Điều Trị Bỏng Toàn Diện (Bản Expert Consult)

The hepatic response to thermal injury
309
the JAK-kinases (JAK-1) and propagation of the signal via
translocation of STATs 1 and 3 to the nucleus, where tran­
scription and translation of acute phase proteins occur. This
rapid initiation of the acute phase response serves a single
purpose: to protect the body from further damage. When the
APR occurs in a balanced fashion, the body is protected and
returns to a homeostatic existence. When there are prolonged
amplifications of proinflammatory cytokines and acute
phase proteins, however, hypercatabolism results, leading to
increased incidence of sepsis, multi-organ failure, morbidity,
and mortality.11,12,112–114
Vitamin metabolism
Vitamins are requisite components of many biological func­
tions including energy production and utilization, inflam­
mation, wound healing, metabolism, and antioxidation.
Vitamin deficiencies are caused by the burn-induced hyper­
metabolic response, so supplementation is required to main­
tain crucial biological functions.122–124 Vitamin A is reduced
in burn patients, perhaps related to reduced levels of its
transporter – retinol binding protein. Without Vitamin A,
dermal wound repair is substandard, and supplementation
with this vitamin enhances wound healing. Vitamin E is a
critical antioxidant that has profound effects in reducing
lung injury. Because this vitamin is also depleted in the
serum and in the tissue following a burn injury, supplemen­
tation is also recommended. Vitamin D, a necessary nutrient
to maintain bone health, is also reduced following a burn
injury; however studies exploring the efficacy of replacement
therapy are ongoing. Riboflavin and Thiamin, also reduced
by burn injury and trauma, are important participants in
energy generation, protein metabolism, and wound repair.
Thiamin is a key co-factor for energy generation in the Krebs
cycle, for glucose oxidation, and for the formation of colla­
gen. Riboflavin decreases post-burn; due to its role as a
coenzyme in oxidation-reduction reactions, this vitamin
should also be supplemented.122–124 Post-burn reduction of
folic acid negatively impacts DNA and RNA synthesis. Folate
utilization is also impaired by inadequate availability of
Vitamin B12 and methionine. Folate deficiency, therefore, can
also occur as a result of deficient levels of these two nutrients.
Energy generating and protein metabolic processes rely on
the coenzymes Vitamin B complex with B6 and B12, neces­
sitating adequate levels of these vitamins. Supplementation
should be in the form of a multi-vitamin in order to have
adequate levels of these necessary components. Additional
functions of these vitamins include fatty acid catabolism
(Vitamin B12) and metabolism of amino acids (Vitamin B6).
The antioxidant/free radical scavenging properties of Vitamin
C are crucial following a burn injury. As part of the hyper­
metabolic response, an elevation in free radicals including
superoxide, peroxide, and hydroxyl are thought to increase
burn-induced vascular permeability. Administration of
Vitamin C may reduce microvascular permeability, which
would reduce fluid replacement in turn, improving patient
outcomes.125
Coagulation and clotting factors
Homeostasis of clotting is complex, and a severe burn injury
alters the coagulation cascade.126 A major thermal injury
is shifted to increase acute phase proteins.13,16,22,26 This shift
in production of acute phase proteins represents a repriori­
tization of liver function to meet new metabolic demands,
heighten the immune and inflammatory responses, and
support coagulation and wound healing.13,16,22,26 Tradition­
ally, acute phase proteins have been divided into two
subcategories based on whether they were mediated by IL-1-
like cytokines such as IL-1 or TNF (type I acute phase pro­
teins, e.g. haptoglobin or α1-acidglycoprotein) or IL-6-like
cytokines, including IL-6 or IL-11(type II acute phase
proteins, e.g. α2-macroglobulin and fibrinogen).13 With
the discovery of new transcription factors, cytokines, and
chemokines, it is no longer clear whether these categories
reflect biological function or whether the lines have been
blurred between the categories. As more evidence supports
frequent communication between the type I and type II
acute phase proteins, this strict division appears to be an
artificial categorization that is no longer representative of
function or response. While acute phase protein synthesis
is upregulated, constitutive hepatic proteins, including
albumin, transthyretin, transferrin, and retinol binding
protein, are downregulated.109–112 Relative to normal levels,
albumin and transferrin expression decreases by 50–70%
following a severe burn.109–112 Two mechanisms downregu­
late the production of these proteins: first the liver shifts
from synthesizing constitutive proteins to acute phase pro­
teins, coupled with extensive loss of constitutive proteins
due to capillary leakage. These proteins are lost into the
massive extravascular space and burn wound. The loss
of these proteins following trauma, however, may be
harmful to patient outcome. Albumin and transferrin are
important transporter proteins and contribute to regulation
of both osmotic pressure and plasma pH.109–112 Due to the
exclusive roles that these proteins play, reduction in their
synthesis has been used to monitor recovery and predict
mortality.11,12,112–115
As noted above, cytokines also mediate the acute phase
response. The temporal, biphasic modulation of proinflam­
matory cytokine expression is highly regulated and predict­
able. Immediately following a burn, there is an increase in
IL-1, IL-6, IL-8, and TNF expression that peaks between 2-
and 10-fold above normal levels. After approximately 12
hours, there is a slight decrease in expression, followed by
another increase before the overall levels begin to decline.
As a testament to the extreme nature of a burn compared
with other traumatic injuries, both animal and human
studies have revealed that cytokines return to normal levels
within 2 days following a trauma, while the elevation can
last for more than 2 weeks after thermal injury.10,16,26,44,70,116
The signaling cascade modulating this response includes a
multitude of pro- and anti-inflammatory signal transcription
factors including nuclear factor-kappa B (NF-κB), c-jun/c-
fos, tyrosine phosphorylation and activation of intracellular
tyrosine kinases (JAKs), CCAAT/enhancer-binding-proteins
(C/EBPs), STAT1, STAT3, STAT5 (signal transducer and acti­
vator of transcription), latent cytoplasmic transcription
factors, and mitogen-activated protein.57,109,110,117–121 Trans­
cription, translation, and expression of acute phase proteins
are initiated by the action of these signaling molecules.
IL-6 in particular is suspected of being a major – if not the
primary – mediating cytokine. Amplification of the IL-6
signal occurs by activation of glycoprotein 130 (gp 130) and

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310
and other pathological states – improvements in cell recov­
ery, muscle protein synthesis, gut and immune function, and
pro-mitogenic functions.7,134–137 In the immediate post-
trauma and post-burn periods, IGF-I is a key player in regen­
erating the liver and modulating the APR to restore hepatic
homeo­stasis and function.136,137 The influence of hormones
on hepatic recovery and regeneration is an important con­
sideration when trying to restore hepatic function.
Importance of the liver for
post-burn outcomes
Although we have heretofore described liver function under
normal and severe stress conditions, whether liver function
and integrity are essential for favorable outcomes following
a severe burn has yet to be determined. Price et al. found138
an association between impaired liver function and integrity
and unfavorable post-burn outcomes in a retrospective
study; however, no prospective studies have been conducted
to test this. Therefore, we conducted several studies to deter­
mine the relationship between liver function and burn
outcomes. In a review of autopsies from severely burned
children, Barret et al.29 reported the incidence of hepato­
megaly, fatty liver, and sepsis. Some 80% of the patients had
hepatic fatty infiltrate, while an astonishing 100% of patients
had hepatomegaly. Additionally, it was found that the inci­
dence of sepsis was greater in patients with severe fatty infil­
tration of the liver. Since all decedents had hepatomegaly,
whether this occurs in surviving patients or only patients
who do not survive the injury had to be determined. In a
study of 102 severely burned children, burn injury was asso­
ciated with liver enlargement in all patients regardless of
outcome.16 During the first week following a burn injury,
liver size was significantly increased (+185 ± 5%), peaked
during the second post-injury week (+226 ± 19%) and
remained significantly enlarged (+189 ± 10%) at the time of
discharge. Prolonged alteration of the hepatic structure was
indicated by the continued increase in predicted liver weight
(+140–150%) even 6, 9, and 12 months post-burn. Synthe­
sis of hepatic proteins was impaired for at least 12 months
following the burn injury.16 Based on this study, it was con­
cluded that a severe burn injury induced significant enlarge­
ment of the liver concurrent with impaired hepatic protein
synthesis.
Mittendorfer et al. determined the contributions of
hepatomegaly and hepatic steatosis to outcomes following
a severe burn in the well established rodent model.107 Fol­
lowing a 60% TBSA burn, nutritional manipulation was used
to induce fatty liver in a subset of rats. Hepatomegaly and
hepatic steatosis were induced by consumption of a high-fat
diet. If both hepatomegaly and fatty liver were present, post-
burn mortality increased to 40% (compared with 0% in the
control group). Based on these findings, we concluded that
the integrity and function of the liver were crucial for survival
after a severe burn injury, as hepatomegaly, hepatic steatosis,
and liver dysfunction were associated with increased post-
burn mortality.107 Other models have been used to demon­
strate the importance of liver function for the survival after
critical illness.139 In a murine sepsis model, Deutschman
et al.139 found that mice without IL-6 (IL-6 knockouts) were
more likely to die as opposed to their non-IL-6 knockout
activates thrombotic and fibrinolytic responses in a manner
directly proportional to the severity of the sustained injuries.
During the early shock phase following the burn, there is a
decrease in most of the homeostatic markers due to dilu­
tional effects associated with fluid resuscitation and loss or
degradation of plasma proteins to the extravascular space or
the wound. Once resuscitation is achieved, clotting factors
typically return to normal levels. Thrombogenicity increases
later during the post-burn course as a result of decreases in
antithrombin III, protein C, and protein S levels accompa­
nied by activation of fibrinolysis by increased levels of tissue
plasminogen activation factor, resulting in an increase in the
risk of thrombosis. The risk for developing disseminated
intravascular coagulation (DIC) is considerably heightened
by this hypercoagulable state. Post-mortem DIC has been
discovered in 30% of all examined cases, indicating another
association between liver damage and poor outcomes – in
this case, alterations in the clotting cascade.
Hormones
The liver is a major site for hormone synthesis and action.
In vitro and in vivo studies have demonstrated that HGF
accelerates hepatic regeneration, improves hepatic function,
and modulates the acute phase response.127–129 Elevation of
plasma HGF occurs within 30–60 min following injury, pre­
sumably signaling the hepatocytes to begin dividing in order
to meet the anticipated burden.127–129 The initiating signal
that stimulates plasma HGF upregulation, however, is cur­
rently unknown, although it has been hypothesized that
there is either an increase in extrahepatic production of HGF
by the spleen, lung, gut, or kidney or a decrease in excretion
of hepatic HGF.127–129 Hepatocyte mitogenesis, along with
motogenesis and DNA synthesis, are stimulated by this rapid
increase in HGF.27 HGF only has this effect under specific
conditions; when administered to non-injured rats, only a
small number of hepatocytes were induced to initiate DNA
synthesis. This study demonstrated that priming events –
such as those experienced following a burn injury – are
required to enable hepatocytes to respond to mitogenic
signals.27
The authors have demonstrated that the acute phase
response can be returned to homeostasis by administering
recombinant human HGF (rhHGF) following a major
burn.128 By a yet to be identified mechanism, following HGF
administration, constitutive hepatic proteins are increased,
and the acute phase proteins are decreased, reversing the
burn-induced APR. The induction of several transcription
factors, including C/EBPs, is likely how the signaling is medi­
ated.130 During the APR, C/EBPα activation stimulates syn­
thesis of constitutive hepatic proteins,130 while synthesis of
acute phase proteins is reduced by blocking C/EBPβ.130 Addi­
tional beneficial effects are provided by post-burn HGF
administration, including maintenance of total hepatic
protein content, triglyceride levels, and liver weight, which
were not found in burned rats receiving saline.15,16
IGF-I – a 7.7-kDa single-chain polypeptide of 70 amino
acids – is also synthesized in the liver.131 In the body, 95–
99% of IGF-I is bound to one of the six binding proteins,
IGFBP 1–6, for transport.131,132 These hormones are synthe­
sized in the liver following growth hormone stimula­
tion.131–133 The effects mediated by IGF-I are similar in burn

The hepatic response to thermal injury
311
DENVER 2 score >4. Discovery proteomics techniques were
used to determine plasma protein expression at the time of
admission and at the time of peak DENVER 2 score (or
time-matched samples in the non-MOF cohort). In burn
patients, 20 proteins were associated with development of
MOF, the majority of which were synthesized in the liver.
These proteins included acute phase proteins, coagulation
factors, inflammatory proteins, and liver enzymes (unpub­
lished data), supporting the notion that post-burn liver
function and the development of MOF are highly related.
A recent study of 100 pediatric patients who did not receive
anabolic or experimental drugs during their hospital course
has elucidated the differences in potential serum biomarkers
that could be used to differentiate survivors from non-
survivors (unpublished data). The panel of 38 potential
biomarkers included hormones, proteins, cytokines, and
electrolytes. The patient cohorts were similar for age, burn
size, and injury severity. The eight analytes – free fatty acids,
retinol binding protein, transthyretin, albumin, α1-acid
glycoprotein, alanine amino transferase, apolipoprotein A1,
and haptoglobin – could be used to determine if a patient
was at higher risk of dying. Taken together, these studies in
severely burned children and adults indicate that the liver is
crucial for determining survival and post-burn outcomes.
Conclusion
To summarize, the widespread effects of a burn injury impact
almost every organ system, resulting in significant morbidity
and mortality.7 This chapter has explored the liver’s central
role in the response to severe thermal injury. The myriad of
functions of the liver are essential for survival (Fig. 25.5),
and a burn injury alters all of these hepatic responses. Avail­
able data provide strong evidence that the concentrations of
hepatic proteins in the circulation can serve as biomarkers
predictive of post-burn morbidity and mortality. We, there­
fore, interpret these findings as supporting the central role
of the liver in determining patient outcome and propose that
liver damage attenuation and hepatic function restoration
will result in a reduction in post-burn morbidity and mortal­
ity. This hypothesis has gained recent support in a recent
littermates with normal IL-6 expression. Hepatic alterations
were apparent in the IL-6 knockout animals following cecal
ligation and puncture. Cholestasis, steatosis, and hepatocel­
lular injury were not found in the normal mice but were
apparent in the IL-6 knockout animals; liver regeneration
was absent in the septic IL-6 knockout animals, while appar­
ent in the normal mice. This study supported the author’s
conclusion that IL-6 is an important regulator of hepatic
dysfunction and mortality following sepsis. The most inter­
esting finding, however, was the association of a three- to
four-fold increase in mortality in animals with hepatic
damage or dysfunction.139 More recent work has linked sig­
naling via Fas and Fas Ligand (Fas/FasL) to hepatic failure
specifically via apoptosis of hepatocytes140,141 Through a
series of RNA interference studies, Song et al.141 elegantly
demonstrated that reduction in the expression of Fas is pro­
tective during fulminant hepatitis. Silencing Fas prevented
death, leading to the conclusion that hepatic dysfunction
contributes to mortality and restoration of hepatic function
reduces mortality.141 Although investigation of the role of
Fas/FasL in burns is still in its infancy stages, evidence sup­
ports the post-burn induction of Fas/FasL,142 possibly hinting
at the mechanism underlying burn-induced hepatocyte
apoptosis and dysfunction.
As animal models do not fully recapitulate the human
clinical response, prospective clinical studies are necessary
to determine the relationship between liver function and
post-burn outcomes. In a study conducted as part of the
Inflammation and the Host Response to Injury Collabora­
tive Research Program, Finnerty et al. (unpublished data)
used discovery proteomics to compare plasma protein
expression in survivors and non-survivors of severe burn
injuries. Of the 39 proteins that were differentially expressed
between the two groups, 23 of these proteins were produced
in the liver and participated in responses mediated by the
liver. These data strongly support the hypothesis that hepatic
function and integrity affect post-burn outcomes including
survival. We expanded these studies to elucidate the role of
the liver in multi-organ failure. A total of 22 patients,
matched according to burn size and injury severity, were
assigned to two groups: burn patients with no multiple
organ failure (MOF) and those with MOF defined as a
Figure 25.5  Overview of hepatic functions and
responses. (With permission from Jeschke MG. The
hepatic response to thermal injury: is the liver important for
postburn outcomes? Mol Med. 2009;15:337-351.)
Coagulation
• Alterations in
clotting system
Hormonal system
• Alterations in
IGF-I, HGF, GH
Acute phase response
• Increased acute phase proteins
• Decreased constitutive proteins
• Increased cytokines
Biliary system
• Intrahepatic cholestasis
• Impaired intrahepatic
bile acid transporters
Metabolic response
• Hyperglycemia
• Insulin resistance
• Proteolysis
• Lipolysis
• Glycogenolysis
• Gluconeogenesis
Reticuloendothelial system
• Depressed RES response
• Immune compromise
Vitamin metabolism
• Decreased vitamin A,
B12, C, D, E

Total Burn Care
25
312
supported, in part, by NIH KL2RR029875 and NIH
UL1RR029876. Authors have no disclosures to declare.
Further reading
Gauglitz GG, Herndon DN, Kulp GA, et al. Abnormal insulin
sensitivity persists up to three years in pediatric patients post-burn.
J Clin Endocrinol Metab. 2009;94:1656-1664.
Jeschke MG, Chinkes DL, Finnerty CC, et al. Pathophysiologic
response to severe burn injury. Ann Surg. 2008;248:387-401.
Jeschke MG, Micak RP, Finnerty CC, et al. Changes in liver function
and size after a severe thermal injury. Shock. 2007;28:172-177.
Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER
stress and restore glucose homeostasis in a mouse model of type 2
diabetes. Science. 2006;313:1137-1140.
book in which Will Self writes regarding the importance of
the liver, ‘Our livers are more valuable than we are, more
able, more alive.’143
Acknowledgments
This chapter was supported by grants from the American
Surgical Association Foundation, the Shriners Hospitals
for Children (8660, 8760, 8740, 84080, and 9145), the
NIH (R01-GM56687, NIH R01-GM08285, T32 GM008256,
and
P50
GM60338),
the
NIDRR
(H133A020102
and H133A070026), and the CFI Leaders Opportunity
Fund (25407). CCF is an ITS Career Development Scholar
 
Access the complete reference list online at

The hepatic response to thermal injury
312.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Bringham PA, McLoughlin E. Burn incidence and medical care
use in the United States: estimates, trends and data sources.
J Burn Care Rehabil. 1996;17:95-107.
2. World Health Organization (WHO). A graphical overview of the
global burden of injuries. Geneva: The Injury Chart Book; 2002.
3. Palmieri TL, Greenhalgh DG. Topical treatment of pediatric
patients with burns: a practical guide. Am J Clin Dermatol.
2002;3:529-534.
4. Nelson KJ, Beierle EA. Exhaust system burn injuries in children.
J Pediatr Surg. 2005;40:E43-E46.
5. Foglia RP, Moushey R, Meadows L, et al. Evolving treatment in a
decade of pediatric burn care. J Pediatr Surg. 2004;39:957-960.
6. Miller SF, Bessey PQ, Schurr MJ, et al. National Burn Repository
2005: a ten-year review. J Burn Care Res. 2006;27:411-436.
7. Herndon DN, Tompkins RG. Support of the metabolic response
to burn injury. Lancet. 2004;363:1895-1902.
8. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by
beta-blockade after severe burns. N Engl J Med. 2001;345:1223-
1229.
9. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin
therapy in critically ill patients. N Engl J Med. 2001;345:1359-
1367.
10. Finnerty CC, Herndon DN, Przkora R, et al. Cytokine expression
profile over time in severely burned pediatric patients. Shock.
2006;26:13-19.
11. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF
monoclonal antibodies prevent septic shock during lethal
bacteraemia. Nature. 1987;330:662-664.
12. Tracey KJ, Lowry SF, Fahey TJ 3rd, et al. Cachectin/tumor
necrosis factor induces lethal shock and stress hormone
responses in the dog. Surg Gynecol Obstet. 1987;164:415-422.
13. Moshage H. Cytokines and the hepatic acute phase response.
J Pathol. 1997;181:257-266.
14. Jeschke MG, Klein D, Herndon DN. Insulin treatment improves
the systemic inflammatory reaction to severe trauma. Ann Surg.
2004;239:553-560.
15. Jeschke MG, Low JF, Spies M, et al. Cell proliferation, apoptosis,
NF-kappaB expression, enzyme, protein, and weight changes in
livers of burned rats. Am J Physiol Gastrointest Liver Physiol.
2001;280:G1314-G1320.
16. Jeschke MG, Micak RP, Finnerty CC, et al. Changes in liver
function and size after a severe thermal injury. Shock.
2007;28:172-177.
17. Jeschke MG, Rensing H, Klein D, et al. Insulin prevents liver
damage and preserves liver function in lipopolysaccharide-
induced endotoxemic rats. J Hepatol. 2005;42:870-879.
18. Moll KJ. Anatomie. Leber. München: Jungjohann Verlag; 2008.
19. Winkeltau G, Kraas E. Leber. In: Schumpelick V, Bleese NM,
Mommsen U, eds. Chirurgie. Stuttgart: Enke Verlag; 2006:658-
675.
20. Schwartz SI. Liver. In: Schwartz SI, Shires GT, Spencer FC, et al.,
eds. Principles of Surgery. New York: McGraw-Hill; 1999:1395-
1436.
21. Küttler T. Biochemie. In: Küttler T, ed. Biochemie. München:
Jungjohann Verlag; 2004:240-265.
22. Jeschke MG, Barrow RE, Herndon DN. Extended hypermetabolic
response of the liver in severely burned pediatric patients. Arch
Surg. 2004;139:641-647.
23. Wolfe RR, Durkot MJ, Allsop JR, et al. Glucose metabolism in
severely burned patients. Metabolism. 1979;28:1031-1039.
24. Wolfe RR, Herndon DN, Jahoor F, et al. Effect of severe burn
injury on substrate cycling by glucose and fatty acids. N Engl
J Med. 1987;317:403-408.
25. Aarsland A, Chinkes D, Wolfe RR. Contributions of de novo
synthesis of fatty acids to total VLDL-triglyceride secretion during
prolonged hyperglycemia/hyperinsulinemia in normal man.
J Clin Invest. 1996;98:2008-2017.
26. Jeschke MG, Chinkes DL, Finnerty CC, et al. Pathophysiologic
response to severe burn injury. Ann Surg. 2008;248:387-401.
27. Gómez-Lechón MJ, Castelli J, Guillén I, et al. Effects of
hepatocyte growth factor on the growth and metabolism of
human hepatocytes in primary culture. Hepatology.
1995;21:1248-1254.
28. Linares H. Autopsy finding in burned children. In: Carvajal H,
Parks D, eds. Burns in Children. Chicago: Year Book Medical;
1991:1-25.
29. Barret JP, Jeschke MG, Herndon DN. Fatty infiltration of the liver
in severely burned pediatric patients: autopsy findings and
clinical implications. J Trauma. 2001;51:736-739.
30. Steller H. Mechanisms and genes of cellular suicide. Science.
1995;267:1445-1449.
31. Ramzy PI, Wolf SE, Irtun O, et al. Gut epithelial apoptosis after
severe burn: effects of gut hypoperfusion. J Am Coll Surg.
2000;190:281-287.
32. Wolf SE, Ikeda H, Matin S, et al. Cutaneous burn increases
apoptosis in the gut epithelium of mice. J Am Coll Surg.
1999;188:10-16.
33. Horton JW. Left ventricular contractile dysfunction as a
complication of thermal injury. Shock. 2004;22:495-507.
34. Horton JW, White DJ, Maass D, et al. Calcium antagonists
improve cardiac mechanical performance after thermal trauma.
J Surg Res. 1999;87:39-50.
35. Baron P, Traber LD, Traber DL, et al. Gut failure and
translocation following burn and sepsis. J Surg Res. 1994;57:197-
204.
36. Baron PW, Barrow RE, Pierre EJ, et al. Prolonged use of
propranolol safely decreases cardiac work in burned children.
J Burn Care Rehabil. 1997;18:223-227.
37. Ikeda H, Suzuki Y, Suzuki M, et al. Apoptosis is a major mode
of cell death caused by ischaemia and ischaemia/reperfusion
injury to the rat intestinal epithelium. Gut. 1998;42:530-537.
38. Noda T, Iwakiri R, Fujimoto K, et al. Programmed cell death
induced by ischemia-reperfusion in rat intestinal mucosa. Am J
Physiol. 1998;274: G270-G276.
39. Bellas RE, FitzGerald MJ, Fausto N, et al. Inhibition of NF-kappa
B activity induces apoptosis in murine hepatocytes. Am J Pathol.
1997;151:891-896.
40. Boehning D, Patterson RL, Sedaghat L, et al. Cytochrome c binds
to inositol (1,4,5) trisphosphate receptors, amplifying calcium-
dependent apoptosis. Nat Cell Biol. 2003;5:1051-1061.
41. Strasser A, O’Connor L, Dixit VM. Apoptosis signaling. Annu Rev
Biochem. 2000;69:217-245.
42. Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12,
an endoplastic reticulum (ER) resident caspase, through tumor
necrosis factor receptor-associated factor 2-dependent
mechanism in response to the ER stress. J Biol Chem.
2001;276:13935-13940.
43. Klein D, Schubert T, Horch RE, et al. Insulin treatment improves
hepatic morphology and function through modulation of
hepatic signals after severe trauma. Ann Surg. 2004;240:
340-349.
44. Gauglitz GG, Song J, Herndon DN, et al. Characterization of the
inflammatory response during acute and post-acute phases after
severe burn. Shock. 2008;30:503-507.
45. Jeschke MG, Boehning DF, Finnerty CC, et al. Effect of insulin
on the inflammatory and acute phase response after burn injury.
Crit Care Med. 2007;35:S519-S523.
46. Jeschke MG, Gauglitz GG, Song J, et al. Calcium and ER stress
mediate hepatic apoptosis after burn injury. J Cell Mol Med.
2009;13:1857-1865.
47. Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce
ER stress and restore glucose homeostasis in a mouse model of
type 2 diabetes. Science. 2006;313:1137-1140.

