. 2016;45(4):367-374.
61. Russell RG. Bisphosphonates: mode of action and pharmacology. Pedi­
atrics. 2007;119:S150-S162.
62. Klein GL, Wimalawansa SJ, Kulkarni G, et al. The efficacy of acute
administration of pamidronate on the conservation of bone mass
following severe burn injury in children: a double-blind, randomized,
controlled study. Osteoporos Int. 2005;16:631-635.
63. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid
hormone (1-34) on fractures and bone mineral density in post-meno­
pausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.
64. Subbiah V, Madsen VS, Raymond AK, et al. Of mice and men: diver­
gent risks of teriparatide-induced osteosarcoma. Osteoporos Int.
2010;21:1041-1045.
65. Edionwe J, Hess C, Fernandez-Rio J, et al. Effects of whole-body
vibration exercise on bone mineral content and density in thermally
injured children. Burns. 2016;42(3):605-613.
66. Schneider JC, Simko LC, Goldstein R, et al. Predicting heterotopic
ossification early after burn injuries: a risk scoring system. Ann Surg.
2017;266(1):179-184.

276
Micronutrient Homeostasis
METTE M. BERGER, LINDA E. SOUSSE, GORDON L. KLEIN, LUDWIK K. BRANSKI, and
DAVID N. HERNDON
26 
VITAMIN D
Vitamin D is a fat-soluble micronutrient that has been
implicated in a wide array of physiological systems, includ­
ing skeletal muscle, bone health, cardiovascular health,
immune system, and lung function. It has been shown to
reduce inflammatory cytokines and reactive oxygen and
nitrogen species, as well as attenuate cancer, osteoarthritis,
schizophrenia, and depression. Notable risk factors for
decreased vitamin D concentrations include decreased skin
production, use of sunscreen, its decreased bioavailability
and production, liver or kidney dysfunction, malabsorption
disorders, the use of cholesterol-lowering agents, and
increased glucocorticoids.9
Burned children develop a progressive deficiency of
vitamin D as measured by circulating levels of 25-
hydroxyvitamin D and 1,25-dihydroxyvitamin D3. This
result may be confounded by the acute reduction in serum
vitamin D-binding protein10 and albumin.11 Fourteen
months post burn, serum 25-hydroxyvitamin D levels are
low12 and remain low at 2 and 7 years post burn.13 Whereas
serum levels of 1,25-dihydroxyvitamin D3 are normal at 2
years, about 50% of measured values are low at 7 years post
burn, suggesting a progressive vitamin D deficiency.13
During the acute phase, the standard 200 IU/day is
insufficient to maintain vitamin D status as shown in a
Belgian cohort study.14 Failure to provide vitamin D supple­
mentation to burn patients at discharge from hospital may
contribute to vitamin D deficiency. Fifteen adult burned
patients were randomized into either a group that received
quarterly intramuscular injections of 200,000 IU vitamin
D3 with daily oral calcium or into a placebo group.15 After
1 year, calcidiol levels significantly increased in the vitamin
D group. No change in bone health was observed between
groups, but the vitamin D-treated group showed signifi­
cantly improved quadriceps strength when tested at high
velocity.15
In 2009, pediatric burned patients discharged from the
Shriners Hospital for Children in Galveston received daily
supplementation with a multivitamin containing 400 IU of
vitamin D2 for 6 months.16 At that time, circulating levels
of 25-hydroxyvitamin D were still in the insufficient to low
range, without any improvement in lumbar spine bone
density. This was further tested in pediatric burned patients
at the Shriners Hospital for Children in Cincinnati with
100 IU of vitamin D3 in a study that showed no significant
differences in treated or untreated groups.17 Thus the
amount of vitamin D supplementation necessary to main­
tain normal circulating levels of 25-hydroxyvitamin D in
pediatricburned patients is unknown. Chan and Chan cite
200–400 IU/day as required in healthy, nonburned chil­
dren.18 However there is no evidence supporting that
Videos available at
Importance of Vitamins and
Trace Elements
Essential vitamins and trace elements, which are globally
known as “micronutrients,” are fundamental to metabo­
lism; they function as structures of enzymes or as their
cofactors. Their requirements are influenced by the meta­
bolic state and by increased nutritional needs after major
burns.1 The first publications about elevated vitamin
requirements go back to the 1940s and of trace elements
to the 1960s.2 Their homeostasis in burn injury is summa­
rized here.
Vitamins
Ascorbic acid (vitamin C), cholecalciferol (vitamin D), and
α-tocopherol (vitamin E) have all been reported as depleted
in burned patients.3,4
VITAMIN C
Vitamin C is not only an essential nutrient involved in many
anabolic pathways and essential for would healing, but it
also scavenges reactive oxygen species and improves micro­
circulatory flow impairment. Low plasma concentrations of
vitamin C are very common in burned pediatric and adult
patients.
Intravenous infusions of vitamin C have previously been
shown to be beneficial in animal models. Dubick et al.5
infused high doses of ascorbic acid in an ovine model of
40% total body surface area (TBSA) burn injury, which
significantly reduced resuscitation fluid requirements of
burned sheep after 48 hours. Plasma thiobarbituric acid
reactive substances increased fourfold in sham-burned
sheep; this was prevented by the use of the vitamin C infu­
sion. Tanaka et al.6 found that, using high-dose vitamin C,
total tissue water content was reduced and negative inter­
stitial fluid hydrostatic pressure was more positive in a
rodent burned model when compared to unburned animals.
Tanaka et al. showed in before-and-after trials that mega-
doses of ascorbic acid (66 mg/kg/h-1) delivered during the
first 24 hours after injury were associated with a significant
fluid resuscitation requirement reduction and lesser weight
gain,7 suggesting a beneficial role in burn resuscitation.
Randomized trials are still needed. Last, the use of vitamin
C protected the seminiferous tubules and germ cell loss in
burned rats compared to unburned rats,8 but human data
are not yet available.

26  •  Micronutrient Homeostasis
277
requirement in a burned population, and long-term vitamin
D supplementation with levels exceeding 400 IU/day may
be necessary to overcome the postburn deficiency.
Another major factor, however, is the profound change
in skin structure and quality. Burn scar and adjacent areas
of unburned skin can only convert roughly 25% of its
7-dehydrocholesterol precursor to vitamin D3 on exposure
to sunlight.12 Moreover, the amount of 7-dehydrocholesterol
substrate is significantly reduced in both burn scar and
adjacent unburned skin.12 This indicates that, after burn
injury, the skin cannot synthesize normal amounts of
vitamin D regardless of the amount of sun exposure
received. Thus, progressive deficiency in vitamin D will
result without supplementation.
VITAMIN E
It has been previously shown that adult patients with severe
burns are characterized by increased free radical activity
and very low levels of antioxidants; if the redox status of
these patients was not restored, the patients died.19 Vitamin
E is a fat-soluble antioxidant that scavenges peroxyl radicals
and prevents the radical-mediated chain reactions of poly­
unsaturated fatty acids. Recently, it has been shown that
the tissue storage of vitamin E in burned children decreases
by half as early as 3 weeks after injury.20 Burned patients
are entering the operating room with consistently low
vitamin E status, and vitamin E intakes in pediatric burn
patients are less than their requirements.21,22 Furthermore,
it has been shown in burned children that a combination
of antioxidants (vitamin C, vitamin E, and zinc for 7 days;
average of 900 IU/day, 400 IU/day, and 7 IU/day, respec­
tively) increased circulating vitamin E and decreased
malondialdehyde, which is a marker of oxidative stress.
Mechanistic studies in the ovine model of burn and
smoke inhalation using deuterium-labeled vitamin E
showed that the burn increased depletion of liver vitamin
E, suggesting the tissue mobilization of vitamin E.23 These
studies suggested that, in addition to depletion of vitamin E
from the lung and liver, other tissues were also depleted.23
Given the hypermetabolic and hypercatabolic state and
altered lipid metabolism in patients with burn injury, there
is concern that depletion of adipose tissue vitamin E may
reflect a significant level of oxidative stress, which then can
cause secondary organ failure.20
The inflammatory response from excess oxidative and
nitrosative stress in burn injury further impairs the healing
process. Burned children who were supplemented with
vitamins E, C, and zinc needed significantly fewer days to
heal compared to unsupplemented children.24 Increased
wound healing using the nebulization of vitamin E in the
3-week ovine model of burn and smoke inhalation has also
been demonstrated.25 Furthermore, vitamin E has been
shown to be beneficial in the treatment of wounds in a
variety of models, including scar formation from acute sur­
gical wounds26 and in rats with skin lesions from
diabetes.27
VITAMIN K
In a study of serum vitamin K levels in severely burned pedi­
atric patients, Jenkins reported that 91% of children studied
demonstrated low circulating levels in the first month post
burn.28 However, there was no relationship between serum
vitamin K levels and prothrombin time, raising the question
of clinical significance. It should be noted that osteocalcin,
a gamma-carboxylated protein produced by osteoblasts,
is vitamin K dependent. Osteocalcin is used as a standard
index of bone formation and also has been shown to stimu­
late pancreatic insulin production and peripheral insulin
sensitivity.29 Circulating osteocalcin is reported to be low in
the first month following burn injury.30 Therefore, the pos­
sibility remains that low circulating vitamin K levels may
contribute to the reduction in serum osteocalcin and hence
to postburn insulin resistance and the reduction of bone
formation.
Trace Elements
Facts about trace elements have been consolidated during
the past decades. Among them, copper (Cu), iron (Fe), sele­
nium (Se), and zinc (Zn) are involved in antioxidant and
innate and adaptive immune defenses, and deficiencies
largely contribute to the classical complications observed
after major burns, such as persistent inflammatory state,
multiorgan failure, and sepsis. Table 26.1 summarizes some
of these specific alternations. Major burns differ from other
trauma and critically ill patients by the magnitude of the
changes and their mechanisms. Here, we address the
changes affecting the blood compartment, exudative and
urinary losses, their role in inflammation and antioxidant
defenses, and, finally, some considerations about lesser-
known and sometimes toxic trace elements.
BLOOD CONCENTRATIONS
Low blood concentrations (serum and plasma) of several
trace elements in burn patients have been repeatedly
reported since the 1970s31–33 and support recommen­
dations to determine and monitor blood levels after
major burns and to orient repletion in cases of evident
deficit.
Copper: Very low levels of Cu have been shown repeat­
edly in this category of patients. The circulating concen­
trations vary inversely with the size of burns.34,35 This
observation supports the diagnosis of deficiency because
Cu and ceruloplasmin (Cp) usually increase during an
inflammatory response, with Cp being upregulated by
interleukin-1, but this increase does not occur in major
burns. Further wound treatment is often carried out with
silver products (silver-sulfadiazine and silver-containing
hydrofiber dressings): silver penetrates in the body and
antagonizes Cu, contributing to its decrease along with
Cp.36 It is important to note that Cu and Fe metabolism are
tightly linked.37
Selenium: Blood levels of Se decrease very early after
major burns due first to an inflammatory redistribution and
then aggravated by large exudative losses. Se remains low
for several weeks. This is associated with a nearly immediate
depression of the activity of plasma glutathione peroxidase
(GPX-3) (see later discussion).
Zinc: Blood Zn levels decrease within the first hours after
major burns38 and remain very low for weeks, also as the

26  •  Micronutrient Homeostasis
278
Lausanne Lab confirm that serum levels are above reference
levels in adults and Al is detected in the exudates.42
EXUDATIVE AND URINARY LOSSES
In healthy subjects, trace elements are lost through urine
(Se mainly) or feces (Cu, Fe, Zn), with extremely little being
lost to sweat. Increased losses were suspected to occur after
burns but have been difficult to measure precisely until
recently.
Copper: In studies done urinary losses were shown to be
above normal in the 1980s,32,46 being particularly observed
during parenteral nutrition, although excreted amounts
were lesser than the infused quantities. The main losses of
Cu have been shown to occur through exudates during the
open wound phase after major burns: such losses occur
similarly in children.47
Selenium: A 1984 study showed that urinary excretion of
Se was decreased,48 reflecting a deficiency status, with Se
being retained. This deficit was explained by significant
cutaneous losses, shown in the frame of a balance study.49
These findings have been confirmed recently.42
Zinc: Urinary losses of Zn are initially above normal50 as
in other major trauma but then decrease. Significant losses
occur through exudates, reaching about 10% of body
content during the first week.51
Iron: Recently, a study investigating a large palette of
trace elements showed that, in patients with 27% TBSA
burns, Fe was lost in large amounts with exsudates even in
the absence of active bleeding.42
It is important to note that, along with these four elements,
other trace elements are also lost but do not seem to con­
tribute to clinically detectable alterations. Magnesium and
phosphorus losses are substantial and sufficient to explain
the high requirements during the early phase of burns.52
result of the inflammatory redistribution associated with
inflammation39–41 and accompanying high losses.
Iron: After major burns, ferremia decreases nearly imme­
diately and remains low for prolonged periods:37 after the
first week, other mechanisms will maintain the low ferre­
mia, the principal being hemorrhage during surgery, but
also exudative losses.42
Chromium: Animal studies43 show that chromium (Cr)
concentrations decrease in the liver of burned rats, becom­
ing nondetectable after a few days and in muscle very early
on and for several days. Simultaneously, urinary Cr losses
increase. The changes in Cr concentrations were associ­
ated in animals with an early hyperglycemia, hyperinsu­
linemia, and increased secretion of stress hormones. Data
from diabetic patients and patients on parenteral nutri­
tion show that chromium deficiency contributes to insulin
resistance. Preliminary human data from the Lausanne
lab show that Cr is lost in exudates, along with molyb­
denum and manganese:42 clinical significance must be
confirmed.
Aluminum: The impact of aluminum (Al) remains
debated; investigations are few but indicate potential serious
consequences on bone metabolism. Large Al intakes from
albumin were a problem for several years.44 Al loading has
been reported in at least one population of burned adults,10
but no additional reports show Al uptake by either bone or
liver. In pediatric patients suffering severe burns, aurin tri­
carboxylic staining of bone biopsies for Al accumulation at
the bone surface have been negative.11 The Al contamina­
tion of parenteral products has not been seriously addressed
since the U.S. Food and Drug Administration (FDA) recom­
mendation in 1986,45 and because there is no real treat­
ment in case of toxicity, suspicion should be maintained
and blood levels checked in cases of neurological and bone
pain, particularly in children. Preliminary data from the
Table 26.1  Micronutrient requirements and specific burn needs during the acute period (>10% TBSA)
Vit A
(IU)
Vit D
(IU)
Vit E
(IU)
Vit C
(mg)
Vit K
(mcg)
Folate
(mcg)
Cu
(mg)
Fe
(mg)
Se
(mcg)
Zn
(mg)
AGES 0–13 YEARS
Nonburned
1300–2000
600
6–16
15–50
2–60
65–300
0.2–0.7
0.3–8
15–40
2–8
Burned
2500–5000
NRE†
NRE†
250–500
NRE
1,000*
0.8–2.8
NRE
60–140
12.5–25
AGES ≥13 YEARS
Nonburned
2000–3000
600
23
75–90
75–120
300–400
0.9
8–18
40–60
8–11
Burned
10,000
NRE†
NRE†
1,000
NRE
1,000*
4.0
NRE
300–500
25–40
Conversion based on the following: 1 µg of vitamin A = 3.33 IU of vitamin A; 1 µg of calciferol = 40 IU vitamin D; 1 mg of α-tocopherol = 1.5 IU of vitamin E.
NRE, no recommendations established.
*Administered Monday, Wednesday, and Friday.
†Pending Clinical Trial
Sources: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride (1977); dietary reference intakes for thiamin, riboflavin, niacin,
vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline (1988); dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids
(2000); dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium,
and zinc (2001); and dietary reference intakes for calcium and vitamin D (2010). These reports may be accessed at Berger MM, Shenkin
A. J Trace Elem Med Biol. 2007;21(Suppl 1):44–48. Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F. Clin Nutr. Aug 2009;28(4): 378–386;
Singer P, Berger MM, Van den Berghe G, et al. Clin Nutr. Aug 2009;28(4):387–400; Berger MM, Eggimann P, Heyland DK, et al. Crit Care 2006;10(6):R153; Berger
MM, Baines M, Raffoul W, et al. Am J Clin Nutr. May 2007;85(5):1293–1300; Berger MM, Binnert C, Chiolero RL, et al. Am J Clin Nutr. May 2007;85(5):1301–1306.

26  •  Micronutrient Homeostasis
279
Low Se blood concentrations may be corrected by doses in
the magnitude of 10 times RDA.59 Intravenous therapy
beginning the day of injury and combining Cu 3–4 mg/day,
Se 300–400 mcg/day, and Zn 30–40 mg/day resulted in
restoration of low but within-normal ranges of the three
elements in 5–10 days and was associated with normaliza­
tion of the activity of GPX3. The doses required in major
burns are indeed higher than what can be delivered by the
enteral route or that are required in parenteral nutrition. A
recent study of exudates shows that there is a retention of
the Cu, Se, and Zn in the body.42 The just-listed adult
doses59,60 were adapted to children (normalized by body
surface area) and also achieved restoration of blood values
within reference range.61 The clinical results of interven­
tion trials delivering higher doses of trace elements are
numerous: attenuation of oxidative stress;24,62 improved
wound healing (better graft take) probably by means of a
modulation of protein metabolism;63 improved immunity
and reduced infectious complications, especially pulmo­
nary;64 and shortened length of stay.59
Conclusion
Burn injury is marked by a reduction in plasma levels of
most vitamins and trace elements, which are redistrib­
uted mainly to the liver and kidney in order to maximize
the antioxidant and anabolic response to injury. Antioxi­
dant supplementation appears to have beneficial effects
on both morbidity and mortality. While nutritional and
antioxidant requirements of vitamins and trace elements
are increased above RDA during the acute hypermetabolic
phase of major burn injury, the duration and magnitude
of the increased needs in the postburn state remain to be
determined.
Complete references available online at

Further Reading
Berger M. Acute copper and zinc deficiency due to exudative losses:
substitution versus nutritional requirements. Burns. 2006;32:
393.
Berger MM, Baines M, Raffoui W, et al. Trace element supplementation
after major burns modulates anti-oxidant status and clinical course by
way of increased tissue trace element concentrations. Am J Clin Nutr.
2007;85:1293-1300.
Berger MM, Chiolero RL. Anti-oxidant supplementation in sepsis and sys­
temic inflammatory response syndrome. Crit Care Med. 2007;35(suppl):
S584-S590.
Chan MM, Chan GM. Nutritional therapy for burns in children and adults.
Nutrition. 2009;25:261-269.
Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin after
burns. Lancet. 2004;363:291-292.
Voruganti VS, Klein GL, Lu HX, et al. Impaired zinc and copper status in
children with burn injuries: need to reassess nutritional requirements.
Burns. 2005;31:711-716.
ROLE OF TRACE ELEMENTS IN INFLAMMATION
AND ANTIOXIDANT DEFENSES
The inflammation that starts nearly immediately after burn
injury has a major impact on circulating trace elements.
Already in the 1970s, in a study of rats with 20% TBSA,
Van Rij et al.39 showed that 65Zn was rapidly taken up by
liver, spleen, kidney, and wound, with a decrease in the
brain, muscles, and bone: this type of redistribution would
later be called inflammatory-mediated redistribution of micro­
nutrients because it also affects Se and Fe. This type of redis­
tribution pattern has been confirmed by several authors.40,41
Cu and Zn with Se are linked in cytosolic defense against
reactive nitrogen and oxygen species:53 iron adds to the
complexity because it is also essential for immunity. In
superoxide dismutase (SOD), Cu and Zn play major roles,
enabling electron transfer. The plasma activity of SOD is
decreased after major burns.41 Furthermore, Cp plays a role
as neutralizer of ferrous entities. Se is mainly active through
the antioxidant family of glutathione peroxidase enzymes,
which depend on Se for activity, but also through the large
family of selenoproteins. Plasma GPX3 levels are the first to
change, decreasing within hours after burn injury.51 The
redistribution of these trace elements to other compart­
ments reduces their availability as first-line antioxidant
defenses. Se depletion before the injury worsens the antioxi­
dant defense, as shown in burned rats:54 in animals made
Se deficient, a nearly immediate Se supplementation did not
restore their antioxidant defenses after burn.
Antioxidant and immune defenses are tightly coupled,
and Cu, Se, and Zn modulate both the innate and adaptive
immune response through their availability.55 In particular,
Zn deficiency will alter the activity of monocytes, polymor­
phonuclear, natural killer, B, and T cells: the latter are par­
ticularly susceptible to changes in Zn status.55 Cu-dependent
Cp is an acute-phase reactant protein that converts ferrous
iron to its less reactive ferric form to facilitate binding to
ferritin: its ferroxidase activity is important to iron han­
dling. As recently demonstrated,37 a low Cp favors oxidative
reactions. Low Fe levels and inflammation are tightly asso­
ciated, as recently shown by Dubick et al.37 The body has
developed strong defense mechanisms, including Cp,
against this essential but potentially toxic trace element.56
TRACE ELEMENT THERAPY
In the late 1970s, combined Cu and Zn repletion was
attempted in burned children by the enteral route57 but
failed to restore satisfactory blood levels due to the competi­
tion existing between Cu and Zn for absorption at the intes­
tinal level. An animal study showed that a multi-trace
element supply was required to achieve mucosal and carcass
weight gains.58 Successful treatment of deficiency requires
the intravenous route, as shown by randomized studies.