Total Burn Care
25
312.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
48. Wiseman RL, Balch WE. A new pharmacology – drugging
stressed folding pathways. Trends Mol Med. 2005;11:347-350.
49. Cano N, Gerolami A. Intrahepatic cholestasis during total
parenteral nutrition. Lancet. 1983;1:985.
50. Bolder U, Jeschke MG, Landmann L, et al. Heat stress enhances
recovery of hepatocyte bile acid and organic anion transporters
in endotoxemic rats by multiple mechanisms. Cell Stress
Chaperones. 2006;11:89-100.
51. Bolder U, Ton-Nu HT, Schteingart CD, et al. Hepatocyte
transport of bile acids and organic anions in endotoxemic rats:
impaired uptake and secretion. Gastroenterology. 1997;112:214-
225.
52. Knox J, Demling R, Wilmore D, et al. Increased survival after
major thermal injury: the effect of growth hormone therapy in
adults. J Trauma. 1995;39:526-532.
53. Kobayashi M, Takahashi H, Sanford AP, et al. An increase in the
susceptibility of burned patients to infectious complications due
to impaired production of macrophage inflammatory protein 1
alpha. J Immunol. 2002;169:4460-4466.
54. Kobayashi M, Tsuda Y, Yoshida T, et al. Bacterial sepsis and
chemokines. Curr Drug Targets. 2006;7:119-134.
55. Trop M, Schiffrin EJ, Callahan RJ, et al. Effect of acute burn
trauma on reticuloendothelial system phagocytic activity in rats.
II: Comparison of uptake of radiolabelled colloid and bacteria.
Burns. 1990;16:278-280.
56. Trop M, Schiffrin EJ, Carter EA. Role of skin in the burn-induced
reduction of reticuloendothelial phagocytic activity in rats. Burns.
1990;16:57-59.
57. Klein D, Einspanier R, Bolder U, et al. Differences in the hepatic
signal transcription pathway and cytokine expression between
thermal injury and sepsis. Shock. 2003;20:536-543.
58. Hart DW, Wolf SE, Chinkes DL, et al. Determinants of skeletal
muscle catabolism after severe burn. Ann Surg. 2000;232:455-
465.
59. Reiss E, Pearson E, Artz CP. The metabolic response to burns.
J Clin Invest. 1956;35:62-77.
60. Haze K, Yoshida H, Yanagi H, et al. Mammalian transcription
factor ATF6 is synthesized as a transmembrane protein and
activated by proteolysis in response to endoplasmic reticulum
stress. Mol Biol Cell. 1999;10:3787-3799.
61. Hart DW, Wolf SE, Mlcak R, et al. Persistence of muscle
catabolism after severe burn. Surgery. 2000;128:312-319.
62. Norbury WB, Herndon DN. Modulation of the hypermetabolic
response after burn injury. In: Herndon DN, ed. Total Burn Care.
New York: Saunders Elsevier; 2007:420-433.
63. Norbury WB, Herndon DN, Branski LK, et al. Urinary cortisol
and catecholamine excretion following burn injury in children.
J Clin Endocrinol Metab. 2008;93:1270-1275.
64. Sherwood ER, Toliver-Kinsky T. Mechanisms of the inflammatory
response. Best Pract Res Clin Anaesthesiol. 2004;18:385-405.
65. Pereira CT, Herndon DN. The pharmacologic modulation of the
hypermetabolic response to burns. Adv Surg. 2005;39:245-261.
66. Wolfe RR. Review: acute versus chronic response to burn injury.
Circ Shock. 1981;8:105-115.
67. Cuthbertson DP, Angeles Valero Zanuy MA, Leon Sanz ML.
Post-shock metabolic response. 1942. Nutr Hosp. 2001;16:176-
182.
68. Tredget EE, Yu YM. The metabolic effects of thermal injury.
World J Surg. 1992;16:68-79.
69. Cree MG, Zwetsloot JJ, Herndon DN, et al. Insulin sensitivity
and mitochondrial function are improved in children with burn
injury during a randomized controlled trial of fenofibrate. Ann
Surg. 2007;245:214-221.
70. Jeschke MG, Mlcak RP, Finnerty CC, et al. Burn size determines
the inflammatory and hypermetabolic response. Crit Care.
2007;11:R90.
71. Mlcak RP, Jeschke MG, Barrow RE, et al. The influence of age
and gender on resting energy expenditure in severely burned
children. Ann Surg. 2006;244:121-130.
72. Gearhart MM, Parbhoo SK. Hyperglycemia in the critically ill
patient. AACN Clin Issues. 2006;17:50-55.
73. Robinson LE, van Soeren MH. Insulin resistance and
hyperglycemia in critical illness: role of insulin in glycemic
control. AACN Clin Issues. 2004;15:45-62.
74. Khani S, Tayek JA. Cortisol increases gluconeogenesis in humans:
its role in the metabolic syndrome. Clin Sci (Lond).
2001;101:739-747.
75. Wolfe RR, Herndon DN, Peters EJ, et al. Regulation of lipolysis
in severely burned children. Ann Surg. 1987;206:214-221.
76. Gore DC, Jahoor F, Wolfe RR, et al. Acute response of human
muscle protein to catabolic hormones. Ann Surg. 1993;218:679-
684.
77. Carlson GL. Insulin resistance and glucose-induced
thermogenesis in critical illness. Proc Nutr Soc. 2001;60:381-388.
78. Cree MG, Fram RY, Herndon DN, et al. Human mitochondrial
oxidative capacity is acutely impaired after burn trauma. Am J
Surg. 2008;196:234-239.
79. Hunt DG, Ivy JL. Epinephrine inhibits insulin-stimulated muscle
glucose transport. J Appl Physiol. 2002;93:1638-1643.
80. Cree MG, Newcomer BR, Herndon DN, et al. PPAR-alpha
agonism improves whole body and muscle mitochondrial fat
oxidation, but does not alter intracellular fat concentrations in
burn trauma children in a randomized controlled trial. Nutr
Metab (Lond). 2007;4:9.
81. Gustavson SM, Chu CA, Nishizawa M, et al. Glucagon’s actions
are modified by the combination of epinephrine and
gluconeogenic precursor infusion. Am J Physiol Endocrinol Metab.
2003;285:E534-E544.
82. Akita S, Akino K, Ren SG, et al. Elevated circulating leukemia
inhibitory factor in patients with extensive burns. J Burn Care
Res. 2006;27:221-225.
83. Lang CH. Sepsis-induced insulin resistance in rats is mediated by
a beta-adrenergic mechanism. Am J Physiol. 1992;263:E703-E711.
84. Lang CH, Dobrescu C, Bagby GJ. Tumor necrosis factor impairs
insulin action on peripheral glucose disposal and hepatic
glucose output. Endocrinology. 1992;130:43-52.
85. Lang CH, Frost RA, Vary TC. Regulation of muscle protein
synthesis during sepsis and inflammation. Am J Physiol
Endocrinol Metab. 2007;293:E453-E459.
86. Fan J, Li YH, Wojnar MM, et al. Endotoxin-induced alterations
in insulin-stimulated phosphorylation of insulin receptor, IRS-1,
and MAP kinase in skeletal muscle. Shock. 1996;6:164-170.
87. del Aguila LF, Claffey KP, Kirwan JP. TNF-alpha impairs insulin
signaling and insulin stimulation of glucose uptake in C2C12
muscle cells. Am J Physiol. 1999;276:E849-E855.
88. Sell H, Dietze-Schroeder D, Kaiser U, et al. Monocyte
chemotactic protein-1 is a potential player in the negative
cross-talk between adipose tissue and skeletal muscle.
Endocrinology. 2006;147:2458-2467.
89. Jahoor F, Desai M, Herndon DN, et al. Dynamics of the protein
metabolic response to burn injury. Metabolism. 1988;37:330-337.
90. Jahoor F, Herndon DN, Wolfe RR. Role of insulin and glucagon
in the response of glucose and alanine kinetics in burn-injured
patients. J Clin Invest. 1986;78:807-814.
91. Gauglitz GG, Herndon DN, Kulp GA, et al. Abnormal insulin
sensitivity persists up to three years in pediatric patients
post-burn. J Clin Endocrinol Metab. 2009;94:1656-1664.
92. Ikezu T, Okamoto T, Yonezawa K, et al. Analysis of thermal
injury-induced insulin resistance in rodents. Implication of
postreceptor mechanisms. J Biol Chem. 1997;272:25289-25295.
93. Saffle JR, Graves C. Nutritional support of the burned patient.
In: Herndon DN, ed. Total Burn Care. London: Saunders Elsevier;
2007:398-419.
94. DeFronzo RA, Jacot E, Jequier E, et al. The effect of insulin on
the disposal of intravenous glucose. Results from indirect
calorimetry and hepatic and femoral venous catheterization.
Diabetes. 1981;30:1000-1007.

The hepatic response to thermal injury
312.e3
© Copyright 2012 Elsevier, Inc. All rights reserved.
95. Flakoll PJ, Hill JO, Abumrad NN. Acute hyperglycemia
enhances proteolysis in normal man. Am J Physiol. 1993;265:
E715-E721.
96. Chang DW, DeSanti L, Demling RH. Anticatabolic and anabolic
strategies in critical illness: a review of current treatment
modalities. Shock. 1998;10:155-160.
97. Hart DW, Wolf SE, Chinkes DL, et al. Determinants of skeletal
muscle catabolism after severe burn. Ann Surg. 2000;232:455-
465.
98. Przkora R, Barrow RE, Jeschke MG, et al. Body composition
changes with time in pediatric burn patients. J Trauma.
2006;60:968-971.
99. Przkora R, Jeschke MG, Barrow RE, et al. Metabolic and
hormonal changes of severely burned children receiving
long-term oxandrolone treatment. Ann Surg. 2005;242:384-391.
100. Wolfe BM, Walker BK, Shaul DB, et al. Effect of total parenteral
nutrition on hepatic histology. Arch Surg. 1988;123:1084-1090.
101. Aarsland A, Chinkes DL, Sakurai Y, et al. Insulin therapy in burn
patients does not contribute to hepatic triglyceride production.
J Clin Invest. 1998;101:2233-2239.
102. Barrow RE, Mlcak R, Barrow LN, et al. Increased liver weights in
severely burned children: comparison of ultrasound and autopsy
measurements. Burns. 2004;30:565-568.
103. Barrow RE, Wolfe RR, Dasu MR, et al. The use of beta-adrenergic
blockade in preventing trauma-induced hepatomegaly. Ann Surg.
2006;243:115-120.
104. Aarsland A, Chinkes D, Wolfe RR, et al. Beta-blockade lowers
peripheral lipolysis in burn patients receiving growth hormone.
Rate of hepatic very low density lipoprotein triglyceride secretion
remains unchanged. Ann Surg. 1996;223:777-789.
105. Morio B, Irtun O, Herndon DN, et al. Propranolol decreases
splanchnic triacylglycerol storage in burn patients receiving a
high-carbohydrate diet. Ann Surg. 2002;236:218-225.
106. Martini WZ, Irtun O, Chinkes DL, et al. Alteration of hepatic
fatty acid metabolism after burn injury in pigs. JPEN J Parenter
Enteral Nutr. 2001;25:310-316.
107. Mittendorfer B, Jeschke MG, Wolf SE, et al. Nutritional hepatic
steatosis and mortality after burn injury in rats. Clin Nutr.
1998;17:293-299.
108. Deng QG, She H, Cheng JH, et al. Steatohepatitis induced by
intragastric overfeeding in mice. Hepatology. 2005;42:905-914.
109. Gilpin DA, Hsieh CC, Kuninger DT, et al. Effect of thermal
injury on the expression of transcription factors that regulate
acute phase response genes: the response of C/EBP alpha, C/EBP
beta, and C/EBP delta to thermal injury. Surgery. 1996;119:674-
683.
110. Gilpin DA, Hsieh CC, Kuninger DT, et al. Regulation of the acute
phase response genes alpha 1-acid glycoprotein and alpha
1-antitrypsin correlates with sensitivity to thermal injury. Surgery.
1996;119:664-673.
111. Hiyama DT, von Allmen D, Rosenblum L, et al. Synthesis of
albumin and acute-phase proteins in perfused liver after burn
injury in rats. J Burn Care Rehabil. 1991;12:1-6.
112. Livingston DH, Mosenthal AC, Deitch EA. Sepsis and multiple
organ dysfunction syndrome: a clinical-mechanistic overview.
New Horiz. 1995;3:257-266.
113. De Maio A, Mooney ML, Matesic LE, et al. Genetic component
in the inflammatory response induced by bacterial
lipopolysaccharide. Shock. 1998;10:319-323.
114. De Maio A, Torres MB, Reeves RH. Genetic determinants
influencing the response to injury, inflammation, and sepsis.
Shock. 2005;23:11-17.
115. Selzman CH, Shames BD, Miller SA, et al. Therapeutic
implications of interleukin-10 in surgical disease. Shock.
1998;10:309-318.
116. Finnerty CC, Herndon DN, Chinkes DL, et al. Serum cytokine
differences in severely burned children with and without sepsis.
Shock. 2007;27:4-9.
117. Siebenlist U, Franzoso G, Brown K. Structure, regulation and
function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405-455.
118. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell.
1994;76:253-262.
119. Niehof M, Streetz K, Rakemann T, et al. Interleukin-6-induced
tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a
new mechanism of transcriptional regulation by STAT3. J Biol
Chem. 2001;276:9016-9027.
120. Janes KA, Albeck JG, Gaudet S, et al. A systems model of
signaling identifies a molecular basis set for cytokine-induced
apoptosis. Science. 2005;310:1646-1653.
121. Mori K, Ma W, Gething MJ, et al. A transmembrane protein with
a cdc2+/CDC28-related kinase activity is required for signaling
from the ER to the nucleus. Cell. 1993;74:743-756.
122. Chan MM, Chan GM. Nutritional therapy for burns in children
and adults. Nutrition. 2009;25:261-269.
123. Nguyen TT, Cox CS, Traber DL, et al. Free radical activity and
loss of plasma antioxidants, vitamin E, and sulfhydryl groups in
patients with burns: the 1993 Moyer Award. J Burn Care Rehabil.
1993;14:602-609.
124. Manning AJ, Meyer N, Klein GL. Vitamin and trace element
homeostasis following burn injury. In: Herndon DN, ed.
Total Burn Care. Philadelphia: WB Saunders; 2007:251-255.
125. Matsuda T, Tanaka H, Williams S, et al. Reduced fluid volume
requirement for resuscitation of third-degree burns with
high-dose vitamin C. J Burn Care Rehabil. 1991;12:525-532.
126. Sherwood ER, Traber DL. The systemic inflammatory response
syndrome. In: Herndon DN, ed. Total Burn Care. Philadelphia:
WB Saunders; 2007:292-309.
127. Guillen MI, Gomez-Lechon MJ, Nakamura T, et al. The
hepatocyte growth factor regulates the synthesis of acute-phase
proteins in human hepatocytes: divergent effect on interleukin-
6-stimulated genes. Hepatology. 1996;23:1345-1352.
128. Jeschke MG, Herndon DN, Wolf SE, et al. Hepatocyte growth
factor modulates the hepatic acute-phase response in thermally
injured rats. Crit Care Med. 2000;28:504-510.
129. Yamashita Y, Jeschke MG, Wolf SE. Differential expression of
hepatocyte growth factor in liver, kidney, lung, and spleen
following burn in rats. Cytokine. 2000;12:1293-1298.
130. Cho MK, Kim SG. Hepatocyte growth factor activates CCAAT
enhancer binding protein and cell replication via PI3-kinase
pathway. Hepatology. 2003;37:686-695.
131. Humbel RE. Insulin-like growth factors I and II. Eur J Biochem.
1990;190:445-462.
132. Baxter RC. Circulating levels and molecular distribution of the
acid-labile (alpha) subunit of the high molecular weight
insulin-like growth factor-binding protein complex. J Clin
Endocrinol Metab. 1990;70:1347-1353.
133. Jeschke MG, Chrysopoulo MT, Herndon DN, et al. Increased
expression of insulin-like growth factor-I in serum and liver after
recombinant human growth hormone administration in
thermally injured rats. J Surg Res. 1999;85:171-177.
134. Herndon DN, Ramzy PI, DebRoy MA, et al. Muscle protein
catabolism after severe burn, effects of IGF-1/IGFBP3 treatment.
Ann Surg. 1999;229:713-720.
135. Jeschke MG, Finnerty CC, Kulp GA, et al. Combination of
recombinant human growth hormone and propranolol
decreases hypermetabolism and inflammation in severely
burned children. Pediatr Crit Care Med. 2008;9:209-216.
136. Jeschke MG, Herndon DN, Barrow RE. Insulin-like growth factor
I in combination with insulin-like growth factor binding protein
3 affects the hepatic acute phase response and hepatic
morphology in thermally injured rats. Ann Surg. 2000;231:408-
416.
137. Jeschke MG, Herndon DN, Vita R, et al. IGF-I/BP-3
administration preserves hepatic homeostasis after thermal
injury which is associated with increases in no and hepatic
NF-kappa B. Shock. 2001;16:373-379.

Total Burn Care
25
312.e4
© Copyright 2012 Elsevier, Inc. All rights reserved.
138. Price LA, Thombs B, Chen CL, et al. Liver disease in burn injury:
evidence from a national sample of 31,338 adult patients.
J Burns Wounds. 2007;7:e1.
139. Deutschman CS, Cereda M, Ochroch EA, et al. Sepsis-induced
cholestasis, steatosis, hepatocellular injury, and impaired
hepatocellular regeneration are enhanced in interleukin-6 -/-
mice. Crit Care Med. 2006;34:2613-2620.
140. Cheng J, Zhou T, Liu C, et al. Protection from Fas-mediated
apoptosis by a soluble form of the Fas molecule. Science.
1994;263:1759-1762.
141. Song E, Lee SK, Wang J, et al. RNA interference targeting Fas
protects mice from fulminant hepatitis. Nat Med. 2003;9:347-
351.
142. Jeschke MG, Bolder U, Chung DH, et al. Gut mucosal
homeostasis and cellular mediators after severe thermal trauma
and the effect of insulin-like growth factor-I in combination
with insulin-like growth factor binding protein-3. Endocrinology.
2007;148:354-362.
143. Self W. Liver: A fictional organ with a surface anatomy of four
lobes. New York: Viking Books; 2008.

Importance of mineral and bone
metabolism after burn
Burns exceeding 40% total body surface area (TBSA) disrupt
bone and mineral metabolism, both acutely and chronically.
Immediately after burn, calcium (Ca) homeostasis is dis­
rupted and magnesium (Mg) depletion occurs, frequently
affecting management or worsening the patient’s metabolic
status. Long-term consequences include a reduction in bone
formation and an increased risk of fracture due to long-term
loss of bone Ca and chronic progressive vitamin D defi­
ciency. These alterations arise, in part, from burn-induced
hypoparathyroidism and the development of end-organ
resistance to parathyroid hormone (PTH). This chapter will
discuss bone mineral homeostasis, burn-induced disruption
of minerals, mechanisms of burn-induced bone loss, and
options in the management of bone and mineral distur­
bances after burn.
Metabolic actions of calcium, phosphate,
and magnesium
As insoluble elements, minerals are major components of
the inorganic matrix in bone tissue and confer weight-
bearing properties to the skeleton. In the soluble form, Ca,
phosphate (PO4) and Mg play important roles in metabolic
pathways, acting as cofactors and regulators of numerous
intracellular and extracellular systems.
Calcium
Ca plays a major role in neurotransmission, cell depolariza­
tion, impulse propagation, and muscle contractility. In intra­
cellular pathways, after capture by Ca-binding protein or
protein kinase C, Ca serves as a second messenger, mediating
the secretory release of peptides such as amylase, insulin,
and aldosterone. In extracellular metabolism, Ca serves as a
cofactor in blood coagulation, specifically in the conversion
of prothrombin to thrombin and the activation of several
factors in the coagulation cascade.1
Phosphate
PO4 has an integral role in various intracellular processes
that involve the storage and transfer of energy. As a compo­
nent of purine nucleotides such as adenosine-5′-triphosphate
(ATP), PO4 groups are exchanged in multiple metabolic reac­
tions that allow energy-demanding activities in the human
body. Phosphorylation reactions represent the mainstay of
cellular respiration. In the form of phospholipid, PO4 is a
major structural component of cell membranes.1
Magnesium
Mg is essential to the cell and especially the mitochondria.
As a cofactor, Mg plays a fundamental part in the transfer
of PO4 groups. Mg is necessary in reactions requiring ATP
or involving replication, transcription, and translation of
purine nucleotides.1 Because of its important function in
plasma membrane excitability, Mg also serves a role in the
stabilization of conditions characterized by abnormal nerve
excitation or vasospasm.
Homeostasis of calcium, phosphate,
and magnesium
Calcium
Intestinal efficiency to absorb Ca is inversely related to Ca
intake. Fractional absorption can be as low as 20% with high
Ca intake and as high as 70% with low intake.2 The regula­
tory mechanism is shown in Figure 26.1. With high Ca
intake, transient hypercalcemia occurs, followed by suppres­
sion of PTH secretion and PTH-stimulated renal conversion
of 25-hydroxyvitamin D to calcitriol (1,25-dihydroxyvitamin
D). With low Ca intake the reverse occurs. A transient reduc­
tion in serum Ca occurs, followed by a rapid (within 5
minutes) rise in PTH secretion.
These mechanisms are likely mediated by the parathyroid
chief cell Ca-sensing receptor (CaR). The CaR is a membrane-
bound G-protein-coupled protein that may be up- or down­
regulated, in part, by mutations.3 In patients with CaR
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00026-6
Effects of burn Injury on bone and
mineral metabolism
Gordon L. Klein, Noe A. Rodriguez, David N. Herndon
CHAPTER 26 
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IN THIS CHAPTER
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Total Burn Care
26
314
cause autosomal dominant hypophosphatemic rickets, a
phosphate-wasting disorder. FGF-23-mediated renal phos­
phate wasting occurs through downregulation of the type II
sodium–phosphate co-transporters NPT2a and NPT2c.8
Magnesium
Approximately 60% of the body’s Mg is stored in the skel­
eton,1 but not at sites where matrix is calcified. Mg absorp­
tion varies with dietary intake, with about 40% of an average
daily load being absorbed.1 The relationship between Ca and
Mg absorption is described as inverse, but the mechanism of
this is unclear. Renal excretion is the main route of Mg elimi­
nation and it may vary with Mg concentration in serum. A
large paracellular pathway for the intestinal absorption and
secretion of Mg exists and is dependent on luminal Mg con­
centrations. The Mg ion channel, TRPM6, is located in intes­
tinal brush border epithelial cells and may participate in Mg
homeostasis in the gut. Mg is 70% ultrafiltrable in the
serum.1 About 70% of filtered Mg is reabsorbed along the
cortical afferent limb of the loop of Henle.1 Hypermag­
nesemia increases urinary Mg excretion by activating the
renal CaR,9 whereas hypomagnesemia increases loop of
Henle Mg reabsorption and reduces urinary Mg excretion.
Loop diuretics increase urinary Mg excretion. Because little
distal tubular Mg reabsorption occurs, an intravenous fluid
bolus decreases Mg reabsorption and increases urinary Mg
excretion.1
Effect of burn injury on calcium, phosphate,
and magnesium homeostasis
Although the effects of burn injury on mineral ions are not
fully understood, studies from the University of Texas
Medical Branch and Shriners Hospitals for Children in
Galveston describe some of the developments in this area.
In children with >30% TBSA burns, ionized Ca is, on average,
5% below the lower normal limit.10 In addition, serum PTH
levels are too low for ionized Ca levels, indicating hypopara­
thyroidism. Administration of a standard amount of PTH
does not increase urinary cyclic AMP and PO4 excretion,10
pointing to PTH resistance. Mg depletion, encountered in all
the burn patients studied,10,11 impairs hypocalcemia-induced
PTH secretion and imparts resistance to PTH infusion. The
prevalence of Mg depletion may result from resuscitation of
patients with Ringer’s lactate, which lacks Mg. Aggressive
parenteral Mg supplementation produces repletion in 50%
of patients. However, it does not improve hypoparathyroid­
ism,11 making the cause of post-burn hypoparathyroidism
unclear. Sheep studies revealed that an approximate 50%
upregulation of parathyroid CaR occurs after burn injury,5
which is associated, in humans, with decreased circulating
Ca necessary to suppress PTH secretion.3 The proposed
mechanism underlying this phenomenon, known as a
reduced set point for Ca suppression of PTH secretion, is
shown in Figure 26.2. Cytokines, especially IL-1β and IL-6,
are highly produced following the systemic inflammatory
response. These cytokines stimulate parathyroid cell produc­
tion of CaR in vitro.12–14
In a study of 11 adult burn patients, serum concentrations
PO4, and Mg were low, consistent with abnormalities
downregulation, higher circulating Ca is required to
suppress PTH production and secretion, giving rise to
primary hyperparathyroidism.4 In patients with CaR
upregulation less circulating Ca is needed, leading to
hypoparathyroidism.5
PTH normally increases bone resorption and renal tubular
Ca reabsorption to raise serum Ca concentrations. Further­
more, it stimulates the renal enzyme 25-hydroxyvitamin
D-1α hydroxylase to convert 25-hydroxyvitamin D to
1,25-dihydroxyvitamin D or calcitriol. Calcitriol then binds
to intestinal epithelial cells and increases transcellular Ca
absorption by altering cell membrane phospholipids and by
facilitating the intracellular passage of the absorbed Ca
through stimulation of Ca-binding protein synthesis. Thus
the efficiency of Ca absorption is improved.
Intravenous administration of Ca bypasses the intestinal
control mechanism and suppresses parathyroid PTH produc­
tion and kidney calcitriol production. The bone stores 99%
of the body’s Ca.1
Phosphate
In contrast to Ca, the intestine plays no significant regulatory
role in the absorption of PO4. Approximately 80% of dietary
PO4 is absorbed, and the bone stores approximately 90% of
the body’s PO4. Homeostatic control appears to rest prima­
rily within the kidney,6,7 and the regulatory mechanisms are
likely independent.of PTH.6,7 Thus, the renal excretory rate
of PO4 primarily regulates serum PO4 concentrations
and maintains them within a normal range. Fibroblast
growth factor (FGF)-23 is a key regulator of PO4 and
vitamin D metabolism in humans.8 FGF-23 gene mutations
Figure 26.1  Vitamin D and calcium metabolism.
Alters membrane phospholipid
Induces intestinal Ca
binding protein
1,25(OH)2 vitamin D
Dietary Ca↓
Intestine
Blood
Bone
Kidney
Ca
Ca
PTH
PTH
1,25(OH)2 vitamin D
↑ Ca reabsorption
25(OH)
Parathyroid
Thyroid

Effects of burn Injury on bone and mineral metabolism
315
Although fecal Ca losses can be high in burn patients17 and
burn-induced increases in endogenous corticosteroids may
impair intestinal Ca absorption,18 no evidence suggests that
hypocalcemia is caused by corticosteroid-induced impair­
ment of intestinal reabsorption of Ca secreted into the intes­
tinal lumen. Other proposed mechanisms include reduced
bone turnover.15,19 However, upregulation of parathyroid
CaR by inflammatory cytokines followed by a reduction in
set-point for Ca suppression of PTH production remains the
most attractive hypothesis.5,10
Studies of 24 children with massive burns demonstrated
a low serum concentration of 25-hydroxyvitamin D
from as early as 14 months after burn20 up to 7 years,21
correlating with low bone density Z scores.21 Serum 1,25-
dihydroxyvitamin D concentrations were normal 2 years
after injury, but were low at 7 years in 50% of patients.21 This
suggests that these patients became progressively vitamin D
deficient.21
Possible explanations for post-burn hypophosphatemia
include intracellular PO4 accumulation, inadequate intake,
excessive excretion (unlikely in view of documented hypopar­
athyroidism), or loss into the extravascular fluid. In a review,
Dolecek17 found increased urinary PO4 excretion only during
the third and fourth weeks after burn in adults, whereas
hypophosphatemia occurred earlier. Thus, increased urinary
PO4 excretion seen later may be more a function of increased
tissue breakdown and filtered load than of inappropriate or
excessive urinary PO4 losses. There is little documentation of
inadequate PO4 intake following burns. We administer a
minimum of 1.6 g PO4 daily in enteral feedings alone.15
The cause of sustained hypomagnesemia after burn is
unknown, although excessive urinary and fecal losses occur
in adults17 and excessive losses occur in the burn wound.22
Rationale for therapy
Table 26.1 describes treatments for hypocalcemia and
hypophosphatemia. Hypocalcemia, especially during the
resuscitation effort, can potentiate hypokalemia-induced
abnormalities in cardiac muscle23 and block responsiveness
to fluid repletion in shock.23 Parenteral Ca during resuscita­
tion does not benefit non-hypocalcemic patients24–26 unless
they have hyperkalemia, hypomagnesemia, or Ca channel
blocker toxicity.27 Similarly, although caution should be
exercised during massive transfusion with citrate-containing
blood, Ca therapy may not be necessary in normocalcemic
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.28 Treatment should be initiated only when clinical
and electrocardiographic evidence suggests hypocalcemia.
Ca infusions should be administered slowly, as rapid Ca
replacement can produce cardiac arrhythmias.23,28
Hypophosphatemia may cause tissue hypoxemia due to
increased hemoglobin affinity for oxygen and decreased
tissue ATP, metabolic encephalopathy, hemolysis, shortened
platelet survival, myalgias, weakness, and possible impair­
ment of myocardial contractility.29 Hypomagnesemia, 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
observed in Ca homeostasis.15 Six patients had low serum
ionized Ca concentrations, three of them manifesting hypo­
calcemia during the first 48 hours after burn. Four were
hypophosphatemic; this was most prevalent at post-burn
day 7. Five were hypomagnesemic, with this finding
most likely to present on post-burn day 3. One patient dem­
onstrated hypercalcemia and one hyperphosphatemia. No
patient was hypermagnesemic. Elevated ionized Ca or PO4
was always transient. Studies in adults are not yet as detailed
as those in children have been in this regard.
Hypocalcemia cannot be diagnosed from total serum Ca
concentration, owing to variability in serum albumin con­
centrations after burn. Serum 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 eryth­
rocytes of a burn patient.16 Another is increased urinary Ca
excretion, which occurs in burned children and is consistent
with documented secondary hypoparathyroidism.10 Ca loss
in tissue exudates could also contribute to hypocalcemia.
Although the amount of Ca in wound exudates is likely
insufficient to account for post-burn hypocalcemia,17 few
studies have measured Ca content in burn wound
exudates.
Figure 26.2  Mechanisms of bone loss after severe burn.
Parathyroid
Kidney
Skin
Burn
↓ Vit D
synthesis
Vit 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

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26
316
those with creatinine clearance <50 mL/min developing in
the ICU 48 hours after admission ∼20% of admissions. Of
the four hypercalcemia cases described, three responded to
standard doses of bisphosphonates. Onset of hypercalcemia
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 a 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 production
of extracellular matrix; these chondrocytes and matrix
undergo a series of biochemical changes leading to the for­
mation of ossification centers. As these centers expand, car­
tilaginous tissue is replaced by bone and a vascular system
that allows the delivery of nutrients, hormones, and growth
factors. Growth velocity in children is retarded for the first
year after a 40% TBSA burn.35 The underlying mechanism is
unknown, but growth velocity does return to normal35 even
though long-term stunting may result.
The stress and inflammatory response contribute to bone
turnover abnormalities that lead to bone loss. Urinary deox­
ypyridinoline excretion increases the first week after burn.36
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 due to a three- to
eightfold increase in glucocorticoid production37 and a
three- to 100-fold increase in proinflammatory cytokines
produced by the systemic inflammatory response.21 Both
glucocorticoids and inflammatory cytokines stimulate bone
resorption by increasing osteoblast production of the recep­
tor activator of the nuclear transcription factor-κB (RANKL),
which stimulates bone marrow stromal or precursor cells to
differentiate into osteoclasts (bone-resorbing cells).38 Nor­
mally, bone resorption is coupled to bone formation. In
high-turnover situations (i.e. both resorption and formation
are increased) bone loss occurs because once 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 col­
lagen to crystallize into hydroxyapatite with proper binding
sites for Ca and PO4.
Osteoblasts (bone-forming cells) are key part of
normal coupling. They produce RANKL in response to
also causes generalized convulsions, muscle tremors, and
weakness.1
Treatments for maintaining
mineral homeostasis
Acute symptomatic hypocalcemia should be treated with
intravenous Ca. Adults should receive 90–180 mg of ele­
mental Ca over 5–10 minutes to reverse twitching. Infants/
children should receive 20 mg/kg Ca chloride or 200–
500 mg/kg Ca gluconate in four divided doses.30,31 Parenteral
chloride should be used carefully as it may cause phlebitis
and/or acidosis. While hypocalcemia is asymptomatic and
patients can tolerate enteral feeding, milk and/or infant
formula can provide as much as 3 g/day of bioavailable Ca.15
Hypocalcemia can occur despite enteral provision of such
large Ca quantities, making intermittent parenteral admin­
istration 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
>40% TBSA burns ranged between 0.9 and 15 g 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.31 Infants/children with symptomatic hypophosphatemia
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).32
Adult patients who tolerate enteral feeding and consume
an average of 1.6 g/day PO4 should have consumed enough
to treat asymptomatic hypophosphatemia.15 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 <1.5 mEq/L
(1.8 mg/dL or 0.8 mmol/L) usually require parenteral
therapy.33
Hypercalcemia and impaired renal function
following burns
Hypercalcemia with acute renal failure was reported in the
May 2010 issue of Burns.34 Adult patients with serum ionized
Ca ≥1.32 mmol constituted 30% of patient admissions and
Table 26.1  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.

Effects of burn Injury on bone and mineral metabolism
317
differentiation (a feature of glucocorticoid 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 controls.37
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 stroma into osteoclasts. However, this does not
occur. In fact, levels of urinary deoxypyridinoline (a bone
resorption marker) remain quite low.19 Thus, both bone for­
mation 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-1β12,13 and IL-614 stimulate upregulation of the parathy­
roid CaR in vitro. Thus, while the stress response explains
the low-turnover acute bone loss after burn injury, the sys­
temic inflammatory response explains upregulation of the
parathyroid CaR in both humans and sheep. Parathyroid
CaR upregulation provides continuous hypoparathyroidism
post burn and renders the wasted urinary Ca unproductive
in repairing demineralized bone.
In summary, 1 week after burn injury the stress and inflam­
matory responses promote bone loss by increasing bone
resorption and Ca wasting in the urine. By 2 weeks osteo­
blasts are lost, markedly reducing bone replacement. This
hypodynamic bone continues to thin, as resorption is
reduced19 and compensatory bone formation is all but
shut off.
The silent events triggered by burn injury reduce bone
density (Fig. 26.5) in the lumbar spine and appendicular
skeleton (see radiograph in Figure 26.6). The distribution of
lumbar spine bone density Z scores (standard deviation
score) is shifted to the negative in children with >40% TBSA
burns (Fig. 26.5), but not in those with <20% TBSA burns.
glucocorticoids, cytokines (especially IL-1β and IL-6), and
PTH. When stimulated by low serum Ca and downregula­
tion 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
humans39 and animals.40 However, by the second week after
burn, glucocorticoids cause apoptosis of surface osteoblasts.
This disappearance is apparent in iliac crest bone biopsies
(compare normal bone in Figure 26.3 with bone at 2 weeks
after burn in Figure 26.4). Similarly, when tetracycline is
administered to children and adults prior to iliac crest bone
biopsies, tetracycline uptake is markedly reduced, suggesting
a reduction in surface osteoblasts and functioning of the
surviving osteoblasts.41 Finally, fewer markers of osteoblastic
Figure 26.3  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 on the osteoid
surface are osteoblasts.
Figure 26.4  Goldner trichrome stain of an iliac crest bone biopsy of a
burned patient. The blue-green area represents mineralized bone.
Compared to the previous figure, note that osteoblasts are absent on the
osteoid surface.
Figure 26.5  Distribution of lumbar spine bone mineral density (BMD)
Z-scores of severely burned children compared to a standard distribution
curve. Note that the distribution after burn is shifted to the negative side.
Number of patients
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

Total Burn Care
26
318
suggesting that rhGH fails to increase bone formation
acutely. However, daily subcutaneous injection 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.46 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 ques­
tion 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, a rise 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 skeletal loading, and creates a 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.47 recently showed that a 1-year treatment with
0.2 mg/kg/day rhGH (subcutaneous injection) reduces
lumbar spine BMC, increases LBM, and dramatically
decreases circulating PTH. These findings suggest that high-
dose rhGH directly stimulates bone resorption, with second­
ary suppression 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 subcutan­
eous injections, which may reduce compliance. Another
option would be long-term use of the anabolic steroid oxan­
drolone. 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.48 Oxandrolone is not costly
and does not require subcutaneous injections, but it may
produce clitoral hypertrophy. However, no premature growth
plate fusion has been discovered on X-rays, and this
clitoromegaly resolves when the drug is discontinued.
Another drug that has been studied is the bisphosphonate
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 cho­
lesterol biosynthesis pathway, ultimately altering protein
binding to the osteoclastic membrane and inducing apopto­
sis.49 Bisphosphonates remain in bone for a prolonged
period, raising concerns that they may interfere with growth
or bone quality.49 However, most bone resorption is thought
to occur during the first week or two after burns, when glu­
cocorticoids and inflammatory cytokines cause significant
resorption of bone prior to osteoblast apoptosis. Thus, early
use of bisphosphonates may prevent acute bone loss.
In a randomized, double-blind study, children with ≥40%
TBSA burns received 1.5 mg/kg 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 hospitali­
zation.50 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.43 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
Thus, more severe burns trigger the bone loss mechanisms
discussed above.
Burn injury increases the annual extrapolated fracture inci­
dence in boys and girls by 100% and 50%, respectively.42
Thus, burn-induced bone loss increases the risk of fracture
later on. Whereas bone remodeling recovers 1 year after
burn,43 the Z score for at least lumbar spine bone mineral
density (BMD) does not improve.42,43 Given that peak bone
mass is reached at 18–30 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.
Another obstacle to bone recovery is progressive vitamin
D deficiency. The effect of ongoing vitamin D deficiency on
bone density is unclear. In the past, patients were discharged
without vitamin D supplementation. Sunlight exposure was
limited because of heat intolerance due to sweat gland
destruction, and the burn scar could become hyperpig­
mented. At 14 months post burn, biopsies have demon­
strated that UV light converts only 25% of the normal
quantity of 7-dehydrocholesterol into pre-vitamin D3, sug­
gesting that skin is biochemically abnormal more than 1
year after injury.20 Moreover, 7-dehydrocholesterol levels
were significantly lower in burn scar and adjacent normal-
appearing skin than normal control skin,20 pointing to
ongoing problems in cholesterol biosynthesis. The role of
vitamin D deficiency in failed restoration of bone density is
unknown. We found that, 6 months after children were dis­
charged on a vitamin D2 (400 IU)-containing multivitamin,
all but one of eight patients had vitamin D insufficiency.44
Thus, the vitamin D requirement during and after burn
injury remains unknown.44
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 recombinant human growth hormone
(rhGH) from admission throughout hospitalization imme­
diately improves circulating insulin-like growth factor-1
levels but does not raise serum osteocalcin levels to normal,45
Figure 26.6  X-ray as an example of burn-induced osteoporosis 1 year after
trauma.

Effects of burn Injury on bone and mineral metabolism
319
of CaR do not change following 40% burn injury in sheep.53
However, intestinal CaR redistributes following ischemia
reperfusion injury in rats.54 Therefore, one must be certain
that these drugs do not alter the cardiovascular or intestinal
distributions of the CaR and are specific for CaR in the
parathyroid chief cell membrane.
Further reading
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, Herndon DN, Goodman WG, et al. Histomorphometric and
biochemical characterization of bone following acute severe burns
in children. Bone. 1995;17:455-460.
Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in skin
after burns. Lancet. 2004;363:291-292.
Klein GL, Nicolai M, Langman CB, et al. Dysregulation of calcium
homeostasis after severe burn injury in children: possible role of
magnesium depletion. J Pediatr. 1997;131:246-251.
Klein GL, Bi LX, Sherrard DJ, et al. Evidence supporting a role of
glucocorticoids in short-term bone loss in burned children.
Osteoporos Int. 2004;15:468-474.
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.
antagonistic properties like those of rhGH; however, the
effects of pamidronate on bone are immediate.
Pamidronate use is not associated with hypocalcemia,
growth delays, or changes in bone histomorphometry.43,50
The next step in evaluating this drug is to determine whether
fracture rate in pamidronate-treated patients differs from
that in the placebo group and from age- and gender-matched
normal values.42
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.51 However, because rat studies
have demonstrated an increase in osteogenic sarcoma,52 the
US FDA does not allow its use in children. Should this
change, rhPTH would be a potentially effective drug for
adding bone mass in burned children.
The other drug class worth mentioning is the calcilytics,
which are still in clinical trials. These Ca receptor antagonists
would block upregulation of parathyroid CaR, preventing
the fall in circulating Ca, ensuing hypoparathyroidism, and
urinary Ca wasting. Unfortunately, CaR is present in many
tissues, including the heart53 and intestine.54 In cardiovascu­
lar tissue, CaR is primarily present in the heart endothelium
and the intima and endothelial lining cells in major blood
vessels, including the aorta.53 The distribution and quantity
 