279.e1
26  •  Micronutrient Homeostasis
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34. Gosling P, Rothe H, Sheehan T, Hubbard L. Serum copper and zinc
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36. Boosalis M, Shippee R, Talwalker R, McClain C. Topical silver sulfa­
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280
Hypophosphatemia
DAVID W. MOZINGO and ARTHUR D. MASON, Jr.
27 
in other disease states and in certain experimental animal
models, but the extent of their contributions to the post­
burn decrease in serum phosphorus has not been critically
evaluated and is, at present, undefined.
STRESS RESPONSE
In the early postburn period, the classic “fight or flight”
response occurs, with elevation of plasma catecholamines,
glucose, glucagon, and cortisol. Exogenous epinephrine
administration has been associated with the development
of hypophosphatemia, and the profound catecholamine
release accompanying thermal injury may contribute to the
early decrease in serum phosphorus. The mechanism by
which this occurs is uncertain but may be a consequence
of the accompanying hyperglycemia, resulting in a redistri­
bution of phosphorus from the extracellular to the intracel­
lular compartment (see the later section on metabolic
support). In acute clinical states of glucagon excess, tubular
reabsorption of phosphate is impaired in both the proximal
and distal nephron, leading one to expect renal phosphate
wastage.7 Because urinary excretion of phosphate is usually
decreased in the early postinjury period, the importance of
hyperglucagonemia remains uncertain. Administration of
pharmacologic doses of glucocorticoids enhances phospho­
rus excretion and impairs phosphate absorption by the gut
and reabsorption by the kidney. Whether the adrenocortical
response significantly contributes to the hypophosphatemia
after burn injury is not known.
RESUSCITATION AND TOPICAL THERAPY
Administration of large doses of sodium lactate for initial
burn resuscitation may decrease the serum phosphorus
concentration by several mechanisms.8 Lactate is converted
to glucose in the liver, a process requiring high-energy
phosphate availability. Additionally, although it does not
usually occur clinically, metabolic alkalosis induced by
lactate infusion may result in depression of serum phospho­
rus concentration. Alkalosis is associated with an increase
in glycolysis that promotes transfer of phosphorus to the
intracellular space. During resuscitation, alkalemia is
uncommon, and patients are more likely to manifest a mild
metabolic acidosis, which is compensated by hyperventila­
tion, resulting in a normal or mildly alkaline blood pH. Aci­
dosis markedly inhibits renal phosphate reabsorption,
resulting in phosphaturia. The contribution of this mecha­
nism to postburn hypophosphatemia is probably minor;
early renal phosphate wastage is not observed, perhaps
being obscured by diminished glomerular filtration early in
burn injury. In addition, the p-carboxy metabolite of
mafenide acetate strongly inhibits carbonic anhydrase.
Such inhibition diminishes proximal tubular reabsorption
Certain humoral and metabolic responses to thermal and
mechanical trauma that maintain homeostasis and prevent
cellular dysfunction also produce alterations in electrolyte
balance. An example is renal retention of sodium during
the resuscitative phase of burn injury, which alters sodium
balance in the course of preserving intravascular volume.
Despite the markedly increased cardiac output and renal
plasma flow that occur in the subsequent flow phase, a
decrease in blood volume persists and results in sustained
elevation of plasma renin activity, secretion of antidiuretic
hormone, and sodium retention.1 Conversely, the severe
hypophosphatemia that often follows major injury occurs
concomitantly with a 50–100% increase in resting energy
expenditure, leading to a possible deficiency in the high-
energy phosphate compounds essential for cellular metabo­
lism. Thermal injury induces a precipitous decrease in
serum phosphate concentration that reaches its nadir
between the second and fifth postburn days. This phenom­
enon has been recognized for quite some time2 and was
recently confirmed by the authors in a large series of burn
patients.3 Despite aggressive phosphorus supplementation,
normal levels of serum phosphorus are rarely reached
before the 10th postburn day (Fig. 27.1). Of 550 patients
studied, 175 had serum phosphorus concentrations below
2.0 mg/dL, and of these, 49 were below 1.0 mg/dL, with
the lower limit of normal serum phosphorus being 3.0 mg/
dL. Such hypophosphatemia is not exclusive to thermal
injury, having been described after multiple trauma,4 head
injury,5 and elective surgery.6 The exact mechanism by
which thermal injury or severe stress induces hypophos­
phatemia is unknown. Several events associated with burn
injury, however, affect phosphorus metabolism, and these
may combine to produce hypophosphatemia.
Etiology of Postburn
Hypophosphatemia
Many of the pathophysiological changes and therapeutic
interventions that occur during the first postburn week
influence serum phosphorus concentration (Box 27.1).
Hypophosphatemia does not necessarily imply phosphorus
depletion; in the case of burn injury, most patients are
healthy before injury and presumably have normal phos­
phorus stores. Nor do simple calculations of phosphate
balance explain the dramatic decrease in serum levels;
simultaneous reduction of urinary phosphate excretion is
observed, suggesting an extrarenal mechanism. The frac­
tional excretion of phosphate, however, increases during
the early period of diuresis after burn injury (postburn days
2–4), potentially contributing to the decline in serum levels.
The pathophysiological events and therapeutic interven­
tions discussed here are associated with hypophosphatemia

27  •  Hypophosphatemia
281
of phosphate and probably occurs after topical burn wound
treatment with mafenide, but the magnitude of the effect is
unknown.
Expansion of the extracellular fluid volume is also associ­
ated with inhibition of proximal tubular phosphate reab­
sorption. A tight coupling exists between sodium and
phosphate transport across the renal epithelial cell. In
patients with burns, mobilization and excretion of the large
edema volume usually begins by the second postburn day
and continues throughout the next week to 10 days. In
contrast to the relative paucity of phosphate excretion
during the first 24 hours after injury, when glomerular fil­
tration is markedly reduced, a modest loss of phosphate
may occur with diuresis of the edema fluid. In fact, the
diuretic phase is associated with an increase in the frac­
tional excretion of phosphate despite a concomitant reduc­
tion in the serum phosphate concentration.9 Phosphorus
excretion during the natriuretic phase of early burn injury
is consistent with the tight coupling observed in other
diuretic states.
ULCER PROPHYLAXIS
Effective prophylaxis against Curling’s ulcers with H2 antag­
onists and antacid buffering has been a mainstay of burn
care for the past 2 decades. Significant degrees of hypophos­
phatemia and phosphate depletion occur during continu­
ous or chronic administration of phosphate-binding agents
containing magnesium, calcium, and aluminum. These
agents bind not only dietary phosphate but also phosphate
secreted into the intestinal lumen, often resulting in a net
negative phosphate balance. The severity of such hypo­
phosphatemia clearly depends on the dose of phosphate-
binding agents, dietary phosphorus intake, and preexisting
phosphate balance. To reduce alimentary scavenging of
dietary and secreted phosphate, buffering with antacids
containing aluminum phosphate salts (Al2PO4), which do
not bind any additional phosphate, may be used. Sucralfate,
which is also effective in preventing upper gastrointestinal
stress ulceration after thermal injury, is not a buffering
agent, but as a complex salt of aluminum hydroxide, is
capable of binding phosphate. Its administration has also
been associated with the development of hypophosphate­
mia in critically ill patients.10
HYPERVENTILATION
Respiratory alkalosis is often present during the first week
postburn and may be enhanced by anxiety or pain and even
by the inhibition of carbonic anhydrase induced by mafenide
acetate burn cream. As fluid resuscitation progresses, the
respiratory rate and tidal volume progressively increase,
resulting in minute ventilation that may be twice normal.
Mild hyperventilation induces only a slight decline of serum
phosphorus levels; prolonged, intense hyperventilation,
however, may result in serum phosphorus values less than
1.0 mg/dL.11 During respiratory alkalosis, phosphorus vir­
tually disappears from the urine, eliminating renal losses as
the causative mechanism. Respiratory alkalosis induces a
rapid movement of carbon dioxide from the intracellular to
the extracellular space. Intracellular pH increases, activat­
ing glycolysis and increasing the formation of intracellular
phosphorylated carbohydrate compounds. The readily dif­
fusible inorganic phosphate pool supplies the required phos­
phorus, and serum phosphorus concentrations consequently
fall abruptly. The extent to which this mechanism contrib­
utes to postburn hypophosphatemia is uncertain.
METABOLIC SUPPORT
Administration of carbohydrates may play a major role in
the development of postburn hypophosphatemia. Infusion
of glucose solutions or oral intake of carbohydrates pro­
duces mild hypophosphatemia in healthy individuals. This
decrease in serum phosphate is associated with an increase
of inorganic phosphate, adenosine triphosphate (ATP), and
glucose 6-phosphate in muscle cells. The mechanism by
which such carbohydrate administration induces hypo­
phosphatemia is somewhat speculative. Experience with
Serum phosphorus (mg/dL)
Postburn day
2.0
0
2
4
6
8
10
12
14
16
18
20
2.2
2.4
2.6
2.8
3.0
3.2
3.4
3.6
3.8
Fig. 27.1  Serum phosphorus levels abruptly decline with a nadir
between postburn days 2 and 5. The data were obtained from 550
consecutive burn patients admitted to the U.S. Army Institute of Surgi­
cal Research.
Box 27.1  Possible Causes of Postburn
Hypophosphatemia
Fluid resuscitation
■ Volume loading
■ Lactate administration
Carbohydrate administration
■ Enteral alimentation
■ Parenteral hyperalimentation
■ 5% dextrose
Elevated catecholamines
Phosphate-binding antacids or sucralfate
Acid–base disturbance
Electrolyte imbalance
■ Hypokalemia
■ Hypomagnesemia
■ Hypocalcemia
Carbonic anhydrase inhibition (mafenide acetate)

27  •  Hypophosphatemia
282
burn wound surface is a potential source of unquantified
phosphorus loss and may contribute to hypophosphate­
mia.16 In a comparison between burn patients and trau­
matically injured patients, it was shown that urinary
phosphorus clearance, fractional excretion of phosphorus,
and renal threshold phosphate concentrations were not dif­
ferent between the two groups; however, persistent hypo­
phosphatemia persisted in the thermally injured patients.
This may further implicate the wound as a source of early
phosphorus loss.17
ACUTE-PHASE RESPONSE AND SEPSIS
Burn injury is characterized by an abrupt increase in acute-
phase proteins as patients enter the hypermetabolic phase
of burn injury. These same responses are similar to those
observed in the sepsis syndrome. Recently, the development
of hypophosphatemia has been characterized in patients
with the acute-phase response syndrome.17 Similar findings
have been documented in patients with sepsis and infection,
and correlation to increase in levels of cytokines such as
tumor necrosis factor alpha and interleukin-6 has been
made.18 Similar findings were observed in patients with a
variety of infectious diseases, and correlation of high levels
of C-reactive protein and white blood cell (WBC) count
was made with the magnitude of hypophosphatemia.19
Although these reports did not include burn-injured
patients, one may infer that activation of the inflammatory
cascades such as occurs in major thermal injury may con­
tribute to the development of hypophosphatemia.
OTHER ELECTROLYTES
Disorders of electrolyte balance may contribute to the
development of hypophosphatemia. Experimental magne­
sium deficiency in animals may lead to phosphaturia and
phosphorus deficiency, but intentional magnesium defi­
ciency in man results in no change or a slight rise in serum
phosphate.20,21 In individuals with chronic alcoholism,
however, hypomagnesemia and hypophosphatemia are
coexistent. Hypokalemia, which is also exacerbated by mag­
nesium deficiency, may result in phosphate wasting and
hypophosphatemia. The mechanism is uncertain but may
be related to coexistent metabolic alkalosis, diuretic use, or
the underlying illness. Changes in calcium and phosphate
homeostasis and in the regulating hormones calcitonin and
parathyroid hormone (PTH) have been described after
thermal injury.22 Coincident with the early depression of
serum phosphorus, the fraction of ionized calcium was
shown to decrease and remain low, but within the normal
range, for the 14 postburn days studied. Urinary calcium
output was low, about 4.5 mmol/day, and urinary phos­
phate output was as high as 30 mmol/day despite a low
serum phosphorus level. Serum calcitonin levels were sig­
nificantly elevated for up to 2 weeks postinjury, but PTH
remained within the normal range. The magnitude of the
contribution of the classic regulating hormones of calcium
and phosphorus homeostasis to the observed decrease in
serum phosphorus after severe injury is not known with
certainty. Catecholamines and glucagon are known to
induce an increase in calcitonin secretion, and the admin­
istration of pharmacologic doses of calcitonin results in
phosphate-deficient total parenteral nutrition and subse­
quent development of hypophosphatemia has provided
some insight into the etiology.12,13 As carbohydrates are
absorbed, insulin secretion increases, shifting phosphorus
from the extracellular to the intracellular space. If phos­
phate reserve is low, ATP is poorly regenerated because
hypophosphatemia inhibits glucose 3-phosphate dehydro­
genase. Inorganic phosphates in the intracellular pool
become further diminished because of incorporation, ini­
tially as newly synthesized ATP, but eventually as triose
phosphates when the ATP is consumed in the hexokinase
reaction. Glucose utilization by red blood cells (RBCs)
requires ATP at the hexokinase and phosphofructokinase
steps, but regeneration of ATP does not occur during phos­
phate deficiency or acute hypophosphatemia because of a
block at the glucose 3-phosphate dehydrogenase step. In
states of phosphate depletion, the scant phosphate that
enters the RBC is incorporated into 1,3-diphosphoglycerate,
but most is diverted to 2,3-diphosphoglycerate (2,3-DPG),
also preventing complete glycolysis to regain the ATP
consumed.
In thermally injured patients, infusion of dextrose-
containing solutions usually begins 24 hours postburn,
and enteral nutrition, in which most of the calories are
supplied as carbohydrates, is initiated within several days of
injury. These interventions are temporally correlated with
the rapid descent of serum phosphorus concentrations. In
other clinical states, severe hypophosphatemia after the ini­
tiation of enteral or parenteral nutrition is most commonly
associated with the feeding of patients with advanced
protein-calorie malnutrition. When total body phosphorus
is depleted by starvation, serum phosphorus levels usually
remain normal, but carbohydrate administration produces
a rapid marked decline in serum phosphorus concentration.
If untreated, this may result in multisystem organ dysfunc­
tion, respiratory and cardiac failure, or death. Thermally
injured patients are usually well nourished before burn
injury, and the clinical scenario of refeeding hypophospha­
temia may not apply to them. Similar findings, however,
have been described recently in previously well-nourished
surgical intensive care unit patients in whom the initiation
of isotonic enteral feedings resulted in a decrease of serum
phosphorus from normal levels to approximately 1 mg/dL,
a level that is considered to be dangerously low and to
require prompt supplementation.14,15 In addition, the
authors have reported that hypophosphatemia in thermally
injured patients is exacerbated by the initiation of enteral
feeding and occurs regardless of the postburn day when
feeding is initiated.3 This further reduction of serum phos­
phorus during the first postburn week, when levels are
already low, may be particularly hazardous and speaks for
aggressive phosphorus supplementation before and during
the initiation of enteral alimentation.
BURN WOUND PHYSIOLOGY
In patients recovering from thermal injury, the burn wound
itself may act as a significant phosphorus sink. Despite the
overall catabolism accompanying major injury and loss of
lean body mass, healing burn wounds and skin grafts are
anabolic and require phosphorus for normal repair. In addi­
tion, the continued loss of fluid and protein through the

27  •  Hypophosphatemia
283
observation and laboratory studies in circumstances in
which hypophosphatemia occurred as a relatively isolated
event. Phosphorus supplementation has been reported to
reverse these abnormalities, suggesting a cause-and-effect
relationship. Hypofunction of organ systems associated
with phosphorus depletion has been attributed to a lack of
available inorganic phosphate for synthesis of high-energy
phosphorus compounds; breakdown of stored ATP occurs,
and the inorganic phosphate is diverted to other intracel­
lular pathways. Organ system dysfunction after thermal
injury is characterized by early hypofunction and later
hyperfunction of most organ systems. Whether hypophos­
phatemia contributes significantly to the early postburn
depression of function that occurs in multiple organs is not
known. Clearly, some of the clinical manifestations shown
in Box 27.2 are commonly observed in thermally injured
patients, but others are not usually associated with such
injury. Most patients reported to have had complications of
hypophosphatemia have also had a coexistent and severe
illness. It is important to remember that prior cellular injury
has been prerequisite in most instances in which hypophos­
phatemia has been implicated as a cause of organ system
dysfunction. The following discussions of organ system
abnormalities should be interpreted in light of the specific
circumstances under which the observations were made.
CARDIAC DYSFUNCTION
Although the early depression of cardiac function after
burn injury has been attributed to an initial decrease in
circulating blood volume, the search for intrinsic myocar­
dial depression after burn injury and for mediators of such
depression continues. In experimental studies and in clini­
cal material, a correlation between hypophosphatemia and
cardiac decompensation has been reported. Cardiac output,
measured by bolus thermodilution, was impaired in seven
critically ill patients with hypophosphatemia and improved
significantly with phosphorus supplementation.4 In one
experimental study, myocardial contractility was impaired
by phosphorus deficiency and reversed by phosphorus
repletion, suggesting that phosphorus deficiency may be a
cause of heart failure in certain clinical conditions.23 Hypo­
phosphatemic cardiac depression has been described as
occurring in 28.8% of surgical intensive care patients.24
Despite these reports, there appears to be little evidence that
hypophosphatemic cardiomyopathy is a frequently encoun­
tered clinical entity; most patients in whom this mechanism
is invoked have already had a number of other causes for
myocardial dysfunction.25
NEUROMUSCULAR DYSFUNCTION
Varying degrees of areflexic paralysis, paresthesias, sensory
loss, weakness, and respiratory insufficiency have been
reported to be associated with acute hypophosphatemia,
usually induced with feeding malnourished patients.12 A
reduction in available ATP to support respiratory muscle
contraction has been suggested as a mechanism for acute
respiratory failure, and diaphragmatic contractility has
been reported to improve with phosphorus repletion in
mechanically ventilated hypophosphatemic patients.26 Pro­
found generalized muscle weakness associated with
phosphaturia. A direct effect of calcitonin on phosphate
transport in the nephron has been demonstrated. In these
burn patients, it was notable that ionized calcium decreased
slightly but still within the normal range despite very high
levels of calcitonin and normal PTH concentrations. A
slight, although statistically significant, increase in PTH
was observed around the fourth postburn day and may be
related, albeit indirectly through calcium regulation, to
the observed postburn decrease in serum phosphorus
concentration.
SUMMARY
Clearly, multiple factors influence the serum phosphorus
level after burn injury. Fluid resuscitation and subsequent
mobilization of interstitial edema fluids, catecholamine
excess, respiratory alkalosis, the use of phosphate-binding
antacids or sucralfate, hypokalemia, hypomagnesemia, and
the initiation of enteral nutrition have all been associated
with hypophosphatemia in other illnesses and experimental
models. All or most of these factors may be encountered in
the early treatment of burn patients, and the contribution
and relative importance of individual factors to the depres­
sion of serum phosphorus is difficult to analyze. Most likely,
carbohydrate administration, respiratory alkalosis, and
diuresis of edema fluid are the more important etiologic
factors contributing to hypophosphatemia in the early post­
burn course.
Consequences of
Hypophosphatemia
The clinical manifestations of hypophosphatemia (Box
27.2) are mainly those of organ system hypofunction.
These responses have been defined through clinical
Box 27.2  Clinical Manifestations of
Hypophosphatemia
Central nervous system
■ Lethargy, malaise, neuropathy, seizures, coma
Cardiovascular
■ Impaired cardiovascular contractility
■ Decreased response to pressor agents
■ Hypotension
■ Acute cardiac decompensation
Pulmonary
■ Tachypnea
■ Decreased vital capacity
■ Respiratory failure
Gastrointestinal
■ Anorexia, dysphagia
Renal
■ Glycosuria, calciuria, magnesuria, renal tubular acidosis
Musculoskeletal
■ Weakness, myalgia, arthralgia, rhabdomyolysis