Access the complete reference list online at

Effects of burn Injury on bone and mineral metabolism
319.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Favus MJ, Goltzmann D. Regulation of calcium and magnesium.
In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders
of mineral metabolism. 7th ed. Washington DC: American Society
for Bone and Mineral Research; 2009:104-108.
2. Neer RM. Calcium and inorganic phosphate homeostasis. In:
DeGroot LJ, ed. Endocrinology. Philadelphia: WB Saunders;
1989:927-953.
3. Brown EM. Ca 2+-sensing receptor. In: Rosen CJ, ed. Primer on the
metabolic bone diseases and disorders of mineral metabolism. 7th ed.
Washington DC: American Society for Bone and Mineral
Research; 2009:134-141.
4. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism. In:
Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of
mineral metabolism. 7th ed. Washington DC: American Society for
Bone and Mineral Research; 2009:302-306.
5. Murphey ED, Chattopadhyay N, Bai M, et al. Up-regulation of the
parathyroid calcium-sensing receptor after burn injury in sheep: A
potential contributory factor to post-burn hypocalcemia. Crit Care
Med. 2000;28:3885-3890.
6. Klein GL, Coburn JW. Parenteral nutrition: effect on bone and
mineral homeostasis. Annu Rev Nutr. 1991;11:93-119.
7. Portale AA, Halloran BP, Murphy MM, et al. Oral intake of P can
determine the serum concentration of 1,25-dihydroxyvitamin D
by determining production rate in humans. J Clin Invest.
1986;77:7-12.
8. White KE, Econs MJ. Fibroblast growth factor-23. In: Rosen CJ,
ed. Primer on the metabolic bone diseases and disorders of mineral
metabolism. 7th ed. Washington DC: American Society for Bone
and Mineral Research; 2009:112-116.
9. Hebert SC. Extracellular calcium-sensing receptor: Implications
for calcium and magnesium handling by the kidney. Kidney Int.
1996;50:2129-2139.
10. Klein GL, Nicolai M, Langman CB, et al. Dysregulation of calcium
homeostasis after severe burn injury: possible role of magnesium
depletion. J Pediatr. 1997;131:246-251.
11. Klein GL, Langman CB, Herndon DN. Persistent
hypoparathyroidism following magnesium repletion of burn-
injured children. Pediatr Nephrol. 2000;14:301-304.
12. Nielsen PK, Rasmussen AK, Butters R, et al. Inhibition of
PTH secretion by interleukin-1 beta in bovine parathyroid
glands in vitro is associated with an up-regulation of the
Ca-sensing receptor mRNA. Biochem Biophys Res Comm.
1997;238:880-885.
13. Toribio RE, Kohn CW, Capen CC, et al. Parathyroid hormone
(PTH) secretion, PTH mRNA and calcium-sensing receptor mRNA
expression in equine parathyroid cells and effects of interleukin
(IL)-1, IL-6, and tumor necrosis factor-alpha on equine
parathyroid cell function. J Mol Endocrinol. 2003;31:609-620.
14. Canaff L, Zhou X, Hendy GN. The pro-inflammatory cytokine,
interleukin-6, up-regulates calcium-sensing receptor gene
transcription via Stat1/3 and Sp 1/3. J Biol Chem. 2008;283:
13586-13600.
15. Klein GL, Herndon DN, Rutan TC, et al. Bone disease in burn
patients. J Bone Miner Res. 1993;8:337-345.
16. 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.
17. Dolecek R. Calcium-active hormones and post-burn low-calcium
syndrome. In: Dolecek R, Brizio-Moltens L, Moltens A, et al.,
eds. Endocrinology of thermal trauma: pathophysiologic mechanisms
and clinical interpretation. Philadelphia: Lea and Febiger; 1990:
216-237.
18. Hahn TJ, Halstead LR, Teitelbaum SI, et al. Altered mineral
metabolism in glucocorticoid-induced osteopenia: effect of
25-hydroxyvitamin D administration. J Clin Invest. 1979;64:
655-665.
19. 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.
20. Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in
skin after burns. Lancet. 2004;363:291-292.
21. Klein GL, Langman CB, Herndon DN. Vitamin D depletion
following burn injury in children: a possible factor in post-burn
osteopenia. J Trauma. 2002;52:346-350.
22. Berger MM, Rothen C, Cavadini C, et al. exudative mineral
losses after serious burns: a clue to the alterations of
magnesium and phosphate metabolism. Am J Clin Nutr.
1997;65:1473-1481.
23. British Committee for Standardization in Haematology Blood
Transfusion Task Force. Guidelines for transfusion for massive
blood loss. Clin Lab Haematol. 1988;10:265-273.
24. Stueven H, Thompson BM, Aprahamian C, et al. Use of calcium
in pre-hospital cardiac arrest. Ann Emerg Med. 1983;12:136-139.
25. Stueven HA, Thompson BM, Aprahamian C, et al. Calcium
chloride, reassessment of use in asystole. Ann Emerg Med.
1984;13:820-822.
26. Harrison EE, Amey BD. Use of calcium in electromechanical
dissociation. Ann Emerg Med. 1984;13:844-845.
27. Harinan RJ, Mangiardi LM, McAllister RG, et al. Reversal of
cardiovascular effects of verapamil by calcium and sodium.
Differences between electrophysiologic and hemodynamic
response. Circulation. 1979;59:797-804.
28. Dzik WH, Kirkley SA. Citrate toxicity during massive blood
transfusion. Transfusion Med Rev. 1988;2:76-94.
29. Hruska KA, Lederer E. Hyperphosphatemia and
hypophosphatemia. In: Favus MJ, ed. Primer on the metabolic bone
diseases and disorders of mineral metabolism. 4th ed. Philadelphia:
Lipincott Williams and Wilkins; 1999:245-253.
30. Shoback D. Hypocalcemia: definition, etiology, pathogenesis,
diagnosis and management. In: Rosen CJ, ed. Primer on the
metabolic bone diseases and disorders of mineral metabolism. 7th ed.
Washington DC: American Society for Bone and Mineral
Research; 2009:313-316.
31. Carpenter TO. Disorders of mineral metabolism in childhood.
In: Rosen CJ, ed. Primer on the metabolic bone diseases and disorders
of mineral metabolism. 7th ed. Washington DC: American Society
for Bone and Mineral Research; 2009;349-353.
32. Lederer E. Hypophosphatemia: treatment and medication.
In: eMedicine published on-line; updated
7 August 2009; accessed 29 April 2010.
33. Rude RK. Magnesium depletion and hypermagnesemia. In: Rosen
CJ, ed. Primer on the metabolic bone diseases and disorders of mineral
metabolism. 7th ed. Washington DC: American Society for Bone
and Mineral Research; 2009:325-328.
34. Kohut B, Rossat J, Raffoul W, et al. Hypercalcemia and acute renal
failure after major burns: an under-diagnosed condition. Burns.
2010;36:360-366.
35. Rutan RL, Herndon DN. Growth delay in pediatric burn patients.
Arch Surg. 1990;125:392-395.
36. Lebleblici B, Sezgin N, Ulusan SN, et al. Bone loss during the
acute stage following burn injury. J Burn Care Res. 2008;29:763-
767.
37. Klein GL, Bi LX, Sherrard DJ, et al. Evidence supporting a role of
glucocorticoids in short-term bone loss in burned children.
Osteoporos Int. 2004;15:468-474.
38. Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of
osteoprotegerin ligand and inhibition of osteoprotegerin
production by glucocorticoids in osteoblast lineage cells:
potential paracrine mechanisms for glucocorticoid-induced
osteoporosis. Endocrinology. 1999;140:4382-4389.
39. Parisien M, Charhon SA, Arlot M, et al. Evidence for a toxic effect
of aluminum on osteoblasts: a histomorphometric study in
hemodialysis patients with aplastic bone disease. J Bone Miner
Res. 1988;3:259-267.

Total Burn Care
26
319.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
40. Rodriguez M, Felsenfeld AJ, Llach F. Aluminum administration
in the rat separately affects osteoblast and bone mineralization.
J Bone Miner Res. 1990;5:59-67.
41. Parfitt AM, Drezner JK, Glorieux FH, et al. Bone
histomorphometry: Bone histomorphometry: standardization
of nomenclature, symbols and units. Report of the ASBMR
Histomorphometry Nomenclature Committee. J Bone Miner Res.
1987;2:595-610.
42. 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.
43. 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.
44. Klein GL, Herndon DN, Chen TC, et al. Standard multivitamin
supplementation does not improve vitamin D insufficiency after
burns. J Bone Miner Metab. 2009;27:502-506.
45. Klein GL, Wolf SE, Langman CB, et al. Effect of therapy with
recombinant human growth hormone on insulin-like growth
factor system components and serum levels of biochemical
markers of bone formation in children following severe burn
injury. J Clin Endocrinol Metab. 1998;83:21-24.
46. 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.
47. Branski LK, Herndon DN, Barrow RE, et al. Randomized
controlled trial to determine the efficacy of long-term growth
hormone treatment in severely burned children. Ann Surg. 2009
Sept 2 e-published ahead of print. PMID: 19734776.
48. Murphy KD, Thomas S, Mlcak RP, et al. Effects of long-term
oxandrolone administration in severely burned children. Surgery.
2004;136:219-224.
49. Russell RG. Bisphosphonates: mode of action and pharmacology.
Pediatrics. 2007;119(Suppl 2):S150-S162. PMID: 17332236.
50. 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.
51. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid
hormone (1-34) on fractures and bone mineral density in
post-menopausal women with osteoporosis. N Engl J Med.
2001;344:1434-1441.
52. Subbiah V, Madsen VS, Raymond AK, et al. Of mice and men:
divergent risks of teriparatide-induced osteosarcoma. Osteoporos
Int. 2010;21:1041-1045.
53. Klein GL, Enkhbaatar P, Traber DL, et al. Cardiovascular
distribution of the calcium-sensing receptor before and after
burns. Burns. 2008;34:370-375.
54. Bick RJ, Poindexter BJ, Sheikh-Hamad D, et al. Changes in
calcium-sensing receptor and stanniocalcin-1 in the rat small
intestine in response to ischemia-reperfusion injury. Current Topics
in Peptide and Protein Research. 2009;10:37-43.

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©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00027-8
Vitamin and trace element
homeostasis following
severe burn injury
Gordon L. Klein, Noe A. Rodriguez, Ludwik K. Branski, David N. Herndon
Importance of vitamins and trace elements
Although vitamins and trace elements play key roles in
nearly every cell mechanism in the body, we know remark­
ably little about the effects of burn injury on their require­
ments, homeostasis, and metabolism. The published work
on burns and micronutrients has covered the role of vita­
mins and trace elements in homeostasis, wound healing,
and antioxidant properties. We will examine each of these
topics in the context of the available published data.
Homeostasis and requirements of vitamins
following burn injury
Studies of vitamin homeostasis post burn are sparse. Retinol
(vitamin A), α-tocopherol (vitamin E), and ascorbic acid
(vitamin C) have all been reported as low.1,2 Rettmer3 per­
formed functional testing for thiamin (vitamin B1), ribo­
flavin (vitamin B2), and pyridoxine (vitamin B6) in burn
patients and found them to be normal. In a study of serum
vitamin K levels in severely burned pediatric patients,
Jenkins4 reported that 91% of children studied demonstrated
low circulating levels in the first month post burn. There was
no relationship between serum vitamin K levels and pro­
thrombin time, raising the question of clinical significance.
It should be noted, however, that osteocalcin, a γ-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 stimulate pancreatic insulin
production and peripheral insulin sensitivity.5 Circulating
osteocalcin is reported to be low in the first month following
burn injury.6 Therefore, the possibility remains that low
circulating vitamin K levels may contribute to the reduction
in serum osteocalcin and hence to post-burn insulin resist­
ance. For a more detailed discussion of osteocalcin, see
Chapter 26.
Barbosa7 studied burned children randomized to micro­
nutrient supplementation or a supplement consisting of
vitamin C (1.5 times the upper level of intake), vitamin E
(1.35 times the upper intake level) and zinc (twice the rec­
ommended dietary allowance). This formula was given for
7 days starting on day 2 of admission. Serum levels of
vitamin E were increased and lipid peroxidation, as meas­
ured by malondialdehyde, was decreased in the antioxidant
supplementation group. The time of wound healing was also
decreased in the experimental group.
The infusion of vitamin C alone also seems to have some
benefits. Dubick8 infused high doses of ascorbic acid in a
sheep model of 40% TBSA injury. The vitamin C infusion
significantly reduced resuscitation fluid requirements of
burned sheep. Plasma thiobarbituric acid reactive substances
increased fourfold in sham-burned sheep; this was prevented
by the use of the vitamin C infusion. Tanaka9 found in a rat
burn model that with high-dose vitamin C, total tissue water
content was reduced and negative interstitial fluid hydro­
static pressure was more positive than in controls. This
finding suggests that ascorbic acid administration alone
could reduce fluid requirements in burn resuscitation.
The one vitamin that has been studied in more detail in
burned patients is vitamin D. As discussed in Chapter 25,
burned children develop a progressive deficiency of vitamin
D as measured by circulating levels of 25-hydroxyvitamin D.
Although acute measurements of both 25-hydroxyvitamin
D and 1,25-dihydroxyvitamin D, the metabolically active
steroid hormone, have shown that levels can be low, 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 so at 2 and 7 years post burn.13 Whereas serum levels
of 1,25-dihydroxyvitamin D are normal at 2 years, about
50% of measured values are low at 7 years post burn,13 sug­
gesting a progressive vitamin D deficiency.
Failure to provide vitamin D supplementation to burn
patients on discharge from hospital may contribute to the
vitamin D deficiency. Another major factor, however, is the
profound change in skin structure and quality. Burn scar and
adjacent areas of normal appearance can only convert about
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
CHAPTER 27 
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IN THIS CHAPTER
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Total Burn Care
27
322
Agay found a redistribution of Zn and Cu to the liver without
significant changes in levels in muscle and brain.28 Given
the findings of Cunningham18 and Boosalis25 that Zn sup­
plementation exacerbates urinary Zn excretion, it can be
hypothesized that the body cannot take up the supplemental
Zn, and that the redistribution of Zn, rather than elevated
urinary excretion, is responsible for decreased plasma levels.
Consistent with this hypothesis, Zn is also involved in the
inflammatory response and could be redistributed to sites of
barrier disruption such as skin, to be subsequently lost in
wound exudate.
The low level of plasma Cu is partly due to reduced circu­
lating levels of ceruloplasmin.19,23 Even though ceruloplas­
min is an acute-phase reactant stimulated by proinflammatory
cytokines, such as interleukin (IL-)1,11,29 there is also evi­
dence that levels of ceruloplasmin are increased in the burn
wound exudates. Cunningham19 reported a strong relation­
ship between the size of the open wound and the amount
of circulating ceruloplasmin. Gosling20 reported that serum
Cu concentration in severe burns varied inversely with burn
surface area, in contrast to circulating Zn levels, which
showed no such correlation. Furthermore, ceruloplasmin,
like albumin, may be extravasated from the intravascular
compartment and carry Cu with it.
Finally, one other possible contributor to the low plasma
level of Cu is consumption by pathogenic bacteria. Abboud
documented that Pseudomonas aeruginosa strains isolated
from septic patients consumed nearly twice the Cu (ppm/g
biomass) as Gram-positive and Gram-negative control
strains.30 We have not found similar information with regard
to Zn.
Although Zn and Cu may be partly redistributed, there is
no doubt that urinary excretion and exudative loss lead to a
net decrease in Zn and Cu levels after a severe burn. Loss of
Cu has been anecdotally shown to be associated with poor
wound healing and Cu supplementation has resulted in
accelerated wound healing.31 Furthermore, loss of Zn may
lead to abnormalities in type I collagen cross-linking, which
may affect the binding of calcium and phosphate to the
hydroxyapatite crystal in the bone matrix and contribute, in
ways so far undescribed, to the loss of bone (see Chapter
26). Whether loss of Zn affects immune function, as sum­
marized by Keen and Gershwin,32 depends on whether the
amount of Zn in the wound (and possibly in the white
blood cells) is adequate to assure maximum function of
these cells to prevent overwhelming sepsis.
Based on the studies mentioned above, additional Zn and
Cu supplementation must be provided to burn patients.
Voruganti found that a dietary Zn supplementation of
22.5 mg/day, albeit consistent with the recommendation of
Pochon,33 failed to raise plasma Zn levels.26 Moreover, while
the Cu intake in these patients was 2–3 times the dietary
reference intake (3 mg/day for 4–8 year-olds and 5 mg/day
for 9–13 year-olds) normal plasma Cu levels were not
achieved either. Berger has stated in a letter to the editor of
Burns that the Lausanne group provides intravenous trace
element supplementation.34 Zinc is given up to 4–6 times
the nutritional dose and Cu is given in amounts as high as
3–4 mg/day. These supplements have been successful in cor­
recting the losses. Mayes, at the Shriners Hospital in Cincin­
nati, recommends Zn be given as zinc sulfate, 30–220 mg/
day,35 and Pochon recommended Cu be given to children at
both burn scar and adjacent normal-appearing 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 without vitamin D supplemen­
tation, progressive deficiency will result.
In a recent study, children discharged from the Shriners
Hospital in Galveston received daily supplementation with
a multivitamin containing 400 IU of vitamin D2 for six
months.14 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. Therefore, the
amount of vitamin D supplementation necessary to main­
tain normal circulating levels of 25-hydroxyvitamin D is
unknown. Chan and Chan cite 200–400 IU per day as
required in healthy, non-burned children.15 However, there
is no evidence supporting that requirement in a burned
population, and long-term vitamin D supplementation with
levels exceeding 400IU/day may be necessary to overcome
the post-burn deficiency.
Zinc and copper
Zinc (Zn) and Copper (Cu) are essential trace elements. Zinc
has roles in the metabolism of RNA and DNA, signal trans­
duction, and gene expression, and also regulates apoptosis,
thereby playing a ‘ubiquitous role’ in the human organism.16
Copper is involved in the formation of red blood cells, the
absorption of iron from the digestive tract, metabolism of
glucose and cholesterol, and the synthesis of nearly all pro­
teins and enzymes.17 Malnourishment, hereditary diseases,
and prolonged ICU stay can lead to clinical manifestations
of Zn and Cu deficiency. Several groups have reported low
serum concentrations of Zn, Cu, and their corresponding
binding proteins albumin and ceruloplasmin, in burned
patients.18–23 Burn wound exudation and urine excretion are
considered major routes of loss of these elements.18,20,22–26
In patients with moderate to severe burns, Cunningham18
and Boosalis25 found excessive urinary Zn excretion associ­
ated with low plasma Zn levels, especially the plasma sub­
fraction bound to albumin. Zinc supplementation by total
parenteral nutrition resulted in hyperzincuria, albeit not as
pronounced as with oral supplementation.18,25 Voruganti
found elevated urinary Cu and Zn excretion in severely
burned children at admission as well as at hospital dis­
charge.26 The pediatric burn patients in this study received
up to three times the suggested oral intake of Zn and Cu
compared to dietary reference intakes.
The burn wound itself is another source of loss of both Zn
and Cu. In adults, Berger,24 Guo21 and Voruganti26 found that
Zn in wound exudates greatly exceeded excretory losses over
the first week post burn. This was confirmed in severely
burned children with an average burn size of 54% TBSA,
with Zn and Cu concentrations in wound exudates exceeding
plasma concentrations.26
Although excretory and exudative losses of Zn and Cu can
certainly contribute to a fall in plasma levels of these micro­
nutrients, there is evidence for their post-burn redistribution
in the body. Van Rij reported that after a 20% TBSA burn in
the rat, isotope-marked Zn was rapidly taken up by the
wound, spleen, kidney, and liver, whereas a decrease in Zn
levels took place in the brain, muscle, and bone.27 Zinc-
binding protein was demonstrated in the hepatic cytosol.

Vitamin and trace element homeostasis following severe burn injury
323
The other trace element studied is chromium (Cr). Ander­
son found a progressive decrease in liver Cr up to 10 days
after the injury and a brief spike in Cr at 6 h post burn in
rat quadriceps muscle, followed by a progressive reduction
over the next 9 days.44 Urinary Cr losses also increased. Cor­
ticosterone in serum peaked on the first post-burn day, and
non-fasting glucose, circulating insulin and glucagon reached
a maximum on the second post-burn day. Thus Cr may play
a role in the glucose intolerance observed following burn
injury. There are no published recommendations regarding
Cr replacement.
Finally, burn victims seem to accumulate an unwanted
trace element, namely aluminum (Al). Klein described Al
accumulation in serum and bone of adults with burn injury
>40% TBSA, finding Al deposition on the mineralization
front of bones as early as 8 days post burn.10 The sources of
Al contamination in burn injury have been published45 and
attempts to minimize Al loading in these patients may
hasten their skeletal recovery from burn injury.
Antioxidative properties of vitamins and trace
minerals and effect of replacement therapy
A meta-analysis of studies of antioxidant supplementation
in sepsis and the systemic inflammatory response syndrome
by Berger and Chiolero showed that Se supplementation
improves clinical outcomes of infections and organ failure,
glutamine reduces infectious complications in critically ill
patients, and eicosapentaenoic acid combined with trace
elements has an anti-inflammatory response in critically ill
patients and reduces the number of ventilator days.46 These
outcomes have reached the first tier of evidence (level A)
supporting their use. With regard to appropriate dosing, in
another study from the same group43 500 mL of enteral solu­
tion with 30 g of glutamine per day, as well as Se, Zn and
vitamin E, was used for supplementation.47 The authors
found, however, that the entire dose could not be delivered
enterally, and concluded that a dose of 0.5 g/kg/day in asso­
ciation with a high intravenous trace element solution may
be more effective (Table 27.1).
Summary
Burn injury is marked by a reduction in plasma levels of
most vitamins and trace elements, which appear to redistrib­
ute to liver and kidney in order to maximize the antioxidant
response to the injury. Antioxidant supplementation appears
to have beneficial effects on the body’s immune response
and morbidity and mortality. The effects of the reduction in
trace element content of tissues such as bone have not been
studied and may contribute to the loss of bone or bone
mineral experienced by these patients. Also of note is the
finding of ongoing vitamin D deficiency, in part because the
proper supplemental dose is not known, and also because
the skin is no longer able to synthesize normal quantities of
vitamin D from exposure to ultraviolet radiation. True
‘requirements’ of vitamins and trace elements in the post-
burn state have yet to be determined. The effects of severe
burn injury on both the requirements and the bioavailability
of other vitamins remain unknown.
a dose of 0.08 mg/kg copper sulfate/day and to adults at a
dose of 4.5 mg/day.33 When Berger supplemented 21 severely
burned patients with a trace element mixture of Cu, Zn, and
selenium (Se) given intravenously for up to 3 weeks, con­
centrations of the three micronutrients were increased in
both plasma and skin.36 Pneumonia incidence and protein
catabolism decreased compared to the control group,
whereas wound healing rate improved with lower require­
ments for regrafting of excised burn wounds.37
In summary, although the additional supplementation
of Zn and Cu in burned patients is paramount, there is no
agreement on either the dose or the route of administration.
Appropriate criteria on which to base the adequacy of Zn
and Cu supplementation have yet to be developed. Cur­
rently, the best estimates and guidelines can be found in the
work of Mette Berger.38,39
Other trace elements: selenium, chromium,
and aluminum
Selenium (Se) is a trace element which acts as an antioxi­
dant. It is important in the function of lymphocytes, and
hence in cell-mediated immunity. Selenium is lost through
the skin following burn injury and thus selenium deficiency
in burn patients has been documented.40 Plasma, erythro­
cyte and urinary excretion of Se have all been shown to fall
following severe burns.40 Boosalis confirmed these findings
and postulated that there may be an antagonistic relation­
ship between Se and silver applied to burn wounds,41 while
Agay suggests that Se may be redistributed among organs.28
Redistribution between different organ compartments post
burn is another explanation for the observed changes in Se
levels. Agay also reported a reduction of plasma Zn and
Se levels with a sustained increase in serum Cu.28 Selenium
levels increased in kidneys but progressively fell in the liver,
whereas hepatic Zn and Cu increased. Of interest, plasma
and liver glutathione peroxidase fell but was unchanged in
other organs, including the kidney, whereas liver Cu-Zn
superoxide dismutase rose. Thus it is possible that in the rat
the redistribution of Se to the kidney preserves glutathione
peroxidase activity in that organ, while the rise in liver super­
oxide dismutase results from redistribution of Cu and Zn to
the liver and maintains antioxidant activity there. This redis­
tribution hypothesis was suggested by previous work from
this group which demonstrated the early oxidative stress fol­
lowing burns in these animals by measuring the drop in
plasma thiol groups as an indicator of plasma protein
oxidation.42
There are no evidence-based studies that suggest dosing of
Se in burn patients. A recent clinical trial by Berger, however,
showed that supplementation with intravenous trace ele­
ments (Cu 2.5 to 3.1 mg/day, Se 315 to 380 µg/day, and Zn
26.2 to 31.4 mg/day) for 8–21 days versus placebo was asso­
ciated with a significant reduction in pulmonary infectious
complications, mainly due to a reduction of nosocomial
pneumonia in critically ill, burned patients.43 The authors
pointed out that Se deserved special consideration among
the three trace elements provided, as the European general
patient population suffers from a Se deficiency, and provid­
ing Se might act as a ‘reinforcement of endogenous antioxi­
dant defences’.43

Total Burn Care
27
324
Berger MM, Chiolero RL. Anti-oxidant supplementation in sepsis
and systemic 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.
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.
TABLE 27.1  Vitamin and trace element requirements
Age
(years)
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)
0–13
Non-burned
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
≥13 and adults
Non-burned
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.
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 http: // 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.
 
Access the complete reference list online at

*Administered Monday, Wednesday, and Friday.

Vitamin and trace element homeostasis following severe burn injury
324.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. Nguyen TT, Cox CS, Traber DL, et al. Free radical activity and loss
of plasma antioxidants, vitamin E, and sulfhydryl groups in
patients with burns: the 1993 Moyer Award. J Burn Care Rehabil.
Nov-Dec 1993;14(6):602-609.
2. Rock CL, Dechert RE, Khilnani R, et al. Carotenoids and
antioxidant vitamins in patients after burn injury. J Burn Care
Rehabil. May-Jun 1997;18(3):269-278; discussion 268.
3. Rettmer RL, Williamson JC, Labbe RF, et al. Laboratory
monitoring of nutritional status in burn patients. Clin Chem.
Mar 1992;38(3):334-337.
4. Jenkins ME, Gottschlich MM, Kopcha R, et al. A prospective
analysis of serum vitamin K in severely burned pediatric patients.
J Burn Care Rehabil. Jan-Feb 1998;19(1 Pt 1):75-81; discussion
73-74.
5. Ferron M, Hinoi E, Karsenty G, et al. Osteocalcin differentially
regulates beta cell and adipocyte gene expression and affects the
development of metabolic diseases in wild-type mice. Proc Natl
Acad Sci U S A. Apr 1 2008;105(13):5266-5270.
6. Klein GL, Wolf SE, Langman CB, et al. Effects of therapy with
recombinant human growth hormone on insulin-like growth
factor system components and serum levels of biochemical
markers of bone formation in children after severe burn injury.
J Clin Endocrinol Metab. Jan 1998;83(1):21-24.
7. Barbosa E, Faintuch J, Machado Moreira EA, et al.
Supplementation of vitamin E, vitamin C, and zinc attenuates
oxidative stress in burned children: a randomized, double-blind,
placebo-controlled pilot study. J Burn Care Res. Sep-Oct 2009;
30(5):859-866.
8. Dubick MA, Williams C, Elgjo GI, et al. High-dose vitamin C
infusion reduces fluid requirements in the resuscitation of
burn-injured sheep. Shock. Aug 2005;24(2):139-144.
9. Tanaka H, Lund T, Wiig H, et al. High dose vitamin C counteracts
the negative interstitial fluid hydrostatic pressure and early edema
generation in thermally injured rats. Burns. Nov 1999;25(7):
569-574.
10. Klein GL, Herndon DN, Rutan TC, et al. Bone disease in burn
patients. J Bone Miner Res. Mar 1993;8(3):337-345.
11. Klein GL, Herndon DN, Goodman WG, et al. Histomorphometric
and biochemical characterization of bone following acute severe
burns in children. Bone. Nov 1995;17(5):455-460.
12. Klein GL, Chen TC, Holick MF, et al. Synthesis of vitamin D in
skin after burns. Lancet. Jan 24 2004;363(9405):291-292.
13. Klein GL, Langman CB, Herndon DN. Vitamin D depletion
following burn injury in children: a possible factor in post-burn
osteopenia. J Trauma. Feb 2002;52(2):346-350.
14. Klein GL, Herndon DN, Chen TC, et al. Standard multivitamin
supplementation does not improve vitamin D insufficiency after
burns. J Bone Miner Metab. 2009;27(4):502-506.
15. Chan MM, Chan GM. Nutritional therapy for burns in children
and adults. Nutrition. Mar 2009;25(3):261-269.
16. Hambidge KM, Krebs NF. Zinc deficiency: a special challenge.
J Nutr. Apr 2007;137(4):1101-1105.
17. Harris ED. Copper homeostasis: the role of cellular transporters.
Nutr Rev. Sep 2001;59(9):281-285.
18. Cunningham JJ, Lydon MK, Briggs SE, et al.. Zinc and copper
status of severely burned children during TPN. J Am Coll Nutr.
Feb 1991;10(1):57-62.
19. Cunningham JJ, Lydon MK, Emerson R. Low ceruloplasmin levels
during recovery from major burn injury: influence of open wound
size and copper supplementation. Nutrition. 2000;12:83-88.
20. Gosling P, Rothe HM, Sheehan TM, et al. Serum copper and zinc
concentrations in patients with burns in relation to burn surface
area. J Burn Care Rehabil. Sep-Oct 1995;16(5):481-486.
21. Guo Z, Li L, Zhao L. [Changes in contents of Zn, Cu, Fe, Ca, Mg
in serum, urine and blister fluid after burn injury]. Zhonghua
Zheng Xing Shao Shang Wai Ke Za Zhi. May 1997;13(3):195-198.
22. Selmanpakoglu AN, Cetin C, Sayal A, et al. Trace element (Al, Se,
Zn, Cu) levels in serum, urine and tissues of burn patients. Burns.
Apr 1994;20(2):99-103.
23. Shewmake KB, Talbert GE, Bowser-Wallace BH, et al. Alterations
in plasma copper, zinc, and ceruloplasmin levels in patients with
thermal trauma. J Burn Care Rehabil. Jan-Feb 1988;9(1):13-17.
24. Berger MM, Cavadini C, Bart A, et al. Cutaneous copper and zinc
losses in burns. Burns. Oct 1992;18(5):373-380.
25. Boosalis MG, Solem LD, Cerra FB, et al. Increased urinary zinc
excretion after thermal injury. J Lab Clin Med. Dec
1991;118(6):538-545.
26. Voruganti VS, Klein GL, Lu HX, et al. Impaired zinc and copper
status in children with burn injuries: need to reassess nutritional
requirements. Burns. Sep 2005;31(6):711-716.
27. van Rij AM, Hall MT, Bray JT, et al. Zinc as an integral component
of the metabolic response to trauma. Surg Gynecol Obstet. Nov
1981;153(5):677-682.
28. Agay D, Anderson RA, Sandre C, et al. Alterations of antioxidant
trace elements (Zn, Se, Cu) and related metallo-enzymes in
plasma and tissues following burn injury in rats. Burns. May
2005;31(3):366-371.
29. Kupper TS, Deitch EA, Baker CC, et al. The human burn wound
as a primary source of interleukin-1 activity. Surgery. Aug
1986;100(2):409-415.
30. Abboud MM, Saeed HA, Tarawneh KA, et al. Copper uptake by
Pseudomonas aeruginosa isolated from infected burn patients.
Curr Microbiol. Sep 2009;59(3):282-287.
31. Liusuwan RA, Palmieri T, Warden N, et al. Impaired healing
because of copper deficiency in a pediatric burn patient: a case
report. J Trauma. Aug 2008;65(2):464-466.
32. Keen CL, Gershwin ME. Zinc deficiency and immune function.
Annu Rev Nutr. 1990;10:415-431.
33. Pochon JP. Zinc- and copper-replacement therapy—a must in
burns and scalds in children? Prog Pediatr Surg. 1981;14:151-172.
34. Berger MM. Acute copper and zinc deficiency due to exudative
losses – substitution versus nutritional requirements. Burns.
2006;32:393.
35. Mayes T, Gottschlich M, Scanlon J, et al. Four-year review of
burns as an etiologic factor in the development of long bone
fractures in pediatric patients. J Burn Care Rehabil. Sep-Oct
2003;24(5):279-284.
36. Berger MM, Baines M, Raffoul W, et al. Trace element
supplementation after major burns modulates antioxidant status
and clinical course by way of increased tissue trace element
concentrations. Am J Clin Nutr. May 2007;85(5):1293-1300.
37. Berger MM, Binnert C, Chiolero RL, et al. Trace element
supplementation after major burns increases burned skin trace
element concentrations and modulates local protein metabolism
but not whole-body substrate metabolism. Am J Clin Nutr. May
2007;85(5):1301-1306.
38. Berger MM, Raffoul W, Shenkin A. ‘Practical guidelines for
nutritional management of burn injury and recovery’ – a
guideline based on expert opinion but not including RCTs.
Burns. Feb 2008;34(1):141-143.
39. Berger MM, Shenkin A. Update on clinical micronutrient
supplementation studies in the critically ill. Curr Opin Clin Nutr
Metab Care. Nov 2006;9(6):711-716.
40. Hunt DR, Lane HW, Beesinger D, et al. Selenium depletion in
burn patients. JPEN J Parenter Enteral Nutr. Nov-Dec
1984;8(6):695-699.
41. Boosalis MG, Solem LD, Ahrenholz DH, McCall JT, McClain CJ.
Serum and urinary selenium levels in thermal injury. Burns Incl
Therm Inj. Apr 1986;12(4):236-240.
42. Sandre C, Agay D, Ducros V, et al. Early evolution of selenium
status and oxidative stress parameters in rat models of thermal
injury. J Trace Elem Med Biol. 2004;17(4):313-318.
43. Berger MM, Eggimann P, Heyland DK, et al. Reduction of
nosocomial pneumonia after major burns by trace element

Total Burn Care
27
324.e2
© Copyright 2012 Elsevier, Inc. All rights reserved.
supplementation: aggregation of two randomised trials. Crit Care.
2006;10(6):R153.
44. Anderson RA, Sandre C, Bryden NA, et al. Burn-induced
alterations of chromium and the glucose/insulin system in rats.
Burns. Feb 2006;32(1):46-51.
45. Klein GL, Herndon DN, Rutan TC, et al. Risk of aluminum
accumulation in patients with burns and ways to reduce it. J Burn
Care Rehabil. Jul-Aug 1994;15(4):354-358.
46. Berger MM, Chiolero RL. Antioxidant supplementation in sepsis
and systemic inflammatory response syndrome. Crit Care Med.
Sep 2007;35(9 Suppl):S584-S590.
47. Soguel L, Chiolero RL, Ruffieux C, et al. Monitoring the clinical
introduction of a glutamine and antioxidant solution in critically
ill trauma and burn patients. Nutrition. Nov-Dec 2008;24(11-
12):1123-1132.

©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00028-X
Hypophosphatemia
David W. Mozingo, Arthur D. Mason, Jr.
Introduction
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 post-burn days. This phenomenon 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 prior to the tenth
post-burn day (Fig. 28.1). 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 hypo­
phosphatemia is not exclusive to thermal injury, having been
described following multiple trauma,4 head injury,5 and elec­
tive surgery.6 The exact mechanism by which thermal injury
or severe stress induces hypophosphatemia is unknown.
Several events associated with burn injury, however, affect
phosphorus metabolism, and these may combine to produce
hypophosphatemia.
Etiology of post-burn hypophosphatemia
Many of the pathophysiological changes and therapeutic
interventions that occur during the first post-burn week
influence serum phosphorus concentration (Box 28.1).
Hypophosphatemia does not necessarily imply phosphorus
depletion; in the case of burn injury, most patients are
healthy prior to injury and presumably have normal phos­
phorus stores. Nor do simple calculations of phosphate
balance explain the dramatic decrease in serum levels; simul­
taneous reduction of urinary phosphate excretion is observed,
suggesting an extrarenal mechanism. The fractional excre­
tion of phosphate, however, increases during the early period
of diuresis following burn injury (post-burn days 2–4),
potentially contributing to the decline in serum levels. The
pathophysiological events and therapeutic interventions
discussed below are associated with hypophosphatemia
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 post-burn 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 redistribution
of phosphorus from the extracellular to the intracellular
compartment (see section on Metabolic support, below). 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
Since urinary excretion of phosphate is usually decreased
in the early post-injury period, the importance of hyper­
glucagonemia remains uncertain. Administration of phar­
macological doses of glucocorticoids enhances phosphorus
excretion and impairs phosphate absorption by the gut and
reabsorption by the kidney. Whether or not the adrenocorti­
cal response significantly contributes to the hypophos­
phatemia 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 con­
centration by several mechanisms.8 Lactate is converted to
glucose in the liver, a process requiring high-energy phos­
phate availability. Additionally, though it does not usually
occur clinically, metabolic alkalosis induced by lactate infu­
sion may result in depression of serum phosphorus concen­
tration. Alkalosis is associated with an increase in glycolysis
that promotes transfer of phosphorus to the intracellular
CHAPTER 28 
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IN THIS CHAPTER
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Total Burn Care
28
326
phosphate transport across the renal epithelial cell. In
patients with burns, mobilization and excretion of the large
edema volume usually begins by the second post-burn day
and continues throughout the next week to 10 days. In con­
trast to the relative paucity of phosphate excretion during
the first 24 h after injury, when glomerular filtration is mark­
edly 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 fractional excretion of
phosphate despite a concomitant reduction 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-
antagonists and antacid buffering has been a mainstay of
burn care for the past two decades. Significant degrees of
hypophosphatemia and phosphate depletion occur during
continuous or chronic administration of phosphate-binding
agents containing magnesium, calcium, and aluminum.
These agents bind not only dietary phosphate but also phos­
phate 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 pre-existing
phosphate balance. To reduce alimentary scavenging of
dietary and secreted phosphate, buffering with antacids con­
taining aluminum phosphate salts (Al2PO4), which do not
bind any additional phosphate, may be utilized. Sucralfate,
which is also effective in preventing upper gastrointestinal
stress ulceration following 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 hypophosphatemia
in critically ill patients.10
Hyperventilation
Respiratory alkalosis is often present during the first week
post-burn and may be enhanced by anxiety or pain, and even
by the inhibition of carbonic anhydrase induced by mafe­
nide acetate burn cream. As fluid resuscitation progresses,
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 virtu­
ally 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, activating
glycolysis and increasing the formation of intracellular phos­
phorylated carbohydrate compounds. The readily diffusible
inorganic phosphate pool supplies the required phosphorus,
and serum phosphorus concentrations consequently fall
abruptly. The extent to which this mechanism contributes to
post-burn hypophosphatemia is uncertain.
space. During resuscitation, alkalemia is uncommon and
patients are more likely to manifest a mild metabolic acido­
sis, which is compensated by hyperventilation, resulting in
a normal or mildly alkaline blood pH. Acidosis markedly
inhibits renal phosphate reabsorption, resulting in phospha­
turia. The contribution of this mechanism to post-burn
hypophosphatemia is probably minor; early renal phos­
phate 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 dimin­
ishes proximal tubular reabsorption of phosphate and prob­
ably occurs following topical burn wound treatment with
mafenide, but the magnitude of the effect is unknown.
Expansion of the extracellular fluid volume is also asso­
ciated with inhibition of proximal tubular phosphate
reabsorption. A tight coupling exists between sodium and
Figure 28.1  Serum phosphorus levels abruptly decline with a nadir
between post-burn days 2 and 5. The data were obtained from 550
consecutive burn patients admitted to the US Army Institute of Surgical
Research.
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
Box 28.1  Possible causes of post-burn hypophosphatemia
Fluid resuscitation
• volume loading
• lactate administration
Carbohydrate administration
• enteral alimentation
• parenteral hyperalimentation
• 5% dextrose
Elevated catecholamines
Phosphate-binding antacids/sucralfate
Acid–base disturbance
Electrolyte imbalance
• hypokalemia
• hypomagnesemia
• hypocalcemia
Carbonic anhydrase inhibition (mafenide acetate)

Hypophosphatemia
327
aggressive phosphorus supplementation prior to 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
addition, the continued loss of fluid and protein through
the burn wound surface is a potential source of unquan­
tified phosphorus loss and may contribute to hypophos­
phatemia.16 In a comparison between burn patients and
traumatically 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 count was made
with the magnitude of hypophosphatemia.19 Though 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 contribute to the development
of hypophosphatemia.
Other electrolytes
Disorders of electrolyte balance may contribute to the devel­
opment of hypophosphatemia. Experimental magnesium
deficiency in animals may lead to phosphaturia and phos­
phorus deficiency, but intentional magnesium deficiency in
man results in no change or a slight rise in serum phos­
phate.20,21 In chronic alcoholics, however, hypomagnesemia
and hypophosphatemia are coexistent. Hypokalemia, which
is also exacerbated by magnesium deficiency, may result in
phosphate wasting and hypophosphatemia. The mechanism
is uncertain, but may be related to coexistent metabolic alka­
losis, diuretic use, or the underlying illness. Changes in
calcium and phosphate homeostasis, and in the regulating
hormones calcitonin and parathyroid hormone, have been
described after thermal injury.22 Coincident with the early
depression of serum phosphorus, the fraction of ionized
Metabolic support
Administration of carbohydrates may play a major role
in the development of post-burn hypophosphatemia.
Infusion of glucose solutions or oral intake of carbohy­
drates produces mild hypophosphatemia in healthy indi­
viduals. This decrease in serum phosphate is associated
with an increase of inorganic phosphate, ATP, and
glucose 6-phosphate in muscle cells. The mechanism by
which such carbohydrate administration induces hypo­
phosphatemia is somewhat speculative. Experience with
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 since hypo­
phosphatemia inhibits glucose 3-phosphate dehydrogenase.
Inorganic phosphates in the intracellular pool become
further diminished because of incorporation, initially as
newly synthesized ATP, but eventually as triose phosphates
when the ATP is consumed in the hexokinase reaction.
Glucose utilization by red blood cells requires ATP at the
hexokinase and phosphofructokinase steps, but regenera­
tion of ATP does not occur during phosphate deficiency or
acute hypophosphatemia due to a block at the glucose
3-phosphate dehydrogenase step. In states of phosphate
depletion, the scant phosphate that enters the red blood
cell is incorporated into 1,3-diphosphoglycerate, but most
is diverted to 2,3-diphosphoglycerate, also preventing com­
plete glycolysis to regain the ATP consumed.
In thermally injured patients, infusion of dextrose-
containing solutions usually begins 24 h post-burn, 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 clini­
cal states, severe hypophosphatemia following the initiation
of enteral or parenteral nutrition is most commonly associ­
ated 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 multi-system organ dysfunc­
tion, respiratory and cardiac failure, or death. Thermally
injured patients are usually well nourished prior to burn
injury and the clinical scenario of refeeding hypophos­
phatemia 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 post-burn day when
feeding is initiated.3 This further reduction of serum phos­
phorus during the first post-burn week, when levels are
already low, may be particularly hazardous and speaks for

Total Burn Care
28
328
clinical manifestations shown in Box 28.2 are commonly
observed in thermally injured patients, while 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 remem­
ber that prior cellular injury has been prerequisite in most
instances in which hypophosphatemia has been implicated
as a cause of organ system dysfunction. The following discus­
sions of organ system abnormalities should be interpreted
in light of the specific circumstances under which the obser­
vations were made.
Cardiac dysfunction
Although the early depression of cardiac function following
burn injury has been attributed to an initial decrease in
circulating blood volume, the search for intrinsic myocardial
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 hypophosphatemic patients and improved sig­
nificantly with phosphorus supplementation.4 In one exper­
imental study, myocardial contractility was impaired by
phosphorus deficiency and reversed by phosphorus reple­
tion, suggesting that phosphorus deficiency may be a cause
of heart failure in certain clinical conditions.23 Hypophos­
phatemic cardiac depression has been described as occur­
ring in 28.8% of surgical intensive care patients.24 Despite
these reports, there appears to be little evidence that hypo­
phosphatemic cardiomyopathy is a frequently encountered
clinical entity; most patients in whom this mechanism is
invoked have already had a number of other causes for myo­
cardial dysfunction.25
calcium was shown to decrease and remain low, but within
the normal range, for the 14 post-burn days studied. Urinary
calcium output was low, about 4.5 mmol/day, and urinary
phosphate output was as high as 30 mmol/day, despite a low
serum phosphorus. Serum calcitonin levels were signifi­
cantly elevated for up to 2 weeks post-injury, whereas par­
athyroid hormone remained within the normal range. The
magnitude of the contribution of the classic regulating hor­
mones 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 administration of pharmacological doses of calcitonin
results in phosphaturia. A direct effect of calcitonin on phos­
phate transport in the nephron has been demonstrated. In
those burn patients, it was notable that ionized calcium
decreased slightly though still within the normal range,
despite very high levels of calcitonin and normal parathyroid
hormone concentrations. A slight, though statistically sig­
nificant, increase in parathyroid hormone was observed
around the fourth post-burn day and may be related, albeit
indirectly through calcium regulation, to the observed post-
burn decrease in serum phosphorus concentration.
Summary
Clearly, multiple factors influence the serum phosphorus
level following 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 depression of serum phosphorus is
difficult to analyze. Most likely, carbohydrate administra­
tion, respiratory alkalosis, and diuresis of edema fluid are
the more important etiologic factors contributing to hypo­
phosphatemia in the early post-burn course.
Consequences of hypophosphatemia
The clinical manifestations of hypophosphatemia (Box
28.2) are mainly those of organ system hypofunction. These
responses have been defined through clinical observation
and laboratory studies in circumstances in which hypophos­
phatemia occurred as a relatively isolated event. Phosphorus
supplementation has been reported to reverse these abnor­
malities, suggesting a cause and effect relationship. Hypo­
function of organ systems associated with phosphorus
depletion has been attributed to a lack of available inorganic
phosphate for synthesis of high-energy phosphorus com­
pounds; breakdown of stored ATP occurs, and the inorganic
phosphate is diverted to other intracellular pathways. Organ
system dysfunction after thermal injury is characterized by
early hypofunction and later hyperfunction of most organ
systems. Whether hypophosphatemia contributes signifi­
cantly to the early post-burn depression of function that
occurs in multiple organs is not known. Clearly, some of the
Box 28.2  Clinical manifestations of hypophosphatemia
CNS
•
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.

Hypophosphatemia
329
of granulocytes.35 A reduction in granulocyte ATP content
was also documented and amelioration of these white blood
cell 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
Though it is clear that organ system dysfunction may be a
manifestation of severe untreated hypophosphatemia, the
relationship between these specific abnormalities and those
observed in either the hypodynamic or the 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 following burn injury is part
and parcel of the disease process, without bearing on
the post-burn physiological response, but that thus far,
the pathophysiological milieu following thermal injury has
not permitted definition of the contribution of hypophos­
phatemia to the overall post-burn response. Until cause and
effect relationships are defined through ongoing research,
aggressive phosphorus repletion should be approached cau­
tiously following thermal injury. Such therapy does, however,
clearly ameliorate red blood cell 2,3-diphosphoglycerate
depletion, which, in and of itself, supports treatment.
Prevention and treatment
of hypophosphatemia
An unequivocal recommendation to treat hypophos­
phatemia 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 phosphate
repletion initiated when levels drop below 2.0 mg/dL (Fig.
28.2). 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 h. The dose may be
halved for patients with serum phosphorus levels between
1.0 and 2.0 mg/dL.36 Following completion of the infusion,
a repeat serum phosphorus determination should be
obtained, and further treatment based on the post-infusion
plasma concentration. A potential hazard associated with
intravenous administration of phosphate salts is hyperphos­
phatemia, 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 administration of
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 mechani­
cally ventilated hypophosphatemic patients.26 Profound
generalized muscle weakness associated with isolated phos­
phorus depletion has been observed in both clinical and
laboratory studies.27,28 In a study of hypophosphatemia and
muscle phosphate metabolism in patients with burns or
mechanical trauma, no direct correlation was demonstrated
between the serum phosphorus concentration and the high-
energy phosphate content of muscle cells; all these patients,
however, were receiving phosphorus supplementation
during the study.29 If acute hypophosphatemia is superim­
posed on pre-existing cellular injury, potentially reversible
muscle cell dysfunction may extend to irreversible necrosis.30
Several authors have reported severe rhabdomyolysis associ­
ated with severe hypophosphatemia following 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 Hypophosphatemia as the underlying etiology
may often be dismissed since muscle cell destruction results
in release of phosphate and elevation of serum phosphorus.
In the absence of significant hemochromogenuria, the diag­
nosis may not even be suspected. Further investigation is
required to determine whether this ‘asymptomatic’ rhab­
domyolysis is, in fact, an important clinical entity, or merely
an obligate manifestation of critical illness.
Hematologic dysfunction
When untreated, severe hypophosphatemia may lead to red
blood cell dysfunction by alterations in cell shape, survival,
and physiological function. Lack of high-energy phosphate
results in a decrease in erythrocyte 2,3-diphosphoglycerate
and subsequent leftward shift of the dissociation curve, with
a consequent risk of tissue hypoxia.7 Clinical hypophos­
phatemia, with or without previous phosphate depletion,
results in reduced production of 2,3-diphosphoglycerate,
erythrocyte ATP, and other phosphorylated intermediates of
red blood cell glycolysis. In a variety of experimental and
clinical situations, including burn injury and mechanical
trauma, red blood cell 2,3-diphosphoglycerate has been
shown to be reduced in the presence of hypophos­
phatemia.34,35 In thermally injured patients it has been dem­
onstrated that post-burn disturbance of red cell phosphate
metabolism may be prevented by administration of phos­
phorus in the early post-burn course.35 Hypophosphatemia
has also been associated with decreased red cell survival and
decreased red cell 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

Total Burn Care
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330
hypocalcemia, and hypokalemia, as well as maintenance of
acid–base normality, may prevent further renal phosphate
losses and maintain the extracellular phosphate pool.
After the 10th post-burn 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 post-burn 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 following
burn injury. The contribution of hypophosphatemia to
these manifestations remains undefined. Wound fluid losses,
increased circulating catecholamines, intracellular phos­
phate redistribution, and increased fractional excretion of
urinary phosphate, as well as iatrogenic induction of hypo­
phosphatemia through various therapeutic interventions,
have been implicated as contributing to post-burn hypo­
phosphatemia. There may be other pathways regarding
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 prior to interven­
tions such as the initiation of either enteral or parenteral
carbohydrate administration, gastric acid neutralization with
phosphate-binding antacids or sucralfate, and the admini­
stration of diuretics. The nadir of serum phosphorus concen­
tration 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 due to administration of phosphate-binding antacids,
substitution of, or alternation with, antacids containing alu­
minum phosphate should be considered.
For mild asymptomatic hypophosphatemia or for prophy­
laxis 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,
Figure 28.2  The use of this algorithm permits
prompt detection and timely correction of
hypophosphatemia following burn injury.
Monitor serum phosphorus daily*
Phos <2.0 mg/dL
IV therapy indicated
Phos 2.0–3.0 mg/dL
PO therapy indicated
Phos <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 phos following infusion
to guide further replacement
Identify and address potential
contributing factors
Phos 1.0–2.0 mg/dL
Any of several
available formulations
i.e. Phospho-soda
5 mL t.i.d

Hypophosphatemia
331
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
nutrition services: adjustment dietary treatment of patients with
hyponatremia 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.
phosphorus regulation that have not been explored in this
patient population. Phosphatonins have been shown to
be important mediators of phosphorus homeostasis and
could be important mediators in this phenomenon seen in
burn patients.38 Frequent serum phosphate measurement
and prompt phosphorus replacement when hypophos­
phatemia is recognized should minimize any sequelae of
this potentially deleterious electrolyte deficiency.
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.
 