27  •  Hypophosphatemia
284
relationship between these specific abnormalities and those
observed in either the hypodynamic or hyperdynamic
phases of burn injury remains unclear. Clinical experience
dictates that even when severe hypophosphatemia is
avoided, the scenario of early organ system hypofunction
and later hyperfunction persists. This is not to say that the
marked hypophosphatemia observed after burn injury is
part and parcel of the disease process, without bearing on
the postburn physiological response but that thus far, the
pathophysiological milieu after thermal injury has not per­
mitted definition of the contribution of hypophosphatemia
to the overall postburn response. Until cause-and-effect
relationships are defined through ongoing research, aggres­
sive phosphorus repletion should be approached cautiously
after thermal injury. Such therapy does, however, clearly
ameliorate RBC 2,3-DPG depletion, which, in and of itself,
supports treatment.
Prevention and Treatment of
Hypophosphatemia
An unequivocal recommendation to treat hypophosphate­
mia in thermally injured patients should be supported by
evidence that the treatment is of benefit. Such evidence is
somewhat lacking in thermally injured patients, but in
many analogous instances of hypophosphatemia from
other causes, a direct benefit has been ascribed to
repletion.
Serum phosphorus levels should be measured daily
during the early phase of burn care and intravenous phos­
phate repletion initiated when levels drop below 2.0 mg/dL
(Fig. 27.2). Most of the severe adverse effects of hypophos­
phatemia occur with concentrations below 1.0 mg/dL, and
this replacement strategy should prevent the development
of clinically significant hypophosphatemia. Correction of
severe hypophosphatemia with serum phosphorus levels
less than 1.0 mg/dL requires intravenous replacement,
usually with solutions of sodium or potassium phosphate
containing 0.16 mmol/kg body weight (5 mg/kg body
weight) of elemental phosphorus over 6 hours. The dose
may be halved for patients with serum phosphorus levels
between 1.0 and 2.0 mg/dL.36 After completion of the infu­
sion, a repeat serum phosphorus determination should be
obtained, and further treatment should be based on the
postinfusion plasma concentration. A potential hazard
associated with intravenous administration of phosphate
salts is hyperphosphatemia, which may induce metastatic
deposition of calcium phosphate salts and hypocalcemia.
Additionally, when potassium phosphate salts are used,
care must be taken to avoid excessive or too rapid adminis­
tration of potassium. Phosphorus replacement should be
carefully monitored; proceed with great caution in patients
with impaired renal function or evidence of soft tissue
injury or necrosis.
Prevention of hypophosphatemia may be facilitated by
beginning oral phosphorus replacement before interven­
tions such as the initiation of either enteral or parenteral
carbohydrate administration, gastric acid neutralization
with phosphate-binding antacids or sucralfate, and the
administration of diuretics. The nadir of serum phosphorus
isolated phosphorus depletion has been observed in both
clinical and laboratory studies.27,28 In a study of hypophos­
phatemia and muscle phosphate metabolism in patients
with burns or mechanical trauma, no direct correlation
was demonstrated between the serum phosphorus concen­
tration and the high-energy phosphate content of muscle
cells; all of these patients, however, were receiving phos­
phorus supplementation during the study.29 If acute hypo­
phosphatemia is superimposed on preexisting cellular
injury, potentially reversible muscle cell dysfunction may
extend to irreversible necrosis.30 Several authors have
reported severe rhabdomyolysis associated with severe
hypophosphatemia after burns and major trauma.31,32 This
spectacular clinical event is rare but may occur to a lesser,
subclinical, extent in critically ill patients.30,33 Hypophos­
phatemia as the underlying etiology may often be dismissed
because muscle cell destruction results in release of phos­
phate and elevation of serum phosphorus. In the absence
of significant hemochromogenuria, the diagnosis may not
even be suspected. Further investigation is required to
determine whether this “asymptomatic” rhabdomyolysis is,
in fact, an important clinical entity or merely an obligate
manifestation of critical illness.
HEMATOLOGIC DYSFUNCTION
When untreated, severe hypophosphatemia may lead to
RBC dysfunction by alterations in cell shape, survival, and
physiological function. Lack of high-energy phosphate
results in a decrease in erythrocyte 2,3-DPG and subse­
quent leftward shift of the dissociation curve, with a conse­
quent risk of tissue hypoxia.7 Clinical hypophosphatemia,
with or without previous phosphate depletion, results in
reduced production of 2,3-DPG, erythrocyte ATP, and other
phosphorylated intermediates of RBC glycolysis. In a variety
of experimental and clinical situations, including burn
injury and mechanical trauma, RBC 2,3-DPG has been
shown to be reduced in the presence of hypophosphate­
mia.34,35 In thermally injured patients, it has been demon­
strated that postburn disturbance of RBC phosphate
metabolism may be prevented by administration of phos­
phorus in the early postburn course.35 Hypophosphatemia
has also been associated with decreased RBC survival
and decreased RBC deformability, with impaired capillary
transit and the potential for further deficiency of tissue
oxygenation.
White blood cell dysfunction also has been observed as a
result of hypophosphatemia induced by the initiation of
phosphate-free parenteral nutrition and was associated
with depressed chemotactic, phagocytic, and bactericidal
activity of granulocytes.35 A reduction in granulocyte ATP
content was also documented and amelioration of these
WBC abnormalities was coincident with phosphorus reple­
tion. Any correlation between these observations and an
increased risk of infection remains speculative for hypo­
phosphatemic patients in general and burn patients in
particular.
SUMMARY
Although it is clear that organ system dysfunction may be
a manifestation of severe untreated hypophosphatemia, the

27  •  Hypophosphatemia
285
cardiac and infectious complications were seen in the treat­
ment group; however, the authors suggested that these
findings needed further study.
After the 10th postburn day, the phosphorus delivered in
standard liquid enteral formulas and hospital diets is usually
sufficient to maintain serum phosphorus levels above
3.0 mg/dL.
SUMMARY
Thermal injury induces a precipitous decrease in serum
phosphate concentration that reaches its nadir between the
second and fifth postburn days. This phenomenon has been
recognized for some time, but interest in the problem has
been limited. The organ system dysfunctions induced by
hypophosphatemia are in many ways similar to certain of
the pathophysiological changes observed after burn injury.
The contribution of hypophosphatemia to these manifesta­
tions remains undefined. Wound fluid losses, increased
circulating catecholamines, intracellular phosphate redis­
tribution, and increased fractional excretion of urinary
phosphate, as well as iatrogenic induction of hypophospha­
temia through various therapeutic interventions, have
been implicated as contributing to postburn hypophospha­
temia. There may be other pathways regarding phosphorus
concentration typically occurs between 3 and 5 days post­
burn, during the period of edema mobilization, and the
need to initiate phosphorus supplementation should
be anticipated in this interval. Additionally, to temper
the gastrointestinal losses caused by administration of
phosphate-binding antacids, substitution of or alternation
with antacids containing aluminum phosphate should be
considered.
For mild asymptomatic hypophosphatemia and for pro­
phylaxis when worsening of hypophosphatemia is expected,
oral supplementation with any of several available formula­
tions is recommended. Such oral regimens have been shown
to be cost-effective.37 Five milliliters of Phospho-Soda, con­
taining 4.2 mmol/mL of elemental phosphorus, is com­
monly administered three times daily. Correction of other
electrolyte abnormalities, most notably hypomagnesemia,
hypocalcemia, and hypokalemia, as well as maintenance of
acid–base normality, may prevent further renal phosphate
losses and maintain the extracellular phosphate pool. In a
recent publication by Kahn et al., continuous, preemptive
repletion of phosphate by continuous infusion prevented
hypophosphatemia after severe burn injury when com­
pared with responsive repletion in historical control partici­
pants.38 The protocol resulted in less hypophosphatemia
without increasing the risk of hyperphosphatemia. Fewer
Monitor serum phosphorus daily*
Phosphorus <2.0 mg/dL
IV therapy indicated
Phosphorus 2.0–3.0 mg/dL
PO therapy indicated
Phosphorus <1.0 mg/dL
0.16 mmol/kg body
weight of elemental
phosphorus (K or
Na salt) infused over 6 h
0.08 mmol/kg body
weight of elemental
phosphorus (K or
Na salt) infused over 6 h
Continue daily
monitoring
Repeat serum phosphorus after infusion
to guide further replacement
Identify and address potential
contributing factors
Phosphorus 1.0–2.0 mg/dL
Any of several
available formulations
(e.g., Phospho-Soda
5 mL tid)
Fig. 27.2  The use of this algorithm permits prompt detection and timely correction of hypophosphatemia after burn injury. IV, Intravenous; PO, oral;
tid, three times a day.

27  •  Hypophosphatemia
286
Cioffi WG, Vaughan GM, Heironimus JD, et al. Dissociation of blood volume
and flow in regulation of salt and water balance in burn patients. Ann
Surg. 1991;214(3):213-218.
Lennquist S, Lindell B, Nordstrom H, et al. Hypophosphatemia in severe
burns: a prospective study. Acta Chir Scand. 1979;145:1-6.
Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill
patients in an intensive care unit. A prospective study. Arch Surg.
1996;131(10):1043-1047.
Matthews JJ, Aleen RF, Gameli RL. Cost reduction strategies in burn nutri­
tion services: adjustment dietary treatment of patients with hyponatre­
mia and hypophosphatemia. J Burn Care Rehabil. 1999;20(1 Pt 1):80-84.
Miller JS, Simpson J. Medication-nutrient interactions: hypophosphatemia
associated with sucralfate in the intensive care unit. Nutr Clin Pract.
1991;6:199-201.
regulation that have not been explored in this patient popu­
lation. Frequent serum phosphate measurement and
prompt phosphorus replacement when hypophosphatemia
is recognized should minimize any sequelae of this poten­
tially deleterious electrolyte deficiency.
Complete references available online at

Further Reading
Berger MM, Rothen C, Cavadini C, et al. Exudative mineral losses after
serious burns: a clue to the alteration of magnesium and phosphate
metabolism. Am J Clin Nutr. 1997;65(5):1473-1481.

286.e1
27  •  Hypophosphatemia
19. Barak V, Schwartz A, Kalickman I, et al. Prevalence of hypophos­
phatemia in sepsis and infection: the role of cytokines. Am J Med.
1998;104(1):40-47.
20. Haglin L, Burman LA, Nilsson M. High prevalence of hypophosphate­
mia amongst patients with infectious diseases. A retrospective study.
J Intern Med. 1999;246(1):45-52.
21. Whang R, Welt LG. Observations in experimental magnesium deple­
tion. J Clin Invest. 1963;42:305-313.
22. Shils ME. Experimental human magnesium depletion. Medicine (Bal­
timore). 1969;48:61-82.
23. Loven L, Nordstrom H, Lennquist S. Changes in calcium and phos­
phate and their regulating hormones in patients with severe burn
injuries. Scand J Plast Reconstr Surg. 1984;18:49-53.
24. Fuller TJ, Nichols WW, Brenner BJ, et al. Reversible depression in myo­
cardial performance in dogs with experimental phosphorus deficiency.
J Clin Invest. 1978;62:1194-2000.
25. Zazzo JF, Troche G, Ruel P, et al. High incidence of hypophosphatemia
in surgical intensive care patients: efficacy of phosphorus therapy on
myocardial function. Intensive Care Med. 1995;21(10):826-831.
26. Knochel JP. The clinical status of hypophosphatemia. N Engl J Med.
1985;313(7):447-449.
27. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphate­
mia on diaphragmatic contractility in patients with acute respiratory
failure. N Engl J Med. 1985;313:420-424.
28. Lotz M, Nay R, Bartter FC. Osteomalacia and debility resulting from
phosphorus depletion. Trans Assoc Am Physicians. 1964;77:281-295.
29. Lotz M, Zisman E, Bartter FC. Evidence for a phosphorus depletion
syndrome in man. N Engl J Med. 1968;278:409.
30. Loven L, Lennquist S, Liljedahl SO. Hypophosphataemia and muscle
phosphate metabolism in severely injured patients. Acta Chir Scand.
1983;149:743-749.
31. Knochel JP, Barcenas C, Cotton JR, et al. Hypophosphatemia and
rhabdomyolysis. J Clin Invest. 1978;62:1240-1246.
32. Guechot J, Cynober L, Lioret N, et al. Rhabdomyolysis and acute
renal failure in a patient with thermal injury. Intensive Care Med.
1986;12:159-160.
33. Pfeifer PM. Acute rhabdomyolysis following surgery for burns. Anaes­
thesia. 1986;41:614-669.
34. Singhal PC, Kumar A, Desroches L, et al. Prevalence and predictors
of rhabdomyolysis in patients with hypophosphatemia. Am J Med.
1992;92:458-464.
35. Loven L, Anderson E, Larsson J, et al. Muscular high-energy phos­
phates and red-cell 2.3-DPG in post-traumatic hypophosphataemia.
Acta Chir Scand. 1983;149:735-741.
36. Loven L, Larsson L, Nordstrom H, et al. Serum phosphate and
2,3-diphosphoglycerate in severely burned patients after phosphate
supplementation. J Trauma. 1986;26(4):348-352.
37. Perreault MM, Ostrop NJ, Tierney MG. Efficacy and safety of intrave­
nous phosphate replacement in critically ill patients. Ann Pharmaco­
ther. 1997;31(6):683-688.
38. Kahn SA, Bell DE, Stassen NA, Lentz CW. Prevention of hypophospha­
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hypophosphatemia. Arch Intern Med. 1977;137:203-220.
9. Lennquist S, Lindell B, Nordstrom H, et al. Hypophosphatemia
in severe burns. A prospective study. Acta Chir Scand. 1979;145:
1-6.
10. Miller SJ, Simpson J. Medication–nutrient interactions: hypophospha­
temia associated with sucralfate in the intensive care unit. Nutr Clin
Pract. 1991;6:199-201.
11. Mostellar ME, Tuttle EP Jr. The effects of alkylosis on plasma concen­
tration and urinary excretion of inorganic phosphate in man. J Clin
Invest. 1964;43:138-149.
12. Solomon SM, Kirby DF. The refeeding syndrome: a review. JPEN J
Parenter Enteral Nutr. 1990;14(1):90-97.
13. Sheldon GF, Grzyb S. Phosphate depletion and repletion: relation
to parenteral nutrition and oxygen transport. Ann Surg. 1975;
182(6):683-689.
14. Hayek ME, Eisenberg PG. Severe hypophosphatemia following the
institution of enteral feedings. Arch Surg. 1989;124:1325-1328.
15. Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill
patients in an intensive care unit. A prospective study. Arch Surg.
1996;131(10):1043-1047.
16. Berger MM, Rothen C, Cavadini C, et al. Exudative mineral losses after
serious burns: a clue to the alteration of magnesium and phosphate
metabolism. Am J Clin Nutr. 1997;65(5):1473-1481.
17. Dickerson RN, Gervasio JM, Sherman JJ, et al. A comparison of renal
phosphorus regulation in thermally injured and multiple trauma
patients receiving specialized nutrition support. JPEN J Parenter
Enteral Nutr. 2001;25(3):152-159.
18. da Cunah DF, dos Santos VM, Monterio JP, et al. Hypophosphatemia
in acute-phase response syndrome patients. Preliminary data. Miner
Electrolyte Metab. 1998;24(5):337-340.