Access the complete reference list online at

Hypophosphatemia
331.e1
© Copyright 2012 Elsevier, Inc. All rights reserved.
References
1. 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.
2. Nordstrom H, Lennquist S, Lindell B, et al. Hypophosphataemia
in severe burns. Acta Chir Scand. 1977;143:395-399.
3. Mozingo DW, Cioffi WG, Mason AD Jr, et al. Initiation of
continuous enteral feeding induces hypophosphatemia in
thermally injured patients. Proceedings of the 35th World
Congress of Surgery/International Society of Surgery/International
Surgical Week, 22-27 August 1993.
4. O’Connor LR, Weeler WS, Bethune JE. Effects of
hypophosphatemia on myocardial performance in man. N Engl J
Med. 1977;297:901.
5. Polderman KH, Bloemers FW, Peerdeman SM, et al.
Hypomagnesemia and hypophosphatemia at admission in
patients with severe head injury. Crit Care Med. 2000;28(6):
2022-2025.
6. England PC, Duari M, Tweedle DET, et al. Postoperative
hypophosphatemia. Br J Surg. 1979;66:340.
7. Lau K. Phosphate disorders. In: Kokko JP, Tannen RL, eds. Fluids
and electrolytes. Philadelphia, PA: WB Saunders; 1986:398-471.
8. Knochel JP. The pathophysiology and clinical characteristics of
severe 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:
hypophosphatemia 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
concentration 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.
J Parenter Enter 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. 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.
19. Barak V, Schwartz A, Kalickman I, et al. Prevalence of
hypophosphatemia 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
hypophosphatemia 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
depletion. J Clin Invest. 1963;42:305-313.
22. Shils ME. Experimental human magnesium depletion. Medicine.
1969;48:61-82.
23. Loven L, Nordstrom H, Lennquist S. Changes in calcium and
phosphate 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
myocardial 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
hypophosphatemia 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.
Anaesthesia. 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
phosphates 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
intravenous phosphate replacement in critically ill patients. Ann
Pharmacother. 1997;31(6):683-688.
38. Berndt TJ, Schiavi S, Kumar R. ‘Phosphatonins’ and the regulation
of phosphorus homeostasis. Am J Physiol Renal Physiol. 2005;289:
F1170-F1182.

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Nutritional support of
the burned patient
Jeffrey R. Saffle, Caran Graves, Amalia Cochran
Introduction
The metabolic consequences of major burn injury constitute
a major challenge to successful burn treatment. Metabolic
rates of burn patients can exceed twice normal and cause
tremendous wasting of lean body mass within a few weeks
of injury. Failure to satisfy these energy and protein require­
ments results in impaired wound healing, organ dys­function,
susceptibility to infection, and ultimately death. Aggressive
nutritional support is an essential component of burn care
which can reduce mortality and complications, optimize
wound healing, and minimize the devastating effects of
hypermetabolism and subsequent catabolism.
Nutritional therapy is more successful when it is provided
within a comprehensive protocol.1–3 Every burn center
should develop a multidisciplinary protocol that standard­
izes the initial and ongoing assessment, initiation, and
moni­toring of nutritional support for patients with all sizes
of burn injury.
This chapter provides practical guidelines for the nutri­
tional support of burn patients. In attempting to apply
recent research, two difficulties are apparent. First, research
dealing specifically with burn patients is far from complete.
More data are available from trauma and other ICU popula­
tions, and it is often necessary to extrapolate information
from such studies to burn patients, which may not always
be valid. We will attempt to discuss these issues as they arise.
Second, even the results of research in burn patients are
not always consistent: studies of similar therapies may reach
contradictory conclusions, especially in different popula­
tions. Such findings emphasize our imperfect understanding
of complex nutritional physiology. We will summarize new
concepts in this field, but also try to distinguish them from
‘tried and true’ therapies which are widely accepted.
A number of recent publications have attempted to sum­
marize the disparate and voluminous literature on nutrition
into guidelines for care of critically ill patients;1,4–6 specific
guidelines for burn patients have also been published.7,8
These guidelines often fail to agree on the details of nutri­
tional support, which further illustrates our imperfect knowl­
edge of this complicated field. Nutritional support, like
many areas in burn care, is a moving target. The reader will
need to interpret this chapter, and future readings, in this
light.
The hypermetabolism of burn injury
Over 70 years ago, Cuthbertson documented that traumatic
injury produced increased energy utilization and accelerated
losses of skeletal muscle.9 In the 1970s, burn patients were
found to exhibit the most severe hypermetabolism of any
group, with energy expenditure from 60% to 100% above
normal following a major burn, and concomitant catabo­
lism of protein stores.10,11 These studies also demonstrated
the so-called ‘ebb and flow’ response to injury (Fig. 29.1), in
which an initial (12–24 h) reduction in metabolic rate is
followed by a crescendo–decrescendo curve of sustained
hypermetabolism that can persist for weeks.
Early attempts to nourish burn patients with oral diets
often failed due to altered mental status, gastrointestinal
dysfunction, and inhalation injury. Even patients who could
eat were rarely able to tolerate the amount of nutrition
necessary for adequate support. As a consequence, patients
with major burns predictably incurred weight loses of
20% or more within the first few weeks of injury,12,13, with
associated immune compromise and delayed wound healing.
This inanition often proved fatal, as patients succumbed to
respiratory failure, pneumonia, and systemic infection13
(Fig. 29.2).
Mediators of hypermetabolism
The hypermetabolism of burn injury is the product of several
predominant hormonal changes.10,11,14,15 Burn injury causes
marked and sustained elevations of the catabolic hormones
epinephrine, cortisol and glucagon.16 In contrast to unstressed
starvation – in which metabolic rate falls, lipolysis and
ketosis provide energy, and muscle reserves are protected –
this hormonal response to burn injury causes greatly
increased metabolism and accelerated gluconeogenesis and
glycogenolysis. Catabolic hormones oppose the effects of
insulin; as a result, blood sugar levels rise, and protein syn­
thesis and lipogenesis are inhibited.
In this environment, protein breakdown becomes an
obligatory major source of energy. Lipids have limited
‘protein-sparing’ effect. In this setting, even glucose is limited
in its ability to prevent protein wasting.17 As a result, diets
must also be very high in protein to help replace lost lean
body mass.
©2012 Elsevier Ltd, Inc, BV
DOI: 10.1016/B978-1-4377-2786-9.00029-1
CHAPTER 29 
Access the complete reference list online at

Total Burn Care
29
334
therapies, including mechanical ventilation and chemical
sedation/paralysis, also reduce energy requirements.21
As a result, numerous recent reports using indirect calor­
imetry document metabolic rates which, although still ele­
vated, are now more likely to approximate 120–150% of
normal, rather than the 160–200% previously reported.22,23
Nonetheless, both temporal and patient-specific variations
in energy expenditure make it difficult to predict require­
ments for individual patients.
Assessment of nutritional needs
Initial assessment
Patients suffering from diseases such as cancer and AIDS
often present with serious pre-existing nutritional depletion
which must be addressed as part of their ongoing treatment.
A variety of nutritional assessment techniques can be used
both for individuals and in population-based surveys,
including careful clinical evaluation, serum proteins, anthro­
pometric measurements, tests of immune function, etc.
Pre-existing malnutrition can also exist in burn patients,24
but extensive nutritional assessments are rarely helpful for
several reasons. First, burn injury induces major abnormali­
ties in nutritional indices which confound assessment of
pre-burn status: swelling and eschar preclude accurate
anthropometric measurements, serum proteins are rapidly
altered, and immune function is similarly disturbed. A
careful nutritional history and functional status may be the
most meaningful assessments to perform.25 Moreover, satis­
fying ongoing requirements is far more important than com­
pensating for pre-existing deficiencies. Attempting to ‘catch
up’ by providing extra calories and/or protein is ineffective
and likely to increase complications of overfeeding, described
below. Therefore, the primary goal of nutritional support
in burn patients is to satisfy ongoing burn-specific
requirements.
Although these hormonal changes provide a major chal­
lenge to the provision of adequate nutrition, they also
provide mechanisms by which hypermetabolism can be
reduced to facilitate metabolic support. In recent years,
investigators have attempted to ameliorate burn-induced
hypermetabolism by blocking catecholamines with pro­
pranolol, administering the counter-regulatory agents such
as insulin and insulin-like growth factor-1 (IGF-1), or using
anabolic hormones such as growth hormone, testosterone,
or the synthetic anabolic agent oxandrolone.18,19 This rapidly
evolving area of research is discussed in detail in other chap­
ters. Although some of these methods show promise for
clinical use, it must be remembered that the hormonal
milieu that accompanies burn injury is complex and incom­
pletely understood. Additional research will be needed to
confirm the efficacy and safety of these techniques.
Modern burn care and
metabolic requirements
Modern methods of burn treatment have not altered the
nature of burn-induced hypermetabolism but have signifi­
cantly reduced its magnitude. Maneuvers as simple as main­
taining high ambient temperature and relative humidity can
reduce caloric requirements by up to 20%.11 Although burn
excision has not been shown to reduce energy expenditure
directly,20 removing the burn wound and covering wounds
with autograft, allograft, or synthetic substitutes removes the
inflammatory stimulus of the burn wound, reduces infec­
tion, and shortens the duration of hypermetabolism. Other
Figure 29.1  A classic illustration of nitrogen excretion following injury
compared to starvation and other conditions. Burn injury evokes the
most pronounced catabolism of any clinical condition, with nitrogen
excretion exceeding 25 g/day (150 g of protein, almost a half-pound
of lean body mass!). Notice also the dynamic ‘crescendo–decrescendo’
nature of this process: nitrogen excretion (and metabolic rate) rises from
near-normal levels just after injury to reach a maximum at 7–14 days post
burn, declining slowly thereafter throughout recovery. This illustrates the
impossibility of using static formulas to estimate nutritional requirements
accurately at every point throughout the course of burn treatment.
(Reproduced with permission from Long et al., 1979.10)
Nitrogen excretion (g/day)
28
30
24
20
16
12
8
Normal
range
Major burn
Skeletal trauma
Severe sepsis
Infection
Elective op
Partial starvation
Total starvation
4
0
0
10
20
Days
30
40
Figure 29.2  Weight loss following burn injury as documented in the era
before routine nutritional support. Dramatic losses of lean body mass occur
within a week or two of injury, and progress continuously in the absence of
effective nutritional support. By 4–6 weeks patients with major burns have
lost 15% of lean body mass or more: this can be a fatal degree of inanition.
(Reproduced with permission from Wilmore, 197413.)
Postburn time in weeks
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0
1
2
0–19
20–29
30–39
40+
3
4
5
6
7
8
12
Fraction of admission weight

Nutritional support of the burned patient
335
Department of Agriculture.33 The formulas in Table 29.1 use
different variables to predict caloric requirements for specific
patients, and reach very different estimates of energy needs.
Many older formulas such as Curreri’s significantly overesti­
mate modern requirements,22 and none can account for the
major differences in energy expenditure found between
patients. Dickerson et al. reviewed 46 formulas for predict­
ing the caloric needs of burn patients.34 They found that
none of the methods reviewed correlated accurately (±15%
error) with measured energy expenditure in a group of 24
patients. Because post-burn energy expenditure fluctuates
dramatically over the course of treatment (see Fig. 29.1),
static formulas often result in overfeeding early and late in
the post-burn course and underfeeding during periods of
peak energy utilization.
Formulas for estimating caloric requirements
Any protocol for nourishing burn patients must begin
with estimation of their nutritional needs. An array of for­
mulas have been developed for this purpose.26 One early
example, the ‘Curreri formula,’27 has been widely used,
though its accuracy is open to question. To create the
formula, Curreri’s group examined only nine patients
and calculated backwards to estimate the calories that
would have been needed to make up for the patients’ lost
weight. As will be discussed, this is a dubious assumption
at best.
Several popular formulas for adult nutrition are reviewed
in Table 29.1.27–32 These include the ‘dietary reference
index’ (DRI) values for normal people developed by the US
Table 29.1  Commonly used algebraic formulas for caloric needs in nutritional support
Adult formulas
kcal/day: formula1
Daily caloric estimates
for 25 yo male, 85 kg,
180 cm, 48% TBSA
Comments
Harris–Benedict29
Men: 66.5 + 13.8 (W) + 5 (H) − 6.76 (A)
Baseline = 1946 kcal
Estimates basal energy expenditure (BEE).
Best stress adjustment is a factor of 1.5;
results in a % calorie variance of 19 + 24%
If factor 1.5 = 2918 kcal
Women: 655 + 9.6 (W) + 1.85 (H) − 4.68 (A)
kcal/kg (common use)34
35 kcal/kg
2975 kcal
Variance of 23 + 36% from MREE (p = NS)34
DRI33
37 (W)
3145
‘One size fits all’ is convenient, but
inaccurate for many patients, particularly
elderly and obese.
Davies & Lilijedahl28
20 (W) + (70) TBSA
5060
Old (1971) formula grossly overestimates
requirements for patients with very large
injuries.
Ireton-Jones30
Ventilated patient:
1784 − 11(A) + 5(W) + 244(S) + 239 (T) + 804 (B)
2738
This complex formula permits calculations
for trauma and burn patients depending on
ventilatory status, and includes a factor for
Non-ventilated patient:
629 − 11(A) + 25(W) − 609(O)
2479
Curreri27
Age 16–59: 25(W) + 40 (%TBSA)
4045 kcal
Variance of 35 + 35% from MREE (p =
0.001)34 Now rarely used because of marked
Age >60: 20 (W) + 65 (%TBSA)
Pediatric formulas
Formula
Daily caloric estimates
for a 15-month old
male, 11 kg, 0.9 m2
BSA
Comments
DRI33
On-line calculator
899 kcal/day.
If factor 1.2 = 1078 kcal/day
If factor 1.4 = 1258 kcal/day
Varies according to age, weight, and activity
level
Galveston36,37
0–1 Years: 2100 (BSA) + 1000 (BSA X TBSA)
Like the Curreri formula, the Galveston
formula was created with the goal of
maintaining body weight. This may not be
1–11 Years: 1800 (BSA) + 1300 (BSA X TBSA)
2182 kcal/day
12–18 Years: 1500 (BSA) + 1500 (BSA X TBSA)
Curreri Junior35
< 1 Year: RDA + 15 (TBSA)
Extrapolation of the adult Curreri formula,
also with a tendency to over-estimate
calories.
1–3 Years: RDA + 25 (TBSA)
2099 kcal
4–15 Years: RDA + 40 (TBSA)
1For all formulas, W = weight in kilograms; H = height in centimeters; A = age in years; S = sex (male = 1, female = 0); T = Trauma (present = 1, absent = 0); B = burn (present =
1, absent = 0); O = Obesity (present = 1, absent = 0); TBSA = burn size [percent total body surface area]; CI = Calorie intake the previous day; HBE = Harris-Benedict estimates;
T = Temperature (oC); one point for every degree > 37o.

Total Burn Care
29
336
Pediatric formulas
Children present even greater nutritional challenges than
adults. Children have lower tolerance for both under- and
overfeeding. In addition, requirements change significantly
with age, so that different formulas must be used for differ­
ent age groups. Several commonly used formulas for burned
children are also presented in Table 29.1.35–38 These formulas
share the same inherent limitations as adult formulas.
Indirect calorimetry
In recent decades, improved technology for performance of
indirect calorimetry (IC) has permitted routine measure­
ment of energy expenditure at the bedside. IC devices
measure the volume of expired gas and the inhaled and
exhaled concentrations of oxygen and carbon dioxide, per­
mitting calculation of oxygen consumption (VO2) and
carbon dioxide production (VCO2), and hence metabolic
rate.39 Measurements made through tight-fitting face masks,
hoods, or by connection to mechanical ventilators have
proved reliable and reproducible over a wide range of meta­
bolic rates and FiO2.
Measurement of resting energy expenditure (REE) by IC is
usually performed in the early morning with patients at bed
rest. Fluctuations in energy utilization associated with activ­
ity are usually estimated by increasing REE by 10–20%.40 IC
can also detect significant under- or overfeeding through
calculation of the respiratory quotient (RQ) – the ratio of
carbon dioxide produced to oxygen consumed (VCO2/
VO2).41 The body’s metabolism of specific substrates affects
this ratio, providing information about metabolic supply
and demand. For example, in unstressed starvation, utiliza­
tion of fat as a major energy source produces an RQ of 0.7
or less;42 in normal metabolism of mixed substrates, RQ =
0.75 – 0.90. In contrast, the synthesis of fat from carbohy­
drate, which typifies overfeeding, results in an RQ of 1.0 or
greater. In this way, overfeeding can contribute to difficulty
weaning from ventilatory support.43
Delivering estimated needs: How close is
‘close enough’?
Despite the inherent limitations of static formulas for esti­
mating energy requirements, the superiority of IC has not
been proven clinically.44 It is unknown how closely nutri­
tional support must be ‘matched’ to energy requirements;
regular episodes of over- and underfeeding are frequent,
normal, and often unavoidable. Saffle et al. found no differ­
ences in outcomes between patients fed according to the
Curreri formula and those whose nutrition was guided by
IC.45 Recent studies in ICU patients found that <80% of
prescribed calories were actually delivered.46,47 Enteral nutri­
tion was less successful than TPN because of more frequent
interruptions for diarrhea, tube dislodgement, surgery, etc.
In both types of nutrition hyperglycemia sometimes required
feeding to be reduced, whereas dextrose-containing IV fluids
and other infusions, such as propofol, added unplanned
‘empty’ calories. These studies illustrate the ubiquitous prac­
tical difficulties of actually giving patients the nutrition that
is prescribed for them. Abundant experience demonstrates
that either formulas or IC can be used to nourish burn
patients successfully, particularly if this is done within a
multidisciplinary regimen of support. Many units use a goal
of delivering nutrition within 10% of measured (or calcu­
lated) needs as a quality assurance indicator, despite the lack
of evidence for such a practice.
Specific nutrient requirements and
‘pharmaconutrition’
Recent information about the metabolism of specific nutri­
ents has stimulated trials and recommendations for creating
disease-specific regimens for patients in a variety of situa­
tions – including burns – by changing the basic composition
of formulas, and/or providing additives with specific effects
on immune function, inflammation, or wound healing, a
concept termed ‘immunonutrition,’ and recently further
refined as ‘pharmaconutrition.’48 This information, and some
of the evidence that supports it (often incomplete), will be
reviewed here. Table 29.2, discussed below, lists the compo­
sition of a number of commonly available enteral nutrition
products which should help in understanding the quantities
of nutritients required for support.
Carbohydrates
The major energy source for burn patients should be
carbohydrates. Glucose is the preferred fuel for healing
wounds, and accessory metabolic pathways to provide
glucose, including the alanine and Cori cycles, are active in
burn patients.
A major complication of carbohydrate feeding under stress
is glucose intolerance. The hormonal environment of acute
injury causes some degree of insulin resistance in every
patient; many require significant amounts of supplemental
insulin to maintain acceptable blood sugars, especially in
light of recent evidence linking hyperglycemia to infectious
complications and even mortality in ICU populations (see
below). However, refractory hyperglycemia can still require
the reduction or even discontinuation of nutrition until
blood sugar can be controlled. Providing a limited amount
of dietary fat reduces requirements for carbohydrates and
can improve glucose tolerance significantly. In addition, sig­
nificant supplemental protein is also required to replace
catabolic losses.
Requirements and uses of fat
A limited quantity of fat is a required nutrient. Essential fatty
acid deficiency is a well-documented complication of long-
term TPN;14 for this reason modern parenteral formulas
contain significant amounts of lipid, as well as for its ability
to reduce the required glucose load and associated VCO2.
However, the hormonal environment of burn injury sup­
presses lipolysis and limits the utilization of lipids for energy.
For this reason, most authorities recommend that fat com­
prise no more than about 30% of non-protein calories, or
about 1 g/kg/day of intravenous lipids in TPN.14 Most of the
products cited in Table 29.2 meet this target.
It may be desirable to give even less fat. In an animal
model, adverse effects on immune function occurred when
diets contained more than 15% lipids.49 Some clinical

Nutritional support of the burned patient
337
Table 29.2  Composition of a sampling of commercially available adult and pediatric enteral nutrition products (note that all values are per
100 ml of feedings)
Adult formulas
A. ‘Standard’ formulas: These are relatively inexpensive formulas for general use. They provide complete balanced
nutrition, including micronutrients, with moderate amounts of protein and fat primarily for non-stressed patients.
Osmolarity varies; those intended for tube feedings are generally low. Though any of these products can be given orally,
only one (Boost™) is intended for oral use.
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Boost™ (Nestlé)
100
1180
625
17
67
4.2
17
128:1
1.7
16
4.9:1
These are both
inexpensive,
good-tasting
supplements for
oral intake or
gastrostomy
feeds. Not for
small bowel
feeding
Ensure™
(Abbott)
106
1000
620
17
64
3.8
14.4
149:1
2.5
22
NA
Osmolite
(Abbott)*
106
1321
300
14.4
54
4.4
17
125:1
3.5
35
NS
Widely used
relatively
inexpensive
formula for tube
feedings
Nutren 1.0
(Nestlé)
100
1500
300–350
12.7
51
4.0
16
133:1
3.8
33
4.1:1
Available with or
without fiber; also
available in 1.5 or
2.0 kcal/mL
Isosource HN
(Nestlé)*
120
1400
490
16
53
5.3
18
115:1
3.9
29
2.7:1
Relatively
high-protein
formula
*Similar products include Isocal-HN™ (Mead-Johnson) and Jevity™ (Ross) with and without fiber
B. High Calorie Standard Formulas: These are concentrated formulas for use in patients with fluid restrictions. Increased
concentrations of fat and/or carbohydrates mean increased osmolarity, which can contribute to diarrhea.
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Nutren 2.0™
Nestlé*
200
1500
745
19.6
39
8
16
131:1
10
45
4.6:1
Relies on
increased fat to
provide calories
*Similar products include Isosource 1.5™ (Nestlé), and TwoCalHN™ (Abbott)
Continued
research supports this finding,50 leading some authorities to
recommend very low-fat diets in burn patients. However,
popular ‘stress’ enteral formulas typically contain 25–40%
of calories as fat, and some ‘specialty’ formulas – for renal
failure, respiratory failure, or diabetes – contain even more
fat, which limits their usefulness in burn patients. Patients
given TPN may be better off if fat is withheld entirely for
short periods of time (as little as once weekly),1,51 though
this may result in aggravated glucose intolerance.
The composition of administered fat may be even more
important than the quantity. Most common sources contain
mostly omega-6 fatty acids (FFAs) such as linoleic acid,
which are metabolized through synthesis of arachidonic
acid, a precursor of proinflammatory cytokines such as pros­
taglandin E2. Lipids such as fish oil containing a high propor­
tion of omega-3 FFAs are metabolized without elaborating
proinflammatory compounds. Diets high in omega-3 FFAs
have been associated with improved immune response and
possibly improved outcomes,52 and may reduce problems
with hyperglycemia.53 Most experience with omega-3 FFAs
has been obtained with ‘immune-enhancing diets,’ of which
they are a major component (see below). Both the optimal
composition and the optimal dose of fat in nutritional
support remain topics of substantial controversy.

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338
Protein
The hormonal environment of burn injury greatly increases
proteolysis. Provision of carbohydrate and fat calories is only
partially successful in reducing protein catabolism; some
loss of lean body mass is obligatory.54 Increased protein must
be supplied both to satisfy ongoing demands and to provide
substrate for wound healing, immunity, and other functions.
When calories are limited, protein will be used as an energy
source rather than to replenish lost protein stores. The con­
verse, however, is not true: providing calories in excess of
need will not lead to increased protein retention or synthesis
– it will just lead to overfeeding, with its associated risks.
Protein intake above required needs (as in extremely high-
protein/low-carbohydrate diets) also results in protein’s use
as a fuel source through gluconeogenic pathways.
Protein catabolism in burn patients can exceed 150 g/day,
or almost a half-pound of skeletal muscle. Although feeding
supranormal amounts of protein may not reduce breakdown
of endogenous protein stores,55 it facilitates protein synthesis
and reduces negative nitrogen balance. In burned children,
a diet including increased protein (23% of total calories) was
C. High protein critical care and ‘immune-enhancing’ adult formulas: These are formulas to enhance healing in stressed
patients. All have high nonprotein Cal: N2 ratios and provide part of fat as MCT oil for improved absorption. Many contain
additional additives for the purpose of attempting to enhance immune function or healing.
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Impact™ (Nestlé)
100
1500
375
13
53
5.6
22
71:1
2.8
25
1.4:1
Widely used
‘immune-
enhancing’
formula;
supplemented
with arginine,
(12.5 g/L), RNA;
high in w-3 FFAs.
Impact 1.5™
(Nestlé)
150
1500
550
14
38
8.4
22
71:1
6.9
40
1.4:1
Concentrated
formula,
supplemented
with arginine
(18.7 g/L); high in
w-3 FFAs.
Available with
and without fiber.
Impact
Glutamine™
(Nestlé)
130
1300
630
15
46
7.8
24
62:1
4.3
30
1.4:1
Concentrated.
Supplemented
with arginine
(16.3 g/L), GLU
(15 g/L), RNA,
w-3 FFAs.
Contains fiber
10 g/L
Perative™
(Abbott)
130
1500
460
18
55
6.7
20.5
97:1
3.7
25
NA
‘Immune-
enhancing’
formula
supplemented
with arginine
(8 g/L), vitamins
Nutren™
Replete™
(Nestlé)
100
1000
300–350
11.3
45
6.2
25
75:1
3.4
30
2.3:1
Inexpensive,
high-protein
formula. Available
with or without
fiber
Promote™
(Abbott)
100
1000
340
13
52
6.2
25
75:1
2.6
23
NA
High protein
formula. Available
with or without
fiber
Table 29.2  Continued

Nutritional support of the burned patient
339
D. ‘Specialty’ adult formulas: These are examples of formulas for patients with unusual, specific nutritional requirements.
None are well-suited for burn patients, and are generally much more expensive than more standard formulas.
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal1
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Glucerna™
(Ross)*
100
1420
355
11.2
34
4.2
17
125:1
2.3
30
11:1
Complex-
carbohydrate
formula for
diabetics;
Contains fiber.
Used primarily as
an oral nutrient/
supplement
Pulmocare™
(Ross)**
150
1420
470
10.5
28
6.2
17
125:1
9.3
55
4:1
Customized
formula for
pulmonary failure
relies on high fat
content to avoid
excessive VCO2;
limited efficacy in
burn patients. For
tube or oral
feeding
*Similar products include Diabetisource AC™(Nestlé), Nutren Glytrol Diet™ (Nestlé)
**Similar products include Oxepa™ (Abbott), Nutren Pulmonary™ (Nestlé)
E. Elemental/semi-elemental diets: Nutritionally complete diets intended for patients with minimal digestive ability or
absorption problems. Minimal residue, provide protein as peptides and/or free amino acids. Elemental diets are high
osmolarity due to simple sugars and free amino acids; semi-elemental have lower osmolality, and some provide more
balanced carbohydrate, fat, and protein composition.
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal1
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Vital HN™
(Abbott)*
100
1500
500
18.5
73.8
4.2
17
125:1
1.1
9.5
NA
Basic semi-
elemental diet,
low in fat
Optimental™
(Abbott)
100
1422
585
13.9
54
5.1
21
97:1
2.8
25
1:1
High-protein
‘immune-
enhancing’
semi-elemental
formula
supplemented
with arginine
(8 g/L), vitamins
Peptamen AF™
(Nestlé)
120
1500
390
10.7
36
7.6
25
75:1
5.5
39
1.8:1
High-protein
semi-elemental
diet,
supplemented
with w-3 FFAs,
fiber
*Similar products include Tolerex™ (Nestlé)
Continued
Table 29.2  Continued

Total Burn Care
29
340
II. Pediatric formulas
Nutritionally complete, intact protein products formulated to meet the nutrient needs of toddlers and children (>1 year).
May be used as oral supplements or complete enteral nutrition. Not intended for use in infants
Carbs
Protein
Fat
Comments
Brand Name
(Manufacturer)
kcal1
kcal to
meet RDI2
Osm
Gm
%kcal
Gm
%kcal
NPCal:N2
Gm
%kcal
w6:w3
Pediasure
Enteral™ (Ross)*
100
1000
535
13
53
3
12
180:1
4
35
NA
Standard tube
feeding. Available
with or without
fiber
Pediatric
Vivonex™
(Nestlé)
80
1000
360
13
63
2.4
12
200:1
2.4
25
7.7:1
Elemental
formula
supplemented
with Arginine
(1.5 g/L),
glutamine
(3.1 g/L)
*Similar products include Nutren Junior™ (Nestlé)
III. Modular products: These are incomplete products intended as supplements to tube feeding formulas for specific
purposes
Carbohydrates: Polycose™ Powder (Abbott): Glucose polymers, 95 gr (380 kcal)/100 gr powder.
Lipids:
1. MCT Oil™ (Nestlé): Medium-chain triglycerides from coconut oil, 85 gr MCT (767 kcal)/100 mL oil.
2. Microlipid™ (Nestlé): Safflower oil, 50.7 g (456 kcal)/100 mL.
C. Protein:
1. ProPass™ Protein Supplement (Hormel): Powdered whey protein concentrate. One scoop contains 6 g protein, 0.5 g fat.
2. Beneprotein™ (Nestlé): Whey protein supplement. One scoop or packet (7 g) contains 6 g whey protein.
D. Arginine and glutamine supplements
Enterex Glutapac™ (Victus): 10 g glutamine/pkt
Sypmt-X™ (Baxter): Glutamina, 10 g/pkt
Glutasolve™ (Nestlé): 90 kcal, 7 g CHO 15 g glutamine
Arginaid™ (Nestlé) 35 kcal, 4 g CHO, 4.5 g arginine, Vitamins C & E
Juven™ (Abbott): powder contains 66 kcal, 4 g CHO, 7 g each arginine and glutamine
1Abbreviations: ‘mL’ = milliliters of formula to contain; ‘kcal to meet RDI’= Number of calories required to deliver 100 % of recommended dietary intake of micronutrients
(Includes micronutrients not listed); ‘Osm’ = osmolarity, mOsm/kg H20; ‘g’ = grams; ‘%kcal’: %age of total calories; ‘NPCal:N2’ = ratio of non-protein calories to nitrogen; ‘w6:w3’ =
ratio of w6 to w3 fatty acids. Information from manufacturers’ websites as of April, 2010.
2Information from manufacturers’ websites as of April, 2010. The composition of formulas marketed in different countries may be different. All values listed here are for US
products.
Table 29.2  Continued
associated with significantly better immune function, less
bacteremia, and increased survival56 than in a group who
received 17% protein diets. As burn size increases, pro­
gressively more protein is required for positive nitrogen
balance.57,58
Current recommendations call for 1.5–2.0 g/kg/day of
protein for adult burn patients, and up to 3.0 g/kg/day in
children.59,60 With provision of sufficient non-protein calo­
ries, this should result in a calorie:nitrogen ratio of 100 : 1
or less, typical of the ‘stress’ formulas listed in Table 29.2.
Measurement of nitrogen balance and visceral protein
markers may be helpful in assessing the adequacy of nutri­
tional support (see below).
Glutamine
Several amino acids have unique roles in energy delivery
following injury. Alanine (ALA) and glutamine (GLU)
are important transport amino acids, elaborated in large
quantities from skeletal muscle to supply energy to the liver
and healing wounds.54 GLU also serves as a primary fuel for
both enterocytes and lymphocytes and is thus important in

Nutritional support of the burned patient
341
‘Immune-enhancing’ diets
Even the earliest efforts to nourish burn patients sought to
create an ‘ideal’ nutritional mixture by supplementing diets
with eggs or milk.26 Modern efforts have focused on combin­
ing components that appear to improve immune function
and wound healing. In a landmark study, Gottschlich et al.82
found that a group of severely burned children given a
custom-made tube feeding containing omega-3 FFAs, ARG,
histidine, and vitamins A and C had significantly fewer
wound infections, shorter hospital stays, and a trend toward
improved survival compared to two control groups fed
commercially available tube feedings. This experience
quickly led to commercial production of similar multi-
ingredient ‘immune-enhancing diets’ (IEDs).
Subsequent studies of IEDs in a variety of clinical settings
have produced contrary and controversial results. Some have
demonstrated improvements in immunity and wound
healing, and reductions in infections, multiple organ failure,
or hospital stay.83,84 No effect on mortality has been docu­
mented, however, and others have not been uniformly
favorable. These diets may have very different consequences
in different patient groups, with improved outcomes follow­
ing trauma or elective surgery85,86 but deleterious or no
effects in patients with sepsis or pneumonia.1,44,83 Much of
the blame for these inconsistent results has been attributed
to ARG, the exact dosing of which may influence its effects
greatly, as too much could stimulate excessive NO produc­
tion, exaggerate inflammation, and increase pulmonary
dysfunction.87
Little information has been obtained on the use of avail­
able IEDs in burn patients. One small study compared a
highly publicized IED (Impact™) with another commercially
available, high-protein stress solution (Replete™),88 and
found no differences in major outcome variables. Both solu­
tions contained significant amounts of omega-3 FFAs and
significant fat calories, though they differed in their contents
of vitamin A, arginine, and RNA. It should be noted that no
benefit to IEDs have been found in reducing the incidence
of pneumonia,83 which is a frequent and serious problem
for burn patients, particularly those suffering inhalation
injury. Finally, it should be remembered that the high
volume of feedings required by burn patients may mean that
a satisfactory dose of some immune-enhancing nutrients is
delivered even with the use of conventional diets.
These experiences illustrate that our understanding of
nutritional physiology is still limited and may have been
hindered by the rush to create commercially viable ‘cocktails’
for clinical use before understanding the real actions (and
interactions) of their components and their optimal doses.
At present the use of IEDs, particularly ARG, is controversial,
being specifically recommended for burn patients in one
authoritative practice guideline,4 and specifically not recom­
mended in another.5 This issue must await clarification from
future well-designed and large-scale clinical trials. The
emerging field of ‘pharmaconutrition,’ which stresses more
specific and restricted use of nutrients, may benefit this
effort.48 It is safe to say that efforts to provide adequate
amounts of calories and high-quality protein remain the
mainstay of successful burn nutrition, rather than an empha­
sis on a specific formula.
maintaining small bowel integrity, preserving gut-associated
immune function and reducing intestinal permeability fol­
lowing injury.3,61,62 Glutamine is also a precursor of glutath­
ione, an important antioxidant, and improves elaboration of
heat shock proteins which provide cellular protection fol­
lowing stress and trauma.61,63–65
GLU is quickly depleted from both serum and muscle fol­
lowing burn injury, leading to the suggestion that GLU be
considered a ‘conditionally essential’ amino acid in burns.54,66
GLU is almost entirely absent from parenteral nutrition
owing to its instability in solution, which may explain some
of the inferiority of TPN. GLU supplementation has been
associated with some benefits when used in neutropenic
cancer and other patients maintained on TPN.67,68
In clinical trials GLU supplementation has also produced
some improved outcomes in patients with cancer, AIDS,
surgery, trauma, or burns.3,69 However, these benefits were
not consistently seen when comparing post-operative and
ICU patients, provision of ‘low-dose’ (<0.20 g/kg/day) vs
‘high dose’ (>0.20 g/kg/day) GLU, or parenteral vs enteral
administration.63 Some of the best data supporting GLU
supplementation come from burn patients, in whom provi­
sion of 25 g GLU/kg/day or more, given parenterally70 or
enterally,71,72 was associated with reduced infections,
improved visceral protein levels, and reduced mortality and
length of hospitalization. These effects of GLU may be rela­
tively specific to burn injuries.73
Supplementation of enteral nutrition with GLU for burn
patients is not routinely practiced, although this is becoming
more common.74 The amounts of GLU given in clinical trials
are so large (0.25–0.50 g/kg/day) that this could interfere
with the delivery of other amino acids, so it might be prefer­
able to give GLU in addition to the usual quantity of protein
required by burn patients.3 Obviously, many questions
persist regarding the clinical utility of GLU supplementation
in burn care. Further clinical trials with supplementation of
this amino acid are ongoing.
Arginine
Arginine (ARG) is also important in post-burn metabolism.
ARG is synthesized from GLU and stimulates T lymphocytes,
enhances natural killer cell function, and stimulates synthe­
sis of nitric oxide (NO), which is important in stimulating
inflammation and resistance to infection.75–77 ARG supple­
mentation of enteral diets has been associated with improved
immune responsiveness and wound healing,78 and improved
survival in burned guinea pigs.79
Branched-chain amino acids
The branched-chain amino acids (BCAAs) leucine, isoleu­
cine, and valine have been postulated to spare muscle catab­
olism by stimulating protein synthesis and serving as energy
substrates. In clinical trials in trauma and ICU patients,
BCAA-enriched nutrition was associated with improved
nitrogen balance but had no effect on survival.80 In both
animal and clinical studies in burn injury, BCAA-enriched
feeding did not produce improvements in outcome, protein
synthesis, or immune function,81 and they are therefore not
recommended for use.

Total Burn Care
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342
Micronutrients: vitamins and trace elements
In addition to major nutrients, the metabolism of many
so-called ‘micronutrients’ – vitamins and trace elements,
which are important in wound healing and immunity – is
also affected by burn injury.89 These compounds have not
been evaluated extensively in clinical studies, although
depressed serum levels of some compounds have been docu­
mented following burns. A complete list of micronutrients
and their functions is provided in another chapter; excellent
reviews are also available.89,90 Limited data suggest that sup­
plementation of some substances, including vitamins A91,92
and C90) may be beneficial. Additional recent research has
focused on disorders of bone and vitamin D metabolism,93
zinc,94 and selenium.95
A recent survey found that many burn centers provide
some supplementation of trace elements, though perceived
indications and doses varied widely.96 Current reviews rec­
ommend supplementing at least the micronutrients listed
above, and perhaps others.15 However, many commercial
tube feedings contain substantial quantities of these micro­
nutrients, which can approximate the recommendations
listed by Mayes et al.92 The addition of a daily multivitamin
tablet or liquid multivitamins to tube feedings or TPN will
provide far more than DRI recommendations for most
micronutrients at minimal cost and risk. It is unclear whether
additional supplementation is of any value.
Formulas for enteral nutrition
Successful nutrition has been provided to burn patients with
very simple concoctions of milk, eggs, and other nutrients.26
However, commercially prepared enteral formulas offer
several advantages. They are nutritionally complete, and can
be infused through small feeding tubes with minimal clog­
ging. Most are reasonably inexpensive, though some special­
ized formulas can be quite costly.
Table 29.2 lists the nutrient composition of a number of
popular enteral formulas. A bewildering array of products
are available, including fiber-containing diets, elemental
diets, inexpensive supplements, and costly specialized diets
for patients with renal failure, hepatic failure, glucose intol­
erance, etc. Many of these products do not meet the macro­
nutrient needs of burn patients and often limit protein while
providing excess fat and carbohydrate. As an example, Table
29.3 shows the effects of either changing the volume of
enteral nutrition and intravenous fluids (a major source of
calories for some patients), or switching to one of the ‘dia­
betic’ formulas available. Clearly, the choice of formula can
greatly influence both the success of nutrition and the type
and magnitude of complications encountered.
Formulas for TPN
Solutions for TPN must consist of elemental components
that do not require digestion. Dextrose is the main calorie
source, and the high concentrations require delivery through
a central venous catheter. Protein is supplied as an amino
acid solution. As mentioned previously, glutamine is not a
component of TPN. Calorically dense lipids can comprise a
significant proportion of the calories in TPN.
The exact composition of TPN solutions can be tailored to
individual patient needs. ‘Standard’ TPN solution (70%
Table 29.3  Effect of differing volume and type of enteral nutrition
on protein and carbohydrate intake
EXAMPLE 11
Maintenance Feeding and IV
Feedings
IV Dextrose
Total
mL/h
100
200
300
kcal/day
2400
680
3080
Protein, g/day
150
0
150
Carbs, g/day
271
240
511
Fat, g/day
82
0
82
EXAMPLE 2
Decrease feeding, increase IV
Feedings
IV Dextrose
Total
mL/h
50
250
300
kcal/day
1200
1020
2220
Protein, g/day
75
0
75
Carbs, g/day
136
300
436
Fat, g/day
41
0
41
EXAMPLE 32
Changing formula to Glucerna™
Feedings
IV Dextrose
Total
mL/h
100
200
300
kcal/day
2400
680
3080
Protein, g/day
100
0
100
Carbs, g/day
229
240
469
Fat, g/day
131
0
131
1Typical ‘maintenance’ regimen for a patient with major burns, consisting of
100 ml/h of a high-protein ‘stress’ formula (Replete™), plus dextrose-containing
crystalloid solutions to deliver a total fluid volume of 300 mL/h. Note that in
Example 2, decreasing enteral nutrition, which is sometimes done to reduce
glucose intolerance, results in relatively little decrease in total carbohydrate calories
due to the increase in dextrose-containing IV fluid.
2Example 3 shows the result of changing enteral products, using a formula
designed for patients with glucose intolerance. These formulas are typically
high-fat diets, resulting in fewer carbohydrate calories, but more fat and less
protein, which is far from ideal for a stressed burn patient. The total amount of
carbohydrates ‘saved’ by this adjustment is about 42 grams, or about three
servings of starch per day. All three examples illustrate the major contribution to
both total calories, and particularly carbohydrate calories, provided by dextrose-
containing IV fluids.
dextrose, 15% amino acids, and 20% lipid emulsion) may
simplify ordering but often require customizing to meet the
needs of burn patients, who are likely to require increased
amounts of protein and possibly fewer lipid calories. Elec­
trolytes, vitamins, and minerals can be custom ordered, or
standard ‘packages’ can be used. Medications such as insulin
and H2 blockers can be added as well. Box 29.1 is an example
of a protocol for ordering and administering TPN used for
a typical burn patient in our unit.

Nutritional support of the burned patient
343
Box 29.1  Regimen for instituting total parenteral nutrition, adapted from ‘Adult parenteral nutrition orders’, University of Utah
Step One: Calculated Required Energy and Protein Needs:
Example: 25 year-old man, 80 kg in weight. Body surface area = 2.2m2.
1. Indirect calorimetry indicates energy expenditure of 2400 kcal/24 h. To account for fluctuations in energy expenditure, increase measured value
by 20% (480 kcal); total = 2880 non-protein kcal/day.
2. Estimate protein requirements at 2.0 g/kg/day = 160 g protein
Step Two: Order TPN Solution
1. Carbohydrates: Carbohydrates are supplied as 70% dextrose (D70), which contains 2.4 kcal/mL. To give 75% of non-protein calories as dextrose,
calculate:
[(
) ( .
)]
.
/
2880
0 75
2 4
total kcal
calories as dextrose
kcal m
×
÷
L
m L D
= 900
70
2. Fat: The remainder of non-protein calories will be given as lipid emulsion. This is commonly available as 10% (1.0 kcal/mL) or 20% (2.0 kcal/mL)
solution. To give 25% of non-protein calories as lipid, calculate:
[(
) ( .
)]
.
/
2880
0 25
2 0
36
total kcal
calories as lipid
kcal m L
×
÷
=
0
20
m L
lipid em ulsion
%
3. Protein: Protein is supplied as crystalline amino acid solutions at a concentration of 10% (0.1 g/mL), or 15% (0.15 g/mL). To give 160 g of
protein, calculate:
(
)
.
/
%
160
0 15
1067
15
g protein
g m L
m L of
am ino acid solution
÷
=
4. Total volume = 900 mL D70 + 360 mL lipids + 1067 mL amino acids = 2327 mL.
5. Add electrolytes: These can be ordered as customized additions in any quantity, but a standard electrolyte ‘package’ contains (per liter of TPN):
Sodium chloride: 35 mEq
Potassium phosphate: 15 mM (22 mEq potassium)
Magnesium sulfate: 8 mEq
Calcium gluconate: 5 mEq
6. Add vitamins: A standard vitamin ‘package’ contains approximately 100% of recommended dietary allowances of vitamins A, C, D, E, and B12,
pyridoxine, thiamine, riboflavin, niacin, pantothenic acid, folate, and biotin.
7. Add trace elements: A standard ‘package’ contains
Zinc: 2.5 mg
Copper: 1.0 mg
Mn: 0.25 mg
Chromium: 10mg
8. Add customized components: These often include famotidine for stress ulcer prophylaxis, and insulin for glucose intolerance.
9. Add additional water, and calculate infusion rate: If patients require additional fluid, water can be added to the TPN solution as desired. If no
additional water is required, then the goal rate for infusion is 2327 mL ÷ 24 h = 97 mL/h.
Step Three: Protocol for Administration
1. Begin infusion at 20 mL/h via central vein.
2. Increase rate every 4–6 hours by 10–20 mL/h until rate of 120 mL/h is achieved.
Step Four: Begin Monitoring on Nutritional Support
Blood glucose:
1. As infusion is initiated, measure blood glucose every 4 hours. If glucose is ≥ 120 mg/dL, begin administration of exogenous insulin by ‘sliding
scale’, or continuous drip. Consider oral hypoglycemic agents.
2. After goal rate is achieved, measure blood glucose every 6 h.
Daily: Serum electrolytes, Blood urea nitrogen, creatinine.
Twice weekly:
A. Hepatic enzymes (lactate dehydrogenase, alkaline phosphatase, total bilirubin, transaminases)
B. 24-h urine for nitrogen balance
C. Serum transferrin or prealbumin
Serum phosphorus, magnesium, and calcium
Methods of nutritional support
Route of nutrition: parenteral vs enteral
In the 1960s and 1970s, TPN was widely advocated for burn
patients. At the peak of TPN’s popularity, it was estimated
that over 500 000 patients were treated yearly, at a cost of
over $3bn.97 This included burn patients, for whom TPN was
widely advocated.26,98
TPN has now been largely replaced by enteral nutrition
(EN), for both theoretical and practical reasons. Enteral
nutrition directly nourishes the bowel mucosa; some nutri­
ents (e.g., glutamine) may be particularly important in this
regard. The presence of even small amounts of nutrients
within the bowel lumen stimulates the function of intestinal