287
Nutritional Needs and Support
for the Burned Patient
JOSHUA S. CARSON, HOUMAN KHOSROZADEH, WILLIAM B. NORBURY,
and DAVID N. HERNDON
28 
novel physiologic state—a state of prolonged acute injury
for which there is no adapted evolutionary response. In
this state, powerfully adaptive responses to immediate
stress become maladaptive when sustained for a timeline
well beyond those encountered in the evolutionary context
(Fig. 28.1).
The hypermetabolic response to stress is particularly
exaggerated in thermal injuries. The severity of the cata­
bolic response to burn injury cannot be overemphasized.
Decades of clinical and animal research have demonstrated
with increasing depth and detail the ways in which burn
injury profoundly alters the host organism’s metabolism to
upregulate catabolic processes and inhibit anabolic pro­
cesses. The net result is a substantial net loss of lean body
weight with a distinctly exaggerated effect on protein stores.
The pathophysiology of this protein wasting is notable for
a diverse array of endocrine and metabolic factors from the
cellular to the organismal level (Fig. 28.2).1–3
Adrenal hyperactivity in burn patients was well docu­
mented more than 50 years ago, with massive surges in
serum and urinary catecholamine levels seen within hours
of burn. Inappropriate catecholamine and cortisol produc­
tion has since been found to persist for weeks to months
following massive burns, with end organ effects reach­
ing the metabolic, cardiovascular, musculoskeletal, and
immune systems.4–8 A sustained surge of catecholamines
and inflammatory cytokines, along with massive wounds
and profound dysregulation of thermal homeostasis, all
combine and interact to yield enormous increases in resting
energy expenditure.
Distorted thermal regulation plays a significant role in
the increase in resting energy expenditures seen in burn
patients. Destruction of a large portion of the primary
thermoregulatory organ, the skin, leads to an ongoing
drain of body heat via decreased insulation and the facili­
tation of evaporative heat loss. The primary central hyper­
thermia associated with the burn response compounds
this energy drain. Alterations in thalamic temperature
set-point, catecholamine-induced hypermetabolism, and
shunting of mitochondrial energy to heat-producing path­
ways all drive the hyperthermia seen within 24 h of burn
injury. As Wilmore and Pruitt et al. described in 1974,
“Burn patients are internally warm, not [just] externally
cold.” Thus, the burn patient’s metabolism is taxed with
the challenge of generating sufficient heat to maintain
a higher body temperature with less heat-conserving
resources.8
Introduction
The massive burn is as much a metabolic insult as it is
a tissue injury. Clearly resultant tissue defects represent
the critical factor in long-term functional complications
from massive burns. In the acute phase of burn care, a
persistent, overwhelming metabolic response to thermal
injury compromises the functional integrity of virtually
every organ system. This response compromises wound
healing capacity and the integrity of the body’s defense
mechanisms.
The massive burn represents a metabolic “double hit,” a
nutritional challenge of both supply and demand for the
injured patient. The burn wound creates drastically
increased demand for anabolic metabolism for wound
healing while simultaneously triggering a systemic cata­
bolic state. The resulting mismatch between high anabolic
demand and negative anabolic supply (catabolism) leads to
a profound state of functional malnutrition which, in turn,
facilitates rapid debilitation and immunosuppression that
place patients at profound risk for infectious complications.
Addressing these nutritional challenges is thus critical to
effective care for the burn patient.
Metabolic Pathology Associated
With Burn Injury
Following all forms of major trauma, inflammatory and
hormonal responses are activated and greatly influence
metabolic pathways and mechanisms. Nutrient intake,
absorption, and substrate assimilation are all affected
during the different stages of the stress response. Nutrient
requirements will increase but become more difficult to
predict, and enteral or parenteral feeding will often be nec­
essary to meet vastly increased nutritional requirements.
The physiologic response to trauma leads to activation
of an array of processes, many of which increase immedi­
ate energy availability as part of the evolved flight-or-flight
response. It is an evolved response to stress that assists the
organism in overcoming a transient stress. However there
is no adaptive response to the kind of sustained stress state
seen with massive burns because these injuries were not
survivable prior to the development of modern medicine.
By supporting patients through what would otherwise be
nonsurvivable states, modern medical care has created a

28  •  Nutritional Needs and Support for the Burned Patient
288
Nutritional Demand and
Substrate Metabolism in
Burn Patients
INCREASED TOTAL CALORIC DEMAND
Thermal injury triggers a marked increase in global energy
expenditure, driven by a maelstrom of catecholamines,
corticosteroids, and inflammatory cytokines.2,9 In an earlier
era of burn care—prior to the advent of early excision,
pharmacologic interventions for hypermetabolism, and
modern critical care—measurements of energy expendi­
ture in patients with large burns were reported to range
from 1.5 to 2.5 times those found in nonburn controls.
While modern burn care has made significant progress in
countering this hypermetabolic response, contemporary
studies still report an average resting energy expenditure
from 1.3 to 1.5 times those found in nonburn controls.10–12
SUBSTRATE-SPECIFIC REQUIREMENTS
See Fig. 28.3 for a simplified overview of the metabolic
pathways involved in massive burn trauma.
Carbohydrates
The acute metabolic response to burn injury significantly
alters carbohydrate metabolism and demands. Glucose/
carbohydrate metabolism presents the burn physician with
a rather vexing conundrum. On the one hand, failure to
provide adequate carbohydrates results in additional com­
pensatory protein catabolism.13,14 And yet, on the other
hand, the human body has a finite capacity for glucose
oxidation. Multiple studies have demonstrated a limit to the
amount of carbohydrate calories a burn patient can
assimilate—approximately 5 g/kg per day in adult and 7 g/
kg per day in children.15,16 Providing glucose in excess of
these limits will thus result in increasing hyperglycemia
with resultant lactic acidosis (Fig. 28.4).
Unfortunately, with the enormous global energy expen­
diture of the massive burn patients, even a diet with a rea­
sonably low percentage of carbohydrate-based calories can
yield total carbohydrate loads well in excess of these limits
when titrated up to meet full caloric requirements. Unfor­
tunately administration of carbohydrates in excess of the
patient’s capacity for glucose oxidation will only result in
increasing degrees of hyperglycemia, glucosuria, and
hypertriglyceridemia. In such cases, the patient’s nutri­
tional demands simply reach a point where they exceed that
patient’s metabolic capacity.
Guidelines typically recommend providing 50–60% of
calories as carbohydrates in the setting of trauma or burn
injury.17–19 However these same guidelines also recommend
that total carbohydrate provisions not exceed 5 g/kg per
Time
Time
Recovery
phase
Initial injury
Initial injury
Chronic phase
Increased
metabolic rate
Decreased
metabolic rate
Increased
metabolic rate
Decreased
metabolic rate
A
B
Fig. 28.1  Metabolic response to injury and trauma. Burn patients transition from the initial hypermetabolic response directly into a state of chronic
hypermetabolism. (A) Classic ebb and flow phases of the acute stress response. The metabolic rate initially falls below normal and then increases to
supranormal levels before returning to normal. (B) Ebb and flow revisited. In burn patients, the classic ebb and flow pattern is altered. Recurrent bouts
of sepsis superimposed over a baseline of burn-induced proinflammatory stimuli result in a fluctuating metabolic demand, which remains chronically
elevated. (From Ball S, Baudouin SV. Endocrine disorders in the critically ill: the endocrine response to critical illness. In Hall GM, Hunter JM, Cooper MS, editors.
Core topics in endocrinology in anaesthesia and critical care. Cambridge: Cambridge University Press; 2010: 126–131.)
Nitrogen excretion (g/day)
4
16
12
8
20
30
Major burn
Skeletal trauma
Severe sepsis
Infection
Elective op
Partial starvation
Total starvation
Normal
range
28
24
0
0
10
20
Days
30
40
Fig. 28.2  Thermal injury induces a distinctly profound metabolic shift
towards proteolysis. (From Long CL, Blakemore WS. Energy and protein
requirements in the hospitalized patient. JPEN J Parenter Enteral Nutr. 1979
Mar–Apr;3(2):69–71.)

28  •  Nutritional Needs and Support for the Burned Patient
289
this dilemma is to start by titrating enteral formula delivery
up to a rate that delivers 5–7 g/kg per day of carbohydrates
and then provide all further calories in the form of protein
supplementation.
Fats
While lipids are unquestionably critical to effective basic
homeostasis and wound healing, the amount of fat required
to prevent essential fatty acid deficiency is remarkably small
in patients with intact fat stores. Excess fat administration,
on the other hand, can cause significant harm. The hyper­
metabolic response to thermal trauma upregulates lipolysis
of circulating lipids. This surfeit of circulating free fatty
acids is countered by increased hepatic esterification, with
close to 70% of the free fatty acids accumulating in the liver.
To minimize hepatic steatosis, the percentage of dietary
calories from fat should be limited and carefully monitored.
Multiple studies have demonstrated improved outcomes
with lower fat nutrition therapy in burn patients.21–23 Fat
content should make up 3–15% of total calories. Patients
receiving total parenteral nutrition (TPN) for a short period
of time (e.g., less than 10–14 days) can generally be spared
lipid infusion. In those requiring sustained TPN, 0.5–1 g/kg
one to two times per week is sufficient. It should be noted
that nondietary fat calories need to be taken into consider­
ations as well: for example 1% propofol solution carries a
proportional fat load equivalent to that found in a 10%
intralipid emulsion.
It should be noted that the preceding discussion of the
role of fat alimentation in nutritional therapy reflects a lit­
erature that largely predates the application of alternative
day (or 7 g/kg per day in children). Unfortunately provid­
ing 50–60% of calories as carbohydrate in the context of
a nutritional therapy that meets the appropriately calcu­
lated total caloric needs of a burn patient will often result
in doses of carbohydrates well in excess of these recom­
mended limits.11,12,16,18–20 There is no simple, clinically
vetted solution to this challenge. A reasonable approach to
ATP
Mitochondrion
0 AA
TCA
Acetyl-CoA
Lactate
β-OXIDATION
Fatty acyl-CoA
LIPOLYSIS
Fats
Fats
Glucose
GLYCOLYSIS
ATP
Pyruvate
UREA
NH3
Amino
acids
Amino
acids
PROTEIN
TURNOVER
Protein
Albumin
Plasma membrane
Fig. 28.3  Simplified overview of metabolic pathways.
Liver
Oxaloacetate
Glucose
NADH
NAD+
Lactate
Pyruvate
O
CO2
Acetyl CoA
Fats
Krebs cycle
Fig. 28.4  Oxidative decarboxylation of pyruvate is a pivotal step in the
overall oxidative metabolism of carbohydrates and fats. Overwhelm­
ingly high levels of glucose may lead to lactate production, even in the
presence of oxygen. (From Gore DC, Ferrando A, Barnett J, et al. Influence
of glucose kinetics on plasma lactate concentration and energy expendi­
ture in severely burned patients. J Trauma 2000;49:673–677.)

28  •  Nutritional Needs and Support for the Burned Patient
290
ENTERAL NUTRITION
Benefits of Enteral Nutrition
In addition to serving as a means for systemic delivery of
nutrients, enteral nutrition (EN) performs a critical func­
tion in supporting the alimentary tract itself. Enteral feeds
provide direct high-concentration nutrients (e.g., gluta­
mine, alanine), stimulate enteric blood flow, maintain
barrier function by preserving tight-junction integrity, and
induce production and release of mucosal immunoglobulin
and critical endogenous growth factors. These functions are
not replaced with parenteral nutrition (PN).35 After dietary
ingestion, polysaccharides such as fiber and starch undergo
bacterial fermentation in the colonic lumen. Bacterial fer­
mentation provides two functions crucial to intestinal
health: (1) it supports the normal flora of the gut lumen,
which in turn prevents colonization and subsequent infec­
tion (e.g., Clostridium difficile) and (2) it produces acetoac­
etate, propionate, and butyrate (a short-chain fatty acid).
Butyrate appears to be the preferred fuel of colonic mucosa
cells and is therefore essential for mucosal integrity. Both
animal and human studies show that the presence of
enteral feeds (in addition to or in place of PN) is associated
with increased mucosal mass, mucosal oxygenation, brush-
border enzyme synthesis, and villus height when compared
to PN alone.35,36 Clinically enteral feeding has frequently
been found to associate with improved clinical outcomes
both in terms of gastrointestinal and total patient morbidity
and mortality.
Initiation of Feeds
Early Initiation.  Copious data support the safety and
benefit of initiating EN early in the context of traumatic
injury and in burns specifically.37,38 In both clinical and
animal studies of thermal injury and shock, early EN has
consistently been shown to result in improved survival and
function of the enteric mucosa and decreased bacterial
translocation. Perhaps most importantly, early enteral
feeding represents one of the most effective means of meta­
bolic modulation in thermal injury, with a significant blunt­
ing of the catabolic response to thermal injury associated
with early feeding protocols.39–46
Full feeds should not be delivered in the setting of marked
hemodynamic instability and/or high-dose vasopressor
requirements because this runs the risk of inducing or exac­
erbating nonobstructive mesenteric ischemia. However
complete EN can be delivered safely to patients on low to
moderate doses of vasopressors with stable or decreasing
vasopressor requirements.1,17,47
In patients without hemodynamic compromise, feeding
should be initiated rapidly. While the traditional practice
has long been to gradually titrate enteric feeds up to a goal
rate over time, there is reason to suspect that a more aggres­
sive approach may be warranted. Pilot studies have sug­
gested that restarting feeds immediately and at full-goal
postoperatively (rather than titrating) is well tolerated in
burn patients undergoing excision and grafting. The
approach of gradually restarting feeds results in significant
calorie deficits accumulating over the course of care. In
patients still in the midst of resuscitation, though, foregoing
the process of gradually increased feeding rates may
increase the rates of gastric ileus.48,49
fat sources (e.g., fish oil, olive oil, borage oil, etc.). In the
United States, the current standard of care for both enteral
and parenteral fat administration features significant com­
ponents of fats that have been shown to encourage inflam­
mation, most notably omega-6 fatty acids. Alternative fat
sources have become the standard of care in Europe and are
anticipated to receive U.S. Food and Drug Administration
(FDA) approval in this country shortly. While there are still
insufficient data to declare these alternatives superior to the
standard of care, there is certainly sufficient evidence to
warrant future study. As our understanding of the unique
advantages and disadvantages of different fat sources
matures, a reexamination of the role of fat alimentation in
burn nutrition is sure to come due.24
Protein
Proteolysis is the metabolic hallmark of the hypermetabolic
response to thermal injury. As much as 150 g of skeletal
muscle is lost per day in the absence of adequate nutritional
support.6 If not attenuated, ongoing systemic proteolysis
leads to immune dysfunction and retarded wound healing.
Protein requirements of 1.5–2 g/kg per day in burned
adults and 2.5–4 g/kg per day in burned children is well
accepted in clinical practice. Unfortunately there are limits
to the rate of effective protein assimilation as well. Increas­
ing protein intake above these values will often increase
urea load and azotemia, with limited additional impact on
muscle wasting.25–27
Amino acids alanine, arginine, and glutamine play a key
role in wound healing in burn patients. Glutamine plays
an important role in the function of enterocytes and lym­
phocytes, and low plasma glutamine concentrations have
been associated with increased bowel permeability and
increased rates of infection. Copious studies in animal
models of trauma and shock have shown distinct roles
for these particular amino acids in recovering enteral and
immunologic competence.28 Glutamine supplementation
and other “immunotrition” formulas featuring these key
amino acids have been associated with decreased incidents
of infection, shorter hospital stays, and decreased mortal­
ity in the setting of traumatic injury.29–31 While the appro­
priateness and even safety of glutamine supplementation
has recently been called into question by the results of a
large, international randomized controlled trial in critically
ill patients, showing an increased mortality risk in patients
randomized to receive high-dose parenteral glutamine sup­
plements, how these results should be interpreted remains
in question (Fig. 28.5). (See further discussion in the section
on formulas.)
Nutritional Support
In the face of the metabolic storm associated with acute
burn injuries, provision of effective nutritional support is
critical to wound healing, avoidance of complications and,
ultimately, survival. Failure to provide sufficient calories
superimposes starvation over a state of hypercatabolism,
resulting in devastating loss of lean body mass and deple­
tion of the protein-energy pool available to meet the press­
ing needs of wound healing, mucosal integrity, and basic
immunologic defenses.30,32–34

28  •  Nutritional Needs and Support for the Burned Patient
291
can be quite helpful in boosting total protein-caloric
input.
Enteral Access for Feeding
Burn victims, particularly those suffering from larger burns,
frequently prove incapable of eating sufficient quantities to
meet their nutritional needs. Direct enteral feeding (“tube
feeding”) is the route of choice to supplement or replace
oral intake.
Either gastric or small-bowel access tubes can be used for
delivering EN. Gastric feeding access allows for direct
(trophic) feeding of the gastric mucosa. In the immediate
postburn phase of resuscitation, though, gastric dysmotil­
ity can present quite early in response to burn injury and
pose significant risk for aspiration and (particularly in chil­
dren) vagally mediated cardiac events. As such, we recom­
mend placement of a venting naso- or oro-gastrostomy tube
for the duration of initial resuscitation.
The same dysmotility effect does not tend to manifest
in the small bowel as rapidly or as profoundly as in the
stomach. Feeding using a nasojejunal tube advanced past
the ligament of Treitz can be initiated within 6 hours fol­
lowing injury and may help in preempting the onset of
DELIVERING ENTERAL FEEDS
PO Feeding
For the conscious patient with an intact appetite and swal­
lowing function, direct oral intake is the preferred feeding
modality. When prescribing a patient an oral diet, it is essen­
tial that the physician continuously monitor for adequate
intake. In the acute surgical setting, patients may fail to take
in adequate calories due to decreased appetite, depressed
mental status, pain, or any other practical obstacle to
eating. Should a patient consistently fail to meet estimated
caloric needs with a PO diet, consideration should be given
to supplemental feeds via nasoenteric tube.
In those patients continuing to take food orally, careful
monitoring should be maintained to ensure appropriate
nutrition. Left unchecked, patients may frequently under­
eat or take in a disproportionate amount of calories as
sugar or fat. A simple nutritional journal listing all foods
and liquids consumed should be maintained by the nursing
staff, patient, and/or family throughout the day, and dietary
adjustments can be encouraged as needed. In patients
attempting to meet all needs orally (and thus avoid the need
for an enteric access tube), supplemental “protein shakes”
Inflammatory Response
Injury
(wound/trauma/fracture)
Lactate
Cytokines
Arachidonic acid metabolites
Hepatic acute-phase proteins
Oxidizing agents
Glucose
Proteolysis
Glucose
Alanine
Amino acids
Lactate
Catecholamines
Cortisol
Glucagon
Heart/Brain
Amino acids
Muscle
Neuroendocrine Response
Adipose Tissue
Lipolysis
Kidney
Nitrogen wasting
Liver
Fatty acids
Glycogenolysis
Gluconeogenesis
Glycolysis
Lipid complexes
Urea synthesis
Ketones
Urea
Fig. 28.5  Schematic representation of thermal-injury-induced shifts in substrate metabolism.

28  •  Nutritional Needs and Support for the Burned Patient
292
omega-3 fatty acids decrease the production of inflamma­
tory eicosanoids, cytokines, and adhesion molecules. This
occurs directly by replacing arachidonic acid as an eico­
sanoid substrate, inhibiting arachidonic acid metabolism,
and giving rise to antiinflammatory resolvins. The indi­
rect effect occurs through the modulation of transcription
factors that regulate the expression of inflammatory genes.
Omega-3 polyunsaturated fatty acids are potentially useful
antiinflammatory agents and may be beneficial for patients
at risk of acute and chronic inflammatory conditions
(Table 28.2).54
Immune-enhancing formulas consist of nutritional com­
ponents enriched with arginine, glutamine, nucleotides,
and omega-3 fatty acids. Although most formulations are
hyperosmolar at full strength, dilution by 25% to 50% to
make isotonic and hypotonic formulas, respectively, is ini­
tially preferred to minimize the possibility of diarrhea from
excess osmotic load and to facilitate absorption.
A myriad of clinical trials of immunoenhancing nutri­
tional therapies over the past 5–10 years have yielded con­
flicting results ranging from great promise early on to
disappointing and even concerning results from more
recent trials. Most troublesome, the REDOX trial, which
examined the impact of glutamine supplementation in a
large, heterogeneous population of critically ill patients,
found that patients receiving glutamine supplementation
had no benefit but, rather, an actual increase in mortality
as compared to those subjects treated with standard of care.
Naturally this finding has greatly dampened enthusiasm for
glutamine supplementation and immunonutrition in
general.
While application in broader patient populations was dis­
appointing, studies limited to major trauma and burn
patients show a more consistent benefit. It is thus quite
possible that glutamine supplementation and immunonu­
trition can still benefit certain subsets of critically injured
patients, including those with massive burns.29,55–59 Studies
of serum glutamine levels in broad populations of critically
ill patients suggest that not all are deficient. Thus the advan­
tage of immunonutrient supplements may be greater in
populations with a greater risk for deficiency—i.e., premor­
bidly malnourished patients or acutely catabolic trauma
and burn patients.60–65 Finally post-hoc analysis of the
redox data suggested that the majority of the mortality risk
associated with glutamine supplementation could be attrib­
uted to those patients already in multiorgan or renal failure
prior to initiation of treatment. It is therefore quite possible
that glutamine supplementation could prove particularly
beneficial should a different set of exclusion criteria be
applied. Clearly there is significant work to be done before
the precise role of immunonutrient supplementation is
made clear.
PARENTERAL NUTRITION
For decades, the critical-care literature has emphasized the
significant morbidity and even mortality risks associated
with the use of PN. This emphasis on the risks of PN has
led to the widespread dogma that the beneficial impact of
PN can outweigh its risks only when applied to patients
who are otherwise facing prolonged total starvation. More
recent reassessments of PN suggest that the risk profile of
starvation-associated ileus. This approach also allows con­
tinuous feeding during surgeries and physical therapy ses­
sions. It should be noted that some authorities recommend
attempting gastric feeds before resorting to postpyloric
feeding, reasoning that gastric feeds may minimize the risk
of gastric ileus associated with severe injury.
Nasojejunal feeding may be preferable in some settings
because it does not need to be stopped prior to surgery to
prevent aspiration. Contrary to the previously postulated
protective effect of the pyloric sphincter, the largest ran­
domized controlled trial and most recent meta-analysis of
earlier studies indicate that nasogastric and nasojejunal
feeds are associated with comparable rates of pneumonia.50
In the past it was thought that monitoring residual
stomach volumes via gastric tubes prevented aspiration
pneumonia by (1) serving as a marker of enteric feed intol­
erance and (2) alerting the clinician to gastric distension so
that feeds can be held to avert impending reflux and/or
aspiration. Recently large, multiinstitutional clinical trials
have shown that larger gastric residual volumes do not
actually predict aspiration, and forgoing gastric residual
monitoring altogether did not increase the incidence of
pneumonia.51–53 In both studies, increasing or eliminating
the gastric residual volume threshold led to significantly
improved nutritional intakes.
DIET COMPOSITION AND ENTERAL
FEED FORMULAS
Numerous enteral formulations are available and can be
classified according to their composition. Standard formu­
las are sterile, nutritionally complete, and intended for
patients with a normal GI tract who cannot ingest adequate
nutrients and calories by regular oral diets. Modular formu­
las consist of a singular macronutrient as a source of calo­
ries (e.g., fiber, protein) and are generally used by mixing
with standard or specialty formulas (Table 28.1).
In a subset of distinctly hypermetabolic patients, the use
of high-sugar, high-protein diets consisting of 3% fat, 82%
carbohydrate, and 15% protein stimulates protein synthe­
sis, increases endogenous insulin production, and improves
lean body mass accretion.13
Muscle protein degradation is markedly decreased with
the administration of a high-carbohydrate diet compared
with fat-containing diets. Endogenous insulin concentra­
tion is increased, improving the net balance of skeletal
muscle protein by decreasing protein breakdown. (See the
previous discussion on “substrate-specific requirements”
for further discussion of the impact of augmenting various
nutritional components.)
Immunonutrition
As noted earlier, immune dysfunction represents one of
the most critical complications of malnutrition in burn
patients. Specific nutrients, including arginine, omega-3
polyunsaturated fatty acids, glutamine, and nucleotides,
have been shown to modulate the host response in animal
and clinical experiments, with potential improvements in
immune function. Clinically arginine supplementation is
intended to support T lymphocytes and provides a substrate
for the generation of nitric oxide. Inclusion of nucleotides
nonspecifically enhances immune competence. Long-chain