Total Burn Care
29
344
large-diameter tubes placed blindly, which simplifies early
feeding and minimizes clogging. Blenderized diets and inter­
mittent bolus feedings can also be given into the stomach,
reducing expense and the inconvenience of infusion pumps.
A major disadvantage is the tendency of the stomach to
develop ileus, both immediately post burn and in conjunc­
tion with sepsis or stress.
Intestinal feeding requires placement of a tube beyond the
pylorus. Small enteric tubes have been placed inadvertently
into the lung, with catastrophic consequences.119 For that
reason, many facilities prefer fluoroscopic or endoscopic
tube placement, which is safer but inconvenient. Nasoen­
teric tubes are small and comfortable, but clog rather easily
and often dislodge and migrate into the stomach. No clear
data have documented a reduced rate of aspiration using
nasoenteric feeds.120,121 Any regimen of EN, however, requires
careful ongoing monitoring for intolerance and pulmonary
complications.
Many clinicians employ ‘pro-motility’ agents such as meta­
clopromide, erythromycin, or cisapride in conjunction with
enteral nutrition. These agents – particularly erythromycin
– may help enteral tubes pass spontaneously into the small
intestine and can also reduce gastric ileus and feeding
intolerance.122
Developing a program of nutritional support
Nutritional support can be provided most effectively by
developing a comprehensive protocol, which defines respon­
sibilities for all members of the burn team. It has been
repeatedly shown in ICU populations that adherence to such
protocols increases both the success of nutrition and overall
patient outcomes.
Such a regimen begins by defining the level of support
required, which differs greatly for individual patients. For
every patient the goal is to provide adequate nutrition using
the simplest and most physiologic method. All patients
need frequent reassessment to ensure that they are achieving
nutritional goals, to detect complications, and to determine
whether support can be simplified or if escalation is required.
A simple algorithm for determining the level of nutritional
support is shown in Figure 29.3. Applying such an algorithm
proactively may prevent problems developing.
Patients with relatively limited injuries (≤20–25% TBSA)
who are not intubated will generally be able to eat, though
it may take several days until pain, initial ileus and nausea
can be controlled. In this circumstance, a few days of
inadequate nutrition can be permitted if it appears that
the patient will soon be able to eat. Patients who fail to
progress with oral intake, who require major surgery, or
who develop complications will benefit from the early insti­
tution of more formal nutritional support. Early initiation
of enteral feeds may actually prevent the development
of ileus.
Patients who require TPN should be reassessed frequently
for evidence of GI function; even if patients cannot tolerate
all their nutrition enterally, they should be given low-rate
‘trophic’ feeds if possible. These help preserve small bowel
integrity and function and facilitate gradual transition to EN
(and decreasing TPN) as the bowel recovers. Similarly, some
oral intake should be permitted when possible in patients
given EN. Oral intake – even sips of liquid – is of great
cells, maintains microvillous architecture and normal
mucosal function, preserves blood supply to the intestine,99
and may reduce bacterial translocation and preserve gut-
associated immune function.100–102 EN provides ‘first-pass’
delivery of nutrients to the liver, which reduces hyperglyc­
emia and hyperosmolarity. In contrast, TPN appears to be
associated with increased secretion of tumor necrosis factor
(TNF) and other proinflammatory mediators.103 Lipids added
to TPN may enhance inflammation as well, particularly in
pulmonary dysfunction.51 In addition, fatty infiltration of
the liver is common following burn injury; 104 this may be
particularly severe in association with TPN.
In clinical trials, early and aggressive EN has been associ­
ated with fewer infectious complications in trauma and ICU
patients.105,106 In burn patients, TPN supplementation of
enteral nutrition has been associated with substantially
increased mortality.107,108 This is in contrast to a recent meta-
analysis which showed no increased mortality associated
with TPN in ICU patients.109 These differences may be due
to unique metabolic characteristics in burn patients, or may
simply reflect the restriction of TPN use in burn units to the
sickest patients.
In addition to other problems, TPN solutions are far more
expensive than enteral formulas, require more expensive
delivery systems, and mandate more frequent monitoring of
glucose and other blood chemistries. For all these reasons,
enteral nutrition should be considered the route of choice
for the nutritional support of all burn patients with function­
ing (or even partially functioning) gastrointestinal tracts.
Early enteral feeding
A 1984 study in guinea pigs suggested that provision of EN
immediately following burn injury reduced hypermetabo­
lism almost to normal.110 Subsequent studies have not con­
firmed this finding.111,112 However, it appears clear that EN
can be started safely within hours of injury in patients of all
ages, reducing the accumulated ‘calorie deficit’ and improv­
ing overall nutrition.113–115 Duodenal or jejunal feedings can
be continued even during surgical procedures without
increased risk of aspiration, which helps maintain caloric
goals and may also reduce infection.116 Tube feedings should
therefore be started as soon as practically possible following
injury, and certainly within 48 hours. To enhance success,
begin feedings at a rate of 20–40 mL/h (as little as 5 mL/h
in infants) and try to reach the therapeutic goal rate within
24 hours.
However, successful implementation of tube feedings is
often difficult. Nausea, diarrhea, glucose intolerance and
problems with tube placement and maintenance often com­
promise the success of early enteral nutrition.117,118 Some
authorities have recommended supplementing enteral nutri­
tion with TPN early on, until goal rates of tube feedings can
be achieved.4,7 This remains a controversial issue, particularly
in light of recent evidence that TPN supplementation of EN
in burns may be associated with increased mortality.
Gastric vs intestinal feeding
Both gastric and post-pyloric intestinal feedings are
widely used for delivery of EN; both have advantages and
disadvantages. Gastric feeding can be instituted through

Nutritional support of the burned patient
345
high-protein ‘stress’ products provide excessive protein for
the elderly, and so using a standard product may be more
appropriate. Examples of such products are included in Table
29.2. The clinician also needs to evaluate the need for restric­
tions (e.g., potassium, fat) in these patients.
The obese burn patient
Obesity is epidemic in the United States and is rapidly
increasing in other developed nations as well. As much as
two-thirds of the US population is overweight and one-third
is obese, as defined by BMI criteria.123,124 Excessive weight
is clearly associated with a number of major health
problems, including diabetes, cardiovascular disease, and
arthritis, and increases all-cause mortality in the general
population.125–127
Some studies in surgical and ICU patients have demon­
strated the ‘obesity paradox’ of reduced mortality for over­
weight and moderately obese individuals despite an increase
in infections and length of hospital stay (LOS).128–130 Less
information is available in burn patients. One early study
documented increased respiratory and cardiovascular com­
plications including pulmonary emboli among patients who
would today be categorized as morbidly obese.131 A recent
review from the National Burn Repository (NBR) found
increased mortality among patients listed as obese.132
However, the term was not clearly defined, and the incidence
of obesity documented (less than1%), was far too low to
represent its real occurrence. In two pediatric reviews, obese
burned children had longer hospital LOS133 as well as greater
requirements for both ventilatory support and exogenous
insulin.134
psychological benefit to patients and encourages them to
wean from tube feedings quickly as recovery progresses.
Several patient populations merit special consideration in
providing adequate nutritional support.
Infants/children
Adult enteral products provide high renal solute loads, large
protein intakes, and doses of vitamins and minerals that are
inappropriate for children. Infants require relatively high
fluid volumes and should not receive concentrated formulas,
so infant formulas generally provide no more than 20 or
24 kcal/oz (0.66–0.8 kcal/mL). Some popular pediatric
enteral formulas are compared in Table 29.2.
Oral intake in small children is often difficult due to pain,
anxiety and an inability to comprehend the need for ade­
quate intake. Many prefer drinking to eating, and offering
high calorie supplements can be helpful. However, early
initiation of enteral nutritional support can often meet nutri­
ent needs and reduce the stress associated with attempting
to ‘push’ oral intake.
The elderly
Elderly patients are more likely to have pre-existing malnu­
trition than other burn patients.24 Diabetes and its compli­
cations, heart disease, poor dentition, etc., can all affect
nutritional status and complicate the provision of adequate
nutrition. Basal metabolic rate decreases with age and many
elderly patients may not manifest a post-burn hypermeta­
bolic response. Use of indirect calorimetry will help
avoid overfeeding, glucose intolerance, and azotemia. Many
Figure 29.3  An algorithm for determining the
route of nutritional support for burn patients (see
text).1 On admission, patients may require 3–4
days to tolerate adequate oral intake. Patients
who require longer should be considered for
nutritional support.2 Patients should be given
some enteral nutrition even if they still require
TPN for the balance of nutritional support.
Is patient able to eat?1
Begin nutritional support
Oral intake with daily
calorie/protein counts
Yes
No
Yes
No
Yes
No
Continue and reassess daily
Yes
No
Can GI tract be used?2
Enteral nutrition
Adequate intake of
protein and calories
maintained?
Adequate intake of
protein and calories
maintained?
TPN
Yes
No
Initial assessment: burn size ≤ 23% TBSA

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346
The physiologic consequences of obesity are particularly
relevant to burn patients. It is now recognized that fat is not
inert, but plays an active role in metabolic regulation. The
inflammatory hormone leptin, secreted by adipose tissue,
helps direct the CNS to increase or decrease food intake.17
Leptin levels are reduced following burn injury in humans,135
but its role in hypermetabolism remains unclear. Obesity is
also associated with increased secretion of pro-inflammatory
cytokines IL-6, C-Reactive Protein (CRP), and TNF-a, and
anti-inflammatory adipokines.136–138
This hormonal environment establishes obesity as a state
of chronic inflammation similar to low-grade SIRS,138 and
contributes to the ‘metabolic syndrome’ of insulin resistance,
diabetes, and cardiovascular disease; this constellation of
clinical disorders is now recognized as a major worldwide
health problem.139 When injured, these already-primed indi­
viduals may react with exaggerated inflammation, higher
metabolic rates, more rapid and severe muscle wasting and
severe insulin resistance that further drives the use of protein
and carbohydrate for energy.140 Thus even though obese indi­
viduals have greater fat-free mass than nonobese patients,140,141
burned obese patients lose muscle mass more quickly, while
preserving fat mass.142
Obesity presents several practical problems in providing
nutrition in burn care. Obesity complicates assessment of
underlying nutritional status. Many obese patients are
deconditioned and badly nourished, while others fulfill
criteria for ‘fit but fat’.143 Ongoing energy requirements are
also hard to estimate. Using actual body weight in predictive
formulas overestimates energy needs, while using ideal body
weight underestimates them.144 Specific formulas for obesity
have been proposed, but none have been validated in large
reviews.145 As a result, the use of indirect calorimetry is par­
ticularly helpful in obese patients.
Hypocaloric feeding: The nutritional challenges of obesity
have led to use of low-calorie, high-protein diets aimed at
maintaining lean body mass while facilitating weight loss
and blood sugar control.146 In limited trials in ICU patients,
hypocaloric nutrition given enterally147 or parenterally148,149
appeared to be as effective as eucaloric nutrition in maintain­
ing nitrogen balance and clinical outcomes.150 In other
reviews patients who received significantly fewer calories
than targeted demonstrated reduced mortality, ventilator
dependence, and LOS.147,151
Hypocaloric feedings could have a number of theoretical
advantages in feeding obese burn victims. First, accurate esti­
mates of energy expenditure are unnecessary. Because many
nutritional regimens in burn patients often fail to achieve
caloric goals,117,118,151 an intentionally hypocaloric regimen
would be more likely to succeed. By limiting intake, hypoca­
loric regimens might reduce complications of hepatic stea­
tosis, fluid overload, diarrhea, and feeding intolerance.
Importantly, such a program could also greatly reduce
the practical problems of blood sugar control in these
patients.
Highly influential guidelines4 have recommended hypoca­
loric regimens for nutritional support of obese, critically ill
patients. However, this enthusiasm may well be premature.
In a review of clinical trials, Dickerson concluded that
although hypocaloric feedings appear promising, there are
too few data, especially on long-term use, to establish this
regimen as a standard of care.152 In another review, authors
agreed that far too few data existed to obviate concerns
over prolonged starvation and accumulated ‘energy debt,’
which could accompany hypocaloric feeding in acutely ill
patients.144 This would be of particular concern in burn
patients, whose hypermetabolism is both more prolonged
and more serious than in other patient groups. For all these
reasons, hypocaloric nutrition cannot be recommended for
burn patients until its safety can be confirmed in carefully
controlled clinical trials.
Monitoring and complications
Monitoring of nutritional support
Any program of comprehensive nutritional support must
include ongoing monitoring of its adequacy and success. As
mentioned previously, the physiologic changes that accom­
pany burns render many monitors of nutrition difficult or
impossible to interpret. In addition, most of these markers
do not correlate highly with outcomes. Careful assessment
of clinical status, including vital signs, functional improve­
ment, and wound healing, remains the most important form
of nutritional monitoring. A number of parameters are most
useful in identifying and monitoring trends (as opposed to
point estimates) in nutritional status.
Body weight
Change in body weight is an important monitor of nutri­
tional status for the general population, and significant
weight loss – particularly rapid and unplanned – is a power­
ful predictor of mortality.153 However, weight is often mis­
leading in burn patients. Initial fluid resuscitation routinely
adds 10–20 kg to a patient’s weight, and much greater
increases are common. Theoretically, this fluid will dissipate
with diuresis, but the time course for this is unpredictable,
particularly if resuscitation volume is high.154 Additional
fluid shifts which accompany infections, ventilator support,
hypoproteinemia, and elevations in aldosterone and anti­
diuretic hormone lead to wide fluctuations in weight that
have little to do with nutritional status. Even weeks after
injury, patients may have increased total body water and
have almost always lost more lean body mass than is appar­
ent from weight alone.155 And once lost, muscle mass is
difficult to replace. In recent studies, intentionally overfeed­
ing ICU and burn patients to exceed measured energy
expenditure did not reduce ongoing muscle breakdown:
increased caloric intake resulted only in the accumulation of
body fat.156,157
In following weights, try to recognize long-term trends
more than daily variations, and continue monitoring during
the often prolonged rehabilitation phase.
Nitrogen balance
Providing sufficient protein intake is a major goal of nutri­
tional support. Because patients differ widely in their protein
requirements, an ongoing monitor of this parameter is desir­
able. In addition to serum protein measurements (described
below), a widely used test is the assessment of nitrogen
balance. Measurements should be obtained at least weekly
and require accurate collections of urine for determination

Nutritional support of the burned patient
347
of urea nitrogen (UUN) along with concomitant recording
of nitrogen intake; 24-hour collections are often used,
though shorter times can also provide accurate data.158
Nitrogen balance (N2 bal) can then be calculated by formu­
las such as the following:159
N bal
N I
UUN
2
2
1 25
4
=
−
×
+
[ .
(
)]
where N2I = 24-hour nitrogen intake.
This formula contains two constants which can introduce
significant error to calculations. First, UUN is increased by
2–4 g/dL (depending on patient age) to approximate total
urinary nitrogen (TUN). However, TUN may exceed this
value in burn patients,160 leading to underestimation of
nitrogen losses. The formula also multiplies estimated TUN
by 1.25, to account for significant loss of protein-rich exu­
dates from burn wounds. Some formulas do not include this
correction and actual burn wound losses can exceed these
estimates, again leading to overly optimistic estimates of the
adequacy of protein intake. Thus these formulas provide
only an approximation of actual nitrogen balance.
Attainment of nitrogen balance may not always be poss­
ible, especially in the absence of exercise. Inactivity causes
muscle wasting and increased nitrogen excretion even in
healthy people.161 In the early post-burn period patients are
often bedridden, sedated, and/or chemically paralyzed; in
this setting, increasing protein intake only results in increased
nitrogen excretion. This emphasizes the importance of a
team-based protocol in which nutritional and physical
therapy are both provided to maintain muscle mass.
Serum proteins
Burn injury shifts metabolic pathways away from mainte­
nance of those visceral proteins often used as nutritional
markers.162 Serum albumin, an important indicator of
chronic nutritional status, is of much less value in assessing
acute changes. In burn patients, serum albumin levels are
depressed both acutely and chronically; even successful
nutrition will not increase albumin levels for long periods.
Administration of supplemental albumin to improve colloid
oncotic pressure and control edema has not improved clini­
cal or nutritional outcomes, though it may improve labora­
tory values temporarily.163,164
Some other ‘acute-phase’ proteins have been advocated as
more useful markers of nutrition. Prealbumin (or transthy­
retin) has a short half-life, making it theoretically more
responsive to nutritional changes.162 However, prealbumin
levels also fall quickly after injury and rebound slowly. Levels
may correlate with susceptibility to infection but may not
reflect ongoing nutritional status.59,165 Serum transferrin,
retinol-binding protein and others have also been used, but
their clinical usefulness appears equally limited,56,162,166 and
their measurement may be expensive or not routinely avail­
able. Protein markers, if used at all, should be interpreted in
the context of patients’ clinical condition and, like body
weight, evaluated serially to indicate trends.
Other parameters
Abnormal immune function and increased susceptibility to
infection are major consequences of malnutrition. In the
past, markers of immune competence have been used in
nutritional assessment, including total lymphocyte count92
and measurement of delayed-type hypersensitivity (DTH) to
dermal antigens.167,168 These markers have not proved very
useful in burn patients. Acute thermal injury is itself pro­
foundly immunosuppressive; anergy can also be produced
by infection, old age, or other complicating factors, and does
not itself constitute evidence of inadequate nutrition.
There are a few parameters that should be followed rou­
tinely in all patients receiving nutritional support. Burn
injury produces accelerated evaporative water losses, so
hydration status and serum electrolytes, including phospho­
rus, magnesium, and calcium, should be monitored closely.
Liver function abnormalities can result from overfeeding but
can also indicate other serious conditions that complicate
burn treatment, including hepatitis and acalculous cholecys­
titis. The large protein loads required by burn patients result
in increased urinary excretion of nitrogenous wastes and
predispose to elevations of blood urea nitrogen, particularly
in the elderly. Table 29.4 illustrates a protocol for adminis­
tration of TPN to a burn patient, including the recommended
monitoring of nutritional status.
Some new, technically advanced methods are now avail­
able for nutritional monitoring as well. Bioimpedance analy­
sis (BIA) measures the body’s resistance to the passage of
electrical currents; from this information total body water
and the body’s fat-free cell mass can be calculated.169 Dual
X-ray absorptiometry (’DEXA’) scanning measures precise
absorption of radiation by various tissues; it has been used
in clinical studies to measure bone density as well as fat-free
mass.170 Both of these techniques are currently useful prima­
rily in research, but may be used more widely in clinical care
in the future.
As this information suggests, no single parameter is either
universally applicable or reliable for nutritional monitoring
of burn patients. A survey of nutrition practices in 46 burn
centers171 indicated that the most commonly used parameters
were body weight (100% of centers), serum albumin (93%),
nitrogen balance (70%), transferrin (41%), and prealbumin
(26%). In establishing a nutrition protocol, it remains essen­
tial to follow clinical course and wound healing, and it is
reasonable to monitor body weight and one or two indices
of protein status, such as nitrogen balance, transferrin, or
prealbumin. Other tests probably do not add much extra
information and can be reserved for research studies.
Complications of nutritional support
Almost any disorder of homeostasis can complicate nutri­
tional support.
Significant complications can be classified as metabolic
and mechanical. A number of serious metabolic complica­
tions are listed in Table 29.4. These can occur with either
enteral or parenteral nutrition, though most disorders of
glucose and electrolyte homeostasis are both more common
and more severe with TPN.
Overfeeding
As noted previously, it can be difficult both to estimate
the nutrition needed by burn patients and to deliver those
nutrients successfully. Nutrition is often inadequate in
the early post-burn period, a time when ileus, nausea and

Total Burn Care
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348
Table 29.4  Metabolic complications of nutritional support (particularly TPN)
Complication
Description/cause
Frequency
Severity
Diagnosis/treatment
Complications related to overfeeding
Increased VCO2
Overfeeding of carbohydrate calories leads
to increased production of CO2 and
elevation of the Respiratory Quotient. This
can complicate ventilator management and
weaning in patients with significant
pulmonary dysfunction.
Uncommon
Moderate
Suspect in patients who are having difficulty
with ventilator weaning; confirm with
indirect calorimetry. Reduce total calories,
particularly from carbohydrates. Some
‘pulmonary’ formulas have increased fat
calories, which should probably be avoided
in burn patients.
Fatty liver
dysfunction
Presents with hepatomegaly, right upper
quadrant pain, and elevation of hepatic
enzymes. May occur to a mild extent in
many patients, but becomes worse with
prolonged overfeeding and TPN; can lead to
cirrhosis.
Common to
a limited
degree
Mild to severe
Avoid overfeeding, particularly of fats.
Monitor liver enzymes routinely. More
common and more severe in septic patients.
Azotemia
Feeding the large amounts of protein
required by burn patients can lead to
elevations in BUN and creatinine, particularly
when combined with intravascular fluid
depletion.
Common
Mild to severe
Monitor blood chemistries frequently. Avoid
dehydration by providing generous free
water. This may require reducing the protein
load in nutritional support. Azotemia which
does not respond to hydration and reduction
of protein intake should raise concern for
renal failure.
Other Complications of Nutritional Support
Hyperglycemia
Occurs to some degree in almost all
patients on nutritional support; more
common and more severe with TPN. Any
nutritional support regimen should be
started slowly, and monitored regularly.
Common
Moderate to
very severe
Blood glucose MUST be monitored regularly
in all patients. Insulin added to TPN solution
can be helpful; patients may also require a
rigorous protocol using supplemental insulin
and oral hypoglycemic agents. Sustained
hyperglycemia may require slowing/holding
TPN until controlled
Hyperosmolarity
Occurs almost exclusively with TPN:
Prolonged hyperglycemia can cause
dehydration, mental status changes; coma
Rare
Can be
life-threatening
A complication of untreated hyperglycemia.
Close attention to glucose control should
prevent this. Treat by stopping TPN,
hydrating, controlling glucose
Hyperkalemia
Excessive administration of potassium; often
occurs when a ‘standard’ electrolyte solution
is added to TPN without considering
patient-specific issues (i.e., renal failure)
Uncommon
Can be
life-threatening
Routinely monitor potassium, especially
during initiation of TPN. Occurs in association
with hyperglycemia, renal dysfunction, sepsis.
Severe hyperkalemia (≥ 6.0 mEq/L) causes
T-wave elevation, can be fatal. This is a
medical emergency, and mandates
discontinuation of TPN, or change to a
low-potassium enteral formula.
Hypokalemia
Low serum potassium can occur if
electrolytes are not added to TPN. The
institution of TPN causes uptake of
potassium and sudden hypokalemia. This
occurs along with hypophospha temia and
hypomagnesemia – the ‘refeeding’
syndrome.
Uncommon
Moderate to
serious
Monitor potassium routinely, especially
during initiation of TPN and aggressive
glucose control. Can cause weakness,
arrhythmias. Treat by potassium
supplementation. Magnesium deficiency can
contribute to hypokalemia as well.
Hyponatremia/ fluid
overload
Occurs usually when dilute solutions are
used for TPN. Can result in pulmonary
failure, ascites, edema. Use of ‘peripheral’
TPN requires large fluid loads, particularly in
children, and should be avoided. Additional
fluids given with antibiotics and
resuscitation can compound this problem.
Moderately
common
Moderate to
serious
Monitor intake/output, serum sodium.
Nutritional support in renal failure should be
continued, but may require more frequent
dialysis. Severe hyponatremia from any cause
must be corrected gradually (≤0.5 mEq/L/
hour) to avoid severe neurologic
complications.
Hypernatremia/
dehydration
Can occur when insufficient free water is
given. Burn patients may have significant
requirements over and above the fluids
required for TPN.
Moderately
common
Moderate to
serious
Monitor intake/output, serum sodium.
Additional free water can be added to TPN or
given separately. Persistent hyperglycemia
causes obligatory diuresis and dehydration.