28  •  Nutritional Needs and Support for the Burned Patient
293
significantly mitigated these risks. Multiple large trials have
evaluated the use of PN as a supplement to rather than
replacement for EN, with variable results. Large multiinsti­
tutional clinical trials in broader populations of critically ill
patients have found that the use of PN as a supplement to
EN or as a replacement for EN (i.e., TPN) no longer worsens
outcomes even in patients able to tolerate EN. Perhaps most
PN has declined significantly over the past 20 years in the
setting of improving efficacy of contemporary critical care
practices.66–69
Although PN undoubtedly involves significant risks and
morbidity, there is reason to believe that recent advances in
critical care (e.g., improved glycemic control practices,
increased evidence of infection control techniques) have
Table 28.1  Composition of Various Enteral Nutrition Formulations
Formula
kcal/mL
CHO, g/L
(% Calories)
PRO, g/L
(% Calories)
FAT, g/L (%
Calories)
Osmolality
(mOsm/L)
Comments
STANDARD
Similac
0.67
72 (43)
15 (8)
36 (49)
Infant nutrition
Enfamil
0.67
73 (44)
14 (8)
35 (48)
Infant nutrition
Isomil
0.67
68 (41)
18 (10)
37 (49)
Infant nutrition, lactose-free, used in cow protein allergy
Isosource HN
1.2
160 (53)
53 (18)
39 (29)
490
High nitrogen
Ensure Plus
1.5
208 (57)
54 (15)
46 (28)
680
Concentrated calories
Pediasure Enteral
1.0
133 (53)
30 (12)
40 (35)
335
For ages 1–13 years, with fiber, not easily digestible
Jevity 1 Cal
1.06
155 (54)
44 (17)
35 (29)
300
Isotonic nutrition with fiber
Boost Kid Essential
1.0
135 (54)
30 (12)
38 (34)
550–600
Oral or tube feeding
Boost HP
1.0
137 (55)
62 (24)
25 (21)
650
Oral or tube feeding, high protein
Promote
1.0
130 (52)
62 (25)
26 (23)
340
High protein, oral or tube feeding
Promote w/Fiber
1.0
138 (50)
62 (25)
28 (25)
380
Very high protein, oral or tube feeding
Nutren 1.0
1.0
127 (51)
40 (16)
38 (33)
370
With fiber, decreases diarrhea
IMMUNE-ENHANCING
Crucial
1.5
89 (36)
63 (25)
45 (39)
490
With ARG, critical illness, major surgery, transitional feedings,
hydrolyzed protein
Impact
1.0
130 (53)
56 (22)
28 (25)
375
With ARG, GLN, and fiber
Impact GLN
1.3
150 (46)
78 (24)
43 (30)
630
Immunonutrition, GLN, ARG, omega-3 PUFA, nucleic acids
Oxepa
1.5
105 (28)
63 (17)
94 (55)
535
ARDS, acute lung injury, sepsis; concentrated
SPECIALTY
Glucerna
1.0
96 (34)
42 (17)
54 (49)
355
For glucose-intolerant or diabetic patients, low CHO
Nepro
1.8
167 (34)
81 (18)
96 (48)
585
For CKD and patients on dialysis; concentrated
Osmolite1Cal
1.06
144 (54)
44 (17)
35 (29)
300
Isotonic, for use in those intolerant to hyperosmolar nutrition
Vivonex RTF
1.0
175 (70)
50 (20)
12 (10)
630
Transitional feeding, low fat, easily digestible
Vivonex TEN
1.0
210 (82%)
38 (15%)
2.8 (3%)
630
100% free amino acids, very low fat, used for severe trauma
(e.g., burns) or surgery, transitional feeding
Vivonex Plus
1.0
190 (76%)
45 (18%)
6.7 (6%)
650
100% free amino acids, very low fat, used for severe trauma
(e.g., burns) or surgery, transitional feeding
Elecare
0.67
72 (43%)
20 (15%)
32 (42%)
350
Prepared at 9.4 g/60 mL; amino acid-based nutrition
MODULAR
Resource
Benefiber
0.27
66 (100%)
0%
0%
—
Prepared at 4 g/60 mL; tasteless, odorless, soluble fiber, used
for constipation
Resource
Beneprotein
0.83
0%
200 (100%)
0%
—
Prepared at 7 g/30 mL; whey protein, mixed in foods,
protein-calorie malnutrition
From Al-Mousawi A, Branski LK, Andel HL, et al. Ernährungstherapie bei Brandverletzten. In Kamolz LP, Herndon DN, Jeschke MG, editors. Verbrennungen:
diagnose, therapie und rehabilitation des thermischen traumas. German edition, New York: Springer-Verlag; 2009: 183–194.
ARDS, Acute respiratory distress syndrome; ARG, arginine; CHO, carbohydrate; CKD, chronic kidney disease; GLN, glutamine; PRO, protein.
aData extrapolated from Nestle clinical nutrition: Enteral product reference guide. Minneapolis: Nestle, 2010; and Abbott nutrition pocket guide. Abbott Park,
IL: Abbott Laboratories, 2009.

28  •  Nutritional Needs and Support for the Burned Patient
294
Table 28.2  Effect of Omega-3 Polyunsaturated Fatty
Acids on Eicosanoid Synthesisa
Metabolite
Physiologic Action
Omega-3
Effect
AA EICOSANOID
PGE2
Proinflammatory, vasodilatorb
↓
TXA2
Potent platelet aggregation and
vasoconstrictor
↓
LTB4
Proinflammatory, neutrophil chemotaxis
↓
EPA EICOSANOID
TXA3
Mild platelet aggregation
↑
PGI3
Mild platelet disaggregation
↑
RvE1
Potent antiinflammatory
↑
DHA DOCOSANOID
RvD1
Potent antiinflammatory
↑
NPD1
Potent antiinflammatory,
neuroprotective bioactivity
↑
AA, Arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic
acid; LT, leukotriene; NP, neuroprotectin; PG, prostaglandin; PGI,
prostacyclin; Rv, resolvin; TX, thromboxane.
aBiochemical basis of a less inflammatory phenotype.
bProstaglandin E2 has been reported to have dual activity as both a
pro- and antiinflammatory. The latter effect, although weak, has been
reported to be the effect of the induced production of lipoxins.
Table 28.3  Composition of Parenteral Nutrition
Formulations
Caloric Content
Sample Nutritiona
g/dL
kcal/g
kcal/ mL
mOsm/ L
2-IN-1 SOLUTIONS
Dextrose
DW 10%
10
3.4 (CHO)
0.34
505
DW 30%
30
3.4 (CHO)
1.02
1510
DW 70%
70
3.4 (CHO)
2.38
3530
Amino acids
Aminosyn RF 5.2%
5.2
4 (PRO)
0.2
427
Travasol 10%
10
4 (PRO)
0.4
998
Prosol 20%
20
4 (PRO)
0.8
1835
Lipid emulsion
Intralipid 10%
10
11 (FAT)b
1.1
300
Intralipid 20%
20
10 (FAT)b
2
350
Intralipid 30%
30
10 (FAT)b
3
310
CHO, Carbohydrate; PRO, protein.
a3-in-1 solutions: total nutrient admixture (TNA).
bEstimated at 9 kcal/g for fat plus additional calories from glycerol.
Table 28.4  Clinical Conditions Requiring Cautious Use
of Parenteral Nutrition
Condition
Suggested Criteria
Hyperglycemia
Glucose >300 mg/dL
Azotemia
BUN >100 mg/dL
Hyperosmolality
Serum osmolality >350 mOsm/kg
Hypernatremia
Na >150 mEq/L
Hypokalemia
K <3 mEq/L
Hyperchloremic metabolic
acidosis
Cl >115 mEq/L
Hypophosphatemia
Phosphorus <2 mg/dL
Hypochloremic metabolic
alkalosis
Cl <85 mEq/L
BUN, Blood urea nitrogen.
From Mirtallo JM. In Gottschlich MM, editor. The A.S.P.E.N. nutrition support
core curriculum: a case-based approach: the adult patient. Silver Spring, MD:
American Society for Parenteral and Enteral Nutrition; 2007: 268.
convincingly, Harvey et al. randomized 2400 ICU patients
to receive either EN or PN and found no indication of
increased 30-day morbidity or mortality in the PN group.70
While extremely provocative, these findings have not been
tested in burn patients specifically. Such studies would be
well-warranted and should be encouraged.
The utility of supplemental PN (applied liberally) remains
a matter of considerable debate. It is our opinion that sup­
plemental nutrition can be quite helpful when applied selec­
tively, based on the clinician’s assessment of the individual
patient’s metabolic needs and nutritional status. It is our
practice to use supplemental PN in the acute phase of burn
injury response in any patients unable to tolerate enteral
feeds at quantities sufficient to meet (or at least approach)
protein-caloric requirements. Alternatively in those patients
who manifest enteral feeding intolerance in the subacute
phase of their burn injury response, we typically prescribe
supplemental PN only to those with evidence of preexisting
malnutrition at the time of burn.71–73
Prior to receiving PN, patients should be hemodynami­
cally stable and able to tolerate the fluid volume and nutri­
ent content of parenteral formulations; PN should be used
with caution in patients with congestive heart failure, pul­
monary disease, diabetes mellitus, and other metabolic dis­
orders because the significant amounts of fluid and sugar
may be difficult for patients to tolerate (Table 6.9). While
there has been some debate as to the optimal timing for
initiating TPN in patients unable to tolerate adequate EN,
results of recent large randomized controlled trials suggest
that early initiation of TPN is an appropriate general strat­
egy in such patients (Tables 28.3 and 28.4).66,74,75
MEETING PRESCRIBED FEEDING GOALS
Frequently failures to provide adequate nutrition result not
from underprescription, but from unanticipated (and often
undetected) gaps in execution. Even in the setting of a fully
invested care team treating under a clearly articulated
nutritional care plan, calories provided will frequently fall
short of the amount prescribed because, for example,
enteral feeds are held for studies or procedures or inter­
rupted by the clamping of enteral tubes for medication
administration or transport. Even PN may be interrupted
for transportation or compounding delays.76,77 The key to

28  •  Nutritional Needs and Support for the Burned Patient
295
radiologic confirmation. Tubes can also be inserted under
endoscopic or fluoroscopic guidance (Table 28.5). (See the
preceding section on “delivering enteral nutrition” for a
discussion of ways to minimize aspiration risk.)
Unfortunately in burn patients efforts to deliver adequate
nutrition enterally are frequently complicated by the degree
of feeding intolerance manifested by either diarrhea or ileus
(i.e., aperistalsis). GI ileus may reflect an underlying deterio­
ration; therefore monitoring gastric residual volumes serves
as an indicator of intercurrent conditions such as sepsis. In
burn patients specifically, residuals that increase above the
amount of food delivered routinely every hour have been
shown to correlate with the development of bacterial sepsis.
A full sepsis workup should be considered in any critically
ill or injured patient with a sudden increase in gastric resid­
uals over 200 mL.78
Ileus is derived from mesenteric hypoperfusion prior to
adequate resuscitation, and it is reversed once the patient
has been resuscitated. Conversely overresuscitation leads to
GI edema and should also be avoided. The initiation of
minimizing such gaps between prescribed and delivered
calories is awareness, with careful monitoring of delivery.
Once recognized, such gaps can be minimized by making a
conscious effort to keep all feeding interruptions to a
minimum and establishing some mechanism to compen­
sate for anticipated gaps in nutrition. For example, when
prescribing tube feed rates, we often increase the resting
energy expenditure (REE) multiplier to 1.4 or even 1.6 to
compensate for such gaps.
COMPLICATIONS OF NUTRITIONAL SUPPORT
Complications of nasogastric and enteric feeding include
nausea and vomiting, epistaxis, sinusitis, nasal necrosis,
aspiration leading to pneumonia, tube malpositioning, dis­
lodgment, and feeding-associated diarrhea. Fine-bore tubes
are more comfortable but can become blocked easily. Aus­
cultation examination of gastric fluid aspirate and pH
testing can be used to confirm tube position, particularly
for large-bore nasal tubes, although many units prefer
Table 28.5  Complications of Enteral Feeding
Problem
Common Causes
Management
Diarrhea
Medications (e.g., antibiotics, H2 blockers,
laxatives, hyperosmotic, hypertonic
solutions), feeding intolerance
(osmolarity, fat), acquired lactase
deficiency
Measure stool output
Rule out infection (bacterial, viral, parasitic)
Supply fiber
Change medication or formula
Check osmolarity and infusion rate
Replace lost fluids as needed
Administer antimotility medications (e.g., loperamide, codeine)—
Note: do not administer antimotilities until Clostridium difficile
colitis has been ruled out
Nausea and vomiting
Delayed stomach emptying, constipation,
medications, odor and appearance of
formulations
Administer feedings at room temperature
Use isotonic formulations
Use a closed system when possible
Reduce doses of narcotics
Use gastroprokinetic agents (metoclopramide, erythromycin)
Monitor gastric residuals and stool output
Constipation, fecal
impaction
Dehydration, lack or excess of fiber
Monitor fluid balance daily
Rectal disimpaction
Consider the use of cathartics, stool softeners, laxatives, or enemas
Aspiration
pneumonitis
Long-term supine position, delayed
stomach emptying, altered mental status,
malpositioned feeding tube, vomiting,
nonfunctional nasogastric drainage tube
Place head of bed at 45 degrees during feedings
Stop EN if gastric residual volume exceeds 200 mL
Use of nasoduodenal or nasojejunal tubes has not been shown to
decrease aspiration risk (when compared to gastric feeding)
Hypervolemic
hyponatremia
(overhydration)
Excess fluid intake, refeeding syndrome,
organ failure (e.g., liver, heart, kidney)
Monitor fluid balance and body weight daily
Consider fluid restriction
Change formula (avoid low-sodium intake)
Initiate diuretic therapy
Hypernatremia
Dehydration, inadequate fluid intake
Increase free water
Dehydration
Diarrhea, inadequate fluid intake
Determine cause
Increase fluid intake
Hyperglycemia
High content of carbohydrate in feedings,
insulin resistance
Evaluate and adjust feeding formula
Consider insulin regimen
Check for dextrose-based carriers in IV medications
Hypokalemia,
hypomagnesemia,
hypophosphatemia
Diarrhea, refeeding syndrome
Correct electrolyte abnormalities
Determine cause
Reduce rate if refeeding syndrome is present and monitor patient
Hyperkalemia
Excess potassium intake, renal impairment
Change feeding formula
Reduce potassium intake
Consider insulin regimen

28  •  Nutritional Needs and Support for the Burned Patient
296
rapid administration of hyperosmolar solutions may result
in diarrhea, dehydration, electrolyte imbalance, hypergly­
cemia, and loss of potassium, magnesium, and other ions
through diarrhea. Reducing the osmolality by decreasing
formula strength while adjusting the rate is the first step in
addressing this complication. If aggressive administration
of hyperosmolar solute continues, pneumatosis intestinalis
with bowel necrosis and perforation can result. Hyperosmo­
lar nonketotic coma can also occur with enteral feedings.
In some cases, diarrhea may persist even after converting
to isoosmolar feeds, reflecting intestinal failure from shock
and/or ischemic insult. In such situations, it may be neces­
sary to convert to TPN with trophic feeds until intestinal
function returns.
Support with PN offers a distinctly different profile of side
effects. The potential complications associated with the
attendant access requirements (i.e., central lines) must be
considered, particularly given the decreasing use of central
lines for nonnutritional applications in contemporary criti­
cal care. And, of course, the PN formula itself can signifi­
cantly disturb metabolic and electrolyte homeostasis.
Without the benefit of first-pass liver metabolism and
responsive regulation of absorption by the functional intes­
tinal mucosa, the direct infusion of nutritional elements
can result in precipitous, often dangerous shifts in serum
chemistry (Table 28.6).
immediate enteral feeding allows the delivery of calculated
caloric requirements by the third day postinjury. Early
enteral feeding is associated with reduction of hyperme­
tabolism and less intense elevations in glucagon, cortisol,
and catecholamine levels.18,20,45,60
Diarrhea probably represents the most common compli­
cation of EN and typically presents an ongoing challenge
in the management of the massively burned patient. The
source of this diarrhea is multifactorial, making it fairly dif­
ficult to manage. In the setting of shock, diarrhea can rep­
resent mucosal failure from incipient intestinal ischemia. A
variety of medications can contribute to this problem, most
notably antacid agents and antibiotics. Infectious causes
are not particularly common but nonetheless must be ruled
out. Clostridium difficile should always be ruled out due to its
potential for severe deterioration and the risk for contagion
to other patients. Cytomegalovirus enterocolitis can emerge
secondary to burn-associated immunosuppression. Natu­
rally, specific pathogens endemic to the individual patient’s
exposure history should always be considered.
The most common source of diarrhea in burn patients
treated with enteral tube feeds is likely the feeds themselves.
The high osmolar concentration of these feeds, the volume
of feeds required to meet the high caloric requirements of
burn patients, and the gut response to stress all combine to
result in a state of relative solute overload. Inappropriately
Table 28.6  Complications of Parenteral Nutrition
Problem
Common Causes
Management
Hypoglycemia
Excess insulin administration, sudden
cessation of PN infusion
Stop insulin
Start 10% dextrose IV
Give a 50% dextrose ampule before resuming central line
feeding
Hyperglycemia
Excess dextrose concentration, stress-
associated (e.g., sepsis), chromium
deficiency
0.1–0.2 U insulin/g dextrose therapy, SQ or IV insulin
sliding scale, limit dextrose content, consider
discontinuing PN until improved blood glucose control
Hypertriglyceridemia (acceptable
concentrations <400 mg/dL)
Dextrose overfeeding, rapid administration of
intravenous fatty emulsion (>110 mg/kg/h)
Infusion of IVFE should be restricted to less than 30% of
total calories or 1 g/kg/day, given slowly, over no less
than 8 to 10 h, if administered separately
Essential fatty acid deficiency
(e.g., dermatitis, alopecia,
hepatomegaly,
thrombocytopenia, anemia)
1- to 3-week administration of PN lacking
linoleic and alpha-linolenic fatty acid
emulsions
2–4% daily energy requirements should be derived from
linoleic acid, 0.5% from alpha-linolenic acid43 (500 mL
of 10% IVFE over 8–10 h, twice weekly)
Electrolyte and mineral
abnormalities
Inadequate monitoring
Inadequate supplementation in TPN formula
Electrolytes should be checked daily and parenteral
nutrition formulas should be adjusted daily until
electrolytes stabilized
Parenteral iron uncommonly increases risk of
anaphylactic reactions
Azotemia
Dehydration, excess protein, inadequate
carbohydrate calories
Free water, 5% dextrose via a peripheral vein
Metabolic bone disease
(osteoporosis in 41% of those
on long-term home PN)
Unclear, multifactorial (e.g., postmenopausal,
long-term PN, Cushing’s syndrome, Crohn’s
disease, malabsorption, multiple myeloma,
osteogenesis imperfect, corticosteroids,
heparin, immobilization)
Early screening of risk factors, DEXA, management of
premorbid conditions
Special PN considerations: Supplement calcium, P, Mg, Cu
Minimize aluminum contamination, treat metabolic
acidosis, avoid heparin
Elevated liver function
parameters (increased
transaminase, bilirubin,
alkaline phosphatase levels)
Common following initiation; usually
temporary
If persistent, usually caused by amino acid load; reduce
protein delivery
DEXA, Dual-energy x-ray absorptiometry.

28  •  Nutritional Needs and Support for the Burned Patient
297
Refeeding syndrome is a rare but dramatic clinical entity
occasionally seen when initiating nutritional support in
patients with long-standing starvation. It is heralded by the
development of refractory hypokalemia, hypomagnesemia,
and hypophosphatemia. Electrolyte abnormalities can
result in cardiac failure and dysrhythmias, respiratory
failure, neurologic disturbances, and renal and hepatic dys­
function. This should not present a concern in patients
treated with early initiation of nutrition postinjury and
continuous nutritional support.
Nutritional Assessment
and Monitoring
Goal-directed nutritional support is a cornerstone of effec­
tive burn care. Underfeeding can result in stalled wounded
healing, pulmonary compromise, increased immunocom­
promise, and a myriad of secondary and tertiary complica­
tions. Overfeeding is detrimental as well, leading to
hypercapnia and metabolic acidosis, hyperglycemia, hyper­
triglyceridemia, hepatic dysfunction, and azotemia. Thus
an ongoing nutritional assessment is the starting point for
any nutritional therapy.
TOTAL CALORIC REQUIREMENTS
Determining nutritional requirements for patients is essen­
tial to effective care because the provision of inadequate or
excess calories can adversely affect outcome. Caloric
requirements in patients with severe burns are particularly
difficult to predict because energy expenditure varies widely
both from patient to patient and over the course of any
individual patient’s care. Energy demand and the metabolic
response shift gradually with changes in body composition
and acutely with acute physiologic stresses such as opera­
tive interventions or septic episodes.
A variety of equations have been created to estimate
caloric requirements in burn patients (Tables 28.7 and
28.8). Although these are useful for establishing a quick
estimate of caloric needs, their accuracy is limited.79
Because no algorithm can fully accommodate the complex
interactions among surgical stress, wound burden, infec­
tious complications, and metabolism seen in the thermally
injured patient, in situ measurement of REE are particu­
larly valuable in this population.
An evaluation of the metabolic status can be performed
by indirect calorimetry using bedside metabolic carts, which
measure REE using expired gas volumes; oxygen consump­
tion (VO2) and carbon dioxide production (VCO2) are mea­
sured directly as follows:
REE kcal day
VO
mL
VCO
mL
(
)
.
( .
min
.
min )
[
]
[
]
=
+
1 44 3 9
1 1
2
2
These steady-state measurements have been shown to
predict 24-hour energy expenditure with remarkable accu­
racy.79 Measurements obtained are generally reliable and
reproducible over a wide range of catabolic conditions,
metabolic rates, and values of FiO2. Given the significant
changes in energy expenditure occurring over the course of
care, the use of bedside carts for repeated measurements is
Table 28.7  Formulas for Estimating Caloric
Requirements in Adult Burn Patients
Formula
Equation
Comments
HARRIS-BENEDICT61
Men
BEE (kcal/ day) = 66.5 +
(13.75 × W) + (5.00 ×
H) − (6.76 × A)
Multiply BEE by stress
factor of 1.2–2.0
(1.2–1.5 sufficient for
most burns) to
estimate caloric
requirement
Women
BEE (kcal/day) = 655 +
(9.56 × W) + (1.85 ×
H) − (4.68 × A)
CURRERI
Age, 16–59 years
Calories (kcal/day) =
(25 × W) + (40 × %
BSAB)
Specific for burns, may
significantly
overestimate energy
requirements,
maximum 50% BSAB
Age >60 years
Calories (kcal/day) = (20
×W) + (65 × % BSAB)
A, Age (yr); BEE, basal energy expenditure; % BSAB, percentage of total body
surface area burned; H, height (cm); W, weight (kg).
Table 28.8  Formulas for Estimating Caloric
Requirements in Pediatric Burn Patients
Formula
Sex/Age (Years)
Equation (Daily
Requirement in kcal)
WHO
Males 0–3
(60.9 × W) − 54
3–10
(22.7 × W) + 495
10–18
(17.5 × W) + 651
Females 0–3
(61.0 × W) − 51
3–10
(22.5 × W) + 499
10–18
(12.2 × W) + 746
RDA
0–6 months
108 × W
6 months–1 year
98 × W
1–3
102 × W
4–10
90 × W
11–14
55 × W
Curreri junior
<1
RDA + (15 × %BSAB)
1–3
RDA + (25 × %BSAB)
4–15
RDA + (40 × %BSAB)
Galveston infant
0–1
2,100 kcal/m2 BSA +
1,000 kcal/m2 BSAB
Galveston revised
1–11
1,800 kcal/m2 BSA+
1,300 kcal/m2 BSAB
Galveston
adolescent
12+
1,500 kcal/m2 BSA+
1,500 kcal/m2 BSAB
Adapted from Al-Mousawi A, Branski LK, Andel HL, et al. Ernährungstherapie
bei Brandverletzten. In Kamolz LP, Herndon DN, Jeschke MG, editors.
Verbrennungen: diagnose, therapie und rehabilitation des thermischen
traumas, German edition. New York: Springer-Verlag; 2009: 183–194.
BSA, Body surface area; RDA, recommended dietary allowance.

28  •  Nutritional Needs and Support for the Burned Patient
298
muscle mass. Accumulation of fat, on the other hand, fre­
quently occurs in the face of significant malnutrition and
physiologic deterioration. As such, lean body mass serves as
the most appropriate surrogate marker for nutritional well-
being available in the context of acute burn care.
Massive thermal injury induces a profound protein
wasting state. The loss of muscle seen during the acute
response to a massive burn injury represents one of the
most impressive and tangible nutritional phenomena one
can encounter clinically—a muscular young patient pre­
senting with massive burns can easily waste away to a bony,
emaciated appearance over a 2-week period. This negative
nitrogen balance is not simply a product of starvation, but
also a function of an inexorable upregulation of protein
catabolism. Muscle catabolism has been shown to persist in
burn patients, even in the setting of aggressive feeding and
protein supplementation. The net effect of this metabolic
shift is manifest through a rapid and profound loss of lean
body mass.7,12,14,81–83
Obesity
Multiple studies have identified high rates of critical mal­
nutrition in obese patients who, despite generous fat stores,
show markedly low lean body masses—a phenomenon
termed sarcopenic obesity.84,85 Furthermore patients will
often continue to lose lean body mass despite their exces­
sive caloric stores. In patients with sarcopenic obesity,
surgical morbidity and mortality rates correlate far more
closely with lean body mass than with gross mass or any
calculated “ideal” weight. As such, obesity should not be
interpreted as a state of overnourishment, but quite the
opposite.
In the broader critical care literature, there has been a
compelling discussion of the potential benefits of hypocalo­
ric, high-protein feeding regimens in the critically ill obese.84
Given the profoundly hypermetabolic state associated with
thermal injury, use of an “underfeeding” strategy in an
obese burn patient raises considerable concerns for safety
and is probably best reserved for a research setting.
Even in those patients not obese at time of injury, body
composition in burn patients frequently moves toward a
state of sarcopenic obesity. As emphasized earlier, the meta­
bolic shift toward proteolysis persists even in the face of
aggressive nutrition. In the context of this muscle-wasting
milieu, any access or “free” calories available are more likely
to be stored as fat while muscle is broken down during
periods of acute caloric debt. Thus Hart et al. demonstrated
that “increased feeding leads to fat rather than lean mass
accretion.”13
Ideal Body Weight
The term “ideal” is not particularly apt, as there is not a
particular limit to how much lean body mass a patient can
healthfully maintain—with lean body masses for well-
nourished nonobese patients determined by a combination
of environmental and genetic factors. Nonetheless equa­
tions for “ideal body weight” (IBW) are useful in patients
whose total weight is distorted by pathologic processes.
While limited in their accuracy, they do provide rough esti­
mates of baseline weight for patients whose total weight is
distorted by pathologic processes such as chronic morbid
obesity or, particularly in burn patients, massive fluid shifts.
ideal for calculating optimal nutritional requirements in
these extremely metabolically labile patients.
To attain a value for REE, indirect calorimetry is per­
formed with the patient completely at rest—ideally hours
removed from any acute manipulation such as medical or
surgical procedure, rehabilitation therapy, and the like. To
estimate the actual daily energy expenditure, this result
is increased by 10–20% to allow for variability and
activity.79,80
Indirect calorimetry also provides insight into the sub­
strate metabolism balance via the respiratory quotient
(RQ = VCO2/ VO2). An RQ in the range of 0.7 to 1.0 is seen
in the normal uptake of mixed substrates. An RQ of 0.7 or
less is consistent with either an increased portion of fat
calories supplied (or utilized) or underfeeding. On the other
hand, an RQ higher than 1.0 suggests lipogenesis from
either carbohydrate-bias skewed input or overfeeding.
Traditionally nitrogen balances have been used to assess
the balance between protein anabolism and catabolism in
trauma patients. A negative nitrogen balance occurs when
the excretion of nitrogen exceeds the daily intake (i.e., net
catabolism), whereas a positive nitrogen balance is associ­
ated with muscle gain. Unfortunately the variable and often
large quantities of nitrogen lost in the wound exudate of
burn patients make measurement of nitrogen balance dis­
tinctly difficult in these patients.
BODY COMPOSITION
Ultimately body composition and changes therein represent
the most fundamental and meaningful reflection of a
patient’s nutritional status and the efficacy of his or her
nutritional therapy.
Total Body Weight
Although total body weight is the simplest means of follow­
ing global changes in body composition, its value as a reflec­
tion of nutritional status is extremely limited. Changes in
total body weight seen over the short term (i.e., days) are
far more sensitive to fluid shifts than they are reflective of
meaningful changes in tissue mass. Over prolonged periods
of time (e.g., weeks to months), severe decline in total body
weight certainly indicates malnutrition and lean body mass
attrition (presuming, of course, that one corrects for ampu­
tations or massive tissue excisions). However total body
weight measures are largely influenced by significant
changes in body fat seen over the course of acute illness. As
such, even on this longer time-scale, the quantity of change
in total body mass does not necessarily correlate to the
quantity of lean body mass loss, nor does preservation of
total body weight imply conservation of lean body mass.
Muscle and Lean Body Mass
“Lean body mass” refers to nonadipose tissue mass, exclu­
sive of any added mass from acute shifts in water content.
because the total mass of viscera and bone matter do not
change at rates capable of causing significant change in
lean body mass over the course of weeks to months, changes
in lean body mass over such periods are interpreted as
reflections of change in muscle mass. A patient receiving
and assimilating adequate substrate and energy to support
all of his or her physiologic needs will maintain or build

28  •  Nutritional Needs and Support for the Burned Patient
299
response to massive burns creates an immediate, intense,
and persistent strain on the patient’s nutritional status.
The systemic response to burn injury alters essentially
all aspects of energy substrate metabolism. The net total
energy expenditure and requirements are markedly aug­
mented by massive burn. Alterations in glucose metabo­
lism favor gluconeogenesis and limited oxidation capacity.
Alterations in lipid metabolism favor lipogenesis and the
accretion and sequestration of fat in a manner that diverts
energy from critical functions. Finally a surge in proteoly­
sis creates an immediate and prolonged protein-wasting
state that results in profound lean body mass loss and, at
worst, compromises in immune, respiratory, and healing
processes.
Given the immense metabolic challenges created by burn
injury, optimizing nutritional support is essential to improv­
ing outcomes in this patient population. Total calories pro­
vided should be based on ongoing assessment of energy
expenditure, ideally using indirect calorimetry. Providing
calories in excess of the patient’s needs (i.e., overfeeding) is
counterproductive. While carbohydrates delivered will fre­
quently provide the majority of calories given, care should
be taken not to give loads that exceed established limits of
glucose oxidation. Provision of adequate protein is critical
to effective nutritional support, and protein supplementa­
tion is likely the ideal means to augment caloric load when
carbohydrate provision is “maxed out.” The amount of
exogenous fat required to avoid essential fatty-acid defi­
ciencies is relatively modest and can be met with relatively
minimal amounts of fat alimentation. Administration of
excessive amounts of fat-based calories can be detrimental
to care—although significant research is required to deter­
mine how the risk–benefit profile of fat alimentation may
differ with use of alternate fat sources.
EN is the first line of nutritional support in the burn
patient, and enteral feeding should be administered as soon
as possible. While oral feeding is theoretically possible, few
patients with massive thermal injuries will be capable of
meeting their full nutritional needs through oral intake
alone. Typically EN will be provided in part or in whole via
enteric access tubes. The enteral system can be accessed via
the stomach for feeding if necessary, although this may be
compromised by gastroparesis. Postpyloric feeding access
offers the benefit of circumventing the potentially paretic
stomach, thus allowing for more dependable sustained
feeding early in the course of treatment. Care should be
taken to minimize the risk of aspiration by undertaking
frequent assessment for nausea or distention. Routine serial
evaluations of gastric residuals have not been shown to be
beneficial. Care should be taken to minimize interruptions
in feeding to ensure that the gap between calories prescribed
and delivered is minimized as much as possible.
Accurate serial assessment of nutritional status and body
composition is central to identifying patient needs, trajec­
tory, and efficacy of care. Unfortunately serum protein
markers and changes in total body weight are inaccurate
reflections of nutritional status, with poor specificity and
sensitivity. Changes in lean body mass and body composi­
tion represent the ultimate reflection of cumulative nutri­
tional status, and evolving applications of imaging
technology have made routine serial evaluation of lean
body mass feasible.
Derived ideal body weights can be helpful when using
weight-based formulas to determine starting points for
quantitative treatment decisions such as drug doses, tidal
volume settings, endpoint physiologic indices, and the like.
Values for IBW can be found in standardized tables that
relate height to expected weight, or IBW can be estimated
by the following equations:
■ Men: 48 kg for the first 152 cm and 2.7 kg for each
additional 2.54 cm
■ Women: 45 kg for the first 152 cm and 2.3 kg for each
additional 2.54 cm
Clinical Imaging
Dual-Energy X-Ray Absorptiometry.  Dual-energy x-ray
absorptiometry (DEXA) is a useful technique for monitoring
long-term nutritional progress by measuring changes in
body tissue composition, including lean body mass, fat
mass, and bone density. DEXA’s precision, accuracy, and
versatility make it extremely useful in a research setting.
Practically speaking, though, few burn centers have the
infrastructure in place to regularly perform such assess­
ments on critically ill patients.
Computed Tomography and Ultrasound.  More readily
available, high-resolution computed tomography (CT)
scanners have been shown to reliably predict DEXA results.
However significant cost, radiation exposure, and need for
patient transport all serve as barriers to widespread clinical
use. More recently, multiple groups have shown that mea­
surements from a limited bedside ultrasound (US) exam can
be used as an accurate and convenient means of serial
assessment. The thickness of a patient’s quadriceps mea­
sured at bedside has been shown to be powerfully predictive
of CT and DEXA assessments of total lean body mass.86,87
Given its ubiquitous availability, low cost, ease of use, and
minimally invasive nature, bedside ultrasound has signifi­
cant potential for widespread clinical application in nutri­
tional assessment and monitoring. For burn patients, who
are at a uniquely high risk from nutritional morbidity and
frequently present a myriad of unique transportation chal­
lenges, this bedside measure may prove quite valuable.
Albumin and Serum Markers for Nutrition
Serum protein markers, most notably albumin, have dem­
onstrated significant value in assessing nutritional status
and predicting outcomes in the setting of patients consid­
ered for elective surgery. Unfortunately the value of serum
protein levels as indicators of nutritional status is extremely
limited during the acute-phase response to injury, inflam­
mation, infection, and surgical stress. The physiologic stress
response upregulates expression of acute-phase reactive
proteins, with unpredictable effects on “marker” protein
levels. In the setting of acute burn care, presenting albumin
levels or short-term changes therein should not be inter­
preted as being indicative of nutritional progress.34,88,89
Conclusion
Burns involving more than 20% of the total body surface
area represent a massive metabolic injury. The metabolic

28  •  Nutritional Needs and Support for the Burned Patient
300
Gore D. Acute response of human muscle protein to catabolic hormones.
Ann Surg. 1993;218(5):679-684.
Harvey S. A multicentre, randomised controlled trial comparing the clini­
cal effectiveness and cost-effectiveness of early nutritional support via
the parenteral versus the enteral route in critically ill patients (CALO­
RIES). Health Technol Assess. 2016;20(28):1-144.
Heyland D. Enhanced protein-energy provision via the enteral route
feeding protocol in critically ill patients: results of a cluster randomized
trial. Crit Care Med. 2013;41(12):2743-2753.
Khalid IP. Early enteral nutrition and outcomes of critically ill patients
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Reiss EE. The metabolic response to burns. J Clin Invest. 1956;35(1):62-77.
Wolfe R. Caloric Requirements of the burned patient. J Trauma. 1981;21:
712-714.
Yan H. Effects of early enteral arginine supplementation on resuscitation
of severe burn patients. Burns. 2007;33(2):179-184.
Zhou Y. The effect of supplemental enteral glutamine on plasma levels, gut
function, and outcome in severe burns: a randomized, double-blind,
controlled clinical trial. JPEN J Parenter Enteral Nutr. 2003;37(4):
241-245.
The physiologic response to massive thermal injury rep­
resents an enormous nutritional insult. The consequences
of this intense acute malnutrition include compromises in
immune function, wound healing, and mobility—all major
drivers of morbidity and mortality in thermal trauma. As
such, thoughtful and comprehensive nutritional support
based on continuous assessment of nutritional needs is
essential to optimizing outcomes in acute burn care.
Complete references available online at

Further Reading
Boelens P. Reduction of postoperative ileus by early enteral nutrition in
patients undergoing major rectal surgery: prospective, randomized, con­
trolled trial. Ann Surg. 2014;259(4):649-655.
Casaer MP, et al. Impact of early parenteral nutrition on muscle and
adipose tissue compartments during critical illness. Crit Care Med.
2013;41(10):2298-2309.
Garrel DI. Length of care in patients with severe burns with or without
early enteral nutritional support. A retrospective study. J Burn Care
Rehabil. 1991;12(1):85-90.

300.e1
28  •  Nutritional Needs and Support for the Burned Patient
32. Berger MM, Soguel L, Charrière M, et al. Impact of the reduction of
the recommended energy target in the ICU on protein delivery and
clinical outcomes. Clin Nutr. 2017;36(1):281-287.
33. Czapran A. International observational study of nutritional support
in mechanically ventilated patients following burn injury. Burns.
2015;41(3):510-518.
34. Perez-Guisado J. Serum albumin levels in burn people are associated
to the total body surface burned and the length of hospital stay but
not to the initiation of the oral/enteral nutrition. Int J Burns Trauma.
2013;3(3):159-163.
35. Alverdy JE. Total parenteral nutrition promotes bacterial transloca­
tion from the gut. Surgery. 1988;104(2):185-190.
36. Groos SG. Parenteral versus enteral nutrition: morphological
changes in human adult intestinal mucosa. J Submicrosc Cytol Pathol.
1996;28(1):61-74.
37. Barlow R. Prospective multicentre randomised controlled trial of early
enteral nutrition for patients undergoing major upper gastrointestinal
surgical resection. Clin Nutr. 2011;30(5):560-566.
38. Osland E. Early versus traditional postoperative feeding in patients
undergoing resectional gastrointestinal surgery: a meta-analysis.
JPEN J Parenter Enteral Nutr. 2011;35(4):473-487.
39. Deitch E. Intestinal permeability is increased in burn patients shortly
after injury. Surgery. 1990;107(4):411-416.
40. Mochizuki H. Mechanism of prevention of postburn hyper­
metabolism and catabolism by early enteral feeding. Ann Surg.
1984;200(3):297-310.
41. Dominioni L. Enteral feeding in burn hypermetabolism: nutritional
and metabolic effects of different levels of calorie and protein intake.
JPEN J Parenter Enteral Nutr. 1985;9(3):269-279.
42. Guo YH. Early enteral nutrition versus late enteral nutrition for burns
patients: A systematic review and meta-analysis. Burns. 2015.
43. Chiarelli A. Very early nutrition supplementation in burned patients.
Am J Clin Nutr. 1990;51(6):1035-1039.
44. Khorasani E. Effect of early enteral nutrition on morbidity and mor­
tality in children with burns. Burns. 2010;36(7):1067-1071.
45. Lam NN. Early enteral feeding for burned patients – an effective
method which should be encouraged in developing countries. Burns.
2008;34(2):192-196.
46. Venter M. Enteral resuscitation and early enteral feeding in children
with major burns – effect on McFarlane response to stress. Burns.
2007;33(4):464-471.
47. Peng YZ. Effects of early enteral feeding on the prevention of enterogenic
infection in severely burned patients. Burns. 2001;27(2):145-149.
48. Shields B. A pilot review of gradual versus goal re-initiation of enteral
nutrition after burn surgery in the hemodynamically stable patient.
Burns. 2014;40(8):1587-1592.
49. Kesey J. A protocol of early aggressive acceleration of tube feeding
increases ileus without perceptible benefit in severely burned patients.
J Burn Care Res. 2013;34(5):515-520.
50. Davies A. A multicenter, randomized controlled trial comparing early
nasojejunal with nasogastric nutrition in critical illness. Crit Care Med.
2012;40(8):2342-2348.
51. Montejo
J.
Gastric
residual
volume
during
enteral
nutri­
tion in ICU patients: the REGANE study. Intensive Care Med.
2010;36(8):1386-1393.
52. Reignier J. Effect of not monitoring residual gastric volume on risk
of ventilator-associated pneumonia in adults receiving mechanical
ventilation and early enteral feeding: a randomized controlled trial.
JAMA. 2013;309(3):249-256.
53. Deane A. Comparisons between intragastric and small intestinal deliv­
ery of enteral nutrition in the critically ill: a systematic review and
meta-analysis. Crit Care. 2013;17(3):R125.
54. Pontes-Arruda A. Enteral nutrition with eicosapentaenoic acid,
gamma-linolenic acid and antioxidants in the early treatment of sepsis:
results from a multicenter, prospective, randomized, double-blinded,
controlled study: the INTERSEPT study. Crit Care. 2011;15(3):R144.
55. Lin J. A meta-analysis of trials using the intention to treat principle for
glutamine supplementation in critically ill patients with burn. Burns.
2013;39(4):565-570.
56. Coudray-Lucas C. Ornithine alpha-ketoglutarate improves wound
healing in severe burn patients: a prospective randomized dou­
ble-blind trial versus isonitrogenous controls. Crit Care Med.
2000;28(6):1772-1776.
57. De Bandt J. Therapeutic use of branched-chain amino acids in burn,
trauma, and sepsis. J Nutr. 2006;136(1S):308S-313S.
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301
Modulation of the
Hypermetabolic Response after
Burn Injury
ASHLEY N. GUILLORY, CRAIG PORTER, OSCAR E. SUMAN, RAMON L. ZAPATA-SIRVENT,
CELESTE C. FINNERTY, and DAVID N. HERNDON
29 
rehabilitation. Muscle wasting occurs due to an imbalance
in the ratio of protein synthesis to protein breakdown.13
Catabolism of LBM correlates with increased morbidity and
mortality in burn victims. After an LBM loss of 10%, marked
delays in wound healing and higher infection rates propor­
tionally increase as the percentage of LBM loss increases.14
Acutely the net LBM losses from muscle wasting lead to
prolonged mechanical ventilation, inhibition of cough
reflexes, and a delay in mobilization, contributing to
increased mortality in these patients.15 Chronically these
losses reduce strength and the possibility for full rehabilita­
tion. Similar to other characteristics of hypermetabolism,
burn-related cachexia can continue for several years follow­
ing injury.3 Furthermore, persistent protein catabolism has
been hypothesized to account for the growth delay that fre­
quently occurs in our pediatric burn patients.16
LBM wasting is hypothesized to be due to a redistribution
of protein as well as use of the skeletal muscle as a fuel
source.8 Nitrogen balance studies (whole-body and cross-
leg) show persistent muscle breakdown for nearly a year
post-burn.17 Our patients experience an average nitrogen
loss of 20–25 grams per square meter of total body surface
area (TBSA) per day, a rate at which lethal muscle cachexia
becomes imminent in less than 1 month if left untreated.8
Since a significant portion of insulin-stimulated glucose
uptake occurs in the skeletal muscle, significant LBM loss
may contribute to post-burn insulin resistance.18 Flakoll
and coworkers showed that increased plasma glucose levels
stimulated whole-body proteolysis in the absence of changes
in leucine oxidation or nonoxidative disposal.19 While LBM
catabolism is elevated, a decrease in regenerative capacity
occurs, further reducing LBM. Satellite cells, the muscle
stem cells that regenerate skeletal muscle, are impacted by
burn injury. Within the skeletal muscle tissue, although
there is an increase in satellite cell proliferation, there is a
concurrent increase in apoptosis, leading to a net reduction
in satellite cells. The end result of the increase in net protein
breakdown alongside a decrease in satellite cells appears to
be a reduction in total LBM.20
In addition to the alterations in skeletal muscle protein
synthesis, breakdown, and regeneration, oxygen consump­
tion is also greatly increased after burn injury.21 However
the molecular mechanism underlying these alterations
is not clearly defined. Recently Porter and colleagues
reported burn-induced derangements of skeletal muscle
mitochondrial function and posited that these changes
are a key contributor to the mechanism of burn-induced
Introduction
A severe burn elicits a stress response that initially assists
the body in compensating for and adapting to a traumatic
injury. There is an elevation in circulating concentrations
of catecholamines such as epinephrine and norepinephrine
alongside a concurrent increase in inflammatory cytokine
production. This stress response is also associated with a
significant increase in metabolic rate.1–3 Altered protein
and glucose metabolism are key factors contributing to
burn-induced hypermetabolism.4 This hypermetabolic,
hyperinflammatory state promotes muscle protein catabo­
lism and organ failure, among other detrimental effects.5
If this response continues unchecked, as occurs in severely
burned patients, the resultant hypermetabolic state hinders
patient recovery and reintegration into society. Thus the
mechanisms underlying the development and persistence
of the post-burn stress response, as well as interventions
to ameliorate these responses, remain areas of intense
research.
Cardiovascular Dysfunction
One of the most profound and well-documented components
of the burn-induced hypermetabolic response is cardiac dys­
function. Immediately following injury, patients experience
shock accompanied by reduced heart rate, cardiac output,
and contractility. By 2–3 days after injury, the cardiovascular
system rebounds, and heart rate and cardiac work increase
significantly above normal levels.6,7 Post-burn heart rates
approach 160% of those in nonburned, healthy patients.5
Systolic dysfunction and increased myocardial energy
demand also occur.8,9 These alterations in cardiac function
are associated with longer stays in the ICU in addition to
increased morbidity, as quantified by number of surgical
interventions.10 Furthermore tachycardia and energy expen­
diture remained elevated for up to 3 years after the external
wounds were healed, underscoring the longevity of the car­
diovascular response to severe burns.11,12
Skeletal Muscle Catabolism
and Regeneration
Post-burn pathophysiological skeletal muscle catabolism
and loss of lean body mass (LBM) significantly prolong

29  •  Modulation of the Hypermetabolic Response after Burn Injury
302
hyperglycemia in burn patients.38 This is further compli­
cated by catecholamine-mediated glycogen breakdown.35
Impaired mitochondrial function in the liver and the skel­
etal muscle has been associated with altered lipolysis and
insulin signaling post-burn by dampening insulin’s inhibi­
tion of glucose production in the liver and altering glucose
uptake into skeletal muscle.33,38–40 Glucagon and pro-
inflammatory cytokines such as interleukin-6 (IL-6) also
play a role in modulating glycogenolysis, gluconeogenesis,
and insulin signal transduction, resulting in further aug­
mentation of hyperglycemia and insulin resistance.41–49
Alterations in Lipid Metabolism
and Fat Composition
Catecholamine-induced lipolysis increases plasma free fatty
acid concentrations, which contributes to organ steatosis
and insulin resistance in patients with severe burns. Kraft
et al. showed that increased plasma triglyceride levels in
severely burned children correlated with poorer outcomes,
including impaired organ function, thus confirming an
earlier report linking elevated triglycerides with morbid­
ity.50,51 Loss of peripheral subcutaneous fat may also play a
role in the development and persistence of insulin resistance
after a severe burn.52 Recently browning of white adipose
tissue (the adoption of a thermogenic brown phenotype by
hypermetabolism.22 Mitochondrial respiration in severely
burned patients is uncoupled for more than 1 year post-
burn, resulting in increased heat production. This heat
production accounts for nearly a third of the total energy
expenditure of the patient and provides a novel therapeutic
target to alleviate hypermetabolism.23,24
Insulin Resistance and
Hyperglycemia
Hyperglycemia is another common metabolic derangement
in response to burn injury that occurs in both pediatric and
adult burn patients and persists well after the initial dis­
charge from the ICU.7,25,26 Insulin resistance and hypergly­
cemia contribute to poor wound healing as well as muscle
catabolism.27–29 Elevated cortisol and catecholamine levels
increase the delivery of glucose to vital organs, thus inhib­
iting insulin’s anabolic functions.30 Catecholamines impair
glucose disposal and contribute to peripheral insulin resis­
tance by inhibiting both insulin release and glucose uptake
(Fig. 29.1).31,32 The availability of gluconeogenic substrates
such as glycerol lactate and alanine is increased by lipolysis
of adipose tissue, glycogenolysis, and proteolysis of skeletal
muscle post-burn, which augments hepatic glucose pro­
duction (Fig. 29.1).31,33–37 Moreover, elevated blood glucose
levels fail to suppress hepatic glucose release, exacerbating
Burn wound
↑↑20-fold Catecholamines
Serum
↑↑Glucagon
↑↑Cortisol ↑↑Insulin
Bone
↓↓Calcium
↓↓Magnesium
Fat
↑↑Oxygen consumption
Heart
↑↑Cardiac output ↑↑Heart rate
↑↑Nitrogen wasting
↑Fractures
↓Bone mineral content
↓Bone mineral density
↑↑Fatty acids
↑↑Glycerol
↑↑Lactate
Glutamine
Kidney
Ammonia
Liver
Urea Ammonia
Glucose
Glycolysis Lactate
Pyruvate
Lipid complexes
Alanine Glutamine
Muscle
Glucose
Glycolysis Lactate
Pyruvate
Glucose
Intestine
Alanine Ammonia
Glutamine
Fig. 29.1  The effects of metabolic dysfunction after severe burn injury. (From Williams FN, Jeschke MG, Chinkes DL, Suman OE, Branski LK, Herndon DN.
Modulation of the hypermetabolic response to trauma: temperature, nutrition, and drugs. J Am Coll Surg. 2009;208(4):489–502.)

29  •  Modulation of the Hypermetabolic Response after Burn Injury
303
NUTRITIONAL SUPPORT
Adequate nutrition is a critical issue for severely burned
patients because patients treated solely with oral supple­
mentation may still lose one-quarter of their preadmis­
sion weight within the first several weeks.64 The marked
post-burn changes in lipid, carbohydrate, and protein
metabolism determine the caloric needs of each respec­
tive patient. Insufficient nutrition may exacerbate muscle
wasting and prolong wound healing. However high-fat
nutritional intake is associated with obesity and hepatic
steatosis after burn injury, negatively impacting morbidity
and mortality.65,66 Caloric enteral intake guided by energy
expenditure is currently recommended to provide sufficient
energy while avoiding overfeeding, which may exacerbate
hypermetabolism.8,57 Over the past 40 years, several formu­
las have been derived to calculate patient-specific caloric
requirements including the Curreri formula (25 kcal/kg per
day plus 40 kcal/% TBSA burned per day).67–70 Recently,
the European Society for Clinical Nutrition and Metabolism
and the American Society for Parenteral and Enteral Nutri­
tion released guidelines recommending that enteral feeding
begin as soon as possible after admission with 1.5–2 g/kg
and 3 g/kg of protein for severely burned adults and chil­
dren, respectively.71,72 Many ICUs deliver a substantial per­
centage of calories as fat (>25%) because essential fatty acid
deficiency frequently accompanies long-term nutritional
supplementation.73 This approach reduces carbohydrate
requirements and burn-induced glucose intolerance, and,
therefore, dietary compositions of 30–50% fat are now the
standard of care when treating critically ill patients. Unfor­
tunately enhanced fat administration in burn patients is
associated with hepatic steatosis, hypoxemia, hyperlip­
idemia, higher infection rates, and higher postoperative
mortality rates.51,74 Hepatic triglyceride levels are higher,
thereby limiting the utility of exogenous lipids as a post-
burn energy source.33,73,76,77 The incidence of fatty liver is
reduced in patients receiving Vivonex T.E.N. compared to
those fed milk.78 Additional benefits attributed to Vivonex
T.E.N. included improved survival, significantly lower
incidences of sepsis, and reduced length of ICU stay per
%TBSA.78 A high-carbohydrate enteral diet was associated
with a reduction in muscle wasting compared to a high-fat,
low-carbohydrate formula.79 We thus advocate nutritional
regimens for burn patients that reduce fat intake to no more
than 3% of the total energy provided.
EXERCISE
Despite nutritional interventions, cachexia and wound
contractures are common comorbidities of major burns.17
While undergoing the hormone and inflammatory stress
responses, patients with large burns are immobile for
extended periods, further prolonging rehabilitation and
recovery. The utilization of exercise therapy attenuates loss
of muscle mass and function and improves cardiopulmo­
nary function. A regimented exercise program improved
pulmonary and skeletal muscle function in both pediatric
and adult burn patients.80–83 A 12-week exercise program
beginning immediately following discharge from the ICU
also significantly increased percent predicted peak heart rate
and maximal oxygen consumption.84 Progressive resistance
white adipocytes) and the implications this potentially has
for patients with diabetes and/or metabolic syndrome has
become the topic of intense research. White adipose tissue
isolated from severely burned patients underwent brown­
ing, where the development of smaller adipocytes with
more mitochondria in addition to elevated expression of
uncoupling protein 1 were observed.53 This response has
since been confirmed by others, affirming that increased
adrenergic and inflammatory stress in white adipose tissue
post-burn is associated with browning.54 Browning of white
adipose tissue has been proposed to play a role in burn-
induced hypermetabolism, where adipose tissue becomes a
more thermogenic tissue in response to severe burn trauma.
Emphasis of future research should be placed on develop­
ing both nonpharmacologic and pharmacologic therapeu­
tic approaches to attenuate or reverse this hypermetabolic
response in adipose tissue.
Nonpharmacological Modulation
of the Hypermetabolic Response
ENVIRONMENTAL SUPPORT
In addition to acting as a protective barrier, the skin plays
a critical role in insulation and thermoregulation. Burn
patients with extensive burn wounds and skin loss also lose
a significant portion of body water, which is also accompa­
nied by heat loss.55 Despite increased water evaporation and
heat loss, core and skin temperatures are elevated in these
patients.56 Resting energy expenditure is increased more
than twofold post-burn (prior to current treatments such
as early wound excision) but can be reduced by approxi­
mately 30% by increasing the temperature of the room
and using occlusive wound dressings.56 Thus environmen­
tal modulation is a key primary treatment goal that is too
often underutilized.
EARLY WOUND EXCISION AND CLOSURE
The practice of early excision of necrotic tissue and burn
wound closure has improved mortality and morbidity
rates.57–59 Early burn wound closure is also associated with
diminished incidence of excessive scars and joint con­
tractures, which results in faster patient rehabilitation.57
The use of various skin substitutes to cover wounds can
reduce hypermetabolism by restoring the protective barrier
required for thermoregulation and prevention of heat loss
and water evaporation. Of note, blood loss is a critical
issue during these operations, as approximately 5% of the
total blood volume is lost with the excision of every 1% of
the body surface.60,61 Blood loss is a major determinant of
morbidity and mortality, and a variety of techniques need
to be used to control bleeding, including the local appli­
cation of fibrin or thrombin sprays, epinephrine-soaked
pads (1 : 40 000), topically administered epinephrine
(1 : 10 000–1 : 20 000), or electrocautery of blood vessels.62
Additional use of tourniquets for pre-excisional tumescence
with epinephrine and saline may also help limit blood loss.63
Thus novel skin substitutes and therapies to improve wound
healing and prevent blood loss are the focus of ongoing
research.

29  •  Modulation of the Hypermetabolic Response after Burn Injury
304
INSULIN-LIKE GROWTH FACTOR-1
Since the positive effects of rhGH on the post-burn hyper­
metabolic response are predominantly mediated by the
secondary mediator IGF-1, it is not surprising that admin­
istration of recombinant human IGF-1 would have similar
results. Indeed, administration of equimolar amounts
of recombinant human IGF-1 along with its binding
protein, IGFBP-3, attenuated muscle catabolism, restored
gut mucosal integrity, enhanced immune function, and
returned serum concentrations of constitutive proteins
to nonburned levels.104–108 However the administration of
IGFBP-3 was associated with increased neuropathies in this
patient population and is not currently recommended for
clinical use.
OXANDROLONE
The use of oxandrolone, an analog of testosterone possess­
ing only 5% of testosterone’s virilizing androgenic effects,
enhances anabolism of muscle protein by improving the
efficiency of protein synthesis in severely burned chil­
dren.109 Oxandrolone administration decreases loss of body
weight and improves healing of the donor site wound.110
In a large clinical trial by our group, 0.1 mg/kg oxandro­
lone administered twice daily reduced length of the acute
hospitalization, sustained LBM, and improved liver protein
synthesis.111 Severely burned pediatric patients receiv­
ing oxandrolone for 1 year experienced improved growth,
decreased cardiac work, and improved muscle strength.112
Oxandrolone treatment also improved lung function at rest
and during exercise in this patient population.113 These
improvements were maintained for up to 4 years after treat­
ment had ended.112 The benefits of oxandrolone adminis­
tration after burn injury were further enhanced when the
treatment period was increased from 1 to 2 years.114
PROPRANOLOL
The catecholamines norepinephrine and epinephrine
activate cardiac β-adrenergic receptors to increase heart
rate and cardiac work in response to severe burn trauma.
Propranolol is a nonspecific β-adrenergic antagonist
that prevents catecholamine activation of β-adrenergic
receptor-mediated signal transduction. The administration
of propranolol (titrated to decrease heart rate by 15–20%)
diminishes cardiac work and reduces hepatic steatosis, as
shown in several studies.9,77,115–118 Also, administration of
propranolol leads to reduced skeletal muscle catabolism
and increased LBM post-burn, as demonstrated using stable
isotope studies and body composition analysis.5 In the post-
burn environment of heightened protein breakdown and
peripheral lipolysis, propranolol enhances protein synthesis
and improves post-burn morbidity.119,120 Similar to oxandro­
lone, long-term propranolol administration was associated
with decreased cardiac work, resting energy expenditure,
and other key markers of the hypermetabolic, hypercata­
bolic response to burn injury.118 Furthermore patients
treated with propranolol for 12 months showed improved
LBM accretion and reduced bone mass.118 While the major­
ity of investigation into the use of propranolol post-burn
has been in pediatric patients, we have shown that, in adult
exercises maintain or even increase LBM, facilitate the for­
mation of muscle proteins by incorporating amino acids,
enhance muscle strength, and increase walking distances
by 50%.82,85 Celis et al. reported fewer corrective surger­
ies in burned children after resistance exercise training.86
Similarly, Paratz et al. reported that severely burned adults
who participated in an exercise program required fewer
contracture releases.87
Recent studies have shown that exercise training in
adults improves psychosocial outcomes, such as quality of
life, in addition to the expected improvements in physical
function.87 This finding was corroborated by Rosenberg and
colleagues in pediatric patients.88 The combination of exer­
cise training and pharmacological therapies to attenuate
hypermetabolism, such as propranolol or oxandrolone, is
also being investigated. Peak oxygen consumption was sig­
nificantly higher in patients receiving both propranolol and
exercise training.89 The combination of oxandrolone and
exercise resulted in a significant increase in lean body
mass.90 Finally Wurzer et al. reported that the benefits of a
12-week post-ICU discharge exercise program were no
longer apparent at 2 years post-burn, indicating that
patients should continue to exercise to maintain the afore­
mentioned benefits.84
Pharmacological Modulation of
the Hypermetabolic Response
RECOMBINANT HUMAN GROWTH
HORMONE (rhGH)
As demonstrated by our group, during the acute hospital­
ization period, daily intramuscular injection of rhGH
(0.2 mg/kg) reduces the hepatic acute-phase response,
improves muscle protein kinetics, maintains muscular
growth, blunts hypermetabolism, reduces cardiac output,
and decreases donor site healing times by approximately
1.5 days.91–96 Pediatric patients receiving rhGH for 1 year
had significantly higher body weight and LBM at the end of
the treatment period compared to their placebo-treated
counterparts. Additionally rhGH-treated patients had
improved growth as measured by bone mineral content and
height percentiles at both 1 and 2 years after injury.95
Similar improvements with rhGH treatment, such as
increased LBM and muscle strength, have been reported in
burned adults.97
RhGH mediates its effects through its secondary mediator
insulin-like growth factor 1 (IGF-1).98 In patients receiving
rhGH, serum IGF-1 and IGF-binding protein (IGFBP)-3
increased 100% over the levels measured in healthy con­
trols.99 Nevertheless, as demonstrated in a study by Takala
and colleagues, in 532 nonburned critically ill patients,
increased rhGH (0.10 ± 0.02 mg/kg) correlated with
increased morbidity and mortality rates and was associated
with hyperglycemia and insulin resistance.100–102 This may
be reflective of an age-specific effect, however, because in
severely burned children, mortality rates were not affected
by either short- or long-term rhGH administration.95,103
However rhGH-treated burn patients did display an
increased incidence of hyperglycemic episodes and increased
plasma levels of free fatty acids and triglycerides.91

29  •  Modulation of the Hypermetabolic Response after Burn Injury
305
compared to children who received insulin. Therefore,
burned patients receiving insulin had significantly higher
resting energy expenditure and mortality rates than patients
who did not receive insulin.133 These results indicate that,
although attenuating some aspects of the post-burn hyper­
metabolic response, insulin treatment may still contribute
to post-burn morbidities and should be used with caution.
METFORMIN
Metformin is a biguanide drug that corrects hyperglycemia
by stimulating peripheral glucose disposal and blunting
hepatic glucose production. Moreover, unlike insulin, met­
formin is not associated with hypoglycemic events.134–136 In
severely burned patients, metformin not only improved
glucose levels but also improved muscle protein synthe­
sis.136,137 A recent study in burned adult patients confirmed
the benefits of metformin treatment on glucose levels and
insulin resistance.138 Similar to insulin, metformin reduced
the post-burn inflammatory response.138 Insulin sensitivity
was also enhanced with metformin administration.139 One
contraindication of metformin administration in burned
patients is the development of lactic acidosis.140 There has
been one case report of lactic acidosis in a burn patient who
was receiving metformin clinically for type 2 diabetes mel­
litus prior to injury.141 However, in a cohort of 18 metformin-
treated severely burned adult patients, lactic acidosis was
not observed.138 Studies are ongoing to evaluate the inci­
dence of lactic acidosis in burn patients and whether met­
formin will continue to be a valid hyperglycemia treatment
in this patient population. Preliminary data indicate that
metformin is safe and effective in severely burned patients.138
Alternative Therapeutic Options
There have been a variety of drugs investigated to attenuate
the post-burn hypermetabolic hypercatabolic response.
Many of these drugs work to resolve hyperglycemia, such
as
glucagon-like-peptide-1
(GLP-1)
and
peroxisome
proliferator-activated receptor-γ (PPAR-γ) agonists. An
analog of GLP-1, exenatide, decreased burn-induced hyper­
glycemia but required adjunctive insulin therapy to be effec­
tive.142 Fenofibrate, a PPAR-γ agonist, not only improved
plasma glucose levels but also improved insulin signaling in
the muscle and liver, with the end result of increased insulin
sensitivity.38 Fenofibrate also improved skeletal muscle
mitochondrial enzyme activity and respiratory function as
well as whole-body and muscle fat oxidation.38,143 Ketocon­
azole is an antifungal agent that has been shown to reduce
cortisol production, and it was hypothesized that cortisol
reduction would diminish post-burn hypermetabolism and
inflammation. However, despite effectively reducing urine
cortisol levels, ketoconazole did not significantly reduce any
other aspect of the hypermetabolic response.144
Conclusion
The physiologically exhaustive metabolic derangements
accompanying severe burns contribute to morbidity and
mortality in this patient population. Outcomes for these
patients, propranolol administration can reduce blood loss
as well as improve wound healing.121 Thus, β-adrenergic
blockade with propranolol may represent the most effica­
cious anti-catabolic therapy for severe burns.
There are also several published studies that investigated
the use of rhGH in severely burned patients who were also
receiving propranolol. The premise of these studies was that
the co-administration of rhGH and propranolol would have
an additive effect to reduce post-burn hypermetabolism and
catabolism. In a cross-over study of six burned children,
heart rate and the rate of release of free fatty acids were
significantly reduced with co-administration of proprano­
lol and rhGH.119 In a later study, there was no evidence
of an additive effect of combining rhGH and propranolol,
although propranolol did reduce heart rate and energy
expenditure and improve anabolism. This study also did
not find evidence of an anabolic effect of rhGH alone.122 A
prospective randomized control led trial of rhGH and pro­
pranolol co-administration showed that the addition of pro­
pranolol reduced rhGH side effects by reducing peripheral
lipolysis and inflammation.123 These data indicate that the
beneficial effects of these drugs have different mechanisms
and do not display characteristics of a synergistic or addi­
tive relationship.
Recently we investigated whether co-administration
of oxandrolone and propranolol would further improve
post-burn outcomes. Indeed, co-administration of these
drugs decreased duration of growth arrest and increased
growth rate following the resumption of growth in pediat­
ric burned patients.124 Thus oxandrolone, either alone or
with propranolol co-administration, is a viable and promis­
ing therapeutic for attenuating post-burn hypermetabolism
and catabolism.
INSULIN
Like other components of the stress response to burns,
hyperglycemia and insulin resistance persist for up to 3 years
post-injury and may have further long-term health implica­
tions for burn survivors.7,17,27 The most common in-hospital
treatment for post-burn hyperglycemia is insulin adminis­
tration. In addition to its well-known effects on gluconeo­
genesis, proteolysis, and fatty acid synthesis, insulin also
promotes antiinflammatory signaling pathways. Pediatric
burn patients treated with insulin had significantly better
outcomes as evidenced by faster wound healing and reduced
muscle wasting.125–127 Despite these improvements, insulin
administration in this patient population must be performed
cautiously. Studies in critically ill patients using either an
intensive insulin dosing regimen or a continuous hyper­
insulinemic, euglycemic clamp showed that high insulin
doses increased episodes of severe hypoglycemia.128–132 In
addition to the risks associated with high doses of insulin,
it is difficult to maintain a continuous hyperinsulinemic,
euglycemic clamp in severely burned patients because of
their dependence on enteral feeding in the early stages of
recovery. Burned patients also undergo frequent proce­
dures that require the cessation of enteral nutrition, such as
operations and dressing changes. These periods of feeding
cessation result in an increased risk of hypoglycemia.8 In a
study of 243 severely burned children, those who did not
receive insulin had shorter length of stay and no mortality

29  •  Modulation of the Hypermetabolic Response after Burn Injury
306
used in the attenuation of the hypermetabolic and hyper­
catabolic responses. While intensive insulin therapy can
improve mortality and morbidity, there is a need for addi­
tional strategies, such as metformin, that lack the increased
risk of hypoglycemic events associated with insulin treat­
ment. Nonetheless further work is needed to elucidate the
ideal glucose ranges and safety of the aforementioned ther­
apies in this unique patient population.
Complete references available online at

patients have been significantly improved by advances in
nonpharmacologic and pharmacologic therapies (Table
29.1). However therapeutic strategies to abate the persis­
tent hypermetabolism and hyperglycemia remain challeng­
ing. Early burn wound excision and grafting represents
one of the greatest improvements in the past two decades,
improving both morbidity and mortality. Currently the
most effective therapy to reduce the burn-induced hyper­
metabolic and hypercatabolic responses is β-adrenergic
blockade via propranolol administration. rhGH, IGF-1,
and oxandrolone (Table 29.1) have also been successfully
Table 29.1  Summary of the Effects of Various Pharmacologic Interventions on Key Components of the Hypermetabolic
Response to Burn Injury
Drug
Cardiovascular
Skeletal Muscle
Insulin Resistance
Lipid Metabolism
and Fat Composition
rhGH
↓Cardiac output
↑Protein kinetics
↑Body weight
↑Bone mineral content
↑Height percentiles
↑Hyperglycemia
Unknown
IGF-I
Unknown
↓Muscle catabolism
↑Insulin sensitivity
hypoglycemia
Unknown
Oxandrolone
↓Cardiac work
↓Lung function
↑Protein synthesis
↓Loss of lean body mass
↑Growth
↑Muscle strength
No difference
↓Free fatty acids
Insulin
↑Resting energy expenditure
↓Loss of lean body mass
↓Hyperglycemia
↑Liver fat
↑Free fatty acids
↓Fat oxidation
Metformin
↑Resting energy expenditure
↑Protein synthesis
↓Hyperglycemia
↑Insulin sensitivity
Antilipolytic
Fenofibrate
Unknown
↑Mitochondrial enzyme
activity
↓Hyperglycemia
↑Insulin sensitivity
↑Fat oxidation
GLP-1
No difference
Unknown
↓Hyperglycemia
Unknown
Propranolol
↓Cardiac work
↓Tachycardia
↓Resting energy expenditure
↓Skeletal muscle
catabolism
↑Lean body mass
↑Insulin sensitivity
↓Hepatic steatosis
↓Free fatty acids
Ketoconazole
No difference
No difference
No difference
No difference
rhGH + propranolol
↓Resting energy expenditure
↓Cardiac work
↓Skeletal muscle
catabolism
↑Lean body mass
↑Insulin sensitivity
↓Free fatty acids
Oxandrolone +
propranolol
Unknown
↓Duration of growth arrest
↑Growth rate
Unknown
Unknown

306.e1
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307
Etiology and Prevention of
Multisystem Organ Failure
DEREK M. CULNAN, KAREL D. CAPEK, and ROBERT L. SHERIDAN
30 
gut failure, and liver failure also occur. Vasomotor and
cardiac failures are terminal events in both. Survival can be
seen in patients with greater than three organ system fail­
ures, but mortality increases with more failed systems.7
Understanding the progression of the syndrome aids in
prognostication and simplifies decisions regarding termina­
tion of futile efforts.8,9 This chapter discusses the etiology
and prevention of MOF; management will be covered in the
critical care chapter.
Jeschke and Herndon reviewed 573 patients and deter­
mined that burn sizes associated with mortality, sepsis,
infection, and MOF are 60% total body surface area (TBSA)
in children and 40% in adults.10 Kraft and Jeschke moni­
tored MOF in 821 patients to define its course. Respiratory
failure had the highest incidence in the first 5 days. Cardiac
failure occurred throughout the hospital stay. Hepatic
failure increased with hospitalization length and is associ­
ated with high mortality in the late cascade. Renal failure
had an unexpectedly low incidence but was associated with
high mortality in the first 3 weeks. Three or more organ
failures was universally fatal in their cohorts. Overall mor­
tality for patients with MOF was 41% compared to 2%
without.4 The Helsinki Burn Center reported their adult
burn mortalities between 1999 and 2005 as 71 burn
deaths of 1370 patients with 40% caused by MOF and 40%
due to untreatable burn injury. On average, four organ fail­
ures were noted in the deaths, with acute renal failure being
the most common. Sepsis was associated with MOF in all of
their deaths.11
Etiology and Cellular Response
Attempts to define the etiology of MOF range from genomic
and cellular to systemic and epidemiologic. Inadequate oxi­
dative metabolism secondary to hypoperfusion leads to
further organ failure as well as the release of humoral
inflammatory mediators causing further cellular dysfunc­
tion. In ischemia–reperfusion models, oxygen radicals are
generated resulting in peroxidation of cell membrane lipids
and accumulation of activated neutrophils,12 with progres­
sive cellular and whole-organ dysfunction. Critically ill
patients suffer from supply-dependent oxygen consumption
because of defects in cellular oxygen extraction and utiliza­
tion.13,14 This results in inadequate aerobic metabolism
unless supranormal levels of oxygen are supplied.15 Grossly
inadequate delivery of oxygen to cells dependent on aerobic
metabolism can lead to cellular dysfunction, and this may
be followed by organ failures.16
Mitochondrial-specific damage is one of the earliest
responses to burn injury. There is tissue-specific damage to
The cure of many diseases remains unknown.
SOCRATES, CIRCA 400 BC
Videos available at
Introduction
Burn trauma begins via a cutaneous thermal injury with
or without an inhalation injury. These local primary inju­
ries initiate a series of pathophysiologic cascades previously
discussed. Fluid shifts into thermally damaged tissue as well
as global endothelial activation; glycocalyx damage and
systemic inflammation cause burn edema. The resultant
distributive shock combines with humorally mediated myo­
cardial suppression to induce burn shock requiring fluid
resuscitation. Immune hyperactivation, hypermetabolism,
and adrenal hyperreactivity exacerbate this primary injury.
Concomitantly, host defenses such as intact skin1 and
gastrointestinal mucosa2,3 are compromised, resulting in
significant microbial insult from commensal and pathologic
organisms.1 Ultimately, the common lethal end point of
burn trauma and shock is multisystem organ failure (MOF).
In one cohort of 821 severe pediatric burns there was a
19% incidence of MOF with a 100% mortality when involv­
ing three or more organ systems.4
Many scoring systems are currently used to quantify
MOF. The DENVER2 system is widely used in research and
clinical care by scoring pulmonary, renal, hepatic, and
cardiac function from 0 to 3 with a total of 12 points avail­
able (Table 30.1). There is an inflection point after a score
of 3 with significantly increased mortality. The Sequential
Organ Failure Assessment score is based on scores of six
systems from 0 to 4 for pulmonary, coagulation, liver, car­
diovascular, central nervous, and renal (Table 30.2).5 This
definition system, popularized in sepsis and shock arenas,
is at the core of the SEPSIS3 criteria to define septic shock
recently published in the Journal of the American Medical
Association.6
Regardless of the definition used, the more organ systems
fail, the greater the mortality. Currently the best predictive
model for burn mortality is proteomics combined with clini­
cal covariates.4 The time course of these failures and pat­
terns of multiple failures are demonstrated in Fig. 30.1 and
Table 30.3.4 There are two well-described pathways to MOF
in burn patients: early and late.8 The early clinical sequence
is characterized by resuscitation failure leading to adult
respiratory distress syndrome (ARDS), hemodynamic
failure, renal failure, liver failure, gut failure, and sepsis. In
the late cascade seen in patients surviving resuscitation,
pulmonary failure, hemodynamic instability, renal failure,

30  •  Etiology and Prevention of Multisystem Organ Failure
308
Table 30.1  DENVER2 Criteria for Multisystem Organ Failure
Component
Measurement
Score
0
1
2
3
Pulmonary
PaO2/FiO2
≥250
175–249
100–174
<100
Renal
Creatinine
≤1.8
>1.8–2.5
>2.5–5.0
>5.0
Hepatic
Bilirubin
≤2.0
>2.0–4.0
>4.0–8.0
>8.0
Cardiac
Inotropes
See definitions below
Cardiac Score: Scoring for cardiac component is a combination of number and dosage of inotropes administered.
S = small dose, M = moderate dose, L = large dose
Patient receives 0 agents: cardiac score = 0
Patient receives 1 agent:
Patient receives 2 agents:
Dose size
S
M
L
Dose size
(S, S)
(S, M)
M, M)
(L, anything)
Cardiac score
1
2
3
Cardiac score
2
2
3
3
Patient receives 3 or more agents: cardiac score = 3
Table 30.2  Sequential Organ Failure Assessment Criteria
SOFA Score
0
1
2
3
4
WITH RESPIRATORY SUPPORT
Respiration, Pao2/Flo2, mm Hg
>400
≤400
≤399
≤200
≤100
Coagulation, platelets × 103/
mm3
>150
≤150
≤100
≤50
≤20
Liver, bilirubin, mg/dL
(µmol/L)
<1.2 (<20)
1.2–1.9 (20–32)
2.0–5.9 (33–101)
6.0–11.9 (102–204)
>12.0
Cardiovascular, hypotension
No hypotension
MAP <79 mm Hg
Dopamine ≤5 or
dobutamine
(any dose)a
Dopamine >5 or
epinephrine ≤0.1 or
norepinephrine ≤0.1a
Dopamine > 15 or
epinephrine >0.1 or no
epinephrine >0.1a
Central nervous system,
Glasgow Coma Scale score
15
13–14
10–12
6–9
<6
Renal, creatinine, mg/dL
(µmol/L)
<1.2 (<110)
1.2–1.9 (110–170)
2.0–3.4
(171–299)
3.5–4.9 (300–440)
>5.0 (>440)
Or urine output
Or <500 mL/day
Or <200 mL/day
MAP, Mean arterial pressure.
aAdrenergic agents administered for ≥1 h (doses given are in µg/kg/min).
From Dubois MJ, Orellana-Jimenez C, Melot C, et al. Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective,
randomized, controlled, pilot study. Crit Care Med. 2006;34(10):2536–2540.
Max DENVER2 points
Incidence of organ failure
0
0.5
1
1.5
2
2.5
3
Heart
Lung
Liver
Kidney
Days postburn
0
5
10
15
20
25
30
35
40
45
50
55
60
B
% Survival
Days postburn
% Survival
0
10
20
30
40
50
60
70
80
90
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60
No organ
Lung
Heart
Liver
Kidney
100
A
Fig. 30.1  The time course of organ failure over 60 days post burn. (A) The mortality associated with each individual organ failure. (B) DENVER2 scores
associated with each organ failure. (From Kraft R, Herndon DN, Finnerty CC, Shahrokhi S, Jeschke MG. Occurrence of multiorgan dysfunction in pediatric
burn patients: incidence and clinical outcome. Ann Surg. 2014;259(2):381–387.)